JP6782939B2 - Anti-itch agent - Google Patents

Description

The present invention relates to an antipruritic agent.

Itching is a sensation peculiar to the skin and mucous membranes that is defined as "an unpleasant sensation that makes you want to scratch the skin and mucous membranes", and its biological significance is from external sources such as pathogens, insects, and plants. It is considered to be a biological defense signal against harmful substances. This itch is a skin disease such as atopic dermatitis, contact dermatitis, urticaria, psoriasis, allergic disease, and visceral diseases such as jaundice and cirrhosis caused by hemodialysis and cholestasis associated with renal failure. These itchiness is one of the symptoms of urticaria, and since it is a very unbearable and unpleasant sensation, it causes a decrease in QOL (Quality Of Life). In addition, there are also neuropathic pruritus caused by neurological disorders such as postherpetic neuralgia and multiple sclerosis, and psychogenic pruritus associated with parasitological delusions and depression. In addition, this highly intolerable scratching behavior for itching leads to pleasure, promotes the release of endogenous pruritus substances, causes further itching, and causes the formation of secondary skin lesions. Become. Such a vicious cycle of itch is called "itch / scratch cycle" (see Non-Patent Document 1). Therefore, controlling itching is very important in clinical practice and is a therapeutic goal. However, many of these problematic skin diseases are resistant to histamine H1 receptor antagonists (see Non-Patent Document 2), and the development of new antipruritic drugs is desired.

Studies of itch have been conducted primarily in humans due to the lack of animal models and no evaluation method until recent years. Various substances such as histamine are injected intradermally into healthy people to evaluate the presence or absence of itching, and in the case of diseases accompanied by itching such as skin diseases, analysis of pathological changes such as dermatitis rather than itching is the main focus. Therefore, detailed analysis of the mechanism of itch was delayed. Therefore, the development of new drugs for itching of intractable pruritic skin diseases such as H1 receptor antagonist-resistant atopic dermatitis has been delayed. At present, itching mainly using itching substances such as histamine (see Non-Patent Document 3), serotonin (see Non-Patent Document 4), substance P (see Non-Patent Document 5), and tryptase (see Non-Patent Document 6). Model mouse is used. In mice, histamine is not necessarily a strong pruritus substance, and it is limited to some strains such as the ICR strain that show clear scratching behavior (see Non-Patent Document 7). On the other hand, serotonin and 4-methylhistamine (see Non-Patent Document 8) have a strong effect of causing itching, and scratching behavior is observed in most strains of mice (see Non-Patent Document 7). In addition, as a model mouse for itching of atopic dermatitis, a spontaneous type (see Non-Patent Document 9 and Non-Patent Document 10) or a chemical substance-induced type (see Non-Patent Document 11) NC mouse and DS-Nh mouse. (See Non-Patent Document 12), Hairless Mouse (See Non-Patent Document 13) and the like.

Itching is classified into peripheral itch and central itch according to its transmission pathway. Peripheral itch occurs when the C-fiber nerve endings distributed at the epidermal dermal boundary are excited by external stimuli such as mechanical, chemical, and physical stimuli, and the generated activity potential affects the spinal cord, spinal cord thalamus, and thalamus. It reaches the sensory area of the cerebral cortex via and is recognized as itching. On the other hand, central itch is thought to be caused by the binding of an endogenous opioid peptide as a pruritus mediator to opioid μ receptors present in the central nervous system. One of the side effects of morphine is pruritus, which is elicited via central μ-receptors.

Opioid receptors are classified into three types, μ, δ, and κ, and their pharmacological characteristics are analyzed, and clinical application of various opioid receptor agonists and antagonists is being attempted. It has been reported that opioid kappa receptor agonists have an inhibitory effect on various itch models (see Non-Patent Document 14 and Non-Patent Document 15) and are extremely effective especially for intractable pruritus in hemodialysis patients. (See Non-Patent Document 16). It is thought that there are multiple factors that cause pruritus in hemodialysis patients, such as hyperparathyroidism due to abnormal calcium and phosphorus metabolism (see Non-Patent Document 17) and abnormal elongation of nerve fibers to the skin (see Non-Patent Document 18). ), Micro-inflammatory state due to drought or increase in cytokines (see Non-Patent Document 19 and Non-Patent Document 20), and involvement of peripheral functional changes such as increase in histamine and substance P concentrations have been reported (Non-Patent Document 21 and Non-Patent Document 20). See Non-Patent Document 22). It is considered that opioid κ receptor agonists may exert an antipruritic effect on pruritus in hemodialysis patients through activation of opioid κ receptors.

On the other hand, in recent years, there are many splice varieties of opioid μ receptors, and dynorphin A, dynorphin B and neoendorphin, which are κ receptor agonists in vivo, are released via the μ receptor. It has been reported to cause pharmacological effects. It has been reported that these μ-receptor agonists have a different pharmacological mechanism of action from opioids typified by morphine.

Wahlgren CF, J Dermatol, 1999; 26 (11): 770-9 Wahlgren CF, Acta Derm Venereol Suppl (Stockh), 1991; 165: 1-53 Andoh T, Kuraishi Y, Eur J Pharmacol, 2000; 406 (1): 149-52 Yamaguchi T, Nagasawa T, Satoh M, Kurashi Y, Neurosci Res, 1999; 35 (2): 77-83 Andoh T, Nagasawa T, Satoh M, Kuraishi Y, J Pharmacol Exp The, 1998; 286 (3): 1140-5 Ui H, Andoh T, Lee JB, Nojima H, Kurashi Y, Eur J Pharmacol, 2006; 530 (1-2): 172-8 Maekawa T, Nojima H, Kuraishi Y, Jpn J Pharmacol, 2000; 84 (4): 462-6 Paul J Dunford, Kacy N. Williams, Pragnya J. Desai, Lars Karlsson, Daniel McQueen, Robin L. Turmond, J. Allergy Clin17, J. Allergy Clin1 Mazda H, Watanabe N, Geba GP, Spell J, Tsudzuki M, Hiroi J, Matsumoto M, Ushio H, Saito S, Askenase PW, Ra19 (In) 9 Yamaguchi T, Maekawa T, Nishikawa Y, Nojima H, Kaneko M, Kawakita T, Miyamoto T, Kurashii Y, J Dermatol 1 (200) Taniguchi Y, Kohno K, Inoue S, Koya Miyata S, Okamoto I, Arai N, Iwaki K, Ikeda M, Kurimoto M, Int Immunopharm3- Yoshioka T, Hikita I, Asakawa M, Hirazawa T, Deguchi M, Matsutani T, Oku H, Horikawa T, Arimura A, Immunology, 2003; Fujii M, Tomozawa J, Mizutani N, Nabe T, Danno K, Kohno S, Exp Dermatol, 2005; 14 (6): 460-8 Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura K, Endoh T, Utsumi J, Kamei J, Tak2H, Kamei J, Tana -64 Umeuchi H, Togashi Y, Honda T, Nakao K, Okano K, Tanaka T, Nagase H, Eur J Pharmacol, 2003; 477 (1): 29-35 Nakao K, Ando A, Hirakata M, Ando N, Takeshita K, Miyamoto Y, Mochizuki H, Nihon Yakurigaku Zashi, 2010; 135 (5): 205-14 Massry SG, Popovtzer MM, Coburn JW, Makoff DL, Maxwell MH, Kleeman CR, N Engl J Med, 1968; 279 (13): 679-700 Darabi A, Forogh R, Hardwaj G, Watabe M, Goodarzi G, Gross SC, Watabe K, plasmid, 1989; 22 (3): 281-6 Patel TS, Freedman BI, Yoshipovic G, Am J Kidney Dis, 2007; 50 (1): 11-20 Kimmel M, Alscher DM, Dunst R, Braun N, Machelidt C, Kiefer T, Sulten C, van der Kuip H, Pauli Magnus C, Raub U, Kuhlman Tulmann : 749-55 Stockhuber F, Kurz RW, Sort K, Grimm G, Barcke P, Clin Sci (Londo), 1990; 79 (5): 477-82 Kaku H, Fujita Y, Yago H, Naka F, Kawakubo H, Nakano K, Nishikawa K, Suehiro S, Nihon Jinzo Gakkai Shi, 1990;

The present invention has been made based on such a problem, and an object of the present invention is to provide a novel antipruritic agent having an excellent antipruritic effect.

