Novel multifunctional oligopeptide

Abstract

Provided are compounds of formula I, where Q a represents Z or A-Q-B, and Q is a structural fragment of formula II, [Chemical 1] TIFF2026521789000053.tif41128 wherein the wavy line, R and m have the meanings described herein, and A and B have the meanings described herein and may represent a peptide component of formula (IV), [(W) r -Lys-X 1 -T-U-X 2 [Y] n -(W) r -Lys-X 1 -T-U-X 2 -Y(IV)(SEQ ID NO: 1)(where n, r, T, W, X 1 , U, X 2 and Y have the meanings described in the specification), each L independently represents a lipid defined in the specification, D represents one or more optional montelukast moieties, and these compounds are useful in pharmaceuticals including pharmaceutical excipients, adhesives and film-forming materials, and / or in the treatment of conditions characterized by inflammation including wounds, burns, and mucosal disorders such as anorectal diseases, inflammatory bowel diseases, gynecological diseases and dental diseases.

Description

[Technical Field]

[0001] This invention relates to novel peptides as pharmaceutically active ingredients or otherwise, the use of such peptides in human pharmaceuticals, and pharmaceutical compositions containing them. Specifically, this invention relates to the use of such peptides and compositions in the treatment of various pathological conditions, including inflammation. [Background technology]

[0002] Inflammation is typically characterized as a local tissue response to, for example, microbial invasion, a specific antigen, damaged cells, or physical and / or chemical factors. The inflammatory response is usually a protective mechanism that destroys, weakens, or isolates both the harmful substance and the damaged tissue, thereby initiating tissue healing.

[0003] Inflammation can result from physical trauma, infection, certain chronic diseases (e.g., autoimmune diseases such as psoriasis and rheumatoid arthritis), and / or chemical and / or physiological responses to external stimuli (e.g., as part of an allergic reaction). A series of complex events may be involved, in which inflammatory mediators increase blood flow and local vasodilation, leading to redness and heat, fluid exudation, and often local swelling, leukocyte migration to the inflamed area, and pain.

[0004] Many conditions / disorders are characterized by and / or caused by abnormal tissue damage and inflammation. Such conditions typically involve activation of immune defense mechanisms, resulting in effects that are more detrimental than beneficial to the host, and are generally associated with varying degrees of tissue redness or congestion, swelling, hyperthermia, pain, itching, cell death, tissue destruction, cell proliferation, and / or loss of function. Examples include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, psoriasis, glomerulonephritis, and transplant rejection.

[0005] Typically, a series of complex events lead to inflammatory changes such as increased blood flow due to local vasodilation resulting in redness and fever, extravasation of leukocytes and plasma often resulting in local swelling, activation of sensory nerves (causing pain in some tissues), and loss of function. These inflammatory changes are triggered by a cascade of cellular and biochemical events involving cells such as neutrophils, monocytes, macrophages, and lymphocytes, along with inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

[0006] In particular, inflammation plays a crucial role in the wound healing process. Therefore, wounds and burns can be classified as pathological conditions involving inflammation. The conventional view in this field is that anti-inflammatory drugs should not be directly applied to open wounds because they are detrimental to the progression of wound healing.

[0007] Fibrosis is defined by the excessive accumulation of fibrous connective tissue (components of the extracellular matrix, ECM, such as collagen and fibronectin) in and around inflamed or damaged tissue. While collagen deposition is typically a reversible part of wound healing, in cases of severe tissue damage or when the wound healing response itself becomes unregulated, it can often develop into an increasingly irreversible fibrotic response. Furthermore, fibrosis is known to be a major cause of morbidity and death in many chronic inflammatory diseases, as well as in end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure. It is also a pathological feature of many chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus. In addition, fibrosis can influence the pathogenesis of many progressive myopathy, metastasis, and graft rejection.

[0008] Mussel adhesive protein (MAP), also known as Mytilus edulis foot protein (MEFP), is a protein secreted by marine mollusks such as Mytilus edulis, Mytilus coruscus, and Perna viridis. Eleven distinct adhesion protein subtypes are derived from mussels, including collagen pre-COL-P, pre-COL-D, and pre-COL-NG; mussel foot matrix proteins PTMP (proximal filamentous matrix protein) and DTMP (distal filamentous matrix protein); and mfp proteins mfp-2 (sometimes referred to as "mefp-2," and used interchangeably hereafter), mfp-3 / mefp-3, mfp-4 / mefp-4, mfp-5 / mefp-5, mfp-6 / mefp-6, most preferably mfp-1 / mefp-1 (see, for example, Zhu et al., Advances in Marine Science, 2014, 32, 560-568 and Gao et al., Journal of Anhui Agr.Sci., 2011, 39, 19860-19862).

[0009] The majority of mefp-1 consists of 70-90 tandem repeats of the decapeptide: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (see SEQ ID NO: 61, Waite, Int. J. Adhesion and Adhesives, 1987, 7, 9-14). This decapeptide sequence may be isolated as a low molecular weight derivative of a naturally occurring MAP, or it may be synthesized, for example, as described by Yamamoto in J. Chem. Soc., Perkin Trans. 1987, 1, 613-618. See also Dalsin et al., J. Am. Chem. Soc., 2003, 125, 4253-4258.

[0010] Decapeptide analogs, particularly Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2), have also been disclosed. See, for example, U.S. Patent No. 5,616,311 and International Publication No. 96 / 39128, as well as international patent applications, International Publication Nos. 2019 / 007355(A1), International Publication Nos. 2019 / 228307(A1), International Publication Nos. 2021 / 047648(A1), International Publication Nos. 2011 / 110061(A1) and International Publication Nos. 2021 / 110064(A1).

[0011] Japanese Patent Application Publication No. 2003238589(A) discloses specific dipeptides and tripeptides as angiotensin-converting enzyme inhibitors.

[0012] The use of lysine amino acid residues for preparing multi-antigen peptides is disclosed, for example, in Tam Proc. Natl. Acad., Sci. USA, 1988, 85, 5409-5413, Rao et al., J. Am. Chem. Soc., 1994, 116, 6975-6976, U.S. Patent No. 5,229,490, and International Publication No. 2010 / 038220. See also International Patent Application, International Publication No. 2021 / 110064(A1).

[0013] The use of peptide-based scaffolds as drug delivery vehicles has been disclosed. See, for example, Brokx et al, J. Control. Release, 2002, 78, 115-123.

[0014] The use of lipid-peptide conjugates, such as palmitoyl tetrapeptide-7, palmitoyl tripeptide-1, and other palmitoyl oligopeptides, in anti-aging cosmetics is disclosed, for example, in MS Ferreira, Cosmetics. 2000: 7-91. See also Kamysz et al., who disclose palmitoyl tripeptides as antimicrobial agents.

[0015] There is an obvious need for new drugs and / or improved drugs that can be used for the treatment of inflammation and diseases characterized by inflammation.

Summary of the Invention

[0016] According to a first aspect of the present invention, a compound of formula I is provided, L 2 , 2 Q a -D b (I) In the formula, Q a represents Z or A-Q-B, Q is a structural fragment of formula II,

[0017]

Chemical formula

[0018]

Chemical formula

[0019]

Chemical formula

[0020] [ka] During the ceremony, The dash adjacent to the NH group is Q 1 Q 2 and Q 3 From A 1 and / or B 1 , A 2 and / or B 2 These represent the connection points to Z, respectively. The wavy line adjacent to the C=O group is Q 1 Q 2 , and Q 3 Q, Q 1 and Q 2 These represent the connection points to each, m is as defined above, Each L independently represents a lipid, or a derivative of any of these lipids, selected from the group consisting of vitamin A, vitamin E, cholesterol, and one or more lipids comprising one or more carboxylic acid groups, 1 to 50 carbon atoms, and / or one or more cyclic rings, which are linear or branched, saturated or unsaturated, have 1 to 10 carbon-carbon double bonds, and / or are substituted with 1 to 10 -OH groups. t represents an integer selected from 1 to 32. D represents Montelukast, b represents an integer selected from 0 to 16. In each of the cases used above, Z represents a structural fragment of equation IV, [(W) r -Lys-X 1 -TUX 2 -Y] n -(W) r -Lys-X 1 -TUX2 -Y(IV) (Sequence ID 1) During the ceremony, n represents an integer selected from 0 to 4. In each case in which it is used, r independently represents either 0 or 1. In each case in which it is used, W independently represents a sequence of one or two amino acids selected from one or more of the group consisting of Ser, Lys, Ala, DOPA, and 3,4-dihydrocinnamic acid (HCA) residues, provided that, if present, the HCA residue is located at the N-terminus of Z. X 1 However, independently, it represents Pro, Hyp, or jiHyp, T independently represents Ser or pSer, U independently represents Tyr, pTyr, DOPA, Hyp, or Pro. X 2 However, independently, it represents Thr, Ser, Pro, Hyp, or jiHyp, Y independently represents a sequence of 1 to 5 (e.g., 1 to 4) amino acids selected from one or more of the groups Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, and Tyr, and the sequence is optionally terminated by dopamine (or, more appropriately, a "dopamine fragment"). If present, each D is covalently bonded to Z via an amide bond between its respective carboxylic acid residue and one or more NH2 residues of Z. A compound in which each L residue is covalently bonded to Z via an amide bond between each carboxylic acid residue of L and one or more NH2 residues of Z, and / or via an ester bond between each -OH residue of L and one or more carboxylic acid residues of Z. Also provided are positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the compound, and these compounds, positional isomers, stereoisomers, and salts are collectively referred to as "the compounds of the present invention."

[0021] Those skilled in the art can determine whether the Z peptide binds to the rest of the molecule via the N-terminus or the C-terminus. To avoid misunderstanding, Z binds to the rest of the molecule by forming an amide bond.

[0022] Therefore, R is

[0023] [ka] If Z binds to R in this case, Z binds via the N-terminus.

[0024] Preferred compounds of the present invention include compounds in which the lipid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, octadecanediic acid, docosahexaenoic acid, and leukotriene B4 (LTB4), or any derivative thereof.

[0025] More preferred compounds of the present invention also include compounds in which the lipid is a polyunsaturated fatty acid or a derivative thereof. In such embodiments, the derivative may be a specialized pro-resolving mediator (SPM).

[0026] More preferred compounds of the present invention also include compounds in which the lipid is a derivative of a fatty acid such as glycerolipid, glycerophospholipid, sphingolipid, or saccharolipid.

[0027] More preferred compounds of the present invention also include compounds in which the lipid comprises palmitic acid or a derivative thereof. In such embodiments, the derivative may be phosphatidylserine, or more preferably 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine, and most preferably 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS). In such embodiments, the derivative may be phosphatidylethanolamine, or more preferably 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0028] More preferred compounds of the present invention also include compounds in which the lipid comprises stearic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-distearoyl-sn-glycero-3-phospho-L-serine.

[0029] More preferred compounds of the present invention also include compounds in which the lipid comprises oleic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-dioleoyl-sn-glycero-3-phospho-L-serine.

[0030] More preferred compounds of the present invention also include compounds in which the lipid contains palmitoylethanolamide (PEA).

[0031] More preferred compounds of the present invention also include compounds in which the lipid is selected from the group consisting of vitamin E, vitamin A, and cholesterol, or derivatives of any of these. In such embodiments, the cholesterol derivative may be cholesterol-acetic acid.

[0032] More preferred compounds of the present invention also include compounds in which the lipid is a fatty acid having 1 to 50 carbon atoms and / or one or more cyclic rings, being linear or branched, saturated or unsaturated, having 1 to 10 carbon-carbon double bonds and / or being substituted with 1 to 10 -OH groups, or derivatives thereof. In such embodiments, the fatty acid may have 6 to 24 carbon atoms, for example, 6 to 18 carbon atoms. In other embodiments, the fatty acid may have 1 to 6 carbon-carbon double bonds, for example, 1 to 5 carbon-carbon double bonds. In other embodiments, the fatty acid may have 1 to 5 -OH groups, for example, 1 to 2 -OH groups. In other embodiments, the fatty acid may have 1 to 10 cyclic rings, for example, 1 to 8 cyclic rings.

[0033] Further preferred compounds of the present invention include: t represents an integer selected from 1 to 8, or more preferably This includes cases where t represents an integer selected from 1 to 4.

[0034] Further preferred compounds of the present invention include: b represents an integer selected from 0 to 4, or more preferably b includes elements that represent 1.

[0035] As used herein, the terms “dopamine” and “dopamine fragment” refer to a structural fragment of formula I.

[0036] [ka] In the equation, the dashed line represents the connection point to Y.

[0037] As used herein, Palm represents palmitic acid, Stea represents stearic acid, dopamine is as defined above, Olei represents oleic acid, DHA represents docosahexaenoic acid, DPPS represents 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine, LTB4 represents leukotriene B4, and PEA represents palmitoylethanolamide.

[0038] As used herein, Pro represents proline, Ala represents alanine, Ser represents serine, Tyr represents tyrosine, Hyp represents hydroxyproline (including 3-hydroxyproline (3Hyp) and 4-hydroxyproline (4Hyp)), DiHyp represents dihydroxyproline (including 3,4-dihydroxyproline (3,4DiHyp), trans-2,3-cis-3,4-dihydroxyproline, 3,5-dihydroxyproline (3,5DiHyp), and 4,5-dihydroxyproline (4,5DiHyp)), Thr represents threonine, Lys represents lysine, Ala represents alanine, DOPA represents 3,4-dihydroxyphenylalanine, Orn represents ornithine, and Chol-Ac represents cholesterol-acetic acid:

[0039] [ka] (An amide bond can be formed by binding to any free amine group, including Z, at the N-terminus of the amino acid sequence), Dap represents diaminopropionic acid. The 3,4-dihydrocinnamic acid (HCA) residue is essentially a DOPA residue, but lacks an -NH2 group at the 2- or α-position of the carboxylic acid bonded to the N-terminal amino acid (either Lys or Ala).

[0040] In each case in which they are used, Q, Q 1 Q 2 and Q 3 These are the respective carboxylic acid residues of Z and Q, Q 1 Q2 and Q 3 It can be covalently bonded to 0, 1, or 2 Z groups via an amide bond with one or more NH2 residues.

[0041] In this regard, preferred compounds of the present invention include: Either A or B represents Z, and the other is A. 1 -Q 1 -B 1 It represents, or, comfortable Both A and B represent Z, or both are A 1 -Q 1 -B 1 This represents, In each case, Q 1 Preferably, the compound includes a Lys fragment, where Z is defined as described above.

[0042] Further preferred compounds of the present invention include: A 1 and B 1 One of them represents Z, and the other represents A 2 -Q 2 -B 2 To represent, or more preferably, A 1 and B 1 Both represent Z, or both represent A 2 -Q 2 -B 2 This represents, In each case, Q 2 Preferably, the compound includes a Lys fragment, where Z is defined as described above.

[0043] Further preferred compounds of the present invention include: A 2 and B 2 One of them represents Z, and the other represents ZQ. 3 - Represents Z, or more preferably, A 2 and B 2 Both represent Z, or both represent ZQ 3 -Represents Z, In each case, Q 3Preferably, the compound includes a Lys fragment, where Z is defined as described above.

[0044] A more preferred compound of the present invention is: A 1 and B 1 Both represent Z, or A 2 and B 2 The compound contains both of which represent Z.

[0045] Furthermore, a preferred compound of the present invention is one in which m represents 1, 3, or more preferably 4, thereby Q, Q 1 Q 2 and Q 3 One or more of these represent Lys, or more appropriately, a "Lys fragment," which (if necessary) conforms to the definition above as a "structural fragment of formulas II and III'."

[0046] Particularly preferred compounds of the present invention include: Q a However, Z represents, and in the formula, The compound includes a compound in which n is 0, 1, or 4, preferably n is 1, or more preferably n is 0.

[0047] The compounds of the present invention that may be mentioned include compounds in which the N-terminal amino acid residue of the Z component is optionally covalently bonded to montelukast.

[0048] Further compounds of the present invention that may be mentioned include: R represents the following:

[0049] [ka] t represents an integer selected from 1 to 4, and / or The compound includes a compound in which b is 0 or 1.

[0050] The compounds of the present invention that may be mentioned include: In each case in which it is used, W represents a sequence of one or two amino acids, and the amino acids are selected from one or more of the groups Lys, Ala, DOPA, and HCA. T represents Ser, U represents Tyr or DOPA, X 2 However, it represents Ser, Pro, Hyp, or jiHyp, The compound includes a sequence of 1 to 5 (e.g., 1 to 4) amino acids, where the amino acids are selected from one or more of the following groups: Lys, Ala, Pro, Hyp, diHyp, Thr, DOPA, and Tyr.

[0051] The compounds of the present invention that may be mentioned include: One or two amino acids in W represent Ser, T represents pSer, U represents pTyr, Hyp, or Pro. X 2 However, it represents Thr, In Y, 1 to 5 amino acids (for example, 1 to 4 amino acids) are pThr. Y may optionally contain compounds terminated with dopamine.

[0052] Preferred compounds of the present invention include: X 1 However, it represents Hyp, or more preferably Pro, T represents Ser, U represents Tyr or DOPA, X 2 However, it represents Hyp, If W is present, it represents HCA-, HCA-Ala-, Lys-Ala-, DOPA-, DOPA-Ala-, or preferably Ala, and / or The compound comprises a sequence of five, preferably three, more preferably two, or most preferably four amino acids, wherein the amino acids are selected from one or more of the groups Lys, Hyp, Thr, DOPA, and Tyr, and optionally terminated by a dopamine fragment.

[0053] More preferred compounds of the present invention include those in which Y is -Pro-Y 1 -Y 2 -Lys-, or more preferably -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 representing a sequence of 4 amino acids selected from the group of -Lys- and where Y 1 and Y 2 are each independently selected from the group of Pro, Ala, or more preferably Hyp, Thr, DOPA, and Tyr, and optionally terminated by a dopamine fragment, also include compounds.

[0054] When Y represents a sequence of 2 amino acids, preferred compounds of the present invention include those in which the amino acid sequence defined by Y is selected from the group of -Tyr-Pro-, preferably -Thr-Lys-, more preferably -DOPA-Lys- and -Tyr-Lys-, and optionally terminated by a dopamine fragment.

[0055] Even more preferred compounds of the present invention include those in which the amino acid sequence defined by Y is -Thr-Tyr-Hyp-, -Thr-DOPA-Hyp-, -Hyp-Thr-DOPA-, -Hyp-pThr-DOPA-, -Hyp-Thr-Tyr-, -Hyp-Thr-Tyr-Hyp, -Hyp-Thr-DOPA-Hyp-, -Hyp-pThr-DOPA-Hyp-, -Thr-Tyr-Lys-Hyp-, -Thr-DOPA-Lys-Hyp-, preferably -Pro-Thr-DOPA-Lys-, -Pro-Thr-Tyr-Lys-, -Thr-Tyr-Pro-Lys-, -Thr-DOPA-Pro-Lys-, -Tyr-Hyp-Lys-, -Tyr-Pro-Lys-, -DOPA-Hyp-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Ala-Hyp-Lys-, -Thr-Tyr-Lys-, -Thr-Lys-, and more comfortably, -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys-, -DOPA-Lys-, and Selected from the -Tyr-Lys- group, Each of these may optionally contain a compound terminated by a dopamine fragment.

[0056] The compounds of the present invention that may be mentioned include compounds in which W represents Ala.

[0057] In this regard, further compounds of the present invention that may be mentioned include those in which Z is Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 9), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-(Sequence ID 21) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence No. 22) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 23) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 24) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 25) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence No. 26) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 27) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 28) Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (Sequence ID 29) Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID NO: 30) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 31) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 32) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (Sequence ID 33) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 34) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 35) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID NO: 36) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 37) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 38) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 39) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 40) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr (Sequence ID 41) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence No. 42) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 43) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 44) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 45) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 46) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp (Sequence No. 47) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 48) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp (Sequence No. 49) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA (SEQ ID NO: 50) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp (Sequence ID 51) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp-Lys (Sequence ID 52) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Lys (Sequence ID 53) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr (Sequence ID 54) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp (Sequence ID 55) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp-Lys (SEQ ID NO: 56) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Lys (SEQ ID NO: 57) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 58) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 59) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 60) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 61) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA (Sequence ID 62) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (Sequence ID 63) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence No. 64) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 65) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID NO: 66) Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (Sequence ID 67) Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID NO: 68) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 69) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA (Sequence ID 70) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (Sequence ID 71) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-DOPA-Lys (SEQ ID NO: 72) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 73) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID NO: 74), Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (SEQ ID NO: 75) Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID NO: 76) Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (SEQ ID NO: 77) Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (SEQ ID NO: 78) Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 79) Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID NO: 80) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 81), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 82) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 83) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp -Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 84) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 85) This includes compounds selected from the group Ala-Lys-Pro-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 116).

[0058] Preferred compounds of the present invention that may be mentioned include those in which Z is Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (Sequence ID 24) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 28), Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 44), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Lys (SEQ ID NO: 57), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 61) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (Sequence ID 63) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence ID 64) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID NO: 66), Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID NO: 68), Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID NO: 76), Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (Sequence ID 29) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 32) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 46) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 60) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID NO: 70) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence No. 22) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 35), Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 48), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 73), and This includes compounds selected from the group Ala-Lys-Pro-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 116).

[0059] More preferred compounds of the present invention that may be mentioned include those in which Z is Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 9), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 11), and This includes compounds selected from the group Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 12).

[0060] The compounds of the present invention that may be mentioned include compounds in which W is absent.

[0061] In this regard, further compounds of the present invention that may be mentioned include those in which Z is Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (Sequence ID 86) Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (Sequence ID 87) Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (Sequence ID 88) Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (Sequence ID 89) Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 90) Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 91) Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (Sequence ID 19) Lys-Hyp-Ser-Tyr-Hyp-Tyr (Sequence ID 92) Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (Sequence ID 93) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (Sequence ID 94) Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID NO: 95) Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (Sequence ID 96) Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID NO: 97) Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID NO: 98) Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (Sequence ID 99) Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 100) Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 14) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 101) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 102) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence ID 103), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 104) Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 105) Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 106) Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 107) Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 108), and This includes compounds selected from the group Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16).

