Antipruritic agent using pac1 receptor antagonist

Abstract

To provide a novel antipruritic agent having a mechanism of action different from conventional antipruritic agents.SOLUTION: The present invention provides an antipruritic agent comprising a compound represented by the following formula (II): (wherein R is an indazolyl group, an indazolyl group substituted with a halogen atom, a phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with a methyl group, a phenyl group substituted with a cyano group, a phenyl group substituted with a hydroxyl group, an aralkyl group, or an aralkyl group substituted with a hydroxyl group), or a salt thereof, or a solvate thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an antipruritic agent using a PAC1 receptor antagonist.

Background Art

[0002] Itching is one of the skin sensations experienced daily. However, due to the recent increase in the number of patients with allergic diseases, and furthermore, in developed countries, the aging of the population is remarkable, so an increase in various pruritic diseases such as itching associated with dry skin, itching associated with systemic diseases such as kidney diseases and liver diseases is expected.

[0003] The first choice for itching treatment is antihistamines, but they are ineffective for itching associated with skin diseases such as atopic dermatitis and psoriasis, and itching associated with systemic diseases such as kidney diseases and liver diseases. For itching associated with atopic dermatitis, topical steroid drugs and topical tacrolimus drugs are used. However, for topical steroid drugs, skin striae, atrophy, an increase in skin infections associated with reduced local immune function, and topical tacrolimus drugs cause a local burning sensation, and it is said that about 30% of patients do not obtain sufficient effects. For such a patient group, short-term oral administration of steroids or cyclosporine is inevitably performed, but there are concerns about serious adverse effects, and it cannot be used for a long period.

[0004] This year, a new drug (dupilumab) has been introduced for patients with a high severity level for whom treatment with topical steroid / tacrolimus drugs is not sufficiently effective. This drug is a humanized anti-human IL-4 / IL-13 receptor monoclonal antibody, and it is said to be effective in about 40% of patients even with a high severity level. However, since it is a biopharmaceutical, it is expensive (the patient's out-of-pocket cost is tens of thousands of yen per month). Regarding psoriasis, in recent years, a biopharmaceutical (humanized anti-human IL-17 receptor A monoclonal antibody) has been introduced. ​However, it has also become an equally expensive therapeutic drug.

[0005] For the pruritus of patients with renal failure undergoing dialysis and patients with liver failure, the κ-opioid receptor agonist nalflurafine has been used since 2009 and shows a high efficacy rate (effective in 70% of patients), but it is said that there are about 30% of patients who do not obtain sufficient effects.

[0006] Therefore, the development of a new pruritus therapeutic drug with a mechanism of action different from these drugs and available at a low price is still desired.

[0007] PACAP (Pituitary Adenylate Cyclase Activating Polypeptide) was isolated from the ovine hypothalamus in 1989 using rat pituitary adenylate cyclase activity as an index, and its structure was determined. It is a neuropeptide that causes mechanical allodynia (the phenomenon of feeling pain even when touched) via the spinal cord PAC1 receptor (Non-Patent Document 1), but it is not clear what kind of pain it is clinically (in humans) involved in. It is not clear.

[0008] At the animal experiment (mouse / rat) level, it has been suggested that PACAP is involved in peripheral nerve (spinal nerve) nociceptive pain (SNL model) (Non-Patent Document 2), but it is not clear which PACAP receptor (there are at least three types of PACAP receptors: PAC1, VPAC1, and VPAC2) it is involved in.

[0009] Patent Document 1 describes that PACAP has a sweat secretion promoting effect and is useful as a preventive or therapeutic drug for dry skin.

[0010] From an existing compound database in which more than 4 million items are registered in Non-Patent Document 3 the extracted compounds PA-8 and PA-9, together with their structures, have been shown to have PAC1 receptor antagonistic activity and analgesic activity, but their antipruritic activity has not been investigated.

[0011] Compound PA-8 is a compound represented by the following formula (A):

Chemical formula

Chemical formula

[0012] Non-Patent Documents 4 and 5 describe a pyrido[2,3-d]pyrimidine-4,7-dione derivative represented by the following formula (C):

Chemical formula

Prior Art Documents

Patent Documents

[0013]

Patent Document 1

Non-Patent Documents

[0014]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0015] An object of the present invention is to provide a new antipruritic drug having a mechanism of action different from that of conventional antipruritic drugs .

Means for Solving the Problems

[0016] In order to solve the above problems, the present inventors have found that a specific compound has an excellent antipruritic effect among PAC1 receptor antagonist candidate compounds, and have completed the present invention

[0017] That is, the gist of the present invention is as follows (1) The following formula (I):

Chemical formula

Chemical formula

Advantages of the Invention

[0018] The antipruritic agent of the present invention contains a PAC1 receptor antagonist as an active ingredient and is an antihistamine It has a mechanism of action different from that of current antipruritics such as drugs, steroids, and immunosuppressants, and can avoid the adverse effects found in steroids and immunosuppressants.

[0019] In addition, the antipruritic of the present invention has action sites in both the periphery (intradermal) and the center (posterior horn of the spinal cord), so it has high efficacy and there is a possibility that the need for combination therapy can be reduced. Therefore, it is possible to avoid the emergence of unexpected adverse effects associated with combination therapy.

[0020] Since more than 80% of the elderly have dry skin and half of them complain of itching, the need for antipruritic drugs for dry skin-associated pruritus is high in Japan, which is a super-aging society. The antipruritic of the present invention can be expected to improve the quality of life (QOL) of the elderly with itching associated with dry skin.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

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Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Mode for Carrying Out the Invention

[0022] Hereinafter, the present invention will be described in detail.

[0023] In the formula (I), R 1 or R 2 As the C 1-6 -alkyl group represented by, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl R groups (1-methylpropyl group), tert-butyl group, pentyl group, isopentyl group, 1 -ethylpropyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group may be mentioned.

[0024] In the formula (I), R 1 or R 2 The C 1-6 -alkoxy group represented by, for example, me thoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group , sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopent yloxy group, cyclohexyloxy group may be mentioned.

[0025] In the formula (I), R 1 or R 2 The C 2-6 -alkenyloxy group represented by, for example vinyl group, 1-propenyloxy group, allyloxy group, 1-butenyloxy group , 2-butenyloxy (crotyloxy) group, pentyloxy group, 3-methyl-2-b tenyloxy (prenoxy) group, hexyloxy group may be mentioned.

[0026] In the formula (I), R 1 or R 2 The halogen atom represented by, for example, fluorine atom , chlorine atom, bromine atom, iodine atom may be mentioned.

[0027] In the formula (I), R 1 or R 2 The C 1-6 -haloalkyl group represented by, for example trifluoromethyl group may be mentioned.

[0028] In the formula (I), R 1 or R 2 The C 1-6 -haloalkoxy group represented by, for example includes a trifluoromethoxy group.

[0029] In the formula (I), R 1 or R 2 The phenyl group represented by is C 1-6 -alkyl group, C 1-6 -alkoxy group, methylenedioxy group, C 2-6 -alkenyloxy group, aralkyloxy group (for example, benzyloxy group, 4-methylbenzyloxy group, 3-methylbenzyloxy group, 2-methylbenzyloxy group, 4-fluorobenzyloxy group, 3-fluorobenzy loxy group, 4-chlorobenzyloxy group, 3-chlorobenzyloxy group), halogen atom C 1-6 -haloalkyl group, C 1-6 -haloalkoxy group, substituted or unsubstituted phenyl group, acyl group (for example, formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, etc. C 1-6 -aliphatic acyl group; benzoyl group, toluoyl group, etc. a royl group), acyloxy group (for example, formyloxy group, acetoxy group, propanoylo xy group, butanoyloxy group, pentanoyloxy group, hexanoyloxy group, etc. C 1-6 -aliphatic acyloxy group; benzoyloxy group, toluoyloxy group, etc. aroyloxy group), hydroxyl group, carboxyl group, acetamide group, carbamoyl group, cyano group, nitro group etc. It may be substituted with one or more substituents selected from.

[0030] Examples of the compound represented by the formula (I) include R1 is C 1-6 -alkoxy group or C 1-6 -halo Compounds that are alkoxy groups (e.g., trifluoromethoxy group) are preferred.

[0031] In the formula (II), the indazolyl group substituted with a halogen atom represented by R is fluoro At least one halogen atom selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom (preferably a chlorine atom)-substituted indazolyl group is not particularly limited, but preferably a 3-indazolyl group substituted with at least one chlorine atom can be mentioned.

[0032] Examples of the aralkyl group represented by R in the formula (II) include a benzyl group and a phen thyl group.

[0033] The phenyl group and the aralkyl group represented by R in the formula (II) are C 1-6 -alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group , sec-butyl group (1-methylpropyl group), tert-butyl group, pentyl group, iso pentyl group, 1-ethylpropyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group), C 1-6 -alkoxy groups (e.g., methoxy group, eth oxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-but oxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexy loxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group), methylenedioxy group, C 2-6 -alkenyloxy group, aral A ketooxy group (e.g., benzyloxy group, 4-methylbenzyloxy group, 3-methylben zyloxy group, 2-methylbenzyloxy group, 4-fluorobenzyloxy group, 3-flu robenzyloxy group, 4-chlorobenzyloxy group, 3-chlorobenzyloxy group), a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 -haloalkyl group, C 1-6 -haloalkoxy group, a substituted or unsubstituted phenyl group, an acyl group (e.g., form yl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, etc. of C 1-6 -aliphatic acyl group; an aroyl group such as benzoyl group, toluoyl group), an acyloxy group (e.g., formyloxy group, acetoxy group, propanoyloxy group, butanoyloxy group, pentanoyloxy group, hexanoyloxy group, etc. of C 1-6 -aliphatic acyloxy group ; an aroyloxy group such as benzoyloxy group, toluoyloxy group), a hydroxyl group, a carboxy l group, an acetamido group, a carbamoyl group, a cyano group, a nitro group, etc., and may be substituted with one or more substituents selected therefrom.

[0034] As the salt of the compound represented by the formula (I) or (II), a pharmaceutically acceptable salt is preferred and examples thereof include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, meta phosphoric acid, etc., or organic acids such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulf onic acid), etc.