で表されるα−アミノ酸残基であり、化学式（４）において、Ｒ^５及びＲ^６は、それぞれ独立に、水素原子、ハロゲン原子、低級アルキル基、及び、ハロゲン化低級アルキル基から選ばれる１つであり、Ｘは、水素原子、ハロゲン原子、ヒドロキシル基、下記の化学式（５）で表される基、及び、下記の化学式（６）で表される基
−Ｏ−ＣＯ−Ｒ^７ （５）
−Ｏ−ＣＯ−Ｏ−Ｒ^８ （６）
から選ばれる１つであり、化学式（５）のＲ^７、及び、化学式（６）のＲ^８は、それぞれ独立に、Ｃ_１−１６アルキル基、ヒドロキシＣ_１−１６アルキル基、アミノＣ_１−１６アルキル基、（モノ低級アルキル）アミノＣ_１−１６アルキル基、（ジ低級アルキル）アミノＣ_１−１６アルキル基、Ｃ_３−１０シクロアルキル基、Ｃ_３−１０シクロアルキル置換低級アルキル基、Ｃ_２−１６アルケニル基、Ｃ_２−１６アルキニル基、複素環基、アリール基、及び、アリール置換低級アルキル基から選ばれる１つであり、
上記ＡＡ^２は下記の化学式（７）

で表されるＤ−α−アミノ酸残基であり、化学式（７）において、Ｒ^９は、アミノ基、（モノ低級アルキル）アミノ基、低級アシルアミノ基、グアニジノ基、低級アルキル基置換グアニジノ基、イミノ低級アルキル基、ウレイド基、低級アルキル基置換ウレイド基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルホニル基、低級アシル基、及び、ヒドロキシ低級アルキル基から選ばれる１つであり、ｎは１〜４の整数であり、
上記ＡＡ^３は非置換フェニルアラニン残基、置換フェニルアラニン残基、非置換Ｄ−フェニルアラニン残基、及び、置換Ｄ−フェニルアラニン残基から選ばれる１つであり、
上記ＡＡ^４は、下記の化学式（８）
−Ｎ（Ｒ^１０）−ＣＨ（Ｒ^１１）−ＣＯ− （８）
で表されるα−アミノ酸残基、又は、下記の化学式（９）
−Ｎ（Ｒ^１０）−ＣＨ（Ｒ^１１）−ＣＨ（Ｒ^１２）−ＣＯ− （９）
で表されるβ−アミノ酸残基であり、化学式（８）及び化学式（９）において、Ｒ^１０及びＲ^１２は、それぞれ独立に、水素原子、低級アルキル基、低級アルケニル基、低級アルキニル基、アリール基、及び、アリール置換低級アルキル基から選ばれる１つであり、Ｒ^１１は、水素原子、又は、下記の化学式（１０）
−Ｚ−Ｎ（Ｒ^１３）−Ｒ^１４ （１０）
で表される基であり、化学式（１０）において、Ｚは、低級アルキレン基、低級アルケニレン基、及び、低級アルキニレン基から選ばれる１つであり、Ｒ^１３及びＲ^１４は、それぞれ独立に、水素原子、低級アルキル基、アリール基、及び、アリール置換低級アルキル基から選ばれる１つ、又は、Ｒ^１３及びＲ^１４はこれらが結合する窒素原子と一緒になった５員又は６員の含窒素複素環基であることを特徴とするものである。 The antipruritic agent of the present invention has the following general formula (1).
Y ^1- AA ^1- AA ^2- AA ^3- AA ^4- Y ² (1)
Containing a compound represented by or a pharmaceutically acceptable salt thereof,
The above Y ¹ is a hydrogen atom, a lower alkyl group, and a group represented by the following chemical formula (2) R ¹ N = C (R ² ) − (2).
In the chemical formula (2), R ¹ is one selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, and R ² is a lower alkyl group or a lower alkyl group. It is an amino group
The above Y ² is a hydroxyl group or the following chemical formula (3).
−N (R ³ ) R ⁴ (3)
In the chemical formula (3), R ³ and R ⁴ are each independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or are groups represented by , R ³ and R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached.
The above AA ¹ has the following chemical formula (4).

It is an α-amino acid residue represented by, and in the chemical formula (4), R ⁵ and R ⁶ are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group. X is a hydrogen atom, a halogen atom, a hydroxyl group, a group represented by the following chemical formula (5), and a group represented by the following chemical formula (6) -O-CO-R ⁷ (5). )
-O-CO-O-R ⁸ (6)
R ⁷ of chemical formula (5) and R ⁸ of chemical formula (6) are independently selected from C _1-16 alkyl group, hydroxy C _1-16 alkyl group, and amino C _{1-. 16} Alkyl Group, (Mono Lower Alkyl) Amino C _1-16 Alkyl Group, (Di Lower Alkyl) Amino C _1-16 Alkyl Group, C _3-10 Cycloalkyl Group, C _3-10 Cycloalkyl Substituted Lower Alkyl Group, C It is one selected from a _2-16 alkenyl group, a C _2-16 alkynyl group, a heterocyclic group, an aryl group, and an aryl-substituted lower alkyl group.
The above AA ² has the following chemical formula (7).

It is a D-α-amino acid residue represented by, and in the chemical formula (7), R ⁹ is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, or imino. It is one selected from a lower alkyl group, a ureido group, a lower alkyl group substituted ureido group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group, and n is 1 to 1. It is an integer of 4
AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue.
The above AA ⁴ has the following chemical formula (8).
-N (R ¹⁰ ) -CH (R ¹¹ ) -CO- (8)
Α-Amino acid residue represented by, or the following chemical formula (9)
-N (R ¹⁰ ) -CH (R ¹¹ ) -CH (R ¹² ) -CO- (9)
It is a β-amino acid residue represented by, and in the chemical formula (8) and the chemical formula (9), R ¹⁰ and R ¹² are independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, and an aryl, respectively. It is one selected from a group and an aryl-substituted lower alkyl group, and R ¹¹ is a hydrogen atom or the following chemical formula (10).
-Z-N (R ¹³ ) -R ¹⁴ (10)
In the chemical formula (10), Z is one selected from a lower alkylene group, a lower alkenylene group, and a lower alkynylene group, and R ¹³ and R ¹⁴ are independently hydrogen. One selected from an atom, a lower alkyl group, an aryl group, and an aryl-substituted lower alkyl group, or R ¹³ and R ¹⁴ are 5- or 6-membered nitrogen-containing complexes combined with the nitrogen atom to which they are attached. It is characterized by being a ring group.

According to the antipruritic agent of the present invention, it is possible to obtain an excellent antipruritic effect particularly on central pruritus, and a high effect can be obtained in both oral administration and parenteral administration.

It is a graph which shows the suppression rate of the scratching behavior after subcutaneous administration of the compound of Example 1. It is a graph which shows the suppression rate of the scratching behavior after oral administration of the compound of Example 1. It is a graph which shows the suppression rate of the scratching behavior after transdermal administration of the compound of Example 1. FIG. It is a graph which shows the suppression rate of the scratching behavior after subcutaneous administration of the compound of Example 2. It is a graph which shows the suppression rate of the scratching behavior after oral administration of the compound of Example 2. It is a graph which shows the suppression rate of the scratching behavior after transdermal administration of the compound of Example 2. It is a graph which shows the suppression rate of the scratching behavior after subcutaneous administration of the compound of Example 3. It is a graph which shows the suppression rate of the scratching behavior after oral administration of the compound of Example 3. It is a graph which shows the suppression rate of the scratching behavior after transdermal administration of the compound of Example 3. FIG. It is a graph which shows the suppression rate of the scratching behavior after subcutaneous administration of the compound of Example 4. It is a graph which shows the suppression rate of the scratching behavior after oral administration of the compound of Example 4. It is a graph which shows the suppression rate of the scratching behavior after transdermal administration of the compound of Example 4. FIG. It is a graph which shows the suppression rate of the scratching behavior after subcutaneous administration of the compound of Example 5. It is a graph which shows the suppression rate of the scratching behavior after oral administration of the compound of Example 5. It is a graph which shows the suppression rate of the scratching behavior after transdermal administration of the compound of Example 5.

Hereinafter, embodiments of the present invention will be described in detail.

The antipruritic agent according to the present embodiment contains a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
Y ^1- AA ^1- AA ^2- AA ^3- AA ^4- Y ² (1)

In the general formula (1), Y ¹ is ^one selected from a hydrogen atom, a lower alkyl group, and a group represented by the following chemical formula (2).
R ¹ N = C (R ² )-(2)
In the chemical formula (2), R ¹ is ^one selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, and R ² is a lower alkyl group or an amino group.

In the general formula (1), Y ² is a hydroxyl group or a group represented by the following chemical formula (3).
−N (R ³ ) R ⁴ (3)
In the chemical formula (3), R ³ and R ⁴ are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ and R ⁴ are these. Is a 5- or 6-membered nitrogen-containing heterocyclic group combined with a nitrogen atom to which is bonded.

In the general formula (1), AA ¹ is an α-amino acid residue represented by the following chemical formula (4).

In the chemical formula (4), R ⁵ and R ⁶ are one independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, respectively. X is one selected from a hydrogen atom, a halogen atom, a hydroxyl group, a group represented by the following chemical formula (5), and a group represented by the following chemical formula (6).

-O-CO-R ⁷ (5)
-O-CO-O-R ⁸ (6)
R ⁷ of the chemical formula (5) and R ⁸ of the chemical formula (6) are independently C _1-16 alkyl group, hydroxy C _1-16 alkyl group, amino C _1-16 alkyl group, (mono lower alkyl). ) Amino C _1-16 Alkyl Group, (DiLower Alkyl) Amino C _1-16 Alkyl Group, C _3-10 Cycloalkyl Group, C _3-10 Cycloalkyl Substituted Lower Alkyl Group, C _2-16 Alkyl Group, C _{2 -16} Alkinyl group, heterocyclic group, aryl group, and aryl substituted lower alkyl group.

In the general formula (1), AA ² is a D-α-amino acid residue represented by the following chemical formula (7).