[0062] Preferred compounds of the present invention that may be mentioned include those in which Z is Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 91) Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 93) Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 100) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (Sequence ID 94) Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID NO: 97) Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (Sequence ID 99) Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 87), and This includes compounds selected from the group Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID NO: 92).

[0063] More preferred compounds of the present invention that may be mentioned include those in which Z is Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 14) Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16), and This includes compounds selected from the group Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 19).

[0064] The compounds of the present invention that may be mentioned include, optionally, compounds in which the N-terminal amino acid residue of the Z component is covalently bonded to montelukast to form an amide bond with the carboxylic acid group in montelukast.

[0065] Furthermore, peptide compound Z (isolated by arbitrary selection) (i.e., equivalent to the compound of formula I defined above, but lacking L and D, and Q) a A compound that represents Z as defined above, in the formula, Both r and n represent 0. X 1 However, it represents Hyp, or more preferably Pro, T represents pSer, or more preferably, Ser. U represents DOPA, or more preferably Tyr. X 2 However, it represents Hyp, Y represents a sequence of 1 to 5 amino acids, preferably 3, more preferably 4, or most preferably 2, and the amino acids are selected from one or more of the group Lys, Hyp, Thr, DOPA, and Tyr, and optionally terminated with a dopamine fragment, a peptide compound. Also provided are positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0066] The preferred peptide compound Z has the following sequence: Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (Sequence ID 86) Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (Sequence ID 87) Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (Sequence ID 88) Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (Sequence ID 89) Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 90) Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 91) Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (Sequence ID 19) Lys-Hyp-Ser-Tyr-Hyp-Tyr (Sequence ID 92) Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (Sequence ID 93) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (Sequence ID 94) Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID NO: 95) Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (Sequence ID 96) Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID NO: 97) Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID NO: 98) Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (Sequence ID 99) Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 100) Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 14) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 101) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 102) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence ID 103), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 104) Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 105) Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 106) Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 107) Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 108), and The peptide compound Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16), Also provided are positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0067] A more preferred peptide is, Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 91) Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 93) Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 100) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (Sequence ID 94) Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID NO: 97) Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (Sequence ID 99) Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 87), and Lys-Hyp-Ser-Tyr-Hyp-Tyr (Sequence ID 92) Also provided are positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0068] Particularly preferred peptide compounds are Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 14) Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16), and Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (Sequence ID 19) Also provided are positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0069] To avoid misunderstanding, the compounds of the present invention as defined above will be collectively referred to as "the compounds of the present invention" below.

[0070] The compounds of the present invention, whether in salt form or not, include positional isomers within the amino acids of a peptide (e.g., diHyp, Hyp, and Tyr portions), as well as mixtures of such positional isomers. For example, the definition of Tyr includes not only tyrosine (4-hydroxyphenylalanine) but also 2- and 3-hydroxyphenylalanine. The definition of Hyp includes 4-hydroxyproline (4Hyp), 3-hydroxyproline (3Hyp), and 5-hydroxyproline (5Hyp). It is more preferable that the Hyp residue is 4-hydroxyproline. Similarly, the definition of diHyp includes 3,4-dihydroxyproline (3,4diHyp), 3,5-dihydroxyproline (3,5diHyp), and 4,5-dihydroxyproline (4,5diHyp). It is more preferable that the diHyp residue is 3,4-dihydroxyproline (3,4diHyp).

[0071] Furthermore, in addition to the standard central carbon atoms of the amino acids in the compounds of the present invention (which are not exclusive but usually in the L configuration), certain amino acids in the sequence contain additional chiral carbon atoms. All such stereoisomers and mixtures thereof (including racemic mixtures) are within the scope of the present invention. In this regard, the definition of Hyp includes trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, cis-3-hydroxy-L-proline, trans-5-hydroxy-L-proline, and cis-5-hydroxy-L-proline, but the Hyp used in the compounds of the present invention is preferably 4-hydroxy-L-proline. Similarly, the corresponding definition may also apply to diHyp, where the two hydroxyl groups are cis or trans relative to each other. In any case, individual enantiomers of the compounds of formula I that can form part of the compounds of the present invention are within the scope of the present invention.

[0072] The compounds of the present invention may also be in the form of salts. Salts that may be mentioned include pharmaceutically acceptable salts and / or cosmetically acceptable salts, such as pharmaceutically acceptable acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the compound of the present invention with one equivalent or more of a suitable acid or base in optionally a solvent or a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying or filtration). Salts may also be prepared, for example, by exchanging the counterions of the compound of the present invention in salt form with other counterions using a suitable ion exchange resin.

[0073] Preferred salts include, for example, acetates, hydrochlorides, bisulfates, maleates, mesylates, tosylates, alkaline earth metal salts such as calcium and magnesium, or alkali metal salts such as sodium and potassium salts. Most preferably, the compounds of the present invention may be in the form of acetates.

[0074] The compounds of the present invention can be prepared by conventional techniques, for example, by standard amino acid coupling techniques, using standard coupling reagents and solvents, as described below. The compounds of the present invention can be synthesized from available starting materials using appropriate reagents and reaction conditions. Those skilled in the art may, in this regard, refer to "Comprehensive Organic Synthesis" by BMTrost and I. Fleming, Pergamon Press, 1991. Further possible references include "Heterocyclic Chemistry" by J.A. Joule, K. Mills and G.F. Smith, 3 rd Examples include "Comprehensive Heterocyclic Chemistry II" by ARKATRIZKY, CWRees, and EFVScriven, published by Chapman & Hall, Pergamon Press, 1996, and "Science of Synthesis," Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0075] The compounds of the present invention can be isolated from their reaction mixtures and, if necessary, purified using prior art, such as that known to those skilled in the art. Therefore, the preparation process of the compounds of the present invention described herein may include, as a final step, isolation and optionally purification of the compounds of the present invention.

[0076] Those skilled in the art will understand that in the processes described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups. Protection and deprotection of the functional groups may be performed before or after the reaction.

[0077] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and the techniques described below. For example, the protected compounds / intermediates described herein may be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical reaction involved will determine the need and type of protecting group, as well as the sequence for achieving the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis," 5th edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (2014), the disclosures of which are incorporated herein by reference.

[0078] The compounds of the present invention are useful as pharmaceuticals for human or animal use. Therefore, they are indicated as pharmaceuticals (and / or in veterinary medicine), but may also be used as part of cosmetics and / or medical devices.

[0079] The compounds of the present invention may also possess pharmacological activity on their own, but certain pharmaceutically acceptable (e.g., “protected”) derivatives of the compounds of the present invention may exist or be prepared, which may not possess such activity, but may be administered orally and subsequently metabolized or chemically converted to form the compounds of the present invention. Accordingly, such compounds (which may possess some pharmacological activity, provided that such activity is recognizably lower than the activity of the active compound to which they are metabolized / converted) may be described as “prodrugs” of the compounds of the present invention.

[0080] As used herein, a reference to a prodrug includes a compound that forms an experimentally detectable amount of the compound of the present invention within a predetermined time after administration. All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0081] The compounds of the present invention, when they possess pharmacological activity, are particularly useful in the treatment of inflammation.

[0082] The term “treatment of inflammation” includes the treatment of inflammation in any organ of the body, regardless of its cause (including soft tissues, joints, nerves, vascular system, internal organs, mucous membrane surfaces in particular, and skin in particular), and also includes all such inflammatory disorders or conditions, and / or disorders or conditions characterized by inflammation (e.g., as symptoms).

[0083] Inflammatory disorders and / or conditions may (and typically are) characterized by the activation of immune defense mechanisms that produce effects that are more harmful than beneficial to the host. Such conditions are generally associated with varying degrees of tissue redness or congestion, swelling, edema, hyperthermia, pain (including numbness), fluid exudation, itching (pruritus), cell death, and tissue destruction, cell proliferation, and / or loss of function.

[0084] Inflammatory conditions that may be mentioned include arteritis, diabetes, metabolic syndrome, rosacea, asthma and allergies, ankylosing spondylitis, chronic obstructive pulmonary disease, gouty arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, osteoarthritis, pancreatitis, prostatitis, psoriatic arthritis, rheumatoid arthritis, tendinitis, bursitis, Sjögren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis, and related cardiovascular disorders. A condition characterized by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD). Further conditions characterized by inflammation that may be mentioned are Crohn's disease and inflammatory bowel disease, particularly ulcerative colitis. Other medical conditions characterized by inflammation that may be mentioned include gynecological disorders such as cervicitis, vaginitis (e.g., radiation vaginitis), and colpitis; diseases affecting the gastrointestinal tract, such as gastric ulcer formation (e.g., gastritis, gastric ulcers, stress-induced gastritis, gastric cancer, and other gastric mucosal diseases), as well as inflammation associated with gastroesophageal reflux disease (GERD), constipation, gastritis, cancer, and infections (e.g., viral infections such as the common cold or influenza).

[0085] Inflammatory conditions that may be more specifically mentioned include inflammation of the skin or mucous membranes (oral cavity, nasal cavity, eyes, vagina, cervix and / or anorectal mucosa, more specifically including oral cavity or nasal cavity mucosa), such as inflammation resulting from infections (such as viral and / or bacterial infections), or allergic / atopic conditions (such as rhinitis (e.g., allergic rhinitis), pharyngitis, periodontitis, gingivitis, xerosis, conjunctivitis (e.g., allergic conjunctivitis), dermatitis, urticaria (hives), and food allergies), as well as other inflammatory conditions such as herpes, drug eruptions, polymorphic light eruption, sunburn, early symptoms of skin cancer (erythematous skin lesions), pathological alopecia (including after skin grafting), chemical rashes, psoriasis, erythema multiforme, folliculitis, eczema, and otitis externa. A condition that may be mentioned is polymorphic light eruption.

[0086] More specifically, the compounds may be used to treat certain conditions characterized by and / or associated with inflammation. Such conditions may include wounds (including abrasions (scratches), incisions (including surgical incisions), lacerations, punctures, avulsions, bruises, and scars), burns (including inflammation resulting from post-burn surgery such as skin grafts), and other conditions such as hemorrhoids. Wounds may be acute or chronic and / or result from one or more inflammatory disorders as defined herein.

[0087] Wounds of the skin or mucous membranes may result from physical injury inside or outside the membrane surface, or from an underlying physiological disorder (i.e., a symptom thereof).

[0088] Physical (e.g., "open") wounds can be caused by sharp objects (cuts, incisions, punctures) or blunt / mechanical forces (lacerations, abrasions, avulsions), physical blows (bruises), heat or chemicals (burns and blisters), ultraviolet radiation (sunburn), or cold (chilblains or frostbite). Wounds can be superficial (damage to the epidermis and / or dermis only) or full-thickness (damage to the epidermis and / or below the dermis). In severe cases, subcutaneous and / or submucosal tissues such as muscles, bones, joints, and even internal organs may be damaged.

[0089] The compounds of the present invention may be used to alleviate pain (including numbness) associated with inflammation and / or wounds. Specifically, the compounds of the present invention may be used to alleviate procedural pain and / or non-procedural pain. Those skilled in the art will understand that the term “procedural pain” (i.e., surgical pain) refers to acute pain associated with medical investigations and treatments performed for medical purposes. The term “non-procedural” refers to general pain associated with inflammation and / or wounds (e.g., pain associated with dental ulcers, burns, and / or scars) that is not the result of a specific medical intervention.

[0090] The compounds of the present invention can be used not only to treat inflammation, pain (including numbness), and / or pruritus (itching) associated with the wound itself and the healing process, but also to prevent the exudation of bodily fluids from the wound, the risk of infection, and physiological reactions resulting from inflammation and / or the wound healing process, such as scarring and melanin pigmentation.

[0091] A scar is the result of inflammation and / or wound healing, and is a general term for the formation of fibrous tissue that is a consequence of such inflammation / healing.

[0092] The compounds of the present invention may also be useful in suppressing the production of melanin pigmentation, which may or may not be caused by inflammation and / or wound healing. The compounds of the present invention may also be useful in suppressing melanin pigmentation-related disorders such as melasma, freckles, melanin deposition, butterfly rash, and other pigmentation, skin cancer with melanoma, and pigmentation caused by sun exposure or skin diseases such as acne.

[0093] Wounds can also result from (e.g., inflammatory) diseases or disorders. Such wounds may include blisters, and / or ulcers of the skin and mucous membranes. These are common conditions that are often long-lasting and difficult to treat. Skin tissue can often be damaged, removed, liquefied, infected, and / or necrotic. Ulcers, especially if infected, can have secondary health consequences, are difficult to heal, and are costly to treat. They can also cause significant psychological stress and financial loss to patients, affecting both their overall well-being and quality of life.

[0094] Alternatively, the compounds of the present invention are particularly useful for inflammatory skin conditions or diseases such as viral skin diseases, e.g., herpes zoster; bacterial skin diseases; fungal skin diseases; animal-induced skin diseases; sexually transmitted skin diseases; allergy-related skin diseases; autoimmune skin diseases; neutrophilic skin diseases; erythematous popular and squamous dermatosis; connective tissue diseases; vesicular skin diseases; pigmented skin diseases; skin appendage disorders; hereditary skin diseases; skin diseases associated with nutritional and metabolic disorders; skin tumors; psoriasis; acne; eczema and dermatitis, particularly allergic / atopic dermatitis and neurodermatitis; and treatment of mucosal inflammation characterized by, for example, rhinitis, particularly allergic rhinitis; hemorrhoids; chronic obstructive pulmonary disease and ulcerative colitis.

[0095] Psoriasis is a chronic inflammatory skin disease that tends to recur (some patients never recover). Clinical symptoms of psoriasis primarily include erythema and scaling, which can occur anywhere on the body but are more commonly seen on the scalp and hands and feet.

[0096] Acne is a follicular (hair follicle-sebaceous gland) chronic inflammatory skin disease whose development is closely related to major factors such as excessive sebum, obstruction of hair follicle-sebaceous gland ducts (including closed and open comedones), bacterial infection, and inflammatory response. It tends to develop in adolescence and is characterized by pleomorphic skin lesions on the face. Therefore, the term acne includes both common acne and rosacea (i.e., red nose).

[0097] Eczema is an inflammatory skin reaction characterized by intense itching, triggered by various internal and external factors. It has three stages: acute, subacute, and chronic. The acute stage tends to produce exudate, while the chronic stage involves infiltration and hypertrophy. Skin lesions are itchy and frequently recur.

[0098] Dermatitis is a common skin condition characterized by roughness, redness, itching, eczema, and dryness. Small nodules, refractory ulcers, and pigmented spots caused by dermatitis can develop into basal cell carcinoma, squamous cell carcinoma, and malignant melanoma if left untreated. Dermatitis can be caused by a variety of internal and external infectious or non-infectious factors, including substances (contact dermatitis) or allergies (allergic / atopic dermatitis). Seborrheic dermatitis (seborrheic eczema), scarring alopecia and related disorders, and all forms of steroid-dependent dermatitis (photosensitive seborrheic dermatitis; perioral dermatitis; rosacea-like dermatitis; steroid-rosacea, steroid-induced rosacea, iatrosacea, rosacea-like steroid dermatitis, rosacea such as topical corticosteroid-induced rosacea-like dermatitis, and more specifically, facial corticosteroid-dependent dermatitis (FCAD) or facial corticosteroid-dependent dermatitis (FCDD), characterized by flushing, erythema, telangiectasia, atrophy, papules and / or pustules in the facial area after long-term treatment with topical corticosteroids (including uncontrolled use, abuse or misuse), e.g., Xiao et al., J. Dermatol., 2015, 42, 697-702 and Lu et al. (See also al., Clin. Exp. Dermatol., 2009, 35, 618-621)

[0099] Rhinitis is irritation and inflammation of the mucous membrane inside the nose. Common symptoms of rhinitis include nasal congestion, runny nose, sneezing, and postnasal drip. The most common type of rhinitis is allergic rhinitis, caused by allergens such as pollen, dust, mold, or flakes of skin from certain animals. Surprisingly, it has been found that patients with allergic rhinitis treated with the compounds of the present invention experienced relief of itchy eyes, even when the compounds of the present invention were administered intranasally (i.e., into the nasal mucosa).

[0100] Hemorrhoids are swellings caused by large inflammation of hemorrhoidal blood vessels found inside or around the rectum and anus. Symptoms include bleeding after stool passage (i.e., sores), hemorrhoid prolapse, mucus discharge and itching, burning sensation in the anal area, redness, and swelling. Hemorrhoids are thought to be a result of increased abdominal pressure, for example, as a result of constipation or diarrhea.

[0101] Chronic obstructive pulmonary disease (COPD) is the name given to a group of lung conditions that cause difficulty breathing, including emphysema (damage to the alveoli) and chronic bronchitis (long-term airway inflammation). COPD occurs when the lungs become inflamed, damaged, and narrowed. The damage to the lungs is usually irreversible and results in impaired airflow into and out of the lungs. Symptoms of COPD include shortness of breath, a wet cough, frequent chest infections, and persistent wheezing. The most common cause of this disease is smoking, but other risk factors include high levels of air pollution, as well as occupational exposure to dust, chemicals, and smoke.

[0102] The compounds of the present invention may have a positive effect in alleviating erythema, redness and swelling, edema, blisters, and bullous pemphigoid caused by various pathological conditions, including those commonly and specifically mentioned herein, and may inhibit the exudation of subcutaneous fluid and suppress itching and pain caused by such inflammatory conditions.

[0103] Other inflammatory conditions that may be mentioned include: (a) inflammation caused by oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis, and enterocolitis (including bacterial dysentery, chronic amebic dysentery, schistosomiasis, nonspecific ulcerative colitis, and focal enteritis), cervicitis and endometritis, endometritis, inhalation injury, etc., as well as inflammation of the mucous membranes associated with cancer, and inflammation of the mucous membranes such as infections (e.g., viral infections such as the common cold or influenza) that affect the mucosal surface of the oral cavity, nasopharynx, ears, throat, trachea, gastrointestinal tract, cervix, etc. (b) For example, fractures, suppurative infections of bone and joints, inflammation caused by rheumatic bone disease, and orthopedic inflammation associated with suppurative osteomyelitis (acute osteomyelitis, chronic osteomyelitis, localized osteomyelitis, sclerosing osteomyelitis, post-traumatic osteomyelitis), suppurative arthritis; bone tumors (osteoma, osteoid, chondroma), bone cysts, osteoclastoma, primary osteosarcomas (osteosarcoma, chondrosarcoma, osteofibrosarcoma, Ewing's sarcoma, non-Hodgkin lymphoma, myeloma, chordoma), metastatic bone tumors, neoplastic lesions of bone (bone cysts, aneurysmal bone cysts, eosinophilic granuloma, fibrous dysplasia); and rheumatoid arthritis. (c) Neuroinflammation such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, and intercostal neuritis. (d) Inflammation of subcutaneous and submucosal soft tissues, such as myositis, ligamentitis, tendinitis, cystitis, lymphadenitis, fodderitis, tonsillitis, synovitis, and fasciitis, as well as inflammation of soft tissues caused by injury, contusion, or laceration of muscles, ligaments, fascia, tendons, synovial membrane, fat, joint capsules, and lymphatic tissues. (e) Vascular inflammation such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis, as well as vascular inflammation associated with vascular cancer caused by allergic leukocytoclastic vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis. (f) Inflammation of internal organs such as the heart, stomach, intestines, lungs, liver, spleen, kidneys, pancreas, pancreas, bladder, ovaries, and prostate, including but not limited to the treatment of pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, spleenitis, nephritis, pancreatitis (including interstitial cystitis), oophoritis, prostatitis, and gastric ulcers. (g) Inflammation of the eye and surrounding areas, such as conjunctivitis, keratitis (e.g., acute epithelial keratitis, nummular keratitis, interstitial keratitis, discoid keratitis, neurotrophic keratitis, mucosal macular keratitis, herpetic keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, circumcised filarial keratitis, punctate superficial keratitis, ulcerative keratitis, lagophthalmos, actinic keratitis, and acute conjunctival hyperemia during contact lens wear), optic neuritis, macular degeneration of the retina, and retinopathy. (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, and odontogenic ulcers. (i) Rheumatoid arthritis, rheumatoid arthritis, rheumatic bone disease, ankylosing spondylitis, bursitis, Crohn's disease, gout, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, osteoporosis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, scleroderma, Sjögren's syndrome, spondyloarthritis, systemic lupus erythematosus, tendinitis, and other rheumatoid arthritis-related inflammations.

[0104] The compounds of the present invention may also be used for the differentiation and regeneration of bone marrow cells, and for aplastic anemia (for example, by systemic and topical administration).

[0105] The compounds of the present invention may also be used in the treatment of kidney diseases, including end-stage renal disease and its complications (including uremic pruritus).

[0106] The compounds of the present invention can also be used to treat certain specific diseases of the digestive system, such as gastroesophageal reflux disease (GERD), which may be characterized by sourness in the mouth, reflux, heartburn, dysphagia and / or sore throat, increased salivation (heartburn), nausea, chest pain, and cough. GERD can cause injuries to the esophagus, including reflux esophagitis (i.e., inflammation of the esophageal epithelium that can cause ulcers at or around the junction of the stomach and esophagus), esophageal stricture (i.e., persistent narrowing of the esophagus caused by reflux-induced inflammation), Barrett's esophagus (i.e., intestinal metaplasia (i.e., changes in epithelial cells from squamous epithelium to intestinal columnar epithelium of the distal esophagus), and / or esophageal adenocarcinoma (a form of cancer)).

[0107] The compounds of the present invention may also be used to treat certain specific respiratory diseases, including cystic fibrosis, interstitial pneumonia including typical interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, cor pulmonale, and pulmonary embolism. A specific disease condition that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0108] IPF is a diffuse, fatal interstitial lung disease characterized by pathological features including alveolar epithelial damage, widespread proliferation of lung fibroblasts, and excessive deposition of extracellular matrix, ultimately leading to irreversible lung tissue damage. In the later stages of the disease, subjects with IPF experience respiratory failure and death. The compounds of the present invention have been found to be useful in the treatment of IPF and / or in the alleviation of symptoms associated with this disease.

