WO2007145208A1 - Peptide derivative - Google Patents

Abstract

Disclosed is a peptide derivative represented by the general formula: R1N=C(R2)-AA1-AA2-AA3-AA4-Y [wherein R1 represents a hydrogen atom or the like; R2 represents a methyl group or the like; Y represents a methylamino group or the like; AA1 represents a tyrosine residue or the like; AA2 represents a D-arginine residue or the like; AA3 represents a phenylalanine residue or the like; and AA4 represents an N-methyllysine residue or the like] or a salt thereof. The peptide derivative or the salt thereof shows an excellent analgesic effect on various types of pains through subcutaneous or oral administration.

Description

 Specification

 Peptide derivatives

 Technical field

 [0001] The present invention relates to peptide derivatives, and particularly to peptide derivatives having analgesic or anti-nociceptive effects.

 Background art

 [0002] One of the unresolved issues for humanity is "pain".

 “Pain”, that is, pain can be important information that informs you of the occurrence of injury or illness. For example, acute pain, chronic pain, fibromyalgia, neuropathic pain (neuropathic pain), Pain such as pain due to diabetic neuropathy, cancer pain, MSU (urate) -induced knee joint pain, pain due to osteoarthritis of the knee, and pain due to rheumatoid arthritis are currently difficult to remove quickly by treatment. Thus, these pains both day and night can blame the patient, cause him to lose the willingness to fight the disease, and sometimes even bring the patient to complete despair.

 [0003] From the viewpoint of historical viewpoint, human beings have countered this pain with a opium. It is known that the fruit juice of immature poppies is also collected from clay plates left by the Siyumerites of the Mesopotamia civilization 5000 years ago, and has been used as an anesthetic in Greece since around the era. It was. In other words, Aachen is the oldest medicine in human history.

 [0004] On the other hand, morphine obtained from such opium has been found to be an excellent analgesic, especially cancer pain, since it was discovered in 1803 by German pharmacist Zeltuna. It must be used as an analgesic.

[0005] However, such morphine is a narcotic drug and has an addictive nature. It is physically dependent and mentally dependent on multiple administrations, so it causes chronic poisoning, so-called drug addiction, and gradually. It will not work unless you use a large amount. Thus, morphine must be handled and administered with great care. In addition, for severe pain, morphine has a relatively short duration of effect and needs to be administered every short time. There is also a problem that it is difficult to realize home-stage terminal cancer treatment (home hospice) in the case of end-stage cancer, in which the burden on caregivers such as patients and their family members is large as well as people.

 [0006] On the other hand, pain (neuropathic pain and the like) in which morphine is hardly effective is also known, and in such a field, an analgesic having a higher effect than morphine has been demanded.

 [0007] In this way, there is a need for an analgesic that has an effect equal to or greater than that of morphine in a wide range of fields beyond morphine without having narcotic properties, and has a longer duration of effect. It was.

 [0008] Here, since the discovery of the above morphine, the analgesic research has been promoted mainly by the Al force Lloyd's compound related to its chemical structure. In 1975, a peptide compound having morphine-like activity (opio Since the discovery of methionine enkephalin and leucine enkephalin in the brain of pigs, an approach to use peptide derivatives as analgesics has begun.

 [0009] Here, as an analgesic, it is required to be easy to administer and to obtain a long-term anti-nociceptive or analgesic effect by oral or subcutaneous administration, which is less burdensome on the patient. Since both enkephalins are easily degraded by enzymes in the body, no antinociceptive and analgesic effects can be obtained by oral and subcutaneous administration.

 [0010] Delmorphin, isolated and identified from the skin of the South American power El Phyllomedusa sauvagei in 1980, is said to exist in nature except for bacteria! D-Amino acid amino acid residues It contains a group and is resistant to enzymatic degradation in vivo (Non-patent Document 1). With this discovery as a hint, attempts have been made to develop analgesics using synthetic peptide derivatives containing the D-isomer amino acid residue. In particular, in order to obtain high anti-nociceptive or analgesic effects in oral administration. There were difficulties.

 [0011] For example, the peptide derivative TAPA (Tyr—D—Arg—Phe—β synthesized by the present inventors

 -Ala) is 9 times as potent as morphine in subcutaneous administration (Non-patent Documents 2 to 5) o However, the anti-nociceptive effect of TAP A in oral administration was almost the same as that of morphine

[0012] Based on such basic studies, the present inventors have improved the efficacy of anti-nociceptive effects by oral administration. For this purpose, a series of peptide derivatives having an amidino group at the amino terminal were synthesized (Patent Literatures 1 to 3). Of these, the peptide derivative ADAM Β (Ν α-amidino-one [Tyr]-[D— Arg]-[Phe]-[N-methyl j8 Ala] — OH), which causes the strongest antinociceptive action, The nociceptive effect was about 23 times that of morphine, and the anti-invasion effect after oral administration was about 3.8 times that of morphine (Non-patent Document 6).

[0013] Here, when the carboxyl terminus of ADAMB was amidated with the aim of further improving the efficacy of ADAMB, the antinociception in subcutaneous administration was reduced to about one-seventh that of morphine, and the antinociception in oral administration was also reduced. It has dropped to about one-fifth of morphine. Furthermore, when N-methylamidoylation was performed on the carboxyl terminus of AD AMB, the antinociceptive effect in both subcutaneous administration and oral administration was further reduced (Non-patent Document 7). As described above, when the carboxyl terminus of ADAMB is amido or methylamidite, the anti-nociceptive action cannot be enhanced more than ADAMB, but the anti-nociceptive action is reduced.

 [0014] Next, the present inventors have a 1-iminomethyl group at the amino terminal, the first amino acid residue is tyrosine, the second amino acid residue is D-arginine or D-methionine sulfoxide, When a series of peptide derivatives in which the third amino acid residue has a basic skeleton of phenylalanin was synthesized, the anti-nociceptive effect in oral administration was improved, although it was confirmed that it was sufficient (above ADAMB) ( Patent Document 4, Non-Patent Document 8).

 [0015] As described above, morphine can be substituted for morphine, or can be used in fields where morphine cannot be applied due to lack of narcotic properties, and has high anti-nociceptive and analgesic effects in subcutaneous administration and oral administration. The problem of obtaining an excellent analgesic that surpasses the above has not been solved.

 [0016] In order to solve the above problems, the present inventors have further investigated and in order to enhance the antinociceptive action of a peptide derivative having a 1-iminoethyl group at the amino terminal, the carboxyl terminal of this peptide derivative. Attempted modification. In this study, we examined the substitution of ADAMB in which the amino terminal was substituted with an imino lower alkyl group.

[0017] In this case, from the above experimental results in which the carboxyl terminal of ADAMB was amidated, the ADAMB substitution product in which the amino terminal was substituted with an imino lower alkyl group was also similar. Anti-nociceptive activity was expected to decrease when the lupoxyl end was amidoylated.

 However, contrary to this expectation, when the carboxyl terminus of the peptide derivative is amidated, the anti-nociceptive action in subcutaneous administration and oral administration is enhanced, and the duration of the anti-nociceptive action is long. An unexpected result was obtained. Furthermore, it was found that when the carboxyl terminal is methylamidated, the antinociceptive effect in subcutaneous administration and oral administration is further enhanced than in the case of amidation. Thus, the present inventors have found that the novel peptide derivatives described below have an excellent anti-nociceptive action, not only for subcutaneous administration but also for oral administration, and completed the present invention.

 Patent Document 1: International Publication No. W095Z24421

 Patent Document 2: International Publication No. WO97Z10261

 Patent Document 3: International Publication No. WO97Z10262

 Patent Document 4: International Publication No. W099Z33864

 Non-patent literature l: Int. J. Peptide Protein Res., 17: 275 (1981)

 Non-Patent Document 2: Br. J. Pharmacol., 95:15 (1988)

 Non-Patent Document 3: Peptides, 11: 139 (1990)

 Non-Patent Document 4: Neuropharmacol., 32: 689 (1993)

 Non-Patent Document 5: Pharmacol. Biochem. Behav., 24:27 (1986)

 Non-Patent Document 6: Chem. Pharm. Bull, 50: 771-780 (2002)

 Non-Patent Document 7: J. Med. Chem., 45: 5081-5089 (2002)

 Non-Patent Document 8: Chem. Pharm, Bull., 51: 759-771 (2003)

 Disclosure of the invention

 Problems to be solved by the invention

[0019] An object of the present invention is to provide a peptide derivative that exhibits a powerful analgesic action or antinociceptive action not only by subcutaneous administration but also by oral administration. Furthermore, another object of the present invention is to provide a peptide derivative having a long duration of analgesic action or antinociceptive action in both oral administration and subcutaneous administration. Another object of the present invention is to provide a pharmaceutical composition comprising the peptide derivative as an active ingredient. Another object of the present invention is to provide pain, such as neuropathic pain, with a therapeutic agent containing the peptide derivative. (Neuropathic pain), cancer pain, osteoarthritis pain, MSU (urate) -induced knee joint pain, rheumatoid arthritis, etc., and other therapeutic conditions Is to provide.

 Means for solving the problem

[0020] In order to solve the above-mentioned problems, the present inventors, in addition to the above-described investigation, in order to enhance the anti-nociceptive action of a peptide derivative having a 1-iminoethyl group at the amino terminal, We examined the modification of.

 [0021] Here, from the results of the above-mentioned experiment in which the carboxyl terminus of ADAMB is amidated, the ADAMB substituted product in which the amino terminal is substituted with an imino lower alkyl group! However, if the carboxyl terminus is amidated, Anti-nociceptive activity was expected to decrease.

 However, contrary to such expectation, as a result of amidation of the carboxyl terminal of the peptide derivative, the anti-nociceptive action in subcutaneous administration and oral administration is enhanced and the anti-nociceptive action is sustained. It has been found that the results are surprising as time increases. Furthermore, when methyl amide was used at the carboxyl terminus, the anti-invasive effect in subcutaneous administration and oral administration was further enhanced than in the case of amide treatment. Therefore, the present inventors have found that the novel peptide derivatives described below have excellent analgesic action and anti-nociceptive action not only for subcutaneous administration but also for oral administration, and completed the present invention. .

 [0023] As described in claim 1, the present invention provides the following general formula (1):

R ¹ N = C (R ² ) AA ¹ -AA ² -AA ³ -AA ⁴ -Y

 (1) or a pharmaceutically acceptable salt thereof,

R ¹ is ^one selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group, and Y is the following chemical formula: (2)

-N (R ³ ) R ⁴ (2)

In the chemical formula (2), R ³ and R ⁴ are each independently a force selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ and COR ⁴ are 5- or 6-membered nitrogen-containing heterocyclic groups attached together with the nitrogen atom to which they are attached,

The above AA ¹ is represented by the following chemical formula (3)

[Chemical 1]

R ⁵ ', _{R 6}

N

 H

A amino acid residue represented by 3,

In the chemical formula (3), R ⁵ and R ⁶ are each independently one selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group.

 In the chemical formula (3), X represents a hydrogen atom, a halogen atom, a hydroxyl group, a group represented by the following chemical formula (4), and a group represented by the following chemical formula (5).

-O-CO-R ⁷

 (Four)

-O-CO-OR ⁸

(5) is selected from the formula (4), R ′ in formula (4) and R ^{8 in} formula (5) are independent of each other. C alkyl group, hydroxy C alkyl group, amino C alkyl group, (mono low

1-16 1-16 1-16

Secondary alkyl) amino C alkyl group, (di-lower alkyl) amino C alkyl group, C

 1-16 1-16 3-cycloalkyl group, C cycloalkyl-substituted lower alkyl group, C alkenyl group

10 3-10 2-16

 C alkyl group, heterocyclic group, aryl group, and aryl substituted lower alkyl group

2-16

Is one selected from

The above AA ² has the following chemical formula (6)

[Chemical 2]

(6) is a D-a-amino acid residue represented by chemical formula (6), wherein R ⁹ is an amino group, (mono lower alkyl) amino group, lower acylamino group, gua-dino group, 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 N is an integer from 1 to 4, and AA ³ is an unsubstituted phalaranine residue, a substituted phalaranin residue, an unsubstituted D- pheralanine residue, and a substituted D phalalanin Residual force is one that is selected and the above AA ⁴ is represented by the following chemical formula (7) N (R ¹⁰ )-CH (R ⁿ )-CO-

A amino acid residue represented by (7) or the following chemical formula (8) -N (R ¹⁰ ) CH (R ⁿ ) -CH (R ¹² ) CO—

 Β amino acid residue represented by (8),

In chemical formulas (7) and (8), R ^1C> and R ¹² 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. One is

R ¹¹ is a hydrogen atom or the following chemical formula (9) Z-諫¹³ )-R ¹⁴

 A group represented by (9),

In the chemical formula (9), Z is one selected from a lower alkylene group, a lower alkylene group, and a lower alkylene group, and R ¹³ and R ¹⁴ are each independently a hydrogen atom, One selected from alkyl group, aryl group, and aryl substituted lower alkyl group, or R ¹³ and R ¹⁴ are 5- or 6-membered nitrogen-containing heterocycles together with the nitrogen atom to which they are bonded It is a group or a pharmaceutically acceptable salt thereof.

[0024] Further, as described in claim 2, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is water. It is an elementary atom.

[0025] Further, as described in claim 3, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1 or 2, or the pharmaceutically acceptable salt thereof, wherein the R ² is It is a methyl group or an ethyl group.

[0026] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof, as described in claim 4, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. In the salt, AA ³ is represented by the following chemical formula (10): [Chemical 3]

 A amino acid residue represented by (1 0) or the chemical formula (11)

 [Chemical 4]

(11) is a D-a amino acid residue, and in the above chemical formulas (10) and (11), R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, and And a halogenated lower alkyl group.

[0027] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof, as described in claim 5, has the capability of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. In the salt, AA ³ is a phenalanine residue, a D-ferroalanine residue, a p-fluoroferroalanine residue, a D-p-fluoroferroalanine residue, o a trifluoromethylphenolan residue, D — O Trifluoromethylphenolalanine residue and 2, 6 dimethylphenylalanan residue Residue force is a selected amino acid residue.

[0028] The compound of the present invention or a pharmaceutically acceptable salt thereof is as described in claim 6, The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the AA ⁴ is an N-methyllysine residue or an N-methyl-13-alanine residue. Features.

[0029] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, as described in claim 7. In the above chemical formula (3), the salt is characterized by being an X force hydroxyl group.

 [0030] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof, as described in claim 8, is any one of the compounds described in claim 1 to claim 6, or a pharmaceutically acceptable salt thereof. In the above chemical formula (3), X is a hydrogen atom or a halogen atom.

[0031] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof, as described in claim 9, has the power of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. In the chemical formula (3), X is represented by the chemical formula (4) or the chemical formula (5). In the chemical formula (4) and R ⁸ in the chemical formula (5), C alkyl group, hydroxy C alkyl group, amino C alkyl group, (mono-lower alkyl)

1-16 1-16 1-16

 Alkyl) amino C alkyl group, (di-lower alkyl) amino C alkyl group, C

 1-16 1-16 3-10 Chloalkyl group, C cycloalkyl-substituted lower alkyl group, C alkenyl group, C

 3- 10 2- 16 2 From alkynyl, aryl, heterocyclic, and aryl substituted lower alkyl groups

-16

 It is one that is chosen.

[0032] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, as described in claim 10. In the salt, AA ¹ is a tyrosine residue, 2, 6-dimethyl-tyrosine residue, o-silute tyrosine residue, o-alkoxycarbo-rutyrosine residue, o-phenoxycarborutyrosine residue, o It is characterized by the fact that a —acetyl-tyrosine residue and a 2,6-dimethyl-phenylalanine residue are also selected.

[0033] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as described in claim 11. AA ² is characterized in that it is one selected from D-methionine sulfoxide residue, D-arginine residue, and D-citrulline residue.

[0034] Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as described in claim 12. Wherein AA ² is one selected from D—N ⁵ -acetylol-tin residue, D-5-oxonorleucine residue, and D-5 hydroxynorleucine residue. To do.

[0035] The compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as described in claim 13. Wherein R ³ and R ⁴ are each independently one selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group.

[0036] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. An atom, the R ² is a methyl group, the AA ¹ is an o-acetyl tyrosine residue, the AA ² is a D methionine sulfoxide residue or a D arginine residue, and the AA ³ Is a phalalanin residue, the AA ⁴ is an N-methyllysine residue or an N-methyl-j8-alanine residue, and the Y is NH or NH—CH.

 twenty three

 It is a sign.

[0037] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. An atom, the R ² is a methyl group, the AA ¹ is a tyrosine residue, the AA ² is a D methionine sulfoxide residue or a D arginine residue, and the AA ³ is a phenylalanine residue. AA ⁴ is an N-methyllysine residue or N-methyl-13-alanine residue, and Y is NH or NH—CH.

 twenty three

[0038] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. An atom, the R ² is a methyl group, the AA ¹ is an o-acetyl tyrosine residue, the AA ² is a D-methionine sulfoxide residue or a D-arginine residue, and AA ³ is a phenylalanine residue, AA ⁴ is an N-methyllysine residue or N-methyl-1-β-alanine residue, and Υ is one NH-C Η .

 twenty five

[0039] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. An atom, R ² is a methyl group, ΑΑ ¹ is a tyrosine residue, ΑΑ ² is a D-5-hydroxynorleucine residue, and ΑΑ ³ is a ferrolanine residue.上 記⁴ is a メ チ ル -methyllysine residue or Ν-methyl-β-alanine residue, and the Υ is one or one NH-CH.

 twenty three

[0040] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. An atom, the R ² is a methyl group, the ΑΑ ¹ is a tyrosine residue, the ΑΑ ² is a D methionine sulfoxide residue, the エ³ is a ferrolanine residue, and alpha alpha ⁴ is Ν- methyllysine residue or Ν- methyl-β Aranin residues, the Υ is characterized by a ΝΗ or NH- CH.

 twenty three

[0041] Further, the compound of the present invention or a pharmaceutically acceptable salt thereof is the compound according to claim 1, or the pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. R ² is a methyl group, ΑΑ ¹ is a 2,6 dimethyl-tyrosine residue, 上 記² is a D methionyl sulfoxide residue! /, Is a D arginine residue the alpha alpha ³ Hue - a Ruaranin residue, the alpha alpha ⁴ is Ν- methyllysine residue or Ν- methyl-β Aranin residues, the Υ is the ΝΗ or NH- CH

 It is characterized by 2 3.

 [0042] As described in claim 20, the pharmaceutical composition of the present invention effectively comprises at least one of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof. It is a pharmaceutical composition comprising as an ingredient.

[0043] As described in claim 21, the pharmaceutical composition of the present invention comprises at least one of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutical. A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0044] The pharmaceutical composition of the present invention is as described in claim 22, as described in claim 19 or claim 20. In the pharmaceutical composition described above, the pharmaceutical composition is used for prevention and Z or treatment of pain.

 [0045] As described in claim 23, the pharmaceutical composition of the present invention is characterized in that in the pharmaceutical composition according to claim 22, the pain is cancer pain.

[0046] As described in claim 24, the pharmaceutical composition of the present invention is characterized in that, in the pharmaceutical composition according to claim 22, the pain is neuropathic pain.

[0047] As described in claim 25, the pharmaceutical composition of the present invention is characterized in that in the pharmaceutical composition according to claim 22, the pain is pain due to knee osteoarthritis.

[0048] As described in claim 26, the pharmaceutical composition of the present invention is characterized in that in the pharmaceutical composition according to claim 22, the pain is pain due to rheumatoid arthritis.

 The invention's effect

 [0049] According to the compound of the present invention or a pharmaceutically acceptable salt thereof, not only subcutaneous administration but also oral administration can exert a powerful analgesic action or antinociceptive action. The duration of analgesic or antinociceptive action is long in both administration and subcutaneous administration.