In the chemical formula (7), R ⁹ is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, an imino lower alkyl group, a ureido group, a lower alkyl group substituted ureido group, It is one selected from a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group. Note that n is an integer of 1 to 4.

In the general formula (1), AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue.

In the general formula (1), AA ⁴ is an α-amino acid residue represented by the following chemical formula (8) or a β-amino acid residue represented by the following chemical formula (9).
-N (R ¹⁰ ) -CH (R ¹¹ ) -CO- (8)
-N (R ¹⁰ ) -CH (R ¹¹ ) -CH (R ¹² ) -CO- (9)

In the chemical formulas (8) and (9), R ¹⁰ and R ¹² are independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl-substituted lower alkyl group, respectively. There is one. R ¹¹ is a hydrogen atom or a group represented by the following chemical formula (10).
-Z-N (R ¹³ ) -R ¹⁴ (10)
In the chemical formula (10), Z is one selected from a lower alkylene group, a lower alkenylene group, and a lower alkynylene group, and R ¹³ and R ¹⁴ are independently hydrogen atoms, lower alkyl groups, and aryl groups, respectively. , And one selected from the aryl-substituted lower alkyl groups, or R ¹³ and R ^14, are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached.

The antipruritic agent of the present embodiment has a hydrogen atom at the amino terminal, a lower alkyl group, or an unsubstituted or substituted imino lower alkyl group represented by the chemical formula (2) "R ¹ N = C (R ² )-". A compound having a hydroxyl group at the carboxyl end or an unsubstituted or substituted amide group represented by the chemical formula (3) "-N (R ³ ) R ⁴ " or a pharmaceutically acceptable salt thereof. It is characterized by including. Peptide derivatives having such a structure have an excellent antipruritic effect.

In the general formula (1), a preferable example of Y ¹ is one selected from a hydrogen atom and a methyl group, or in the chemical formula (2), R ¹ is a hydrogen atom and R ² is a lower alkyl group or amino. Although it is a group of groups, this antipruritic agent is not limited to this. More preferred examples of R ² include a methyl group, an ethyl group, or an amino group.

In the general formula (1), a preferable example of Y ² is a hydroxyl group, or in the chemical formula (3), both R ³ and R ⁴ are hydrogen atoms, or one is a hydrogen atom and the other is a methyl group. That is, a preferable example of the chemical formula (3) is -NH ₂ or -NH-CH ₃ , but the antipruritic agent is not limited thereto.

The substitution positions of R ⁵ and R ⁶ in the chemical formula (4) representing AA ¹ and R ¹⁵ and R ¹⁶ in the chemical formula (11) or (12) on the benzene ring are not particularly limited.

In the general formula (1), preferred examples of AA ¹ are tyrosine residue, 2,6-dimethyl-tyrosine residue, o-acyl-tyrosine residue, o-alkoxycarbonyl-tyrosine residue, o-phenoxycarbonyl. -Tyrosine residue, o-acetyltyrosine residue, 2,6-dimethyl-phenylalanine residue and the like can be mentioned, but the antipruritic agent is not limited thereto.

In the general formula (1), preferred examples of AA ² are D-arginine residue, D-methionine sulfoxide residue, D-N5-acetylornithine residue, D-5-oxonorleucine residue, and D-citrulin. Residues, D-5-hydroxynorleucine residues and the like can be mentioned, but the antipruritic agent is not limited thereto.

In the general formula (1), AA ³ may be an α-amino acid residue or a D-α-amino acid residue represented by the following chemical formula (11) or (12).

In the chemical formulas (11) and (12), R ¹⁵ and R ¹⁶ are one independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, respectively.

In the general formula (1), preferred examples of AA ³ are phenylalanine residue, p-fluorophenylalanine residue and o-trifluoromethylphenylalanine residue, 2,6.
-Dimethyl-phenylalanine residue, D-phenylalanine residue, D-p-fluorophenylalanine residue, D-o-trifluoromethylphenylalanine residue and the like can be mentioned, but the antipruritic agent is not limited thereto.

In the general formula (1), preferable examples of AA ⁴ include, but are not limited to, a lysine residue, an N-methyl-β-alanine residue, and the like, but the antipruritic agent is not limited thereto.

Regarding the amino acids and their residues described in the present specification, when D-form and L-form are present, especially when not indicated as D-, the amino acids and their residues mean L-amino acids. To do.

In the terms "lower alkyl", "lower alkoxyl", "lower acyl" and "lower alkylene" described herein, "lower" means 1, 2, 3, 4, 5 or 6 carbon atoms. Means to include. In the terms "lower alkenyl", "lower alkynyl", "lower alkenylene" and "lower alkynylene" described herein, "lower" includes 2, 3, 4, 5 or 6 carbon atoms. Means that.

The "alkyl", "alkoxyl", "acyl", "alkylene", "alkenyl", "alkynyl", "alkenylene" and "alkynylene" described herein are linear isomers and branched chain isomers. In any case of. The branched-chain isomer may be any of a branched-chain isomer containing a secondary carbon and a branched-chain isomer containing a tertiary carbon.

Preferred examples of the lower alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, neopentyl group and n-hexyl. There are groups, etc., but the present invention is not limited to these examples. In addition, "C _1-16 alkyl group", "hydroxy C _1-16 alkyl group", "amino C _1-16 alkyl group", "(mono lower alkyl) amino C _1-16 alkyl group" described in the present specification. , "(Dilower alkyl) amino C _1-16 alkyl group" and the like, examples of the "C _1-16 alkyl group" include, in addition to the preferred example of the lower alkyl group, a linear or branched heptyl. Groups, octyl groups, nonyl groups, decyl groups, undecyl groups, dodecyl groups, tridecyl groups, tetradecyl groups, pentadecyl groups, hexadecyl groups and the like are included, but are not limited to these examples. As the C _1-16 alkyl group, a linear or branched C _6-12 alkyl group is preferable, and a C _8-10 alkyl group is more preferable. Particularly preferred are C ₈ and C ₁₀ linear or branched alkyl groups.

The "lower alkoxyl group" described herein refers to an alkoxyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Preferred examples of the lower alkoxyl group include, but are not limited to, methoxy group, ethoxy group and the like.

As _{"C 3-10} cycloalkyl group" described in the present specification, the _{"C 3-10} cycloalkyl group" of the _{"C 3-10} cycloalkyl substituted lower alkyl group", both the number of carbon atoms 3, Refers to 4, 5, 6, 7, 8, 9 or 10 cycloalkyl groups. Preferred examples of the C _3-10 cycloalkyl group include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, adamantyl group and the like. The "C _3-10 cycloalkyl group" in the "C _3-10 cycloalkyl substituted lower alkyl group" described in the present specification may be substituted with any carbon atom of the lower alkyl group, and the carbon atom of the lower alkyl group may be substituted. It may be replaced with any number of carbon atoms. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 C _3-10 cycloalkyl group may be substituted with a carbon atom at an arbitrary position.

The "C _2-16 alkenyl group" and "C _2-16 alkynyl group" described in the present specification are any alkenyl group and alkynyl group having 2 to 16 carbon atoms, respectively. , Linear or branched chain type. The position and number of double bonds and triple bonds contained in the C _2-16 alkenyl group and the C _2-16 alkenyl group are not particularly limited. A preferable example of the C _2-16 alkenyl group is a vinyl group or ethenyl. Groups, 2-propenyl groups, cis-1-propenyl groups, trans-1-propenyl groups and the like, but are not limited to these examples. Preferred examples of the C _2-16 alkynyl group include an ethynyl group and a 2-propynyl group, but the present invention is not limited to these examples.

The "heterocyclic group" described herein is a saturated, unsaturated or partially unsaturated sum consisting of at least one atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom and a carbon atom. Refers to a cyclic compound. Preferred examples of the heterocyclic group include, but are not limited to, a pyridyl group, a furanyl group, a thiophenyl group and the like. When R ³ and R ⁴ in the chemical formula (3) and R ¹³ and R ¹⁴ in the chemical formula (10) represent a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. There is. The nitrogen-containing heterocyclic group may be, for example, a 5- to 6-membered saturated or partially unsaturated heterocyclic group containing one or two or more nitrogen atoms as atoms for reforming the ring. Preferred examples of the nitrogen-containing heterocyclic group include, but are not limited to, pyrrolidino group, piperidino group, 3,4-dehydropyrrolidino group, pyridinio group and the like.

The "aryl group" described herein and the "aryl group" in the "aryl-substituted lower alkyl group" refer to an aromatic substituent consisting of one or more rings. Preferred examples of the aryl group include, but are not limited to, a phenyl group, a naphthyl group, an anthraceniryl group, a phenanthryl group and the like. The "aryl group" in the "aryl-substituted lower alkyl group" described in the present specification may be substituted with any carbon atom of the lower alkyl group, and may be substituted with any number of carbon atoms among the carbon atoms of the lower alkyl group. You may be doing it. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 aryl group may be substituted with a carbon atom at an arbitrary position. Preferred examples of the aryl-substituted lower alkyl group include, but are not limited to, a benzyl group, a phenethyl group and the like.