[0109] The compounds of the present invention are effective in treating the following pulmonary and / or fibrotic conditions (whether otherwise specified herein): pulmonary fibrosis, renal fibrosis, hepatic fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, status asthmatics, bronchiectasis, upper respiratory tract infections (including the common cold and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, reckettsia, radiation pneumonitis, pneumococcal pneumonia (including staphylococcus, streptococcus, and gram-negative bacilli), pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis, and nocardiosis), pulmonary mycosis, cryptococcosis, lung abscess, anaphylactic pneumonia, exogenous allergic alveolitis, and pulmonary eosinophilia (Loeffler's syndrome). It is particularly useful in the treatment of obstructive pulmonary emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis / acidosis, acute lung injury, interstitial lung disease, empyema, pulmonary fibroma, and cor pulmonale.

[0110] Specific mucosal disorders and diseases for which the compounds of the present invention are useful include, for example, anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, fissures, anal itching, anal sinusitis, warts, and rectal prolapse; inflammatory bowel diseases including Crohn's disease, especially ulcerative colitis; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as periodontitis.

[0111] The compounds of the present invention may further possess antioxidant effects by increasing SOD (superoxide dismutase) production and reducing lipid oxidation. Therefore, the compounds of the present invention may be considered to have antioxidant properties.

[0112] The compounds of the present invention may also possess antipyretic properties that enable the treatment of fever and / or alleviate its symptoms, for example, by reducing the body temperature of the subject and resulting in a reduction of fever. Therefore, the compounds of the present invention and formulations containing them may be considered antipyretics.

[0113] The compounds of the present invention are particularly useful in the following treatments; Skin diseases including acne, rosacea, dermatitis, seborrheic dermatitis, neurodermatitis, eczema, melanin pigmentation, scarring (fibrosis), alopecia, seborrheic alopecia, scarring alopecia, and paronychia; Oral diseases including periodontitis, gingivitis, oral mucositis (including radiation-induced mucositis), tooth sensitivity (hemodia), and gingival recession; Gynecological diseases including vaginitis, vulvitis, leukoplakia of the external genitalia, cervix, lateral genital incision and radiation vaginitis; and / or Inflammatory bowel disease (IBD), including ulcerative colitis, proctitis, radiation proctitis, hemorrhoids, and sinusitis.

[0114] A further aspect of the present invention provides a method for treating inflammation, inflammatory disorders, and / or disorders / conditions characterized by inflammation (for example, as a symptom), comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0115] To avoid misunderstanding, in the context of this invention, the terms “treatment,” “therapy,” and “treatment” include therapeutic or palliative treatment for patients in need of treatment, as well as prophylactic treatment and / or diagnosis for patients susceptible to inflammation and / or inflammatory disorders.

[0116] The compounds of the present invention may further possess antiviral properties that enable the treatment of viral infection or viral disease by interfering with viral replication within the host, in contrast to the treatment of any viral infection or any symptoms of a viral infection, such as pain and / or inflammation. Such antiviral properties may also enable the prevention of the development of such infection or disease, the protection of cells within the host from (e.g., further) viral infection, the prevention or cessation of the spread of viral infection or disease (within a single host or from one host to a new host), or the prevention of viral reactivation after a waiting period in the host.

[0117] A further aspect of the present invention provides a method for treating a viral infection, comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0118] Viral infections that may be mentioned include those caused by viruses of the following families: adenoviridae (e.g., adenoviruses), papillomaviridae (e.g., human papillomavirus), polyomaviridae (e.g., BK virus; JC virus), herpesviridae (e.g., herpes simplex virus type 1; herpes simplex virus type 2; varicella-zoster virus; Epstein-Barr virus; human cytomegalovirus; human herpesvirus type 8), poxviridae (e.g., smallpox), and hepadnaviridae (e.g., hepatitis B virus). , parvoviridae (e.g., parvovirus B19), astroviridae (e.g., human astrovirus), caliciviridae (e.g., norovirus; Norwalk virus), picoraviridae (e.g., coxsackievirus, hepatitis A virus; poliovirus; rhinovirus), coronaviridae (e.g., severe acute respiratory syndrome virus), flaviviridae (e.g., hepatitis C virus; yellow fever virus; dengue virus; West Nile virus; tick-borne encephalitis virus), retroviridae (e.g., human immunodeficiency virus; human Immunodeficiency virus (HIV), togaviridae (e.g., rubella virus), arenaviridae (e.g., lassa virus), bunyaviridae (e.g., hantavirus; Crimean-Congo hemorrhagic fever virus; Hantan virus), filoviridae (e.g., Ebola virus; Marburg virus; Raven virus), orthomyxoviridae (e.g., influenza viruses including influenza A virus (e.g., H1N1 and H3N2 viruses), influenza B virus, or influenza C virus), paramyxoviridae (e.g., measles virus; mumps virus; parainfluenza virus, respiratory syncytial virus), rhabdoviridae (e.g., rabies virus), hepeviridae (e.g., hepatitis E virus), reoviridae (e.g., rotavirus; orbivirus; cortivirus;Viruses not assigned to a specific family, such as the vannavirus and hepatitis D virus.

[0119] More specifically, viruses that may be mentioned include herpes simplex virus type 1 and type 2, human papillomavirus, influenza virus, and parainfluenza virus.

[0120] The compounds of the present invention may further possess antibacterial and / or bacteriostatic properties that enable the treatment of bacterial infections or diseases by inhibiting the growth or proliferation of bacteria within the host, in contrast to the treatment of any symptoms of any bacterial infection or disease, such as pain and / or inflammation. Therefore, the compounds of the present invention may be considered bactericides and / or preferably bacteriostatic agents.

[0121] Such antimicrobial properties may also enable the prevention of the development of such infections or diseases, the protection of cells within a host from (e.g., further) bacterial infections, the prevention or cessation of the spread of bacterial infections or diseases (within a single host or from one host to a new host), or the prevention of bacterial reactivation after a waiting period in the host.

[0122] A further aspect of the present invention provides a method for treating a bacterial infection, comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0123] The compounds of the present invention may further possess anticancer properties that enable the treatment of cancer itself, i.e., by interfering with cancer, as opposed to the treatment of any symptoms of cancer, such as pain and / or inflammation. Such anticancer properties may also include preventing the onset of such disease, for example by preventing such onset by treating inflammation.

[0124] According to another aspect of the present invention, a method for treating cancer is provided, comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0125] Specific cancers that may be mentioned include oral cancer, nasopharyngeal cancer, middle ear cancer, conjunctival cancer, pharyngeal cancer, tracheal cancer, esophageal cancer, stomach cancer, intestinal cancer, cervical cancer, endometrial cancer, and skin cancer, which are caused by oral mucositis (including severe oral mucositis), rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophagitis, gastritis, enterocolitis, cervix, endometritis, and erythematous skin lesions. A specific skin cancer that may be mentioned is basal cell carcinoma.

[0126] Visceral fibrotic conditions that may be mentioned include acute and / or severe internal fibrotic conditions characterized by excessive accumulation of fibrous connective tissue (as described above) in and around inflamed or damaged tissue. For this reason, the formulations of the present invention may be useful in the treatment or prevention of fibrosis (as described above) and the morbidity and death associated therewith. For this reason, visceral (e.g., acute and / or severe) fibrotic conditions that can be treated with the formulations of the present invention include fibrosis of the liver, kidneys, lungs, cardiovascular system including the heart and vascular system, pancreas, spleen, central nervous system (neurofibrosis), myelofibrosis, eyes, vagina, cervix, and other organs.

[0127] Visceral inflammatory conditions include any severe condition (i.e., a condition requiring intensive medical treatment) or a condition that may develop into one; conditions in which certain inflammatory elements are evident that may be characterized by detectable inflammation; and conditions in which the disease is evident (or anticipated) and / or life-threatening.

[0128] Inflammatory conditions that may be referred to include acute disorders or conditions of one or more viscera characterized by inflammation (e.g., as a symptom), such as acute visceral injury in one or more viscera (including any of the aforementioned viscera) (i.e., conditions requiring immediate medical intervention, or conditions that may develop into conditions requiring immediate medical intervention). By treating such acute inflammatory disorders, the formulations of the present invention may prevent or inhibit the onset of symptoms (acute or chronic) associated with such conditions, and may inhibit the progression of morbidity and / or death associated with such conditions.

[0129] Therefore, acute inflammatory conditions that may be mentioned include conditions such as peritonitis, pancreatitis, colitis, proctitis (including radiation proctitis), gastritis, duodenitis, pharyngitis, GERD, periodontitis, and stomatitis. Specific acute inflammatory conditions that may be mentioned include acute lung injury, airway injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and acute injury to one or more organs (including any of those mentioned above), such as inflammation, injury, and / or failure of multiple organs.

[0130] Such conditions may be caused by internal or external trauma (e.g., injury or burns), or by infections caused by viruses, bacteria, or fungi.

[0131] For example, proctitis (including eosinophilic, gonococcal, and / or ulcerative proctitis) can be caused by inflammatory bowel disease, infections, radiation (e.g., for cancer), drugs such as antibiotics, surgery, or allergic conditions such as food intolerance.

[0132] For example, multi-organ inflammation, injury, and / or failure may result from extensive and / or traumatic external injury, including traumatic and / or extensive burns. Traumatic external burns are understood to include second-degree, more specifically third-degree and fourth-degree burns. Extensive external burns are understood to include burns affecting at least about 10% of the patient's body surface area, such as at least about 20% or at least about 15%. External (and internal) burns may result from exposure to heat, chemicals, etc.

[0133] Acute inflammatory and / or fibrotic conditions may also result from sepsis or septic shock, which can be caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and SARS in particular can be caused by viruses such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2).

[0134] Therefore, in addition, one or more of the aforementioned (e.g., acute) inflammatory conditions may result in some form of internal tissue damage and / or dysfunction of associated internal tissues (and in fact, this is likely in some cases). As such, associated tissues include (e.g., mucosal) tissues such as airway epithelium. Such tissue damage can also lead to one or more of the fibrotic conditions described above. For example, SARS disease, caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19), is known to often result in fibrosis arising from one or more of many factors, including inflammation.

[0135] In this regard, the compounds and salts thereof of the present invention find particular utility in the treatment of related inflammatory and / or fibrous conditions, given that such conditions are often characterized by one or more comorbidities. Conditions “characterized by comorbidities” include the fact that the primary condition in question simultaneously causes (or is caused by) another further medical condition, including (in fact preferably) those described above, and these conditions may interact with and / or overlap with each other in some way.

[0136] Therefore, A method for treating at least one inflammatory and / or fibrous disorder or condition in one or more internal organs of a patient, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof directly to a patient requiring such treatment, A method for treating two or more inflammatory and / or fibrous disorders or conditions of one or more internal organs of a patient, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof directly to a patient in need of such treatment, and A method is provided for reducing the incidence of morbidity and / or death associated with or potentially associated with one or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs in a patient, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof directly to a patient in need of such treatment.

[0137] In addition, the compounds of the present invention may be used in the treatment of conditions characterized by immunosuppression and immunodeficiency disorders, in the treatment of patients with impaired immune systems, and / or for the restoration of normal function of a patient's immune system.

[0138] Conditions characterized by immunosuppression (or immunodeficiency disorder) include primary immunodeficiency disorder (PIDD), which is typically a rare congenital disorder and usually inherited. Therefore, PIDD includes humoral immunodeficiency disorders, e.g., unclassifiable immunodeficiency, selective immunoglobulin deficiency (e.g., IgA deficiency), transient hypogammaglobulinemia in infants, X-linked agammaglobulinemia; cellular immunodeficiency disorders, e.g., chronic mucocutaneous candidiasis, DiGeorge syndrome, X-linked lymphoproliferative syndrome; combinations of humoral and cellular immunodeficiency disorders, e.g., ataxia telangiectasia, hyperimmuneglobulinemia E syndrome, severe combined immunodeficiency, Wiscott-Aldrich syndrome; phagocytic immunodeficiency, e.g., Chediak-Higashi syndrome, chronic granulomatous disease, cyclic neutropenia, leukocyte adhesion disorders; and complement deficiencies, e.g., complement component 1 (C1) inhibitor deficiency (or hereditary angioedema), C3 deficiency, C4 deficiency, and C5, C6, C7, C8, and / or C9 deficiency.

[0139] However, the immunodeficiency disorders treated according to the present invention are preferably secondary immunodeficiency disorders (SIDDs), which are more common than PIDDs and tend to develop in later life, and SIDDs include immunodeficiency disorders caused by secondary factors such as aging, malnutrition (e.g., nutritional deficiencies), chronic disorders, one or more chemical agents (e.g., drugs), and / or (e.g., ionizing) radiation.

[0140] For the purposes of this invention, the term "SIDD" may also include physical and / or mental stress, which may act to impair the patient's immune system.

[0141] Physical stress can be caused by trauma (injury, infection, surgery), strenuous physical labor / excessive effort (e.g., overtraining), environmental pollution (pesticides, herbicides, toxins, heavy metals, insufficient light, radiation, noise, electromagnetic fields), disease (viruses, bacteria, or fungal pathogens), fatigue, insufficient oxygen supply, hypoglycemia, hormonal and / or biochemical imbalances, dietary stress (malnutrition, food allergies and hypersensitivity, unhealthy eating habits), dehydration, substance abuse, dental problems, and musculoskeletal misalignment / imbalance.

[0142] Mental stress can include various forms of psychological and / or psychosocial stress, such as emotional stress (e.g., negative emotions like resentment, fear, frustration, sadness, anger, grief / bereavement), cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, attachment, self-criticism, self-loathing, unattainable perfection, anxiety, panic attacks, and a general feeling of being out of control), perceptual stress (beliefs, roles, attitudes, values, meanings, and / or purposes), death / loss of a loved one, interpersonal difficulties (with a partner, siblings, children, extended family, employer, or colleague), lack of social support (e.g., friends and / or isolation), and economic stress (e.g., unemployment, loss of investments, loss of savings, bankruptcy, foreclosure, etc.).

[0143] Disorders that may cause immunodeficiency in patients include cancer; blood disorders, such as aplastic anemia, leukemia, and multiple myeloma; sickle cell disease and Down syndrome; infections, such as viral infections including varicella, cytomegalovirus, Epstein-Barr virus, HIV, measles, and bacterial infections; diabetes; visceral diseases, such as chronic kidney disease, nephrotic syndrome, chronic hepatitis, and liver failure; systemic lupus erythematosus; alcoholism and chronic burns; and surgery, such as splenectomy.

[0144] Drugs that can cause immunodeficiency in patients include: anticonvulsants, e.g., lamotrigine, phenytoin, valproate; immunosuppressants, e.g., azathioprine, cyclosporine, everolimus, leflunomide, mycophenolate, mofetil, sirolimus, tacrolimus, tofacitinib; and biologics, e.g., abatacept, adalimumab, anakinra, basiliximab, certolizumab, daclizumab, etanercept, golimumab, infliximab, ixekizumab, muromonab (OKT3), natalizumab, rituximab. Secukinumab, tocilizumab, ustekinumab, vedolizumab; and in particular, corticosteroids, including naturally occurring corticosteroids such as cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, and progesterone, and naturally occurring precursors and intermediates of corticosteroid biosynthesis, and other derivatives of naturally occurring corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, and 11-deoxycortisol Luticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β, 17α, 21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone and 18-hydroxyprogesterone, and synthetic corticosteroids. Hydrocortisone-type (group A) drugs, such as cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteplate, hydrocortisone butyrate, hydrocortisone valerate, thixocortol and thixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolonone, fluprednisolone, loteprednol, prednicarbate and triamcinolone;Acetonides and related substances (Group B), such as amcinonides, budesonides, desonides, fluocinolonecetonides, fluocinonides, halcinonides, triamcinolone acetonides, ciclesonides, deflazacort, formotoluol, fludroxycortide, flunisolide, and fluocinolone acetonides;

[0145] (Beta)methasone type (group C), for example beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halomethasone, mometasone and mometasone furoate, alclomethasone and alclomethasone propionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, crocortolone, desoxymethasone, diflorasone, difluocortolone, flurolon, flumetasone, fluocortin, flupredniden and flupredniden acetate, fluticasone, fluticasone Examples include furanates and propionates such as fluticasone, meprednisone, paramethazone, prednylidene, rimexolone, and urobetasol; progesterone types, such as flugestone, fluorometholone, medrizone, and prepediolon acetate; and progesterone derivatives (progestins), such as chlormadinone acetate, cyproterone acetate, medroguestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; and other corticosteroids, such as cortibazole and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one. Specific corticosteroids that may be mentioned include cortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.

[0146] However, drugs that can cause immunodeficiency in patients that can be specifically mentioned include cancer chemotherapy treatments such as alemtuzumab, busulfan, cyclophosphamide, and melphalan.

[0147] Specific SIDDs that may be mentioned include those caused by radiation therapy used to treat conditions such as cancer (i.e., radiation-induced immunosuppression).

[0148] Ionizing radiation not only suppresses the immune system as described above, but can also alter the function of the immune system in irradiated organs in other ways. For example, increased levels of inflammatory mediators such as NF-κB and SMAD2 / 3, as well as cytokines such as IL-1, IL-2, IL-6, IL-8, IL-33, tumor necrosis factor (TNF-α), transforming growth factor beta (TGF-β), and interferon gamma (IFN-γ), are associated with the release of prostaglandins and free radicals, including reactive oxygen species (ROS) and nitric oxide (NO). High doses of radiation exposure that may occur during accidental exposure (e.g., as a result of a nuclear or radiation disaster) may cause inflammatory responses and / or wounds that may persist for several years thereafter and / or destroy the function of the irradiated organs.

[0149] The compounds of the present invention can be used not only to provide immune-restorative effects, but also to simultaneously promote wound recovery and / or healing. This is particularly useful considering the fact that wounds associated with such pathological conditions are difficult, if not impossible, to treat appropriately in terms of radiation-induced immunosuppressive effects and the absence of a normal endogenous inflammatory response.

[0150] By providing the aforementioned immune restoration effect, this enables the body's immune system and local inflammatory response to be more effective. In this regard, the compounds of the present invention can be used to promote further wound healing while, however, not further impairing the patient's immune system (in the manner in which corticosteroids do when used to treat inflammation), and also to provide an anti-inflammatory effect.

[0151] According to a further aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition characterized by inflammation and / or a condition characterized by inflammation or a wound in a patient having or being vulnerable to a condition characterized by immunosuppression, including the treatment of radiation-induced conditions characterized by inflammation and / or a wound.

[0152] Diseases that are themselves radiation-induced and / or can give rise to radiation-induced immunosuppression (including those characterized by inflammation and / or a wound) include those that can occur after accidental exposure to radiation (commonly known as "radiation poisoning"), or those that can occur as a result of intentional and / or targeted exposure to radiation, for example, in the treatment of diseases such as cancer (e.g., ionizing) radiotherapy.

[0153] Radiation therapy is, for example, a type of cancer treatment that uses an external beam of high energy to kill cancer cells. Radiation therapy most often uses X-rays, but protons or other types of energy can also be used. Radiation therapy can be used as primary cancer treatment, as neoadjuvant therapy (to shrink a cancerous tumor before surgery), as adjuvant therapy (to prevent the growth of cancer cells after surgery), to relieve symptoms caused by advanced cancer, or in combination with two or more of the above. Radiation therapy may also be used in combination with other treatments such as chemotherapy.

[0154] Disorders characterized by inflammation and / or wounds of the mucosa and / or skin that can result from exposure to radiation are often associated with the part of the body being targeted / irradiated. For example, · Radiation-induced dermatitis and mucositis can occur in the skin or mucosa, respectively, at a location that can be close to the part of the body being irradiated. For example, radiation-induced oral mucositis can occur after irradiation of the head or neck. · Irradiation-induced encephalitis can also occur after irradiation of the head or neck. · Radiation pneumonitis and / or radiation esophagitis often result from radiation therapy for lung cancer, breast cancer, lymphoma, thymoma, or esophageal cancer.

[0155] Radiation therapy targeting the abdomen, pelvis, or rectum (e.g., for treating cervical cancer, prostate cancer, bladder cancer, or rectal cancer) can cause one or more of radiation bowel disease (or radiation enteritis including radiation colitis and radiation small bowel colitis), radiation hepatitis, radiation myelitis, radiation vaginitis, particularly radiation proctitis.

[0156] Particularly, radiation proctitis or radiation rectal disorder is a pathological condition characterized by damage to the rectum after exposure to radiation during radiotherapy. The inflammation can be acute (acute radiation proctitis and related radiation colitis) or chronic (e.g., radiation-associated vascular ectasias (RAVE) and chronic radiation rectal disorder).

[0157] The initial symptoms of acute radiation proctitis include pelvic pain, diarrhea, and tenesmus, but radiation damage to the rectum often causes urinary incontinence and rectal bleeding, and in severe cases, wounds, strictures, and / or fistulas.

[0158] Therefore, for example, in the treatment of radiation-induced disorders for cancer therapy, including radiation proctitis, radiation colitis, and radiation-induced dermatitis as defined above, the compounds and salts of the present invention can be used, • It may treat wounds associated with such disorders and / or promote wound recovery and / or healing, while simultaneously providing an immune-restorative effect, and / or It may be used to promote further wound healing without damaging the patient's immune system, while also providing a more direct anti-inflammatory effect.

[0159] According to two further embodiments of the present invention, (i) Methods for treating radiation-induced conditions characterized by immunosuppression and (ii) inflammation and / or wounding, and A method is provided for treating inflammation and / or wounds associated with radiation-induced immunodeficiency disorders while simultaneously restoring the normal function of the patient's immune system. This method involves administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need.

[0160] The treatment methods and uses described above are particularly useful, for example, when damage induced by radiation for cancer therapy results from irradiation of the lower abdominal region as described above.