[0035] Examples of the solvate of the compound represented by the formula (I) or (II) or a salt thereof include, for example, a hydrate Examples include substances.

[0036] The compound represented by the formula (I) can be produced, for example, according to the methods described in Shi, D. Q. et al. J. Heterocyclic Chem . 2009, 46, 1331-1334, or Tu, S. et al. Bioorg. Med. Chem. Lett. 2006, 16, 3578 -3581, as shown below.

[0037] [Chemical formula] (In the formula, R 1 and R 2 are as defined in the formula (I).)

[0038] That is, the corresponding aromatic aldehyde compound, 2,4-diamino-6-hydroxypyrimidine (also known as 2,6-diaminopyrimidin-4(3H)-one) and Meldrum's acid are (i) reacted in water in the presence of triethylbenzylammonium chloride under heating, (ii) reacted under heating under microwave irradiation, or (iii) reacted in an organic solvent under heating to produce the target compound (I).

[0039] The compound represented by the formula (II) can be produced, for example, according to the method described in JP-T-2006-510596, as shown below.

[0040] [Chemical formula] (In the formula, R is as defined in the formula (II).)

[0041] That is, the corresponding amine compound is reacted with itaconic acid to obtain γ-lactam carboxylic acid After converting to , it is reacted with histamine in the presence of a condensing agent (e.g., carbodiimide). Thus, the target compound (II) can be produced.

[0042] To purify the product obtained as described above, commonly used methods, such as column chromatography using silica gel or the like as a carrier, or recrystallization using methanol, ethanol, chloroform, dimethyl sulfoxide, n - hexane - ethyl acetate, water, etc. can be used. The elution solvent for column chromatography includes methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof. gel, etc. as a carrier, or recrystallization using methanol, ethanol, chloro form, dimethyl sulfoxide, n - hexane - ethyl acetate, water, etc. can be used. The elution solvent for column chromatography includes methanol, ethanol, chloro form, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof. form, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof. etc. can be mentioned.

[0043] The above - mentioned compound can be formulated in combination with a conventional pharmaceutical carrier as an antipruritic agent. The dosage form is not particularly limited and can be appropriately selected and used as needed, including oral agents such as tablets, capsules, granules, fine granules, powders, sustained - release preparations, solutions, suspensions, emulsions, syrups, elixirs, etc., and parenteral agents such as injections, suppositories, etc. There is no particular limitation on the dosage form, and it can be appropriately selected and used as needed. Oral agents include tablets, capsules, granules, fine granules, powders, sustained - release preparations, solutions, suspensions, emulsions, syrups, elixirs, etc., and parenteral agents include injections, suppositories, etc. For example, oral agents are produced by conventional methods using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, inorganic salts, etc. In addition to these, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, etc. can be appropriately added. For example, oral agents are produced by conventional methods using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, inorganic salts, etc. In addition to these, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, etc. can be appropriately added.

[0044] Examples of binders include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinyl pyrrolidone Examples of binders include starch, dextrin, gum arabic, gelatin, hydroxy propyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxy

[0045] propyl cellulose, crystalline cellulose, ethyl cellulose, polyvinyl pyrrolidone propyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxy propyl cellulose, crystalline cellulose, ethyl cellulose, polyvinyl pyrrolidone include macro goals and the like.

[0046] Examples of the disintegrant include starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and the like.

[0047] Examples of the surfactant include sodium lauryl sulfate, soy lecithin, sucrose fatty acid ester, polysorbate 80, and the like.

[0048] Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol, and the like.

[0049] Examples of the fluidity promoter include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate,

[0050] The injection is manufactured according to a conventional method, and generally, distilled water for injection, physiological saline, glucose aqueous solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. can be used as the diluent. Furthermore, if necessary, bactericides, preservatives, stabilizers, isotonic agents, soothing agents, etc. may be added. Also, from the viewpoint of stability, after filling into a vial or the like, it can be It is not.

[0051] Other parenteral preparations include suppositories for rectal administration, external preparations for topical administration (for example, eye drops, ointments, pastes), etc., and are manufactured according to conventional methods.

[0052] The formulated antipruritic agents vary depending on the dosage form, administration route, etc. For example, they can be administered 1 to 4 times a day for a period of from 1 week to 3 months.

[0053] To exhibit the intended effect as an oral preparation, it varies depending on the patient's age, weight, and degree of the disease. However, in the case of an ordinary adult, as the weight of the compound of the formula (I) or (II), for example, 0.1 ~1000 mg, preferably 1~500 mg, is appropriately taken in several divided doses per day. It is appropriate.

[0054] To exhibit the intended effect as a parenteral preparation, it varies depending on the patient's age, weight, and degree of the disease. However, in the case of an ordinary adult, as the weight of the compound of the formula (I) or (II), for example, 0. 1~1000 mg, preferably 1~500 mg, is appropriately administered by intravenous injection, intravenous drip injection, subcutaneous injection, intramuscular injection , intraperitoneal administration, intrathecal (subarachnoid space) administration.

[0055] The antipruritic agent of the present invention can be used for treating and / or preventing dry skin diseases such as dry skin and xeroderma, allergic dermatitis such as contact dermatitis and atopic dermatitis, psoriasis, itching associated with insect bites, plant allergies, athlete's foot and scabies. It can be used for treating and / or preventing itching.

[0056] This specification includes the contents described in the specification and drawings of Japanese Patent Application No. 2019-034313, which is the basis of the priority of the present application. It includes the contents described therein.

Examples

[0057] Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereto. It is not limited to these.

[0058] [Example 1] Synthesis of Pyrido[2,3-d]pyrimidine Derivatives [Chemical formula]

[0059] Literature 1) According to the method described in the literature, under an Ar atmosphere, commercially available aldehydes (1a, b, d, e, f , g, j, k, m, n, o, p, q, r) or aldehydes known from the literature (1c, h, i , l, s, t) ethylene glycol (0.5 mL) solution of aldehyde (1.00 mmol) was sequentially added with 2,4-diamino-6-hydroxypyrimidine (0.67 mmol) and malonic acid drum acid (1.00 mmol) at room temperature, and stirred at 100 °C for 20 hours. After cooling, the reaction solution was filtered and further washed with methanol (0.5 mL × 3) to obtain pale yellow crystals 2a~u. 2-Amino-5-(4-ethoxy-3-methylphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,

[0060] 7-dione (2a) Yield: 46%; mp: >300 °C; IR (KBr): 3455, 3166, 2856, 2699, 1578, 1477 cm ; -1 ; 1 H N MR (400 MHz, DMSO-d6): δ 10.55 (1H, br s), 10.01 (1H, s), 6.90 (1H, d, J = 2.4 H z), 6.84 (1H, dd, J = 8.8, 2.4 Hz), 6.77 (1H, d, J = 8.8 Hz), 6.51 (2H, br s), 4 .00 (1H, d, J = 7.6 Hz), 3.95 (2H, q, J = 7.0 Hz), 2.88 (1H, dd, J = 16.0, 7.6 H z), 2.42 (1H, d, J = 16.0 Hz), 2.07 (3H, s), 1.29 (3H, t, J = 7.0 Hz); 13 C NMR ( 100 MHz, DMSO-d6): δ 171.10, 161.42, 156.45, 155.20, 154.95, 135.08, 128.74, 12 5.49, 124.61, 111.22, 92.07, 63.14, 32.12, 16.21, 14.83; MS (EI) m / z 314(M+).

[0061] 2-Amino-5-(4-ethoxy-3-methoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4 ,7-dione (2b) Yield: 37%; mp: >300 ℃; IR (KBr): 3462, 3309, 2850, 2743, 1582, 1521 cm -1 ; 1 H N MR (400 MHz,DMSO-d6): δ 10.57 (1H, br s), 10.02 (1H, s), 6.84 (1H, d, J = 2.3 H z), 6.78 (1H, d, J = 8.7Hz), 6.53 (1H, dd, J = 8.7, 2.3 Hz), 6.50 (2H, br s), 4. 05 (1H, d, J = 7.7 Hz), 3.92 (2H, q,J = 6.9 Hz), 3.69 (3H, s), 2.88 (1H, dd, J = 16.4, 7.7 Hz), 1.27 (3H, t, J = 6.9 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.34, 161.47, 156.43, 155.01, 148.89, 146.63, 136.09, 117.65, 112.90, 111.24, 92.03, 63.73, 55.38, 38.71, 32.44, 14.81; MS (EI) m / z 330 (M+).

[0062] 2-Amino-5-(3-methoxy-4-propoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine- 4,7-dione (2c) Yield: 38%; mp: >300 ℃; IR (KBr): 3450, 3167, 2959, 2876, 1652, 1591 cm -1 ; 1 H N MR (400 MHz,DMSO-d6): δ 10.57 (1H, br s), 10.03 (1H, br s), 6.83 (1H, d, J = 2. 3 Hz), 6.79 (1H, d, J = 8.4 Hz), 6.52 (1H, dd, J = 8.4, 2.3 Hz), 6.51 (2H, br s) , 4.05 (1H, d, J = 7.9 Hz), 3.82 (2H, t, J = 7.1 Hz), 3.69 (3H, s), 2.88 (1H, dd , J = 16.4, 7.9 Hz), 1.67 (2H, sext, J = 7.1 Hz), 0.92 (3H, t, J = 7.1 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.22, 161.69, 158.44, 157.50, 146.831, 145.48, 137. 33, 117.79, 113.05, 111.44, 99.65, 69.86, 55.57, 38.73, 32.52, 22.20, 10.53; MS (EI) m / z 344 (M+).

