KR20020038400A - Ring-peptide compounds combining disulfide bond acting to melanocortin receptors - Google Patents

Abstract

PURPOSE: Provided is a cyclic peptide type compound which are bound by disulfide bond and specifically acts on a receptor of melanocortin. Also, provided is a composition which contains the above compound as an active ingredient. CONSTITUTION: The cyclic peptide type compound is represented by the formula(1) or (2) in which W is C1-10 alkyl; each E1, E2, E3, E4, E5, E6 and E7 is amino acid or its derivative; sulfur atoms of E2 and E7 are bound together; and each a, b is individually 0 or 1. The compound contains the cyclic peptide compound bound by disulfide bond as an active ingredient and acts on melanocortin receptor as antifungal agent or antagonist.

Description

Ring-peptide compound bound with distalide {RING-PEPTIDE COMPOUNDS COMBINING DISULFIDE BOND ACTING TO MELANOCORTIN RECEPTORS}

[Industrial use]

The present invention relates to a cyclic peptide-type compound that is bound by disulfide to act on the melanocortin receptor. In particular, it relates to peptides, peptide derivatives, or small molecule agonists that exhibit specificity to melanocytes, which act as anti- or antagonists of melanocytes.

[Prior art]

Pro-opiomelanocortin (POMC; Pro-opiomelanocortin) is derived from the POMC gene and is mainly expressed in the hypothalamus, pituitary gland, and brain stem of the brain. It is a neuropeptide such as melanocyte stimulating hormone (beta), β-MSH, γ-MSH, adrenocorticotrophic hormone (ACTH), and shows physiological effects. Melanocortin peptides regulate various physiological phenomena according to their affinity for each of the melanocortin receptors, known for skin pigmentation, body temperature, inflammation, appetite and behavioral control [Mountjoy KG, et al., Mol Cell Endocrinol 1997]. , 128 (1-2): 171 to 7].

Melanocortin receptors belong to the G-protein receptor and all five types have been identified so far and have been cloned. Melanocortin receptor 1 is expressed in melanocytes and macrophages, and in melanocytes, the color of skin and hair is determined by controlling melanin pigment. Melanocortin receptor 2 is expressed in the adrenal and adipose tissues and is well known for the mediating function of parathyroid hormone secretion by adrenal cortex stimulating hormone in the adrenal glands. Melanocortin receptors 3, 4, and 5 are thought to mediate central nervous system action by melanocortin peptides, which are expressed not only in the terminal but also in the brain, resulting in effects on behavior, learning, memory, appetite, nerve development and regeneration. . To date, melanocortin receptor 3 is known to be involved in erectile dysfunction and inflammatory response, and melanocortin receptor 4 is associated with obesity and diabetes. However, studies on the specificity of action of each receptor have been insufficient [Haskell-Luevano C, et al., Drug News Perspect 1999, 12 (4): 197-205].

Of these, melanocortin receptor 4 has been shown to play an important role in appetite control by genetic studies in humans actively related to obesity, and studies using artificial or natural mutations or knockout mice in animals. Lu D, Willard D, et al., Nature 1994, 371 (6500): 799-802; Huszar D et al., Cell 1997, 88 (1): 131-41; Hinney A, et al., J Clin Endocrinol Metab 1990, 84 (4): 1483-6].

As the melanocortin receptors are found to be involved in the regulation of various important physiological phenomena, the search for agonists or antagonists is active, and they are mainly studied through the structural activity correlation with peptides that change the combination of amino acids. . NDP-MSH (Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Po-Val-NH ₂ ) and MTII (Ac-Nle-c) [Asp-His-DPhe-Arg-Trp-Lys] -NH ₂ ) is α-MSH (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-) for melanocytein receptor 1, 3, 4, 5 Arg-Trp-Gly-Lys-Po-Val-NH ₂ ) (Haskell-Luevano C, et al., J Med Chem 1997 May 23; 40 (11): 1738-48). The abbreviations for amino acids used above were named according to the IUPAC-IUB Joint Conference on Biochemical Nomenclature for Amino Acids and Peptides (Eur. J. Biochem. 1984, 158, 9-31). In particular, the melanocortin receptor-acting peptide MTII is absorbed by the subcutaneous injection route and then passed through the Blood Brain Barrier (BBB) to show effects on the central nervous system [Dorr RT, et al., Life Sci 1996; 58 (20): 1777-84].