The "lower acyl group" described in the present specification and the "lower acyl group" in the "lower acylamino group" are both acyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms, that is, alkanoyl groups. Point to. Preferred examples of the lower acyl group include, but are not limited to, a formyl group, an acetyl group and the like. The "lower acyl group" in the "lower acylamino group" described in the basic specification substitutes one or both of the hydrogen atoms of the amino group. Preferred examples of the lower acylamino group include, but are not limited to, a monoacetylamino group, a diacetylamino group and the like.

The "halogen" described herein may be any of fluorine, chlorine, bromine or iodine. The substitution position, number, and type of the halogen atom to be substituted with the "lower halogenated lower alkyl group" described in the present specification are not particularly limited, and any of monohalogenated lower alkyl groups to per-halogenated lower alkyl groups can be used. is there. If two or more halogen atoms are present, they may be the same or different. Preferred examples of the halogenated lower alkyl group include a chloromethyl group, a bromomethyl group, a fluoromethyl group, a 2-chloroethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group and the like. Is not limited to these examples.

The "hydroxyl group" in the "hydroxy lower alkyl group" or "hydroxy C _1-16 alkyl group" described in the present specification may be substituted with any carbon atom among the carbon atoms of the alkyl group, and the alkyl group may be substituted. It may be replaced with any number of carbon atoms among the carbon atoms. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 hydroxyl group may be substituted with a carbon atom at an arbitrary position. Preferred examples of the "hydroxy lower alkyl group" and the "hydroxy C _1-16 alkyl group" include, but are not limited to, a hydroxymethyl group and a 2-hydroxyethyl group.

The "amino group" in the "amino C _1-16 alkyl group" described in the present specification may be substituted with any carbon atom among the carbon atoms of the C _1-16 alkyl group, and the carbon atom of the alkyl group may be substituted. It may be replaced with any number of carbon atoms. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 amino group may be substituted with a carbon atom at an arbitrary position. Preferred examples of the "amino C _1-16 alkyl group" include, but are not limited to, an aminomethyl group and a 2-aminoethyl group.

The "(monolower alkyl) amino group" described in the present specification and the "(monolower alkyl) amino group" in the "(monolower alkyl) amino C _1-16 alkyl group" are both the number of carbon atoms. Refers to one in which 1, 2, 3, 4, 5 or 6 alkyl groups are substituted with one hydrogen atom of the amino group. Preferred examples of the "(monolower alkyl) amino group" described in the present specification and the "(monolower alkyl) amino group" in the "(monolower alkyl) amino C _1-16 alkyl group" are methylamino. There are groups, ethylamino groups, etc., but the examples are not limited to these. The "(dilower alkyl) amino group" in the "( _dilower alkyl) amino C _1-16 alkyl group" described in the present specification means 1, 2, 3, 4, 5 or 6 carbon atoms. An alkyl group in which each of the two hydrogen atoms of the amino group is substituted. The lower alkyl group substituting each hydrogen atom may be the same lower alkyl group or a different lower alkyl group. Examples of the (dilower alkyl) amino group include, but are not limited to, a dimethylamino group, a diethylamino group and the like. In the "(monolower alkyl) amino C _1-16 alkyl group" described herein, the (monolower alkyl) amino group may be substituted anywhere in the carbon atom of the C _1-16 alkyl group. The amino group further represents that it is substituted with the one lower alkyl group. Preferred examples of the (monolower alkyl) amino C _1-16 alkyl group include 3- (methylamino) -n-pronyl group, 2- (ethylamino) -n-pentyl group and the like. Not limited to. In the "(dilower alkyl) amino C _1-16 alkyl group" described herein, the (dilower alkyl) amino group may be substituted anywhere in the carbon atom of the C _1-16 alkyl group. The amino group is further substituted with the two lower alkyl groups. Preferred examples of the (dilower alkyl) amino C _1-16 alkyl group include, but are not limited to, 2- (dimethylamino) ethyl group, 2- (diethylamino) ethyl group and the like.

The compound represented by the general formula (1) has methyl-AA ^1- AA ^2- AA ^3- AA ⁴ -amide or methyl-AA ¹ when Y ¹ is a methyl group and Y ² is -NH _2. It is expressed as −AA ² −AA ³ −AA ⁴ −NH ₂ . In the compound represented by the general formula (1), Y ¹ is represented by "R ¹ N = C (R ² )-" of the chemical formula (2), R ¹ is a hydrogen atom, and R ² is a methyl group. Yes, when Y ² is -NH ₂ , 1-iminoethyl-AA ^1- AA ^2- AA ^3- AA ⁴ -amide or 1-iminoethyl-AA ^1- AA ^2- AA ^3- AA ^4- NH ₂ Will be done. In the compound represented by the general formula (1), Y ¹ is represented by "R ¹ N = C (R ² )-" of the chemical formula (2), both R ¹ and R ² are hydrogen atoms, and Y ² When is -NH _2, it is expressed as 1-iminomethyl-AA ^1- AA ^2- AA ^3- AA ⁴ -amide or 1-iminomethyl-AA ^1- AA ^2- AA ^3- AA ^4- NH ₂ . In the compound represented by the general formula (1), Y ¹ is represented by "R ¹ N = C (R ² )-" of the chemical formula (2), R ¹ is a hydrogen atom, and R ² is -NH _2. When Y ² is -NH _2, it is expressed as amidino-AA ^1- AA ^2- AA ^3- AA ⁴ -amide or amidino-AA ^1- AA ^2- AA ^3- AA ^4- NH ₂ .

The compound represented by the general formula (1) has methyl-AA ^1- AA ^2- AA ^3- AA ⁴ -methylamide or methyl-when Y ¹ is a methyl group and Y ² is -NH-CH _3. It is represented as AA ^1- AA ^2- AA ^3- AA ^4- NH-CH ₃ . In the compound represented by the general formula (1), Y ¹ is represented by "R ¹ N = C (R ² )-" of the chemical formula (2), R ¹ is a hydrogen atom, and R ² is a methyl group. Yes, when Y ² is -NH-CH ₃ , 1-iminoethyl-AA ^1- AA ^2- AA ^3- AA ⁴ -methylamide or 1-iminoethyl-AA ^1- AA ^2- AA ^3- AA ^4- NH- Represented as CH ₃ . In the compound represented by the general formula (1), Y ¹ is represented by "R ¹ N = C (R ² )-" of the chemical formula (2), both R ¹ and R ² are hydrogen atoms, and Y ² When is -NH-CH ₃ , 1-iminomethyl-AA ^1- AA ^2- AA ^3- AA ⁴ -methylamide or 1-iminomethyl-AA ^1- AA ^2- AA ^3- AA ^4- NH-CH ₃ Will be done. In the compound represented by the general formula (1), Y ¹ is represented by "R ¹ N = C (R ² )-" of the chemical formula (2), R ¹ is a hydrogen atom, and R ² is -NH _2. And when Y ² is -NH-CH ₃ , with amidino-AA ^1- AA ^2- AA ^3- AA ⁴ -methylamide or amidino-AA ^1- AA ^2- AA ^3- AA ^4- NH-CH ₃ . expressed.

In the present specification, when Y ¹ is a hydrogen atom in the general formula (1), "H-" is not described at the leftmost end of the structure of the peptide derivative, and the amino group of the amino acid at the amino terminal is not substituted. Indicates that there is. Further, in the present specification, when Y ² is a hydroxyl group in the general formula (1) and "-OH" is described at the carboxyl end of the peptide derivative, the carboxyl group of the amino acid at the carboxyl terminal is not substituted. Indicates that there is.

In the present specification, the term "amino acid residue" is used in the usual meaning in the field of peptide chemistry, and more specifically, an amino group and a carboxyl group having an α-position relationship in an α amino acid, or β. It means the remaining structure of amino acids having a β-position relationship, excluding hydrogen atoms and hydroxyl groups, respectively. The notation of amino acid residues is described in the Biochemistry Dictionary (3rd edition, Tokyo Kagaku Dojin, published on October 8, 1998), WIPO standard ST. In accordance with the "Guidelines for Preparation of Specifications, etc. Containing Base Sequences or Amino Acid Sequences" published by the Japan Patent Office in 25 and July 2002. If it contains a D-amino acid residue, indicate that fact. That is, in the chemical formula (1), when the i-th amino acid residue represented by "-AA ^i- " (i is an integer of 1 to 4) is, for example, a tyrosine residue, "-[Tyr]-", In the case of D-arginine residue, it is represented by abbreviated notation with three letters of the alphabet such as "-[D-Arg]-", but in the case of modified amino acid residue, 2,6-dimethyl-tyrosine residue. In the case of "-[2,6-dimethyl-Tyr]-", in the case of N-methyllysine residue, "-[N-MeLys]-", in the case of N-methyl-β-alanine residue, "-[ N-MeβAla]-", and in the case of D-methionine sulfoxide residue, it is expressed as"-[D-Met (O)]-", respectively.

The lysine residue or Lys in the present specification has a structure represented by the following chemical formula (13).

The N-methyl-β-alanine residue or N-MeβAla in the present invention has a structure represented by the following chemical formula (14).

The D-methionine sulfoxide residue or D-Met (O) in the present invention has a structure represented by the following chemical formula (15).

