Novel multifunctional oligopeptides

Abstract

A compound of formula I, L t - Q a - D b (I) wherein: Q a represents Z or A-Q-B, and Q is a structural fragment of formula II, (II) wherein: the wavy line, R and m have the meanings given in the description, and wherein A and B have the meanings given in the description, but can represent the 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) wherein n, r, T, W, X 1 , U, X 2 and Y have the meanings given in the description, each L independently represents a lipid as defined in the description, and D represents one or more optional montelukast moieties, is useful in medicine, including as a pharmaceutical excipient, adhesive and film forming material, and / or is useful in the treatment of conditions characterised by inflammation, including wounds, burns and mucosal disorders, such as anorectal disease, inflammatory bowel disease, gynaecological disease and dental disease.

Description

Technical Field

[0001] This invention relates to novel peptides, the use of such peptides as pharmaceutically active ingredients or otherwise in human medicine, and pharmaceutical compositions comprising said peptides. In particular, this invention relates to the use of these peptides and compositions in the treatment of a variety of conditions, including inflammation. Background Technology

[0002] Inflammation is typically characterized as a localized tissue response to the invasion of, for example, microorganisms, certain antigens, damaged cells, or physical and / or chemical agents. The inflammatory response is generally a protective mechanism that disrupts, dilutes, or isolates harmful agents and damaged tissue, and that initiates tissue healing.

[0003] Inflammation can be caused by physical trauma, infection, some chronic diseases (e.g., psoriasis and autoimmune diseases such as rheumatoid arthritis), and / or chemical and / or physiological responses to external stimuli (e.g., as part of an allergic reaction). It can involve a complex series of events in which inflammatory mediators increase blood flow and dilate local blood vessels, leading to redness and heat, fluid exudation, often resulting in local swelling, white blood cell migration to the inflamed area, and pain.

[0004] Many conditions / disorders are characterized by and / or caused by abnormal, damaging inflammation of the tissues. These conditions are typically characterized by the activation of immune defense mechanisms, resulting in a greater harm than benefit to the host, and are usually 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 complex series of events leads to inflammatory changes, such as increased blood flow through local vasodilation, resulting in redness and heat; extravasation of white blood cells and plasma, often leading to local swelling; activation of sensory nerves (leading to pain in some tissues); and loss of function. These inflammatory changes are triggered by a series of cellular and biochemical events involving cells such as neutrophils, monocytes, macrophages, and lymphocytes; and inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

[0006] Furthermore, inflammation plays a crucial role in the wound healing process. Therefore, wounds and burns can be classified as inflammation-related conditions. The conventional wisdom in this field is that anti-inflammatory drugs should not be applied directly to open wounds, as this would hinder 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. Although collagen deposition is typically a reversible part of wound healing, it can often evolve into a progressively irreversible fibrotic reaction if tissue damage is severe or if the wound healing response itself becomes disordered. Furthermore, fibrosis is known to be a leading cause of morbidity and death in many chronic inflammatory diseases, as well as end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure. It is also a pathological feature of many chronic autoimmune diseases, such as scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus. Fibrosis may also influence the pathogenesis of many progressive muscle diseases, metastases, and transplant rejection.

[0008] Mussel adhesion protein (MAP) (also known as purple mussel ( Mytilus edulis Mefloppin (mefp) is a protein produced by marine mollusks such as the purple mussel and the thick-shelled mussel. Mytilus coruscus ) and jade mussels ( Perna viridis The proteins secreted by mussels. Eleven independent adhesin subtypes have been identified from mussels, including collagen pre-COL-P, pre-COL-D, and pre-COL-NG; mussel foot matrix proteins PTMP (proximal filament matrix protein) and DTMP (distal filament matrix protein); and mfp proteins mfp-2 (sometimes referred to as "mefp-2", which can be used interchangeably below), mfp-3 / mefp-3, mfp-4 / mefp-4, mfp-5 / mefp-5, mfp-6 / mefp-6, and the most preferred 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] A key portion of mefp-1 consists of 70 to 90 tandem repeats of the following decapeptide sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 61; see Waite, Int. J. Adhesionand Adhesives ,1987, 7 (9-14). This decapeptide sequence can be isolated as a low molecular weight derivative of naturally occurring MAP, or it can be synthetic, for example, as described by Yamamoto. J. Chem. Soc., Perkin Trans. ,1987, 1See also Dalsin et al., 613-618. J. Am. Chem. Soc. ,2003, 125 , 4253-4258.

[0010] Also disclosed are decapeptide analogs, notably Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2). See, for example, US 5,616,311 and WO 96 / 39128, and international patent applications WO 2019 / 007355 A1, WO 2019 / 228307 A1, WO 2021 / 047648 A1, WO 2011 / 110061 A1 and WO 2021 / 110064 A1.

[0011] Japanese patent application JP 2003238589 A discloses certain dipeptides and tripeptides that act as angiotensin-converting enzyme inhibitors.

[0012] The use of lysine amino acid residues in the preparation of multiantigenic peptides has been disclosed in, for example, Tam. Proc. Natl. Acad., Sci. USA ,1988, 85 , 5409-5413, Rao et al., J. Am. Chem. Soc. ,1994, 116 See also US Patent Application WO 2021 / 110064 A1, 6975-6976, US 5,229,490, and WO 2010 / 038220. See also International Patent Application WO 2021 / 110064 A1.

[0013] The use of peptide-based scaffolds as drug delivery mediators 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 has been disclosed in, for example, MS Ferreira. Cosmetics. 2000, 7 , 91 See also Kamysz et al., who disclosed palmitoyl tripeptide as an antimicrobial agent.

[0015] There is clearly a need for new and / or improved medicines that can be used to treat inflammation and conditions characterized by inflammation. Summary of the Invention

[0016] According to a first aspect of the invention, a compound of formula I is provided. L t -Qa -D b (I) in: Q a Represents Z or AQB; Q is a structural segment of equation II. (II) in: The wavy line represents the attachment point of Q to A and / or B; R is selected from: , ,and Where R represents In this case, one wavy line represents the attachment point with the rest of the Q segment, and the other wavy line represents the attachment point with the Z group. m represents an integer from 1 to 4; A and B independently represent Z or A 1 -Q 1 -B 1 ; A 1 and B 1 Independently represent Z or A 2 -Q 2 -B 2 ; A 2 and B 2 Independently represent Z or ZQ 3 -Z; Q 1 Q 2 and Q 3 Independently represent the structural fragment of expression III. (III) in: The wavy lines adjacent to the NH group represent Q. 1 Q 2 and Q 3 With A 1 and / or B 1 A 2 and / or B 2 The attachment point of Z; The wavy lines adjacent to the C=O group represent Q. 1 Q 2 and Q 3 With Q, Q 1 and Q 2 Attachment point; m is as defined above; Each L independently represents one or more lipids selected from vitamin A, vitamin E, cholesterol, and fatty acids, wherein the fatty acids contain one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, and the lipids are straight-chain or branched, saturated or unsaturated lipids having between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10 -OH groups, or derivatives of any of these lipids. 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 above cases where it is used, Z represents the structural fragment of expression IV. [(W) r -Lys-X 1 -TUX 2 -Y] n -(W) r -Lys-X 1 -TUX 2 -Y (IV) (SEQ ID No: 1) in: n represents an integer selected from 0 to 4; In each case where it is used, r independently represents 0 or 1; In each case of its use, 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, when present, the HCA residues are located at the N-terminus of Z. X 1 Independently represent Pro, Hyp, or diHyp; T independently represents Ser or pSer; U independently represents Tyr, pTyr, DOPA, Hyp, or Pro; X 2 Independently represent Thr, Ser, Pro, Hyp, or diHyp; Y independently represents a sequence of 1 to 5 (such as 1 to 4) amino acids selected from one or more of the group consisting of Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, the sequence optionally terminated by dopamine (or more appropriately, "dopamine fragment"). If present, each D is covalently bonded to Z via an amide bond between its corresponding carboxylic acid residue and one or more NH2 residues of Z; and Each L residue is covalently bonded to Z via an amide bond between the corresponding carboxylic acid residue of L and one or more NH2 residues of Z and / or via an ester bond between the corresponding -OH residue of L and one or more carboxylic acid residues of Z. And the regioisomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of the compounds, which are collectively referred to below as "the compounds of the present invention".

[0017] Technicians will be able to determine whether the Z peptide is attached to the rest of the molecule via its N- or C-terminus. To avoid ambiguity, Z attaches to the rest of the molecule by forming an amide bond.