Therefore, much research on the screening and selection of agonists and antagonists of peptides, peptide analogues or small molecule types that act on melanocytes and specific to each is necessary.

In view of the problems of the prior art, an object of the present invention is to provide a cyclic peptide-type compound that binds to melanocytes receptors with excellent dissipide.

Another object of the present invention is a composition comprising a cyclic peptide-type compound coupled to the disulfide as an active ingredient skin cosmetics or tanning cosmetic composition, a composition for external application of skin, and inflammation, erectile dysfunction, diabetes, pathological hypotony It is to provide a composition for the prevention and treatment of MCR hyperactivity and dysfunction-related diseases, such as a composition for the treatment of withdrawal symptoms, obesity, and opioid poisoning.

1, 2, 3 and 4 are graphs showing the results of the receptor binding test to determine whether the transformed HEK293 cells express the melanocortin receptor.

The present invention to achieve the above object,

It provides a cyclic peptide-type compound which is bound by disulfide represented by the formula (1) or (2):

[Formula 1]

[Formula 2]

In the formula 1, or 2,

The sulfur element of E _{2 and} the sulfur element of E ₇ are bonded with disulfide;

a and b are each 0 or 1;

W is alkyl having 1 to 10 carbon atoms,

Alkyl having 1 to 10 carbon atoms containing nitrogen or oxygen,

Alkyl having 1 to 10 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 10 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur or oxygen,

Alkyl having 1 to 10 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 10 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino,

Alkyl having 1 to 10 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 10 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino;

E ₁ is an amino acid or a derivative of amino acids represented by Formula 3 below,

[Formula 3]

(Wherein

Each A ₁ and A ₂ is the same or different alkyl,

_One of A ₁ and A ₂ is hydrogen and the rest

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkyl amino, carboxylic acid, or amide,

Aromatic compounds in which hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide is substituted and comprises nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

E ₂ is an amino acid represented by Formula 4 or a derivative thereof,

[Formula 4]

(Wherein

A ₃ is hydrogen, alkyl having 1 to 3 carbons,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

E ₃ is an amino acid represented by Formula 5 or 6 or a derivative thereof,

[Formula 5]

(Wherein

n is 0, 1, or 2,

Each of A ₅ and A ₆ is hydrogen, alkyl of 1 to 3 carbon atoms, hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, or

Or A ₅ and A ₆ are connected to each other, each of alkyl having 1 to 3 carbon atoms,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

[Formula 6]

(Wherein

Each of A ₇ and A ₈ is the same or different alkyl,

Any one of A ₇ and A ₈ is hydrogen, and the other is alkyl having 1 to 3 carbons,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

E ₄ is an amino acid or a derivative of amino acids represented by Formula 7, or 8,

[Formula 7]

(In the above formula,

n is 0, 1, or 2,

Each of A ₉ and A ₁₀ is hydrogen, alkyl of 1 to 3 carbon atoms, hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, or

Or A ₉ and A ₁₀ are connected to each other, each having 1 to 3 carbon atoms,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

[Formula 8]

(Wherein

Each of A ₁₁ and A ₁₂ is the same or different alkyl,

Any one of A ₁₁ and A ₁₂ is hydrogen, and the other is alkyl having 1 to 3 carbons,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

E ₅ is an amino acid or a derivative of amino acid represented by Formula 9 below,

[Formula 9]

(Wherein

Each of A ₁₃ and A ₁₄ is the same or different alkyl,

Any one of A ₁₃ and A ₁₄ is hydrogen, and the other is alkyl having 1 to 3 carbons,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

E ₆ is an amino acid or a derivative of amino acids represented by Formula 10 below,

[Formula 10]

(Wherein

Each of A ₁₅ and A ₁₆ is the same or different alkyl,

One of A ₁₅ and A ₁₆ is hydrogen, and the other is alkyl having 1 to 3 carbons,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide;

E ₇ is an amino acid or a derivative of amino acid represented by Formula 11 below,

[Formula 11]

(Wherein

A ₁₇ is hydrogen, alkyl having 1 to 3 carbons,

C1-C3 alkyl containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound,

Aromatic compounds,

Aromatic compounds containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen,

Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide,

Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or

Alkyl having 1 to 3 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide.