In the compound represented by the general formula (1), Y ¹ is one selected from a hydrogen atom and a methyl group, or is represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. Yes, R ² may be one selected from a methyl group, an ethyl group, and an amino group. That is, Y ¹ in the general formula (1) is a hydrogen atom and one selected from a methyl group, or a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. Yes, R ² is one selected from a methyl group, an ethyl group, and an amino group, and Y ² is a hydroxyl group or a group represented by the chemical formula (3), and is in the chemical formula (3). R ³ and R ⁴ are each independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ and R ⁴ are the nitrogen atoms to which they are bonded. It is a 5- or 6-membered nitrogen-containing heterocyclic group combined, AA ¹ is an α-amino acid residue represented by the chemical formula (4), and R ⁵ and R ⁶ in the chemical formula (4) are, respectively. It is one independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and X is a hydrogen atom, a halogen atom, a hydroxyl group, and chemical formulas (5) and (6). R ⁷ or R ⁸ of the chemical formula (5) or (6), respectively, selected from the group consisting of C _1-16 alkyl group, hydroxy C _1-16 alkyl group, amino C _1-16 alkyl group, respectively, (Mono lower alkyl) Amino C _1-16 alkyl group, (Dilower alkyl) Amino C _1-16 alkyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkyl substituted lower alkyl group, C _2-16 alkenyl Selected from the group consisting of groups, C _2-16 alkynyl groups, heterocyclic groups, aryl groups, and aryl substituted lower alkyl groups, AA ² is a D-α-amino acid residue represented by chemical formula (7). , R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, an imino lower alkyl group, a ureido group, a lower alkyl group substituted ureido group, Selected from the group consisting of a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group, n in the chemical formula (7) is an integer of 1 to 4, and AA ³ is non-. It is one selected from a substituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue, and AA ⁴ is an α-amino acid residue represented by the chemical formula (8). Or β-a represented by the chemical formula (9) R ¹⁰ and R ¹² in the chemical formulas (8) and (9), which are minoic acid residues, are independently hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, aryl group, and aryl substituted lower. One selected from alkyl groups, R ¹¹ is a hydrogen atom or a group represented by the chemical formula (10), and Z in the chemical formula (10) is a lower alkylene group, a lower alkenylene group, and a lower group. One selected from the alkynylene group, R ¹³ and R ¹⁴ are independently selected from a hydrogen atom, a lower alkyl group, an aryl group, and an aryl substituted lower alkyl group, or R ¹³ and R, respectively. Reference numeral ¹⁴ may be a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), Y ² is represented by a hydroxyl group or a chemical formula (3), and both R ³ and R ⁴ in the chemical formula (3) are hydrogen atoms, or one of them. Is a hydrogen atom and the other is a combination of methyl groups. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are both hydrogen atoms, or one is a hydrogen atom and the other is a combination of methyl groups, and AA ¹ is a chemical formula (4). Represented α-amino acid residues, R ⁵ and R ⁶ in the chemical formula (4) are each independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group. Yes, X is selected from the group consisting of hydrogen atom, halogen atom and hydroxyl group and chemical formulas (5) and (6), and R ⁷ or R ⁸ of chemical formula (5) or (6) is independent of each other. , C _1-16 alkyl group, hydroxy C _1-16 alkyl group, amino C _1-16 alkyl group, (mono lower alkyl) amino C _1-16 alkyl group, (dilower alkyl) amino C _1-16 alkyl group, Group consisting of C _3-10 cycloalkyl group, C _3-10 cycloalkyl substituted lower alkyl group, C _2-16 alkenyl group, C _2-16 alkynyl group, heterocyclic group, aryl group, and aryl substituted lower alkyl group. AA ² is a D-α-amino acid residue represented by the chemical formula (7), and R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino. Consists of a group, a lower alkyl group-substituted guanidino group, an imino lower alkyl group, a ureido group, a lower alkyl group-substituted ureido group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group. Selected from the group, n in the chemical formula (7) is an integer of 1-4, AA ³ is an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue. AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid residue represented by the chemical formula (9), and is selected from the chemical formulas (8) and (9). ) R ¹⁰ and R ¹ Reference numeral ² is one independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group, and R ¹¹ is a hydrogen atom or a chemical formula. The group represented by (10), Z in the chemical formula (10) is one selected from a lower alkylene group, a lower alkylene group, and a lower alkylylene group, and R ¹³ and R ¹⁴ are independent of each other. , One selected from hydrogen atoms, lower alkyl groups, aryl groups, and aryl-substituted lower alkyl groups, or R ¹³ and R ¹⁴ contain 5 or 6 members combined with the nitrogen atom to which they are attached. It may be a nitrogen heterocyclic group. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ¹ may be an α-amino acid residue represented by the chemical formula (4), and X in the chemical formula (4) may be a hydroxyl group. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). X in 4) is a hydroxyl group, R ⁵ and R ⁶ are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and AA ² is a chemical formula. It is a D-α-amino acid residue represented by (7), and R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group. , Imino lower alkyl group, ureido group, lower alkyl group substituted ureido group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower acyl group, and hydroxy lower alkyl group selected from the chemical formula (7). ) Is an integer of 1 to 4, and AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue. AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid residue represented by the chemical formula (9), and R ¹⁰ and R ¹² in the chemical formulas (8) and (9) are. , Each independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group, and R ¹¹ is a hydrogen atom or a chemical formula (10). ), And Z in the chemical formula (10) is one selected from a lower alkylene group, a lower alkylene group, and a lower alkylylene group, and R ¹³ and R ¹⁴ are independently hydrogen. Atomic, lower alkyl, aryl, and a One selected from reel-substituted lower alkyl groups, or R ¹³ and R ^14, may be 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ¹ may be an α-amino acid residue represented by the chemical formula (4), and X in the chemical formula (4) may be a hydrogen atom or a halogen atom. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). X in 4) is a hydrogen atom or a halogen atom, and R ⁵ and R ⁶ are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, respectively, and AA. Reference numeral ² is a D-α-amino acid residue represented by the chemical formula (7), and R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, or a lower alkyl group. Selected from the group consisting of a substituted guanidino group, an imino lower alkyl group, a ureido group, a lower alkyl group substituted ureido group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group. In the chemical formula (7), n is an integer of 1 to 4, and AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue. AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid residue represented by the chemical formula (9), and R ¹⁰ and R ¹⁰ in the chemical formulas (8) and (9). R ¹² is one independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group, and R ¹¹ is a hydrogen atom or a lower alkyl group. It is a group represented by the chemical formula (10), and Z in the chemical formula (10) is one selected from a lower alkylene group, a lower alkalinylene group, and a lower alkylylene group, and R ¹³ and R ¹⁴ are independent of each other. Hydrogen atom, lower alkyl group, aryl group , And one selected from the aryl-substituted lower alkyl groups, or R ¹³ and R ^14, may be 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ¹ may be a tyrosine residue or a 2,6-dimethyl-tyrosine residue. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached, AA ¹ is a tyrosine residue or 2,6-dimethyl-tyrosine residue, and AA ² Is a D-α-amino acid residue represented by the chemical formula (7), and R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, or a lower alkyl group substitution. Selected from the group consisting of guanidino group, imino lower alkyl group, ureido group, lower alkyl group substituted ureido group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower acyl group, and hydroxy lower alkyl group. In (7), n is an integer of 1 to 4, and AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue. Yes, AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid residue represented by the chemical formula (9), and R ¹⁰ and R in the chemical formulas (8) and (9). Reference numeral ¹² is one independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group, and R ¹¹ is a hydrogen atom or a chemical formula. It is a group represented by (10), and Z in the chemical formula (10) is one selected from a lower alkylene group, a lower alkalinylene group, and a lower alkylylene group, and R ¹³ and R ¹⁴ are independent of each other. , A hydrogen atom, a lower alkyl group, an aryl group, and an aryl substituted lower alkyl group, or R ¹³ and R ¹⁴ contain 5 or 6 members together with the nitrogen atom to which they are bonded. It may be a nitrogen heterocyclic group. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ¹ is an o-acyl-tyrosine residue, an o-alkoxycarbonyl-tyrosine residue, an o-phenoxycarbonyl-tyrosine residue, an o-acetyltyrosine residue or 2, It may be a 6-dimethyl-phenylalanine residue. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached, and AA ¹ is an o-acyl-tyrosine residue, an o-alkoxycarbonyl-tyrosine residue, o. -Phenoxycarbonyl-tyrosine residue, o-acetyltyrosine residue or 2,6-dimethyl-phenylalanine residue, AA ² is a D-α-amino acid residue represented by the chemical formula (7), and the chemical formula ( R ⁹ in 7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, an imino lower alkyl group, a ureido group, a lower alkyl group substituted ureido group, a lower alkylthio group. , A lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group. N in the chemical formula (7) is an integer of 1 to 4, and AA ³ is an unsubstituted phenylalanine residue. It is one selected from a group, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue, and AA ⁴ is an α-amino acid residue represented by the chemical formula (8), or an α-amino acid residue. It is a β-amino acid residue represented by the chemical formula (9), and R ¹⁰ and R ¹² in the chemical formulas (8) and (9) are independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, and a lower alkynyl group, respectively. , An aryl group, and an aryl-substituted lower alkyl group, R ¹¹ is a hydrogen atom or a group represented by the chemical formula (10), and Z in the chemical formula (10) is a lower alkylene. It is one selected from a group, a lower alkenylene group, and a lower alkynylene group, and R ¹³ and R ¹⁴ are independently selected from a hydrogen atom, a lower alkyl group, an aryl group, and an aryl substituted lower alkyl group, respectively. One, Alternatively, R ¹³ and R ¹⁴ may be 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ² may be a D-arginine residue or a D-methionine sulfoxide residue. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). R ⁵ and R ⁶ in 4) are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and X is a hydrogen atom, a halogen atom, and a hydroxyl group. And R ⁷ or R ⁸ of the chemical formula (5) or (6) are independently selected from the group consisting of the chemical formulas (5) and (6), respectively, with a C _1-16 alkyl group and a hydroxy C _1-16. Alkyl group, amino C _1-16 alkyl group, (mono lower alkyl) amino C _1-16 alkyl group, (dilower alkyl) amino C _1-16 alkyl group, C _3-10 cycloalkyl group, C _3-10 cyclo Selected from the group consisting of alkyl-substituted lower alkyl groups, C _2-16 alkenyl groups, C _2-16 alkynyl groups, heterocyclic groups, aryl groups, and aryl substituted lower alkyl groups, AA ² is a D-arginine residue or A D-methionine sulfoxide residue, AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue, and AA ⁴ is The α-amino acid residue represented by the chemical formula (8) or the β-amino acid residue represented by the chemical formula (9), and R ¹⁰ and R ¹² in the chemical formulas (8) and (9) are independent of each other. Is one selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group, and R ¹¹ is represented by a hydrogen atom or a chemical formula (10). Z in the chemical formula (10) is a lower alkylene group. It is one selected from a lower alkenylene group and a lower alkynylene group, and R ¹³ and R ¹⁴ are independently selected from a hydrogen atom, a lower alkyl group, an aryl group, and an aryl-substituted lower alkyl group, respectively. , Or, R ¹³ and R ¹⁴ may be 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are attached. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ² is a DN ⁵ -acetylornithine residue, a D-5-oxonorleucine residue, a D-citrulline residue or a D-5-hydroxynorleucine residue. In some cases. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). R ⁵ and R ⁶ in 4) are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and X is a hydrogen atom, a halogen atom, and a hydroxyl group. And R ⁷ or R ⁸ of the chemical formula (5) or (6) are independently selected from the group consisting of the chemical formulas (5) and (6), respectively, with a C _1-16 alkyl group and a hydroxy C _1-16. Alkyl group, amino C _1-16 alkyl group, (mono lower alkyl) amino C _1-16 alkyl group, (dilower alkyl) amino C _1-16 alkyl group, C _3-10 cycloalkyl group, C _3-10 cyclo Selected from the group consisting of alkyl-substituted lower alkyl groups, C _2-16 alkenyl groups, C _2-16 alkynyl groups, heterocyclic groups, aryl groups, and aryl substituted lower alkyl groups, AA ² is DN ⁵ -acetyl. Ornithine residue, D-5-oxonorleucin residue, D-citrulin residue or D-5-hydroxynorleucin residue, AA ³ is an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D- It is one selected from a phenylalanine residue and a substituted D-phenylalanine residue, and AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid represented by the chemical formula (9). R ¹⁰ and R ¹² in the chemical formulas (8) and (9) are residues, respectively, independently of a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group. R ¹¹ is a hydrogen atom or a chemical formula. The group represented by (10), Z in the chemical formula (10) is one selected from a lower alkylene group, a lower alkenylene group, and a lower alkynylene group, and R ¹³ and R ¹⁴ are independent of each other. , A hydrogen atom, a lower alkyl group, an aryl group, and an aryl substituted lower alkyl group, or R ¹³ and R ¹⁴ contain 5 or 6 members together with the nitrogen atom to which they are attached. It may be a nitrogen heterocyclic group. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ³ may be a phenylalanine residue. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are each independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). R ⁵ and R ⁶ in 4) are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and X is a hydrogen atom, a halogen atom, and a hydroxyl group. And R ⁷ or R ⁸ of chemical formula (5) or (6) are independently selected from the group consisting of chemical formulas (5) and (6), respectively, C _1-16 alkyl group and hydroxy C _1-16. Alkyl group, amino C _1-16 alkyl group, (mono lower alkyl) amino C _1-16 alkyl group, (dilower alkyl) amino C _1-16 alkyl group, C _3-10 cycloalkyl group, C _3-10 cyclo Selected from the group consisting of an alkyl-substituted lower alkyl group, a C _2-16 alkenyl group, a C _2-16 alkynyl group, a heterocyclic group, an aryl group, and an aryl substituted lower alkyl group, AA ² is represented by the chemical formula (7). R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, or an imino lower alkyl group. , A ureido group, a lower alkyl group substituted ureido group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group, and n in the chemical formula (7) is 1. It is an integer of ~ 4, AA ³ is a phenylalanine residue, and AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid residue represented by the chemical formula (9). , R ¹⁰ and in chemical formulas (8) and (9) R ¹² is one independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl substituted lower alkyl group, and R ¹¹ is a hydrogen atom or an aryl substituted lower alkyl group. It is a group represented by the chemical formula (10), and Z in the chemical formula (10) is one selected from a lower alkylene group, a lower alkenylene group, and a lower alkynylene group, and R ¹³ and R ¹⁴ are independent of each other. In addition, one selected from a hydrogen atom, a lower alkyl group, an aryl group, and an aryl-substituted lower alkyl group, or R ¹³ and R ¹⁴ are five or six members combined with a nitrogen atom to which they are bonded. It may be a nitrogen-containing heterocyclic group. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ³ is a p-fluorophenylalanine residue, an o-trifluoromethylphenylalanine residue, a 2,6-dimethylphenylalanine residue, a D-phenylalanine residue, and D-p-. It may be a fluorophenylalanine residue or a Do-o-trifluoromethylphenylalanine residue. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are each independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). R ⁵ and R ⁶ in 4) are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and X is a hydrogen atom, a halogen atom, and a hydroxyl group. And R ⁷ or R ⁸ of chemical formula (5) or (6) are independently selected from the group consisting of chemical formulas (5) and (6), respectively, C _1-16 alkyl group and hydroxy C _1-16. Alkyl group, amino C _1-16 alkyl group, (mono lower alkyl) amino C _1-16 alkyl group, (dilower alkyl) amino C _1-16 alkyl group, C _3-10 cycloalkyl group, C _3-10 cyclo Selected from the group consisting of an alkyl-substituted lower alkyl group, a C _2-16 alkenyl group, a C _2-16 alkynyl group, a heterocyclic group, an aryl group, and an aryl substituted lower alkyl group, AA ² is represented by the chemical formula (7). R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, or an imino lower alkyl group. , A ureido group, a lower alkyl group substituted ureido group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group, and n in the chemical formula (7) is 1. An integer of ~ 4, AA ³ is a p-fluorophenylalanine residue, an o-trifluoromethylphenylalanine residue, a 2,6-dimethylphenylalanine residue, a D-phenylalanine residue, a D-p-fluorophenylalani. Residue or Deo-trifluoromethylphenylalanine residue, AA ⁴ is an α-amino acid residue represented by the chemical formula (8) or a β-amino acid residue represented by the chemical formula (9). Yes, R ¹⁰ and R ¹² in the chemical formulas (8) and (9) are independently selected from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, and an aryl-substituted lower alkyl group, respectively. One, R ¹¹ is a hydrogen atom or a group represented by the chemical formula (10), and Z in the chemical formula (10) is selected from a lower alkylene group, a lower alkenylene group, and a lower alkynylene group. R ¹³ and R ¹⁴ are each independently selected from a hydrogen atom, a lower alkyl group, an aryl group, and an aryl substituted lower alkyl group, or R ¹³ and R ¹⁴ are bonded to each other. It may be a 5- or 6-membered nitrogen-containing heterocyclic group combined with a nitrogen atom. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), AA ⁴ may be a lysine residue or an n-methyl-β-alanine residue. That is, Y ¹ in the general formula (1) is ^{one selected} from a hydrogen atom, a lower alkyl group, and a group represented by the chemical formula (2), and R ¹ in the chemical formula (2) is a hydrogen atom. It is one selected from a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group or an amino group, and Y ² is a hydroxyl group or a chemical formula (3). R ³ and R ⁴ in the chemical formula (3) are each independently selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ And R ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups combined with the nitrogen atom to which they are bonded, and AA ¹ is an α-amino acid residue represented by the chemical formula (4), which is a chemical formula (4). R ⁵ and R ⁶ in 4) are independently selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group, and X is a hydrogen atom, a halogen atom, and a hydroxyl group. And R ⁷ or R ⁸ of chemical formula (5) or (6) are independently selected from the group consisting of chemical formulas (5) and (6), respectively, C _1-16 alkyl group and hydroxy C _1-16. Alkyl group, amino C _1-16 alkyl group, (mono lower alkyl) amino C _1-16 alkyl group, (dilower alkyl) amino C _1-16 alkyl group, C _3-10 cycloalkyl group, C _3-10 cyclo Selected from the group consisting of an alkyl-substituted lower alkyl group, a C _2-16 alkenyl group, a C _2-16 alkynyl group, a heterocyclic group, an aryl group, and an aryl substituted lower alkyl group, AA ² is represented by the chemical formula (7). R ⁹ in the chemical formula (7) is an amino group, a (monolower alkyl) amino group, a lower acylamino group, a guanidino group, a lower alkyl group substituted guanidino group, or an imino lower alkyl group. , A ureido group, a lower alkyl group substituted ureido group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group, and a hydroxy lower alkyl group, and n in the chemical formula (7) is 1. An integer of ~ 4, AA ³ is one selected from an unsubstituted phenylalanine residue, a substituted phenylalanine residue, an unsubstituted D-phenylalanine residue, and a substituted D-phenylalanine residue, and AA ⁴ is a lysine residue. Group or n- It may be a methyl-β-alanine residue. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