 According to the present invention, a high analgesic action or an antinociceptive action is obtained for extremely wide pains such as heat-stimulated pain, neuropathic pain, and puncture pain, and the effect is high and its duration is long. Therefore, it can be applied as a new comprehensive analgesic that surpasses conventional morphine in addition to its lack of narcotic properties, and it can be applied not only to patients who suffer from pain but also to surrounding medical personnel and patient families. The burden on caregivers can be eliminated or reduced. In addition, because of the extremely effective anti-nociceptive action against these three different types of pain, morphine has been applied for its narcotic properties, such as collagen disease and currently unexplained pain. It is highly possible to apply it to various fields where pain could not be achieved and various pains where morphine was effective.

 Brief Description of Drawings

 [0050] FIG. 1 is a graph showing the time course of antinociception after subcutaneous administration of the compound of Example 1.

FIG. 2 is a graph showing a dose-response curve when the compound of Example 1 is administered subcutaneously. 圆 3] A graph showing the change over time of the antinociception after subcutaneous administration of the compound of Example 2.

圆 4] A graph showing a dose-response curve when the compound of Example 2 is administered subcutaneously.圆 5] A graph showing the change over time in the antinociceptive effect after oral administration of the compound of Example 2.

 FIG. 6 is a graph showing a dose response curve when the compound of Example 2 was orally administered. [7] This is a graph showing the time course of the antinociceptive effect after subcutaneous administration of the compound of Example 3.

 FIG. 8 is a graph showing a dose-response curve when the compound of Example 3 is administered subcutaneously. 9) A graph showing the change over time in the antinociceptive effect after subcutaneous administration of the compound of Example 4.

 FIG. 10 is a graph showing a dose-response curve when the compound of Example 4 is administered subcutaneously. 圆 11] It is a graph showing the time course of the antinociceptive effect after oral administration of the compound of Example 4.

 FIG. 12 is a graph showing a dose-response curve when the compound of Example 4 is orally administered. 圆 13] This is a graph showing the change over time of the antinociception after subcutaneous administration of the compound of Example 5.

 FIG. 14 is a graph showing a dose-response curve when the compound of Example 5 is administered subcutaneously. 15: A graph showing the change over time in the antinociception after subcutaneous administration of the compound of Example 6.

 FIG. 16 is a graph showing a dose-response curve when the compound of Example 6 is administered subcutaneously. [17] FIG. 16 is a graph showing a change with time of the antinociception after oral administration of the compound of Example 6.

FIG. 18 is a graph showing a dose-response curve when the compound of Example 6 is orally administered. FIG. 19 is a graph showing the change over time in the antinociceptive effect after subcutaneous administration of the compound of Example 7.

 FIG. 20 is a graph showing a dose-response curve when the compound of Example 7 is administered subcutaneously. 圆 21] It is a graph showing the time course of the antinociceptive effect after oral administration of the compound of Example 7.

 [FIG. 22] A graph showing a dose-response curve when the compound of Example 7 is orally administered. [23] FIG. 22 is a graph showing a change with time of the antinociception after subcutaneous administration of the compound of Example 8.

 FIG. 24 is a graph showing a dose-response curve when the compound of Example 8 is administered subcutaneously. 25] This is a graph showing the time course of the antinociceptive effect after subcutaneous administration of the compound of Comparative Example 1.

圆 26] is a graph showing a dose-response curve when the compound of Comparative Example 1 is administered subcutaneously. 圆 27] is a graph showing the change over time of the antinociception after oral administration of the compound of Comparative Example 1.

 FIG. 28 is a graph showing a dose-response curve when the compound of Comparative Example 1 is orally administered. (29) This is a graph showing the time course of the antinociception after subcutaneous administration of the compound of Comparative Example 2.

圆 30] is a graph showing a dose-response curve when the compound of Comparative Example 2 is administered subcutaneously. 圆 31] is a graph showing the time course of the antinociception after oral administration of the compound of Comparative Example 2.

FIG. 32 is a graph showing a dose-response curve when the compound of Comparative Example 2 is orally administered. FIG. 33 is a graph showing the change over time in the antinociceptive effect after subcutaneous administration of the compound of Comparative Example 3.

[34] A graph showing a dose-response curve when the compound of Comparative Example 3 is administered subcutaneously.

FIG. 35 shows the time course of the antinociceptive effect after subcutaneous administration of the compound of Comparative Example 4.

36] A graph showing a dose-response curve when the compound of Comparative Example 4 is administered subcutaneously.

FIG. 37 is a graph showing the relationship between oral dose and AUC.

FIG. 38 is a graph showing the relationship between subcutaneous dose and AUC.

[Figure 39] Draft showing the relationship between subcutaneous administration of SS8225-04 J: and AUC in a nerve injury model.

 FIG. 40 is a graph showing the time course of administration of SS8225-04 subcutaneously in a nerve injury model from administration of stimulation threshold (gram weight) at J: Mo. O. 125 mgZkg.

FIG. 41 is a graph showing the time course of administration of SS8225-04 subcutaneously in a nerve injury model after administration of the stimulation threshold (gram weight) at J: Mo. O. 25 mgZkg.

FIG. 42 is a graph showing changes over time from administration of the stimulation threshold value (gram weight) when SS8225-04 is administered subcutaneously in a nerve injury model with J: 0.5 mgZkg.

FIG. 43 is a graph showing the change over time from the administration of the stimulation threshold value (gram weight) when SS8225-04 subcutaneous administration J: is 0.7 mgZkg in a nerve injury model.

FIG. 44: Daraf showing the relationship between subcutaneous administration of SS8225-07 in the nerve injury model J: and AUC.

 FIG. 45 is a graph showing the time course of SS8225-07 administered subcutaneously in a nerve injury model after administration of stimulation threshold (gram weight) at J: Mo. O. 125 mgZkg.

FIG. 46 is a graph showing the time course of administration of SS8225-07 subcutaneously in a nerve injury model after administration of the stimulation threshold (gram weight) at mosquito O. 25 mgZkg.

[Figure 47] SS8225-07 administered subcutaneously in a nerve injury model J: Stimulation threshold at 0.5 mgZkg The graph which shows a time-dependent change from administration of a value (gram weight).

 FIG. 48 is a graph showing the change over time from the administration of the stimulation threshold value (gram weight) when the subcutaneous dose of SS8225-07 in the nerve injury model is 1. OmgZkg.

 FIG. 49 is a graph showing the relationship between AUC and the subcutaneous dose of morphine in a nerve injury model.

FIG. 50 is a graph showing the change over time from administration of the stimulation threshold (gram weight) when the subcutaneous dose of morphine in the nerve injury model is 2.5 mgZkg.

 FIG. 51 is a graph showing the change over time from administration of the stimulation threshold (gram weight) when the subcutaneous dose of morphine in the nerve injury model is 3.5 mgZkg.

 FIG. 52 is a graph showing the change over time of the stimulation threshold (gram weight) when the subcutaneous dose of morphine in the nerve injury model is 5 mgZkg.

 FIG. 53 is a graph showing the change over time of the stimulation threshold (gram weight) when the subcutaneous dose of morphine in the nerve injury model is 7 mgZkg.

 FIG. 54 is a graph showing the change over time from the administration of the stimulation threshold (Durham weight) when the subcutaneous dose of morphine in the nerve injury model is 10 mgZkg.

 FIG. 55 is a graph showing the time course of antinociception in the Tille Pressure test after subcutaneous administration of SS8225-04.

 FIG. 56 is a graph showing a dose-response curve of SS8225-04 when administered subcutaneously.

 FIG. 57 is a graph showing the time course of antinociception in the Till Pressure Test after oral administration of SS8225-04.

 FIG. 58 is a graph showing a dose-response curve of SS8225-04 at the time of oral administration.

 FIG. 59 is a graph showing the time course of antinociception in the Tille Pressure test after subcutaneous administration of SS8225-07.

 FIG. 60 is a graph showing a dose-response curve of SS8225-07 when administered subcutaneously.

 FIG. 61 is a graph showing the time course of antinociception in the Tille Pressure test after oral administration of SS8225-07.

 FIG. 62 is a graph showing a dose-response curve of SS8225-07 after oral administration

FIG. 63 is a graph showing the time course of the antinociceptive effect in the til pressure test after subcutaneous administration of morphine. FIG. 64 is a graph showing a dose-response curve of morphine after subcutaneous administration

 FIG. 65 is a graph showing the time course of antinociception in the Tille Pressure test after oral administration of morphine.

 FIG. 66 is a graph showing a dose-response curve of morphine after oral administration.

FIG. 67 is a graph showing the relationship between oral dose and AUC.

FIG. 68 is a graph showing the relationship between subcutaneous dose and AUC.

 FIG. 69 is a graph showing the change over time in the antinociceptive effect of oral morphine administration in a knee osteoarthritis model.

 FIG. 70 is a graph showing the time course of the antinociceptive effect of oxycodone administered orally in a knee osteoarthritis model.

 FIG. 71 is a graph showing the time course of the antinociceptive effect of SS8225-04 administered orally in a knee osteoarthritis model.

 FIG. 72 is a graph showing the change over time in the antinociceptive effect of SS8225-07 administered orally in a knee osteoarthritis model.

 FIG. 73 is a graph showing the relationship between morphine dose and AUC.

FIG. 74 is a graph showing the relationship between oxycodone dosage and AUC.

FIG. 75 is a graph showing the relationship between the dose of SS8225-04 and AUC.

FIG. 76 is a graph showing the relationship between the dose of SS8225-07 and AUC.

[77] This is a graph showing the relationship between the dose of each drug and AUS in the knee osteoarthritis model.

[78] This is a graph showing the relationship between the dose of each drug and% MPU in the knee osteoarthritis model.

 FIG. 79 is a graph showing the change over time after administration of the stimulation threshold (gram weight) for oral administration of morphine in a rheumatoid arthritis pain model (results on the CFA non-administered side foot).

 FIG. 80 is a graph showing the change over time after administration of the stimulation threshold (gram weight) of oral administration of morphine in a rheumatoid arthritis pain model (results on the CFA-administered foot).

FIG. 81 is a graph showing the changes over time after administration of the stimulation threshold (gram weight) when SS8225-04 was administered orally in a rheumatoid arthritis pain model (results on the CFA non-administered side foot). FIG. 82 is a graph showing changes over time after administration of the stimulation threshold (gram weight) of SS8225-04 administered orally in a rheumatoid arthritis pain model (results on the CFA-administered foot).

 FIG. 83 is a graph showing the relationship between oral dose and AUC.

 FIG. 84 is a graph showing the relationship between oral dose and unit time AUC.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0051] The compound according to the present invention or a pharmaceutically acceptable salt thereof is a peptide derivative compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as described above.

[0052] R ¹ N = C (R ² ) -AA'-AA ^ AA ^ AA ^ Y

 (1)

In chemical formula (1), 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.

[0054] Y is represented by the following chemical formula (2). In the chemical formula (2), R ³ and R ⁴ are each independently a force selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, or R ³ and R ⁴ R ⁴ is a 5-membered nitrogen-containing heterocyclic group or a 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded.

[0055] -N (R ³ ) R ⁴

 (2)

[0056] AA ¹ is an a amino acid residue represented by the following chemical formula (3).

[0057] [Chemical 5]

 (3)

In the chemical formula (3), R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, A primary alkyl group and a halogenated lower alkyl group are one selected.

[0059] In the chemical formula (3), X is a hydrogen atom, a halogen atom, a hydroxyl group, a group represented by the following chemical formula (4), and a basic force represented by the chemical formula (5). Is one.

[0060] -O-CO-R ⁷

 (Four)

[0061] -O-CO-O -R ⁸

 (Five)

[0062] In the chemical formulas (4) and (5), R ⁷ and R ⁸ are each independently a C1 alkyl group.

 1-16

 , Hydroxy C alkyl group, amino C alkyl group, (mono lower alkyl) amino C

 1-16 1-16 1-alkyl group, (di-lower alkyl) amino C alkyl group, C cycloalkyl group, C

16 1-16 3-10

 A cycloalkyl-substituted lower alkyl group, a c alkenyl group, a c alkynyl group,

3- 10 2- 16 2- 16

 Aryl group, heterocyclic group, and aryl group-substituted lower alkyl group.

[0063] AA ² is a D a amino acid residue represented by the following chemical formula (6).

 [0064] [Chemical 6]

_

 (6)

In the chemical formula (6), R ⁹ is an amino group, (mono-lower alkyl) amino group, lower acylamino group, gua-dino group, lower alkyl group-substituted gua-dino group, imino lower alkyl group. , Ureido group, lower alkyl group-substituted ureido group, lower alkylthio group, lower alkylsulfuryl group, lower alkylsulfonyl group, lower acyl group, and hydroxy lower alkyl group. It is an integer of ~ 4.

[0066] AA ³ is an unsubstituted phalalanin residue, a substituted phalalanin residue, an unsubstituted D It is one of the choices of keralanine residues and substituted D phalalanine residues.

[0067] AA ⁴ is an a amino acid residue represented by the following chemical formula (7), or a chemical formula (8

) Is a β amino acid residue.

[0068] N (R ¹⁰ ) CH (R ¹ CO—

 (7)

[0069]-N (R ¹⁰ ) — CH (R ¹ CH (R ¹² ) — CO—

 (8)

In the chemical formulas (7) and (8), R ^1C> and R ¹² are each independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, or an aryl substituted lower alkyl. One of the basic forces is selected, and R ¹¹ is a hydrogen atom or an amino group represented by the following chemical formula (9).

[0071] -ZN (R ¹³ ) -R ¹⁴

 (9)

In the chemical formula (9), Z is one selected from a lower alkylene group, a lower alkylene group, and a lower alkylene group, and R ¹³ and R ¹⁴ are each independently Or a hydrogen atom, a lower alkyl group, an aryl group, or an aryl substituted substituted lower alkyl group, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are bonded. It is a membered nitrogen-containing heterocyclic group or a six-membered nitrogen-containing heterocyclic group.

[0073] The compound of the present invention has an unsubstituted or substituted lower alkyl group at the amino terminal, that is, a group represented by "R ¹ N = C (R ² )" in the formula (1), Further, it is characterized in that it has an unsubstituted or substituted amide group at the carboxyl terminal, that is, a group represented by the formula (2) “—N (R ³ ) R ⁴ ”. The fact that a peptide derivative having such a functional group introduced has strong and long-lasting anti-nociceptive and analgesic effects when administered orally and subcutaneously has a power that could not be predicted by the prior art.

In chemical formula (1), a preferred example of R ¹ is a hydrogen atom, but the present invention is not limited thereto. A preferred example of R ² is a lower alkyl group, but the present invention is not limited thereto. A more preferred example of R ² is a methyl group or an ethyl group.

[0075] In the chemical formula (2) representing Y, R ³ and R ⁴ are preferred, for example, both are hydrogen atoms. Or a preferred example of Y is NH or NH—CH, one of which is a hydrogen atom and the other is a katyl group.

 twenty three

 It is not limited.

[0076] The substitution position on the benzene ring of R ⁵ and R ⁶ in the chemical formula (3) representing AA ¹ and R ¹⁵ and R ¹⁶ in the chemical formula (10) or (11) is not particularly limited.

[0077] In the chemical formula (1), preferred examples of AA ¹ include tyrosine residues, 2, 6 dimethyl-tyrosine residues, o acyl-tyrosine residues, o alkoxy carbo-routyrosine residues, o phenoxycarbo-leutyrosine residues, o Powers including acetylyl tyrosine residue, 2, 6 dimethylroof-lualanine residue, etc. The present invention is not limited to these.

In the chemical formula (1), preferable examples of AA ² include D-arginine residue, D-methionine sulfoxide residue, D—N ⁵ acetylortin residue, and D-5-oxonorpoxine residue. Group, D citrulline residue, D-5-hydroxynorleucine residue and the like, but the present invention is not limited thereto.

[0079] AA ³ may be an α-amino acid residue or a D-a amino acid residue represented by the following chemical formula (10) or (11).

 [0080] [Chemical 7]

[0081] [8]

In chemical formulas (10) and (11), R ^{1 &} and R ^lb are each independently one selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a halogenated lower alkyl group. is there.

[0083] In the chemical formula (1), preferable examples of AA ³ include ferrolanine residue, p-fluoro-lauranin residue and o-trifluoromethylphenyl-lanalanin residue, 2, 6-dimethylsulfone. 1S The present invention is not limited to these, including -lualanine residue, D-ferroalanine residue, Dp-fluorophenylalanine residue, Do-trifluoromethylphenolan residue.

In chemical formula (1), preferred examples of AA ⁴ include N-methyllysine residue, N-methyl β-alanine residue and the like. The present invention is not limited to these.

 [0085] In the present specification, analgesic activity and antinociceptive activity are used as terms that mean an action to stop pain. The difference between the two is that the former is mainly used for humans, whereas the latter is mainly used for experimental animals. In this specification, the effects of the present invention are used interchangeably. It is done.

 [0086] For the amino acids and their residues described herein, when the D-form and L are present, especially when not indicated as D-, the amino acid and its residues are L-amino acids. Means.

[0087] In the terms of "lower alkyl", "lower alkoxyl", "lower acyl" and "lower alkylene" described herein, "lower" means 1, 2, 3, 4, 5 or 6 Means containing carbon atoms. In the terms of “lower alkenyl”, “lower alkynyl”, “lower alkylene” and “lower alkylene” described herein, “lower” means 2, 3, 4, 5 or Means containing 6 carbon atoms.

[0088] As used herein, "alkyl", "alkoxyl", "acyl", "alkylene", "alkenyl", "alkyl", "alkylene" and "alkylene" Either a straight-chain isomer or a branched-chain isomer may be used. The branched isomer may be either a branched isomer containing a secondary carbon or a branched isomer containing a tertiary carbon.

 [0089] Preferred examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and a neopentyl group. , N-hexyl group and the like, but are not limited to these examples. In addition, “C alkyl group”, “hydroxy C alkyl group”, “amino C

 1—16 1—16 1—16 alkyl group ”,“ (mono-lower alkyl) amino C alkyl group ”,“ (di-lower alkyl) amino ”

 1-16

 Preferred examples of the “c alkyl group” in the “C alkyl group” and the like

1-16 1-16

 In addition to preferred examples of the alkyl group, linear or branched heptyl group, octyl group, nor group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group Forces that are not limited to these examples, etc. C alkyl group

 1-16

 For example, linear or branched C alkyl groups are preferred. C alkyl groups are more preferred.

 6- 12 8- 10

 Good. Particularly preferred are C and C linear or branched alkyl groups.

 8 10

 [0090] As used herein, "lower alkoxyl group" refers to an alkoxyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Preferable examples of the lower alkoxyl group include a methoxy group and an ethoxy group, but are not limited to these examples.

 [0091] A "C cycloalkyl group" and a "C cycloalkyl-substituted lower group" described in the present specification

 3- 10 3- 10

 The “C cycloalkyl group” in the “alkyl group” means that the number of carbon atoms is 3, 4, 5, 6

 3- 10

 , 7, 8, 9 or 10 cycloalkyl groups. Preferred of the C cycloalkyl group

 3- 10

 Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group, and the like, but are not limited to these examples. As described in this specification,

“C cycloalkyl group” in “C cycloalkyl-substituted lower alkyl group” is low

3- 10 3- 10

Any carbon atom of the lower alkyl group which may be substituted with any carbon atom of the secondary alkyl group may be substituted. For example 1 to 4, more preferably 1 2 and particularly preferably 1 C cycloalkyl group is placed on the carbon atom at any position.

 3-10

 May be replaced.