In another aspect, the present invention is a skin peptide comprising a cyclic peptide-type compound bound by the disulfide represented by the formula (1) or (2) having excellent binding ability to the melanocortin receptor, its pharmaceutically acceptable salts, hydrates, solvates as an active ingredient Or prevention of diseases related to MCR hyperactivity and hypofunction, including cosmetic compositions for sunburn, compositions for external application of skin, and compositions for the treatment of inflammation, erectile dysfunction, diabetes, morbid appetite, obesity, and withdrawal symptoms after opioid poisoning And it provides a therapeutic composition.

Hereinafter, the present invention will be described in more detail.

The cyclic peptide-type compound bound to the disulphide of the present invention modulates the activity of the melanocortin receptors, and thus, the cosmetic composition for skin whitening or suntan, the composition for external application of skin, and inflammation, erectile dysfunction, diabetes, pathological hypogonadism, obesity, and It is useful for the prevention and treatment of MCR hyperactivity and dysfunction-related diseases such as the composition for the treatment of withdrawal symptoms after opioid poisoning.

In the present invention, the cyclic peptide-type compound bound by the disulfide is represented by Chemical Formula 1.

In the general formula (1) of the present invention, preferred WC = O is selected from the group consisting of an acetyl group, 3-phenylpropionyl group, 4-phenylbutyl group and 5-phenylvaleryl group.

In formula (1) or (2) of the present invention, preferred E ₁ is noleucine.

In formula (1) or (2) of the present invention, preferred E ₂ is cysteine.

In formula (1) or (2) of the present invention, preferred E ₃ is histidine, or proline.

In formula (1) or (2) of the present invention, preferred E ₄ is phenylalanine.

In formula (1) or (2) of the present invention, preferred E ₅ is arginine.

In formula (1) or (2) of the present invention, preferred E ₆ is tryptophan.

In formula (1) or (2) of the present invention, preferred E ₇ is cysteine.

The compounds of the present invention may have asymmetric carbon centers and may exist as racemates, racemic compounds, diastereomeric mixtures, or individual diastereoisomers, all of these isomeric forms being included in the present invention.

The cyclic peptide-type compound bound to the disulfide of the present invention is prepared by the following general synthetic method. This method manufactures one by one from the C terminal.

a) repeating the reaction of adding piperidine to 4- (2 ', 4'-dimethoxyphenyl-Fmoc-aminomethyl) phenoxy resin to remove 9-fluorenyl methoxy carbonyl (Fmoc);

b) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluranium hexafluorophosphate with the C-terminal amino acid on the desired sequence in the resin from which Fmoc has been removed in step a) Adding hydroxy benzotriazole, and diisopropylamine, respectively, to prepare a peptidyl-resin having extended peptide bonds;

c) removing Fmoc used for the C-terminal amino acid bound to the resin by adding piperidine to the peptidyl-resin prepared in step b);

d) amino acid, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluranium hexafluorophosphate, hydroxy, of the following sequence in the resin from which Fmoc was removed in step c): Adding benzotriazole and diisopropylamine, respectively, to prepare a peptide-resin;

e) repeating steps c) and d) above using amino acids conforming to the desired sequence to produce the desired peptide sequence;

f) adding trifluoro acetic acid, triisopropyl silane, and water to the peptidyl resin prepared in step e), separating it from the resin through a glass filter, and distilling under reduced pressure to recrystallize with ethyl ether;

g) purifying the disulphide bond formed by adding dimethyl sulfoxide (DMSO) to the peptide recrystallized in step f) by liquid chromatography and lyophilizing.

In the above production method, the piperidine concentration in steps a) and c) is preferably 15-25%.

In the above preparation method, the C terminal amino acids of steps b) and d) are equivalent to 4 equivalents of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluranium hexafluorine relative to the resin. It is preferred that lophosphate and hydroxy benzotriazole each add 1 equivalent to amino acid and diisopropylamine add 2 equivalents to amino acid.