[0018] Therefore, when Z is attached to R, when R is At that time, Z is attached through the N end.

[0019] Preferred compounds of the present invention include these compounds, wherein the lipids are selected from palmitic acid, stearic acid, oleic acid, octadecanoic acid, docosahexaenoic acid and leukotriene B4 (LTB4) or derivatives of any of these lipids.

[0020] Further preferred compounds of the present invention include those wherein the lipids are polyunsaturated fatty acids or derivatives thereof. In such embodiments, the derivatives may be specialized pro-resolving mediators (SPMs).

[0021] Further preferred compounds of the present invention include those wherein the lipids are derivatives of fatty acids, such as glycerolipids, glycerophospholipids, sphingolipids, or glycolipids.

[0022] Further preferred compounds of the present invention include those wherein the lipid is palmitic acid or a derivative thereof. In such embodiments, the derivative may be phosphatidylserine, or more preferably, 1,2-dipalmitoyl-sn-glycerol-3-phosphate-1-serine, and most preferably, 1,2-dipalmitoyl-sn-glycerol-3-phosphate-1-serine (DPPS). In such embodiments, the derivative may be phosphatidylethanolamine, or more preferably, 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE).

[0023] Further preferred compounds of the present invention include those wherein the lipid is stearic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-distearyl-sn-glycerol-3-phosphate-l-serine.

[0024] Further preferred compounds of the present invention include those wherein the lipid is oleic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-dioleoyl-sn-glycerol-3-phosphate-L-serine.

[0025] Further preferred compounds of the present invention include those wherein the lipid is palmitamide ethanol (PEA).

[0026] Further preferred compounds of the invention include those wherein the lipids are selected from vitamin E, vitamin A, and cholesterol, or derivatives of any of these lipids. In such embodiments, the cholesterol derivative may be cholesterol-acetic acid.

[0027] Further preferred compounds of the invention include those wherein the lipids are fatty acids comprising 1 to 50 carbons and / or one or more cyclic rings, are straight-chain or branched, saturated or unsaturated lipids having between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10 -OH groups, or derivatives thereof. In such embodiments, the fatty acid may have 6 to 24 carbons, such as 6 to 18 carbons. In other embodiments, the fatty acid may have 1 to 6 carbon-carbon double bonds, such as 1 to 5 carbon-carbon double bonds. In other embodiments, the fatty acid may have 1 to 5 -OH groups, such as 1 to 2 -OH groups. In other embodiments, the fatty acid may have 1 to 10 cyclic rings, such as 1 to 8 cyclic rings.

[0028] Further preferred compounds of the present invention include these compounds, wherein: t represents an integer selected from 1 to 8; or more preferably... t represents an integer selected from 1 to 4.

[0029] Further preferred compounds of the present invention include these compounds, wherein: b represents an integer selected from 0 to 4; or more preferably... b represents 1.

[0030] As used herein, the terms "dopamine" and "dopamine fragment" refer to the structural fragment of Formula I. The wavy line represents the attachment point with respect to Y.

[0031] As used in this article, 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-glycerol-3-phosphate-L-serine, LTB4 represents leukotriene B4, and PEA represents palmitamide ethanol.

[0032] As used in this article, 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. (It can form an amide bond by attaching to any free amine group (including the N-terminus of amino acid sequence Z), and Dap represents diaminopropionic acid. 3,4-Dihydrocinnamic acid (HCA) residues are essentially DOPA residues, but unlike carboxylic acids attached to N-terminal amino acids (Lys or Ala), they do not have a -NH2 group at the 2- or α-carbon position.

[0033] In each case where they are used, Q, Q 1 Q 2 and Q 3 Each can interact with Q and Q through the corresponding carboxylic acid residue of Z. 1 Q 2 and Q 3 The amide bond between one or more NH2 residues is covalently bonded to zero, one or two Z groups.

[0034] In this respect, preferred compounds of the present invention include these compounds, wherein: One of A or B represents Z, and the other represents A. 1 -Q 1 -B 1 Or more preferably, Both A and B represent Z, or both represent A. 1 -Q 1 -B 1 , In each case, Q 1 Preferably, it represents the Lys segment, and Z is as defined above.

[0035] Further preferred compounds of the present invention include these compounds, wherein: A 1 and B 1 One of them represents Z, and the other represents A. 2 -Q2 -B 2 Or more preferably, A 1 and B 1 Both represent Z or both represent A 2 -Q 2 -B 2 , In each case, Q 2 Preferably, it represents the Lys segment, and Z is as defined above.

[0036] Further preferred compounds of the present invention include these compounds, wherein: A 2 and B 2 One of them is represented by Z, and the other is represented by ZQ. 3 -Z; or more preferably, A 2 and B 2 Both represent Z or both represent ZQ 3 -Z, In each case, Q 3 Preferably, it represents the Lys segment, and Z is as defined above.

[0037] More preferred compounds of the present invention include these compounds, wherein: A 1 and B 1 Both represent Z; or A 2 and B 2 All represent Z.

[0038] Further preferred compounds of the present invention include these compounds, wherein m represents 1, 3 or more preferably 4, such that Q, Q 1 Q 2 and Q 3 One or more of the representations of Lys, or more appropriately, the “Lys fragment” as defined above as “structural fragments of Equations II and III” (as the case may be).

[0039] The particularly preferred compounds of the present invention include these compounds, wherein: Q a Let Z represent the number of digits; where Z is the number of digits. n is 0, 1 or 4, preferably n is 1, or more preferably n is 0.

[0040] The compounds of the present invention that may be mentioned include these compounds, wherein the amino acid residues at the N-terminus of the Z component are optionally covalently bonded to montelukast.

[0041] Other compounds of the present invention that may be mentioned include these compounds, wherein: R represents t represents an integer selected from 1 to 4; and / or b is 0 or 1.

[0042] The compounds of the present invention that may be mentioned include these compounds, wherein: In each case where it is used, W represents a sequence of one or two amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Ala, DOPA and HCA; T stands for Ser; U represents Tyr or DOPA; X 2 This indicates Ser, Pro, Hyp, or diHyp; Y represents a sequence of 1 to 5 (e.g., 1 to 4) amino acids, wherein the amino acids are selected from one or more of the group consisting of Lys, Ala, Pro, Hyp, diHyp, Thr, DOPA, and Tyr.

[0043] The compounds of the present invention that may be mentioned include these compounds, wherein: One or two amino acids in W represent Ser; T represents pSer; U represents pTyr, Hyp, or Pro; X 2 Indicates Thr; Five amino acids (such as 1 to 4) in Y are pThr; Y is optionally terminated by dopamine.

[0044] Preferred compounds of the present invention include these compounds, wherein: X 1 Indicates Hyp or more preferably Pro; T stands for Ser; U represents Tyr or DOPA; X 2 Hyp; If present, W represents HCA-, HCA-Ala-, Lys-Ala-, DOPA-, DOPA-Ala-, or preferably Ala; and / or Y represents a sequence of 5, preferably 3, more preferably 2 or most preferably 4 amino acids, wherein the amino acids are selected from one or more of the group consisting of Lys, Hyp, Thr, DOPA and Tyr, and the sequence is optionally terminated by a dopamine fragment.

[0045] Preferred compounds of the present invention also include those compounds, wherein Y represents a sequence of four amino acids selected from the group consisting of: -Pro-Y 1 -Y 2 -Lys- or more preferably, -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 -Lys-, where Y 1 and Y 2 Each of the sequences is independently selected from the group consisting of Pro, Ala, or more preferably Hyp, Thr, DOPA, and Tyr, and the sequences are optionally terminated by a dopamine fragment.

[0046] When Y represents a sequence of two amino acids, preferred compounds of the present invention include those compounds, wherein the amino acid sequence defined by Y is selected from the group consisting of -Tyr-Pro-, preferably -Thr-Lys-, and more preferably -DOPA-Lys- and -Tyr-Lys-, optionally terminated by a dopamine fragment.

[0047] Further preferred compounds of the present invention include those compounds wherein the amino acid sequence defined by Y is selected from the group consisting of: -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 preferably, -Hyp-Thr-Tyr-Lys-; -Hyp-Thr-DOPA-Lys-; -Thr-Tyr-Hyp-Lys-; -Thr-DOPA-Hyp-Lys-; -DOPA-Lys-; and -Tyr-Lys- Each of these is optionally terminated via a dopamine fragment.

[0048] The compounds of the present invention that may be mentioned include these compounds, wherein W represents Ala.