[0161] Further provided are methods for reducing the incidence of radiation-induced morbidity and / or mortality in patients characterized by inflammation and / or wounds (e.g., ionizing radiation-induced injuries) or related thereto, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0162] Conditions in which the compounds of the present invention are particularly useful include: skin inflammation, physiological reactions resulting from skin inflammation and / or wound healing processes, e.g., scarring and melanin pigmentation; inflammation and fibrosis of the scalp and hair follicles, including conditions characterized by pathological hair loss, such as seborrheic dermatitis, scarring alopecia and related conditions (e.g., seborrheic alopecia and fibrous alopecia); gastritis, gastric ulcers, stress-induced gastritis; GERD; IBD, including Crohn's disease, ulcerative colitis, and / or proctitis, radiation proctitis; arthritis; macular degeneration of the retina; differentiation and regeneration of bone marrow cells, and aplastic anemia; stress; and IPF, ALI / ARDS, uremic pruritus, COPD, asthma, bronchitis (including chronic bronchitis), vasculitis, pancreatitis, multiple organ injury, and / or viral infections.

[0163] In addition, the compounds of the present invention may be used in non-therapeutic cosmetic treatments such as anti-aging.

[0164] Therefore, a further aspect of the present invention is the non-therapeutic use of the compounds of the present invention in anti-aging, for example, by promoting skin integrity so that the skin has the appearance of younger skin.

[0165] A further aspect of the present invention is a cosmetic composition comprising the compound of the present invention. Such a composition may provide anti-aging properties.

[0166] "Patients" include reptiles, birds, and preferably mammals (especially humans).

[0167] According to the present invention, the compounds of the present invention are administered in the form of pharmaceutical formulations comprising compounds in pharmaceutically acceptable dosage forms, preferably topically or systemically, for example, orally, intravenously, or intra-arterial (including intravascular and other perivascular devices / dosage forms (e.g., stents)), intramuscularly, cutaneously, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, intravaginally, percutaneously, transnasally, or pulmonaryly (e.g., trachea or bronchi), for example, by direct injection, or by any other parenteral route, preferably topically or by any other parenteral route.

[0168] Administration by inhalation (e.g., intranasally) is particularly useful when the condition to be treated is an inflammation resulting from rhinitis or a viral infection of the respiratory tract (e.g., upper respiratory tract infections such as colds and influenza).

[0169] Lung administration is particularly useful when the condition to be treated is COPD or IPF. The topical administration form may be enhanced, for example, by using a powder aerosol or by creating a spray containing the active ingredient by means of an aqueous mist using a suitable atomization technique or device such as a nebulizer.

[0170] Anorectal administration is particularly useful when the condition to be treated is hemorrhoids or ulcerative colitis using a suitable delivery means such as a solution of the foam to be injected or a suppository.

[0171] Administration to the lower digestive tract can also be achieved by parenteral, particularly oral delivery, using standard delayed release or sustained release coating techniques known to those skilled in the art. In particular, separate portions of the upper or lower intestine can be targeted. For example, colonic administration can also be achieved by means of colon-targeted drug delivery means administered first orally or parenterally.

[0172] The compounds of the present invention may alternatively be administered by direct systemic parenteral administration. Such administration may be useful in the treatment of one or more of the aforementioned disorders or conditions of one or more of the patient's internal organs.

[0173] The compounds of the present invention are preferably administered by intradermal injection, inhalation, or topical administration (e.g., to the skin or mucosal surface, such as the oral mucosa, ocular mucosa, nasal mucosa, vaginal mucosa, rectal mucosa, colonic mucosa, esophageal mucosa, throat, or the peri - dental area, gingiva and / or teeth).

[0174] The internal organs that may be mentioned include the stomach, intestine, pancreas, liver, spleen, bladder, vascular system, ovaries, prostate, preferably the heart and kidneys, more preferably the lungs.

[0175] Standard delayed-release or sustained-release techniques known to those skilled in the art may be used for non-oral administration methods, such as subcutaneous or intramuscular depot formation techniques, or as an alternative to parenteral administration.

[0176] Therefore, pharmaceutically acceptable formulations for use in the above-described routes of administration may include the compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, which can be selected in full consideration of the intended direct parenteral administration route and standard pharmacokinetics. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may not have adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate release or release regulation of the compound of the present invention.

[0177] Therefore, the formulation for injection may be in the form of an aqueous formulation such as a suspension and / or more preferably a solution (an optional buffered aqueous formulation such as a physiological saline-containing formulation (e.g., a solution), a phosphate-containing formulation (e.g., a solution), an acetate-containing formulation (e.g., a solution), or a volat-containing formulation (e.g., a solution), or a lyophilized powder that can be reconstituted with a vehicle such as an aqueous vehicle before use (e.g., injection).

[0178] The formulation for injection may contain other suitable excipients known to those skilled in the art, such as solvents (e.g., water), co-solvents, solubilizers (e.g., cyclodextrin), wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, volume extenders, and / or protective agents.

[0179] The formulation for injection is preferably buffered to a physiologically acceptable pH value (e.g., about 4.5 to about 9.5, e.g., about 6 to about 9, e.g., about 6.5 to about 8.5 pH) using a buffer and / or pH adjuster as described herein by standard technique, and / or may further contain a tonic modifier (such as sodium chloride).

[0180] Notwithstanding the foregoing, preferred modes of delivery of the compounds of the present invention include a suitable (e.g., pharmaceutically and topically acceptable) vehicle suitable for application to the skin and / or suitable mucosal surfaces, and / or topical delivery to the site of inflammation (e.g., mucous membranes including the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or more preferably the skin) in commercially available formulations, but may also include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, or pulmonary delivery.

[0181] Administration by injection is particularly useful for administering the compound of the present invention in the form of a suspension solution, for example, into the dermis (e.g., intradermal injection), joint cavity, or eye.

[0182] Intradermal injection (e.g., intradermal) administration is particularly useful for administering the compounds of the present invention into the dermis in the form of a solution or suspension (e.g., a skin filler). This is particularly useful as a means of administration for melanin pigmentation therapy as described above, or for the use of the compounds of the present invention in the treatment of wrinkles, for example.

[0183] Administration by injection is particularly useful, for example, for filling surgical sites in the nasal cavity, anal fistulas, and spaces between the gums and tooth roots or sinuses. It is especially useful for shaping and / or lubricating supports.

[0184] The compounds of the present invention will generally be administered in the form of one or more pharmaceutical formulations, for example, mixed with an adjuvant, diluent, or carrier (e.g., pharmaceutically acceptable) which can be selected in full consideration of the intended route of administration (e.g., topical administration to the relevant mucous membrane (including the lungs) or preferably to the skin) and standard pharmaceutical or other (e.g., cosmetic) practices. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may not have adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate release or release regulation of the compounds of the present invention.

[0185] Suitable pharmaceutical formulations are either commercially available or can be found in literature, e.g., Remington, The Science and Practice of Pharmacy, 22 nd edition,Pharmaceutical Press(2012), and Martindale-The Complete Drug Reference,38 th The compounds can be prepared according to the techniques described in Edition, Pharmaceutical Press (2014) and the documents referenced therein, and the relevant disclosures of all such documents are incorporated herein by reference. Otherwise, the preparation of suitable formulations containing the compounds of the present invention can be achieved by those skilled in the art using conventional techniques in ways not of the present invention.

[0186] The compounds of the present invention may be in the form of aqueous formulations such as emulsions, suspensions and / or solutions (for example, buffered aqueous formulations (e.g., solutions) such as physiological saline-containing formulations (e.g., solutions), phosphate-containing formulations (e.g., solutions), acetate-containing formulations (e.g., solutions), or volate-containing formulations (e.g., solutions), or lyophilized powders.

[0187] The compounds of the present invention can further and / or alternatively be combined with suitable excipients to prepare the following: • Gel formulations (suitable gel matrix materials therefor include cellulose derivatives, carbomers and alginates, tragacanth gum, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, noncellulose polysaccharides, sugars such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and especially hyaluronic acid), • Lotion (Suitable matrix materials for this include cellulose derivatives, glycerin, noncellulose polysaccharides, polyethylene glycol of different molecular weights, and propanediol), • Paste or ointment (suitable paste matrix materials for this purpose include glycerin, petrolatum, paraffin, polyethylene glycol of different molecular weights, etc.) • Cream or foam (suitable excipients therefor (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycol of different molecular weights, sodium dodecyl sulfate, aliphatic alcohol sodium polyoxyethylene ethersulfonate, corn gluten powder, and acrylamide), • Powdered aerosol (suitable excipients therefor include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol, and polysorbate, e.g., dry powder inhalants), and / or • Liquids, such as mouthwash, oral, inhalation, or facial water (aerosol) sprays (suitable excipients for which include viscosity modifiers such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohol, water, preservatives, sweeteners, flavorings, etc.), • Injectable solutions or suspensions (which may be aqueous or otherwise, and suitable excipients therefor include solvents and co-solvents, solubilizers, wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers, and / or pH adjusters, volume expanders, protective agents, and tonic modifiers), certain injectable solutions or suspensions that may be mentioned include skin fillers (e.g., injectable fillers or soft tissue fillers), particularly when the compounds of the present invention are combined with hyaluronic acid. Oral tablets (suitable excipients therefor include binders, e.g., syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose, or polyvinylpyrrolidone; fillers, e.g., lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, e.g., magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, e.g., sodium lauryl sulfate).

[0188] Moisturizers, such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic acid / capric triglyceride, etc.; and / or antioxidants, such as vitamins and glutathione; and / or pH adjusters, such as acids, bases, and pH buffers, may also be included in such formulations as needed. Furthermore, surfactants / emulsifiers, such as hexadecanol (cetyl alcohol), fatty acids (e.g., stearic acid), sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (e.g., glyceryl monostearate), polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, polyoxylglycerides, lauryl dimethicone The formulation may contain amine oxide, bile salts (e.g., sodium deoxycholate, sodium cholate), lipids (e.g., fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenol, glycolipids, polyketides), phospholipids, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), sugar esters, polysorbates, etc.; preservatives, such as phenoxyethanol, ethylhexylglycerin, etc.; and thickeners, such as acryloyldimethyltaurate / VP copolymer. Specifically, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, octanoic acid / capric acid glyceride, etc., may be included, especially in cream formulations.

[0189] The compounds of the present invention and (e.g., pharmaceutical) formulations containing them (e.g., solutions, gels, creams, ointments, lotions, foams, pastes, and / or dry powders as described above) can be further combined with a suitable matrix material to prepare bandages or therapeutic patches for application to biological surfaces such as skin or mucous membranes. For this purpose, such formulations may be used to impregnate a matrix material such as gauze, nonwoven fabric, or silk paper. Alternatively, the therapeutic patch may be, for example, a band-aid, facial mask, eye mask, hand mask, foot mask, etc.

[0190] While petrolatum may be used when applying such bandages to wounds, the inventors have also found that bandages can be prepared without the need for petrolatum by combining a PEG (e.g., PEG400)-based ointment with a matrix material.

[0191] The compounds of the present invention may also be used in combination with solid supports (such as nasal dressings (e.g., for stopping nosebleeds), skin scaffolds (e.g., in wound healing), or artificial bone (e.g., in bone grafts / transplants)).

[0192] The compounds of the present invention may be administered for inhalation in the form of a suspension, dry powder, or solution. Suitable inhalation devices include pressurized metered-dose inhalers (pMDIs) that are manually or exhaled and can be used with or without a standard spacer device, dry powder inhalers (DPIs) which may be single-dose or multi-dose power-assisted, and soft mist inhalers (SMIs) or nebulizers in which aerosol drugs in a fine mist are delivered at a slower rate than, for example, a spray supplied using a pMDI.

[0193] In pMDI, the compounds of the present invention may be administered as a pressurized suspension of finely ground particles dispersed in a propellant (e.g., together with excipients such as HFA, mannitol, lactose, or sorbitol) or as an ethanol solution to deliver one or more metered doses of about 20 to about 100 μL in each action. Action can be performed manually (e.g., by pressing) or by inhalation (respiratory action) and is accompanied by a spring-driven flow trigger system.

[0194] In a DPI, the compounds of the present invention may be administered alone or in combination with a larger particle-sized inert excipient (e.g., mannitol) in the form of micronized drug particles (size between about 1 and about 5 μm) in a capsule that can be pre-filled in the device or manually filled. Upon inhalation from the DPI, the drug particles may break down and disperse into the airways.

[0195] In SMI, the compound of the present invention can be stored as a solution in a cartridge filled into the device. A spring can release the dose to a micropump so that when a button is pressed, the dose is released and a jet stream of the drug solution is released.

[0196] The compounds of the present invention can also be administered in the form of a fine mist of aerosolized solution using various nebulizers. Examples of nebulizers include respiratory-enhanced jet nebulizers (in which case, with the assistance of a compressor, an airflow moves through a jet to aerosolize the drug solution), respiratory-operated jet nebulizers (after the patient inhales, with the assistance of a compressor, an airflow moves through a tube to aerosolize the drug solution), ultrasonic nebulizers (a piezoelectric crystal vibrates, causing aerosolization by heating and resulting in atomization), and vibrating mesh nebulizers (a piezoelectric crystal vibrates a mesh plate to cause aerosolization, providing very fine droplets without significantly changing the temperature of the solution during atomization).

[0197] A further aspect of the present invention provides a process for preparing a pharmaceutical composition / formulation as defined herein, comprising associating a compound of the present invention as defined above with one or more pharmaceutically acceptable excipients as defined above.

[0198] The compounds of the present invention may also be used in therapeutic combination with one or more growth factors selected from platelet-derived growth factors (including platelet-derived growth factor, PDGF); osteosarcoma-derived growth factor (ODGF); epidermal growth factor (EGF); transforming growth factor (TGFα and TGFβ); fibroblast growth factor (αFGF, βFGF); insulin-like growth factor (IGF-I, IGF-II); nerve growth factor (NGF); interleukin-type growth factors (IL-1, IL-1, IL-3); erythropoietin (EPO); and colony-stimulating factor (CSF).

[0199] A further aspect of the present invention provides a (e.g., pharmaceutical) composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, such as an adjuvant, diluent, or carrier. Preferred formulations are suitable for topical application to mucous membranes (including oral and / or nasal mucosa, lungs, anorectal region, and / or colon), or more preferably to the skin, and therefore include a topically acceptable adjuvant, diluent, or carrier.

[0200] Accordingly, pharmaceutical compositions comprising the compounds of the present invention, which are suitable for topical administration (e.g., to mucous membranes including the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin), are presented, and the use of such formulations in the treatment of disorders including inflammation, inflammatory disorders, and / or conditions characterized by inflammation (e.g., as symptoms) by direct topical administration (e.g., to mucous membranes including the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin) is further provided.

[0201] To avoid misunderstanding with respect to this aspect of the present invention, topical formulations comprising the compounds of the present invention can be used in the treatment of any inflammatory disorder, including any inflammatory condition described herein, including the treatment of inflammation, and / or any inflammatory condition as referred to, defined, or described herein. Similarly, topical formulations comprising the compounds of the present invention that may be referred to include all of those referred to, defined, or described herein. All of the relevant disclosures herein are incorporated herein by reference in combination with this aspect of the present invention.

[0202] Topical formulations (e.g., based on a liquid or (e.g., aqueous) solution) containing the compounds of the present invention may be particularly useful for wound healing and may alleviate pain (including numbness), as well as pruritus / itchiness, particularly associated with the wound itself and the wound healing process. Such topical formulations containing the compounds of the present invention may also be particularly useful in preventing and / or inhibiting the exudation of bodily fluids from a wound after a burn or wound, particularly during the acute inflammatory phase, e.g., the first 48 hours. This prevents the risk of infection and other physiological reactions. Such topical formulations containing the compounds of the present invention may also be particularly useful in preventing and / or inhibiting scarring and melanin pigmentation (see above), whether or not they are related to the wound.

[0203] The administration of the compounds of the present invention may be continuous or intermittent. The mode of administration may be determined by the timing and frequency of administration, but in the case of therapeutic treatment of inflammation, it may also be determined by the severity of the condition.

[0204] Depending on the disorder being treated, the patient, and the route of administration, the compounds of the present invention may be administered to patients requiring treatment at different therapeutically effective doses.

[0205] Similarly, the amount of the compound of the present invention in the formulation is determined by the severity of the condition being treated and the patient, but may also be determined by those skilled in the art.

[0206] In any case, medical practitioners or other persons skilled in the art can routinely determine the most suitable actual dosage for an individual patient according to the severity of the condition and the route of administration. The dosages described herein are examples of average cases, and of course, there may be individual cases where higher or lower dosage ranges are appropriate, and these are also within the scope of the present invention.

[0207] The dosage can be administered once to four times a day (for example, three times).

[0208] An appropriate concentration of the compound of the present invention in the aqueous solution product can be about 0.01 (for example, about 0.1) to about 15.0 mg / mL, calculated as the free (non-salt) peptide in all cases.

[0209] An appropriate topical dosage of the compound of the present invention is about 0.1 (for example, about 0.5) to about 20 μg / cm 2 calculated as the free (non-salt) compound in all cases, including a treatment area of about 1 to about 10 μg / cm 2 ) of the treatment area, and is within the range of about 0.05 to about 50 μg / cm 2 of the treatment area, such as a treatment area of about 0.05 to about 50 μg / cm 2 of the treatment area.

[0210] Appropriate doses of the compound of the present invention for intranasal administration (e.g., by inhalation) range from about 0.01 μg to about 2000 mg, for example, about 0.1 μg to about 500 mg, or 1 μg to about 100 mg. Specific doses for intranasal administration that may be mentioned include about 10 μg to about 1 mg, particularly a dose of about 0.1 mg (i.e., about 100 μg). Intranasal administration of about 0.1 mg of the compound of the present invention per day has been found to be particularly effective in treating conditions related to inflammation of the nasal cavity and mucosa, such as rhinitis (e.g., allergic rhinitis) and / or conditions associated with rhinosinusitis surgery.

[0211] Appropriate doses of the compound of the present invention for pulmonary administration (e.g., by inhalation) are in the range of about 0.01 μg to about 2000 mg, for example, about 0.1 μg to about 500 mg, or 1 μg to about 100 mg. Specific doses for pulmonary administration that may be mentioned include doses of about 10 μg to about 10 mg, particularly doses of about 0.6 mg (i.e., 60 μg) to 6 mg (for example, for use in the treatment of COPD or IPF).

[0212] The pH value of the formulation containing the compound of the present invention is preferably in the range of about 1.0 to about 9.0 (for example, about 3.0 to about 8.0).

[0213] In any case, the dose administered to mammals, particularly humans, must be sufficient to produce a therapeutic response in the mammal over a reasonable time frame (as described above) in the context of the present invention. Those skilled in the art will recognize that the precise dose and composition, as well as the selection of the most appropriate delivery regimen, are also influenced, in particular, by the pharmacological properties of the formulation, the nature and severity of the condition being treated, the physical and mental state of the recipient, and the age, condition, weight, sex and response of the patient being treated, the stage / severity of the disease, and genetic differences among patients.

[0214] Therefore, the compounds of the present invention are useful in pharmaceuticals for human or animal use. In this regard, as described above, the compounds of the present invention that possess an appropriate degree of relevant pharmacological (or biological) activity themselves can be used as pharmaceuticals for human and / or animal use.

[0215] Certain compounds of the present invention, particularly those of formula I, may possess adhesive properties in addition to the aforementioned biological activity.

[0216] These adhesive properties stem from the fact that the relevant W and / or U groups can crosslink with each other to form a three-dimensional network.

[0217] Such compounds of the present invention may adhere to a number of substrates, including inorganic substrates such as glass and metal, and organic substrates such as biological tissue.

[0218] In this regard, such compounds of the present invention may also be used as wound surface repair products, wound surface protection products, medical biological adhesive products, medical coating products, industrial coating products (for example, in corrosion prevention in ships, electronic equipment, pipelines, etc.), biochemical reagents, medical products, sterilization products, culture vessels for cell culture, etc.

[0219] Such compounds of the present invention may form films on the wound surfaces of various skin and mucous membranes, such as burns, ulcers, frostbite, and pressure ulcers, to aid in healing. Such compounds of the present invention may also be used in surgical procedures, such as closing surgical incisions, bonding fractured bones, bonding mucous membranes, and coating human implants such as artificial bones, cartilage brackets, periosteum, artificial joints, dental implants, occlusion stents, spinal fixation devices, spinal spacers, and organ patches.

[0220] According to a further aspect of the present invention, a compound of formula I is provided as an adhesive or film-forming material.

[0221] As mentioned above, naturally occurring MAPs are known for their adhesive properties, but it is important to remember that such adhesive properties may arise from the fact that they are high molecular weight linear peptides that can exist in multiple conformations, enabling intermolecular reactions / crosslinking of DOPA residues within the molecule, and thus adhesion. Conversely, it is surprising to the applicant that the compounds of the present invention, as defined above, are not linear polypeptides or proteins, but rather, for example, multiple branched low molecular weight residues, and yet possess similar properties (adhesive or biological) to naturally occurring MAPs.

[0222] Such crosslinking may be carried out by various chemicals (iodine vapor, glutaraldehyde, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC / NHS), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), or other water-soluble condensing agents) or by enzymatic means (e.g., tyrosinase, or as described below).

[0223] Regardless of the level of pharmacological activity that the compounds of the present invention may possess, they may, in any case, be combined (and / or further combined) with active pharmaceutical ingredients as or as part of pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers) in combination therapy (described below) or by performing a function, as part of a medical device and / or as part of a drug-medical device combination.

[0224] Accordingly, certain compounds of the present invention may be described as novel, multifunctional excipients that can be used in a variety of applications in the pharmaceutical field. In this regard, such compounds of the present invention include those that can be used as adhesives and / or film-forming agents (as described above). Furthermore, such compounds of the present invention and / or different compounds of the present invention can be used as alternatives and / or even further as release-delay polymers, binders, suspending agents, gelling agents, coating agents, diluents, or carriers for active ingredients (drugs) of varying solubility.