In the above production method, the total amount used as 92.5% of trifluoroacetic acid of step f), 2.5% of triisopropyl silane, and 5% of water is preferably added 10 mL per 1 g of peptide-resin.

In the preparation method, 4 mL of 0.25 mmol of the dimethyl sulfoxide (DMSO) of step g) is preferred.

Formulas 1a to 1g list representative peptides of the present invention.

[Formula 1a]

[Formula 1b]

[Formula 1c]

[Formula 1d]

[Formula 1e]

[Formula 1f]

[Formula 1g]

The linear form of all the peptides of Formulas 1a to 1g was made using ABI's peptide synthesizer 431 A. All reactions in the synthesizer were made through a solid phase peptide reaction that linked the C terminus of the peptide to the solid resin and then extended the peptide bonds.

The amino acid used in each step of the solid phase reaction should have a protecting group suitable for the nature of each reaction, in the embodiment of the present invention the N-terminal is 9-fluorenyl methoxy carbonyl (Fmoc), the amino acid side chain protecting group Amino acids containing functional groups (Pr.) Which are stable to base and easily removed from acids were used.

Scheme 1 below illustrates the general synthetic steps of the peptides used in the present invention.

Scheme 1

The present invention will be described in more detail with reference to the following examples. However, an Example is for illustrating this invention and is not limited only to these.

Example 1

Example 1 Acetyl-Norusyl-Cyclo [Cysteinyl-Histidyl-Dphenylalanyl-Alginyl-Tryptiphyl-Cysteine] -amide Synthesis

0.25 mmol of 9-fluorenyl methoxy carbonyl (Fmoc) of 4- (2 ', 4'-dimethoxyphenyl-Fmoc-aminomethyl) phenoxy resin was removed twice with 15% piperidine. . 1 mmol of C-terminal amino acid, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluranium hexaphosphate (HBTU) and hydroxy benzotriazole (HOBT), respectively 2 mmol diisopropylamine (DIEA) was added. At this time, the resin was used after sufficiently infiltrating N-methylpyrrolidone (NMP). At the beginning and end of all the reactions on the instrument, it was sufficiently washed with NMP or methylene chloride (DCM).

The C-terminal amino acid Fmoc, which is bound to the resin, is again removed by piperidine and the next amino acid is bound, again in the same manner as the method used for the first amino acid binding. By repeating the above two steps to make a peptide of the desired sequence, the sequence of amino acids used in this order is N ^α 9-fluorenylmethoxycarbonyl-cysteine (S-triphenylmethyl), N ^α 9-flu Orenylmethoxycarbonyl-tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran- 5-sulfonyl), N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-histidine (N ^im triphenylmethyl), N ^α 9-fluorenylmethoxy Carbonyl-cysteine (S-triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl-norucine, and acetic acid in that order.

To separate from the resin and to remove the protecting groups of each amino acid, 9.25 mL of trifluoroacetic acid (TFA), 0.25 mL of triisopropyl silane, and 0.5 mL of water were added per 1 g of the resin-peptide, followed by stirring for 1 to 1.5 hours. The reaction solution was separated from the resin through a glass filter, and the separated solution was distilled under reduced pressure and then recrystallized with cold ethyl ether. The recrystallized peptide was dissolved in 4 mL of DMSO, stirred for 10 days to form disulfide bond, purified by reverse phase-high performance liquid chromatography (RP-HPLC) and lyophilized to obtain 7.9 mg (purity of 90% or more). Mass spectrometry was performed. MS / [M + H] ⁺ = 1005

Example 2 Acetyl-Cyclo [Cysteinyl-Histidyl-Dphenylalanyl-Alginyl-Tryptiphyl-D Cysteine] -amide Synthesis

Synthesis was carried out in the same manner as in Example 1. However, the order of amino acids used to make peptides of the desired sequence is N ^α 9-fluorenylmethoxycarbonyl- (D) cysteine (S-triphenylmethyl), N ^α 9-fluorenylme Oxycarbonyl-tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran-5- Sulfonyl), N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-histidine (N ^im triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl -Cysteine (S-triphenylmethyl), followed by acetic acid. It was purified, dried and frozen and mass analyzed. MS / [M + H] ⁺ = 890