[0063] 2-Amino-5-(3,4-diethoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dio ne (2d) Yield: 41%; mp: >300 ℃; IR (KBr): 3188, 2977, 2868, 1653, 1635 cm -1 ; 1 H NMR (40 0 MHz, DMSO-d6): δ 10.57 (1H, s), 10.01 (1H, s), 6.81 (1H, d, J = 1.8 Hz), 6.78 (1H, d, J = 8.8 Hz), 6.53 (1H, dd, J = 8.8, 1.8 Hz), 6.50 (2H, br s), 4.03 (1H, d, J = 7.8 Hz), 3.93 (2H, q, J = 6.9 Hz), 3.92 (2H, q, J = 6.9 Hz), 2.87 (1H, d d, J = 16.0, 7.8 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.26 (3H, t, J = 6.9 Hz); 13 C NM R (100 MHz, DMSO-d6): δ 171.27, 161.47, 156.42, 154.97, 148.11, 146.87, 136.19, 117.94, 113.45, 112.69, 92.07, 63.83, 63.78, 38.66, 32.37, 14.82; MS (EI) m / z 3 44 (M+).

[0064] 2-Amino-5-(3,4-difluorophenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2e) ne (2e) Yield: 34%; mp: >300 ℃; IR (KBr): 3471, 3161, 1646, 1592 cm -1 ; 1 H-NMR (400 MHz, DMSO-d6): δ 10.62 (1H, br s), 10.13 (1H, br s), 7.32 (1H, dt, J = 10.8, 8.4 Hz ), 7.18 (1H, ddd, J = 10.8, 8.4, 2.4 Hz), 6.95 (1H, m), 6.57 (2H, br s), 4.12 (1 H, d, J = 7.2 Hz), 2.94 (1H, dd, J = 16.3, 7.2 Hz); 13 C NMR (125 MHz, DMSO-d6): δ 170.86, 161.41, 156.68, 155.24, 149.02, 147.17, 141.45, 122.88, 117.41 (d, J = 17.0 Hz), 115.62 (d, J = 17.0 Hz), 91.05, 38.22, 32.24; MS (EI) m / z 292 (M+).

[0065] 2-Amino-5-(3-bromo-4-ethoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7 -dione (2f) Yield: 40%; mp: >300 ℃; IR (KBr): 3458, 3080, 2863, 2751, 1540, 1475 cm -1 ; 1 H N MR (400 MHz, DMSO-d6): δ 10.57 (1H, br s), 10.09 (1H, s), 7.30 (1H, d, J = 2.4 H z), 7.06 (1H, dd, J = 8.0, 2.4 Hz), 6.99 (1H, d, J = 8.0 Hz), 6.56 (2H, br s), 4 .09 (1H, m), 4.04 (2H, q, J = 7.1 Hz), 2.90 (1H, dd, J = 16.2, 6.7 Hz), 1.31 (3H , t, J = 7.1 Hz); 13 C NMR (100 MHz, DMSO-d6): δ170.93, 161.39, 156.55, 155.10, 153.29, 137.33, 130.87, 126.80, 113.77, 110.89, 91.53, 64.39, 38.47, 31.82, 14.5 8; MS (EI) m / z 379 (M+).

[0066] 2-Amino-5-(3-ethoxy-4-methoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4 ,7-dione (2g) Yield: 45%; mp: >300 ℃; IR (KBr): 3461, 3160, 2841, 1591, 1516 cm -1 ; 1 H NMR (40 0 MHz, DMSO-d6): δ 10.58 (1H, br s), 10.03 (1H, s), 6.82 (1H, d, J = 2.4 Hz), 6 .80 (1H, d, J = 8.4 Hz),6.55 (1H, dd, J = 8.4, 2.4 Hz), 6.50 (1H, br s), 4.04 (1 H, d, J = 7.8 Hz), 3.96 - 3.88 (2H, m), 3.68 (3H, s), 2.87 (1H, dd, J = 16.0, 7.8 Hz), 1.28 (3H, t, J = 7.2 Hz); 13 C NMR (100 MHz, DMSO - d6): δ 171.30, 161.55, 156 .51, 155.00, 147.88, 147.66, 136.10, 117.81, 112.20, 111.90, 92.11, 63.68, 55.54, 38.72, 32.42, 14.83; MS (EI) m / z 330 (M+).

[0067] 5 - (3 - Allyloxy - 4 - methoxyphenyl) - 2 - amino - 5,8 - dihydro - 3H,6H - pyrido[2,3 - d]pyrimidine - 4,7 - dione (2h) Yield: 35%; mp: >300 ℃; IR (KBr): 3462, 3169, 1636, 1617, 1591 cm -1 ; 1 H NMR (40 0 MHz, DMSO - d6): δ 10.58 (1H, br s), 10.02 (1H, s), 6.84 (1H, d, J = 2.0 Hz), 6 .81 (1H, d, J = 8.4 Hz), 6.57 (1H, dd, J = 8.4, 2.0 Hz), 5.99 (1H, ddd, J = 17.6, 10.4, 5.2 Hz), 5.36 (1H, dd, J = 17.6, 2.0 Hz), 5.22 (1H, dd, J = 10.4, 2.0 Hz) , 4.46 (2H, d, J = 5.2 Hz), 4.03 (1H, d, J = 7.2 Hz), 3.68 (3H, s), 2.87 (1H, dd, J = 15.8, 7.2 Hz);13 C NMR (100 MHz, DMSO-d6): δ 171.16, 158.72, 156.11, 154.9 9, 147.79, 147.55, 136.10, 133.95, 118.27, 117.88, 112.81, 112.09, 92.02, 69.10, 55.65, 32.41; MS (EI) m / z 342 (M+).

[0068] 2-Amino-5-(4-methoxy-3-propoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine- 4,7-dione (2i) Yield: 41%; mp: >300 ℃; IR (KBr): 3463, 3160, 2846, 1695, 1591, 1539, 1516 cm -1 ; 1 H NMR (400 MHz, DMSO-d6): δ 10.58 (1H, br s), 10.03 (1H, s), 6.82 (1H, d, J = 2.4 Hz), 6.80 (1H, dd,J = 8.4, 2.4 Hz), 6.55 (1H, d, J = 8.4 Hz), 6.51 (2H, br s), 4.04 (1H, d, J = 7.2 Hz), 3.84-3.81 (2H, m), 3.67 (3H, s), 2.87 (1H, dd, J = 16.4, 7.2 Hz), 1.68 (2H, sext, J = 6.8 Hz), 0.94 (3H, t, J = 6.8 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.24, 161.48, 156.43, 154.96, 148.04, 147.68, 136.14, 1 17.78, 112.27, 112.04, 92.06, 69.63, 55.61, 38.66, 32.38, 22.12, 10.46; MS (EI) m / z 344 (M+).

[0069] 2-Amino-5-(3-ethoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione ( 2j): Yield: 43%; mp: >300 ℃; IR (KBr): 3447, 3170, 2854, 1592, 1539 cm -1 ; 1 H NMR (40 0 MHz, DMSO-d6): δ 10.58 (1H, br s), 10.06 (1H, s), 7.15 (1H, t, J = 7.8 Hz), 6 .72 (1H, dd, J = 7.8, 2.4 Hz), 6.70 (1H, dd, J = 7.8, 2.4 Hz), 6.66 (1H, d, J = 2.4 Hz), 6.53 (2H, br s), 4.07 (1H, d, J = 7.4 Hz), 3.94 (2H, q, J = 6.0 Hz), 2. 91 (1H, dd, J = 16.3, 7.4 Hz), 1.28 (3H, t, J = 6.0 Hz); 13 C NMR (100 MHz, DMSO- d6): δ 171.04, 161.40, 158.57, 156.59, 155.03, 145.32, 129.28, 118.56, 113.19, 111.58, 91.65, 62.78, 38.50, 32.86, 14.65; MS (EI) m / z 300 (M+).

[0070] 5-(3-Allyloxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2k) Yield: 45%; mp: >300 ℃; IR (KBr): 3085, 2855, 2727, 1520 cm -1 ; 1 H NMR (400 MHz, DMSO-d6): δ 10.58 (1H, br s), 10.06 (1H, s), 7.15 (1H, t, J = 7.6 Hz), 6.76 (1 H, dd, J = 7.6, 2.4 Hz), 6.71 (2H, m), 6.53 (2H, br s), 6.00 (1H, ddd, J = 17.4, 10.6, 5.5 Hz), 5.36 (1H, dd, J = 17.4, 1.6 Hz), 5.23 (1H, dd, J = 10.6, 1.6 Hz) , 4.48 (2H, d, J = 5.5 Hz), 4.07 (1H, d, J = 7.5 Hz), 3.89 (1H, dd, J = 16.2, 7. 5 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.09, 161.41, 158.26, 156.58, 155.06, 14 5.35, 133.75, 129.48, 118.78, 117.56, 113.43, 112.03, 91.60, 68.11, 38.50, 32.86 ; MS (EI) m / z 312 (M+).

[0071] 2-Amino-5-(3-chloro-4-ethoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4, 7-dione (2l) Yield: 30%; mp: >300 ℃;1 1H NMR (400 MHz, DMSO-d6): δ 10.60 (1H, br s), 10.09 ( 1H, s), 7.15(1H, s), 7.02 (2H, s), 6.55 (2H, br s), 4.06 (1H, d, J = 8.0 Hz), 4. 05 (2H, q, J = 7.0 Hz), 2.91 (1H, dd, J = 16.0, 8.0 Hz), 1.31 (3H, t, J = 7.0 Hz ); 13 13C NMR (100 MHz, DMSO-d6): δ 171.0, 161.38, 156.52, 155.11, 153.38, 136.81, 127.90, 126.09, 121.07, 113.90, 91.53, 64.28, 38.42, 31.87, 14.57.

[0072] 2-Amino-5-(3-chlorophenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione ( 2m) Yield: 35%; mp: >300 ℃; 1 1H NMR (400 MHz, DMSO-d6): δ 10.61 (1H, br s), 10.11 ( 1H, s), 7.30(1H, t, J = 8.0 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.16 (1H, s), 7.11 (1 H, d, J = 8.0 Hz), 6.57 (2H, br s), 4.13 (1H, d, J = 8.0 Hz), 2.95 (1H, dd, J = 16.0, 8.0 Hz); 13 13C NMR (100 MHz, DMSO-d6): δ 170.85, 161.42, 156.76, 155.18, 14 6.35, 133.07, 130.46, 126.49, 126.41, 125.20, 91.61, 38.24, 32.72.