[0049] In this regard, further compounds of the invention may be mentioned, including those compounds wherein Z is selected from the group consisting of: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID No: 21) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID No: 22) Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 23) Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 24) Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 25) Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 26) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 27) Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No: 28) Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID No: 29) Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys(SEQ ID No: 30) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID No: 31) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 32) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID No: 33) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID No: 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(SEQ ID No: 38) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 39) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No: 40) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No: 41) Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID 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(SEQ ID No: 45) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 46) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID No: 47) Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No: 48) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp(SEQ ID 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(SEQ ID No: 51) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp-Lys(SEQ ID No: 52) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Lys(SEQ ID No: 53) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr(SEQ ID No: 54) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp(SEQ ID No: 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(SEQ ID No: 59) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 60) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No: 61) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No: 62) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No: 63) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID 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(SEQ ID No: 67) Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys(SEQ ID No: 68) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID No: 69) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No: 70) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID No: 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-A la-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-H yp-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-Hy p-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) Ala-Lys-Pro-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 116).

[0050] Preferred compounds of the present invention that may be mentioned include these compounds, wherein Z is selected from the group consisting of: Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 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(SEQ ID No: 61); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID No: 63); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID No: 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 (SEQ ID No. 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(SEQ ID No: 46); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 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 (SEQ ID 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 Ala-Lys-Pro-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 116).

[0051] More preferred compounds of the present invention may be mentioned, wherein Z is selected from the group consisting of: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 11); and Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 12).

[0052] The compounds of the present invention that may be mentioned include these compounds, wherein W is not present.

[0053] In this regard, further compounds of the invention may be mentioned, including those compounds wherein Z is selected from the group consisting of: Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 86); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 88); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 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 (SEQ ID No: 19); Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92); Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID No: 93) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 95); Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 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(SEQ ID No: 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(SEQ ID No: 101); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 102); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID No: 103); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 104); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID No: 105); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 106); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID No: 107); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 108); and Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16).

[0054] Preferred compounds of the present invention that may be mentioned include these compounds, wherein Z is selected from the group consisting of: 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 (SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97); Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); and Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92).

[0055] More preferred compounds of the present invention may be mentioned, wherein Z is selected from the group consisting of: 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 (SEQ ID No: 19).

[0056] The compounds of the present invention that may be mentioned include these compounds, wherein the amino acid residues at the N-terminus of the Z component are optionally covalently bonded to montelukast, forming an amide link with the carboxylic acid group in montelukast.

[0057] Further, a (optionally isolated) peptide compound Z is provided (i.e., a compound equivalent to the compound of formula I as defined above, but wherein L and D are absent, and Q is not present). a (represented by Z as defined above), where: Both r and n represent 0; X 1 Indicates Hyp or more preferably Pro; T represents pSer or more preferably Ser; U represents DOPA or more preferably Tyr; X 2 It represents Hyp; and Y represents a sequence of 1 to 5, preferably 3, more preferably 4, or most preferably 2 amino acids, wherein said amino acids are selected from one or more of the group consisting of Lys, Hyp, Thr, DOPA, and Tyr, and said sequence optionally terminated by a dopamine fragment. And regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0058] Preferred peptide compounds Z include those with the following sequences: Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 86); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 88); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 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 (SEQ ID No: 19); Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92); Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID No: 93) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 95); Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 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(SEQ ID No: 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(SEQ ID No: 101); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No: 102); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID No: 103); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 104); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID No: 105); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 106); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID No: 107); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 108); and Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16), And regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0059] More preferred peptides may be selected from the group consisting of: 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 (SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97); Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); and Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92), And regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0060] Particularly preferred peptide compounds may be selected from the group consisting of: 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 (SEQ ID No: 19), And regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

[0061] To avoid ambiguity, the compounds of the present invention as defined above are collectively referred to as "the compounds of the present invention" in the following text.

[0062] The compounds of the present invention, whether in salt form or other forms, include regioisomers within the amino acids of a peptide (e.g., the diHyp, Hyp, and Tyr moieties), and mixtures of such regioisomers. For example, Tyr is defined to include not only tyrosine (4-hydroxyphenylalanine) but also 2- and 3-hydroxyphenylalanine. Hyp is defined to include 4-hydroxyproline (4Hyp), 3-hydroxyproline (3Hyp), and 5-hydroxyproline (5Hyp). More preferably, the Hyp residue is 4-hydroxyproline. Similarly, diHyp is defined to include 3,4-dihydroxyproline (3,4diHyp), 3,5-dihydroxyproline (3,5diHyp), and 4,5-dihydroxyproline (4,5diHyp). More preferably, the diHyp residue is 3,4-dihydroxyproline (3,4diHyp).

[0063] In addition to the standard central carbon atom of the amino acids in the compounds of the present invention (which is generally, but not exclusively, L-configured), certain amino acids in the sequence contain additional chiral carbon atoms. All such stereoisomers and mixtures thereof (including racemic mixtures) are included within the scope of the present invention. In this respect, 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; however, it is preferred that the Hyp used in the compounds of the present invention is 4-hydroxy-L-proline. Similarly, the corresponding definitions can be applied to diHyp, where the two hydroxyl groups may also be cis or trans relative to each other. In any case, individual enantiomers of Formula I compounds that can form part of the compounds of the present invention are included within the scope of the present invention.

[0064] The compounds of this invention can be in the form of salts. Salts that may be mentioned include pharmaceutically acceptable and / or cosmetically acceptable salts, such as pharmaceutically and / or cosmetically acceptable acid addition salts and base addition salts. Such salts can be formed by conventional means, for example by reacting the compound of this invention with one or more equivalents of a suitable acid or base, optionally in a solvent or in a salt-insoluble medium, followed by removing the solvent or medium using standard techniques (e.g., in a vacuum, by freeze-drying or by filtration). Salts can also be prepared by exchanging the anti-charged ion of the compound of this invention in salt form with another anti-charged ion, for example using a suitable ion exchange resin.

[0065] Preferred salts include, for example, acetates, hydrochlorides, hydrogen sulfates, maleates, methanesulfonates, toluenesulfonates, alkaline earth metal salts (such as calcium and magnesium salts), 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.

[0066] The compounds of the present invention can be prepared by conventional techniques, such as 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 suitable reagents and reaction conditions. In this regard, those skilled in the art may in particular refer to… Comprehensive Organic Synthesis ", BM Trost and I. Fleming, Pergamon Press, 1991. Other references that may be used include " Heterocyclic Chemistry “, J.A. Joule, K. Mills, and G.F. Smith, 3rd edition, published by Chapman & Hall,” Comprehensive Heterocyclic Chemistry II “, AR Katritzky, CW Rees and EFV Scriven, Pergamon Press, 1996 and “ Science of Synthesis ”, Volume 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0067] The compounds of the present invention can be isolated from their reaction mixtures and, if necessary, purified using conventional techniques known to those skilled in the art. Therefore, the methods for preparing the compounds of the present invention as described herein may include isolating and optionally purifying the compounds of the present invention (as a final step).

[0068] Those skilled in the art will understand that, in the methods described above and below, it may be necessary to protect the functional groups of the intermediate compound by protecting groups. Protection and deprotection of functional groups can be carried out before or after the reaction.

[0069] Protecting groups can be applied and removed using techniques well known to those skilled in the art and described below. For example, standard deprotection techniques can be used to chemically convert the protected compound / intermediate described herein into an unprotected compound. The type of chemistry involved will determine the need for and type of protecting groups, as well as the sequence of synthesis. The use of protecting groups is fully described in "..." Protective Groups in Organic Synthesis “, 5th edition, TW Greene & P.GM Wutz, Wiley-Interscience (2014), the contents of which are incorporated herein by reference.”

[0070] The compounds of this invention are intended for use in human and animal medicine. Therefore, although they may also be used in cosmetics and / or as part of medical devices, they are indicated as pharmaceuticals (and / or in veterinary science).

[0071] The compounds of the present invention may therefore also possess pharmacological activity, but certain pharmaceutically acceptable (e.g., "protected") derivatives of the compounds of the present invention may exist or can be prepared, said derivatives may not possess such activity, but said derivatives may be administered and subsequently metabolized or chemically transformed to form the compounds of the present invention. Such compounds (which may possess some pharmacological activity, provided that this activity is significantly lower than that of the active compounds obtained by their metabolism / transformation) can therefore be described as "prodrugs" of the compounds of the present invention.