[0225] The compounds of the present invention, which are particularly useful as pharmaceutical excipients, may be used in large-scale production, may exist without significant toxicity risks, may be described as such, and may be listed as "Generally Recognized as Safe (GRAS)" by the U.S. Food and Drug Administration (FDA).

[0226] Such compounds of the present invention may also be used as excipients in veterinary medicine and in cosmetics.

[0227] A further aspect of the present invention provides a pharmaceutical formulation comprising an active pharmaceutical ingredient mixed with a pharmaceutically acceptable excipient system (such as a pharmaceutically acceptable adjuvant, diluent, or carrier system), wherein the excipient system comprises one of the many compounds of the present invention.

[0228] Furthermore, the compounds of the present invention can be combined with active pharmaceutical ingredients and thus used as part of a drug-medical device combination, which comprises one or more active pharmaceutical ingredients and one or more compounds of the present invention, and the one or more compounds of the present invention constitute a medical device component of that combination.

[0229] Those skilled in the art will understand that when used as a medical-device component of a medical device or a combination of a drug and a medical device, or as part thereof, the relevant compounds of the present invention will be used in pharmaceuticals for human or animal use in combination with active pharmaceutical ingredients in a manner that optionally affects the structure and / or one or more functions of the human or animal body, achieving its primary intended purpose without exerting a chemical effect inside or on the human or animal body (in a manner that optionally does not depend on the compounds of the present invention being metabolized to achieve any of its primary intended purposes).

[0230] In this regard, the compounds of the present invention can be combined with a number of known pharmacoactive ingredients, and can be combined as follows, regardless of whether the compounds of the present invention are used. • In combination therapy, as a separate active pharmaceutical ingredient, • As a medical device, or as part thereof, • As a drug-medical device combination, or as a part of such medical device, As a pharmaceutically acceptable excipient.

[0231] Such patients may also (and / or already) be receiving therapy based on the administration of one or more of the other known pharmacoactive ingredients, meaning that they have received, in addition to, and / or subsequently, prescription doses of one or more of the active ingredients referred to herein, prior to, in addition to, and / or after, treatment with the compounds of the present invention.

[0232] Pharmaceutical agents that can be administered simultaneously with the compounds of the present invention include any agents or drugs that can produce certain physiological effects in living subjects, particularly mammals and especially human subjects (patients), regardless of their therapeutic or prophylactic ability for a particular disease or condition.

[0233] Furthermore, the compounds of the present invention, such as those that can be crosslinked as described above, may be used as pharmaceutical excipients and may be mixed with such pharmaceutically active ingredients before or after crosslinking and / or at least partial crosslinking, as described above, in order to form a stable pharmaceutical composition in which the compounds of the present invention act as excipients such as carriers. When used in this manner, it may be found that the compounds of the present invention may positively influence the physical, chemical, and / or biological properties of such active ingredients, including their physical and / or chemical stability and / or their metabolism after administration.

[0234] Pharmaceutical agents that may be used in conjunction with the compounds of the present invention may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antiparasitic agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing agents (growth factors).

[0235] The biological activators may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antiparasitic agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing agents (growth factors).

[0236] Non-limiting examples of anti-inflammatory agents that may be used include: rheumatic diseases and / or arthritis (such as cataphram, betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodolac, meclofenamet, sarsalate, methylprednisolone, and piroxicam); osteoarthritis (such as sulindac, meloxicam, fenoprofen, etoricoxib, and nabumetone); inflammation and its symptoms, e.g., fever, pain, itching and / or swelling (me Phenamic acid, indomethacin, aspirin, ketrolac, fluorometholone, loteprednol, hydrocortisone, fluorometholone, bromfenac, prednisolone acetate, indomethacin, and ibuprofen, etc.); allergies and their symptoms (pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, rhodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, emestine fumarate). (fumarate), olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudophedrine, fexofenadine, terfenadine, loratadine, alexis, etc.); respiratory diseases including asthma and / or COPD (budesonide, ciclesonide, nedocromil, dexamethasone, ambroxol, and pranlukast, etc.); skin diseases (mometasone, triamcinolone, desonide, sulfacetamide, tacrolimus, allantoin, triamcinolone, etc.); mastocytosis (cromolyn, etc.); gout (diclofenac, febuxostat, etc.); conjunctivitis (hydrobenzoyl phosphate, pranoprofen, zinc sulfate, etc.); eye diseases (dextran 70, thyroxine / liothyronine, and ocular extracts (ocular) This includes extractives used in the treatment of any of the aforementioned known or commercially available pharmaceutically acceptable salts, as well as any combination of the aforementioned compounds and / or salts.

[0237] Anti-inflammatory agents that may be mentioned include endogenous (and / or exogenous) lipid-based anti-inflammatory, anti-inflammatory molecules or mediators, such as lipoxins, resolvins, and protectins. Pro-inflammatory agents that may be mentioned include prostaglandins (e.g., latanoprost, prostaglandin E1, and prostaglandin E2) and leukotrienes (e.g., leukotriene B4).

[0238] Non-limiting examples of antibiotics that may be used include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomisocin, gentamicin, cetylpyridinium, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, clindamycin, metronidazole, azithromycin, mafenide, sulfamethoxazole, paracetamol, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, cephalexin, moxifloxacin, any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0239] Non-exclusive examples of antiviral drugs that may be used include tobramycin ribavirin, acyclovir, moloxidine, foscarnet, ganciclovir, idoxuridine, trifluridine, brivudine, vidarabine, entecavir, terbivudine, foscarnet, zidovudine, didanosine, zalcitabine, stabudine, lamivudine, abacavir, emtricitabine, nevirapine, delavirdin, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir, darunavir, telaprevir, and boceprevir. This also includes simeprevir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir pivoxil, homivirsen, podophyllox, imiquimod, synecatechins, interferon α2b (recombinant, human), any pharmaceutically acceptable known or commercially available salt of any of the above, and any combination of any of the above compounds and / or salts.

[0240] Non-limiting examples of anesthetics that may be used include articaine, dextropropoxifen, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxin, benzocaine, dibucaine, diclonin, tetracaine, bupivacaine, and any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0241] Non-limiting examples of wound regenerative agents that may be used include basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, human; yeast), rhEFG(I), acid fibroblast growth factor (recombinant, human), granulocyte-macrophage-stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, etaclizine, retinoids, deproteinized calf blood extract, carraghenate, amiotide, and any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0242] Such pharmaceutical active ingredients include those that, along with the compounds of the present invention, can be administered topically to, for example, the surface of the skin or mucous membranes.In this regard, preferred active ingredients from the above list include cyclosporine, chondroitin, loteprednol, fluorometholone, bromfenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, emestine fumarate, olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, Alexis, dexamethasone, ambroxol), sulfase Tamide, tacrolimus, allantoin, triamcinolone, cromolyn, nedocromil, diclofenac, hydrobenzol, pranoprofen, zinc sulfate, dextran 70, thyroxine / liothyronine, eye extract, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomycin, gentamicin, cetylpyridinium, neomycin Roxithromycin, silver sulfadiazine, clarithromycin, sulfamethoxazole, chloramphenicol, tobramycin ribavirin, acyclovir, moloxidine, foscarnet, ganciclovir, interferon-α2b (recombinant, human), alticaine, dextropropoxifen, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxin, benzocaine, dibucaine, diclonin, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human) This also includes recombinant bovine, epidermal growth factor (recombinant human; yeast), rhEFG(I), acid fibroblast growth factor (recombinant human), granulocyte-macrophage-stimulating factor (recombinant human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, retinoids, calf blood deproteinized extract, carrageenan, amiotide, and any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0243] Other pharmaceutically active ingredients that can be administered simultaneously with the compound of the present invention include those that can be administered to treat one of the gastrointestinal disorders described above.

[0244] Non-specific examples of gastrointestinal medications include oxalazine (orthalazine), sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, and live Bacillus (Clostridium butyricum). (Bacteria such as Butyricum, Licheniformis, Cereus), probiotics (such as Bifidobacterium), tegafur, nifuratel, amoxicillin, ampicillin, nistatin, allicin, cefadroxyl, diclonin, carmoful, fluorouracil, mosapride, sodium carbosulfan, thrombin, pantoprazole, cimetidine, cisapride, ethylenediaminediacetamide, nimustine, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azasetron, lentinan, bismuth salts (e.g., aluminates, quer). Potassium phosphate, for example, in combination with magnesium salts, magnesium trisilicate, bicarbonate, vitamin U, aluminum hydroxide, belladonna extract, famotidine and calcium carbonate, magnesium hydroxide, hydrotalcite, proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, or esomeprazole, etc.), glycine, trypsin, allantoin, aluminum hydroxide, sodium L-glutaming alenate, rebampette, rotundine, quxipite, lafutidine, thymic protein, Hericium erinaceus (Lion's Mane mushroom)This includes erinaceus), ylsogladine maleate, nizatidine, L-glutamine and sodium azulene sulfonate (sodium guarenate), ranitidine, bismuth citrate, lactobacillin, bisacorzine, dimethylsiloxane, Clostridium butyricum, loperamide hydrochloride, dibazol, secnidazole, zinc acetate, montmorillonite, tegafur / gimeracil / oteracil, famotidine, oteracil, doxifluridine, capecitabine, or any known or commercially available pharmaceutically acceptable salt of any of the above.

[0245] Pharmaceutical active ingredients that may be mentioned for use in combination with the compounds of the present invention include active ingredients useful for treating inflammation and / or inflammatory disorders (other anti-inflammatory agents).

[0246] Anti-inflammatory agents that may be used in combination with the compounds of the present invention in the treatment of inflammation include therapeutic agents useful for treating inflammation and / or diseases characterized by inflammation as one of its symptoms, including those described above. Depending on the pathological condition being treated, such anti-inflammatory agents may include, for example, NSAIDs (e.g., aspirin), aminosalysates (e.g., 5-aminosalicylic acid (mesalazine)), leukotriene receptor antagonists (e.g., montelukast, pranlukast, and zafirlukast), corticosteroids, analgesics, and certain enzymes such as trypsin, as described below. The compounds of the present invention can also be combined with leukotrienes (e.g., cysteinylleukotriene and leukotriene B4).

[0247] Other preferred agents that can be combined with the compounds of the present invention include LTB4 (for treating wounds and burns), NSAIDs (e.g., aspirin), or montelukast (for treating inflammation in general), and trypsin (e.g., for treating inflammation of mucous membranes associated with viral infections).

[0248] The compounds of the present invention may also be combined with other therapeutic agents known to cause inflammation as a side effect when administered.

[0249] The conjugates of the present invention may also be combined with stem cells (e.g., totipotent, omnipotent, pluripotent (embryonic or induced pluripotent stem cells, etc.), compound pluripotent (mesenchymal stem cells, etc.), minimal pluripotent (hematopoietic stem cells, etc.), or unipotent (muscle stem cells, etc.)).

[0250] Other known pharmacoactive ingredients can also be administered in combination with the compounds of the present invention in many ways.

[0251] For example, the compounds of the present invention may be “combined” with a pharmaceutically active ingredient (or other pharmaceutically active ingredient) (or “therapeutic agent”) for the same administration in the same (e.g., pharmaceutical) formulation, or for separate (simultaneous or sequential) administration in different (e.g., pharmaceutical) formulations.

[0252] Therefore, such combination products provide an administration of the compound of the present invention in combination with a therapeutic agent (or other therapeutic agent), and may therefore be presented as separate formulations (at least one of which contains the compound of the present invention and at least one of which contains a therapeutic agent (or other therapeutic agent)) or as a combination formulation (i.e., a single formulation containing the compound of the present invention and a therapeutic agent (or other therapeutic agent)).

[0253] Therefore, (1) A formulation (for example, a pharmaceutical) comprising the compound of the present invention, another pharmaceutically active ingredient, and optionally a pharmaceutically acceptable inactive excipient (for example, an adjuvant, diluent, or carrier), (the formulation is hereinafter referred to as a "combination formulation"), and (2) A parts kit, comprising the following components: (A) The compound of the present invention in the form of a pharmaceutical formulation (e.g., a drug) mixed with an optionally pharmaceutically acceptable inactive excipient (e.g., an adjuvant, diluent, or carrier), and (B) optionally comprising another pharmaceutically active ingredient in the form of a pharmaceutical formulation (e.g., a pharmaceutical) mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, A parts kit is further provided, wherein components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0254] In a further aspect of the present invention, a process is provided for preparing a combination formulation (1) as defined herein, comprising associating a compound of the present invention, another pharmaceutically active ingredient, or therapeutic agent with at least one (e.g., pharmaceutically acceptable) excipient.

[0255] In a further aspect of the present invention, a process is provided for preparing a component kit (2) as defined above herein, wherein the process includes relating components (A) and (B). As used herein, reference to relating means making the two components suitable for administration together with each other.

[0256] Therefore, in relation to the process for preparing the parts kit as defined above, “associating” two components with each other means that the two components of the parts kit are (i) Provided separately (i.e., independently of each other) and subsequently combined for use in combination therapy, or (ii) They may be packaged and presented together as separate components of a “combination pack” for use in combination therapy.

[0257] Therefore, it is a parts kit, (I) one of the components (A) or (B) as defined herein, (II) A parts kit is further provided which includes instructions for using the component in combination with the other component of the two components.

[0258] In relation to the above-mentioned parts kit, the compounds of the present invention may be provided in the form of a (e.g., pharmaceutical) formulation mixed with one or more additional pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers), however, if the compounds of the present invention are provided primarily for the purpose of performing their function as a medical device or excipient, they may not be provided with such additional pharmaceutically acceptable excipients. In any case, it is preferable that the (other) pharmaceutically active ingredients of the parts kit be provided in the form of a pharmaceutical formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0259] The parts kits described herein may contain two or more appropriate amounts / doses of the compounds of the present invention (for example, formulations containing them) and / or two or more appropriate amounts / doses of other pharmaceutically active ingredients (for example, formulations containing them) to provide repeated doses. If two or more formulations containing any of the above or their amounts / doses exist, such formulations may be the same or different with respect to the dosage of any of the compounds, chemical compositions and / or physical forms.

[0260] With respect to the parts kits described herein, “administration in combination with ~” includes the administration of each component sequentially, separately, and / or simultaneously throughout the course of treatment of the relevant pathological condition.

[0261] Therefore, with respect to the combination products of the present invention, the term "administered in combination with ~" means that the two components of the combination product (the compound of the present invention and the other pharmaceutically active ingredient) are administered together or in sufficiently close time intervals (optionally, repeatedly) over the course of treatment of the relevant pathological condition, to enable a greater beneficial effect to the patient than if either the compound of the present invention or the other agent (e.g., a formulation containing the other agent) were administered alone or without the other component over the same course of treatment (optionally, repeatedly). The determination of whether the combination provides a greater beneficial effect with respect to the treatment of a particular pathological condition and over a series of treatments depends on the pathological condition being treated or prevented, but can be conventionally achieved by those skilled in the art.

[0262] Furthermore, in the context of the parts kit according to the present invention, the term “combined with ~” includes the fact that one or the other of the two components may be administered before, after, and / or concurrently with (optionally repeated) the administration of the other component. When used in this context, the terms “co-administered” and “administered simultaneously with ~” include the fact that the individual amounts / doses of the relevant compounds of the present invention and other active pharmaceutical ingredients are administered within 48 hours (e.g., 24 hours) of each other.

[0263] With respect to the above-mentioned combined preparations and parts kits, the other active pharmaceutical ingredients are preferably anti-inflammatory agents or drugs known to cause inflammation as a side effect, as described above.

[0264] Whenever the term “about” is used herein in the context of quantities such as the concentration and / or dose of the active ingredients and / or compounds of the present invention, molecular weight, or pH, it should be understood that such variables are approximations and may therefore vary by ±10%, for example, ±5%, and preferably ±2% (for example, ±1%) from the numerical values ​​specified herein. In this regard, the term “about 10%” means, for example, ±10% for the numerical value 10, i.e., 9% to 11%.

[0265] The compounds of the present invention have a wide variety of applications, including the following: • Uses as a biological activator in various pathological conditions characterized by inflammation (whether the condition itself is an organic inflammatory disease, is related to inflammation, or is characterized by inflammation (e.g., wounds or burns)), and / or in the aforementioned surgical and / or cosmetic applications. • In combination therapy, or ○Pharmacologically acceptable excipients (e.g., adjuvants, diluents, or carriers), ○ Medical devices, and / or ○It has the advantage of being used in combination with active pharmaceutical ingredients by performing a more inactive function as either or as part of the medical device portion of a drug-medical device combination.

[0266] The compounds, uses, and methods described herein, whether used or otherwise intended for use in the treatment of any of the aforementioned conditions, including inflammation, inflammatory disorders, or disorders characterized by inflammation as a symptom (including wounds), may have advantages over similar compounds or methods (treatments) known in the prior art, such as being more convenient, effective, less toxic, having a broad range of activity, being potent, having fewer side effects, or possessing other useful pharmacological properties that surpass similar compounds or methods (treatments). [Brief explanation of the drawing]

[0267] [Figure 1] The results of ear swelling in mouse models treated with xylene and test compounds A, B, and C are shown. [Figure 2] The results of ear swelling in mouse models treated with xylene and test compounds D, E, F, G, and H are shown. [Figure 3] The results of ear swelling in mouse models treated with xylene, test compounds E, I, J, and palmitic acid + DMSO are shown. [Figure 4] The results of ear swelling in mouse models treated with xylene and test compound E are shown. [Figure 5] The results of the radiation oral mucositis score in a hamster model treated with test compound E are shown. [Figure 6] The results for mechanical pain thresholds in SD rat models treated with test compound E and lidocaine are shown. [Figure 7] The results of the 5-FU-induced oral mucositis score in SD rat models treated with test compound E are shown. [Figure 8]The results for human subjects with rosacea treated with test compound E are shown. [Figure 9] The results regarding the severity of esophagitis in GERD rat models treated with test compounds K, L, and M are shown. [Examples]

[0268] Example 1 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 3) Fmoc-Lys(Boc)-Wang resin (9.32 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0269] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column, and the resin was immersed for approximately 30 minutes. Next, the DCM was removed by vacuum filtration.

[0270] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0271] A 20% piperidine solution (200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd, Shandong, China) was added to DMF as a deprotection solution and the mixture was reacted for 20 minutes. The solution was then removed by vacuum filtration, and the column was washed six times with DMF.

[0272] Fmoc-Tyr(tBu)-OH (4.14 g, 9 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g, 9 mmol; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g, 9 mmol; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After a 30-minute reaction, a Kaiser test was performed using a small amount of resin, and the yellow and colorless gel of the solution indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0273] The above coupling process was repeated to couple the remaining amino acids in the same amount (molar): Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and palmitic acid.

[0274] After coupling with palmitic acid, the resin was washed three times each with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL; Xilong Scientific Co., Ltd., Guangdong, China). The resin was vacuum-dried for approximately 2 hours. 130.0 mL (i.e., 10 mL per gram of dry resin) of a solution consisting of 95% trifluoroacetic acid (TFA, Macklin, Shanghai, China), 2.5% water, and 2.5% triisopropylsilane (Tis, Macklin, Shanghai, China) was added to immerse the peptide-containing compound bound to the resin. After approximately 2 hours of cutting, the solid support was removed by filtration, and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1300 mL (i.e., 10 mL per 1 ml of filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was vacuum-dried for approximately 2 hours to obtain 4.51 g of the crude title compound.

[0275] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu Corporation, Japan). The analytical column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient of solvent A concentration from 5% to 90% over 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL).

[0276] The target peak eluted at 35.232 minutes, had the expected molecular weight (MS: m / z 1421.7), and had a purity of 64.564%.

[0277] Next, 4.5 g of the crude product was dissolved in 90 mL of pure water and purified using an NP7010C semi-preparation apparatus (Hanbon Sci.&Tech.Co.,Ltd., Jiangsu, China). The preparative column model was a Dubhe-C18 model (Hanbon Sci.&Tech.Co.,Ltd., Jiangsu, China) (50 × 250 mm, 100 Å column, detection: UV at 220 nm). A suitable elution gradient was calculated from the LCMS detection step (solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient of solvent A concentration from 50% to 80% in 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu Corporation, Japan) (the same column as above, except that a linear gradient was used from solvent A concentration of 50% to 75% over 25 minutes).

[0278] Next, for the anion exchange step, fractions with a purity higher than 90% were mixed together. This was achieved using an NP7010C preparative apparatus (preparative column model: Dubhe-C18 model (above)). The fractions were diluted once with pure water and packed directly into the column. The column was then washed with pure water, 3.2% ammonium acetate for approximately 20 minutes, followed by pure water for another 10 minutes at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% HAc in MeCN, solvent B: 0.1% HAc in water, linear gradient of solvent A concentration from 50% to 80% over 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fractions with a purity higher than 95% were mixed and lyophilized to obtain 1.64 g of the purified title compound.

[0279] Example 2 Stea-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 4) The title compound was prepared using essentially the same process as described in Example 1 above, except that stearic acid was used in place of palmitic acid in the final coupling step, in equal amounts (moles).

[0280] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.37 g). Analysis showed that the target peak eluted at 36.231 min had a purity of 60.287% with the expected molecular weight (MS: m / z 1449.8).

[0281] Next, 4.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.52 g of the pure title compound was obtained.

[0282] Example 3 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10) The title compound was prepared using essentially the same method as described in Example 1, except that the coupling step was carried out using the same amounts (moles) of Fmoc-4-Hyp(tBu)-OH, Fmoc-DOPA(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and palmitic acid in that order.

[0283] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.56 g). Analysis showed that the target peak eluted at 30.746 min was 65.128% pure with the expected molecular weight (MS: m / z 1437.7).

[0284] Next, 4.5 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.57 g of the pure title compound was obtained.

[0285] Example 4 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-Dopamine (SEQ ID NO: 109) The title compound was synthesized from Lys as the initial amino acid using Fmoc-Lys(Boc)-Wang resin, using a process almost identical to that described in Example 1 above. Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and palmitic acid were coupled using the same process as described in Example 1 above.