[0073] 2-Amino-5-(3-bromophenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2 n) Yield: 25%; mp: >300 ℃; 1 H NMR (400 MHz, DMSO-d6): δ 10.61 (1H, br s), 10.12 ( 1H, s), 7.38(1H, d, J = 8.0, 1.8 Hz), 7.31 (1H, t, J = 1.8 Hz), 7.24 (1H, t, J = 8.0 Hz), 7.14 (1H, d, J= 8.0 Hz), 6.57 (2H, br s), 4.12 (1H, d, J = 8.0 Hz), 2. 95 (1H, dd, J = 16.2, 8.0 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 170.81, 161.40, 15 6.74, 155.18, 146.63, 130.77, 129.38, 129.30, 125.57, 121.78, 91.03, 38.25, 32.7 1.

[0074] 2-Amino-5-(3-trifluoromethoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4 ,7-dione (2o): Yield: 23%; mp: >300 ℃; 1 H NMR (400 MHz, DMSO-d6): δ 10.64 (1H, br s), 10.15 ( (1H, s), 7.40(1H, t, J = 8.0 Hz), 7.17 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 6.58 (2 H, broad singlet), 4.18 (1H, d, J = 7.2 Hz), 2.97 (1H, double doublet, J = 16.2, 7.2 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.26, 161.71, 156.92, 155.40, 148.72, 146.70, 130.66, 120.2 2 (q, J = 254.60 Hz), 119.21, 119.08, 116.41, 91.23, 38.31, 32.81.

[0075] 2-Amino-5-(3-methoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2p) Yield: 35%; mp: >300 ℃; 1 H NMR (400 MHz, DMSO-d6): δ 10.60 (1H, broad singlet), 10.07 ( 1H, s), 7.17(1H, t, J = 7.6 Hz), 6.75 (1H, double doublet, J = 7.6, 2.4 Hz), 6.71 (1H, d, J = 2.4 Hz), 6.70 (1H, s),6.54 (2H, broad singlet), 4.08 (1H, d, J = 7.2 Hz), 3.69 (3H, s), 2.92 (1H, double doublet, J = 16.0, 7.2 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.24, 161.45, 159.34, 156.54, 155.11, 145.32, 129.53, 118.56,112.85, 111.29, 91.65, 54.91, 38 .51, 32.89.

[0076] 2-Amino-5-(3-propoxyphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2q) Yield: 32%; mp: >300 ℃; 1 H NMR (400 MHz, DMSO-d6): δ 10.58 (1H, br s), 10.05 ( 1H, s), 7.15(1H, t, J = 8.0 Hz), 6.74-6.67 (3H, m), 6.52 (2H, br s), 4.07 (1H, d , J = 8.0 Hz), 3.84 (2H,t, J = 6.4 Hz), 2.91 (1H, dd, J = 16.4, 8.0 Hz), 1.69 (2 H, sext, J = 6.4 Hz), 0.94 (3H, t, J= 6.4 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 17 1.09, 161.47, 158.76, 156.62, 155.05, 145.34, 129.50, 118.54, 112.19, 111.74, 91 .68, 68.76, 38.52, 32.89, 22.05, 10.47.

[0077] 2-Amino-5-biphenyl-3-yl-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2r) Yield: 37%; mp: >300 ℃; 1 H NMR (400 MHz, DMSO-d6): δ 10.58 (1H, br s), 10.09 ( 1H, s), 7.53(2H, dd, J = 8.0, 1.2 Hz), 7.42 (5H, m), 7.32 (2H, t, J = 8.0 Hz), 7 .01 (1H, d, J = 8.0 Hz), 6.51 (2H, brs), 4.17 (1H, d, J = 7.6 Hz), 2.95 (1H, dd, J = 16.0, 7.6 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.38, 161.86, 155.22, 144.66, 140.62, 140.46, 129.37, 129.21, 127.71, 126.94, 126.85, 125.65, 125.20, 91.95, 6 2.93, 38.71, 33.17.

[0078] 2-Amino-5-(3-ethylphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2 s) Yield: 37% ; mp: >300 ℃; 1 H NMR (400 MHz, DMSO-d6): δ 10.60 (1H, br s), 10.07 (1H, s), 7.15 (1H, t, J = 8.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.00 (1H, s), 6.91 (1H, d, J = 8.0 Hz), 6.53 (2H, br s), 4.08 (1H, d, J = 7.2 Hz), 2.93 (1H, dd, J = 16.6, 7.2 Hz), 2.52 (2H, q, J = 7.6 Hz), 1.13 (3H, t, J = 7.6 Hz); 13 C NMR (10 0 MHz, DMSO-d6): δ 171.27, 161.52, 156.60, 155.09, 143.76, 128.43, 126.14, 125. 87, 123.66, 91.75, 62.82, 32.95, 28.24, 15.61.

[0079] 2-Amino-5-(3-propylphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione ( 2t) Yield: 18%; mp: >300 °C; 1 1H NMR (400 MHz, DMSO-d6): δ 10.57 (1H, br s), 10.05 ( 1H, s), 7.14(1H, t, J = 7.6 Hz), 6.98 (1H, d, J = 7.6 Hz), 6.97 (1H, s), 6.91 (1 H, d, J = 7.6 Hz), 6.52 (2H, br s), 4.07 (1H, d, J = 8.0 Hz), 2.92 (1H, dd, J = 16.2, 8.0 Hz), 1.52 (2H, sext, J = 7.2 Hz), 0.86 (3H, t, J = 7.2 Hz); 13 13C NMR (1 00 MHz, DMSO-d6): δ 171.20, 161.48, 156.59, 155.04, 143.66, 142.24, 128.32, 126 .63, 126.43, 123.73, 91.75, 38.87, 37.38, 32.90, 24.18, 13.74.

[0080] 2-Amino-5-(3-butylphenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione (2 u) Yield: 30%; mp: >300 °C; 1 1H NMR (400 MHz, DMSO-d6): δ 10.57 (1H, br s), 10.01 ( (1H, s), 7.13 (1H, t, J = 7.6 Hz), 6.98 (1H, d, J = 7.6 Hz), 6.97 (1H, s), 6.90 (1 H, d, J = 7.6 Hz), 6.52 (2H, br s), 4.07 (1H, d, J = 8.0 Hz), 2.92 (1H, dd, J = 16.4, 8.0 Hz), 1.48 (2H, quin, J = 7.4 Hz), 1.27 (2H, sext, J = 7.4 Hz), 0.87 (3 H, t, J = 7.4 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.16, 161.46, 156.59, 155.04 , 143.66, 142.42, 128.33, 126.59, 126.39, 123.67, 91.76, 38.70, 34.93, 33.20, 32 .90, 21.82, 13.82.

[0081] 1) Tu, S. et al. Bioorg. Med. Chem. Lett. 2006, 16, 3578 - 3581. 2) Muskinja, J. et al. Med. Chem. Res. 2016, 25, 1744 - 1753. 3) McDonald, B. et al. Org. Lett. 2015, 17, 98 - 101. 4) U.S. Patent Application Publication No. 2015 / 0210682 5) Japanese Patent Publication No. 2010 - 526138 6) Wang, B. et al. Eur. J. Org. Chem. 2009, 22, 3688 - 3692. 7) WO2008 / 136756 8) Shi, D. Q. et al. J. Heterocyclic Chem. 2009, 46, 1331 - 1334.

[0082] [Example 2] Synthesis of PA-9 Derivative [Chemical Formula]

[0083] Literature 1) According to (Special Table 2006-510596 Gazette), under an Ar atmosphere, amines 1a-d (1.0 eq) and itaconic acid (1.0 eq) were mixed at room temperature and gradually heated from 60 °C to 150 °C . After heating at 150 °C for 30 minutes, it was cooled to room temperature, and carboxylic acids 2a-d were obtained as pale yellow solid. To a DMF solution of carboxylic acids 2a-d (1.0 eq), dicyclohexyl carbodiimide (DCC) (1.2 eq), 1-hydroxybenzotriazole (HOBt) (1.2 eq) and histamine (1.2 eq) were sequentially added at room temperature and stirred for 15 hours . The crude product obtained by distilling off the solvent was purified by silica gel chromatography (CH2Cl2:MeOH = 5:1) and further washed with EtOAc:MeOH = 5:1 (0.5 mL × 3) to obtain 3a-d as white solids .

[0084] 1-(4-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidinecarboxylic acid (2a) 1 H NMR (400 MHz, Pyridine-d5): δ 10.74 (1H, br s), 7.73 (1H, d, J = 2.1 Hz), 7.4 5 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 2.1, 8.6 Hz), 4.65 (1H, dd, J = 13.0, 7 .6 Hz), 4.44 (1H, t, J =7.6 Hz), 3.40 (1H, quint, J = 7.6 Hz), 2.77 (1H, dd, J = 17.6, 7.6 Hz), 2.60 (1H, dd, J = 17.6, 7.6 Hz).

[0085] 1-(5-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidinecarboxylic acid (2b) 1 1H NMR (400 MHz, Pyridine-d5): δ 11.53 (1H, br s), 7.38 (1H, d, J = 8.4 Hz), 7.1 4 (1H, dd, J = 8.4, 7.2 Hz), 6.93 (1H, d, J = 7.2 Hz), 4.67 (1H, dd, J = 13.0, 7. 5 Hz), 4.52 (1H, t, J = 7.5 Hz), 3.39 (1H, quint, J = 7.5 Hz), 2.76 (1H, dd, J = 17.5, 7.5 Hz), 2.57 (1H, dd, J = 17.5, 7.5 Hz).

[0086] 1-(6-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidinecarboxylic acid (2c) 1 1H NMR (400 MHz, Pyridine-d5): δ 11.63 (1H, br s), 7.71 (1H, d, J = 9.0 Hz), 7.4 8 (1H, d, J = 1.7 Hz), 6.88 (1H, dd, J = 9.0, 1.7 Hz), 4.65 (1H, dd, J = 13.0, 7 .7 Hz), 4.44 (1H, t, J = 7.7 Hz), 3.40 (1H, quint, J = 7.7 Hz), 2.68 (1H, dd, J = 17.1, 7.7 Hz), 2.60 (1H, dd, J = 17.1, 7.7 Hz).