In the compound represented by the general formula (1), Y ¹ is one selected from a hydrogen atom and a methyl group, or a group represented by the chemical formula (2), and R ¹ in the chemical formula (2). Is a hydrogen atom, R ² is one selected from a methyl group, an ethyl group, and an amino group, and Y ² is a hydroxyl group or a group represented by the chemical formula (3), and has a chemical formula ( In 3), R ³ and R ⁴ are both hydrogen atoms, or one is a hydrogen atom and the other is a combination of methyl groups, and AA ¹ is a tyrosine residue and a 2,6-dimethyl-tyrosine residue. , O-acyl-tyrosine residue, o-alkoxycarbonyl-tyrosine residue, o-phenoxycarbonyl-tyrosine residue, o-acetyltyrosine residue or 2,6-dimethyl-phenylalanine residue, AA ² is D -Methylthionin sulfoxide residue, D-arginine residue, D-citrulin residue, D-N5-acetylornithine residue, D-5-oxonorleucine residue or D-5-hydroxynorleucine residue, AA Reference numeral ³ denotes a phenylalanine residue, a D-phenylalanine residue, a p-fluorophenylalanine residue, a Dp-fluorophenylalanine residue, an o-trifluoromethylphenylalanine residue or a D-o-trifluoromethylphenylalanine residue. AA ⁴ may be a lysine residue or an n-methyl-β-alanine residue. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