[0072] As used herein, references to prodrugs will include compounds that, upon administration, form experimentally detectable amounts of the compounds of the present invention within a predetermined time period. All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0073] When the compounds of the present invention have pharmacological activity, they are particularly useful in the treatment of inflammation.

[0074] The term “treatment of inflammation” includes the treatment of inflammation (regardless of cause) in any organ of the body, including soft tissues, joints, nerves, vascular systems, internal organs, especially mucosal surfaces, particularly the skin, and also includes all such inflammatory disorders or conditions, and / or disorders or conditions characterized by inflammation (e.g., as symptoms).

[0075] Inflammatory disorders and / or conditions can (and typically) be characterized by the activation of immune defense mechanisms that produce effects that are more harmful than beneficial to the host. Such conditions are usually associated with varying degrees of tissue redness or congestion, swelling, edema, hyperthermia, pain (including aches), fluid exudation, itching (pruritus), cell death and tissue destruction, cell proliferation and / or loss of function.

[0076] Inflammatory conditions that may be mentioned include arteritis, diabetes, metabolic syndrome, rosacea, asthma and allergies, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), gouty arthritis, inflammatory bowel diseases (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 disease state characterized by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD). Other disease states characterized by inflammation that may be mentioned are inflammatory bowel diseases, including Crohn's disease and, especially, ulcerative colitis. Other disease states characterized by inflammation that may be mentioned are gynecological conditions such as cervicitis, vaginitis (e.g., radiation vaginitis), and colpitis. Diseases affecting the gastrointestinal tract, such as gastric ulcer diseases (e.g., gastritis, gastric ulcers, stress-induced gastritis, gastric cancer, and other gastric mucosal diseases) as well as gastroesophageal reflux disease (GERD), constipation, and gastritis; inflammation associated with cancer and infections (e.g., viral infections such as the common cold or influenza).

[0077] Inflammatory conditions that may be mentioned more specifically include inflammation of the skin or mucous membranes (including the mucous membranes of the mouth, nose, eyes, vagina, cervix, and / or anorectal region, especially the oral or nasal mucosa), such as inflammation caused by infections (such as viral and / or bacterial infections), or allergic / atopic conditions (such as rhinitis (e.g., allergic rhinitis), pharyngitis, periodontitis, gingivitis, dry eye, conjunctivitis (e.g., allergic conjunctivitis), dermatitis, urticaria (hives), and food allergies); as well as other inflammatory conditions such as herpes, drug eruption, polymorphic light eruption, sunburn, early signs of skin cancer (erythematous dermatitis), pathological hair loss (including post-skin grafting), chemical rashes, psoriasis, erythema multiforme, folliculitis, eczema, and otitis externa. A disease state that may be mentioned is polymorphic light eruption.

[0078] More specifically, the compounds can be used to treat certain conditions characterized by and / or associated with inflammation. Such conditions can include wounds (including abrasions (scratches), incisions (including surgical incisions), lacerations, punctures, avulsions, bruises, and scarring) and burns (including inflammation following burns caused by surgical procedures such as skin grafts) and other conditions (such as hemorrhoids). Wounds can be acute or chronic and / or can be caused by one or more inflammatory disorders as defined herein.

[0079] Wounds on the skin or mucous membranes can be caused by internal or external physical damage to the membrane surface, or by an underlying physiological disorder (i.e., its symptoms).

[0080] Physical (e.g., "open") wounds can be caused by: sharp objects (cuts, incisions, punctures) or blunt objects / mechanical forces (tears, abrasions, avulsions), physical impacts (bruises), heat or chemicals (burns and blisters), ultraviolet radiation (sunburn), or cold (frostbite). Wounds can be superficial (damage to the epidermis and / or dermis only) or full-thickness wounds (damage beneath the epidermis and / or dermis). In severe cases, subcutaneous and / or submucosal tissues, such as muscles, bones, joints, and even internal organs, may be damaged.

[0081] The compounds of this invention can be used to relieve pain (including aches) associated with inflammation and / or wounds. In particular, the compounds of this invention can be used to relieve procedural and / or non-procedural pain. Those skilled in the art should understand that the term "procedural pain" (i.e., surgical pain) refers to acute pain associated with medical research and treatment performed for healthcare purposes. The term "non-procedural" refers to general pain associated with inflammation and / or injury (e.g., pain associated with oral ulcers, burns, and / or scars) and is not the result of a specific medical intervention.

[0082] The compounds of this invention can not only be used to treat inflammation, pain (including aches) and / or pruritus (itching) associated with the wound itself and the healing process, but also to prevent fluid leakage from the wound, the risk of infection, and to prevent physiological reactions (such as scar formation and melanin deposition) caused by inflammation and / or the wound healing process.

[0083] Scar formation is a result of inflammation and / or wound healing, and is a general term for the formation of fibrous tissue as a result of such inflammation / healing.

[0084] The compounds of this invention can also be used to inhibit the production of melanin, which may or may not be caused by inflammation and / or wound healing. The compounds of this invention can also be used to inhibit disorders associated with melanin deposition, such as melasma, freckles, melanosis, malar rashes and other pigmentation disorders, skin cancer with melanoma, and pigmentation disorders or skin diseases (like acne) caused by sun exposure.

[0085] Wounds can also occur as a result of (e.g., inflammatory) diseases or disorders. Such wounds can 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 may frequently be damaged, removed, liquefied, infected, and / or necrotic. Ulcers can lead to secondary health consequences (especially if they are infected), are difficult to heal, and are expensive to treat. They can also cause significant psychological stress and financial loss to patients, thus affecting overall well-being and quality of life.

[0086] In alternatives, inflammatory skin diseases or conditions in which the compounds of the present invention are found particularly useful include viral skin diseases (such as herpes zoster), bacterial skin diseases, fungal skin diseases, animal-caused skin diseases, sexually transmitted skin diseases, allergy-related skin diseases, autoimmune skin diseases, neutrophilic skin diseases, erythematous epidemic and squamous skin diseases, connective tissue diseases, bullous skin diseases, pigmented skin diseases, skin appendage disorders, hereditary skin diseases, skin diseases related to nutritional and metabolic disorders, skin tumors, psoriasis, acne, eczema and dermatitis (especially allergic / atopic dermatitis and neurodermatitis), and in the treatment of mucosal inflammation characterized, for example, rhinitis (especially allergic rhinitis), hemorrhoids, chronic obstructive pulmonary disease and ulcerative colitis.

[0087] Psoriasis is a chronic inflammatory skin disease with a tendency to relapse (and some patients never recover throughout their lives). The clinical manifestations of psoriasis primarily include erythema and scaling. It can occur all over the body, but is more commonly observed on the scalp and extremities.

[0088] Acne is a follicular (pilosebaceous unit) chronic inflammatory skin disease that is closely associated with major factors such as excessive sebum production, blockage of the pilosebaceous duct (including closed comedones and open comedones), bacterial infection, and inflammatory response. It tends to occur in adolescence and is characterized by polymorphic skin lesions on the face. Therefore, the term acne includes acne vulgaris and rosacea (i.e., rhinophyma).

[0089] Eczema is an inflammatory skin reaction characterized by intense itching, caused by a variety of internal and external factors. It has three phases: acute, subacute, and chronic. In the acute phase, there is a tendency for exudation, while the chronic phase includes infiltration and hypertrophy. The skin lesions are typically itchy and prone to recurrence.

[0090] Dermatitis is a common skin condition characterized by roughness, redness, itching, eczema, and dryness. If left untreated, small patches, persistent ulcers, and pigmented spots caused by dermatitis can develop into basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Dermatitis can be caused by a variety of internal and external infectious or non-infectious factors, including substances (contact dermatitis) or allergies (anaphylactic / atopic dermatitis). This also includes seborrheic dermatitis (seborrheic eczema), cicatricial alopecia and related conditions, and all forms of steroid-dependent dermatitis (including photosensitive seborrheic dermatitis; perioral dermatitis; rosacea-like dermatitis; rosacea, such as steroid-rosacea, steroid-induced rosacea, iatrosacea, rosacea-like steroid dermatitis, topical corticosteroid-induced rosacea-like dermatitis; and more particularly facial corticosteroid-addictive dermatitis (FCAD) or facial corticosteroid-dependent dermatitis (FCDD), characterized by flushing, erythema, telangiectasia, atrophy, papules and / or pustules in the facial area after prolonged use (including uncontrolled use, abuse or misuse) of topical corticosteroids; see, for example, Xiao et al., J. Dermatol. ,2015, 42 , 697-702 and Lu et al., Clin. Exp. Dermatol. ,2009, 35 , 618-621).