[0087] 1-(7-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidinecarboxylic acid (2d) 1 H NMR (400MHz, Pyridine-d5): δ 11.66 (1H, br s), 7.67 (1H, d, J = 8.7 Hz), 7.3 0 (1H, d, J = 7.3 Hz), 6.86 (1H, dd, J = 8.7, 7.3 Hz), 4.71 (1H, dd, J = 13.4, 7 .4 Hz), 4.48 (1H, t, J =7.4 Hz), 3.42 (1H, quint, J = 7.4 Hz), 2.78 (1H, dd, J = 17.6, 7.4 Hz), 2.61 (1H, dd, J = 17.6, 7.4 Hz).

[0088] N-[2-(1H-imidazol-4-yl)ethyl]-1-(4-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidineca rboxamide (3a) mp: 190-191 ℃; IR (KBr): 3566, 3437, 3306, 1695, 1636, 1558, 1508 cm -1 ; 1 H NMR (400MHz, Pyridine-d5): δ 9.00 (1H, br s), 7.96 (1H, s), 7.61 (1H, d, J = 7.4 Hz ), 7.14 (1H, t, J = 7.4 Hz), 7.15(1H, s), 6.98 (1H, d, J = 7.4 Hz), 4.72 (1H, t, J = 9.1 Hz), 3.96-3.85 (3H, m), 3.26 (1H, dd, J = 15.6, 9.1 Hz), 3.11 (2H, t, J = 6.8 Hz), 2.78 (1H, dd, J = 15.6, 9.1 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 169.5 6, 168.62, 147.59, 134.59, 131.61, 126.70, 123.80, 119.28, 116.97, 115.67, 107.1 1, 48.23, 36.47, 32.61, 26.57.

[0089] N-[2-(1H-imidazol-4-yl)ethyl]-1-(5-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidineca rboxamide (3b) Yield: 24% over two steps; mp: 208 - 209 ℃; IR (KBr): 3735, 3649, 3097, 1684, 165 3, 1558, 1508 cm -1 ; 1 H NMR (400MHz, Pyridine-d5): δ 9.04 (1H, br s), 8.05 (1H, s), 7.69 (1H, d, J = 9.6Hz), 7.68 (1H, s), 7.27 (1H, d, J = 9.6 Hz), 7.71(1H, s) , 5.09 (1H, dd, J = 13.6, 8.4 Hz), 4.73 (1H, t, J = 8.4 Hz), 3.94 - 3.86 (3H, m), 3.28 (1H, dd, J = 14.8, 8.4 Hz), 3.11 (2H, t, J = 6.6 Hz), 2.84 (1H, dd, J = 14. 8, 8.4 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 169.63, 168.21, 145.55, 134.50, 133.7 9, 131.92, 127.15, 123.19, 118.50, 118.39, 116.85, 108.13, 48.33, 38.747, 36.33, 32.92, 26.53.

[0090] N-[2-(1H-imidazol-4-yl)ethyl]-1-(6-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidineca rboxamide (3c) Yield: 17% over two steps; mp: 196-198 ℃; IR(KBr): 3290, 3213, 3101, 1683, 1636 , 1558, 1508cm -1 ; 1 H NMR (400MHz, Pyridine-d5): δ 9.12 (1H, br s), 8.30 (1H, s) , 7.83 (1H, s), 7.66 (1H, d, J = 9.2 Hz), 7.25 (1H, s), 6.96 (1H, d, J = 9.2 Hz) , 5.03 (1H, dd, J = 13.0, 8.3 Hz), 4.71 (1H, t, J = 8.3 Hz), 3.91-3.84 (3H, m), 3.27 (1H, dd, J = 15.2, 8.3 Hz), 3.12 (2H, t, J = 6.4 Hz), 2.87 (1H, dd, J = 15. 2, 8.3 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 169.79, 168.28, 147.25, 134.03, 132.7 4, 132.42, 131.35, 121.77, 119.93, 116.53, 115.03, 106.65, 48.23, 38.21,36.25, 3 2.92, 25.47.

[0091] N-[2-(1H-imidazol-4-yl)ethyl]-1-(7-chloro-1H-indazol-3-yl)-5-oxo-3-pyrrolidinecarboxamide (3d) rboxamide (3d) Yield: 36% over two steps; mp: 238-239 ℃; IR(KBr): 3319, 3231, 3213, 1663, 1636 , 1558, 1508cm -1 ; 1 H NMR (400MHz, Pyridine-d5): δ 9.02 (1H, br s), 8.49 (1H, s) , 7.76 (1H, s), 7.52 (1H, d, J = 7.5 Hz), 7.40 (1H, d, J = 7.5 Hz), 6.98 (1H, s) , 6.88 (1H, t, J = 7.5 Hz), 5.13 (1H, dd, J = 14.6, 8.5 Hz), 4.81 (1H, t, J = 8. 5 Hz), 3.95-3.86 (3H, m), 3.26 (1H, dd, J = 16.2, 8.5 Hz), 3.11 (2H, t, J = 6.8 Hz), 2.83 (1H, dd, J = 16.2, 8.5 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 169.56, 168 .32, 144.32, 134.51, 133.83, 133.30, 125.80, 120.48, 119.42, 119.04, 116.84, 109 .42, 48.36, 38.77, 36.32, 32.95, 26.57.

[0092] Literature 2) (Special Table 2012-529476 Gazette), in an Ar atmosphere, itaconic acid (1.2eq) was added to an aqueous solution (3mL) of amine 1e~j (1.0eq) at room temperature, and for 20 hours It was heated under reflux with stirring. After cooling to room temperature, the precipitated solid was collected by filtration to obtain carboxylic acids 2e - j. To a mixed solution of carboxylic acids 2e - j (1.0 eq) in CH2Cl2 and DMF, 1 - ethyl -3-(3 - dimethylaminopropyl)carbodiimide (EDC) (1.2 eq), 4 - dimethylaminopyridine (DMAP) (0.1 eq) and histamine (1.2 eq) were sequentially added at room temperature and stirred for 15 h. The solvent was distilled off, and the crude product obtained was purified by silica gel column chromatography (CH2Cl2:MeOH = 10:1) to obtain 3e - j as white solids.

[0093] N - [2 - (1H - imidazol - 4 - yl)ethyl] - 1 - phenyl - 5 - oxo - 3 - pyrrolidinecarboxamide (3e) Yield: 63%; mp: 149 - 151 ℃; IR (KBr): 3675, 3306, 1678, 1643, 1558 cm -1 ; 1 1H NMR (400 MHz, Pyridine - d5): δ 9.11 (1H, t, J = 5.8 Hz),7.90 (1H, s), 7.72 (2H, d, J = 8.4 Hz), 7.28 (2H, t, J = 8.4 Hz), 7.09 (1H, s), 7.06 (1H, t, J = 8.4 Hz), 4.1 3 (1H, dd, J = 9.6, 8.3 Hz), 3.93 (1H, t, J = 8.3 Hz), 3.83 (2H, q, J = 7.5 Hz), 3.47 (1H, quint, J =8.3 Hz), 3.14 (1H, dd, J = 16.7, 8.3 Hz), 3.08 (2H, t, J = 7.5 Hz), 2.84 (1H, dd, J = 16.7, 8.3 Hz); 1313C NMR (100 MHz, DMSO-d6): δ 172.16, 171.96, 139.22, 134.58, 133.95, 128.70, 124.00, 119.36, 116.83, 50.73, 38.66, 3 5.66, 35.43, 26.38.

[0094] N-[2-(1H-imidazol-4-yl)ethyl]-1-(4-methylphenyl)-5-oxo-3-pyrrolidinecarboxamide (3f) Yield: 93%; mp: 176 - 178 ℃; IR (KBr): 3306, 3088, 1675, 1639, 1556 cm -1 ; 1 1H NMR (400 MHz, Pyridine-d5): δ 9.10 (1H, t, J = 5.8 Hz), 7.91 (1H, s), 7.64 (2H, d, J = 7.2 Hz), 7.08 (2H, t, J = 7.2 Hz), 7.07 (1H, s), 4.14 (1H, dd, J = 9.6, 8.0 Hz), 3.92 (1H, t, J = 8.0 Hz), 3.83 (2H, q, J = 7.2 Hz), 3.46 (1H, quint, J = 8. 0 Hz), 3.14 (1H, dd, J = 17.6, 8.0 Hz), 3.08 (2H, t, J = 7.2 Hz), 2.84 (1H, dd, J = 17.6, 8.0 Hz), 2.13 (3H, s); 13 13C NMR (100 MHz, DMSO-d6):δ 172.17, 172.10, 1 37.00, 134.86, 134.44, 133.26, 129.30, 119.58, 117.04, 51.00, 39.17, 36.02, 35.8 4, 27.01, 20.63.

[0095] 1-(4-chlorophenyl)-N-[2-(1H-imidazol-4yl)ethyl]- 5-oxo-3-pyrrolidinecarboxamide (3g) Yield: 93%; mp: 196-198 ℃; IR (KBr): 3119, 3017, 1695, 1647, 1558 cm -1 ; 1 H NMR (400MHz, Pyridine-d5): δ 9.16 (1H, t, J = 5.2 Hz), 7.95 (1H, s), 7.71 (2H, d, J = 8.4 Hz), 7.30 (2H, d,J = 8.4 Hz), 7.11 (1H, s), 4.10 (1H, dd, J = 9.4, 8.3 Hz ), 3.92 (1H, t, J = 8.3 Hz), 3.83 (2H, q, J = 6.7 Hz), 3.50 (1H, quint, J = 8.3 Hz), 3.11 (1H, dd, J = 17.5, 8.3 Hz), 3.09 (2H, t, J = 5.7 Hz), 2.85 (1H, dd, J = 17.5, 8.3 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 172.20, 171.68, 137.90, 134.43, 133.95, 128.36, 127.49, 120.60, 116.62, 50.47, 38.74, 35.62, 35.30, 26.52.