 [0092] The "C alkyl group" and the "C alkyl group" described in the present specification are respectively

 2—16 2—16

 Any of the alkenyl and alkenyl groups having 2 to 16 carbon atoms, which are linear or branched. C alkenyl group and C alkke

 2-16 2-16

The position and number of double bonds and triple bonds contained in each of the -alkyl groups are not particularly limited. V, The preferred alkyl group is, for example, a vinyl group, ie, an ether group, 2

 2-16

 Forces such as propeninole group, cis-l propeninole group, trans-1-propeninole group, etc. are not limited to these examples. Preferred examples of the C alkynyl group include

 2-16

 Forces with groups, 2-propyl groups, etc. The present invention is not limited to these examples.

[0093] The "heterocyclic group" described in the present specification is a saturated, unsaturated or unsaturated group composed of at least one kind of atom and carbon atom, which is also selected from a group force consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Refers to a partially unsaturated cyclic compound. Preferable examples of the heterocyclic group include, but are not limited to, a pyridyl group, a furanyl group, and a thionyl group. R ³ and R ^{4 in the} chemical formula (2) and R ¹³ and R ¹⁴ in the chemical formula (9) represent a 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. May represent. The nitrogen-containing heterocyclic group may be, for example, a 5- or 6-membered saturated or partially unsaturated heterocyclic group containing 1 or 2 or more nitrogen atoms as a ring reforming atom. Preferable examples of the nitrogen-containing heterocyclic group include pyrrolidino group, piperidino group, 3,4-dehydropyrrolidino group, pyridio group and the like. The present invention is not limited to these examples.

The “aryl group” and the “aryl group” in the “aryl substituted lower alkyl group” described herein refer to an aromatic substituent having one or more ring forces. Preferable examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, and the like, but are not limited to these examples. The “aryl group” in the “aryl substituted lower alkyl group” described herein may be substituted with any carbon atom of the lower alkyl group as V, and any number of carbon atoms among the carbon atoms of the lower alkyl group. Replace it with! / !. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 aryl group may be substituted with a carbon atom at any position. The aryl substituted lower alkyl group Preferable examples include benzyl group and phenethyl group, but are not limited to these examples.

 [0095] The "lower acyl group" described in the present specification and the "lower acyl group" in the "lower acylamino group" are both an 1, 2, 3, 4, 5 or 6 carbon atom acyl group. That is, an alkanoyl group. Preferable examples of the lower acyl group include a formyl group and a acetyl group, but are not limited to these examples. The “lower acyl group” in the “lower acyl acyl group” described in the basic specification replaces one or both of the hydrogen atoms of the amino group. Preferable examples of the lower acylamino group include a monoacetylamino group, a diacetylamino group, and the like, but are not limited to these examples.

 [0096] The "no, rogen" described in the present specification may be a deviation of fluorine, chlorine, bromine or iodine. There are no particular restrictions on the position, number, and type of halogen atoms that are substituted for the “halogen-lower alkyl group” described in the present specification, and there is a shift from monohalogenated lower alkyl groups to perhalogenated lower alkyl groups. Is available. When 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, and a 2,2,2-trifluoroethyl group. The present invention is not limited to these examples.

 [0097] "Hydroxy lower alkyl group" or "hydroxy C alkyl group" described in the present specification

 1-16

 The “hydroxyl group” in can be substituted with any number of carbon atoms of the alkyl group which may be substituted with any carbon atom of the alkyl group. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 hydroxyl group may be substituted with a carbon atom at any position. Preferred examples of the “hydroxy lower alkyl group” and the “hydroxy C alkyl group” include a hydroxymethyl group, 2-hydride

 1-16

 A force S with a mouth quichetyl group, etc., is not limited to these examples.

[0098] The "amino group" in the "amino C alkyl group" described in the present specification is C alkyl.

1-16 1-16 Any number of carbon atoms of the alkyl group which may be substituted with any carbon atom of the group may be substituted. For example, 1 to 4, more preferably 1 to 2, particularly preferably 1 amino group may be substituted with a carbon atom at any position. The Preferred examples of the “amino C alkyl group” include an aminomethyl group, 2-amino group, and the like.

 1-16

 Although there are til groups and the like, it is not limited to these examples.

[0099] The "(mono lower alkyl) amino group" and the "(mono lower alkyl) amino group" in the "(mono lower alkyl) amino C alkyl group" described herein are both the number of carbon atoms.

-16

 Is one in which 1, 2, 3, 4, 5 or 6 alkyl groups replace one hydrogen atom of an amino group. Preferred examples of the “(mono lower alkyl) amino group” described herein and the “(mono lower alkyl) amino group” in the “(mono lower alkyl) amino C alkyl group” include,

1-16

 Examples thereof include, but are not limited to, a methylamino group and an ethylamino group. “(Dilower alkyl) amino” in the “(Dilower alkyl) amino C alkyl group” described in this specification

 1-16

 “Group” refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms substituted for each of two hydrogen atoms of an amino group. The lower alkyl group for substituting each hydrogen atom may be the same lower alkyl group or different lower alkyl groups. Examples of the (di-lower alkyl) amino group include, but are not limited to, a dimethylamino group and a jetylamino group. As used herein, “(mono-lower alkyl) amino C alkyl group” means that the (mono-lower alkyl) amino group is a C alkyl group.

1-16 1-16 This represents that the amino group which may be substituted on any of the elementary atoms is further substituted with one lower alkyl group. Preferred of the (mono-lower alkyl) amino C alkyl group ヽ

 1-16

 Examples include 3- (methylamino) -n-propyl group and 2- (ethylamino) -n-pentyl group, but are not limited to these examples. The “(di-lower alkyl) amino C alkyl group” described in the present specification refers to a carbon atom in which the (di-lower alkyl) amino group is a C alkyl group.

1-16 1-16

 This means that the amino group which may be substituted anywhere on the elementary atom is further substituted with two lower alkyl groups. Preferred examples of the (di-lower alkyl) amino C alkyl group, eg

 1-16

 Examples include 2- (dimethylamino) ethyl group and 2- (jetylamino) ethyl group, but are not limited to these examples.

[0100] In the compound of the present invention, when R ¹ is a hydrogen atom, R ² carbyl group and Y is 1 NH in the chemical formula (1), ¹ -iminoethyl 1 AA ¹ — AA ² — AA ³ — AA ⁴ — amide or 1

 2

—Iminoethyl 1 AA ¹ — AA ² — AA ³ — AA ⁴ — Expressed as NH. The compounds of the present invention

 2

In Formula (1), when R ¹ and R ² are both hydrogen atoms and Y is —NH, Methyl ^{- AA 2 - AA 3 - AA} 4 - amide or Iminomechiru - AA ² - AA ³ - represented as AA ⁴ -NH. In the compound of the present invention, R ¹ is a hydrogen atom in the chemical formula (1).

 2

When R ² is a methyl group and Y is one NH—CH, 1-iminoethyl one AA ¹ — AA ²

 Three

-AA ³ -AA ⁴ -methylamide or 1-iminoethyl AA ¹ -AA ² -AA ³ -AA ⁴ -NH -CH In the compound of the present invention, R ¹ and R ² are both hydrogen in the chemical formula (1)

Three

When the atom is Y and NH is CH—iminomethyl- AA— AA ² — AA ³ — AA ⁴ —

 Three

Methylamide or iminomethyl- AA ¹ — AA ² — AA ³ — AA ⁴ — NH— CH Book

 Three

In the specification, when the leftmost end of the structure of the peptide derivative is not displayed as ¾ = ² )-"," iminomethyl "or" 1-iminoethyl- ", the amino group of the amino terminal amino acid is not substituted. It shows that there is. Further, in the present specification, when “one OH” is described at the carboxyl terminus of the peptide derivative, it indicates that the carboxyl group of the amino acid at the carboxyl terminus is unsubstituted.

 [0101] In the present specification, the term "amino acid residue" is used in the ordinary sense in the field of peptide science, and more specifically, an amino group in the α-position in an α-amino acid and It means the remaining structure obtained by removing a hydrogen atom and a hydroxyl group from a carboxyl group or an amino group and a force lpoxyl group in a β-position in a β-amino acid, respectively. The notation of amino acid residues is described in the Biochemical Dictionary (3rd edition, Tokyo Kagaku Dojin, published on October 8, 1998), WIPO Standard ST. 25, and “Base Sequence or According to the “Guidelines for the creation of specifications including amino acid sequences”. If it contains D amino acid residues, this is indicated. That is, in the chemical formula (1), when the i-th amino acid residue represented as “one AAi one” (i is an integer of 1 to 4) is, for example, a tyrosine residue, “one [Tyr] —”, D —In the case of an arginine residue, in the case of a force-modified amino acid residue represented by an abbreviation by three letters, such as “one [D—Arg] —”, in the case of a 2, 6 dimethyl-tyrosine residue, “One [2, 6 dimethyl-Tyr] —”, N-methyllysine residue, “One [N—MeLys] —”, N-methyl-j8-alanine residue, “One [N—Me j8 Ala ] — ”And D-methionine sulfoxide residues are represented as“ one [D Met (O)] ”, respectively.

[0102] The N-methyllysine residue or N-MeLys in the present specification is represented by the following chemical formula (12). It has the structure represented.

 [Chemical 9]

 (1 2)

[0104] The N-methyl-13-alanine residue or N-Mej8Ala in the present invention has a structure represented by the following chemical formula (13).

[0105] [Chemical 10]

 ( 13)

[0106] The D-methionine sulfoxide residue or D-Met (O) in the present invention has a structure represented by the following chemical formula (14).

[0107] [Chemical 11]

( 14) In the compound of the present invention, the amino terminal may be a 1-iminoethyl group or an iminopropyl group. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is a hydrogen atom, R ² is a methyl group or an ethyl group, and R ³ and R ⁴ forces in the chemical formula (2) are independently hydrogenated. R ³ and R ⁴ are selected from the group consisting of atoms, hydroxyl groups, lower alkyl groups and lower alkoxyl groups, or R ³ and R ⁴ are 5- or 6-membered nitrogen-containing heterocycles together with the nitrogen atom to which they are attached. R ⁵ and R ⁶ in the chemical formula (3) are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkyl group, and a no-rogenated lower alkyl group. X in 3) is selected as a hydrogen atom, a halogen atom and a hydroxyl group, and a group force that is powerful with chemical formulas (4) and (5), and R ⁷ or R ⁸ force in chemical formula (4) or (5), respectively. Independently, C alkyl group, hydroxy

 1-16

 C alkyl group, amino C alkyl group, (mono-lower alkyl) amino C alkyl group

1-16 1-16 1-16 group, (di-lower alkyl) amino C alkyl group, C cycloalkyl group, C cyclo

 1-16 3-10 3-10 Alkyl-substituted lower alkyl group, C alkenyl group, C alkynyl group, aryl

 2- 16 2- 16

R ⁹ in the chemical formula (6) is selected from an amino group, a (mono-lower alkyl) amino group, a lower acylamino group, a gua- From a dino group, a lower alkyl group-substituted gua-dino 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 Group power is selected, n in chemical formula (6) is an integer power of 1 to 4, and AA ³ in chemical formula (1) is an unsubstituted or substituted phenylalanine residue, unsubstituted or substituted D— two Ruaranin is at or residue, the R ^1C> and R ¹² force their respective independent in the chemical formula (7) and (8), a hydrogen atom, a lower alkyl group, lower alkenyl group, Grade alkynyl group, C

 6 Allele group and aryl-substituted alkyl group power is selected and combined.

In formulas (7) and (8), R ¹¹ is selected from a hydrogen atom and a group force that is powerful with chemical formula (9), and Z in chemical formula (9) is a lower alkylene group, lower alkene group, and lower group. Alkylene group power is selected and R ¹³ and R ¹⁴ in chemical formula (9) are independently selected as hydrogen atom, lower alkyl group, aryl group and aryl group substituted lower alkyl group power. Force, or R ¹³ and R ¹⁴ are combined It may be a compound represented by the chemical formula (1), which represents a 5-membered or 6-membered nitrogen-containing heterocyclic group together with a nitrogen atom. The present invention may provide these compounds and their pharmaceutically acceptable salts.

In the compound of the present invention, the carboxyl terminal may be an amide group or a methylamide group. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from a group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and R ² in the chemical formula (1) is , Lower alkyl group force group force selected, R ³ and R ⁴ in chemical formula (2) are both hydrogen atoms, one is a hydrogen atom and the other is a cation group, and X in chemical formula (3) Are selected from hydrogen atoms, halogen atoms, and hydroxyl groups, and group forces that have the same forces as chemical formulas (4) and (5), and R ⁵ and R ⁶ in chemical formula (3) are independently hydrogen atoms, halogen atoms, , Lower alkyl group and halogenated lower alkyl group force are selected, and R ⁷ or R ⁸ force in chemical formula (4) or (5) is independently selected from C alkyl group, hydroxy C alkyl group, amino C alkyl group.

 1-16 1-16 1-16 group, (mono-lower alkyl) amino C alkyl group, (di-lower alkyl) amino C alkyl

 1-16 1-16 alkyl group, c cycloalkyl group, C cycloalkyl-substituted lower alkyl group, C

 3- 10 3- 10 2-1 Alkenyl, C alkynyl, aryl, substituted aryl alkyl and

6 2-16

Heterocyclic group power Group power is selected, and R ⁹ in chemical formula (6) is an amino group, (mono lower alkyl) amino group, lower acylamino group, gua-dino group, lower alkyl group-substituted gua-dino group, imino group. 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 are selected from a group of chemical formulas In 6), n is an integer power of 1 to 4, and AA ³ in formula (1) is an unsubstituted or substituted phenylalanine residue, an unsubstituted or substituted D-phenylalanine residue. and R ^1C> and R ¹² force each independently in the chemical formula (7) and (8), a hydrogen atom, a lower alkyl group, a lower Aruke - group, lower alkyl groups, C Ariru group and § Lumpur substituted lower

 6-10

Alkyl group force Group force is selected, R ¹¹ in chemical formulas (7) and (8) is selected as a group force consisting of a hydrogen atom and chemical formula (9), and Z in chemical formula (9) is a low-grade alkylene From the group consisting of a group, a lower alkylene group and a lower alkylene group R ^ld and R ¹⁴ in the chemical formula (9) are each independently selected from the group forces of hydrogen atom, lower alkyl group, aryl group, and aryl substituted lower alkyl group, or R ¹³ and R ^{14 14} may be a compound represented by the chemical formula (1), which represents a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. The present invention may provide these compounds and their pharmaceutically acceptable salts. In the compound of the present invention, X in the chemical formula (3) may be a hydroxyl group. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and the R in the chemical formula (1) is selected. ² force Group force that also has a lower alkyl group force is selected, and R ⁴ in chemical formula (2) is independently a group force consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group. R ³ and R ⁴ are 5-membered or 6-membered nitrogen-containing heterocyclic groups together with the nitrogen atom to which they are bonded, are X-force hydroxyl groups in the chemical formula (3), and R in the chemical formula (3). ⁵ and R ⁶ forces respectively independent a hydrogen atom, a halogen atom, is selected a lower alkyl group and a Harogeni匕低loweralkyl group or Ranaru groups force, is R ⁹ in the chemical formula (6), Ami Group, (mono-lower alkyl) amino group, lower acylamino group, gua-dino group, lower alkyl group-substituted gua-dino group, imino lower alkyl group, ureido group, lower alkyl group-substituted ureido group, lower alkylthio group, lower group Alkylsulfinyl group, lower alkylsulfonyl group, lower acyl group and hydroxy lower alkyl group group power is selected, n in chemical formula (6) is selected from an integer of 1 to 4, and AA ³ in chemical formula (1) is non- R ^1G and R ¹² forces in chemical formulas (7) and (8) are each independently a hydrogen atom, lower alkyl, substituted or substituted phenylalanine residue, unsubstituted or substituted D-phenolanine residue Group, lower alkenyl group, lower alkynyl group, C aryl group and aryl substituted substituted alkyl group

 6-10

The group force is selected, and R ¹¹ in the chemical formulas (7) and (8) is selected from the group consisting of a hydrogen atom and the chemical formula (9), and Z in the chemical formula (9) is a lower alkylene group, Alkellene group and lower alkylene group force group force selected, R ¹³ and R ¹⁴ forces in formula (9), each independently a hydrogen atom, lower alkyl group, aryl group, and aryl substituted lower alkyl group force Group power to be selected Power is , R ¹³ and R ¹⁴ may be a compound represented by the chemical formula (1), which represents a 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. The present invention may provide these compounds and pharmaceutically acceptable salts thereof.

In the compound of the present invention, X in the chemical formula (3) may be a hydrogen atom or a halogen atom. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, and in the chemical formula (1) R ² is selected as a group force consisting of lower alkyl group force, and R ³ and R ⁴ forces in chemical formula (2) are each independently selected group force consisting of hydrogen atom, hydroxyl group, lower alkyl group and lower alkoxyl group. Or R ³ and R ⁴ are a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, and X in chemical formula (3) is a hydrogen atom or a halogen atom And R ⁶ in chemical formula (3) are independently selected from the group forces of hydrogen atom, halogen atom, lower alkyl group and halogenated lower alkyl group, and R in chemical formula (6) ⁹ is an amino group, (mono-lower alkyl) amino group, lower acylamino group, gua-dino group, lower alkyl group-substituted gua-dino group, imino lower alkyl group, ureido group, lower alkyl group-substituted urea group, lower An alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group and a hydroxy lower alkyl group are selected, and n in the chemical formula (6) is selected as an integer force of 1 to 4, AA ³ in the chemical formula (1) is an unsubstituted or substituted phalalanin residue, an unsubstituted or substituted D-ferroalanine residue, and R ^1C> in the chemical formulas (7) and (8) and R ¹² each independently represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a C aryl group or an aryl group.

 6-10

The group force of the lower alkyl group is selected and R ¹¹ in the chemical formulas (7) and (8) is selected as the hydrogen atom and the group power of the chemical formula (9), and Z in the chemical formula (9) is R ¹³ and R ¹⁴ in formula (9) are each independently selected from the group consisting of a hydrogen atom, a lower alkyl group, an aryl group, a lower alkylene group, a lower alkylene group, and a lower alkylene group. Group and aryl substituted lower alkyl group forces group force selected, or do R ¹³ and R ¹⁴ represent a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached? The compound represented by the chemical formula (1) There are cases. The present invention may provide these compounds and their pharmaceutically acceptable salts.

In the compound of the present invention, AA ¹ in the chemical formula (1) may be a tyrosine residue or a 2,6-dimethyl-tyrosine residue. That is, in the compound of the present invention, R 1 in the chemical formula (1) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and R ² in the chemical formula (1) is a lower alkyl group. Force selected from the group of basic forces, and the power of R ³ and R ⁴ in formula (2), each independently selected from the group of hydrogen atoms, hydroxy groups, lower alkyl groups and lower alkoxyl groups. Alternatively, R ³ and R ⁴ are 5-membered or 6-membered nitrogen-containing heterocyclic groups together with the nitrogen atom to which they are attached, and AA ¹ in formula (1) is a tyrosine residue or 2, 6— a dimethyl Chiru tyrosine residue, R ⁹ in the chemical formula (6) is an amino group, (mono-lower alkyl) amino group, a lower Ashiruamino group, guaiacolsulfonate - Jinomoto, lower alkyl group substituted guaiacolsulfonate - Jinomoto, Imi Roh low A group force including an 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 is also selected, and n in the chemical formula (6) is An integer force of 1 to 4 is selected, and AA ³ in the chemical formula (1) is an unsubstituted or substituted fulleran residue or an unsubstituted or substituted D-furanlanin residue, and has the chemical formula (7) And R ^1G and R ¹² forces in (8) each independently from a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a C aryl group and an aryl substituted lower alkyl group.