[0091] Rhinitis is an irritation and inflammation of the mucous membranes 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 certain animal dander. Surprisingly, it has been found that even when the compounds of the present invention are applied nasally (i.e., to the nasal mucosa), patients with allergic rhinitis treated with the compounds of the present invention experience relief from eye itching.

[0092] Hemorrhoids are swelling caused by inflammation of the blood vessels in or around the rectum and anus. Symptoms include bleeding after bowel movements (i.e., injury), prolapsed hemorrhoids, mucus discharge, and itching, pain, redness, and swelling in the anal area. Hemorrhoids are thought to be a result of increased abdominal pressure, such as as a result of constipation or diarrhea.

[0093] Chronic obstructive pulmonary disease (COPD) is a name for 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 leads to impaired airflow into and out of the lungs. Symptoms of COPD include shortness of breath, expectorant cough, frequent chest infections, and persistent wheezing. The most common cause of the disease is smoking, but other risk factors include high levels of air pollution and occupational exposure to dust, chemicals, and fumes.

[0094] The compounds of this invention can have a positive effect in alleviating erythema, redness and swelling, edema, blisters and bullous pemphigoid caused by various conditions, including those mentioned herein, and can inhibit the exudation of subcutaneous tissue fluid and suppress itching and pain caused by such inflammatory conditions.

[0095] Other inflammatory conditions that may be mentioned include: (a) Mucosal inflammation, such as oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis and enterocolitis (including bacterial dysentery, chronic amoebic dysentery, schistosomiasis, nonspecific ulcerative colitis and regional enteritis), cervicitis and cervical endometritis, endometritis, inflammation caused by inhalation injury, etc., and mucosal inflammation associated with cancers and infections (e.g., viral infections, such as the common cold or influenza) affecting mucosal surfaces (such as those in the oral cavity, nasopharynx, ear, larynx, trachea, gastrointestinal tract, cervix, etc.).

[0096] (b) Orthopedic inflammation associated with, for example, fractures, purulent infections of bones and joints, inflammation caused by rheumatic bone diseases and purulent osteomyelitis (acute, chronic, local, sclerotic, post-traumatic), purulent arthritis; bone tumors (osteosarcoma, osteoid osteoma, chondroma), bone cysts, osteoclastoma, primary osteosarcoma (osteosarcoma, chondrosarcoma, osteofibrosarcoma, Ewing sarcoma, non-Hodgkin's lymphoma, myeloma, chordoma), metastatic bone tumors, bone tumor-like lesions (bone cysts, aneurysmal bone cysts, eosinophilic granulomas, fibrous dysplasia); and rheumatic arthritis.

[0097] (c) Neurological inflammation, such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, intercostal neuritis, etc.

[0098] (d) Subcutaneous and submucosal soft tissue inflammation, such as myositis, ligamentitis, tendinitis, panniculitis, cystitis, lymphadenitis, bubonadentitis, tonsillitis, synovitis, fasciitis, and soft tissue inflammation caused by injury, contusion, or tear of muscles, ligaments, fascia, tendons, synovium, fat, joint capsules, and lymphatic tissue.

[0099] (e) Vascular inflammation, such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis, as well as vascular inflammation associated with vascular carcinoma caused by allergic leukocytoclastic vasculitis, polyarteritis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis.

[0100] (f) Inflammation of internal organs (such as the heart, stomach, intestines, lungs, liver, spleen, kidneys, pancreas, bladder, ovaries, and prostate), including but not limited to pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, spleen, nephritis, pancreatitis, cystitis (including interstitial cystitis), oophoritis, prostatitis, and gastric ulcers.

[0101] (g) Inflammation of the eye and surrounding area, such as conjunctivitis, keratitis (e.g., acute epithelial keratitis, nummular keratitis, interstitial keratitis, discoid keratitis, neurotrophic keratitis, myxomatous keratitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, onchocercal keratitis, superficial punctate keratitis, ulcerative keratitis, exposure keratitis, photokeratitis, and acute red eye from contact lenses), optic neuritis, macular degeneration, retinopathy, etc.

[0102] (h) Inflammation of the gums and mouth, such as periodontitis, gingivitis, oral ulcers, etc.

[0103] (i) Inflammation associated with rheumatic diseases, such as rheumatic vasculitis, 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, etc.

[0104] The compounds of this invention can also be used for the differentiation and regeneration of bone marrow cells and for aplastic anemia (e.g., by systemic and topical application).

[0105] The compounds of this invention can also be used to treat kidney diseases, including end-stage renal disease and its complications (including uremic pruritus).

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

[0107] The compounds of this invention can also be used to treat certain specific respiratory diseases, such as cystic fibrosis, interstitial pneumonia (including common interstitial pneumonia), allergic pneumonia, asbestosis, emphysema, pulmonary heart disease, and pulmonary embolism. A specific disease condition that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0108] Interstitial lung disease (IPF) is a diffuse and fatal interstitial lung disease characterized by alveolar epithelial damage, massive proliferation of pulmonary 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 this invention have been found to be useful for treating IPF and / or alleviating symptoms associated with the disease.

[0109] The compounds of this invention are also particularly useful for treating the following lung and / or fibrotic conditions (whether or not otherwise mentioned herein): pulmonary fibrosis, renal fibrosis, liver fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, status asthmaticus, bronchiectasis, upper respiratory tract infections (including the common cold and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, rickettsial pneumonia, radiation pneumonia, and pneumococcal disease (including Staphylococcus aureus, Streptococcus pneumoniae, etc.). Pneumonia caused by cocci and Gram-negative bacilli, pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis and nocardiosis), pulmonary fungal infections, cryptococcosis, lung abscess, allergic pneumonia, extrinsic allergic alveolitis, pulmonary eosinophilia (including Leoffer's syndrome and eosinophilia), obstructive emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis / acidosis, acute lung injury, interstitial lung disease, empyema, pulmonary fibroma and cor pulmonale.

[0110] The compounds of this invention are useful for specific mucosal disorders and diseases, including, for example, anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, fissures, anal pruritus, anal sinusitis, warts, and rectal prolapse; inflammatory bowel diseases, including Crohn's disease, particularly ulcerative colitis; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as periodontitis.

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

[0112] The compounds of the present invention may also have antipyretic properties, which allow for the treatment of fever and / or relief of its symptoms; for example, by lowering the body temperature of the subject, this results in a reduction of fever. Therefore, the compounds of the present invention and formulations containing them can be considered antipyretics.

[0113] The compounds of this invention are particularly useful for treatment: Skin conditions, including acne, rosacea, dermatitis, seborrheic dermatitis, neurodermatitis, eczema, hyperpigmentation, scarring (fibrosis), hair loss, seborrheic alopecia, cicatricial alopecia, and paronychia; Oral diseases, including periodontitis, gingivitis, oral mucositis (including radiation-induced mucositis), tooth sensitivity, and gingival recession; Gynecological diseases, including vaginitis, vulvitis, leukoplakia of the external genitalia, cervicitis, episiotomy, and radiation vaginitis; and / or Inflammatory bowel disease (IBD) includes ulcerative colitis, proctitis, radiation proctitis, hemorrhoids, and anal cryptitis.

[0114] According to another aspect of the invention, a method is provided for treating inflammation, inflammatory disorders, and / or disorders / conditions characterized by inflammation (e.g., as a symptom), the method comprising administering the compound of the invention or a salt thereof to a patient in need of such treatment.

[0115] To avoid ambiguity, in the context of this invention, the terms “treatment,” “therapeutic,” and “method of treatment” include therapeutic or palliative treatment for patients in need and preventative 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, such as those contrasting with the treatment of any symptoms (e.g., pain and / or inflammation) of any viral infection or disease, which allow for the treatment of viral infections by their very nature, i.e., by interfering with viral replication within the host. Such antiviral properties may also allow for the prevention of the onset of such infections or diseases, protection of host cells from (e.g., further) viral infection, prevention or cessation of the spread of viral infections or diseases (within a single host, or from one host to a new host), or allow for the prevention of viral reactivation after latency in the host.