[0096] N-[2-(1H-imidazol-4-yl)ethyl]-1-(4-fluorophenyl)-5-oxo-3-pyrrolidinecarboxamide (3h) Yield: 94%; mp: 232 - 234 ℃; IR (KBr): 3140, 3126, 1688, 1645, 1570 cm -1; 1 1H NMR (400 MHz, Pyridine - d5): δ 9.13 (1H, t, J = 4.8 Hz), 7.72 - 7.68 (2H, m), 7.92 (1H, s), 7.11 (1H, s), 7.09 - 7.04 (2H, m), 4.12 (1H, dd, J = 12.2, 8.7 Hz), 3.92 (1H, t, J = 8.7 Hz), 3.84 (2H, t, J = 7.0 Hz), 3.49 (1H, quint, J = 8.7 Hz), 3.14 (1 H, dd, J = 17.2, 8.7 Hz), 3.09 (2H, t, J = 7.0 Hz), 2.85 (1H, dd, J = 17.2, 8.7 Hz); 13 13C NMR (100 MHz, DMSO - d6): δ 172.05, 171.90, 158.44 (d, J = 240.3 Hz), 13 5.64, 134.62, 134.14, 121.35 (d, J = 7.6 Hz), 116.81, 115.25 (d, J = 22.0 Hz), 5 0.92, 38.92, 35.68, 35.58, 26.72.

[0097] N - [2 - (1H - imidazol - 4 - yl)ethyl] - 1 - (4 - methoxyphenyl) - 5 - oxo - 3 - pyrrolidinecarboxamide (3i) Yield: 95%; mp: 151 - 153 ℃; IR (KBr): 3239, 3075, 1684, 1635, 1568 cm -1 ; 1 1H NMR (400 MHz, Pyridine-d5): δ 9.08 (1H, t, J = 5.2 Hz), 7.91 (1H, s), 7.68 (2H, d, J = 8.6 Hz), 7.10 (1H, s), 6.92 (2H, d, J = 8.6 Hz),4.16 (1H, dd, J = 9.4, 8.4 H z), 3.93 (1H, t, J = 8.4 Hz), 3.84 (2H, q, J = 7.6 Hz), 3.62 (3H, s), 3.46 (1H, quint, J = 8.4 Hz), 3.15 (1H, dd, J = 17.1, 8.4 Hz), 3.09 (2H, t, J = 7.6 Hz), 2 .84 (1H, dd, J = 17.1, 8.4 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 171.97, 171.57, 1 55.80, 134.65, 134.26, 132.41, 121.20, 116.80, 113.82, 55.20, 51.03, 38.95, 35.6 8, 35.62, 26.81.

[0098] N-[2-(1H-imidazol-4-yl)ethyl]-1-(4-cyanophenyl)-5-oxo-3-pyrrolidinecarboxamide ( 3j) Yield: 69%; mp: 211-212 ℃; IR (KBr): 3151, 3019, 2231, 1703, 1646, 1558 cm -1 ; 1 H NMR (400MHz, Pyridine-d5): δ 9.17 (1H, t, J = 5.2 Hz), 7.92 (1H, s), 7.83 (2H , d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.11 (1H, s), 4.12 (1H, dd, J = 9.6, 8.4 Hz), 3.96 (1H, t, J = 8.4 Hz), 3.84 (2H, t, J = 7.0 Hz), 3.51 (1H, quint, J = 8.4 Hz), 3.16 (1H, dd, J = 17.2, 8.4 Hz), 3.10 (2H, t, J = 7.0 Hz), 2.88 (1H, dd, J = 17.2, 8.4 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 173.28, 171.75, 143.03, 1 34.67, 133.06, 119.03, 118.93, 105.53, 51.51, 38.98, 36.03, 35.39, 26.85.

[0099] Literature 1) (Japanese Patent Laid-Open No. 2006-510596), under an Ar atmosphere, amine 1k - m (1.0 eq) and itaconic acid (1.0 eq) were mixed at room temperature and gradually heated from 60°C to 150°C . After heating at 150°C for 30 minutes, it was cooled to room temperature to obtain carboxylic acids 2k - m . To a mixed solution of carboxylic acids 2k - m (1 eq) in CH2Cl2 and DMF, EDC (1.2 eq ), DMAP (0.1 eq) and histamine (1.2 eq) were sequentially added at room temperature and stirred for 15 hours. The solvent was distilled off, and the resulting crude product was purified by silica gel chromatography (CH2 Cl2:MeOH = 10:1) to obtain 3k - m as white, yellow and red foamy solids respectively .

[0100] N-[2-(1H-imidazol-4-yl)ethyl]-1-(2-hydroxyphenyl)-5-oxo-3pyrrolidinecarboxamide (3k) Yield: 40%; IR (KBr): 3651, 3265, 3213, 1684, 1670, 1558 cm -1 ; 1 H NMR (400 MHz, Pyridine-d5): δ 9.08 (1H, br s), 7.91 (1H, s), 7.42 (1H, d, J = 8.8 Hz), 7.21-7 .15 (2H, m), 7.10 (1H, s), 6.92-6.88 (1H, m), 4.30 (1H, dd, J = 9.2, 7.5 Hz), 4. 10 (1H, t, J = 7.5 Hz), 3.85 (2H, q,J = 6.4 Hz), 3.47 (1H, quint, J = 7.5 Hz), 3 .13 (1H, dd, J = 16.4, 7.5 Hz), 3.06 (2H, t, J =6.4 Hz), 2.83 (1H, dd, J = 16.4, 7.5 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 172.52, 172.22, 152.77, 134.68, 128.30, 128.24, 125.48, 119.12, 118.74, 116.87, 116.74, 51.68, 38.98, 37.09, 34.39, 26. 85.

[0101] N-[2-(1H-imidazol-4-yl)ethyl]-1-(3-hydroxyphenyl)-5-oxo-3pyrrolidinecarboxamide (3l) Yield: 58%; IR (KBr): 3790, 3439, 3337, 1684, 1653, 1558 cm -1 ; 1 H NMR (400 MHz, Pyridine-d5): δ 8.97 (1H, br s), 8.09 (1H, s), 7.93 (1H, s), 7.28 (1H, t, J = 8 .2 Hz), 7.20 (1H, d, J =8.2 Hz), 7.13 (1H, s), 6.98 (1H, d, J = 8.2 Hz), 4.29 (1 H, dd, J = 9.0, 8.3 Hz), 3.98 (1H, t, J = 8.3 Hz), 3.89 (2H, q, J = 6.9 Hz), 3.3 6 (1H, quint, J = 8.3 Hz), 3.21 (1H, dd, J = 17.1, 8.3 Hz), 3.09 (2H, t, J = 6.9 Hz), 2.82 (1H, dd, J = 17.1, 8.3 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 172.07, 17 1.93, 157.55, 140.28, 134.68, 129.38, 111.17, 109.78, 106.63, 50.84, 39.00, 35.9 9, 35.54, 26.89.

[0102] N-[2-(1H-imidazol-4-yl)ethyl]-1-(4-hydroxyphenyl)-5-oxo-3pyrrolidinecarboxamide (3m) Yield: 54%; IR (KBr): 3585, 3251, 3190, 1684, 1653, 1558 cm -1 ; 1 H NMR (400 MHz, Pyridine-d5): δ 11.49 (1H, br s), 8.97 (1H, br s), 7.93 (1H, s), 7.76 (2H, dd, J = 8.6, 2.4 Hz), 7.15 (2H, dd, J = 8.6, 2.4 Hz), 7.14 (1H, s), 4.29 (1H, td, J = 8.4, 2.1 Hz), 3.95 (1H, td, J = 8.4, 2.1 Hz), 3.90 (2H, q, J = 6.3 Hz), 3.39 ( 1H, quint, J = 8.4 Hz), 3.22 (1H, ddd, J = 16.7,8.4, 2.1 Hz), 3.10 (2H, t, J = 6 .3 Hz), 2.84 (1H, ddd, J = 16.7, 8.4, 2.1 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 17 2.52, 171.86, 154.61, 135.20, 131.48, 122.05, 115.61, 51.67, 39.49, 36.23, 36.09 , 27.40.

[0103] Literature 1) (Special Table 2006 - 510596 Gazette), under an Ar atmosphere, amine 1n (1 .0 eq) and itaconic acid (1.0 eq) were mixed at room temperature and gradually heated from 60 °C to 150 °C . After heating at 150 °C for 30 minutes, it was cooled to room temperature to obtain carboxylic acid 2n. Carboxylic acid 2n (1.0 eq) in a mixed solution of CH2Cl2 and DMF, DCC (1.2 eq), HO Bt (1.2 eq) and histamine (1.2 eq) were sequentially added at room temperature and stirred for 15 hours . The solvent was distilled off, and the resulting crude product was purified by silica gel chromatography (CH2Cl2:M eOH = 10:1) to obtain 3n as a white solid.

[0104] N-[2-(1H-imidazol-4-yl)ethyl]-1-(1H-pyrazol-3-yl)-5-oxo-3-pyrrolidinecarboxamide (3n) Yield: 30%; mp: 213 - 211 °C; IR (KBr): 3676, 3320, 3203, 1689, 1652, 1635, 1557 c m -1 ; 1 1H NMR (400 MHz, Pyridine - d5): δ 12.24 (1H, br s), 9.00 (1H, br s), 8.03 ( 1H, s), 7.88 (1H, s), 7.56 (1H,s), 7.10(1H, s), 4.78 (1H, dd, J = 12.6, 8.1 Hz), 4.26 (1H, t, J = 8.1 Hz), 3.82 (2H,q, J = 6.7 Hz), 3.69 (1H, quint, J = 8.1 Hz) , 3.22 (1H, dd, J = 15.3, 8.1 Hz), 3.06 (2H, t, J = 6.7 Hz), 2.72 (1H, dd, J = 1 5.3, 8.1 Hz); 13 13C NMR (100 MHz, DMSO - d6): δ 169.67, 168.26,162.33, 138.77, 138. 73, 134.64, 134.53, 89.01, 47.04, 38.87, 36.72, 33.00, 26.97.