 6-10

The group force is selected, and R ¹¹ in the chemical formulas (7) and (8) is selected from the group consisting of a hydrogen atom and the chemical formula (9), and Z in the chemical formula (9) is a lower alkylene group, Alkellene group and lower alkylene group force group force selected, R ¹³ and R ¹⁴ forces in formula (9), each independently a hydrogen atom, lower alkyl group, aryl group, and aryl substituted lower alkyl group force Group force is selected Force ヽ is the chemical formula (1) in which R ¹³ and R ¹⁴ represent a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. In some cases. The present invention may provide these compounds and pharmaceutically acceptable salts thereof.

[0113] In the compound of the present invention, AA ¹ in the chemical formula (1) is an o-acyl-tyrosine residue, It may be a lucoxycarbo-leutyrosine residue, an O-phenoxycarbo-tyrosine residue, an o-acetylyltyrosine residue, or a 2,6-dimethyl-feruylalanine residue. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and R ² in the chemical formula (1) is selected. Is selected as a group force consisting of a lower alkyl group, and R ³ and R ⁴ in the chemical formula (2) are each independently selected as a group force consisting of 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 together with the nitrogen atom to which they are attached, and AA ¹ in chemical formula (1) is o-acyl-tyrosine Residue, o-alkoxycarbo-routine mouth-synthetic residue, o-phenoxycarbo-routyrosine residue, o-acetylyltyrosine residue, or 2,6-dimethyl-phenyluraranine residue, represented by chemical formula (6) R ⁹ is an amino group, (mono-lower alkyl) amino group, lower acylamino group, gua-dino group, lower alkyl group-substituted gua-dino group, imino lower alkyl group, ureido group, lower alkyl group-substituted ureido group, lower group An alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower acyl group and a hydroxy lower alkyl group are selected from the group group, and n in Formula (6) is selected from an integer force of 1 to 4, and a chemical formula AA ³ in (1) is an unsubstituted or substituted phenalanine residue, and is an unsubstituted or substituted D-ferroanine residue, and R ^1C> and R ¹² in chemical formulas (7) and (8) are Each independently a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, C aryl group and aryl

 6-10

Substituted lower alkyl group power Group power is selected, and R ¹¹ in chemical formulas (7) and (8) is selected as a group power consisting of a hydrogen atom and chemical formula (9), and Z in chemical formula (9) is lower alkylene Group, lower alkylene group, and lower alkylene group force are selected, and R ¹³ and R ¹⁴ in chemical formula (9) are each independently hydrogen atom, lower alkyl group, aryl group, and aryl substitution. A lower alkyl group or selected from the group R ¹³ and R ¹⁴ represent a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, It may be a compound represented by (1). The present invention may provide these compounds and pharmaceutically acceptable salts thereof. In the compound of the present invention, AA ² in the chemical formula (1) may be a D-arginine residue or a D-methionine sulfoxide residue. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group force consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and R ² in the chemical formula (1) is a lower alkyl group. Selected from a group of basic forces, and R ³ and R ⁴ in the chemical formula (2) are each independently selected from the group force consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, or R ³ and R ⁴ are 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, and X in the chemical formula (3) is a hydrogen atom, a halogen atom or a hydroxyl group. Or a functional group represented by chemical formula (4) or (5), wherein R ⁵ and R ⁶ in chemical formula (3) are each independently a hydrogen atom, a halogen atom, a lower alkyl group, or a halogenated lower group. Rukiru group strength Group power is selected, and R ⁷ and R ⁸ in chemical formulas (4) and (5) are each independently C alkyl group, hydroxy C alkyl

 1-16 1-16 group, amino C alkyl group, (mono-lower alkyl) amino C alkyl group, (di-lower alkyl group)

 1-16 1-16

Rualkyl) amino C alkyl group, C cycloalkyl group, C cycloalkyl substitution

 1-16 3-10 3-10

Lower alkyl group, C alkenyl group, C alkynyl group, aryl group, heterocyclic group

 2- 16 2- 16

And Aryl substituted lower alkyl group power is selected and AA ² in chemical formula (1) is a D-arginine residue or D-methionine sulfoxide residue, and AA ³ in chemical formula (1) is non- Substituted or substituted phenylalanine residue, unsubstituted or substituted D—phenylalanine residue, and R ^1C> and R ¹² forces in chemical formulas (7) and (8) are independently hydrogen atoms. , Lower alkyl group, lower alkenyl group, lower alkynyl group, C

 6 Allele group and aryl-substituted alkyl group power is selected and combined.

In Formulas (7) and (8), R ¹¹ is selected as a hydrogen atom and a group force that is powerful with Chemical Formula (9), and Z in Chemical Formula (9) is a lower alkylene group, lower alkene group, or lower group. Alkylene group power is selected and R ¹³ and R ¹⁴ in chemical formula (9) are independently selected as hydrogen atom, lower alkyl group, aryl group and aryl group substituted lower alkyl group power. In the case of the compound represented by the chemical formula (1), wherein R ¹³ and R ¹⁴ represent a 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. There is. The present invention relates to these compounds and their pharmaceutically acceptable. May provide acceptable salts.

In the compound of the present invention, AA ² in the chemical formula (1) is a D—N ⁵ -acetylol-tin residue, D-5-oxonorleucine residue, D citrulline residue or D-5-hydroxynorleucine residue. May be a group. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and R ² in the chemical formula (1) is a lower alkyl group. A group selected from the group consisting of a group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, each independently selected from the group consisting of R ³ and R ⁴ in formula (2). Or R ³ and R ⁴ are 5-membered or 6-membered nitrogen-containing heterocyclic groups together with the nitrogen atom to which they are bonded, and X in the chemical formula (3) is a hydrogen atom, halogen atom, An atom or a hydroxyl group, or a functional group represented by chemical formula (4) or (5), wherein R ⁵ and R ⁶ in chemical formula (3) are each independently a hydrogen atom, halogen atom, lower alkyl Group and halogen The selected group force becomes lower alkyl force, R ⁷ and R ⁸ in Formula (4) and (5) are each independently, C alkyl group, hydroxyalkyl C alkyl group, Amino C

 1— 16 1— 16

 Alkyl group, (mono-lower alkyl) amino C alkyl group, (di-lower alkyl) amino

1— 16 1— 16

C alkyl group, C cycloalkyl group, C cycloalkyl substituted lower alkyl

1— 16 3-10 3-10

Group, C alkyl group, C alkyl group, aryl group, heterocyclic group and aryl group

2- 16 2- 16

Substituted lower alkyl group power Group power is selected, and AA ² in chemical formula (1) is DN ⁵ acetyloltin residue, D- ^5- oxonorleucine residue, D citrulline residue or D 5 hydroxynorleucine residue AA ³ in the chemical formula (1) is an unsubstituted or substituted phalalanin residue, an unsubstituted or substituted D-ferroalanine residue, and R in the chemical formulas (7) and (8) ^1C> and R ¹² are each independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a C aryl group or an aryl group.

 6-10

The group force of the lower alkyl group is selected and R ¹¹ in the chemical formulas (7) and (8) is selected as the hydrogen atom and the group power of the chemical formula (9), and Z in the chemical formula (9) is R ¹³ and R ¹⁴ in formula (9) are each independently selected from the group consisting of a hydrogen atom, a lower alkyl group, an aryl group, a lower alkylene group, a lower alkylene group, and a lower alkylene group. Group and aryl substituted lower alkyl group The force selected, or R ¹³ and R ¹⁴ are represented by the chemical formula (1), which represents a 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. It may be a compound. The present invention may provide these compounds and their pharmaceutically acceptable salts.

In the compound of the present invention, AA ³ in the chemical formula (1) may be a phenylalanine residue. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, and in the chemical formula (1) R ² is selected as a group force consisting of lower alkyl group force, and R ³ and R ⁴ forces in chemical formula (2) are each independently selected group force consisting of hydrogen atom, hydroxyl group, lower alkyl group and lower alkoxyl group. Or R ³ and R ⁴ are a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, and X in chemical formula (3) is hydrogen, chlorine, fluorine and hydroxyl And a group consisting of the chemical formulas (4) and (5), and the R ⁵ and R ⁶ forces in the chemical formula (3) are each independently a hydrogen atom, a halogen atom, a lower alkyl group and a halogen atom.グ ル ー プ Group power consisting of lower alkyl groups is also selected, and R ⁷ and R ⁸ in chemical formulas (4) and (5) are independently C alkyl group, hydroxy C alkyl group, amino-C alkyl group, (moly

1-16 1-16 1-16

(Lower alkyl) amino C alkyl group, (dilower alkyl) amino C alkyl group,

 1-16 1-16

 C cycloalkyl group, C cycloalkyl-substituted lower alkyl group, C alkene

3- 10 3- 10 2-16 group, C alkyl group, aryl group, aryl substituted lower alkyl group and heterocyclic group

2- 16

R ⁹ in the chemical formula (6) is selected from the group consisting of an amino group, a (mono-lower alkyl) amino group, a lower acylamino group, a guazino group, a lower alkyl group-substituted guadino group, and an imino lower group. 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 power are selected, and n in the chemical formula (6) Is an integer force of 1 to 4, AA ³ in chemical formula (1) is a fluoranin residue, R ^1C> and R ¹² in chemical formulas (7) and (8) are each independently a hydrogen atom, Lower alkyl group, lower alkenyl group, lower alkynyl group, C aryl group and aryl substitution

 6-10

Lower alkyl group power Group power is selected, and R ¹¹ in chemical formulas (7) and (8) is , A hydrogen atom, and a group force having the chemical formula (9) are selected, and Z in the chemical formula (9) is selected from the group consisting of a lower alkylene group, a lower alkylene group, and a lower alkylene group, R ¹³ and R ¹⁴ in (9) are each independently selected from the group consisting of a hydrogen atom, a lower alkyl group, an aryl group and an aryl substituted lower alkyl group, or R ¹³ and R ¹⁴ are It may be a compound represented by the chemical formula (1), which represents a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to be bonded. The present invention may provide these compounds and their pharmaceutically acceptable salts.

The compound of the present invention comprises AA ³ in the chemical formula (1) ³ -fluoro-ferranin residue, o-trifluoromethyl furanine residue, 2,6-dimethyl furanalanine residue, D-faranine residue It may be a residue, a D—p-fluoroferroalanine residue or a D—o—trifluoromethylphenolan residue. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from a group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, and R ² in the chemical formula (1) is Selected from the group group consisting of a lower alkyl group and a group force consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group independently of each other in the R ³ and R ⁴ forces in the chemical formula (2). The selected force, or R ³ and R ⁴ are a 5- or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, and X in chemical formula (3) is hydrogen, chlorine , and fluorine and hydroxyl groups, the formula (4) and (5) and are grouped force selected consisting, R ⁵ and R ⁶ in the formula (3) are each independently a hydrogen atom, a halogen atom, a lower alkyl group and a halo Ni匕低loweralkyl group mosquitoゝRanaru Gurupukakara selected, Structural Formula (4) and R ⁷ and R ⁸ forces each independently in (5), C alkyl group, hydro

 1-16

Xyloxy alkyl group, amino C alkyl group, (mono-lower alkyl) amino C alkyl group

1-16 1-16 1-16 Kill group, (Dilower alkyl) amino C alkyl group, C cycloalkyl group, C

 1-16 3-10 3-10 Chloalkyl-substituted lower alkyl group, C alkenyl group, C alkynyl group, aryl

 2- 16 2- 16

A group selected from the group consisting of an alkyl group, an aryl substituted lower alkyl group and a heterocyclic group, wherein R ⁹ in the chemical formula (6) is an amino group, a (mono-lower alkyl) amino group, a lower acylamino group, a guazino Group, lower alkyl group-substituted gua-dino group, imino lower alkyl group, ureido Group, consisting of a group, a lower alkyl group-substituted ureido group, a lower alkylthio group, a lower alkylsulfuric group, a lower alkylsulfonyl group, a lower acyl group and a hydroxy lower alkyl group, and n in the chemical formula (6) is 1 to An integer force of 4 is selected, and AA ³ in Formula (1) is D-ferroalanine residue, p-fluoro-furanine residue, o-trifluoromethylphenol-alanine residue, D-p-fluorophe- A lulanin residue or a D-o-trifluoromethylphenyl-lanalanin residue, wherein R ^1G and R ¹² forces in chemical formulas (7) and (8) are each independently a hydrogen atom, a lower alkyl group, a lower alkene- Group, lower alkynyl group, C aryl group and aryl substituted lower alkyl group

 6-10

The group force is selected, and R ¹¹ in the chemical formulas (7) and (8) is selected from the group force consisting of a hydrogen atom and the chemical formula (9), and Z in the chemical formula (9) is a lower alkylene group, a lower alkenyl group. Len group and lower alkylene group force group force selected, R ¹³ and R ¹⁴ forces in formula (9), each independently a group consisting of hydrogen atom, lower alkyl group, aryl group, and aryl substituted lower alkyl group force Force Selected Force ヽ is represented by the chemical formula (1), wherein R ¹³ and R ¹⁴ represent a 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded. In some cases. The present invention may provide these compounds and pharmaceutically acceptable salts thereof.

In the compound of the present invention, AA ⁴ in the chemical formula (1) may be an N-methyllysine residue or an n-methyl-β-alanine residue. That is, in the compound of the present invention, R ¹ in the chemical formula (1) is selected from the group force consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, and R ² in the chemical formula (1) is a lower alkyl group. Selected from a group of basic forces, and R ³ and R ⁴ in the chemical formula (2) are each independently selected from the group force consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group and a lower alkoxyl group, or R ³ and R ⁴ are 5-membered or 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, and X in the chemical formula (3) is hydrogen, chlorine, fluorine and hydroxyl group. And the chemical group powers (4) and (5) are selected, and R ⁵ and R ⁶ in the chemical formula (3) are each independently a hydrogen atom, a halogen atom, a lower alkyl group, or a halogenated lower alkyl group. R ⁷ and R ⁸ in the chemical formulas (4) and (5) are each independently selected from the group consisting of a kill group, C alkyl group, hydroxy C alkyl Kill group, amino c alkyl group, (mono-lower alkyl) amino C alkyl group, (di-low

1-16 1-16

Secondary alkyl) amino C alkyl group, C cycloalkyl group, C cycloalkyl group

 1-16 3-10 3-10

Substituted lower alkyl group, C alkenyl group, C alkynyl group, aryl group, aryl

 2- 16 2- 16

Selected from the group consisting of alkyl group substituted lower alkyl group and heterocyclic group, R ⁹ force amino group, (mono-lower alkyl) amino group, lower acylamino group, gua-dino group, lower group in chemical formula (6) Group consisting of 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 In formula (6), n is an integer force of 1 to 4, and AA ³ in formula (1) is an unsubstituted or substituted furanine residue force, unsubstituted or substituted D-phenyl R ^1C> and R ¹² forces in chemical formulas (7) and (8) are each independently a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl Group, C

6-10 group and aryl substituted lower alkyl group group power is selected, and AA ⁴ in chemical formula (1) is N-methyllysine residue or N-methyl-1-β-alanine residue. ) In some cases. The present invention may provide these compounds and their pharmaceutically acceptable salts.

The compounds of the present invention is a compound represented by the general formula (1) is selected R ¹ forces a hydrogen atom in the formula (1), a hydroxyl group, a lower alkyl group and a lower alkoxyl group value becomes group, R ² in the chemical formula (1) is selected from the group consisting of lower alkyl group forces, and the R ³ and R ⁴ forces in the chemical formula (2) are both hydrogen atoms, one is a hydrogen atom and the other is an S methyl group, ΑΑ ¹ is a tyrosine residue, 2, 6-dimethyl-tyrosine residue, ο-acyl-tyrosine residue, ο-alkoxy carbo-routy tyrosine residue, ο-phenoxycarbo-routine tyrosine residue, ο-acetyl-tyrosine residue or 2, 6-dimethyl-phenolan residue, ΑΑ ² is D-methionine sulfoxide residue, D-arginine residue, D-citrulline residue, D- Ν ⁵ -acetyl-orthine residue, A D-5-Okisono Ruroishin residues or D-5-hydroxy-norleucine residue, alpha alpha ³ is Hue - Ruara nin residue, D- Hue - Ruaranin residues, .rho. Furuorofe - Ruaranin residues, D- ρ—Fluoropherulanin residue, ο—Trifluoromethylferrolanine residue or D—ο In some cases, it is a compound represented by the chemical formula (1), which is a trifluoromethylphenolanine residue, and AA ⁴ is an N-methyllysine residue or an N-methyl-β-alanine residue. The present invention may provide these compounds and their pharmaceutically acceptable salts.

[0120] Preferable examples of the compound of the present invention include 1 iminoethyl- [2, 6 dimethyl-Tyr]

 -[D-Arg]-[Phe] — [N—Me j8 Ala] —amide, 1—iminoethyl mono [Tyr] — [D—Arg] — [Phe] — [N—Me jS Ala] —amide, 1 —Iminoethyl— [2, 6 Dimethyl-Ty r]-[D— Met (O)]-[Phe] — [N—Me j8 Ala] —Amido, 1—Iminoethyl [Tyr] — [D— Met (O) ] — [Phe] — [N—Me jS Ala] —amide, 1-iminoethyl— [2, 6-dimethyl- Tyr]-[D— Met (O)]-[Phe]-[N— MeLys] —amide, 1-Iminoethyl [Tyr]-[D-Met (O)]-[Phe]-[N—MeLys] —Amido, 1-Iminoethyl— [Tyr]-[D— Met (O)]-[Phe] — [N—Me j8 Ala] -methylamide, 1-iminoethyl [Tyr]-[D-Met (O)]-[Phe]-[N-MeLys] -methylamide, but is not limited to these. The present invention may provide these compounds and pharmaceutically acceptable salts thereof.

 [0121] Preferable examples of the compound of the present invention include 1-iminoethyl- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe]-[N-Me, substituted with a carboxyl terminal force methylamide group. β Ala] —Methylamide, 1-Iminoethyl— [Tyr]-[D— Arg]-[Phe] — [N—Me j8 Ala] —Methylamide, 1 Iminoethyl- [2, 6-dimethyl-Tyr] — [D— Met ( O)] [Phe] [N—Me j8 Ala] methylamide and 1 iminoethyl- [2, 6-dimethyl-Tyr]-[D-Met (O)]-[Phe]-[N-MeLys] -methylamide However, it is not limited to these. The present invention may provide these compounds and their pharmaceutically acceptable salts.

[0122] Preferable examples of the compound of the present invention include iminopropyl- [2,6-dimethyl-Tyr]-[D-Arg]-[Phe [N-] substituted with 1-iminoethyl group minopropyl group at the amino terminal. Me j8 Ala] Amido, iminopropyl [Tyr] [D—Arg] — [Phe] [N— Me β Ala] —Amido, iminopropyl— [2, 6 Dimethyl- Tyr]-[D— Met (O)] — [Phe ] — [N—Me j8 Ala] —amide, iminopropyl mono [Tyr]-[D— Met (O)]-[Phe]-[N-Me β Ala] —amide, iminopropyl mono [2, 6 dimethyl mono Tyr ]-[D— Met ( O)] — [Phe]-[N-MeLys] —amide, iminopropyl [Tyr]-[D— Met (O)] — [Phe]-[N-MeLys] —amide, iminopropyl [Tyr]-[ D—Met (O)] — [Phe]-[N-Me β Ala] —Methylamide, iminopropyl— [Tyr] — [D—Met (O)] — [Phe] — [N-MeLys] —Methylamide, iminopropyl — [2, 6 Dimethyl-Tyr]-[D—A rg]-[Phe] — [N—Me j8 Ala] —Methylamide, iminopropyl [Tyr]-[D—Arg]-[Phe] — [N— Me j8 Ala] —Methylamide, iminopropyl— [2,6, —Dimethyl—Tyr]-[D-Met (O)]-[Phe]-[N—Me β Ala] —Methylamide and iminopropyl— [2, 6 Dimethyl Tyr]-[D- Met (O)]-[Phe]-[N-MeLys]-methylamide, but is not limited to these. The present invention may provide these compounds and their pharmaceutically acceptable salts.