Example 3 Acetyl-Norusyl-Cyclo [Cysteinyl-Histidyl-Dphenylalanyl-Alginyl-Tryptiphyl-D Cysteine] -amide Synthesis

Synthesis was carried out in the same manner as in Example 1. However, the order of amino acids used to make peptides of the desired sequence is N ^α 9-fluorenylmethoxycarbonyl- (D) cysteine (S-triphenylmethyl), N ^α 9-fluorenylme Oxycarbonyl-tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran-5- Sulfonyl), N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-histidine (N ^im triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl -Cysteine (S-triphenylmethyl), N ^alpha 9-fluorenylmethoxycarbonyl-norucine, and acetic acid. After purification, the product was lyophilized to give 23 mg (more than 90% purity), which was analyzed by mass spectrometry. MS / [M + H] ⁺ = 1003

Example 4. 3-Phenylpropane carboxyl-cyclo [cysteinyl-histidyl-Dphenylalanyl-arginyl-tryptiphyl-cysteine] -amide synthesis

Synthesis was carried out in the same manner as in Example 1. However, the order of amino acids used to make peptides of the desired sequence is N ^α 9-fluorenylmethoxycarbonyl-cysteine (S-triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl Tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran-5-sulfonyl) , N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-histidine (N ^im triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl-cysteine ( S-triphenylmethyl), 3-phenylpyrionic acid. This was purified and lyophilized to yield 13 mg (purity of 90% or more). MS / [M + H] ⁺ = 980

Example 5. 4-Phenylbutane carboxyl-cyclo [cysteinyl-histidyl-Dphenylalanyl-arginyl-tryptiphyl-cysteine] -amide synthesis

Synthesis was carried out in the same manner as in Example 1. However, the order of amino acids used to make peptides of the desired sequence is N ^α 9-fluorenylmethoxycarbonyl-cysteine (S-triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl Tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran-5-sulfonyl) , N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-histidine (N ^im triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl-cysteine ( S-triphenylmethyl) and 4-phenylbutanoic acid. This was purified and lyophilized to give 22 mg (more than 90% purity). MS / [M + H] ⁺ = 994

Example 6. 5-Phenylpentane carboxyl-cyclo [cysteinyl-Dphenylalanyl-arginyl-tryptiphyl-cysteine] -amide synthesis

Synthesis was carried out in the same manner as in Example 1. However, the order of amino acids used to make peptides of the desired sequence is N ^α 9-fluorenylmethoxycarbonyl-cysteine (S-triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl Tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran-5-sulfonyl) , N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-histidine (N ^im triphenylmethyl), N ^α 9-fluorenylmethoxycarbonyl-cysteine ( S-triphenylmethyl) and 5-phenylpentanoic acid. This was purified and lyophilized to give 19 mg (more than 90% purity). MS / [M + H] ⁺ = 871

Example 7 Acetyl-Norusyl-Cyclo [Cysteinyl-Prolyl-Dphenylalanyl-Alginyl-Tryptophil-D Cysteine] -amide Synthesis

Synthesis was carried out in the same manner as in Example 1. However, the order of amino acids used to make peptides of the desired sequence is N ^α 9-fluorenylmethoxycarbonyl- (D) cysteine (S-triphenylmethyl), N ^α 9-fluorenylme Oxycarbonyl-tryptophan (N ^im t-butyloxycarbonyl), N ^α 9-fluorenylmethoxycarbonyl-arginine (N ^g 2,2,4,6,7-pentamethyl dihydrobenzofuran-5- Sulfonyl), N ^α 9-fluorenylmethoxycarbonyl- (D) phenylalanine, N ^α 9-fluorenylmethoxycarbonyl-proline, N ^α 9-fluorenylmethoxycarbonyl-cysteine (S-triphenyl Methyl), N ^α 9-fluorenylmethoxycarbonyl-norucine and acetic acid. This was purified and lyophilized to give 3 mg (more than 90% purity). MS / [M + H] ⁺ = 963

Example 8

In order to investigate the activity of the peptide compound of the present invention prepared in Examples 1 to 7 and the human melanocortin receptor was carried out as follows. Receptor binding experiments are a method of indirectly determining whether a substance has affinity for a receptor through competition with a known ligand. In the present invention, the specified substances are well known as MCR ligands [ ¹²⁵ I] -NDP- The degree of inhibition of MCR receptor binding of α-MSH was measured by gamma counter to determine the affinity (Ki) of the substances. In the cAMP assay, when the melanocyte secretory activity is increased, the amount of cAMP is increased in the cell, thereby quantifying the amount of receptor activity.