[0105] Literature 1) According to Japanese Patent Publication No. 2006 - 510596, under an Ar atmosphere, amine 1o - r (1.0 eq) and itaconic acid (1.0 eq) were mixed at room temperature and gradually heated from 60 °C to 150 °C . After heating at 150 °C for 30 minutes, it was cooled to room temperature and purified by silica gel chromatography (CH2Cl2:MeOH = 30:1) to obtain carboxylic acid 2o - r. To a mixed solution of carboxylic acid 2o - r (1.0 eq) in CH2Cl2 and DMF, DCC (1.2 eq), was added. HOBt (1.2 eq) and histamine (1.2 eq) were sequentially added at room temperature and stirred for 15 hours. The solvent was distilled off, and the resulting crude product was purified by silica gel chromatography (CH2Cl2 :MeOH = 10:1) to obtain 3o~r as a yellow solid or white foamy solid.

[0106] N-[2-(1H-imidazol-4yl)ethyl]-5-oxo-1-(phenylmethyl)- 3-pyrrolidinecarboxamide (3 o) Yield: 29%; IR (KBr): 3271, 3155, 1670, 1652, 1558 cm -1 ; 1 H NMR (400MHz, Pyridin e-d5): δ 8.85 (1H, br), 7.92 (1H, s), 7.33 - 7.25 (5H, m), 7.08 (1H, s), 4.56 (1H , d, J = 14.6 Hz), 4.48 (1H, d, J = 14.6 Hz), 3.85 (2H, q, J = 6.5 Hz), 3.67 (1H , t, J = 8.0 Hz), 3.39 (1H, t, J = 8.0 Hz), 3.25 (1H, quint, J = 8.0 Hz), 3.10 ( 1H, dd, J =17.0, 8.0 Hz), 3.05 (2H, t, J = 6.5 Hz), 2.72 (1H, dd, J = 17.0, 8.0 Hz).

[0107] N-[2-(1H-imidazol-4-yl)ethyl]-1-[(2-hydroxyphenyl)methyl]-5-oxo-3-pyrrolidinecar boxamide (3p) Yield: 30%; IR (KBr): 3748, 3738, 3651, 1684, 1653, 1558 cm-1 ; 1 H NMR (400 MHz, P yridine-d5): δ 11.36 (1H, br s) 8.81 (1H, t, J = 5.8 Hz), 7.84 (1H, d, J = 1.2 H z), 7.34 (1H, dd, J = 7.5, 1.3 Hz), 7.13 (1H, td, J = 7.5, 1.3 Hz), 7.08 (1H, dd , J = 7.5, 1.3 Hz), 7.03 (1H, s), 6.81 (1H, td, J = 1.3, 7.5 Hz), 4.74 (1H, d, J = 15.2 Hz), 4.65 (1H, d, J = 15.2 Hz), 3.82 (1H, dd, J = 9.6, 8.2 Hz), 3.77 (2H , q, J = 6.6 Hz), 3.57 (1H, t, J = 8.2 Hz), 3.22 (1H, quint, J = 8.2 Hz), 3.03 (1 H, dd, J = 16.5, 8.2 Hz), 2.99 (2H, t, J = 6.6 Hz), 2.63 (1H, dd, J = 16.5, 8.2 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 172.57, 172.18, 155.26, 134,67, 128.78, 128. 38, 122.58, 119.03, 115.21, 49.63, 40.57, 38.94, 35.93, 33.91, 26.87.

[0108] N-[2-(1H-imidazol-4-yl)ethyl]-1-[(3-hydroxyphenyl)methyl]-5-oxo-3-pyrrolidinecar boxamide (3q) Yield: 40%; IR (KBr): 3734, 3647, 3623, 1684, 1653, 1558 cm-1 ; 1 H NMR (400 MHz, P yridine-d5): δ 8.83 (1H, br s), 7.93 (1H, s), 7.24 (2H, d, J = 7.9 Hz), 7.22 (1H , s), 7.09 (1H, s), 7.08(1H, d, J = 7.9 Hz), 6.88 (1H, d, J = 7.9 Hz), 4.57 (1H, d, J = 14.6 Hz), 4.48 (1H, d, J = 14.6 Hz), 3.84 (2H, q, J = 6.1 Hz), 3.72 (1H, t, J = 8.1 Hz), 3.45 (1H, t, J = 8.1 Hz), 3.23 (1H, quint, J = 8.1 Hz), 3.09 (1 H, dd, J = 16.0, 8.1 Hz), 3.05 (2H, t, J = 6.1 Hz), 2.67 (1H, dd, J = 16.0, 8.1 Hz); 13 C NMR (100 MHz, DMSO-d6): δ 172.31, 172.05, 157.63, 138.14, 134.66, 134. 18, 129.55, 118.17, 116.90, 114.41, 114.30, 49.14, 45.31, 38.88, 35.89, 26.78.

[0109] N-[2-(1H-imidazol-4-yl)ethyl]-1-[(4-hydroxyphenyl)methyl]-5-oxo-3-pyrrolidinecar boxamide (3r) Yield: 29%; IR (KBr): 3651, 3271, 3213, 1663, 1653, 1558 cm -1 ; 1 H NMR (400 MHz, P pyridine-d5): δ 8.85 (1H, br s), 7.91 (1H, s), 7.28 (2H, d, J = 7.6 Hz), 7.10 (2H , d, J = 7.6 Hz), 4.55 (1H, d, J = 14.6 Hz), 4.44 (1H, d, J = 14.6 Hz), 3.91 - 3.7 1 (2H, m), 3.70 (1H, dd, J = 8.8, 7.9 Hz), 3.45 (1H, t, J = 7.9 Hz), 3.26 (1H, q uint, J = 7.9 Hz), 3.11 (1H, dd, J = 15.0, 7.9 Hz), 3.06 (2H, t, J = 7.4 Hz), 2. 71 (1H, dd, J = 15.0, 7.9 Hz); 13 C NMR (100 MHz, DMSO-d6) : δ 172.15, 156.66, 1 34.68, 129.07, 126.80, 115.30, 48.93, 44.83, 38.94, 35.83, 34.03, 26.89.

[0110] 1) Japanese Patent Publication No. 2006 - 510596 2) Japanese Patent Publication No. 2012 - 529476 3) Saczewski, F. et al. Bioorg. Med. Chem. 2011, 19, 321 - 329 4) Mestichelli, P. et al. Org. Lett. 2013, 15, 5448 - 5451 5) Commercially available, Aurora Building Blocks, A17.818.885 6) Commercially available, Aurora Building Blocks, A21.884.126

[0111] [Example 3] Evaluation of drug efficacy using a serotonin (5-HT)-induced pruritus model mouse (Figure 1) 5-HT (50 nmol, 10 μL) was intradermally injected into the lumbar region (intradermal injection, i.d.). The scratching behavior, such as biting, licking, and scratching the injection site, was measured every 5 minutes for its behavioral time. Intrathecal pretreatment (3 0 minutes before) with PA-8 (0.1, 1 nmol) almost completely suppressed 5-HT-induced scratching behavior. On the other hand, the effect of pretreatment with the peptidergic PACAP receptor antagonist PACAP6-38 (P6-38: 100 pmol) was not significant. SLN shows the effect when physiological saline is administered instead of 5-HT ACSF is the abbreviation of artificial cerebrospinal fluid and is the solvent for P6-38 and PA-8.

[0112] [Example 4] Evaluation of drug efficacy using a dry skin pruritus model mouse This test was carried out with reference to the method of Miyamoto et al. (Miyamoto T., Nojima H., Shinkado T., et al.: Itch-associated response induced by experimental dry skinin mice, Jpn. J. Phamacol., 88, 285-292, 2002), which is a test system published as a method for evaluating itch in animals. Reference was made to carry out the test.

[0113] Forty 5-week-old ICR mice were individually placed in cages and acclimated for 1 week, and the rostral back was shaved 3 days before the start of the test (treatment method A). The 40 shaved mice were divided into groups of 8 each and orally administered (p.o.) with PA-8 at 3 mg / kg, 10 mg / kg, and 30 It was divided into five groups: an oral (p.o.) administration group at mg / kg, a comparison group, and a control group.

[0114] <PA-8 Administration Group> In the PA-8 administration group, mice subjected to hair removal treatment (treatment method A) were anesthetized with ether, and a 2×2 cm cotton soaked in a mixed solution of acetone (A): diethyl ether (E) (1:1) was applied to the rostral back for 15 seconds, and then a cotton soaked in ion-exchanged water (W) was applied for 30 seconds [hereinafter, this series of treatments will be abbreviated as AEW treatment (treatment method B)]. The AEW treatment was performed once every 8 hours for 5 days, for a total of 10 times. On the day after the AEW treatment, PA-8 was orally administered at 3 mg / kg, 10 mg / kg, or 30 mg / kg, and behavioral observation was carried out for 1 hour starting from 30 minutes later (treatment method C). / kg, 10 mg / kg, or 30 mg / kg orally, and behavioral observation was carried out for 1 hour starting from 30 minutes later (treatment method C).

[0115] <Comparison Group> In the comparison group, the above AEW treatment (treatment method B) was performed on the mice subjected to hair removal treatment (treatment method A), and a 10% aqueous DMSO solution (solvent) was orally administered.

[0116] <Control Group> In the control group (Naive), only the hair removal treatment (treatment method A) was performed. The outline of the procedure of the behavioral experiment using dry skin scratching model mice is shown in Figure 2, and the results of evaluating the scratching time of each group are shown in Figure 3.

[0117] From Figure 3, it can be seen that by orally administering PA-8, the scratching behavior induced by the AEW treatment was significantly suppressed.

[0118] [Example 5] Pharmacodynamic Evaluation 1 Using PACAP Receptor-Expressing Cultured Cells Mouse PAC1 receptor-expressing CHO cells (PAC1 / CHO cells) and mouse VPAC1 ​​​​Using receptor-expressing CHO cells (VPAC1 / CHO cells), the effect of each compound on the phosphorylation of CREB (cAMP-responsive element-binding protein) was examined by Western blot analysis using an anti-phosphorylated CREB (pCREB) antibody. That is, after treatment with compounds (PA-8, compound 2j, and compound 2o) at 10 pM to 10 nM and

[0119] their solvent DMSO (VEH: phosphate buffer containing 0.1% DMSO) for 30 minutes, PAC 1 nM was added, and protein recovery was performed 30 minutes after PACAP stimulation.