As a preferable compound represented by the general formula (1), Y ¹ is a hydrogen atom and Y ² is a hydroxyl group, [2,6-dimethyl-Tyrosine]-[D-Arg]-[Phe]-. [N-MeβAla] -OH, [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -OH, [2,6-dimethyl-Tyr]-[D-Met (O)]-[ Phe]-[N-MeβAla] -OH, [Tyrosine]-[D-Met (O)]-[Phe]-[N-MeβAla] -OH, [2,6-dimethyl-Tyr]-[D-Arg ]-[Phe]-[Lys] -OH, [Tyr]-[D-Arg]-[Phe]-[Lys] -OH, [2,6-dimethyl-Tyr]-[D-Met (O)] -[Phe]-[Lys] -OH, [Tyr]-[D-Met (O)]-[Phe]-[Lys] -OH, but not limited to these. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

As a preferable compound represented by the general formula (1), Y ¹ is a hydrogen atom and Y ² is an amino group, [2,6-dimethyl-Tyr]-[D-Arg]-[Phe]-. [N-MeβAla] -amide, [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -amide, [2,6-dimethyl-Tyr]-[D-Met (O)]-[ Phe]-[N-MeβAla] -amide, [Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -amide, [2,6-dimethyl-Tyr]-[D-Arg ]-[Phe]-[Lys] -amide, [Tyr]-[D-Arg]-[Phe]-[Lys] -amide, [2,6-dimethyl-Tyr]-[D-Met (O)] -[Phe]-[Lys] -amide, [Tyr]-[D-Met (O)]-[Phe]-[Lys] -amide, but not limited to these. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

Preferred compounds represented by the general formula (1) are methyl- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe, in which Y ¹ is a methyl group and Y ² is a hydroxyl group. ]-[N-MeβAla] -OH, Methyl- [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -OH, Methyl- [2,6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -OH, Methyl- [Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -OH, Methyl- [2,6 -Dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -OH, Methyl- [Tyr]-[D-Arg]-[Phe]-[Lys] -OH, Methyl- [2,6 -Dimethyl-Tyr]-[D-Met (O)]-[Phe]-[Lys] -OH, Methyl- [Tyr]-[D-Met (O)]-[Phe]-[Lys] -OH Yes, but not limited to these. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

Preferred compounds represented by the general formula (1) are methyl- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe, in which Y ¹ is a methyl group and Y ² is an amino group. ]-[N-MeβAla] -amide, methyl- [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -amide, methyl- [2,6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -amide, methyl- [Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -amide, methyl- [2,6 -Dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -amide, methyl- [Tyr]-[D-Arg]-[Phe]-[Lys] -amide, methyl- [2,6 -Dimethyl-Tyr]-[D-Met (O)]-[Phe]-[Lys] -amide, methyl- [Tyr]-[D-Met (O)]-[Phe]-[Lys] -amide Yes, but not limited to these. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

Preferred compounds represented by the general formula (1) are 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Arg, in which Y ¹ is a 1-iminoethyl group and Y ² is a hydroxyl group. ]-[Phe]-[N-MeβAla] -OH, 1-iminoethyl- [Tyrosine]-[D-Arg]-[Phe]-[N-MeβAla] -OH, 1-iminoethyl- [2,6-dimethyl] -Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -OH, 1-iminoethyl- [Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] ] -OH, 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -OH, 1-iminoethyl- [Tyr]-[D-Arg]-[Phe ]-[Lys] -OH, 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[Lys] -OH, 1-iminoethyl- [Tyr]-[ There are, but are not limited to, D-Met (O)]-[Phe]-[Lys] -OH. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

Preferred compounds represented by the general formula (1) are 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Arg, in which Y ¹ is a 1-iminoethyl group and Y ² is an amino group. ]-[Phe]-[N-MeβAla] -amide, 1-iminoethyl- [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -amide, 1-iminoethyl- [2,6-dimethyl] -Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -amide, 1-iminoethyl- [Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] ] -Amide, 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -amide, 1-iminoethyl- [Tyr]-[D-Arg]-[Phe ]-[Lys] -amide, 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[Lys] -amide, 1-iminoethyl- [Tyr]-[ There are, but are not limited to, D-Met (O)]-[Phe]-[Lys] -amides. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

As a preferable compound represented by the general formula (1), Y ¹ is an amidino group and Y ² is a hydroxyl group. Amidino- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe ]-[N-MeβAla] -OH, Amidino- [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -OH, Amidino- [2,6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -OH, Amidino- [Tyrosine]-[D-Met (O)]-[Phe]-[N-MeβAla] -OH, Amidino- [2,6 -Dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -OH, Amidino- [Tyr]-[D-Arg]-[Phe]-[Lys] -OH, Amidino- [2,6 -Dimethyl-Tyr]-[D-Met (O)]-[Phe]-[Lys] -OH, Amidino- [Tyr]-[D-Met (O)]-[Phe]-[Lys] -OH Yes, but not limited to these. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

Preferred compounds represented by the general formula (1) are amidino- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe, in which Y ¹ is an amidino group and Y ² is an amino group. ]-[N-MeβAla] -amide, amidino- [Tyr]-[D-Arg]-[Phe]-[N-MeβAla] -amide, amidino- [2,6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -amide, amidino- [Tyr]-[D-Met (O)]-[Phe]-[N-MeβAla] -amide, amidino- [2,6 -Dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -amide, amidino- [Tyr]-[D-Arg]-[Phe]-[Lys] -amide, amidino- [2,6 -Dimethyl-Tyr]-[D-Met (O)]-[Phe]-[Lys] -amide, amidino- [Tyr]-[D-Met (O)]-[Phe]-[Lys] -amide Yes, but not limited to these. The antipruritic agent may contain these compounds or pharmaceutically acceptable salts thereof.

The compound represented by the general formula (1) includes any optically active substance or racemate, diastereoisomers, or any mixture thereof. Moreover, as a preferable example of a pharmaceutically acceptable salt of the compound represented by the general formula (1), an acid addition salt such as a hydrochloride salt, an acetate salt or paratoluenesulfonic acid, an ammonium salt or an organic amine salt and the like There are, but are not limited to, base addition salts, arbitrary hydrates and solvates of peptide derivatives in free and salt forms, and the like. The compound represented by the general formula (1) includes a compound that is a dimer or a multimer of the peptide derivative represented by the general formula (1) and the C-terminal and n-terminal of these peptide derivatives. Cyclic compounds may also be included.

The antipruritic agent contains at least one of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The antipruritic agent may include at least one compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. This antipruritic agent can be applied by oral administration or parenteral administration, and in the case of parenteral administration, for example, it can be applied by intravenous administration, subcutaneous administration, rectal administration, transmucosal administration, or transdermal administration. is there. Various dosage forms suitable for these routes of administration are known to those skilled in the art, and those skilled in the art will appropriately select a dosage form suitable for the desired dosage form and, if necessary, one or more pharmaceuticals available in the art. It is possible to produce a formulation in the form of an antipruritic agent using a generally acceptable carrier or formulation additive. As the active ingredient of this antipruritic agent, a hydrate or solvate of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof may be used. The dose is not particularly limited, but for example, in the case of transdermal administration or transmucosal administration, the single dose is 0.1 to 10 mg, and in the case of oral administration, the single dose is 1 to 100 mg. It can be administered 2-3 times daily. Alternatively, usually about 0.1 to 1,000 mg, preferably about 1 to 300 mg per day for adults can be administered. In addition, the dose can be set in association with parameters such as the patient's weight, age, genotype, and medical condition.