Step 1: Cloning the Melanocotin Receptor (MCR)

The primers for polymerase chain reaction (PCR) corresponding to the 5 'and 3' ends of each gene were designed and synthesized from the nucleotide sequences of human MCRs 1, 3, 4, and 5. The primer has a restriction enzyme recognition site at the 5 'end to facilitate cloning with a human cell expression vector, and the corresponding 3' primer inserts an end codon and a restriction enzyme recognition site to start protein synthesis at the start codon. To complete at the end codon.

Four types of human MCRs 1, 3, 4 and 5 were amplified using the above primers by PCR using cDNA made from human brain tissue as a template. The gene fragment obtained by cutting the amplified gene with the restriction enzyme was inserted into a human cell expression vector (eg, pcDNA3 expression vector) to complete an expression vector containing four types of MCR 1, 3, 4, and 5 genes. After obtaining a large amount of this, HEK293 cells, which are human kidney cells, were transformed.

Step 2: Construction of Permanent Cell Line Expressing Melanocortin Receptor

In order to investigate whether the HEK293 cells transformed in step 1 express MC-R, a ligand of MCR and NDPα-MSH and radiolabeled I ¹²⁵ NDP-αMSH (Amersham, USA) are described below. Receptor binding experiments were performed as described.

As shown in Figures 1, 2, 3, and 4, the transformed cells were serially diluted in a medium containing 750 ug / mL G418 (Geneticin) to form colonies from one cell, The cell lines were isolated to identify the best cell lines by comparing their binding properties with the I ¹²⁵ NDP-MSH ligand, a derivative of αMSH. MC1R was 114 times and MC3R was 57 times. , MC4R was selected 26 times, MC5R was selected 30 colonies were used in the receptor binding test and cAMP analysis of the following experimental examples.

Step 3: receptor binding test

The MC 1R, 3R, 4R, and 5R permanently expressed cell lines (HEK) described in step 2 contain 4.5 g / 100 mL glucose, 10% fetal calf serum, 100 units / mL penicillin and stereptomycin, 200 ug / mL geneticin. Overlaid on each other in 96 well Petri dishes using DMEM medium. Receptor binding test of the test materials after the removal of the medium to wash the cells in the reaction buffer and the test material of various concentrations (10 ^-11 M ~ 10 ^-5 M) in each well, 0.1 nM [ ¹²⁵ I] -NDPα-MSH Was put into a competition assay (competition assay) for 40 minutes.

After incubation, the unbound [ ¹²⁵ I] -NDPα-MSH was removed, and the remaining radioactivity was measured by an automatic gamma counter (Wallac). The concentration of the test substance (IC ₅₀ ) that inhibited specific binding by 50% was calculated using Ki = Ki value was obtained using the formula of IC ₅₀ / (1+ [L] / Kd). These measurements were analyzed using Prism Software and the Kd values for each receptor of [ ¹²⁵ I] -NDPα-MSH were determined by saturation analysis at 12 concentrations (0.02-8 nM). . In order to measure specific binding, a measurement except for non-specific binding in total binding was used, and non-specific binding was measured in the presence of 3uM NDP-α-MSH.

As a result of measuring the binding of the test substances obtained by the above method to the receptors, the Ki values were as shown in Table 1 below.

TABLE 1

Classification Ki MC4R MC1R MC3R MC5R Compound of Example 1 1 μM or less - - - Compound of Example 2 1 μM or more - - - Compound of Example 3 1 μM or less - - - Compound of Example 4 1 μM or less - - - Compound of Example 5 1 μM or less - - - Compound of Example 6 1 μM or more - - - Compound of Example 7 1 μM or less - - -

Step 4: cAMP Analysis

MC3R and MC4R-expressing HEK cell lines were cultured in 24 well dishes for 2-3 days, and when the number of cells reached an appropriate level, the cells were washed with PBS, treated with a predetermined amount (1nM to 10uM) of test substance, and the cells were pulverized after 10 minutes. The amount of was measured in comparison with the control. Table 2 below shows the results at the 10 uM concentration.