[0120] Figure 4A shows the data in PAC1 / CHO cells. PA-8 suppressed CREB phosphorylation by PACAP (1 nM) at the concentrations used (10 pM to 10 nM) ( n = 5; Figure 4A). On the other hand, in the study using VPAC1 / CHO cells, CREB phosphorylation by PACAP (1 nM) was not suppressed at the concentrations used (10 pM to 10 nM) (n = 3; Figure 4B). That is, it can be said that PA-8 is a PAC1 receptor-selective antagonist. .

[0121] Figure 4C shows the effect of compound 2j (10 pM to 10 nM) in PAC1 / CHO cells. However, it suppressed CREB phosphorylation by PACAP (1 nM) in a concentration-dependent manner (n = 4) . Figure 4D similarly shows the effect of compound 2o (10 pM to 10 nM). Compound 2o also suppressed CREB phosphorylation by PACAP (1 nM) at the concentrations used (10 pM to 10 nM) (n = 4). In particular, compound 2o showed a slightly stronger inhibitory effect on CREB phosphorylation than PA-8. ​

[0122] The PA-8 used in the above experiments was a commercially available compound purchased from Namiki Shoji Co., Ltd. Used.

[0123] [Example 6] Drug efficacy evaluation 2 using cultured cells expressing PACAP receptor Using mouse PAC1 receptor expressing CHO cells (PAC1 / CHO cells), PACAP stimulation was performed. In response to phosphorylation of CREB (cAMP-responsive element-binding protein) caused by stimulation The effect of each compound on the expression of CREB was examined by Western blot analysis using anti-phosphorylated CREB (pCREB) antibody. Figures 5A and 5B show the results of the ELISA assay using PA-9 and compound 3d (10 pM), respectively. Although both of them inhibited CREB phosphorylation by PACAP (1 nM), The inhibition was concentration-dependent (n=4-5).

[0124] [Example 7] Effect of intradermal administration of PACAP to the lumbar region When PACAP (1-1,000 pmol) was administered intradermally (10 μL) to the lumbar region, The mice showed itching behavior such as biting, licking, and scratching the injection site. No such effect was observed with vasoactive intestinal peptide (VIP) (100 pmol). Therefore, this effect is thought to be mediated through the PAC1 receptor (Figure 6).

[0125] [Example 8] Itching behavior induced by intradermal administration of PACAP was significantly increased by simultaneous intradermal administration of PA-8. Alternatively, it can be suppressed by prior subcutaneous administration of naltrexone (NTX).

[0126] Biting and licking induced by intradermal administration (10 μL) of PACAP (100 pmol) The scratching behavior was dose-dependently induced by simultaneous intradermal administration of PA-8 (0.01-1 nmol). Suppressed (Fig. 7A). SLN indicates intradermal administration of physiological saline. DMSO (10% solution, dissolved in physiological saline) is the solvent for PA-8. Also, when the opioid receptor antagonist naltr exone (NTX: 1 mg / kg) is subcutaneously administered 15 minutes before intradermal administration of PACAP, the induction of scratching behavior by intradermal administration of PACAP (100 pmol) is significantly suppressed (Fig. 7 B). SLN indicates administration of physiological saline instead of NTX.

[0127] [Example 9] The scratching behavior induced by intradermal administration of PACAP is suppressed by co-intradermal administration of PA-8 or compound 2o.

[0128] The biting, licking, and scratching behaviors induced by intradermal administration of PACAP (100 pmol) into the lumbar region (10 μL) are dose-dependently suppressed by co-intradermal administration of PA-8 (0.01 - 1 nmol) or compound 2o (0.01 - 1 nmol) (Fig. 8). SLN indicates intradermal administration of physiological saline. VEH (10% DMSO solution, dissolved in physiological saline) is the solvent for PA-8 and compound 2o.

[0129] [Example 10] The scratching behavior induced by intradermal administration of PACAP is suppressed by co-intradermal administration of PA-9 or compound 3d.

[0130] The biting, licking, and scratching behaviors induced by intradermal administration of PACAP (100 pmol) into the lumbar region (10 μL) are dose-dependently suppressed by co-intradermal administration of PA-9 (0.01 - 1 nmol) or compound 3d (0.01 - 1 nmol) (Fig. 9). SLN indicates intradermal administration of physiological saline. VEH (10% DMSO solution, dissolved in physiological saline) is the solvent for PA-9 and compound 3d. ​​​​​

[0131] [Example 11] Scratching behavior induced by intradermal administration of chloroquine is inhibited by intrathecal pretreatment with PA-8 or PA-9, but not by co-intradermal administration. It is not inhibited.

[0132] Chloroquine (100 μg / 10 μL) was injected intradermally (i.d.) into the lumbar region. The behavior of biting, licking, and scratching the injection site was defined as scratching behavior, and the behavior time was measured every 5 minutes. Intrathecal pretreatment (10 minutes before, i.t.) with PA-8 (1 nmol) or PA-9 (1 nmol) almost completely inhibited chloroquine-induced scratching behavior, but not co-intradermal administration (Co-i.d.) (Figure 10). DMSO (10% solution, dissolved in saline) is the solvent for PA-8 or PA-9.

[0133] [Example 12] Scratching behavior induced by intradermal administration of Compound 48 / 80 is inhibited by intrathecal pretreatment with PA-8 or PA-9, but not by co-intradermal administration. It is not inhibited.

[0134] Compound 48 / 80 (100 μg / 10 μL) was injected intradermally (i.d.) into the lumbar region. The behavior of biting, licking, and scratching the injection site was defined as scratching behavior, and the behavior time was measured every 5 minutes. Intrathecal pretreatment (10 minutes before, i.t.) with PA-8 (1 nmol) or PA-9 (1 nmol) almost completely inhibited Compound 48 / 80-induced scratching behavior, but not co-intradermal administration (Co-i.d.) (Figure 11). DMSO (10% solution, dissolved in saline) is the solvent for PA-8 or PA-9 It is as follows.

[0135] [Example 13] Efficacy evaluation using atopic dermatitis model mice This test was carried out with reference to the test system published as a method for evaluating itch in animals by Kitamura et al. (Kitamura A., Takata R., Aizawa S., et al.: A murine model of atopic dermatitis can be generated by painting the dorsal skin with hapten twice 14 days apart, S cientific Rep., 8:5988, 2018).

[0136] Fifty-week-old ICR mice (30 mice) were individually caged and acclimated for one week, and the lumbar region was shaved 3 days before the start of the test. On the day of the start of the experiment, tape stripping was performed for the purpose of destroying the function of the skin barrier, and 0.15% 2,4-dinitrofluorobenzene (DNFB) solution [acetone / olive oil (3:1)] was applied to the shaved lumbar region of the mice using a 100 μL pipette. Seven days later, 0.15% DNFB solution was applied again, and video observation was performed for 1 hour 2 hours later. The 30 shaved mice were divided into 5 groups of 6 mice each: PA-8, orally administered at 30 mg / kg (p.o .), compound 2o, orally administered at 30 mg / kg (p.o.), PA-9, 30 mg / kg orally (p.o.) administration group, compound 3d, 30 mg / kg (p.o.) administration group, solvent administration group (VEH: orally administered 10% DMSO aqueous solution). Oral administration was performed 30 minutes before video observation.

[0137] The outline of the procedure of the behavioral experiment using atopic dermatitis model mice is shown in Fig. 12, and the scratching of each group The results of the evaluation of time are shown in Figure 13. From Figure 13, PA-8, PA-9, or their derivatives Oral administration of the compounds (compound 2o and compound 3d) reduced the scratching induced by DNFB treatment. It can be seen that the itch-inducing behavior was significantly suppressed.

[0138] [Example 14] Drug efficacy evaluation using psoriasis model mice This test was performed using the van der Fischer method, a published test system for assessing pruritus in animals. ts et al. (van der Fits L., Mourits S., Voerman JSA., et al.: Imiquimod-Induced Psor iasis-Like Skin Inflammation in Mice Is Mediated via the IL-23 / IL-17 Axis, J. Im munol., 182, 5836-5845, 2009) was used as a reference.

[0139] Five-week-old ICR mice (20 mice) were individually housed in cages and allowed to acclimate for one week. The lumbar region of the mice was shaved 3 days before the experiment. A commercially available imiquimod cream ( 5% Beserna Cream (Mochida Pharmaceutical Co., Ltd.) 62.5 mg was applied once daily for 5 days. A psoriasis model was created. 24 hours after the final application on the fifth day, video observation was performed for 1 hour. Twenty shaved mice were divided into four groups: one group was given PA-8 at 30 mg / kg orally (po); Compound 2o, 30 mg / kg oral (po), PA-9, 30 mg / kg oral (po) po), Compound 3d, 30 mg / kg (po), and vehicle (VE H: Oral administration of 10% DMSO aqueous solution) was performed 30 minutes before video observation. Went there.

[0140] The results of evaluating the scratching time of each group are shown in Fig. 14. From Fig. 14, it can be seen that by orally administering PA-8, PA-9 or their derivatives (Compound 2o, Compound 3d), the scratching behavior induced by imiquimod application was significantly suppressed.

[0141] All publications, patents and patent applications cited in this specification are hereby incorporated by reference in their entirety. ​

Claims

1. A compound represented by the following formula (II): 【Chemical 1】 (In the formula, R is an indazolyl group, an indazolyl group substituted with a halogen atom, a phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with a methyl group, a phenyl group substituted with a cyano group, a phenyl group substituted with a hydroxyl group, an aralkyl group, or an aralkyl group substituted with a hydroxyl group.) An antipruritic agent containing the compound represented by the formula, a salt thereof, or a solvate thereof.

2. The antipruritic agent according to claim 1, wherein in the formula (II), R is an indazolyl group or an indazolyl group substituted with a halogen atom.

3. The antipruritic agent according to claim 1, wherein in the formula (II), R is an indazolyl group substituted with a halogen atom.

4. The antipruritic agent according to claim 1, wherein in the formula (II), R is an indazolyl group substituted with a chlorine atom.

5. The antipruritic agent according to any one of claims 1 to 4 for treating and / or preventing itching associated with contact dermatitis, atopic dermatitis, dry skin and / or psoriasis.

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