[0117] According to another aspect of the invention, a method for treating a viral infection is provided, the method comprising administering the compound of the 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 from the following families: Adenoviridae (e.g., adenovirus), Papillomaviridae (e.g., human papillomavirus), Polyomaviridae (e.g., BK virus; JC virus), Herpesvirusidae (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), hepatoviridae (e.g., hepatitis B virus), parvoviridae (e.g., parvovirus B19), astroviridae (e.g., human astrovirus), calicivirusidae (e.g., norovirus; Norwalk virus), pituriviridae (e.g., Coxsackievirus, hepatitis A virus; poliovirus; rhinovirus), coronavirusidae (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; HIV), clovenviridae (e.g., rubella virus), arenaviridae (e.g., Lassa virus), Bunyaviridae (e.g., hantavirus; Crimean-Congo hemorrhagic fever virus; hantavirus). Viruses, including the Filoviridae family (e.g., Ebola virus; Marburg virus; Ravn virus), Orthomyxoviridae family (e.g., influenza viruses, including influenza A viruses (e.g., H1N1 and H3N2 viruses), influenza B viruses, or influenza C viruses), Paramyxoviridae family (e.g., measles virus; mumps virus; parainfluenza virus, respiratory syncytial virus), Rhabdoviridae family (e.g., rabies virus), Hepatitis Viridae family (e.g., hepatitis E virus), Reoviridae family (e.g., rotavirus; circovirus; coltivirus; Banna virus), and viruses not assigned to a family (such as hepatitis D virus).

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

[0120] The compounds of the present invention may further possess antibacterial and / or bacterial inhibitory properties, as in contrast to the treatment of any symptoms (such as pain and / or inflammation) of any bacterial infection or disease, said properties allowing for the treatment of bacterial infections by their very nature, i.e., by interfering with the growth or proliferation of bacteria in the host. Therefore, the compounds of the present invention can be considered bactericides and / or preferably bacterial inhibitors.

[0121] Such antibacterial properties can also allow for the prevention of the onset of such infection or disease, protection of host cells from (e.g., further) bacterial infection, prevention or cessation of the spread of bacterial infection or disease (within a single host or from one host to a new host), or prevention of the reactivation of bacteria after they have been latent in the host.

[0122] According to another aspect of the invention, a method for treating bacterial infections is provided, the method comprising administering the compound of the invention or a salt thereof to a patient requiring such treatment.

[0123] As disclosed herein, the compounds of the present invention may further possess anticancer properties, such as those contrasting with the treatment of any symptoms of cancer (e.g., pain and / or inflammation), which may allow for the treatment of cancer in its essence, i.e., by interfering with cancer. Such anticancer properties may also include prevention of the onset of the disease, for example by treating inflammation and thus preventing its onset.

[0124] According to another aspect of the invention, a method for treating cancer is provided, the method comprising administering the compound of the 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, conjunctivitis, laryngitis, pharyngitis, laryngitis, tracheitis, esophagitis, gastritis, enterocolitis, cervicitis, endometritis, and skin cancer caused by oral mucositis (including severe oral mucositis), rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheal cancer, esophageal cancer, stomach cancer, intestinal cancer, cervical cancer, endometrial cancer, and skin cancer. A specific skin cancer that may be mentioned is basal cell carcinoma.

[0126] Visceral organ fibrosis can be mentioned, including acute and / or severe visceral fibrosis, characterized by excessive accumulation of fibrous connective tissue (as described above) in and around inflamed or damaged tissue. Therefore, the formulations of the present invention can be used to treat or prevent fibrosis (as described above) and the associated morbidity and mortality. Thus, visceral organ fibrosis (e.g., acute and / or severe) that can be treated with the formulations of the present invention includes fibrosis of the liver, kidneys, lungs, cardiovascular system (including the heart and vascular system), pancreas, spleen, central nervous system (neurofibrosis), myelofibrosis, eyes, vagina, cervix, etc.

[0127] Inflammatory conditions of internal organs include any serious condition (i.e., a condition requiring intensive medical treatment) or any condition that can develop into a serious condition, in which some inflammatory component is evident (because it can be characterized by detectable inflammation), and in which the onset is obvious (or anticipated) and / or life-threatening.

[0128] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of visceral organs (i.e., one or more conditions requiring immediate medical intervention or potentially developing into conditions requiring immediate medical intervention), characterized by inflammation (e.g., as a symptom) in one or more visceral organs (including any of the organs mentioned above), such as acute internal injury. By treating such acute inflammatory disorders, the formulations of the present invention can prevent or halt the development of symptoms (acute or chronic) associated with such conditions, and can also halt the progression of morbidity and / or death associated with such conditions.

[0129] Therefore, acute inflammatory conditions that can 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 can be mentioned include acute injury to one or more internal organs (including any of those mentioned above), such as acute lung injury, inhalation injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and multi-organ inflammation, injury, and / or failure.

[0130] Such conditions may be caused by internal or external trauma (e.g., injury or burns), or by infection such as a virus, bacteria, or fungus.

[0131] For example, proctitis (which includes eosinophilic, gonorrheal, and / or ulcerative proctitis) can be caused by inflammatory bowel disease, infection, radiation (e.g., for cancer), medications (such as antibiotics), surgery, or allergic conditions (such as food intolerance).

[0132] For example, multi-organ inflammation, injury, and / or failure can be caused by extensive and / or traumatic external injuries, including traumatic and / or extensive external burns. Traumatic external burns will be understood to include second-degree burns, and more specifically, third-degree and fourth-degree burns. Extensive external burns should be understood to include burns covering at least approximately 10% of the patient's body surface area, such as at least approximately 15%, including at least approximately 20%. External (and internal) burns can be caused by exposure to heat, chemicals, etc.

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

[0134] Therefore, in addition, one or more of the aforementioned (e.g., acute) inflammatory conditions may (and indeed will be very likely in some cases) lead to some form of internal tissue damage and / or dysfunction of related internal tissues. Related tissues include (e.g., mucosal) tissues, such as the respiratory epithelium. Such tissue damage may also cause one or more of the fibrotic conditions mentioned above. For example, SARS disease caused by the novel coronavirus SARS-CoV-2 (2019 coronavirus disease or COVID-19) is known to cause fibrosis in many cases, which is caused by one or more of a variety of factors, including inflammation.

[0135] In this regard, given that such conditions are typically characterized by one or more comorbidities, the compounds of the present invention and their salts are particularly useful in treating related inflammatory and / or fibrotic conditions. By the term "characterized by comorbidities," we assume that the primary condition in question simultaneously causes (and indeed preferably) one or more other medical conditions, including those described above, which may influence each other and / or overlap in some way.

[0136] Therefore, the following is provided: A method for treating at least one inflammatory and / or fibrotic disorder or condition of one or more visceral organs in a patient, the method comprising direct systemic parenteral administration of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment; A method for treating one or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs in a patient, the method comprising direct systemic parenteral administration of the compound of the invention or a pharmaceutically acceptable salt thereof to the patient requiring such treatment; and A method 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, the method comprising direct systemic parenteral administration of the compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0137] In addition, the compounds of the present invention can be used to treat conditions characterized by immunosuppression and immunodeficiency disorders, to treat patients with impaired immune systems, and / or to restore the normal function of a patient's immune system.

[0138] Conditions characterized by immunosuppression (or immunodeficiency disorders) include primary immunodeficiency disorder (PIDD), which is typically a rare congenital disorder that is usually hereditary. Therefore, PIDD includes humoral immune deficiency disorders, such as common variant immunodeficiency diseases, selective immunoglobulin deficiency (e.g., IgA deficiency), transient hypogammaglobulinemia of the newborn, and X-linked agammaglobulinemia; cellular immune deficiency disorders, such as chronic mucocutaneous candidiasis, Digeorg syndrome, and X-linked lymphoproliferative syndrome; combined humoral and cellular immune deficiency disorders, such as ataxia-telangiectasia, hypergammaglobulinemia E syndrome, severe combined immunodeficiency, and Wiskott-Aldrich syndrome; phagocytic immune deficiency disorders, such as Chédiak-Higashi syndrome, chronic granulomatous disease, periodic neutropenia, and leukocyte adhesion deficiency; and complement deficiency disorders, such as complement component 1 (C1) inhibitor deficiency (or hereditary angioedema), C3 deficiency, C4 deficiency, and C5, C6, C7, C8, and / or C9 deficiency.

[0139] However, we prefer that the immunodeficiency disorder treated according to the present invention is secondary immunodeficiency disorder (SIDD), which is more common than PIDD and tends to develop later in life. SIDD includes immunodeficiency disorders caused by secondary factors such as old age, 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 stress and / or psychological stress that may impair a patient's immune system.