TABLE 2

division cAMP analysis MC4R MC3R Compound of Example 1 activation - Compound of Example 2 activation - Compound of Example 3 activation - Compound of Example 4 activation - Compound of Example 5 activation - Compound of Example 6 activation - Compound of Example 7 activation -

As described above, the cyclic peptide-type compound bound by the disulphide of the present invention is excellent in the melanocortin 1,3,4,5 receptor binding ability, so that the skin composition or cosmetic composition for tanning, the composition for external treatment of skin, and inflammation, erection There is an excellent effect in the prevention and treatment of MCR hyperactivity and dysfunction-related diseases, such as a composition for the treatment of insufficiency, diabetes, morbid appetite, obesity, and withdrawal symptoms after opioid poisoning.

Claims (27)

A cyclic peptide-type compound bonded with disulfide represented by the formula (1) or (2): [Formula 1] [Formula 2] In the formula 1, or 2, The sulfur element of E _{2 and} the sulfur element of E ₇ are bonded with disulfide; a and b are each 0 or 1; W is alkyl having 1 to 10 carbon atoms, Alkyl having 1 to 10 carbon atoms containing nitrogen or oxygen, Alkyl having 1 to 10 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 10 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur or oxygen, Alkyl having 1 to 10 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 10 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino, Alkyl having 1 to 10 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or Alkyl having 1 to 10 carbon atoms including nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, or alkylamino; E ₁ is an amino acid represented by Formula 3 or a derivative thereof, [Formula 3] Where Each A ₁ and A ₂ is the same or different alkyl, _One of A ₁ and A ₂ is hydrogen and the rest C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; E ₂ is an amino acid represented by Formula 4 or a derivative thereof, [Formula 4] Where A ₃ is hydrogen, alkyl having 1 to 3 carbons, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; E ₃ is an amino acid represented by Formula 5 or 6 or a derivative thereof, [Formula 5] Where n is 0, 1, or 2, Each of A ₅ and A ₆ is hydrogen, alkyl of 1 to 3 carbon atoms, hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, or Or A ₅ and A ₆ are connected to each other, each of alkyl having 1 to 3 carbon atoms, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; [Formula 6] Where Each of A ₇ and A ₈ is the same or different alkyl, Any one of A ₇ and A ₈ is hydrogen, and the other is alkyl having 1 to 3 carbons, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; E ₄ is an amino acid or a derivative of amino acids represented by Formula 7, or 8, [Formula 7] In the above formula, n is 0, 1, or 2, Each of A ₉ and A ₁₀ is hydrogen, alkyl of 1 to 3 carbon atoms, hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, or Or A ₉ and A ₁₀ are connected to each other, each having 1 to 3 carbon atoms, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbons substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-C3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; [Formula 8] Where Each of A ₁₁ and A ₁₂ is the same or different alkyl, Any one of A ₁₁ and A ₁₂ is hydrogen, and the other is alkyl having 1 to 3 carbons, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; E ₅ is an amino acid represented by Formula 9 or a derivative thereof, [Formula 9] Where Each of A ₁₃ and A ₁₄ is the same or different alkyl, Any one of A ₁₃ and A ₁₄ is hydrogen, and the other is alkyl having 1 to 3 carbons, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; E ₆ is an amino acid represented by Formula 10 or a derivative thereof, [Formula 10] Where Each of A ₁₅ and A ₁₆ is the same or different alkyl, One of A ₁₅ and A ₁₆ is hydrogen, and the other is alkyl having 1 to 3 carbons, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or C1-3 alkyl containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide; E ₇ is an amino acid or a derivative of amino acid represented by Formula 11 below, [Formula 11] Where A ₁₇ is hydrogen, alkyl having 1 to 3 carbons, C1-C3 alkyl containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound, Aromatic compounds, Aromatic compounds containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound containing nitrogen, sulfur, or oxygen, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Aromatic compounds substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and comprising nitrogen, sulfur, or oxygen, Alkyl having 1 to 3 carbon atoms substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide, Alkyl having 1 to 3 carbon atoms substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide and substituted with an aromatic compound comprising nitrogen, sulfur, or oxygen, or Alkyl having 1 to 3 carbon atoms containing nitrogen, sulfur, or oxygen substituted with an aromatic compound substituted with hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxylic acid, or amide. [Claim 2] The cyclic peptide type according to claim 1, wherein WC = O in Chemical Formula 1 is bonded by a disulphide selected from the group consisting of acetal group, 3-phenylpropionyl group, 4-phenylbutal group, and 5-phenylvalenyl group. compound. The cyclic peptide-type compound of claim 1, wherein E ₁ of Formula 1 or 2 is bound by disulfide, which is noruscine. The cyclic peptide-type compound of claim 1, wherein E ₂ of Chemical Formula 1 or 2 is bound by disulfide, which is cysteine. The cyclic peptide-type compound of claim 1, wherein E ₃ of Formula 1 or 2 is bound to diselide, which is histidine or proline. The cyclic peptide-type compound of claim 1, wherein E ₄ of Formula 1 or 2 is bound by disulfide, which is phenylalanine. The cyclic peptide-type compound of claim 1, wherein E ₅ of Formula 1 or 2 is bound by disulfide, which is arginine. The cyclic peptide-type compound of claim 1, wherein E ₆ of Formula 1 or 2 is bound by disulfide, which is tryptophan. The cyclic peptide-type compound of claim 1, wherein E ₇ of Formula 1 or 2 is bound by disulfide, which is cysteine. The method of claim 1, wherein the compound of Formula 1 or 2 has an asymmetric carbon center and is present in any one of racemates, racemic compounds, diastereomeric mixtures, and individual diastereomers. Ring-peptide compound to be bound. The cyclic peptide-type compound of claim 1, wherein the cyclic peptide-type compound is bonded with a disulfide represented by the following Chemical Formula 1a: [Formula 1a] The cyclic peptide-type compound of claim 1, wherein the cyclic peptide-type compound is bonded with a disulfide represented by the following Chemical Formula 1b: [Formula 1b] The cyclic peptide-type compound of claim 1, wherein the cyclic peptide-type compound is bonded with a disulfide represented by the following Chemical Formula 1c: [Formula 1c] The cyclic peptide-type compound of claim 1, which is bound by a disulfide represented by the following Chemical Formula 1d: [Formula 1d] The cyclic peptide-type compound of claim 1, wherein the cyclic peptide-type compound is bonded with a disulfide represented by the following Chemical Formula 1e: [Formula 1e] The cyclic peptide-type compound of claim 1, wherein the cyclic peptide-type compound is bonded with a disulfide represented by the following Chemical Formula 1f: [Formula 1f] The cyclic peptide-type compound of claim 1, wherein the cyclic peptide-type compound is bound by disulfide represented by the following Chemical Formula 1g: [Formula 1g] Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds MCR hypothermia treatment composition comprising at least one substance selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Composition for preventing MCR hypofunction, comprising one or more substances selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Cosmetic composition for skin whitening comprising a. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Pharmaceutical composition for skin whitening comprising at least one substance selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds A composition for treating diabetes comprising at least one substance selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Inflammation treatment composition comprising a substance selected from the group consisting of at least one as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Composition for the treatment of erectile dysfunction comprising at least one substance selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Appetite lowering composition comprising at least one substance selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Composition for the treatment of obesity comprising at least one substance selected from the group consisting of as an active ingredient. Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Cyclic peptide-type compounds; Ii) bonded with a disulphide represented by the formula (1) or (2) according to claim 1; Pharmaceutically acceptable salts of cyclic peptide-type compounds; Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable hydrates of cyclic peptide-type compounds; And Iii) bonded with a disulphide represented by the formula (1) or (2) of claim 1; Pharmaceutically acceptable solvates of cyclic peptide compounds Composition for the treatment of withdrawal symptoms after opioid poisoning comprising at least one substance selected from the group consisting of as an active ingredient.