 [0123] Preferable examples of the compound of the present invention include 1-minoethyl [2, 6 dimethyl-Tyr, wherein the amino terminal is substituted with 1 iminoethyl group or iminobutyl pill group, and the carboxyl terminal is substituted with ethylamide group. ]-[D—Arg]-[Phe] — [N—Me j8 Ala] —ethylamide, 1-iminoethyl— [Tyr]-[D-Arg]-[Phe] — [N—Me j8 Ala] — Tyramide, 1 iminoethyl- [2, 6 dimethyl-Tyr] — [D—Met (O)] — [Phe] [N—Me j8 Ala] Ethylamide, 1 iminoethyl- [Tyr] — [D— Met (O)] [P he ] — [N—Me j8 Ala] —Ethylamide, 1-Iminoethyl— [2, 6 Dimethyl-Tyr]-[D-Met (O)]-[Phe]-[N-MeLys] —Ethylamide, 1-Iminoethyl— [ [Ty r] [D-Met (O)]-[Phe] [N-MeLys] Ethylamide, iminopropyl [2, 6-dimethyl- Tyr]-[D-Arg]-[Phe] — [N—Me j8 Ala] — Ethylamide, iminopropyl — [ [Tyr]-[D-Arg]-[Phe] — [N—Me j8 Ala] —Ethylamide, iminop pill— [2, 6 Dimethyl— Tyr]-[D— Met (O)]-[Phe] — [ N—Me j8 Ala]-Ethylamide, Iminopropyl— [Tyr]-[D-Met (O)]-[Phe] — [N—Me j8 Ala] — Ethylamide, Iminopropyl— [2, 6 Dimethyl Tyr]-[D — Met (O)] — [Phe]-[N-MeLys] —Ethylamide and iminopropyl— [Tyr]-[D— Met (O)]-[Ph e] [N-MeLys] Ethylamide, It is not limited. The present invention may provide these compounds and pharmaceutically acceptable salts thereof.

[0124] As a preferred example of the compound of the present invention, the amino terminal is 1 iminoethyl group or iminob 1 Iminoethyl mono [2, 6 dimethyl- Tyr]-[D— Arg]-[Phe]-[N— Me j8 Ala]-Dimethyl substituted with a pill group at the mouth and substituted with a dimethylamide group at the carboxyl end Amido, 1-iminoethyl— [Tyr]-[D-Arg]-[Phe] — [N—Me j8 Ala] —Dimethylamide, 1 iminoethyl- [2, 6 dimethyl-Tyr] — [D— Met (O)] — [P he] [N—Me j8 Ala] -dimethylamide, 1 iminoethyl [Tyr] — [D— Met (O)] — [Phe] — [N—Me j8 Ala] —dimethylamide, 1 iminoethyl [2, 6 dimethyl- [Tyr] [D-Met (O)] [Phe] [N—MeLys] —Dimethylamide, 1 Iminoethyl-[Tyr]-[D-Met (O)]-[Phe]-[N—MeLys] —Dimethylamide , Iminopropyl— [2, 6 dimethyl—Tyr]-[D-Arg]-[Phe] — [N—Me j8 Ala] —dimethylamide, iminopropyl— [Tyr]-[D-Arg]-[Phe]- [N—Me β Ala] —dimethylamide, iminopropyl mono [ 2, 6 Dimethyl-Tyr]-[D—Met (O)] — [Phe]-[N—Me β Ala] -Dimethylamide, iminopropyl [Tyr] — [D—Met (0)] One [Phe] [N—Me β Ala] —Dimethylamide, Iminopropyl— [2, 6 Dimethyl-Tyr]-[D—Met (O)]-[Phe]-[N—MeLys] —Dimethylamide and Iminopropyl— [Tyr] — [D— Met ( O)] [Phe] [N-MeLys] -dimethylamide, but is not limited to these. The present invention may provide these compounds and their pharmaceutically acceptable salts.

[0125] The compounds of the present invention include all optically active isomers or racemates, diastereoisomers or any mixture thereof. In addition, preferable examples of the pharmaceutically acceptable salt of the compound of the present invention include acid addition salts such as hydrochloride, acetate, or paratoluenesulfonic acid, base addition such as ammonium salt and organic amine salt. Examples include, but are not limited to, salts, free hydrates, and any hydrates and solvates of peptide derivatives in salt form. The compounds of the present invention include compounds that are dimers or multimers of peptide derivatives represented by the general formula (1), and cyclic compounds in which the C-terminal and n-terminal of these peptide derivatives are bonded. There is a case. Here, it is considered that the compound of the present invention exerts analgesic action or anti-nociceptive action by acting on the nervous system ovoid receptor.

[0126] The present invention provides a pharmaceutical composition for use in the prevention and Z or treatment of pain, particularly pain. The present invention relates to the manufacture of a medicament for use in the prevention and Z or treatment of pain. Or a pharmaceutically acceptable salt thereof. The present invention provides a method for preventing and / or treating rash pain comprising the step of administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to an animal including a human.

 [0127] The pharmaceutical composition of the present invention contains at least one of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention may contain at least one compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. The compound of the present invention or a pharmaceutically acceptable salt thereof is included as an active ingredient. The pharmaceutical composition of the present invention can be used for the purpose of general pain prevention and Z or treatment, neuropathic pain prevention and Z or treatment, cancer pain prevention and Z or treatment, In addition to parenteral administration such as intravenous administration, subcutaneous administration, and rectal administration, application is possible by oral administration, transmucosal administration, or transdermal administration. Various dosage forms suitable for these administration routes are known to those skilled in the art, and those skilled in the art appropriately select a dosage form suitable for the desired dosage form, and, if necessary, one or more available in the art. Pharmaceutical preparations in the form of pharmaceutical compositions can be prepared using pharmaceutically acceptable carriers or pharmaceutical additives. For example, for transmucosal administration, intranasal administration agents such as nasal drops and intranasal sprays or oral administration agents such as sublingual agents are suitable. As an active ingredient of the medicament of the present invention, a hydrate or solvate of the compound of the present invention 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 LOmg, and in the case of oral administration, the single dose is 1 to LOOmg. can do. Alternatively, about 0.1 to 1,000 mg, preferably about 1 to 300 mg per day for an adult can be administered. The dose can be set in association with parameters such as the patient's weight, age, genotype, and medical condition.

[0128] The pharmaceutical composition of the present invention comprises tablets, granules (fine granules), capsules, injections (intravenous infusions), patches, suppositories, suspensions and emulsions, pastes, ointments, creams. , Lotions, nasal drops, eye drops, and the like, but are not limited thereto. The pharmaceutical composition of the present invention may be gradually released for the purpose of maintaining the duration for a long time. [0129] The pharmaceutically acceptable carrier or formulation additive contained in the pharmaceutical composition of the present invention includes, but is not limited to, a stabilizer, a surfactant, a solubilizer, an adsorbent and the like. Absent. The pharmaceutically acceptable carrier or pharmaceutical additive contained in the pharmaceutical composition of the present invention is selected according to the dosage form of the pharmaceutical composition of the present invention listed above.

 [0130] The production method of the compound of the present invention is not particularly limited, but the compound can be synthesized by a solid phase method and a liquid phase method usually used for usual peptide synthesis. In the examples of the present specification, the production methods of the representative compounds of the compounds of the present invention are explained specifically and in detail. Accordingly, those skilled in the art can refer to these examples, select appropriate raw material compounds and reagents, and make appropriate modifications and / or modifications to the reaction conditions and reaction steps as necessary. It is possible to easily produce the compound of the present invention. Various excellent protective groups such as amino groups and condensing agents for condensation reactions are known, and referring to the following examples, for example: “Protein Engineering—Basics and Applications” edited by Satoshi Suzuki Maruzen Co., Ltd. (199 2) and references cited therein; M. Bondanszky, etal., "PeptideSynthesis", JohnWiley & Sons, n. Y., 1976; and JM StewartandD. J. Young, "Solid PhasePeptideSynthesis, WH FreemanandCo., SanFrancisco, 1969, etc. The solid phase method can be used as appropriate by using various commercially available peptide synthesizers such as Model 430A manufactured by Perkin 'Elmaichi' Japan, Shimadzu Corporation. It may be convenient to use PSSM-8, etc. Commercially available products such as resin and reagents used in the synthesis are easily available.

[0131] The antinociceptive action of the compound of the present invention can be quantitatively evaluated by animal experiments using the tail flick method, the tail pre ssure method and the like. The Till Flick method will be described in detail in the examples of the present specification. The pressure stimulation method is described in Patent Documents 3 and 4. Briefly, pressure stimulation was applied to the ridge of the mouse at a rate of lOmmHgZ seconds, and the pressure indicating behavior such as stroking and itching at the stimulation site was measured, and this was used as the pain response threshold. The maximum stimulation pressure was lOOmmHg. As a mouse to be used for the experiment, a mouse that responds to a pressure of 40 to 50 mmHg was selected in the preliminary experiment. For each type of drug to be administered and the dosage conditions, several to tens of mice under the same conditions were subjected to pressure stimulation at regular time intervals after administration, and the pain response threshold was measured. Pain response threshold measurement Based on the value:

 % of MPE = (Pt-Po) / (Pc-Po) X 100

 (In the formula, Po is a pain response threshold before drug administration; Pt is a pain response threshold t minutes after drug administration; Pc is a maximum threshold [J. of MPE) was calculated and the anti-nociceptive effect was quantified.

 The following examples further illustrate the present invention, but the present invention is not limited to these examples. By referring to this example, or by modifying-modifying the method of this example, or by appropriately selecting starting materials or reaction reagents, the present invention represented by the general formula (1) can be used. The compound can be easily produced. In the examples, the meaning of the amino acid group is the same as that usually used. When an amino acid in which D form and L form exist is mentioned, unless specifically indicated as D, the amino acid means L-amino acid. In addition, the following abbreviations may be used, and similar abbreviations may be used when not specifically indicated. The notation of iminomethyl- [Phe]-, Boc- [Phe], etc. indicates that the nitrogen atom at the amino terminal of phenylalanine is modified with an iminomethyl group or a t-butoxycarbonyl group, respectively.

 [0133] The meanings of the abbreviations used in the description of the following examples are as follows.

 Boc: t-butoxycarbonyl

 BrZ: 2-bromobenzyloxycarbonyl (Bromobenzyloxycarbonyl)

 Bzl: benzyl

 C1Z: 2-chlorobenzyloxycarbonyl

 D-Arg: D-anoreginine

 D Met (O): D-methionine sulfoxide (refers to a group having a structure in which one oxygen atom is bonded to the sulfur atom of D-methionine.)

 DMF: N, N dimethylformolemamide

 DMT: 2, 6 Dimethylol-tyrosine

 HF: anhydrous hydrogen fluoride

 HOBt: 1-hydroxybenzotriazole

HPLC: high-performance liauid chromatograp y)

 N—Me j8 Ala: N-methyl-β-alanine (refers to a group having a structure in which one methyl group is bonded to the nitrogen atom of the α-amino group of j8-alanine.)

 Ν— MeLys: N-methyllysine (refers to a group having a structure in which one methyl group is bonded to the nitrogen atom of lysine a-amino group.)

 N-MeLys (ClZ): C1Z— N-methyllysine (group having a structure in which one methyl group is bonded to the nitrogen atom of the oc-amino group of lysine and one C1Z group is bonded to the nitrogen atom of the ε-amino group. )

 Phe: Huerulanin

 TFA: trifluoroaceticacid

 Tos: p—Toluenesulfonyl

 Tyr: Tyrosine

 WSCD: Water-soluble carbodiimide, specifically 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide.

 [0134] 1. SS8225—Peptide

 Peptide derivatives synthesized as examples and comparative examples in the present specification are given serial numbers SS8225-1, 2, 3,... (Hereinafter referred to as “SS8225-peptide”;). Table 1 below shows the corresponding relationship between SS8225-peptides and DNA structures in Examples and Comparative Examples in the present specification. Comparative Examples 1 and 2 are morphine and oxycodone, respectively. Peptide derivative SS8225-22 was used as a reference example because it was used to explain the synthesis method.

また、本明細書における実施例 1な 、し 8の化合物は以下の化学式（15)な 、し (2)で表される構造を有する。 [0137] [化 12] [0135] [Table 1]

In addition, the compounds of Examples 1 and 8 in this specification have the structures represented by the following chemical formulas (15) and (2). [0137] [Chemical 12]

 (1 5)

[0141] [Chemical 16] [8ΐ ^] [ε ^ το]

(Ο Ζ)

(6 L)

608T90 / .00Zdf / X3d 39

(2 1) [Chemical 19]

( twenty two )

 2. Synthesis of starting amino acid derivatives

 (1) Obtaining starting amino acid derivatives

The reagents used for the synthesis of the peptide derivatives described below are commercially available products or can be easily prepared by those skilled in the art. Of the starting amino acid derivatives used in peptide synthesis reactions, Boc- [N-MeLys (C1Z)] OH is, for example, Anaspec (An aspec) from Boc- [N-Me β Ala] -OH, for example from Watanabe Chemical Co., Ltd., Boc- [Phe] -OH, Boc- [D-Arg (Tos)]-OH, Boc- [Tyr (BrZ)] — OH, Boc- [D-Met] —OH, and the like are available, for example, from Peptide Laboratories.

[0146] (2) Starting amino acid derivative: Boc— [N— MeLys (ClZ)] — Synthesis of NH

 2

 Boc— [N— MeLys (ClZ)] — Dissolve OH, HOBt, and NH CI in DMF.

 Four

 SCD was added and stirred, and then stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain Boc- [N-MeLys (ClZ)]-NH as an oil.

 2

 [0147] (3) Synthesis of starting amino acid derivative: Boc— [N— MeLys (ClZ)] o— Bzl

 Boc— [N—MeLys (ClZ)] — OH and Bzl—Br were dissolved in DMF, stirred with triethylamine under cooling, and then stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain Boc- [N-MeLys (CIZ)]-o-Bzl as an oil.

 [0148] (4) Synthesis of starting amino acid derivative: Boc— [N—Me β Ala] o—Bzl

 Boc— [N—Me j8 Ala] —OH and Bzl—Br were dissolved in DMF, stirred with triethylamine under cooling, and then stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain Boc— [N-Me | 8 Ala] —o—Bzl as an oil.

 [0149] (5) Starting amino acid derivative: Boc— [N—Me j8 Ala] — Synthesis of NH Boc— [N—Me j8

 2

 Ala] -OH, HOBt and NH CI are dissolved in DMF, and WSCD is stirred under cooling.

 Four

 Thereafter, the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain Boc— [N—Me j8 Ala] —NH as a white solid.

 2

 [0150] (6) Synthesis of starting amino acid derivatives: Boc— [N—Me j8 Ala] —NHCH

 Three

 Boc— [N—Me j8 Ala] — Dissolve OH, HOBt and NH3CH.CI in DMF

 Three

WSCD was added and stirred, and then stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine. After drying the organic layer with magnesium sulfate, the solvent Was concentrated under reduced pressure to obtain Boc— [N—Me | 8 Ala] —NHCH as a colorless oil.

 Three

 [0151] (7) Starting amino acid derivative: Boc [N MeLys (ClZ)] —Synthesis of NHCH

 Three

 Boc-[N-MeLys (ClZ)]-OH, HOBt and NH CH 'CI are dissolved in DMF and cooled

 3 3

 Below, WSCD was added and stirred, and then stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. After drying the organic layer over magnesium sulfate, the solvent is concentrated under reduced pressure to give Boc- [N-MeLys (C1Z)] -NHCH as a colorless oil

 Three

 Obtained as a thing.

[0152] 3. Synthesis of SS8225 peptide

 (Synthesis of D SS8225-22 SS8225 09, 01, 02 and 12 described in the examples and comparative examples in this specification were synthesized in the same manner as SS8225-22 listed in Table 1 as reference column f. The synthesis of SS8225-22 is explained as follows: Boc— [N—MeLys (C1Z)] Starting from —NH, the amino-terminal Boc group is dissolved in Tos—OH, TFA and dioxane hydrochloride.

2

 Removal with liquid gave Tos-OH · N-MeLys (CIZ) —NH. Then Tos— OH

 2

 MeLys (CIZ) — NH, Boc— [Phe] —OH and HOBt dissolved in DMF

 2

 The CD was collected and stirred at room temperature overnight. Ethyl acetate was added to the reaction solution and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain Boc— [Phe] [N-MeLys (CIZ)] — NH. Similarly, sequentially B

 2

 oc— [D— Arg (Tos)] — OH, Boc— [Tyr (BrZ)] — Condensing OH, Boc— [Tyr (BrZ)]-[D-Arg (Tos)]-[Phe] [N- MeLys] —NH was obtained. Next, the amino terminal B

 2

 The oc group was removed with TFA, and the resulting TFA 'Tyr (BrZ) [D— Arg (Tos)] [Phe] [N -MeLys] -NH, acetoimidate ethyl hydrochloride and triethylamine were dissolved in DMF.

 2

 I understood. The solution was stirred at room temperature for 2 hours 30 minutes. Concentrate the reaction solution under reduced pressure, add cold water to precipitate it, filter the precipitate, and dry it. 1-Iminoethyl— [Tyr (BrZ)] — [D— Arg (T os)] — [Phe] [N -MeLys] —NH was obtained. Next, 1 iminoethyl- [Tvr (BrZ)]

 2

 [D— Arg (Tos)] — [Phe] [N-MeLys] — NH is cooled from 3 ° C to 15 ° C

 2

, And treated with a solution of HFZp-cresol (85Zl5) for 1 hour. After distilling off HF under reduced pressure, the resulting residue was dissolved in water, loaded onto an ion exchange resin, and eluted with 1% aqueous acetic acid solution. 1-Iminoethyl mono [Tyr]-[D-Arg]-[Phe ]-[N-MeLys] — NH 'Rough purification of acetic acid I got a thing. Next, it was preparatively purified by reverse phase HPLC and freeze-dried to obtain SS8225-22 (1-Iminoethyl- [Tyr]-[D-Arg]-[Phe]-[N-MeLys] -NH) 'acetic acid. It was.

 2

 [0153] (2) SS8225— Synthesis of 09, 01, 02 and 12

 Boc— [N—MeLvs (C1Z)] — NH is used as the starting material in the same manner as SS8225-22.

 2 SS8225-1 (Comparative Example 3) as the mino acid derivative, SS8225-17 (Comparative Example 6) as the starting amino acid derivative, Boc- [N-MeLys (CIZ)]-o-Bz 1 — Me j8 Ala] — NH as the starting amino acid derivative SS8225— 01 and 02 (Examples 1 and 2)

2

 Each was synthesized.

[0154] (3) Synthesis of SS8225-06

 Boc-[N-MeLys (CIZ)]-Starting from NH, the Boc group at the amino terminal is Tos—OH

 2

 , Removed with TFA and dioxane hydrochloride solution, Tos—OH'N—MeLvs (ClZ) —NH

 Got 2 Next, Tos—OH · Ν—MeLys (C1Z) —NH, Boc— [Phe] —OH and HOBt

 2

 It melt | dissolved in DMF, WSCD was added under cooling and it stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain Boc- [Phe] — [N-MeLys (CIZ)] — NH. In the same manner, Boc- [D-Met] -OH, Boc [Ding 71: (8)]-011

2

 Condensation gave Boc— [Tyr (BrZ)] [D—Met] — [Phe] [N—MeLys] —NH.