This antipruritic agent includes tablets, granules (fine granules), capsules, injections (intravenous drip), patches, suppositories, suspensions and emulsions, pastes, ointments, creams, lotions, and nasal drops. It may be provided in the form of a drug, eye drop, etc., but is not limited thereto. The antipruritic agent may be sustained-release for the purpose of maintaining its duration for a long period of time.

Pharmaceutically acceptable carriers or pharmaceutical additives contained in the antipruritic agent include, but are not limited to, stabilizers, surfactants, solubilizers, adsorbents and the like. The pharmaceutically acceptable carrier or pharmaceutical additive contained in the antipruritic agent is selected according to the dosage form of the antipruritic agent listed above.

The method for producing the compound represented by the general formula (1) is not particularly limited, but the compound can be synthesized by the solid phase method and the liquid phase method usually used for peptide synthesis. Various excellent protecting groups such as amino groups and condensing agents for condensation reactions are known. Refer to the following examples, and for example: Koichi Suzuki, "Protein Engineering-Basics and Applications" Maruzen ( Co., Ltd. (1992) and the literature cited therein; Bondanzaky, etal. , "PeptideSynthesis", John Willey & Sons, n. Y. , 1976; and J.M. M. Stewartand D. J. Young, "SolidPhasePeptideSynthesis", W. et al. H. Freemand Co. , San Francisco, 1969, etc., and can be appropriately selected and used. In the solid phase method, it may be convenient to use various commercially available peptide synthesizers, for example, model 430A manufactured by Perkin Elmer Japan Co., Ltd., PSSM-8 manufactured by Shimadzu Corporation, and the like. Commercially available products such as resins and reagents used for synthesis can be easily obtained.

The antipruritic effect of opioid μ receptor agonists was investigated using the pruritus-related behavior (scratching) induced by the pruritus substance 4-methyl-histamine as an index.

(Examples 1 to 5)
1.1 Animals used In the experiments, ddY male mice weighing 21 g to 24 g were used. Mice were bred in a constant environment of room temperature 22 ± 2 ° C., humidity 50 ± 5%, and light-dark cycle (light period 7:00 to 19:00, dark period 19:00 to 7:00) until they were subjected to experiments, and solidified. Feed (F2: manufactured by Funabashi Farm Co., Ltd.) and tap water were allowed to be freely ingested. The experiment was conducted in accordance with the Tohoku Pharmaceutical University Experimental Regulations and the experimental plan approved by the Tohoku Pharmaceutical University Animal Experiment Committee.

1.2 Drugs used 4-Methyl-histamine (manufactured by TOCRIS) was used as the pruritus substance in all of Examples 1 to 5. As the antipruritic agent, the synthetic peptides shown in Table 1 were used in Examples 1 to 5, respectively. The structures of the compounds used in Examples 1 to 5 are represented by chemical formulas (16) to (20), respectively. These drugs are dissolved in physiological saline (manufactured by Fuso Yakuhin Kogyo Co., Ltd.) for subcutaneous administration (s.c.) and oral administration (po.) Of the neck, and jojoba oil (jojoba oil) for transdermal administration (application). It was dissolved in Wako Pure Chemical Industries, Ltd.) and used.

The synthetic peptide used in Example 4 was synthesized as follows. Fmoc / Meβ / Ala / OH, Fmoc / Phe / OH, Fmoc / D / Arg (Pbf) / OH, Fmoc / Dmt (tBu) / OH, and Link Amide Resin (start of C-terminal synthesis) as reagents for peptide synthesis. Resin) (both manufactured by Watanabe Chemical Industry Co., Ltd.) were prepared. H · Dmt (tBu) -D · Arg (Pbf) -Phe- Meβ · Ala · NH ₂ · by Fmoc / PyBOP / HOBt method using solid phase automatic peptide synthesizer PSSM-8 (manufactured by Shimadzu Corporation) Resin was synthesized. After synthesis, O-Methylisourea of the N-terminal 1M (manufactured by Sigma · Aldrich) and 4 ° C., allowed to react for 24 hours, Amidino-Dmt (tBu) -D · Arg (Pbf) -Phe-Meβ · Ala · NH 2 · Resin Was synthesized. Then, the reaction was carried out in a 90% TFA / 5% anisole / 5% thioanisole (v / v / v) solution at room temperature for 3 hours to cut out from Resin and deprotect the side chains. Then, the peptide cut out by HPLC was purified (purification purity of 98% or more). The mass number of the obtained peptide was confirmed by MALDI-TOF-MS or LC-MS. As a result, m / z; theoretical value 638.5 (M + H ⁺ ) and experimental value 638.7.

The synthetic peptide used in Example 5 was synthesized as follows. As reagents for peptide synthesis, Fmoc, Lys (Boc), OH, and Link Amide Resin (C-terminal synthesis initiation resin) (both manufactured by Watanabe Chemical Industry Co., Ltd.) were prepared. Was synthesized H · Dmt (tBu) -D · Arg (Pbf) -Phe- Lys (Boc) · NH 2 · Resin in a manner similar to the synthetic peptide of Example 4. Then, the resin was cut out and the side chain was deprotected in the same manner as in Example 4. Then, the peptide cut out by HPLC was purified (purification purity of 98% or more). The mass number of the obtained peptide was confirmed by MALDI-TOF-MS or LC-MS. As a result, the theoretical value was 639.7 (M + H ⁺ ) and the experimental value was 639.7.

1.3 Administration method For the administration of 4-methyl-histamine, which is an pruritus substance, the back and neck of the mouse was plucked 24 hours before the measurement in a size of 1 cm × 1 cm, and the hair was intradermally administered at a rate of 50 μl / mouse. i.d.). The antipruritic agent was administered subcutaneously to the neck (s.c.), orally (po.), Or transdermally (application). Subcutaneous cervical administration (s.c.) and oral administration (po.) Of antipruritic agents were performed at a ratio of 0.1 ml / 10 g, and percutaneous administration (application) was performed using a micropipette at 20 μl / mouse. It was applied to the dorsal neck where the hair was removed at the rate of. The dose of antipruritic agent was adjusted to vary the concentration of antipruritic agent in the solution.

1.4 Behavioral observations The pruritus-related behaviors were observed using the scratching behavior (scratching) of the hind limbs as an index. Mice were placed one by one in a transparent plastic gauge (22 cm x 15 cm x 12.5 cm) for measurement in advance, left for about 1 hour to confirm the disappearance of self-issued behavior, and then an antipruritic agent was administered. , 4-Methyl-histamine, which is an pruritus substance, was administered. The time from administration of the antipruritic agent to administration of 4-methyl-histamine was 30 minutes, 60 minutes, 120 minutes, or 180 minutes, and Table 2 shows After30min, After60min, After120min, or After180min. Described. For pruritic behavior, 4-methyl-histamine was administered intradermally (id), and the duration of scratching behavior (Scratching) was measured for 30 minutes immediately after the administration.

1.5 Experimental Results Figures 1 to 15 show the dose-response curves when the antipruritic agent was subcutaneously (s.c.), orally (po.) Or transdermally (applied) in each example. Is shown. Table 2 shows the seconds of 4-methyl-histamine-induced scratching behavior when antipruritic agents were administered subcutaneously (s.c.), Orally (po.), And transdermally (application). It shows the ID ₅₀ value of suppression with respect to the number. In Table 2, the numbers before the parentheses are the average values, and the numbers in the parentheses are the confidence limit values.

As shown in FIGS. 1 to 15 and Table 2, an anti-itch effect was observed in each of the examples. Among them, in the case of subcutaneous administration (s.c.) and oral administration (po.), Amidino- [Tyrosine]-[D-Arg]-[Phe]-[N-MeβAla]-of Example 2 Extremely strong suppression of scratching behavior was observed in OH. Further, in the case of transdermal application, extremely strong scratching behavior (scratching) in [2,6-dimethyl-Tyr]-[D-Arg]-[Phe]-[Lys] -amide of Example 5 ) Was suppressed. That is, it was found that according to this antipruritic agent, an excellent antipruritic effect can be obtained, and a high effect can be obtained in both oral administration and parenteral administration.

(Comparative Example 1)
Other than the use of amidino- [2,6-dimethyl-Tyr]-[D-Arg]-[NH (CH ₂ ) ₃ ] -Ph (Ph represents a phenyl group) as an antipruritic agent. The antipruritic effect was examined in the same manner as in Examples 1 to 5. No antipruritic effect was observed when 20 μg / 20 μL was applied and when 10 mg / kg was orally administered.

Although the present invention has been described above with reference to embodiments and examples, the present invention is not limited to the above embodiments and examples, and can be variously modified.

It can be used as an antipruritic agent.

Claims (1)

An antipruritic agent comprising at least one of a group consisting of a compound having the structure of the chemical formula (16), the chemical formula (17), the chemical formula (18), the chemical formula (19), or the chemical formula (20). ..

Images