[0141] Physical stress can be caused by: trauma (injury, infection, surgery), strenuous physical labor / overexertion (e.g., overtraining), environmental pollution (pesticides, herbicides, toxins, heavy metals, insufficient light, radiation, noise, electromagnetic fields), illness (viral, bacterial, or fungal agents), fatigue, insufficient oxygen supply, hypoglycemia, hormonal and / or biochemical imbalances, dietary stress (nutritional deficiencies, food allergies and sensitivities, unhealthy eating habits), dehydration, substance abuse, dental irritation, and musculoskeletal misalignments / imbalances.

[0142] Mental stress can include a variety of forms of psychological and / or psychosocial stress, such as emotional stress (e.g., negative emotions such as resentment, fear, depression, sadness, anger, grief / anger); cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, attachment, self-criticism, self-loathing, unrealistic perfectionism, anxiety, panic attacks, and often uncontrollable feelings); perceptual stress (beliefs, roles, attitudes, values, meaning and / or purpose); the death / loss of a loved one; relationship difficulties (with a partner, siblings, children, extended family, employer, colleagues); lack of social support (e.g., friends and / or isolation); and financial stress (e.g., due to unemployment, investments, 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; Down syndrome; infections such as viral infections (including chickenpox, cytomegalovirus, EB virus, HIV, and measles) and bacterial infections; diabetes; diseases of internal organs such as chronic kidney disease, nephrotic syndrome, chronic hepatitis, and liver failure; systemic lupus erythematosus; alcoholism and chronic burns; and surgeries such as spleen removal.

[0144] Medications that may cause immunodeficiency in patients include antiepileptic drugs such as lamotrigine, phenytoin, and valproic acid; immunosuppressants such as azathioprine, cyclosporine, everolimus, leflunomide, mycophenolate mofetil, sirolimus, tacrolimus, and tofacitinib; biologics such as abatacept, adalimumab, anaprox, baliximab, cetuzumab, daliximab, etanercept, golimumab, infliximab, ixekizumab, moroximateb (OKT3), nateximab, rituximab, secukinumab, tocilizumab, uterotium tumefaciens, and vedolizumab; and especially corticosteroids, such as naturally occurring corticosteroids including cortisol (hydrocortisone), aldosterone, and corticosteroids. Cortisone, cortisone, pregnenolone, progesterone; and naturally occurring precursors and intermediates in the biosynthesis of corticosteroids; and other naturally occurring derivatives of corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 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, including those of the hydrocortisone type (Group A), such as cortisone acetate and hydrocortisone acetate propionate. Acetate), hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tecortisone and tecortisone neovalerate, prednisolone, methylprednisolone, prednisone, chlorprednisolone, chlorprednisolone alcohol, difluprednisolone, fluocinolone, fluocinolone, flusperidone, fluprednisolone, chlorprednisolone, prednicarbamate and triamcinolone; acetone compounds and related substances (Group B), such as ancinonide, budesonide, desonide, fluocinolone cetonide, fluocinonide, halcinonide, triamcinolone acetonide, cyclosporine, defcodone, formocorta, fluocinolone cetonide, flunisolone cetonide and fluocinolone acetonide;Those of the (beta)methasone type (Group C), such as beclomethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluclomethasone, halometasone, mometasone and mometasone furoate, aclomethasone and aclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, clocotropone, deshydroxymethasone, difluralasone, difluocortolone, fluclochlor, flumethasone, flucodone, fluprednisolone and fluprednisolone acetate, fluticasone, fluticasone furoate and fluticasone propionate, methylprednisolone, peramisone, prednisolone, limexolone and ubetasol; those of the progesterone type, such as fluoroprogesterone, flumethasone, medroxyprogesterone acetate and prebediolone. acetate); and progesterone derivatives (progestins), such as chlordygesterone acetate, cyproterone acetate, medroxyprogesterone acetate, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; as well as other corticosteroids, such as dicambazol and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androst-1,4,6-trien-3-one. Specific corticosteroids that may be mentioned include cortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.

[0145] However, drugs that may cause immunodeficiency in patients can be specifically mentioned, such as chemotherapy treatments for cancer, including alemtuzumab, busulfan, cyclophosphamide, and melphalan.

[0146] Specific SIDDs that can be mentioned include those caused by radiation therapy used to treat barriers such as cancer (i.e., radiation-induced immunosuppression).

[0147] Ionizing radiation not only suppresses the immune system in the ways described above, but can also alter the function of the immune system in irradiated organs in other ways. For example, elevated levels of inflammatory mediators (such as NF-κB and SMAD2 / 3) and cytokines (such as IL-1, IL-2, IL-6, IL-8, IL-33, tumor necrosis factor (TNF-α), transforming growth factor β (TGF-β), and interferon-γ (IFN-γ)) are associated with the release of prostaglandins and free radicals (including reactive oxygen species (ROS) and nitric oxide (NO)). Exposure to high doses of radiation that may occur during accidental exposures (e.g., due to nuclear or radiological disasters) can lead to inflammatory responses and / or trauma that may persist for years thereafter and / or impair the function of irradiated organs.

[0148] The compounds of this invention can not only provide immune recovery but also simultaneously promote wound healing and / or regeneration. This is particularly useful given the fact that trauma associated with radiation-induced immunosuppression and the absence of a normal endogenous inflammatory response is difficult (if not impossible) to treat properly.

[0149] By providing the aforementioned immune-restoring effects, the body's immune system and local inflammatory response can become more effective. In this respect, the compounds of the present invention can also be used to provide anti-inflammatory effects while promoting further wound healing, but in a manner that does not further damage the patient's immune system (i.e., the manner in which corticosteroids are used to treat inflammation).

[0150] According to another aspect of the invention, the use of the compounds of the invention or pharmaceutically acceptable salts thereof in the manufacture of an agent for treating inflammation and / or conditions characterized by inflammation or trauma in patients suffering from or susceptible to conditions characterized by immunosuppression, said treatment including treatment of radiation-induced conditions characterized by inflammation and / or trauma.

[0151] Diseases that are themselves radiation-induced and / or may be caused by radiation-induced immunosuppression (including those characterized by inflammation and / or trauma) include those that may occur after accidental exposure to radiation (often referred to as “radiation poisoning”) or after intentional and / or targeted exposure to radiation (e.g., due to (e.g., ionizing) radiotherapy for treating diseases such as cancer).

[0152] Radiation therapy is a type of treatment, such as cancer treatment, that uses an external beam of high energy to kill cancer cells. Radiation therapy most commonly uses X-rays, but protons or other types of energy can also be used. Radiation therapy can be used as a primary cancer treatment, as neoadjuvant therapy (to shrink cancerous tumors before surgery), as adjuvant therapy (to prevent cancer cell proliferation after surgery), to alleviate symptoms caused by advanced cancer, or a combination of two or more of the above. Radiation therapy can also be used in combination with other treatments, such as chemotherapy.

[0153] Disorders characterized by inflammation and / or trauma of mucous membranes and / or skin, which may be caused by radiation exposure, are often associated with the targeted / irradiated body part. For example: Radiation-induced dermatitis and mucositis can occur, respectively, in the skin or mucous membranes, possibly near the irradiated body part. For example, radiation-induced oral mucositis may occur after irradiation of the head or neck; Radiation-induced encephalitis can also occur after irradiation of the head or neck; and Radiation pneumonia and / or radiation esophagitis are usually caused by radiation therapy for lung cancer, breast cancer, lymphoma, thymic tumors, or esophageal cancer.

[0154] Radiation therapy targeting the abdomen, pelvis, or rectum (e.g., for cervical cancer, prostate cancer, bladder cancer, or rectal cancer) can lead to one or more of the following: radiation enteropathy (or radiation colitis, including radiation colitis and radiation enterocolitis), radiation hepatitis, radiation myelitis, radiation vaginitis, and especially radiation proctitis.

[0155] In particular, radiation proctitis or radiation rectal disease is a condition characterized by damage to the rectum following exposure to radiation during radiotherapy. The inflammation can be acute (acute radiation proctitis and associated radiation colitis) or chronic (e.g., radiation-associated vasodilation (RAVE) and chronic radiation rectal disease).

[0156] The initial symptoms of acute radiation proctitis include pelvic pain, diarrhea, and tenesmus, but radiation damage to the rectum usually causes incontinence and rectal bleeding, and severe cases can lead to trauma, stenosis, and / or fistulas.