 2 Next, the amino terminal Boc group was removed with TFA, and the resulting TFA. Tyr (BrZ) — [D—Met]-[Phe]-[N-MeLys] —NH, acetimido acid ethyl hydrochloride and triethylamine

 2

 Was dissolved in DMF. The solution was stirred at room temperature for 2 hours 30 minutes. Concentrate the reaction solution under reduced pressure and precipitate with cold water. The precipitate is collected by filtration and dried. 1 Iminoethyl- [Tyr (BrZ)]-[D-Met]-[Phe]-[N— MeLys] — NH Got. Next, 1-iminoethyl- [T

 2

 yr (BrZ)]-[D-Met] [Phe] [N—MeLys] — Cool NH from 3 ° C to 5 ° C

 2

 Then, the solution was treated with a solution of HFZp-cresol (85Zl5) for 1 hour. After distilling off the HF under reduced pressure, the resulting residue was dissolved in water, loaded onto an ion exchange resin, and eluted with 1% aqueous acetic acid. 1-Iminoethyl mono [Tyr]-[D-Met]-[ Phe]-[N—MeLys] —NH 'Acetic acid crude

 2

A product was obtained. Next, 1 Iminoethyl- [Tyr] — [D-Met] [Phe] [N-MeLys] NH · Acetic acid crude product was dissolved in acetic acid aqueous solution, and hydrogen peroxide was added for 1 hour 30 minutes. Stir. The reaction solution was separated and purified by reverse phase HPLC, and lyophilized to obtain acetic acid 338225-06 (Example 6).

 [0155] Since hydrogen peroxide was used when D-Met was converted to D-Met (O), this derivative was D-methionine- (S) -sulfoxide and D-methionine- (R). —A mixture containing sulfoxide.

 [0156] (4) Synthesis of SS8225-10, 03, 04, 11, 05, 07 and 08

 Boc— [N—MeLvs (ClZ)] — NH is the starting material in the same way as SS8225-06.

 2 SS8225-10 and 05 as Comparative Example 4 and Example 5) as the mino acid derivative, SS8225-11 (Comparative Example 5) as the starting amino acid derivative from Boc- [N-MeLys (C1Z)]-o-Bzl , B oc— [N—Me j8 Ala] — Starting from NH as an amino acid derivative SS8225-03 and 04 (

 2

 Examples 3 and 4) were prepared using Boc- [N-Me j8 Ala] -NHCH as the starting amino acid derivative.

 Three

 SS8225-07 (Example 7) was converted to Boc— [N—MeLys (ClZ)] — NHCH as the starting amino acid.

 Three

 SS8225-08 (Example 8) was synthesized as a noic acid derivative.

[0157] 4. Results of NMR analysis of SS8225-peptide

 The NMR analysis data for each of the SS8225-peptide is JEOL JEOIJN

Measurement was performed at 270 MHz and room temperature using M—EX270.

[0158] NMR analysis data of SS8225-01 (Example 1)

 — NMR (D O) δ: 7.30-7.10 (5H, m), 6.49 (2H, s), 5.10—4.88 (1H

 2

 , m), 4.20 (1H, q, J = 5.3Hz), 4.02— 3.87 (1H, m), 3.68— 3.32 (2H, m), 3.25-2.67 (9H, m), 2.35 (2H, t, J = 6.8Hz), 2.16 (2.6H, s), 2.1 1 (6H, s), 1.92 (0.4H, s), 1.24—0.64 (4H, m)

[0159] NMR analysis data of SS8225-02 (Example 2)

 — NMR (D O) δ: 7.30-7. 10 (5H, m), 7.01 (2H, d, J = 8.0Hz), 6.7

 2

 3 (2H, d, J = 8.0Hz), 5.09—4.89 (1H, m), 4.34 (1H, t, J = 7.7Hz), 3.99 (1H, q, J = 6.0Hz), 3.54— 3.45 (2H, m), 3.08— 2.67 (9H, m), 2.34 (2H, t, J = 6.9Hz), 2. 11 (2.6H, s), 1.96 (0.4H, s) l.33— 0.62 ( 4H, m)

[0160] NMR analysis data of SS8225-03 (Example 3) ''('ΗΙ) 09 ー 08''( ^Ζ Η · Ζ = Γ' ΗΙ) Ζ 6 '' ( ^Z UZ 8 = ΓΡ ΉΖ) £

L · 9 '( ^Ζ Η2 · 8 = ΓΡ' Η2) Ι0 'L''Η9) 90 Ί ~ £ Ί-9 (Ο α) 丽 Ν— Η _τ

^ — ^ Measure (SM) 80-9SS8SS [39 TO] (ra ΉΖ) Ζ £ Ί-Ζ9 Ί '^' ΗΖ) 98 Ί ~ 0 £ 'Ζ' ( ^s 'U £) Z' Ζ '( ^s ' Η ε) 6 'Ζ' ^ ΉΙ) £ 9 'Ζ-ΟΟ ΉΖ ΉΖ) Ζ Έ-89 Έ' (^ 'HI) S6 Έ-εΐ

'' ( ^Ζ Η9 · Ζ = Γ 'ΗΙ) Ζ2''^' HI) S8 86 '' ( ^Ζ Η8 = ΓΡ 'Η2) 8

9 · 9 '( ^Ζ Η 8 = ΓΡ' Η2) Ζ6 9 'Η9) 90 Ί → Ζ' 9 (Ο α) 丽 Ν— Η _τ

¾H NO) (LM)-ZZSSS 910] (ra * HS) 98 Ό-9Ζ Ί '' HII) 9 ^ Ί- 'Z' ( ^s ' HS)

Z 'Z' (m 'H6) 89' 2-91 Έ '(^' HI) 00 '→ Z''( ^Ζ Η0 · Ζ = Γ' HI) 9S

'' (m 'HI) 09 ー 08''( ^Ζ Η9 · Ζ = Γ' Ηΐ) 0 '9' ( ^Ζ Η0 · 8 = ΓΡ 'UZ) L

L · 9 '( ^Ζ Η0 · 8 = ΓΡ' Η2) 90 'L''H9) SI Ί- Ί-9 (Ο α) 丽 Ν— Η _τ

 ^ — ^ Measure 90-9SS8SS [S9T0]

 (ra * HS) 98 Ό-

OS Ί '(m' H8) 9S '1-86 Ί' ( ^s ' Η9) εΐ 'Ζ' ( ^s ' HS) 8I 'Ζ' ( ^s ' HS) I9 'Ζ' (^ 'Η6) 8Ζ' Ζ → Ζ Έ '^ ΉΖ) 06 Έ 6S' (^ 'ΗΙ) 9Ζ', one S8 '' (m 'Η

1) 96 '^ -ΟΙ' 9 '( ^s ' HS) S9 9' (^ 'H9) SI Ί ~ £' 9 (Ο a) H NH _x

 ^ — ^ Measure 90-9SS8SS [29 TO]

 (

^ 'HS) 0 Ί-8Ζ' Κ ^ 'Η9) 96 Ί-LZ' Ζ '( ^Ζ Η9 9 = Γ ΉΖ) ^ £' Ζ '( ^s ' Η ε) 6' Ζ '^' UL) ZL 'Z-90 ΉΖ ΉΖ) ££ Έ-99 Έ' ΗΙ) 00 'One OS

'(ΖΗ9 · Ζ = Γ' Ηΐ) ε '' ^ 'ΗΙ) 06 80' 9 '( ^Ζ Η0 8 = ΓΡ' Η2) 9

L · 9 '( ^Ζ Η0 · 8 = ΓΡ' Η2) εθ 'L''Η9)0Ι' -SS '9 (Ο α) 丽 Ν— Η _τ

¾H NO) (H} ¾i) ^ 0-9SS8SS [Ϊ9Ϊ0] (ra ΉΖ) 0 £ Ί-Ζ9 Ί '(m ΉΖ) 06 Ί-ΙΟ' Ζ '( ^s ' Η9) ΙΙ' Ζ '( ^s ' Η ε) 9Ι 'Ζ' ( ^Ζ Η8 9 = Γ ΉΖ) ^ £ 'Ζ' ( ^s ¾ε) 8 'Ζ' ^ 'UL) IL' Ζ-ίΖ · ε '(

 ^ 'HS) 9S · ε— 89 · ε' ΗΙ) 96 Έ-εχ '(^' Ηΐ) εχ ', One οε' (^ 'Η

1) 06 '^ -ΟΙ' 9 '( ^s ' Η2) Ι9 9' (^ 'H9) SI Ί ~ Ζ £' 9 (Ο Q) HPVN-H _T

608T90 / .00Zdf / X3d 89 31 (1H, t, J = 7.1 Hz), 4. 20— 3. 95 (1H, m), 3. 08— 2. 73 (9H, m), 2. 65-2. 43 (6H, m ), 2. 31— 1. 92 (5H, m), 1. 75— 1. 38 (6H, m), 1. 25— 0. 78 (2H, m)

 [0166] 5. Anti-nociceptive action, part 1 (Evaluation by Till's flick method)

 (1) Experimental animals ddY male mice (Japan SLC) weighing 22-25 g were used as experimental animals. Animals should be kept in a constant environment at room temperature 22 ± 2 ° C, humidity 55 ± 5%, light / dark 12 hours cycle (light period 9: 00-21: 00, dark period 21: 00-09: 00) until the experiment. Was raised. The animals were allowed to freely consume mouse chow (F2, Funabashi Farm, Funabashi Pass) and tap water.

[0167] (2) Drugs to be administered and administration methods Among the SS8225-peptides synthesized as described above, SS8225-01, 02, 03, 04, 05, 06, 07, and 08 are shown in the f column as the execution f. SS82 25-09, 10, 11, and 12 were used as administered drugs in a row. In addition, morphine and oxycodone were also used as administered drugs in order to compare the efficacy with other drugs. The administration solution was 0.03125-20mg (mgZkg) of SS8225-01, 02, 03, 04, 05, 06, 07, 08, 09, 10, 11 and 12 per lkg of mouse body weight. Adjust the concentration of each drug to 0.1 mL per 10 g of mouse body weight according to the dosage conditions of morphine or oxycodone from 0.89 to 67.5 mg (mg / kg), and dilute in Ringer's solution. did. In addition, the administration solution containing only Ringer's solution was used as an experimental control. In order to acclimatize the mouse to the measurement environment, the mouse was left in the measurement plastic cage for 60 minutes and then the latency before drug administration was measured for each mouse according to the Till 'flicker method described below. Radiation heat irradiation was performed on a 2 cm portion from the tail end of the mouse, and the time taken for each mouse to shake its tail in response to the thermal stimulus was measured as the latency before drug administration. Individual mice with a latency of 2.5-3.5 seconds before drug administration were selected for drug administration. The administration solution of one dosage condition of one kind of drug was administered to 10 mice to form one experimental group. The body weight of each mouse was measured, and the volume of the administration solution was adjusted so that the volume was 0.1 mL per 10 g of mouse body weight. Two administration methods, subcutaneous administration (s. C) and oral administration (po), were used. For subcutaneous administration, a 27-gauge needle was used to inject 0.1 mL (0.1 mLZlOg) of the administration solution into the back of the mouse per 10 g of mouse body weight. For oral administration, Mau The administration solution of 0.1 mL (0.1 mLZlOg) per lOg was administered using an oral sonde.

[0168] (3) Evaluation method of anti-nociceptive effect As an index of the anti-nociceptive effect, the anti-nociceptive effect according to each administration method and dose condition of each drug using the Till'frick method, which is a heat noxious stimulus, is used. Was evaluated quantitatively. After the drug administration, at each measurement time set at intervals of 15, 30, or 60 minutes, the experimental group for each drug administration method and dose condition was placed 2 cm from the tip of the mouse tail. Radiation heat irradiation was performed, the latency until each mouse individual swings its tail was measured, and this latency was defined as a pseudo pain threshold. To minimize damage to the stimulation site, the maximum stimulation time (cut-offtime) was 10 seconds. The antinociception was quantitatively evaluated by ⁰ / oMPE (% of maximum possible effect) calculated from the following formula (I).

 [0169] [Equation 1]

(T2-T1)

 ) MPE = X 100

 (Tc-Tl)

[0170] In the above formula, T1 represents the latency (seconds) before drug administration, T2 represents the latency (seconds) after drug administration, and Tc represents the maximum stimulation time (cut-off time).

[0171] The% MPE of each individual of 10 mice was calculated for each dose condition of each drug, and the average value and standard error (mean SEM) were plotted on the vertical axis, and the time after administration was plotted on the horizontal axis. Thus, graphs showing the time course of% MPE were prepared (Figs. 1, 3, 5, 7, 7, 9, 11, 13, 15, 15, 17, 19, 21, 23). Figure 25, Figure 27, Figure 29, Figure 31, Figure 33 and Figure 3 5). At the same measurement time for each drug, and ⁰ / OMPE data for each individual experimental groups at each dose, the dispersion of the two-way and ⁰ / OMPE data of each individual experimental group in Ringer's solution control experiment After processing by analysis (two-way ANOVA), a risk rate of less than 5% was judged to be significant according to Bonferroni post-test.

[0172] In the present specification, the duration of antinociception at each dosage condition is shown in Fig. 1, 3, 5, 7, 9, 11, 11, 13, 15, 15, 17, 19, 21, 23, 25, 27, 29, 31, 31, 33 and 35 In the graph showing the time course of% MPE, the curve showing the time course of% MPE for each dose condition showed a significant difference in anti-nociceptive activity of less than 5% after the first administration compared to Ringer's control. The time from when the last significant difference in anti-nociceptive activity was less than 5%. In the present specification, the duration of the antinociceptive action for each drug refers to the duration of the antinociceptive action at a dosage condition having the longest duration.

[0173] For each drug, the time course data of% MPE for each dose condition was analyzed using a curve analysis program (GraphPad Prism software, version 3.0, GraphPadSoftware, San Diego, CA, USA) 50% effective dose (ED) and 95

 50

 % Confidence limits were calculated and graphs of dose-response curves were generated (B and D in Figures 1-12). ED was expressed in units of mgZkg. In the present specification, each of the respective drugs

50

 The ED for each administration method is the most effective for each drug 'administration method.

 50

 This refers to the ED value at the dose condition, that is, the minimum value of ED at each dose condition.

 50 50

 In this specification, when comparing the strength and weakness of each drug's antinociception,

 The 50 value represents how many times the ED value of another drug.

 50

[0174] (4) Results of anti-nociceptive test Results of Examples 1 to 8 and Comparative Examples 1 to 6 are shown in Table 2 and FIG. 3, FIG. 5, FIG. 7, FIG. 9, FIG. 11, 1, 13, 15, 15, 17, 19, 19, 21, 23, 25, 27, 29, 31, 31, 33 and 35 Shown in In these graphs showing the change in% MPE over time, if the upper limit of the standard deviation plotted for each dose condition and time after administration is marked with *, the dose condition indicates that the This means that the significant difference in nociceptive effect is less than 5%. If the upper limit of the standard deviation is marked with * (*) in the above graph, the significant difference in the antinociceptive effect compared to the Ringer's control is less than 1% of the risk rate at that dose condition. Means. From these figures, for each drug, the time at which the curve of the time course of the antinociceptive effect in subcutaneous administration and oral administration becomes maximum can be obtained as the peak action time. For the Examples and Comparative Examples in Table 2, the columns for Subcutaneous ED and Oral ED indicate that the other values are the action peaks for each drug. ED at peak time, i.e. 50% effective dose, the range within

 50

 Represents the 95% confidence limit of the ED in Subcutaneous administration due to weak anti-nociceptive effect

 50

 If the ED is greater than 0.5 mgZkg, it is expressed as “> 0 · 5”.

When 50 50 is greater than 10 mg / kg, it is expressed as “> 10”.

[0175] [Table 2]

[0176] Of the above graphs, those shown in Figs. 1 to 4, 7 to 10, 13 to 16, 19, 19, 20, 23 to 26, 29, 30, and 33 to 36. The graph is a graph showing the test results of subcutaneous administration, and is shown in FIGS. 5, 6, 11, 12, 12, 17, 18, 21, 22, 22, 27, 28, 31, 31 and 32. Is a graph showing the test results of oral administration. Among these, the figures with odd figure numbers indicate the time course of anti-nociceptive effects after administration. The vertical axis is% MPE (no unit) and the horizontal axis is time (unit is minutes). B and D show dose response curves, where the vertical axis is% MPE and the horizontal axis is the dose (unit is mgZkg). <Example 1>

 Figures 1 and 2 show the anti-nociception of Example 1 (SS8225-11: 1 iminoethyl- [DMT]-[D- Arg]-[Phe]-[N-Me | 8 Ala]-NH) administered subcutaneously. Result of action test

 2

 Show fruit. Subcutaneous administration of the peptide derivative SS8225-11 produced a dose-dependent and significant anti-nociceptive effect. ED value at 90 minutes after subcutaneous administration, which is the peak time of action

 50 was 0.12 mgZkg with a 95% confidence limit of 0.0-0.20 mgZkg, and the duration of 0.5 mgZkg and 0.25 mgZkg administered subcutaneously was more than 7 hours.

<Example 2>

 Figures 3 and 4 show the anti-nociception of Example 2 (SS8225-12: 1-iminoethyl mono [Tyr]-[D- Arg] [Phe] [N-Me | 8 Ala] -NH) administered subcutaneously. Results of action test

 2

 Indicates. Subcutaneous administration of the peptide derivative SS8225-12 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 90 minutes after subcutaneous administration, which is the peak time of action, is

 50

At 0.06 mgZkg, the 95% confidence limit was 0.03—0.1 lOmgZkg, and the duration of 0.125 mgZkg sc was 6 hours. FIG. 5 and FIG. 6 show the results of an antinociception test when Example 2 was orally administered. Even when administered orally, dose-dependent antinociception occurred. The ED value at 4 hours after oral administration, which is the peak action time, is 4

 50

 At OmgZkg, the 95% confidence limit was 3.97-4. LOmgZkg, and the duration of oral lOmgZkg was 10 hours.

<Example 3>

 7 and 8 show that Example 3 (SS8225- 13: 1 Iminoethyl- [DMT] — [D-Met — (0)] — [Phe] — [N—Me | 8 Ala] —NH) was administered subcutaneously. Anti-nociceptive action test

 2

 Results of experiments are shown. Subcutaneous administration of the peptide derivative SS8225-13 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 90 minutes after subcutaneous administration, which is the peak time of action, is 0.08 mgZkg, and the 95% confidence limit is 0.06—0.12 mgZkg.

50

 The duration by subcutaneous administration of mgZkg was 7 hours.

[0180] <Example 4>

FIG. 9 and FIG. 10 show the case where Example 4 (SS8225- 14: 1 Iminoethyl- [Tyr] — [D—Met (O)]-[Phe] — [N—Me | 8 Ala] —NH) was administered subcutaneously. Of anti-nociceptive testing Results are shown. Subcutaneous administration of the peptide derivative SS8225-14 produced a dose-dependent and significant anti-nociceptive effect. ED at 90 minutes after subcutaneous administration, which is the peak time of action

 The 50 value was 0.05 mgZkg, the 95% confidence limit was 0.01--0. LlmgZkg, and the duration by subcutaneous administration of 0.125 mg Zkg was 7 hours. 11 and 12 show the results of an antinociception test when Example 4 was administered orally. Even when administered orally, a dose-dependent and significant antinociception occurred. The ED value at 180 minutes after oral administration, which is the peak time of action, is 2.53 mg / kg, and the 95% confidence limit is 2.17-2.95 mg / kg.

 50

 The duration of oral administration of lOmgZkg was more than 10 hours.

[0181] <Example 5>

 FIG. 13 and FIG. 14 show the results of administration of Example 5 (SS8225-19: 1 Iminoethyl- [DMT]-[D-Met (O)]-[Phe]-[N-MeLys] -NH) subcutaneously. Nociceptive test

 2

 The results are shown. Subcutaneous administration of the peptide derivative SS8225-19 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 120 minutes after subcutaneous administration, which is the peak time of action, is 0.1 lOmgZkg, the 95% confidence limit is 0.04—0.22 mgZkg, 0.25 m

50

 The duration by subcutaneous administration of gZkg was 7 hours.