[0286] After coupling palmitic acid to the resin, the resin was washed three times with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL). The resin was then vacuum-dried for approximately 2 hours.

[0287] The peptide-containing compound bound to the resin was immersed in 120.0 mL of a solution containing 2% trifluoroacetic acid (TFA) in DCM (i.e., 10 mL per gram of dry resin). After approximately 2 hours of cleavage, the solid support was removed by filtration, and the filtrate was collected under reduced pressure. The filtrate was then concentrated by rotary distillation under reduced pressure. After removing all solvent, 100 mL of DMF was added to the flask to dissolve the solid, and dopamine hydrochloride (1.71 g, 9 mmol; Aladdin, Shanghai, China), TBTU (2.89 g), and DIPEA (2.33 g) were added to the reaction solution. The reaction was complete after 30 minutes. Precipitation of the final solution was carried out by adding 1200 mL (i.e., 10 mL per 1 ml of final solution) of saturated citric acid (Aladdin, Shanghai, China) aqueous solution, and the precipitate was collected by filtration. Next, 120 mL (i.e., 10 mL per g of solid) of a solution containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to the precipitate to dissolve the peptide-containing solid. Deprotection was performed during side chain cleavage. After cleavage for approximately 2 hours, the solution was precipitated with 1200 mL (i.e., 10 mL per ml of filtrate) of diethyl ether, and the precipitate was collected by filtration. The precipitate was vacuum-dried for approximately 2 hours. Finally, 4.25 g of the crude title compound was obtained.

[0288] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.38 g). Analysis showed that the target peak eluted at 32.173 min had a purity of 55.395% with the expected molecular weight (MS: m / z 1556.9).

[0289] Next, 4.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.39 g of the pure title compound was obtained.

[0290] Example 5 Olei-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 5) The title compound was prepared using essentially the same process as described in Example 1 above, except that oleic acid was used in place of palmitic acid in the final coupling step.

[0291] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.41 g). Analysis showed that the target peak eluted at 35.877 min had a purity of 61.737% with the expected molecular weight (MS: m / z 1447.8).

[0292] Next, 4.4 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.55 g of the pure title compound was obtained.

[0293] Example 6 Olei-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 13) The title compound was prepared using essentially the same process as described in Example 5 above, except that Fmoc-DOPA(acetonide)-OH was used in the corresponding coupling step in the same amount (moles) as Fmoc-Tyr(tBu)-OH.

[0294] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.53 g). Analysis showed that the target peak eluted at 35.124 min had a purity of 62.522% with the expected molecular weight (MS: m / z 1479.8).

[0295] Next, 4.5 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.52 g of the pure title compound was obtained.

[0296] Example 7 DHA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 6) The title compound was prepared using essentially the same process as described in Example 1 above, except that docosahexaenoic acid was used in place of palmitic acid in the final coupling step, in equal amounts (moles).

[0297] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.47 g). Analysis showed that the target peak eluted at 35.877 min had a purity of 63.228% with the expected molecular weight (MS: m / z 1493.8).

[0298] Next, 4.4 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.57 g of the pure title compound was obtained.

[0299] Example 8 (Compound E) Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (Sequence ID 17) The title compound was synthesized using essentially the same procedure as described in Example 1 above, except that appropriate amino acids were used in a valid peptide coupling sequence.

[0300] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 3.59 g). Analysis showed that the target peak eluted at 29.947 min was 70.223% pure with the expected molecular weight (MS: m / z 1136.4).

[0301] Next, 3.5 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.21 g of the pure title compound was obtained.

[0302] Example 9 Olei-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (Sequence ID 15) The title compound was prepared using essentially the same process as described in Example 6 above, except that appropriate amino acids and fatty acids were used in a valid peptide coupling sequence.

[0303] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 3.65 g). Analysis showed that the target peak eluted at 30.093 min had a purity of 71.943% with the expected molecular weight (MS: m / z 1178.6).

[0304] Next, 3.6 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.25 g of the pure title compound was obtained.

[0305] Example 10 (Compound N) DPPS-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 7) The title compound was prepared using essentially the same process as described in Example 1, except that Fmoc-DPPS-OH was used in place of palmitic acid in the final coupling step. After coupling Fmoc-DPPS-OH to the resin, a deprotection step was performed to remove the Fmoc protection on the DPPS. The resin was washed three times with DMF (200 mL each time). 20% piperidine solution (200 mL) in DMF was added as the deprotection solution, reacted for 20 minutes, and then removed under vacuum. The remaining steps were then carried out essentially in the same manner as described in Example 1.

[0306] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 5.77 g). Analysis showed that the target peak eluted at 48.284 min had a purity of 53.933% with the expected molecular weight (MS: m / z 1814.2).

[0307] Next, 5.7 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.79 g of the pure title compound was obtained.

[0308] Example 11 (Compound O) LTB4-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 8) The title compound was prepared using essentially the same process as described in Example 1 above, except that LTB4 was used in place of palmitic acid in the final coupling step.

[0309] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.39 g). Analysis showed that the target peak eluted at 33.877 min had a purity of 57.847% with the expected molecular weight (MS: m / z 1501.8).

[0310] Next, 4.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.38 g of the pure title compound was obtained.

[0311] Example 12 (Compound M) Montelukast-Ala-lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm)(Sequence ID 2) Fmoc-Lys(Boc)-Wang resin (9.15 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0312] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column, and the resin was immersed for approximately 30 minutes. Next, the DCM was removed by vacuum filtration.

[0313] 200 mL of a 30% trifluoroacetic acid (TFA, Macklin Biochemical Co. Ltd., Shanghai, China) solution in DCM was added to the column and reacted with the resin for approximately 30 minutes to remove the Boc protecting group on the Lys. The TFA solution in DCM was then removed by vacuum filtration.

[0314] The resin was washed six times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co Ltd, Shandong, China).

[0315] Palmitic acid (2.31 g, 9 mmol; Macklin Biochemical Co. Ltd., Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, a Kaiser test was performed using a small amount of resin, and the yellow and colorless gel of the solution indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0316] After coupling palmitic acid to the side chain of the lysine resin, other amino acids were coupled in essentially the same process and order as described in Example 1 above. First, Fmoc-Tyr(tBu)-OH was coupled, followed by Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH, except that montelukast sodium was used instead of palmitic acid in the final coupling step. The amounts of amino acids, montelukast sodium, TBTU, and DIPEA in these coupling steps were also the same as in Example 1 (in moles).

[0317] After coupling with montelukast sodium, the same procedure was repeated to obtain a further batch of the crude title compound (yield 5.86 g). Analysis showed that the target peak eluted at 43.848 min had a purity of 52.432% with the expected molecular weight (MS: m / z 2011.9).

[0318] Next, 5.8 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.63 g of the pure title compound was obtained.

[0319] Example 13 Olei-Ala-lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm) (SEQ ID NO: 2) The title compound was prepared using essentially the same process as described in Example 10 above, except that oleic acid was used in place of montelukast sodium in the final coupling step.

[0320] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 4.37 g). Analysis showed that the target peak eluted at 46.129 min had a purity of 51.237% with the expected molecular weight (MS: m / z 1686.2).

[0321] Next, 4.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.51 g of the pure title compound was obtained.

[0322] Example 14 Palm-Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (Sequence No. 20) The title compound was synthesized using essentially the same procedure as described in Example 8 above, except that appropriate amino acids were used in a valid peptide coupling sequence.

[0323] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 3.51 g). Analysis showed that the target peak eluted at 28.847 min had a purity of 68.983% with the expected molecular weight (MS: m / z 1152.5).

[0324] Next, 3.5 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.16 g of the pure title compound was obtained.

[0325] Example 15 DPPS-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (Sequence ID 18)

[0326] The title compound was synthesized using essentially the same procedure as described in Example 10 above, except that appropriate amino acids were used in a valid peptide coupling sequence.

[0327] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 5.03 g). Analysis showed that the target peak eluted at 43.288 min had a purity of 65.039% with the expected molecular weight (MS: m / z 1616.0).

[0328] Next, 5.0 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.1 g of the pure title compound was obtained.

[0329] Example 16 Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Chol-Ac)-NH2 (Sequence ID 110) The title compound was synthesized using essentially the same procedure as described in Example 12, except that Fmoc-Lys(Boc)-AM resin (6.98 g, USUN pharma, Jiangsu, China) was used as the starting material, compared to Example 12. After deprotecting the side chain of the Fmoc-Lys(Boc)-AM resin, cholesterol-acetic acid (autosynthesized) was coupled to the side chain of the Fmoc-Lys-AM resin. The title compound was obtained using appropriate amino acids in a reasonable peptide coupling sequence, similar to Example 12.

[0330] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 3.84 g). Analysis showed that the target peak eluted at 37.822 min had a purity of 61.438% with the expected molecular weight (MS: m / z 1323.7).

[0331] Next, 3.8 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.3 g of the pure title compound was obtained.

[0332] Example 17 Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-PEA (SEQ ID NO: 111) The title compound was synthesized from lysine as the first amino acid, using Fmoc-Lys(Boc)-CTC resin (7.23g, USUN Pharma, Jiangsu, China) as the solid support.

[0333] The peptide sequence Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16) was synthesized using essentially the same procedure as described in Example 1, except that appropriate amino acids (Boc-Lys(Boc)-OH was used in the final coupling step) were used in a reasonable peptide coupling sequence, compared to Example 1.

[0334] After coupling Boc-Lys(Boc)-OH to the resin, the resin was washed three times with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL). The resin was vacuum-dried for approximately 2 hours.

[0335] 100.0 mL of a solution containing 2% trifluoroacetic acid (TFA) in DCM (i.e., 10 mL per gram of dry resin) was added to immerse the peptide-containing compound bound to the resin. After approximately 2 hours of cleavage, the solid support was removed by filtration, and the filtrate was collected under reduced pressure. The filtrate was concentrated by rotary distillation under reduced pressure. After removing all solvent, PEA (1.8 g, CAS: 544-31-0; Macklin, Shanghai, China) was added to the flask, followed by pyridine (100 mL) to dissolve the solid, and then phosphorus oxychloride (0.3 ml, Adamas-beta Co. Ltd., Shanghai, China) was added to the reaction solution. After 3 hours of reaction, the reaction was complete. Precipitation of the final solution was carried out by adding 1000 mL (i.e., 10 mL per 1 ml of final solution) of saturated citric acid (Aladdin, Shanghai, China) aqueous solution, and the precipitate was collected by filtration. To the precipitate, 100 mL (i.e., 10 mL per g of solid) of a solution containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to dissolve the peptide-containing solid. Deprotection was performed during side chain cleavage. After cleavage for approximately 2 hours, the solution was precipitated with 1000 mL (i.e., 10 mL per ml of filtrate) of diethyl ether, and the precipitate was collected by filtration. The precipitate was vacuum-dried for approximately 2 hours. Finally, 3.87 g of the crude title compound was obtained.

[0336] Analysis revealed that the target peak eluted at 30.449 minutes had a purity of 58.323% with the expected molecular weight (MS: m / z 1179.5).

[0337] Next, 3.8 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 1.2 g of the pure title compound was obtained.

[0338] Example 18 (Compound K) (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)2-Lys (SEQ ID NO: 113) Fmoc-Lys(Fmoc)-Wang resin (10.23 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column. Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column, and the resin was immersed for approximately 30 minutes. The DCM was removed by vacuum filtration. The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0339] A 20% piperidine solution (200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd, Shandong, China) was added to DMF as a deprotection solution, and the reaction was allowed to proceed for 20 minutes. The solution was removed by vacuum filtration, and the column was washed six times with DMF.

[0340] Fmoc-Lys(Boc)-OH (8.43 g, 18 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 5.78 g, 18 mmol; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 4.66 g, 18 mmol; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After a 30-minute reaction, a Kaiser test was performed using some of the resin, and the yellow and colorless gels of the solution indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0341] The title compound was prepared using essentially the same process as described in Example 8 above, except that the amounts of amino acids, palmitic acid, and bonding agents (TBTU and DIPEA) were doubled (molar).

[0342] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 6.68 g). Analysis showed that the target peak eluted at 30.665 min had a purity of 57.542% with the expected molecular weight (MS: m / z 2383.1).

[0343] Next, 6.6 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.76 g of the pure title compound was obtained.

[0344] Example 19 (Compound P) (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 114) The title compound was synthesized using substantially the same procedure as described in Example 18 above, except that appropriate amino acids were used in a valid peptide coupling sequence.

[0345] The same procedure was essentially repeated to obtain a further batch of the crude title compound (yield 8.53 g). Analysis showed that the target peak eluted at 32.192 min had a purity of 52.821% with the expected molecular weight (MS: m / z 2953.7).

[0346] Next, 8.5 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 3.2 g of the pure title compound was obtained.

[0347] Example 20 (Compound L) Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm)-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm) (SEQ ID NO: 115) Fmoc-Lys(Dde)-Wang resin (9.97 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0348] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column, and the resin was immersed for approximately 30 minutes. The DCM was removed by vacuum filtration.

[0349] Side chain coupling process: 1. Resin cleaning: The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China). 2. Deprotection: A 5% hydrazine monohydrate (Merck KGaA, Darmstadt, Germany) solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. The solution was removed by vacuum filtration, and the column was washed six times with DMF. 3. Coupling: Palmitic acid (2.31 g, 9 mmol; Merck KGaA, Darmstadt, Germany) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g, 9 mmol; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g, 9 mmol; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, a Kaiser test was performed using a small amount of resin, and the yellow and colorless gel of the solution indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0350] After coupling the side chain palmitic acid, amino acids were coupled to the resin.

[0351] Amino acid coupling process: 1. Resin cleaning: The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China). 2. Deprotection: A 20% piperidine solution (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) in DMF (DBLK, 200 mL) was added as a deprotection solution and reacted for 20 minutes. The solution was removed by vacuum filtration, and the gel was washed six times with DMF. 3. Coupling: Fmoc-Tyr(tBu)-OH (4.14 g, 9 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g, 9 mmol; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g, 9 mmol; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After a 30-minute reaction, a Kaiser test was performed using some of the resin, and the yellow and colorless gels of the solution indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0352] The above coupling process was repeated to couple the following amino acids in equal amounts (moles): Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and then Fmoc-Lys(Dde)-OH.

[0353] After coupling Fmoc-Lys(Dde)-OH, the Dde side chain protecting group was removed, and then palmitic acid was coupled to the side chain using essentially the same method as described above.

[0354] After coupling palmitic acid to the side chain of a deprotected lysine residue, the following amino acids were coupled in equal amounts (moles) using essentially the same method as above: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, and then Boc-Lys(Boc)-OH.

[0355] After coupling Boc-Lys(Boc)-OH, the resin was washed three times with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time, Xilong Scientific Co., Ltd., Guangdong, China). The resin was vacuum-dried for approximately 2 hours.

[0356] MS:m / z 2254.9 A further batch of the crude title compound was obtained by repeating essentially the same procedure as described in Example 1 (yield 6.3 g). Analysis showed that the target peak eluted at 31.282 min had the expected molecular weight (MS: m / z 2254.9). The purity was 50.872%.

[0357] Next, 6.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.01 g of the pure title compound was obtained.

[0358] Example 21 Compound E Cream-1: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E cream contained a mixture of the substances listed in Table 1 below. The components of Phase A were mixed, heated to 85°C, and stirred at 85°C for 30 minutes. Phase B was added, the mixture was homogenized for 5 minutes, and then stirred and cooled. When the temperature dropped to 45°C, the raw materials of Phase C were added, and the mixture was homogenized for 1 minute. Phase D was added, and the mixture was homogenized for 3 to 5 minutes until the system was homogenized to obtain Compound E cream-1.

[0359] [Table 1]

[0360] Example 22 Compound E oral spray: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E oral spray contained a mixture of the substances listed in Table 2 below. The components of Phase A were mixed, heated to 85°C, and stirred at 85°C for 30 minutes. When the temperature dropped to 45°C, the pre-mixed raw materials of Phase B were added. The mixture was stirred for 3 to 5 minutes until Phase B dissolved and the system became homogeneous, yielding Compound E oral spray.

[0361] [Table 2]

[0362] Example 23 Compound E Facial Spray-1: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E Facial Spray-1 contained a mixture of the substances listed in Table 3 below. The components of Phase A were mixed, heated to 85°C, and stirred at 85°C for 30 minutes. When the temperature dropped to 45°C, Phase B was added. The mixture was stirred for 3 to 5 minutes until Phase B dissolved and the system became homogeneous, yielding Compound E Facial Spray-1.

[0363] [Table 3]

[0364] Example 24 Compound E Facial Spray-2: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Facial spray-2 of compound E contained a mixture of the substances listed in Table 4 below. The components of phase A were mixed and heated to 85°C. The mixture was stirred at 85°C for 30 minutes. When the temperature dropped to 45°C, phase B was added and stirred for 3-5 minutes until phase B dissolved and the system became homogeneous to obtain facial spray-2 of compound E.

[0365] [Table 4]

[0366] Example 25 Compound E mouthwash-1: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E mouthwash contained a mixture of the substances listed in Table 5 below. The components of Phase A were mixed, heated to 85°C, and stirred at 85°C for 30 minutes. When the temperature dropped to 45°C, Phase B was added, and the mixture was stirred for 3 to 5 minutes until Phase B dissolved and the system became homogeneous, yielding Compound E mouthwash-1.

[0367] [Table 5]

[0368] Example 26 Compound E Cream-2: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E Cream-2 and its placebo sample each contained a mixture of the following substances listed in Tables 6 and 7 below. The components of Phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The components of Phase B were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The solution of Phase B was transferred to the solution of Phase A and homogenized for 5 minutes. The sample was cooled until the system was homogenized to obtain Compound E Cream-1 or its placebo sample.

[0369] [Table 6]

[0370] [Table 7]

[0371] Example 27 Compound E Hair Care Essence: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E hair care essence and its placebo sample contained the following substances listed in Tables 8 and 9 below, respectively. The components of Phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was cooled until the system was homogenized to obtain Compound E hair care essence or its placebo sample.

[0372] [Table 8]

[0373] [Table 9]

[0374] Example 28 Compound E mouthwash-2: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E mouthwash-2 and its placebo sample each contained a mixture of the following substances listed in Tables 10 and 11. The components of Phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was cooled until the system was homogenized to obtain Compound E mouthwash-2 or its placebo sample.

[0375] [Table 10]

[0376] [Table 11]

[0377] Example 29 Compound E form: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound E-form

[0378] [Table 12]

[0379] Compound E-form Compound 2 contained a mixture of the following substances listed in Table 13. The components of Phase A were mixed and stirred for 30 minutes until the system was homogenized. Sodium hydroxide was added while stirring to adjust the pH of the solution to 6.5-7.0 to obtain Compound E-form Compound 2.

[0380] [Table 13]

[0381] Formulation-3: Compound E-form formulation-3 contained a mixture of the following substances listed in Table 14 below. The procedure for preparing Compound E-form formulation-3 was the same as the procedure described for formulation-2.

[0382] [Table 14]

[0383] Example 30 Compound E gel: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) The preparation of compound E gel contained a mixture of the following substances listed in Table 15. The components of phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was cooled until the system was homogenized to obtain compound E gel.

[0384] [Table 15]

[0385] Example 31 Ear swelling mouse model Test compound: Compound A: Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 3) Compound B: Stea-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 4) Compound C: Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10) Twenty-five healthy male BALB / c mice, 6-8 weeks old and with an average weight of 18-25g (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China), were housed for approximately one week prior to the experiment. The housing conditions were 25-27°C, 74% humidity, and a 12-hour light-dark cycle. The mice were given free access to food and water. These mice were then randomly divided into five groups (5 mice per group), as shown in Table 16 below.

[0386] [Table 16]

[0387] The left ear of each mouse was used as an autocontrol, and the right ear of each mouse was treated with a different agent: 20 μl of xylene (Shanghai Aladdin Bio-Chem Technology Co., LTD, Shanghai, China) was applied to both the inner and outer surfaces of each mouse's right ear. The ear began to swell after approximately 4 minutes. Next, in each group, 40 μl of the drug was applied to the right ear. The mice were returned to their cages.

[0388] Dexamethasone acetate cream (0.75 mg / g, China Resources Group) was purchased from a local pharmacy. Compounds A-C were synthesized by the Chinese Peptide Company as described above. 15 mg of each compound (powder) was dissolved in 10 ml of physiological saline to prepare a 1.5 mg / ml solution. The resulting solution was applied to mice as appropriate.

[0389] Mice were sacrificed by neck dislocation after 40 minutes. Both ears were amputated. Using an 8 mm diameter skin pouch (Electron Microscopy Sciences, POBox 550, 1560 Industry Road, Hatfield, PA19440), a portion of the ear was taken from the same area on both ears. The weight was recorded, and the swelling rate was calculated using this data, which is shown in Table 17 and Figure 1 below. Swelling percentage (%) = (Weight of right ear - Weight of left ear) / Weight of left ear × 100%

[0390] [Table 17]

[0391] The results showed that all three compounds could significantly reduce xylene-induced ear swelling in a mouse model. Their effect was slightly weaker than that of dexamethasone.

[0392] Example 32 Ear swelling mouse model Test compound: Compound D: DHA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 6) Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound F:Olei-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 5) Compound G: Olei-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 13) Compound H:DPPS-Ala-Lys-Pro-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 112) The experimental procedure and recording of results were the same as those described in Example 31 above. Ear swelling was induced in mice with xylene. 35 mice were divided into seven groups as shown in Table 18 below, and the results are shown in Table 19 and Figure 2 below.

[0393] [Table 18]

[0394] [Table 19]

[0395] The results showed that all five compounds were effective in reducing the swelling rate in xylene-treated mouse models, but not to the same extent as treatment with dexamethasone.

[0396] Example 33 Ear swelling mouse model Test compound: Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) Compound I: Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16) Compound J:Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2) Palmitic acid + DMSO The experimental procedure and recording of results were the same as those described in Example 31 above. Ear swelling was induced in mice using xylene. 35 mice were divided into seven groups as shown in Table 20 below, and the results are shown in Table 21 and Figure 3 below.

[0397] [Table 20]

[0398] [Table 21]

[0399] Example 34 Ear swelling mouse model Test compound: Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 17) The experimental procedure and recording of results were the same as those described in Example 31 above. Ear swelling was induced in mice with xylene. The mice were divided into eight groups as shown in Table 22 below, and the results are shown in Table 23 and Figure 4 below.

[0400] [Table 22]

[0401] [Table 23]

[0402] The results demonstrate that compound E is effective as an anti-inflammatory agent in a mouse ear swelling model, providing guidance for future clinical use of anti-inflammatory agents. Compound E also exhibits good dose-dependent effects in reducing inflammation.

[0403] Example 35 Pain relief in radiation-induced oral mucositis Two patients had received radiation therapy to the head and neck. Both patients had experienced severe oral mucositis and oral mucosal ulcers, diagnosed as Grade 4 (the most severe level). The patients also experienced high levels of pain and difficulty eating. The patients were suggested to use a 1 mg / ml × 5 ml solution of compound E as a mouthwash three times a day. After 5 days, both patients reported very positive feedback. The VAS pain score decreased from 8 to 1 in one patient and from 7 to 3 in the other. The latter patient also reported a significant reduction in oral mucus caused by infection and inflammatory exudate. Therefore, compound E was demonstrated to be effective in treating oral mucositis.

[0404] Example 36 Relief of itching in neurodermatitis A 28-year-old male presented with a persistent itchy and scaly skin lesion on his left elbow. He had been diagnosed with neurodermatitis one year prior. The patient had previously used glucocorticoids to treat the lesion, but the effect was temporary. The itching worsened with stress. The patient tried a spray of 3 mg / ml compound E solution. After one spray on the lesion, the itching symptoms were completely relieved approximately 30 minutes later. The patient reported that the itching symptoms stopped during the day following the administration.

[0405] Example 37 Radiation mucositis in a golden hamster model Thirty-two healthy male LVG Syrian Golden hamsters (Beijing Chairs River Experimental Animal Technology Co., Ltd.), 6-8 weeks old and with an average weight of 93-101g, were housed for approximately one week prior to the experiment. Housing conditions: 25-27°C, 74% humidity, 12-hour light-dark cycle, free access to food and water. The hamsters were randomly divided into four groups (8 hamsters per group), as shown in Table 24 below.

[0406] [Table 24]

[0407] After anesthesia, the left cheek pouch of the animal was pulled out, fixed to a homemade restraint device, and exposed to radiation. The rest of the body was shielded with 3.5 mm thick lead. The radiation dose was 40 Gy (Precision X-ray Inc., X-RAD 320). After awakening, the animal was returned to its cage. Photographs were taken and evaluated every two days. The evaluation was performed according to Sonis scoring criteria (0 - cheek pouch was completely healthy with no erythema or telangiectasia; 1 - erythema and telangiectasia were present, but the mucosa was intact; 2 - severe erythema with surface mucosal erosion; 3 - formation of a mucosal ulcer with a cumulative size of approximately 25% of the cheek pouch surface area; 4 - ulcer with a cumulative size of approximately 50% of the cheek pouch surface area; 5 - continuous ulcer covering almost the entire surface area of ​​the cheek pouch mucosa). The results are shown in Table 25 and Figure 5 below.

[0408] [Table 25] Note: The data in the table are expressed as mean ± standard deviation (mean ± SD), and eight animals were used for statistical analysis in each group. * P<0.05, ** A P<0.01 indicates a comparison between each treatment group and the model control group. Compound E was shown to improve radiation-induced mucositis in hamsters according to Sonis scoring criteria and SOM duration. Compound E showed good dose-dependent efficacy in this model. Therefore, compound E is shown to have potential to alleviate symptoms in patients with mucositis in clinical practice.

[0409] Example 38 Pain relief in Sprague Dawley (SD) rats Forty-eight healthy male SD rats (Beijing Chairs River Experimental Animal Technology Co., Ltd.), aged 7-8 weeks and with an average weight of 180-220g, were housed and reared for approximately one week prior to the experiment. Rearing conditions: 25-27°C, 74% humidity, 12-hour light-dark cycle, free access to food and water. These rats were randomly divided into six groups (8 rats per group), as shown in Table 26 below, and the results are shown in Figure 6.

[0410] [Table 26]

[0411] All animals were pre-trained to allow rats to adapt to external stimuli. Oral mucosal ulcers were then induced with acetic acid (Sigma-Aldrich). The ulcerated areas of the rats were stimulated using Von Frey filaments (Danmic Aesthesio) (0.008g, 0.04g, 0.02g, 0.04g, 0.07g, 0.16g, 0.4g, 0.6g, 1.0g, 1.4g, 2.0g, 4.0g), and the mechanical pain threshold was measured. Each level of stimulation was applied five times consecutively with a 15-second interval between each test until a positive response was obtained three or more times under a particular level of stimulation. This value was recorded as the mechanical pain threshold. To prevent damage to the rat mucosa and avoid impact on subsequent tests, the maximum detection intensity of von Frey was set to 4.0g.

[0412] Compound E was shown to alleviate acetic acid-induced pain in SD rats, demonstrating pain-relieving effects comparable to lidocaine. Compound E showed good dose-dependency in this model. Therefore, compound E is shown to be able to alleviate symptoms associated with oral mucosal ulcers in patients.

[0413] Example 39 5-FU-induced oral mucositis in SD rats Forty healthy male SD rats, 7-8 weeks old and with an average weight of 180-220g (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China), were housed and reared for approximately one week prior to the experiment. Rearing conditions: 25-27°C, 74% humidity, 12-hour light-dark cycle, free access to food and water. These rats were randomly divided into five groups (8 rats per group) as shown in Table 27 below.

[0414] [Table 27]

[0415] Three days prior to injection of the test compound, rats were intraperitoneally injected with 5-FU (MCE, China) at a dose of 50 mg / kg and a dose volume of 2 ml / kg. One day prior to injection of the test compound, rats were further intraperitoneally injected with 5-FU, followed by anesthesia by inhalation of 2.5% isoflurane (Sigma-Aldrich).

[0416] The animals were placed in a right supine position, and the upper and lower jaws of the rats were opened using a homemade mouthpiece to expose the right buccal mucosa. A 6 mm filter paper was placed on the right buccal mucosa, and 80% acetic acid (5 μL, Sigma-Aldrich) was dropped onto the filter paper. After maintaining contact for 20 seconds, the filter paper was removed, and any residual liquid on the buccal mucosa was wiped away with a cotton swab. The sham surgery group was treated using the same method, but 5 μL of physiological saline was dropped onto the filter paper.

[0417] Twenty-four hours after treatment with acetic acid, the ulcer score of all animals except those in the placebo group was assessed and they were reclassified accordingly. Animals were treated according to the study plan described in Table 27 and assessed daily using the following criteria: 0 - Normal mucosal appearance without erythema or congestion; 1 - Oral mucosa with erythema or congestion, but the mucosa is intact; 2 - Extensive erythema of the oral mucosa with punctate diffuse ulcers; 3 - Flakely ulcers of the oral mucosa covering less than one-quarter of the buccal mucosa area (+); 4 - Oral mucosal ulcers covering less than half of the buccal mucosa area (++); 5 - Buccal mucosal ulcers covering more than half of the area (+++).

[0418] The results (Figure 7) show that compound E improved 5-FU and acetate-induced mucositis scores and accelerated ulcer recovery in the mucosa in SD rats. Compound E showed good dose-dependent effects in this model. Therefore, compound E is shown to have the potential to alleviate symptoms in patients with mucositis in clinical practice.

[0419] Example 40 Wound healing effect of HaCaT - Cell scratch assay After the cell seeding rate reached 40% to 60% in a 96-well plate, the following were added: In the control group, 200 μL of culture medium containing 10% PBS (Sigma) was added to each well; in the positive control group, 200 μL of culture medium containing 10% DMSO was added to each well; in the sample group, 200 μL of culture medium containing the corresponding concentration of the sample was added to each well; and in the zero group (no cell inoculation), 200 μL of cell culture medium was added. After administration, the 96-well plates were cultured in a culture incubator (37°C, 5% CO2). After 24 hours of cell incubation, the supernatant was discarded and MTT diluted standard solution (0.5 mg / mL) was added. The 96-well plates were incubated in the dark at 37°C for 2 hours. After incubation, the supernatant was discarded and 100 μL of DMSO was added to each well. OD values ​​were read at 490 nm.

[0420] The results showed that compound E did not exhibit cytotoxicity at its effective dose.

[0421] A 200 μL pipette gun hang was used on a 24-well plate covered with cells and marked "damaged." The cells were washed three times with PBS to remove scratched cells. After treatment with compound E at concentrations of 0.001%, 0.004%, and 0.008% (m / V), the cell healing rate of human cutaneous immortalized keratinocytes (HaCaT) (ATCC) was significantly increased (p<0.01), demonstrating that compound E is effective in cell repair. Thus, compound E was shown to effectively promote cell healing in vitro, consistent with in vivo results, and compound E was shown to effectively promote healing in clinical practice.

[0422] Example 41 No immunosuppressive effect - In vitro Peripheral Blood Mononuclear Cell (PBMC) study PBMCs were resuscitated and stained with Celltrace. T cell concentration was adjusted to 0.1 M (50 μL) per well using 1640 complete culture medium. 50 μL of LPS (Sigma-Aldrich) was added to the cells four times. 100 μL of blank medium / compound E or medium containing different concentrations of dexamethasone / 0.4% DMSO+ at the highest concentration was added separately to the corresponding wells. The LPS group was incubated for 24 hours. Cell supernatant was collected and the secretion of relevant inflammatory factors was detected. Cell proliferation and viability were detected using flow cytometry.

[0423] The results showed that under the conditions of this experiment, compound E did not have an immunosuppressive effect. Compared to dexamethasone, compound E does not cause immunosuppressive effects and is therefore safer for clinical use by reducing the risk of infection.

[0424] Example 42 In vitro anti-inflammatory effect in keratinocytes The blank control group was given culture medium. The model control group was given culture medium containing LPS (Sigma-Aldrich). The positive control group was given culture medium containing LPS and dexamethasone, and the sample group was given culture medium containing LPS and a constant concentration of compound E. These groups were exposed for 24 hours. After incubation, the cell supernatant was collected and stored in an ultracold freezer at -80°C. The content of IL-1α, IL-6, IL-8, and TNF-α was measured according to the instructions of the ELISA kit (R&D Systems).

[0425] The results showed that compound E effectively reduced inflammatory factors in keratinocytes, thus suggesting that compound E may be useful in alleviating inflammation associated with clinical skin diseases.

[0426] Example 43 In vitro anti-inflammatory effects in macrophages The blank control group was given culture medium. The added model control group was given culture medium containing LPS (Sigma-Aldrich). The positive control group was given culture medium containing LPS and dexamethasone, and the sample group was given culture medium containing LPS and a constant concentration of compound E. The groups were exposed for 24 hours. After incubation, the cell supernatant was collected and stored in an ultracold freezer at -80°C. The levels of IL-6, TNF-α, and NO were measured according to the instructions of the ELISA kit (R&D Systems).

[0427] The results showed that compound E effectively reduced inflammatory factors in macrophages, thus suggesting that compound E may be useful in alleviating inflammation associated with clinical diseases.

[0428] Example 44 In vitro oil control of sebaceous gland cells The blank control group was given 2 mL of cell culture medium. The model group was given 2 mL of cell culture medium containing linoleic acid (MCE, China). The positive control group was given 2 mL of cell culture medium containing linoleic acid and retinoic acid, and the sample group was given 2 mL of cell culture medium containing linoleic acid and the test concentration sample. These groups were incubated in a carbon dioxide incubator for 48 hours. After incubation, the supernatant was discarded, the cell layer was washed with 1 mL of PBS, 500 μL of paraformaldehyde was added and fixed at room temperature for 5 minutes, the cell layer was washed twice with 1 mL of PBS, 500 μL of Nile Red dye was added and incubated at 37°C in the dark for 15 minutes. The cell layer was washed twice with 1 mL of PBS, the cells were observed under an inverted phase-contrast fluorescence microscope and photographs were recorded.

[0429] The results showed that compound E is effective in controlling the oil content of sebaceous gland cells. Therefore, compound E is shown to have the potential to effectively reduce oil secretion in patients' skin for clinical use.

[0430] Example 45 Acute oral toxicity in mice at the Institute for Cancer Research (ICR) The animals (Beijing Chairs River Experimental Animal Technology Co., Ltd.) were divided into two cages, one for males and one for females, with five animals in each cage. Before the experiment, the animals were fasted overnight, but their water intake was not restricted. Using a maximal test, the animals were weighed, and the toxin was administered by force feeding at a volume of 2 mL / 100 g and a dose of 5000 mg / kg body weight. The animals were poisoned once every 24 hours. After poisoning, the animals were fasted for 3 to 4 hours. After poisoning, the animals' abnormal condition was observed daily, autopsies were performed on animals that died during the observation period, and the animals were euthanized at the end of the observation period. Tissue and organ abnormalities were observed macroscopically, and histopathological examinations were performed as needed. The results are shown in Table 28 below.

[0431] [Table 28]

[0432] The results showed that the LD50 of compound E in ICR mice exceeded 5000 mg / kg, and according to the acute oral toxicity rating, it was non-toxic. Therefore, compound E is safe at very high doses in ICR mice, and based on previous animal data, compound E has also been shown to have good safety in a clinical setting.

[0433] Example 46 Acute percutaneous toxicity in SD rats The animals (Beijing Chairs River Experimental Animal Technology Co., Ltd.) were divided into two cages, one for males and one for females, with five animals in each cage. The test area was approximately 30-40 cm². 2 The experiment was conducted as follows: Before the experiment, the animals were allowed to acclimate to the laboratory environment for three days to ensure that the registered animals were healthy and free from skin damage. Approximately 24 hours before the experiment, the hair on the back of the animal's torso in the area to be contaminated was trimmed. Care was taken to ensure that the skin was not damaged during hair removal. This experiment employed a maximum toxic dose test at 2180 mg / kg. After weighing the animals, the test substance was moistened with water and applied uniformly to the area of ​​skin on the animal's back. The skin was covered with a thin film and secured with non-irritating adhesive tape. The skin was closed and covered to prevent contact for 24 hours. After poisoning, residual test substance was removed with warm water. After poisoning, the animals were observed daily for any abnormalities, autopsies were performed on animals that died during the observation period, and the animals were euthanized after the observation period. Tissues were observed for abnormalities with the naked eye, and histopathological examinations were performed as needed. The observation period was 14 days. During the observation period, the weight of the active substance was recorded on days 0, 1, 7, and 14 (D0-14). The results are shown in Table 29 below.

[0434] [Table 29]

[0435] The results indicate that the LD50 dose of compound E in SD rats was ≥2180 mg / kg, showing slight toxicity. Therefore, compound E is safe at high doses in SD rats, and based on previous animal data, compound E has been shown to have good safety in clinical use.

[0436] Example 47 Efficacy of compound E against human acne Compound E was applied to adult subjects for 28 consecutive days under normal conditions, according to the instructions for use, to evaluate its effectiveness in reducing acne, controlling oiliness, moisturizing, repairing, and soothing acne, as well as its mildness (non-irritating) and suitability for sensitive skin. The study included 32 Chinese adult men and women with sensitive skin (7 men, 25 women, aged 19-43 years (mean age 27.91 ± 6.82 years)), all of whom met the inclusion and exclusion criteria. Compound E was used twice daily at a fingertip unit for a total of 28 days. The cream dosage was based on fingertip units (FTU), where one fingertip unit refers to the amount of cream squeezed from a 5mm opening tube to the first interphalangeal joint of the index finger (approximately 0.5g).

[0437] Images were acquired using VISIA7, and skin color, redness area, and porphyrin were analyzed using IPP. Images were acquired using Antera3D (Miravex Limited, Ireland), and acne volume was analyzed. Skin hydration was measured using Corneometer® CM825 (Courage+Khazaka electronic GmbH, Germany). Skin transepidermal water loss was measured using Tewameter® TM HEX5 (Courage+Khazaka electronic GmbH, Germany). Skin sebum was measured using Sebumeter SM815 (Courage+Khazaka electronic GmbH, Germany). Dermatologist evaluations and self-assessments were performed.

[0438] The results are shown in Tables 30 and 31 below.

[0439] [Table 30]

[0440] [Table 31]

[0441] Results from a study of 32 Chinese men and women with sensitive skin showed that, under evaluation conditions, the product possessed anti-acne, oil-controlling, moisturizing, repairing, and soothing effects, was mild (non-irritating), and suitable for sensitive skin. Therefore, compound E was shown to be able to effectively alleviate acne and to have significant skin benefits for patients using it.

[0442] Example 48 Efficacy of compound E against human gingivitis (ongoing) The objective of the clinical trial was to test the efficacy of compound E as a novel ingredient for use in a gingival protective peptide mouthwash and for the suppression of gingivitis. The trial included 70 subjects aged 18-60 years with gingivitis, and the estimated number of subjects to complete the entire trial was ≥60, i.e., ≥30 per group.

[0443] The selection criteria were as follows: 1) good general health and no systemic diseases; 2) age 18-60 years, male or female; 3) having more than 20 intact teeth, no large restorations on the gingival margin, and no untreated cavities, severe gingival recession, or severe periodontal disease; 4) modified Quigley-Hein plaque index ≥ 1.5; 5) Loe-Silness gingival index ≥ 2.0, bleeding index ≥ 2.0.

[0444] Clinical evaluation criteria and methods: 1) Plaque Index (PI): 0 = No plaque; 1 = Scattered plaque spots on the cervical margin of the tooth; 2 = Thin, continuous band of plaque (up to 1 mm wide) on the cervical margin; 3 = Band of plaque wider than 1 mm wide but covering less than 1 / 3 of the tooth crown; 4 = Plaque covering at least 1 / 3 to less than 2 / 3 of the tooth crown; 5 = Plaque covering more than 2 / 3 of the tooth crown. 2) Gingival Index (GI): 0 = Normal gingiva; 1 = Mild inflammation, slight discoloration, slight edema, no bleeding on probing; 2 = Moderate inflammation, shiny gingiva, redness, edema, hyperplasia, or bleeding on probing; 3 = Severe inflammation, marked redness, edema, tendency for spontaneous bleeding. 3) Bleeding Index: 0 = Healthy-looking gums, no inflammation or bleeding; 1 = Discoloration due to inflammation, no bleeding on probing; 2 = Spot bleeding after probing; 3 = Bleeding spreads towards the marginal gingiva after probing; 4 = Bleeding fills and overflows the gingival sulcus; 5 = Spontaneous bleeding.

[0445] The test product was a mouthwash consisting of the following ingredients: 0.05% ammonium chloride, 0.02% galactose trichloride, 0.01% water-soluble menthol, 0.03% compound E, and water for injection. The placebo was the same formulation but without compound E. The pH of the mouthwash was 6.0.

[0446] All participants were provided with a soft toothbrush and toothpaste and randomized to either the test product group or the placebo group. After baseline data collection, participants were instructed to use the designated toothpaste and toothbrush twice daily, once in the morning and once in the evening, after meals, applying toothpaste to the entire length of the toothbrush head and brushing for 3 minutes. Then, 30 seconds after brushing, participants were instructed to use 10 ml of mouthwash, rinse thoroughly, spit out the mouthwash, and refrain from eating or drinking for 30 minutes. Efficacy was evaluated after 1 month. Plaque index, gingival index (GI), and bleeding index were assessed by dentists. Efficacy was expressed as the mean index score for each group.

[0447] The results showed that the plaque index, gingival index (GI), and bleeding index in compound E were lower than those in the placebo group one month after treatment (test vs. placebo: 1.22±0.76 vs. 1.87±0.60; 1.42±0.8 vs. 1.77±0.95; 1.69±0.12 vs. 2.19±0.59).

[0448] Therefore, compound E was shown to be effective in alleviating gingivitis and to have a significant benefit for patients using it.

[0449] Example 49 Efficacy of compound E against seborrheic dermatitis of the scalp The test product was prepared as described in Example 27 above. The study included 66 healthy subjects aged 25–60 years, and the estimated number of subjects to complete the entire study was ≥60, i.e., ≥30 per group.

[0450] The selection criteria were: 1) hair length ≥ 3 cm, 2) no severe hair loss and hair follicles covering at least 70% of the scalp, 3) dandruff level ≥ 3 points, and 4) subjective experience of scalp itchiness and redness.

[0451] Participants were randomly divided into a test group and a placebo group. After a two-week rinse-off period, participants began using either the test product, Compound E Hair Care Essence, or a placebo when they washed their hair every two days using the provided shampoo. The test product was applied evenly to the scalp once daily, 3 ml each time, using a scalp applicator on dry hair. When using the product after washing the hair, the hair needed to be dried before application.

[0452] The efficacy was evaluated after 28 days. The evaluation included measurements of scalp sebum content (Sebumeter SM815, Courage+Khazaka electronic GmbH, Germany), stratum corneum water content (Corneometer CM825, Courage+Khazaka electronic GmbH, Germany), and transdermal water diversion loss rate (Tewameter, Courage+Khazaka electronic GmbH, Germany) by experimental technicians. The overall condition of the scalp, itchiness, dandruff, dryness, and redness were evaluated by dermatologists.

[0453] The results indicate that compound E can effectively suppress oil secretion, increase water content, and repair the scalp's skin barrier. It also reduced itching, decreased the severity of dandruff, and reduced scalp dryness and redness (Table 32 below).

[0454] [Table 32]

[0455] Therefore, compound E was shown to be effective in alleviating symptoms associated with seborrheic dermatitis and to have a significant benefit for patients using it.

[0456] Example 50 Treatment of rosacea A 31-year-old woman was diagnosed with rosacea. The patient had small pink or red bumps on her face. She experienced redness (flushing) around her mouth and felt warmth, heat, itchiness, or pain. She sometimes felt a burning or stinging sensation when using water or skincare products. The woman used Compound E cream (described in Example 26) twice daily for 7 days. Her redness and itchiness decreased, and the bumps disappeared (Figure 8).