[0182] <Example 6>

 FIG. 15 and FIG. 16 show the results of administration of Example 6 (SS8225—20: 1 iminoethyl- [Tyr]-[D-Met (O)] — [Phe]-[N-MeLys] —NH 3) subcutaneously. Of nociceptive testing

 2

 Results are shown. Subcutaneous administration of the peptide derivative SS8225-20 produced a dose-dependent and significant anti-nociceptive effect. ED at 90 minutes after subcutaneous administration, which is the peak time of action

 The 50 value was 0.18 mgZkg, the 95% confidence limit was 0.07-0.43 mgZkg, and the duration of 0.25 mgZ kg subcutaneously was 5 hours. FIG. 17 and FIG. 18 show the results of an antinociception test when Example 6 was orally administered. Even when administered orally, a dose-dependent and significant anti-nociceptive effect was expressed. The ED value at 120 minutes after oral administration, which is the peak time of action, is 6.02 mgZkg, and the 95% confidence limit is 4.37—28 mgZkg.

 50

 The duration of oral administration of lOmgZkg was 7 hours.

<Example 7>

Fig. 19 and 20 20 f, row 7 (SS8225—23: 1—Iminoethinole [Tyr] — [D—Me t— (O)] — [Phe] — [N— Me | 8 Ala] — NHCH)

 Three

 The result of the test is shown. Subcutaneous administration of the peptide derivative SS8225-23 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 60 minutes after subcutaneous administration, which is the peak time of action, is 0.05 mg / kg, and the 95% confidence limit is 0.03—0.09 mg / kg.

 50

 The duration of 125 mg Zkg subcutaneous administration was 5 hours. 21 and 22 show the results of an antinociception test when Example 7 was orally administered. Even at the time of oral administration, a dose-dependent and significant anti-nociceptive effect was expressed. The ED value at 180 minutes after oral administration, which is the peak time of action, is 2.51 mg / kg, and the 95% confidence limit is 2.23-2.83 mg / kg.

 50

 Yes, the duration of oral administration of lOmgZkg was 8 hours.

<Example 8>

 FIG. 23 and FIG. 24 show the results when Example 8 (SS8225-24: 1-iminoethyl- [Tyr]-[D-Met (O)]-[Phe]-[N-MeLys] -NHCH) was administered subcutaneously. Anti-nociceptive test

 Three

 Results of experiments are shown. Subcutaneous administration of the peptide derivative SS8225-24 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 90 minutes, the peak time for subcutaneous administration, is 0.1 mgZkg, and the 95% confidence limit is 0.05-0.24 mgZkg, 0.25 mgZ

50

 Duration by subcutaneous administration of kg was 5 hours.

[0185] <Comparative Example 1>

 FIG. 25 and FIG. 26 show the results of an antinociception test when Comparative Example 1 (morphine) was administered subcutaneously. Subcutaneous administration of morphine produced a dose-dependent and significant anti-nociceptive effect. The ED value at 2.5 minutes after subcutaneous administration, which is the peak time of action, is 2.51 mgZkg.

 50

 The 95% confidence limit was 1.48-4. 26 mgZkg, and the duration of 5 mgZkg administered subcutaneously was 90 minutes. FIG. 27 and FIG. 28 show the results of the antinociception test when Comparative Example 1 (morphine) was orally administered. Even when administered orally, a dose-dependent and significant anti-nociceptive effect was expressed. The ED value at 29 minutes after oral administration, which is the peak time of action, is 29.

 50

At 92 mgZkg, the 95% confidence limit was 26.37—33.95 mgZkg, and the duration of oral administration at 67.5 mg / kg was 5 hours.

[0186] <Comparative Example 2>

Figures 29 and 30 show the anti-nociceptive effects of Comparative Example 2 (oxycodone) administered subcutaneously. Results of experiments are shown. Subcutaneous administration of oxycodone produced a dose-dependent and significant anti-nociceptive effect. The ED value at 1.2 minutes after subcutaneous administration, which is the peak time of action, is 1.21 mg

 50

 At Zkg, the 95% confidence limit was 0.95-1.54 mgZkg, and the duration of 1.75 mgZkg subcutaneously was 90 minutes. Figures 31 and D show the results of an antinociceptive test when Oral Administration of Comparative Example 2 (oxycodone). Dose-dependent and significant anti-nociceptive effects were observed even when administered orally. The ED value at 45 minutes after oral administration, which is the peak time of action, is 7.82 mgZkg, 95% confidence limit is 6.46-9.47 mgZkg, 20 mg

50

 The duration of oral administration of Zkg was 5 hours.

[0187] <Comparative Example 3>

 FIG. 33 and FIG. 34 show the results of an antinociception test when Comparative Example 3 (SS8225 1: DMT— [D—Arg] [Phe] [N—MeLys] 2 —NH 2) was administered subcutaneously. Peptide invitation

 2

 Subcutaneous administration of conductor SS8225-1 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 90 minutes, the peak time of action, is 0.44 mgZkg, and the 95% confidence limit is

 50

 It was 0. 33-0. 59mgZkg. The duration of lmgZkg subcutaneous administration was 5 hours. When the peptide derivative SS8225-1 was administered orally, the ED value for antinociception was

 50 lOmgZkg was exceeded.

[0188] <Comparative Example 4>

 Figures 35 and 36 show the results of an antinociception test when Comparative Example 4 (SS8225-5: DMT— [D—Met (O)] — [Phe] — [N—MeLys] —NH) was administered subcutaneously. Indicates. Pep

 2

 Subcutaneous administration of the tide derivative SS8225-5 produced a dose-dependent and significant anti-nociceptive effect. The ED value at 90 minutes, the peak time of action, is 0.28 mgZkg, 95% reliable.

 50

 The limit was 0.21-0.39 mgZkg, and the duration by subcutaneous administration of 0.5 mgZkg was 6 hours. When the peptide derivative SS8225-5 was administered orally, the ED value for antinociception exceeded lOmgZkg.

 50

 [0189] <Comparative Example 5>

Comparative Example 5 (SS8225- 16: 1 Iminoethyl- [Tyr] — [D—Met (O)] [Phe]-[N-MeLys] OH) was administered subcutaneously and orally, and as a result, SS8 225 — The ED value of antinociception when subcutaneously administered 16 exceeds 0.5 mgZkg, and oral The ED value for antinociception when administered exceeded lOmgZkg (not shown).

 50

 [0190] <Comparative Example 6>

 Comparative Example 6 (SS8225-17: 1-Iminoethyl- [DMT]-[D-Arg]-[Phe]-[N-MeLys] OH) was administered as a result of an antinociceptive effect when administered subcutaneously and orally. — The ED value of anti-nociceptive effect when 17 was administered subcutaneously was found to exceed 0.5 mgZkg.

 50

 The ED value of the antinociceptive effect when administered orally is over lOmgZkg.

 50

 Results were obtained (not shown).

[0191] From the results of the above-mentioned anti-nociceptive activity test (Till'flick method), the peptide derivatives of the examples include compounds that reach an oral ED of 2.5 mgZkg.

 50

 10 times more potent than the antinociceptive effect of oral administration of oxycodone and several times more potent than the antinociceptive effect of oxycodone and the peptide derivative of the comparative example. The compound of the present invention has an ED value at the peak action time after subcutaneous administration.

 50 0. 12 mgZkg or less, which is more than 20 times more potent than that of morphine under the skin and more than 10 times more potent than that of oxycodone. Although the peptide derivative of the comparative example has a stronger antinociceptive effect in subcutaneous administration than oxycodone, the antinociceptive effect in oral administration is weaker than that of oxycodone. Further, the duration of the antinociceptive action of the compound of the present invention is equal to or longer than that of morphine, and may reach 10 hours, twice that of morphine. Therefore, the compound of the present invention was proved to have a strong anti-nociceptive effect particularly in oral administration. Therefore, it can be used as a medicine for the prevention and / or treatment of pain, particularly as an excellent oral medicine.

 [0192] From the results of oral administration and subcutaneous administration of these drugs, AUC (time response curve and baseline showing the relationship between time after administration (elapsed time) and% MPE) The area enclosed is calculated, and the relationship between the dose and AUC is shown in FIG. 37 and FIG. 38 as a graph with the AUC on the vertical axis and the dose on the logarithmic horizontal axis.

[0193] From these figures, in SS8225-04 and SS8225-07 according to the present invention, in order to obtain the same AUC, a dose of 1Z20 to 1Z50 or less of the dose of morphine is obtained in both oral administration and subcutaneous administration. In addition, it is understood that when the dose is relatively large, an anti-nociceptive effect can be obtained that is extremely high that cannot be obtained with the usual dose of morphine. It is understood.

 [0194] 6. Anti-nociceptive action test, 2 (Alodinian experiment)

 Next, we examined the antinociception in a nerve injury model that assumed neuropathic pain (neuropathic pain).

 [0195] <Nerve injury model>

 As a nerve damage model, a model devised by Seltzer et al. (Partial sciati c nerve ligation: PSL moire) was used.

 [0196] That is, Nembutal (manufactured by Dainippon Pharmaceutical Co., Ltd.) diluted 7-fold with Ringer's solution (manufactured by Fuso Yakuhin Kogyo Co., Ltd.) was placed into the peritoneal cavity of the mouse using a 6-gauge injection needle (Terumo). ) And administer anesthesia. Under anesthesia, place the mouse on its face, incise the skin over the femur, incise the fascia below it, further cut the gap between the biceps femoris, and then connect the sciatic nerve as follows: Fixed. In other words, the sciatic nerve was peeled off quickly so that it was not damaged, and 1Z3 ~: LZ2 around the sciatic nerve in the right lower limb was used with a venous weakened needle for blood vessels 000 panel hole (Natsume Seisakusho) and nylon suture No. 9 — Completely ligated with 0 (Natsume Seisakusho). Thereafter, the incised skin was sutured with silk suture No. 2 (manufactured by Natsume Seisakusho Co., Ltd.) using an external high-angle needle 1 panel needle (Natsume Seisakusho Co., Ltd.) and bred until the measurement date.

 [0197] <Measurement method>

 Measurement of alodiure in the above-mentioned nerve injury model animals was performed by the von Frey Filament method 7 days after nerve ligation.

 [0198] That is, after placing model animals one by one in a compartment with a floor-like mesh, and confirming that the locomotor activity disappeared after about 1 to 2 hours, each drug solution (morphine, SS8225-0 4, or SS8225-07) was transdermally administered in a predetermined amount.

 [0199] After that, several types of filaments with different stimulation intensities (Touch— Test Sensory Evaluat or Instruction, Nort Coast Medical, Inc. (North Coast Medical)) were used. It was measured perpendicularly to the filament and until the filament was bent, and the threshold value that caused the escape reaction at that time was measured as the gram weight ("gram" in the figure (1 gram weight is 0.00011N)).

[0200] For comparison, stimulation was similarly applied to the left hind limb, which did not perform nerve ligation. The threshold was examined. From the obtained results, AUC (time after administration (elapsed time) / area surrounded by a time response curve and a baseline in a graph showing a relationship with oMPE) was calculated. The anti-allody effect was divided by AUC divided by the measurement time and compared as the strength of action per unit time.

 [0201] <Test results>

 By administering each dose of SS8225—04 (0.125 to 0.7 mg / kg subcutaneously) and SS8225—07 (0.125 to: LmgZkg subcutaneously) morphine (2.5 to LOmgmgZkg subcutaneously) Alodiure was measured.

 [0202] At this time, SS8225-04 was used! /, And the results were shown in Fig. 39 (graph showing the relationship between the subcutaneous dose of SS8225-04 and AUC), and Figs. — Subcutaneous doses of 04 (per mouse body weight) are 0.125 mgZkg (body weight), 0.25 mg / kg (body weight), 0.5 mg / kg (body weight)! / ヽ ί or 0.7 mg / kg (Weight)) [This, SS8225-07 is used! The results when SS8225-07 is used are shown in Fig. 44 (graph showing the relationship between the subcutaneous dose of SS825-07 and AUC), and Figs. 45 to 48 (SS8225, respectively). — When the subcutaneous dose of 07 (per body weight) is 0.125 mgZkg (body weight), 0.25 mgZkg (body weight), 0.5 mgZkg (body weight) or 1.0 mgZkg (body weight), respectively, and morphine is used The results of Fig. 49 (graph showing the relationship between the subcutaneous dose of morphine and AUC) and Figs. 50 to 53 (each subcutaneous dose of morphine (per body weight) were 2.5 mgZkg ( Heavy), 3. 5mgZkg (body weight), 5 mg / kg (body weight), the 7MgZkg (body weight) or LOmgZkg (body weight)), respectively.

 [0203] From these graph powers, the peptide derivatives of the present invention, SS8225-04 and SS8225-07, show a high anti-nociceptive effect, and the dose for obtaining the same anti-nociceptive effect is 1Z10 compared to morphine. It was confirmed that ˜1Z20 was sufficient, and that the duration of the anti-nociceptive action at that time was about twice as long as that of morphine.

[0204] Neuropathic pain is known to have resistance to morphine, an opioid, with alodysia as the main symptom. In this experiment as well, a significant attenuation of anti-allodynia was observed in the left hind limb ligated with the sciatic nerve by subcutaneous administration of morphine. However, at each dose of SS822 5-04 and SS8225-07, an attenuation of the anti-allody was recognized. I couldn't help it. From these results, it was revealed that SS8225-04 and SS8225-07 differed from monolehine in that the anti-allody effect was not diminished.

 [0205] As described above, even in an experiment with a nerve damage model assuming a neuropathic pain, the present invention [the peptide derivatives SS8225-04 and SS8225-07ίMA 高! And it was confirmed that it has an anti-allody effect that does not attenuate.

 [0206] 7.Anti-nociceptive action, part 3 (Tail—pressre test, pressure stimulation test)

 A pressure stimulation test was conducted to examine the possibility of application to the above-mentioned Till'flick method (thermal stimulation) and anti-nociceptive effects on pain other than neuropathic pain in a nerve injury model

[0207] <Measuring method>

 The above-described peptide derivatives of the present invention, SS8225-04 and SS8225-07, and morphine as an anti-nociceptive drug that has been used in the prior art, are used in the prescribed amounts, subcutaneously or orally administered to the ridge of mice. Pressure was applied to the part at a rate of 133 Pa (lOmmHg) Z seconds, and the pressure that showed behavior such as struggling and itching to the stimulation site was measured, and this was used as the pain response threshold. In the experiment, mice that responded to a pressure of 532 to 665 Pa (40 to 50 mmHg) in advance were used. The maximum stimulation pressure was 1333 Pa (100 mmHg).

 At this time. / oMPE was calculated by the formula (I) as described above.

 [0208] <Test results>

 Figure 55 shows the time course of the antinociception in the Till Pressure Test after subcutaneous administration of SS8225-04, Figure 56 shows the dose-response curve at that time, and Till after oral administration of SS822 5-04 A graph showing the time course of the antinociception in the pressure test is shown in FIG. 57, and a graph showing the dose-response curve is shown in FIG.

[0209] Fig. 59 shows a graph showing the change over time of the antinociception in the til pressure test after subcutaneous administration of SS8225-07, and Fig. 60 shows a graph showing the dose-response curve at that time. A graph showing the time course of antinociception in the till pressure test after oral administration of 07 is shown in FIG. 61, and a graph showing the dose-response curve at that time is shown in FIG. [0210] Furthermore, a graph showing the time course of antinociception in the Tille pressure test after subcutaneous administration of morphine is shown in Fig. 63, and a graph showing the dose-response curve at that time is shown in Fig. 64. Oral administration of morphine A graph showing the time course of the antinociception in the later pressure test is shown in FIG. 65, and a graph showing the dose-response curve at that time is shown in FIG.

 [0211] From these graph powers, the peptide derivatives of the present invention, SS8225-04 and SS8225-07, show a high anti-nociceptive effect, and the dose to obtain the same anti-nociceptive effect as compared with morphine is 1Z10. ~ 1Z20 is sufficient, and the duration of antinociception is 6 hours or more after subcutaneous administration (subcutaneous administration) or 12 hours or more (oral administration). It was confirmed that it was much longer.

 [0212] Here, AUC was calculated from the results of oral administration and subcutaneous administration of these drugs, and the relationship between the dose and AUC was plotted with the AUC on the vertical axis and the dose on the logarithmic horizontal axis. Figure 67 and Figure 68 show the results as a draft.

 [0213] From these figures, in SS8225-04 and SS8225-07 according to the present invention, in order to obtain the same AUC, both oral administration and subcutaneous administration were performed at dosages of 1Z100 to 1Z20 of morphine dosage. This is sufficient, and if the dose is relatively high, the usual dose of morphine is far from possible!ヽ It is understood that an anti-nociceptive effect can be obtained.

 [0214] 8. Anti-nociceptive activity test, part 4 (Anti-nociceptive activity test when MSU-induced knee pain was artificially generated assuming pain due to knee osteoarthritis)

 MSU-induced knee joint pain was artificially generated as a model of pain due to osteoarthritis of the knee, and its antinociceptive effect on this pain was evaluated in comparison with that of morphine and oxycodone.

 [0215] <Laboratory animal>

In the experiment, SD male rats weighing 170 to 190 g were used. Breeding in a constant environment of 12 hours light / dark cycle (light period; 7:00 to 19:00, long period; 19:00 to 7:00), room temperature 23 ± 1 ° C, humidity 52 ± 2% did. The animals used are allowed to freely take solid feed (solid feed for experimental animals: F2, Funabashi Farm, Chiba) and tap water for at least 2 days. Preliminarily reared in the laboratory.

 [0216] <Study drug>

 Morphine (Sankyo), oxycodone (Marincklot), SS8225-04 and SS8225-07 were used. All test drugs were dissolved in Ringer's solution (Fusan Yakuhin).

 [0217] <Administration of inflammatory substance (sodium urate salt needle crystal; MSU)>

 1 mL of a dispersion medium (10% polyoxyethylene sorbitan monoleate (Tween 80; Nacalai Testa) -containing physiological saline) was suspended per MSUO.lg. After anesthetizing the animal with diethyl ether, the surface of the left hind limb knee joint of the subject animal was wiped with 70% ethanol cotton, and the above suspension was administered as a bolus into the left hind limb knee joint cavity.

[0218] <Measurement of both hind limb plantar load and calculation of both hind limb plantar load ratio (ppr)>

 Using the plantar load measuring device, the load applied to the plantar of both hind limbs was measured and recorded. The measurement time at each time point was 45 seconds. The calculated value obtained by dividing the measured load on both hind limbs by V and the load value exerted on the left hind limb by the load value exerted on the right hind limb was designated as ppr (paw-pressure ratio).

[0219] <Calculation of maximum effective response rate (% MPE)>

 Antinociceptive activity was evaluated using the maximum effective response rate (% MPE) calculated from the following formula (Π).

[0220] [Equation 2]

 (pprl— pprO)

 % MPE = X 100 …… (II)

 (1 -pprO)

[0221] In the formula, pprO and pprl were the ratios of plantar loads of both hind limbs before and after drug administration, respectively. The ED value of anti-nociceptive action is GraphPad Prism.

 50

 version 4.00a; San Diego, CA, USA: data graphing software).

[0222] <Calculation of area under the curve (AUC)> The strength of the anti-nociceptive action was expressed by calculating the AUC in the time course of the anti-nociceptive action using the above graph pad prism. In addition, the ED value of anti-nociceptive action is

 50

 For each measurement, “100% (theoretical maximum value at each measurement) X measurement time (minutes)” was set as the theoretical maximum AUC and calculated using the above graph pad prism.