[0457] Example 51 Gastroesophageal reflux (GERD) in rats Test compound: Compound K: (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)2-Lys (SEQ ID NO: 113) Compound L: Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm)-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm) (SEQ ID NO: 115) Compound M: Montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm) (SEQ ID NO: 2)

[0458] Twenty SPF-grade male Wistar rats weighing 280-350g were provided by Zhejiang Charles River Experimental Animal Technology Co., Ltd., certificate number: 20211103Aaz0600000356.

[0459] Prior to the surgery, the rats were housed and kept for approximately one week before the experiment. The housing temperature was 25-27°C, the humidity was 74%, and the rats were given alternating 12-hour periods of light and darkness, with free access to food and water.

[0460] Rats were randomly divided into five groups, with four rats in each group. The groups were as follows: placebo group, model group, compound K group, compound L group, and M group. The rats were anesthetized by 2% isoflurane inhalation and placed in a supine position. The surgical site was shaved with clippers and the skin was disinfected with iodine. A 2 cm incision was made along the midline of the abdomen, 0.5 cm below the xiphoid process, to open the abdominal cavity and expose the surgical field. Connective tissue was separated and cut between the liver and stomach. The vascular bundle between the spleen and the gastric fundus was ligated and cut to completely free the gastric fundus. The gastric fundus was rotated slightly to the left to expose the left side of the gastroesophageal junction in the field of view. Using a pair of sharp scissors, a 5 mm longitudinal incision was made in the muscle along the distal esophagus to expose the gastroesophageal junction.

[0461] The dorsal side of the esophagus was gently separated from the blood vessels posterior to the esophagus. A small cotton swab was inserted between the esophagus and the blood vessels. Using sharp surgical scissors, two 5 mm longitudinal incisions were made at the gastroesophageal junction and at the proximal end of the duodenum adjacent to the pylorus. For the duodenal incision, blood vessels were avoided and the incision was positioned on the opposite edge of the mesentery. The incisions were anastomosed precisely mucosal to mucosal opposition using 8-0 prolen intermittent sutures. Three to four sutures were made dorsally and two to three anteriorly. The abdominal cavity was irrigated with saline solution and the abdominal wall and skin were closed. The surgery was performed on each rat except for the sham surgery group. After anesthesia and laparotomy, the lower esophagus, duodenum, and gastric fundus were separated without incision in the sham surgery group.

[0462] Postoperatively, the rats were fasted and deprived of water for 30 hours, and then given glucose via tail vein infusion at a rate of 8 ml / animal once daily for two consecutive days. To prevent infection, the rats were also given 50,000 IU of penicillin intramuscularly once daily for three consecutive days. One week after surgery, the rats were subjected to various interventions by forced feeding as described in Table 33 below.

[0463] [Table 33] 500 mg each of compounds K, L, and M (GL Biochem, Shanghai, China) were completely suspended in 10 ml of 0.5% CMC-Na (carboxymethylcellulose sodium, Chemical Reagent Co., Ltd., China) solution to obtain three test solutions with a concentration of 50 mg / ml.

[0464] The intervention was performed once daily for two weeks. Body weight was measured every three days. After the two-week intervention, the animals were euthanized and their thoracic cavities were opened. The esophagus was dissected and incised longitudinally to expose the anastomosis site. The severity of esophagitis was assessed according to the scoring criteria in Table 34 below.

[0465] [Table 34]

[0466] Figure 9 shows the results regarding the severity of esophagitis, demonstrating that montelukast and pranlukast were able to reduce the severity of esophagitis in a rat GERD model.

[0467] Example 52 PK testing: Device-assisted transdermal administration Test sample: Compound E: A 1 mg / ml solution was prepared by dissolving 1 mg of compound E in 1 ml of physiological saline. Compound E+PL429:PL429 (Guangzhou Jizhou Trading Co., Ltd.) is a transdermal enhancer. 0.5% PL429 was added to the above solution.

[0468] Twenty-seven SPF-grade male SD rats weighing 250-300g were provided by Zhejiang Charles River Experimental Animal Technology Co., Ltd., housed, and reared for approximately one week prior to the experiment. The rearing temperature was 25-27°C, humidity 74%, and a 12-hour light-dark cycle, with free access to food and water. As shown in Table 35 below, the rats were randomly divided into three groups of nine rats, with three sampling points in each group.

[0469] [Table 35]

[0470] The device used was a high-pressure transdermal nutritional supplementation device (Guangzhou Tuonasi Beauty Instrument Co., Ltd., China).

[0471] Remove hair from the injection site (skin on the left side of the spine) to a length of 4.0 cm. 2 The area was shaved. The area of ​​administration was 3 cm². 2 The area was marked. The administration was performed on intact skin (undamaged).

[0472] Sample preparation: Approximately 200 μL of whole blood was collected from the carotid artery of each animal group at each time point and injected into an EP tube containing EDTA-K anticoagulant. Immediately, the tube was shaken by hand and placed in moist ice. The sample was centrifuged at 1800 g for 10 minutes at 4°C. Within 2 hours, the plasma was separated and stored at -80°C. Simultaneously, skin tissue was collected from the administration site. Before collecting the tissue sample, the site was washed with saline solution and dried. After collection, the sample was stored at -80°C for further analysis.

[0473] The results are shown in Table 36 below.

[0474] [Table 36]

[0475] The results indicate that a large amount of compound E remained in the skin tissue after topical application. Neither the transdermal enhancer nor the device significantly increased plasma exposure. However, the device was able to increase the local concentration. This demonstrates beneficial properties for the topical application of compound E.

[0476] Example 53 Skin pigmentation: Device-assisted transdermal administration - 1 Test sample: Compound E: A 1 mg / ml solution was prepared by dissolving 1 mg of compound E in 1 ml of physiological saline.

[0477] device Dermashine pro (Huons Meditech, Republic of Korea) is an automated mesotherapy injector that utilizes vacuum pressure. It has been used to replenish moisture and nutrients to the skin.

[0478] A 56-year-old woman presented with hyperpigmentation on her check face after a beach trip. During her stay at the beach, she was exposed to sunlight, which caused skin redness. A few days later, hyperpigmentation appeared. She went to a beauty salon for treatment. She was treated with compound E via Dermashine injection into her entire face. The solution was filtered through a 0.22 μm Minisart® High Flow filter (Sartorius, Germany). A total of 3 ml of the solution was injected. The treatment was repeated after two weeks. One week after the second injection, the hyperpigmentation had disappeared, and the dullness and roughness of the skin had significantly improved.

[0479] Example 54 Skin pigmentation: Device-assisted transdermal administration - 2 Test sample: Compound K:(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)2-Lys (SEQ ID NO: 113) was dissolved in physiological saline to prepare a 1 mg / ml solution.

[0480] A 32-year-old woman visited the clinic due to hyperpigmentation on both sides of her face after giving birth to a baby girl. Six months postpartum, the woman desired treatment for her face. She went to a beauty salon and was advised to undergo non-invasive treatment using the aforementioned solution. A high-pressure transdermal nutritional device (Guangzhou Tuonasi Beauty Instrument Co., Ltd, China) was used to enhance the absorption of the solution. Treatment was performed weekly. After two months, her skin was firmer and the discoloration had disappeared.

[0481] Example 55 LPS-induced lung injury in rats Test compound: Compound N:DPPS-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 7) Compound O:LTB4-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 8) Compound M: Montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm) (SEQ ID NO: 2)

[0482] A total of 67 male SD rats were randomly assigned, according to their body weight, to a normal control group (10 rats) and a model group (57 rats) for the initial grouping. The normal control group received sodium chloride via intraperitoneal injection and tracheal spray. The model group received lipopolysaccharide (LPS) via intraperitoneal injection and tracheal spray to induce a model of acute lung injury (2 mg / kg intraperitoneal injection on day 0, 4 mg / kg tracheal spray on day 1, with an interval of approximately 16 hours). After LPS was sprayed into the trachea of ​​the animals on day 1, the model group animals were again randomly assigned, according to their body weight, as follows: vehicle control group, test compound N group (0.5 mg / kg), test compound O group (0.5 mg / kg), test compound M group (0.5 mg / kg), and positive control group (2.5 mg / kg). The normal control group was not regrouped. The normal control group and the vehicle control group received intravenous injection of 0.9% sodium chloride solution. The test substance groups N, O, and M were given the corresponding doses of intravenous injection once daily for one day, and the positive control group received intraperitoneal injection of dexamethasone sodium phosphate once daily for one day. On the second day, the animals were anesthetized and euthanized, and lung lavage fluid tests and lung weight index tests were performed.

[0483] Bronchoalveolar lavage fluid (BALF): Compared to the corresponding indicators in animals in the vehicle control group, the mean values ​​of WBC, Neut, Lymph, and Mono were significantly reduced in the test substance compound N, compound O, and compound M groups, as well as in the positive control group. The maximum reductions in WBC were approximately 62%, 74%, 84%, and 87%, respectively, showing statistically significant differences. The maximum reductions in Neut were approximately 73%, 79%, 92%, and 93%, respectively, showing statistically significant differences. The maximum reductions in Lymph were approximately 65%, 76%, 82%, and 84%, respectively, showing statistically significant differences. The maximum reductions in Mono were approximately 71%, 85%, 88%, and 91%, respectively, showing statistically significant differences.

[0484] Total Protein: Compared to the total protein in BALF of animals in the vehicle control group, the mean total protein values ​​in the test substance compounds N, O, and M, as well as in the positive control group, showed a significant decrease. The maximum decrease in total protein was approximately 68%, 72%, 77%, and 56%, respectively, and these differences were statistically significant.

[0485] Lung Mass Index: Compared to the lung mass index of animals in the vehicle control group, the mean lung mass index of the test substance compounds N, O, and M, as well as the positive control group, showed a significant decrease. The maximum decrease in lung mass index was approximately 20%, 23%, 25%, and 29%, respectively, and these differences were statistically significant.

[0486] Inflammatory Factors: Compared to serum and BALF, inflammatory factors (Ang-2, LTD4) were significantly reduced in animals in the vehicle control group, test substance compound N, compound O, and compound M groups, and the positive control group. The maximum reductions in serum Ang-2 were approximately 25%, 31%, 40%, and 46%, respectively. The maximum reductions in Ang-2 indices in BALF were approximately 25%, 27%, 37%, and 55%, respectively, with statistically significant differences observed in the positive control group. The maximum reductions in serum LTD4 indices were approximately 35%, 32%, 37%, and 32%, respectively. The maximum reductions in LTD4 in BALF were approximately 5%, 15%, 10%, and 25%, respectively.

[0487] In summary, under the conditions of this study, the test substances, compounds N, O, and M administered intravenously once daily at a dose of 0.5 mg / kg, reduced total white blood cell count, neutrophil count, total protein, lung weight index, serum Ang-2 and LTD4, and BALF index in a rat model of acute lung injury, indicating that these compounds are effective in treating acute lung injury.

[0488] Example 56 Compound P form: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 114) The preparation of compound P-form contained a mixture of the substances listed in Table 37 below.

[0489] [Table 37]

[0490] The components of phase A were mixed and stirred for 30 minutes until the system was homogenized. Sodium hydroxide was added while stirring to adjust the pH of the solution to 6.5.0, and the form of compound P was obtained.

[0491] This form is intended to be used as an anti-inflammatory agent for repairing vaginal mucosal damage caused by injury and surgery.

[0492] Example 57 Compound P-gel: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 114) The compound P gel preparation contained a mixture of the substances listed in Table 38 below.

[0493] [Table 38]

[0494] The components of phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was cooled until the system was homogenized to obtain compound P gel.

[0495] This gel is intended to be used as an anti-inflammatory agent in the repair of colorectal mucosal damage caused by injury and surgery.

[0496] Example 58 Compound P tablet: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 114) The preparation of compound P tablets involved a mixture of the substances listed in Table 39 below.

[0497] [Table 39]

[0498] The components of phase A were sieved through a 100-mesh sieve. Pharmaceutical adjuvants were sequentially added to compound P and mixed uniformly. When adding the pharmaceutical adjuvants, 50% ethyl alcohol was used as a wetting agent, and the mixture was continuously stirred to ensure uniform wetting. The humidity of the material was adjusted, and a soft material was prepared that could be kneaded by hand into a ball and dispersed by light pressure. The prepared soft material was sieved through a 20-mesh standard sieve to obtain wet granules.

[0499] The prepared moist granules were spread uniformly on a tray to a granule layer thickness of 2 cm to 3 cm. The granules were dried at 55°C for 1 hour, and the drying process was accelerated by rotating the granules every 15 minutes to ensure uniform drying until the moisture content was less than 3%.

[0500] The dried granules were sifted again to adjust their size, mixed with a certain amount of the lubricant magnesium stearate, and placed in a tablet press to obtain compound P tablets.

[0501] This tablet is intended for use as an anti-inflammatory agent, as well as for repairing gastrointestinal mucosal damage caused by injury and surgery.

Claims

1. A compound of formula I, L ｔ－ Q ａ -D ｂ (I) During the ceremony, Q ａ However, it represents Z or A-Q-B, Q is a structural fragment of equation II, 【Chemistry 1】 During the ceremony, The wavy line represents the connection point from Q to A and / or B. R is, 【Chemistry 2】 Selected from the group consisting of, R is, 【Transformation 3】 When representing this, one of the wavy lines represents the bond point to the rest of the Q fragment, and the other wavy line represents the bond point to the Z group. m represents an integer from 1 to 4. A and B independently determine Z or A １ - Q １ -B １ This represents, A １ and B １ are each independently Z or A ２ -Q ２ -B ２ represent, A ２ and B ２ However, independently, Z or Z-Q ３ - Represents Z, Q １ Q ２ and Q ３ However, independently, it represents a structural fragment of formula III, 【Chemistry 4】 During the ceremony, The dashed line adjacent to the NH element is Q １ Q ２ and Q ３ From A １ and / or B １ A ２ and / or B ２ These represent the connection points to Z, respectively. The wavy line adjacent to the C=O group is Q １ Q ２ , and Q ３ Q, Q １ and Q ２ These represent the connection points to each, m is as defined above, Each L independently represents a lipid, or a derivative of any of these lipids, selected from the group consisting of vitamin A, vitamin E, cholesterol, and one or more lipids comprising one or more carboxylic acid groups, 1 to 50 carbon atoms, and / or one or more cyclic rings, which is linear or branched, saturated or unsaturated, has 1 to 10 carbon-carbon double bonds, and / or is substituted with 1 to 10 -OH groups. t represents an integer selected from 1 to 32. D represents Montelukast, b represents an integer selected from 0 to 16, In each of the cases used above, Z represents a structural fragment of formula IV, [(W) ｒ -Lys-X １ -T-U-X ２ -Y] ｎ -(W) ｒ -Lys-X １ -T-U-X ２ -Y(IV) (Sequence No. 1) During the ceremony, n represents an integer selected from 0 to 4. In each case in which it is used, r independently represents either 0 or 1. In each case in which it is used, W independently represents a sequence of one or two amino acids selected from one or more of the group consisting of Ser, Lys, Ala, DOPA, and 3,4-dihydrocinnamic acid (HCA) residues, provided that, if present, the HCA residue is located at the N-terminus of Z. X １ However, independently, it represents Pro, Hyp, or the Hyp. T independently represents Ser or pSer, U independently represents Tyr, pTyr, DOPA, Hyp, or Pro. X ２ However, independently, it represents Thr, Ser, Pro, Hyp, or the Hyp, Y independently represents a sequence of 1 to 5 (e.g., 1 to 4) amino acids selected from one or more of the group Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, and the sequence is optionally terminated by dopamine (or more appropriately, a “dopamine fragment”). If present, each D has one or more NH residues of its respective carboxylic acid residue and Z. ２ It is covalently bonded to Z via an amide bond with the residue. Each L residue is a carboxylic acid residue of L and one or more NH residues of Z. ２ A compound covalently bonded to Z via an amide bond with a residue, and / or via an ester bond between each of the -OH residues of L and one or more carboxylic acid residues of Z, Also, positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the said compound.

2. The compound according to claim 1, wherein the lipid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, octadecanediic acid, docosahexaenoic acid, and leukotriene B4, or any derivative thereof.

3. The compound according to claim 2, wherein the lipid is palmitic acid or a derivative thereof.

4. The compound according to claim 3, wherein the derivative is palmitoylethanolamide (PEA).

5. The compound according to claim 3, wherein the derivative is phosphatidylserine.

6. The compound according to claim 3, wherein the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine, phosphatidylethanolamine, or 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine.

7. The compound according to claim 3, wherein the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine.

8. The compound according to claim 2, wherein the lipid is stearic acid or a derivative thereof.

9. The compound according to claim 8, wherein the derivative is 1,2-distearoyl-sn-glycero-3-phospho-L-serine.

10. The compound according to claim 2, wherein the lipid is oleic acid or a derivative thereof.

11. The compound according to claim 10, wherein the derivative is 1,2-dioleoil-sn-glycero-3-phospho-L-serine.

12. The compound according to claim 1, wherein the lipid is selected from the group consisting of vitamin E, vitamin A, cholesterol, or any derivative thereof.

13. The compound according to claim 12, wherein the cholesterol derivative is cholesterol-acetic acid.

14. Q ａ A compound according to any one of claims 1 to 13, wherein Z is represented.

15. The compound according to any one of claims 1 to 14, wherein n represents 0.

16. The compound according to any one of claims 1 to 15, wherein W, if present, represents Ala.

17. X １ A compound according to any one of claims 1 to 16, wherein Pro is represented.

18. The compound according to any one of claims 1 to 17, wherein T represents Ser.

19. The compound according to any one of claims 1 to 18, wherein U represents Tyr or DOPA.

20. X ２ A compound according to any one of claims 1 to 19, wherein the compound represents Hyp.

21. The compound according to any one of claims 1 to 20, wherein Y represents a sequence of four amino acids, and the amino acids are selected from one or more of the group Lys, Hyp, Thr, DOPA, and Tyr, and optionally terminated with a dopamine fragment.

22. The sequence of amino acids defined by Y is -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys-, -DOPA-Lys-, and Selected from the group -Tyr-Lys-, The compound according to claim 21, wherein each of these is optionally terminated with a dopamine fragment.

23. Z is Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 9), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 12), Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (Sequence ID 14), Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 16), and The compound according to claim 22, selected from the group Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 19).

24. A compound according to any one of claims 1 to 23, for use in pharmaceuticals for human or animal use.

25. A compound according to any one of claims 1 to 23, for use as a pharmaceutical product.

26. A pharmaceutical preparation comprising the compound described in any one of claims 1 to 25.

27. The pharmaceutical formulation according to claim 26, further comprising a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

28. The pharmaceutical formulation according to claim 26 or 27, wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier is suitable for topical administration, is adapted, and / or presented in packaging, and is a topical adjuvant, diluent, or carrier.

29. A pharmaceutical preparation according to any one of claims 26 to 28, in the form of a gel, spray, cream, ointment, or dry powder.

30. A pharmaceutical preparation according to any one of claims 26 to 29, further comprising a pharmaceutical active ingredient or a further pharmaceutical active ingredient.

31. It is a parts kit, and its components are: (A) A compound according to any one of claims 1 to 23, or a pharmaceutical preparation according to any one of claims 26 to 30, (B) A pharmaceutical preparation comprising a pharmaceutically active ingredient or a further pharmaceutically active ingredient mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, A parts kit in which components (A) and (B) are provided in a form suitable for administration in combination with the other.

32. The pharmaceutical formulation according to claim 30, or the parts kit according to claim 31, wherein the pharmaceutical active ingredient is an anti-inflammatory agent, an anti-inflammatory agent, an antibiotic, an antibacterial and / or antiparasitic agent, an antiviral agent, an anesthetic, and / or a wound healing agent.

33. The pharmaceutical preparation or parts kit according to claim 32, wherein the pharmaceutically active ingredient is an anti-inflammatory agent.

34. A compound according to any one of claims 1 to 23, a formulation according to any one of claims 26 to 30, 32, or 33, or a parts kit according to any one of claims 31 to 33, for use in the treatment of inflammation, inflammatory disorders, and / or disorders characterized by inflammation.

35. Use of a compound according to any one of claims 1 to 23, a formulation according to any one of claims 26 to 30, 32, or 33, or a parts kit according to any one of claims 31 to 33, for the manufacture of a pharmaceutical for the treatment of inflammation, inflammatory disorders, and / or disorders characterized by inflammation.

36. A method for treating inflammation, inflammatory disorders, and / or disorders characterized by inflammation, comprising administering to a patient in need of such treatment a compound according to any one of claims 1 to 23, a formulation according to any one of claims 26 to 30, 32, or 33, or a parts kit according to any one of claims 31 to 33.

37. The compound, formulation, or parts kit for use according to claim 34, the use according to claim 35, or the method according to claim 36, wherein the injury characterized by inflammation is a wound or burn, or causes a wound or burn.

38. The compound, formulation, or parts kit for use, use, or method according to claim 37, wherein the disorder causing the wound is hemorrhoids or ulcerative colitis.

39. The compound, formulation, or parts kit, use, or method for use according to any one of claims 24 to 38 (as necessary), wherein the compound or a salt thereof is administered topically in the form of a topical formulation.

40. The compound, formulation, or parts kit, use, or method for use according to claim 39, wherein the associated pathological condition is treated by direct topical administration to the skin.

41. The compound, formulation, or parts kit, use, or method for use according to claim 39, wherein the aforementioned related pathological condition is treated by direct local administration to the mucosal surface.

42. A compound, formulation, or parts kit, use, or method for use according to any one of claims 24 to 41 (as necessary), wherein the compound is administered by oral, intravenous, skin or subcutaneous, nasal, intramuscular, intraperitoneal, lung, or anorectal delivery.

43. A compound, formulation, or parts kit, use, or method for use according to any one of claims 30 to 42 (as necessary), wherein the compound according to any one of claims 1 to 23 functions as an excipient, as a medical device, or as a component of a medical device in a drug-medical device combination.

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