 [0223] <Experimental method>

 Four hours after MSU administration, the plantar load was measured twice, and each ppr was calculated. The average value was defined as the ratio of the plantar load of both hind limbs before drug administration. After measuring the plantar load of both hind limbs before drug administration, Ringer's solution or Ringer's solution in which the test drug is dissolved is orally administered at a rate of 0.1 mL per lOOg of rat's body weight. The sole load was measured once.

 [0224] <Statistical analysis>

 Statistical processing was performed using the above graph pad prism. After the two-way analysis of variance process, a post-test is performed using the Bonferroni method, and a risk rate of less than 5% is judged to be significant, and less than 5% (P 0. 05) and less than 1% In the same way as in the case of the Till 'flick method, it is displayed with "*" and "* *".

 [0225] <Experimental result>

The results of examining the effects of each test drug on the pain induced by administering MSU into the hindlimb knee joint cavity of rats are shown in FIGS. That is, with respect to the time course of ⁰ / oMPE after oral administration, the results for each dose of morphine, oxycodone, SS8225-04 and SS8225-07 are shown in FIGS. 69 to 72, respectively. The results of AUS and SS8225-07 are shown in Fig. 73-76. Fig. 77 shows a graph with AUC on the vertical axis and dose on the logarithmic horizontal axis, and Fig. 78 shows a graph with% MPU on the vertical axis and dose on the logarithmic horizontal axis. It was.

[0226] From these FIG. 69 to FIG. 72, the duration of action by oral administration is as follows: morphine, oxycodone, SS8225-04 and SS8225-07, administration groups [300 !, 120 minutes, 420 minutes and 360 minutes, duration of action of oxycodone, SS8225-04 and SS8225-07 is 0.4, 1.4 and 1.2 times respectively compared to morphine results It turns out that it is. In addition, the peak of action is morphine, oxycodone, SS8225-04 and SS8225-07. This is 90 minutes, 60 minutes, 180 minutes, and 120 minutes, respectively. Monolehine, talented xycodone, SS8225-04 and SS8225-07

 50

 Group (37.23 (17.65 to 78.56) mg / kg, 10.35 (8.09 to 13.25) mg / kg, 15.84 (11.24 to 22. 32) mg / kg, and 16. 95 (3.17-90.5 9) mgZkg, and the antinociceptive effects of oxycodone, SS8225-04 and SS8225-07 are about 3.6 times each compared to morphine , About 2.4 times and about 2.2 times, great strength.

[0227] In addition, a comparative study was performed using Fig. 73 to Fig. 76, which are diagrams showing the results of calculating AUC in the time course of antinociception. The AUC for oral administration is 1 283 in the Ringer's solution group, 1724, 4485 and 13883 in the morphine 15, 30 and 60 mgZkg groups, and 2525 in the oxycodone 7.5, 15 and 30 mgZkg groups, respectively. , 6363 and 10562, SS8225-04 for 7.5, 15 and 30 mgZkg, respectively, 6410, 8133 and 24702, SS8225-07 for 7.5, 15 and 3031 ₈ / 1¾ for each group 2919, 7894 and 20162. ED value of AUC ί, monoleine, aged xycodone, SS8225-04 and SS8225-07

50

 86.38 (48.89 to 152.6) mg / kg, 49.35 (9.98 to 243.9) mg Zkg, 34.10 (3.36 to 345.8) mgZkg and 40. 38 (31.08-52.48) mg / kg, an anti-nociceptive effect of aged xycodone, SS8225—04 and SS8225—07 about 1.8 times, 2.5 times and About 2.1 times more powerful.

 [0228] Also, according to Fig. 77 and Fig. 78, in the model experiment of pain due to knee osteoarthritis, SS82 25-04 and SS8225-07 have a higher anti-nociceptive effect than monolehine, which is equal to or higher than oxycodone I understand that.

 [0229] 9. Anti-nociceptive effect test, part 5 (Test in artificially generated inflammatory pain model assuming pain caused by rheumatoid arthritis)

 In mice in which inflammatory pain was generated using adjuvant, the nociceptive effect of SS8 225-04 according to the present invention upon oral administration was examined in comparison with morphine.

 [0230] <Animal used>

For the experiment, ddY male mice (Japan SLC) weighing 15-20 g were used. Animals are real Alum cycle for 12 hours until use in the test (light period 7:00 to 19:00, season 19:00 to 7:00) Raised in a constant environment at room temperature 23 ± 1 ° C and humidity 52 ± 2% . Animals were given free access to water and mouse chow (F2, Funabashi Farm) and were kept in the laboratory for at least 2 days.

 [0231] <Use drug>

 Complete Freund's Adjuvant (hereinafter also referred to as “CFA”) (SIGMA), morphine and SS8225-04 were used. Morphine and SS8225-04 were dissolved in Ringer's solution and administered orally.

 [0232] <Inflammatory pain model>

 In the inflammatory pain model, mice were fixed with no anaesthesia, and 25 μL of Freund's complete adjuvant (CFA) was injected subcutaneously into the left hind limb using the 30 gauge needle (Terumo). Made. Then, it reared on the above-mentioned rearing conditions until the measurement day.

 [0233] <Measurement method>

 Measurement of the antinociceptive effect in inflammatory pain model animals was performed 5 days after CFA administration by the von Frey filament method, as in the above-mentioned nerve injury model. The drug was administered orally.

 [0234] <Data analysis method>

 Changes in the threshold after drug administration were measured over time, and AUC was calculated from the obtained results. The anti-nociceptive activity was expressed as a total AUC value or a unit time AUC value (Α UCZmin) obtained by dividing AUC by the measurement time, and then compared. The ED value for antinociception is the unit time AUC value.

 50

 Calculated by setting the upper limit of 2.0 to 2.0 and converting the measured value to a percentage of the upper limit

[0235] <Experimental result>

 Inflammatory pain model

 On day 5 of CFA administration, the pain threshold for the CFA non-administered foot was about 0.50 g weight, whereas the pain threshold for the CFA treated foot was about 0.25 g weight. In this way, an obvious inflammatory halodia was observed.

[0236] <Anti-nociceptive effects of morphine> The results of morphine anti-nociceptive experiments are shown in Fig. 79 (results on the non-CFA-administered side foot) and Fig. 80 (results on the CFA-administered side foot) However, it varies greatly from individual to individual, and the data 60 minutes after administration of morphine lOOmgZkg varied particularly remarkably, so the data are omitted in FIGS. 70 and 80).

 [0237] Oral administration of morphine (35, 70, or 100 mg / kg) produced a dose-dependent antinociception peaking at 30 minutes after administration, and its duration was 360 minutes. When the anti-invasion action was compared between the CFA non-administered foot and the CFA-administered foot, the total AUC value and unit time in the CFA-administered foot were the same as the total AUC value and unit time in the CFA-untreated foot. Each AUC value was about 60%. The total AUC value in the lOOmgZkg oral administration group was 556 in the CFA non-administered foot and 328 in the CFA-administered foot. On the other hand, using the unit time AUC value (AUCZmin), the ED

 When the 50 values were calculated, the ED values in the CFA non-administered foot and the CFA administered foot were

 50 were 67.88 mgZkg and 113. OmgZkg, respectively. The unit time AUC value in the lOOmgZkg oral administration group was 1.545 in the CFA non-administered paw and 0.910 in the CFA-administered paw.

 [0238] <Anti-nociceptive action of SS8225-04>

 The results of an antinociceptive action test for SS8225-04 are shown in Fig. 81 (results on the non-CFA-treated side foot) and Fig. 82 (results on the CFA-treated side foot)

[0239] Oral administration of SS8225-04 (7, 10, some 14 mg / kg) [From this, a dose-dependent anti-nociceptive action peaking at 300 minutes after the onset occurred, but its duration Was very persistent compared to morphine at 720 minutes. When the anti-nociceptive effect was compared between the CFA non-administered foot and the CF A-administered foot, the total AUC value and unit time AUC value in the CFA-administered foot were determined as the total AUC value and unit time in the CFA non-administered foot. Each AUC value was about 60%. The total AUC value in the 14 mgZkg oral administration group was 1058 in the CFA non-administered paw and 577 in the CFA administration paw, which was approximately twice that of the morphine lOOmgZkg administration group. On the other hand, when the ED value of the anti-invasion action was calculated using the unit time AUC value (AUCZmin), it was found in the CFA non-administered foot and the CFA administered foot. The ED values are 9.849 and 17.04 mgZkg, respectively.

50

 Both non-administered and CFA-administered feet were 6.6 to 6.9 times higher than morphine. The unit time AUC value in the 14 mgZkg oral administration group was 1.470 in the CFA non-administered paw and 0.814 in the CFA administration paw.

 [0240] Here, AUC and AUC per unit time (unit time AUC) were calculated from the results of oral administration with SS8225-04 and morphine, and the relationship between the dose and AUC Fig. 83 is a graph showing the dose on the horizontal axis of the logarithm, and the relationship between the dose and the short-term AUC is shown in the unit time AUC on the vertical axis and the dose on the logarithmic horizontal axis. The graph is shown in Figure 84.

 [0241] From FIG. 83, in SS8225-04 according to the present invention, in order to obtain the same AUC, the dosage of 1Z100 to 1Z50 of the morphine dosage is sufficient, and furthermore, when the dosage is relatively large Is understood to have an extremely high anti-nociceptive effect, which is far from obtainable with normal morphine doses. Further, in FIG. 84, in order to obtain the same AUC per unit time, in SS8225-04, administration of 1Z8 to 1Z4 of morphine dose is sufficient.

 [0242] It should be noted that the above is a force for comparison with morphine and other conventional drugs having anti-nociceptive effects for comparison of anti-nociceptive effects. The present invention can also be applied to other fields where conventional drugs are not used, and such a case is naturally included in the present invention.

[0243] 10. Assessment of acute toxicity

 According to the present invention, the ED (subcutaneous administration) in Table 2 of SS8225-04 is 0.05 mg / k.

 50

 The acute toxicity was evaluated using doses of lOOmg Zkg, 50mgZkg, 25mgZkg, and 6.25mgZkg, which are 2000 times, 1000 times, 500 times, and 125 times this value.

 [0244] As experimental animals, ddY male mice weighing 22 to 25 g were used, and 5 mice were used each, and the number of deaths within 72 to 96 hours after administration was examined. Similarly, the ED (subcutaneous administration) in Table 2 of Morphine was 2.51 mgZkg.

 50

The number of deaths was examined in the same manner using OOOmgZkg and 500mgZkg respectively. Result The results are shown in Table 3.

[0245] [Table 3]

 [0246] [Table 4]

表 4より、本発明に力力る SS8225— 04で ίま ED (皮下投与）の値の 2000倍及び

Table 4 shows that SS8225-04, which is powerful in the present invention, is 2000 times the value of ί or ED (subcutaneous administration) and

 50

 The mortality rate when administered 1000 times was 20%, the mortality rate was 0% when administered 500 times, but morphine was given 400 times the ED (subcutaneous dose) value. Is death

 50

 It was found that the mortality rate was 100%, and it was confirmed that SS8225-04, which also contributes to the present invention, has a sufficiently low acute toxicity.

Claims

Claims General formula (1) R1N = C (R2) AA1-AA2-AA3-AA4-Y  (1) or a pharmaceutically acceptable salt thereof, R ¹ is ^one selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group, R ² is a lower alkyl group, and Y is the following chemical formula: (2) -n (R ³ ) R ⁴  (2) In the chemical formula (2), R ³ and R ⁴ are each independently a force 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 attached together with the nitrogen atom to which they are bonded, The above AA ¹ is represented by the following chemical formula (3) [Chemical 1]

 A amino acid residue represented by (3), In the chemical formula (3), R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, A secondary alkyl group and a halogenated lower alkyl group, one of which is selected. In the chemical formula (3), X is a hydrogen atom, a halogen atom, a hydroxyl group, a group represented by the following chemical formula (4), And a group represented by the following chemical formula (5): O—CO—R.  (4) O— CO— O— R Wherein R ^{7 in} chemical formula (4) and R ^{8 in} chemical formula (5) are each independently a C alkyl group, a hydroxy C alkyl group, an amino C alkyl group, (mono Low 1-16 1-16 1-16 Secondary alkyl) amino C alkyl group, (di-lower alkyl) amino C alkyl group, C  1-16 1-16 3-cycloalkyl group, C cycloalkyl-substituted lower alkyl group, C alkenyl group 10 3-10 2-16  C alkyl group, heterocyclic group, aryl group, and aryl substituted lower alkyl group 2-16 Is one selected from The above AA ² has the following chemical formula (6) [Chemical 2] R ⁹ I

(6) is a D-a-amino acid residue represented by chemical formula (6), wherein R ⁹ is an amino group, (mono lower alkyl) amino group, lower acylamino group, gua-dino group, 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 alkyl group Sil group and hydroxy lower alkyl group power are one selected, n is an integer of 1 to 4, and AA ³ is an unsubstituted phalaranine residue, a substituted phalaranine residue, an unsubstituted D-phenol. -Luranine residue and substituted D-ferulanine residue power is one selected, and the above AA ⁴ is represented by the following chemical formula (7) N (R ¹⁰ )-CH (R ⁿ )-CO- A amino acid residue represented by (7) or the following chemical formula (8) N (R ¹⁰ )-CH (R ⁿ )-CH (R ¹² )-CO- Β amino acid residue represented by (8), In chemical formulas (7) and (8), R ^1C> and R ¹² 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. One is R ¹¹ is a hydrogen atom or the following chemical formula (9) Z-諫¹³ )-R ¹⁴  A group represented by (9), In the chemical formula (9), Z is one selected from a lower alkylene group, a lower alkylene group, and a lower alkylene group, and R ¹³ and R ¹⁴ are each independently a hydrogen atom, One selected from an alkyl group, an aryl group, and an aryl-substituted lower alkyl group, or R ¹³ and R ¹⁴ include a 5-membered or 6-membered atom together with the nitrogen atom to which they are bonded. A compound represented by chemical formula (1) or a pharmaceutically acceptable salt thereof, which is a nitrogen heterocyclic group [2] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom. [3] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ² is a methyl group or an ethyl group. [4] The above AA ³ is represented by the following chemical formula (10)  [Chemical 3]

 A amino acid residue represented by 0 or the chemical formula (11)  [Chemical 4]

In the above chemical formulas (10) and (11), R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, and a no, a rogen. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the lower alkyl group strength is one selected. The above AA ³ is a phalaranin residue, a D pheraranin residue, p-fluorophenol. -Luran residue, D—p-fluorophenyl-lanalanin residue, o—trifluoromethylphenylalanine residue, D—o—trifluoromethylphenylalanine residue, and 2, 6 — The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is an amino acid residue having a group power that is also a dimethylphenolalanine residue. [6] The compound according to any one of claims 1 to 5, wherein AA ⁴ is an N-methyllysine residue or an N-methyl-1-β-alanine residue, or a pharmaceutically acceptable salt thereof. Salt.  [7] The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein X is a hydroxyl group in the chemical formula (3).  [8] In the above chemical formula (3), X is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. .  [9] In the chemical formula (3), X is represented by the chemical formula (4) or the chemical formula (5). In (4) and R ^{8 in} the chemical formula (5) are independently C alkyl  1-16 group, hydroxy C alkyl group, amino C alkyl group, (mono lower alkyl) amino  1-16 1-16  C alkyl group, (di-lower alkyl) amino C alkyl group, C cycloalkyl group 1-16 1-16 3-10 group, C cycloalkyl-substituted lower alkyl group, C alkyl group, C alkyl The compound according to any one of claims 1 to 6, which is one selected from 3- 10 2-16 2-16 group, aryl group, heterocyclic group, and aryl group-substituted lower alkyl group. Or a pharmaceutically acceptable salt thereof. [10] the alpha alpha ¹ tyrosine residues, 2, 6-dimethyl chromatography tyrosine residues, o-Ashiruchiroshin residues, o-alkoxycarbonyl - Ruchiroshin residues, o-Fuenokishikarubo - Ruchiroshi down residues, o-Asechiru The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein a tyrosine residue and a 2,6-dimethylphenylalanine residue are also selected. [11] The above alpha alpha ² is, D- methylol O Nin sulfoxide residues, D- arginine residues and, is one which is also selected D- shea Torurin residues force, any one of claims 1 to 9 Or a pharmaceutically acceptable salt thereof. [12] ΑΑ ² above is D— Ν ⁵ — acetylortin residue, D— 5-oxonorleucine residue And the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, which is one selected from D-5 hydroxynorleucine residues. [13] The method according to any one of claims 1 to 9, wherein R ³ and R ⁴ are each independently one selected from a hydrogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxyl group. A compound according to item 1 or a pharmaceutically acceptable salt thereof. [14] The R ¹ is a hydrogen atom, the R ² is a methyl group, and the AA ¹ is. -Acetyl tyrosin residue, AA ² is a D methionine sulfoxide residue or D arginine residue, AA ³ is a ferrolanine residue, and AA ⁴ is an N-methyllysine residue or N —Methyl-13-alanine residue, where Y is NH or NH—CH  2 3 or a pharmaceutically acceptable salt thereof according to claim 1. [15] The R ¹ is a hydrogen atom, the R ² is a methyl group, the AA ¹ is a tyrosine residue, and the AA ² is a D-methionine sulfoxide residue or a D-arginine residue. AA ³ is a ferroalanine residue, AA ⁴ is an N-methyllysine residue or N-methyl-j8-alanine residue, and Y is —NH or —NH—CH. Claim  twenty three  Item 6. The compound according to Item 1 or a pharmaceutically acceptable salt thereof. [16] The above R ¹ is a hydrogen atom, the R ² is a methyl group, the AA ¹ is. -Acetyl tyrosin residue, AA ² is a D methionine sulfoxide residue or D arginine residue, AA ³ is a ferrolanine residue, and AA ⁴ is an N-methyllysine residue or N 2. A methyl-13-alanine residue, wherein Y is —NH—CH.  twenty five  Or a pharmaceutically acceptable salt thereof. [17] The R ¹ is a hydrogen atom, the R ² is a methyl group, the AA ¹ is a tyrosine residue, the AA ² is a D-5-hydroxynorleucine residue, and the AA ³ is a phenolic residue, said AA ⁴ is an N-methyllysine residue or an N-methyl-β-alanine residue, and said Υ is —ΝΗ or NH—CH. Compound or  twenty three  Is a pharmaceutically acceptable salt thereof. [18] The R ¹ is a hydrogen atom, the R ² is a methyl group, the ΑΑ ¹ is a tyrosine residue, the ΑΑ ² is a D-methionine sulfoxide residue, and the ΑΑ ³ Is a phalalanin residue, and 上 記⁴ above is a Ν-methyllysine residue or Ν-methyl-13-alanine residue. The compound according to claim 1, wherein Y is —NH or NH—CH.  twenty three  Pharmaceutically acceptable salt of [19] The R ¹ is a hydrogen atom, the R ² is a methyl group, the AA ¹ is a 2,6 dimethyl-tyrosine residue, and the AA ² is a D methionyl sulfoxide residue! /, Is a D-arginine residue, the AA ³ is a ferroalanine residue, the AA ⁴ is an N-methyllysine residue or an N-methyl-13-alanine residue, and the Y is —NH or  2  2. The compound according to claim 1, which is NH-CH, or a pharmaceutically acceptable salt thereof.  Three  [20] A pharmaceutical composition comprising, as an active ingredient, at least one of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.  [21] A pharmaceutical composition comprising at least one of the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  [22] The pharmaceutical composition according to claim 19 or 20, which is used for prevention and Z or treatment of pain.  23. The pharmaceutical composition according to claim 22, wherein the pain is cancer pain. 24. The pharmaceutical composition according to claim 22, wherein the pain is neuropathic pain.  25. The pharmaceutical composition according to claim 22, wherein the pain is pain due to knee osteoarthritis.  26. The pharmaceutical composition according to claim 22, wherein the pain is pain due to rheumatoid arthritis.