[0157] Therefore, in the treatment of disorders caused by irradiation (more particularly, irradiation of the lower abdominal region) used for, for example, cancer therapy, the compounds of the present invention and their salts can be used to: Provides immune restoration while treating trauma associated with this disorder and / or promoting the recovery and / or healing of said trauma; and / or It provides a more direct anti-inflammatory effect without further damaging the patient's immune system, and can also be used to promote further wound healing.

[0158] According to two other aspects of the invention, the following is provided: A method for treating radiation-induced conditions characterized by (i) immunosuppression and (ii) inflammation and / or trauma; and A method for treating patients with inflammation and / or trauma associated with radiation-induced immunodeficiency disorders, while restoring normal immune system function. The method includes administering the compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need.

[0159] The treatments and uses described above are particularly useful when the irradiation-induced disorder, as described above, is caused by irradiation of the lower abdominal region, such as in cancer therapy.

[0160] A further provision provides a method for reducing the incidence of radiation-related morbidity and / or death (e.g., ionizing radiation-induced disorders) in patients characterized by inflammation and / or trauma, the method comprising administering the compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0161] Conditions in which the compounds of the present invention are found to be particularly useful include skin inflammation, physiological responses resulting from skin inflammation and / or wound healing processes such as scarring and melanin deposition; scalp and hair follicle inflammation and fibrosis, including seborrheic dermatitis, conditions characterized by pathological hair loss (including scarring alopecia and related conditions such as seborrheic alopecia and fibrotic alopecia); gastritis, gastric ulcers, and stress-induced gastritis; GERD; IBD, including Crohn's disease, ulcerative colitis and / or proctitis, radiation proctitis; arthritis; macular degeneration; 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, multi-organ injury, and / or viral infections.

[0162] In addition, the compounds of this invention can be used in non-therapeutic cosmetic treatments, such as anti-aging.

[0163] Therefore, another aspect of the invention is the non-therapeutic use of the compounds of the invention in anti-aging, for example by promoting skin integrity in a way that gives the skin a more youthful appearance.

[0164] Another aspect of the invention is a cosmetic composition comprising the compounds of the invention. Such a composition can provide anti-aging properties.

[0165] "Patients" include reptile patients, avian patients, and preferred mammalian (especially human) patients.

[0166] According to the present invention, the compounds of the present invention are preferably administered topically or systemically, for example, orally, intravenously or intra-arterially (including via intravascular and other perivascular devices / dosage forms (e.g., stents)), intramuscularly, through the skin, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, intravaginally, intradermally, transdermally, via the nose, via the lungs (e.g., trachea or bronchi), for example by direct injection or by any other parenteral route, preferably topically, or by any other parenteral route, in the form of a pharmaceutical preparation comprising one or more of the compounds, in one or more pharmaceutically acceptable dosage forms.

[0167] When the condition to be treated is rhinitis or inflammation caused by a viral infection of the airways (e.g., an upper respiratory tract infection, such as the common cold and influenza), inhalation (e.g., nasal administration) is particularly useful.

[0168] Lung administration is particularly useful when the condition to be treated is COPD or IPF. Topical application can be enhanced by producing a spray containing the active ingredient, for example by using a powder aerosol or by using appropriate nebulization techniques or devices (such as a nebulizer) with the aid of water mist.

[0169] When the condition to be treated is hemorrhoids or ulcerative colitis, rectal administration is particularly useful, using appropriate means of delivery such as injectable foam solutions or suppositories.

[0170] Administration to the lower gastrointestinal tract can also be achieved via parenteral delivery, particularly via oral delivery, using standard delayed or extended release coating techniques known to those skilled in the art. Specifically, different portions of the upper or lower intestine can be targeted. For example, colonic administration can also be achieved using a drug delivery method that initially targets the colon via oral or parenteral administration.

[0171] In an alternative, the compounds of the present invention can be administered via direct systemic parenteral administration. This administration can be used in methods for treating one or more of the aforementioned disorders or conditions affecting one or more internal organs of a patient.

[0172] The compounds of the present invention are preferably administered by intradermal injection, inhalation, or by topical application (such as on the skin or mucous membrane surface (such as oral mucosa, ocular mucosa, nasal mucosa, vaginal mucosa, rectal mucosa, colonic mucosa, esophageal mucosa), throat, or around the teeth, gums, and / or teeth).

[0173] Internal organs that may be mentioned include the stomach, intestines, pancreas, liver, spleen, bladder, vascular system, ovaries, prostate, with the heart and kidneys being preferred, and the lungs being even more preferred.

[0174] Standard delayed-release or extended-release techniques known to those skilled in the art can be used for administration methods other than oral administration, such as subcutaneous or intramuscular reservoir formation techniques or alternative methods via parenteral administration.

[0175] Therefore, pharmaceutically acceptable formulations for the aforementioned routes of administration may comprise the compounds of the present invention mixed with pharmaceutically acceptable adjuvants, diluents, or carriers, which may be selected with due consideration to the intended route of direct parenteral administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may be free of harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate or modulated release to the compounds of the present invention.

[0176] Therefore, formulations for injection may be in the form of aqueous formulations, such as suspensions and / or more preferably solutions (e.g., (optionally) buffered aqueous formulations (e.g., solutions), such as formulations containing physiological saline (e.g., solutions), phosphate formulations (e.g., solutions), acetate formulations (e.g., solutions), or borate formulations (e.g., solutions), or lyophilized powders that can be reconstituted with a medium (such as an aqueous medium) prior to use (e.g., injection).

[0177] Formulations for injection may include other suitable excipients known to those skilled in the art, such as solvents (e.g., water), cosolvents, solubilizers (e.g., cyclodextrin), wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, swelling agents, and / or protective agents.

[0178] Preparations for injection are preferably buffered to a physiologically acceptable pH value (e.g., pH between about 4.5 and about 9.5, such as between about 6 and about 9, such as between about 6.5 and about 8.5) using standard techniques, and / or may further contain a tension modifier (such as sodium chloride).

[0179] While the preferred delivery methods described above for the compounds of the present invention include topical application to sites of inflammation (e.g., mucous membranes, including oral and / or nasal mucosa, lungs, anorectal region and / or colon), or more preferably skin, using suitable (e.g., pharmaceutically acceptable and topically acceptable) media and / or commercially available formulations suitable for application to the skin and / or appropriate mucosal surfaces, they may also include oral, intravenous, skin or subcutaneous, nasal, intramuscular, intraperitoneal or pulmonary delivery.

[0180] Injection is particularly useful for applying the compounds of the invention in the form of a suspension solution to, for example, the dermis (e.g., intradermal injection), joint cavity, or eye.

[0181] Intradermal injection (e.g., intradermal administration) is particularly useful for applying the compounds of the invention, in solution or suspension form (e.g., dermal fillers), into the dermis. This is particularly useful as a means of administration for the treatment of melanin pigmentation as described above, or for the use of the compounds of the invention in the treatment of, for example, wrinkles.

[0182] Injection is particularly useful for filling (e.g., surgical sites in the nasal cavity, anal fistulas, spaces between the gums and tooth roots, or sinuses). It is especially useful for shaping support and / or lubrication.

[0183] The compounds of the present invention are typically administered in the form of one or more pharmaceutical formulations, for example, mixed with (e.g., pharmaceutically acceptable) adjuvants, diluents, or carriers, the form of which may be chosen appropriately taking into account the intended route of administration (e.g., topical application to the relevant mucous membranes (including the lungs) or preferably 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 be free of harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate or modulated release to the compounds of the present invention.

[0184] Suitable pharmaceutical formulations may be commercially available or prepared in other ways according to techniques described in literature, such as Remington. The Science and Practice of Pharmacy , 22nd edition, Pharmaceutical Press (2012) and Martindale - The Complete Drug Reference, The 38th edition of Pharmaceutical Press (2014) and the documents mentioned therein, all of which contain relevant disclosures, are hereby incorporated by reference. In other respects, those skilled in the art can, without inventive step, prepare suitable formulations comprising the compounds of the present invention using conventional techniques.

[0185] The compounds of the present invention may be in the form of aqueous formulations such as emulsions, suspensions and / or solutions (e.g., (optionally) buffered aqueous formulations (e.g., solutions), formulations such as those containing physiological saline (e.g., solutions), formulations containing phosphate (e.g., solutions), formulations containing acetate (e.g., solutions) or formulations containing borate (e.g., solutions)) or lyophilized powders.

[0186] The compounds of the present invention can be further and / or combined with suitable excipients in alternative embodiments to prepare: Gel formulations (for said gel formulations, suitable gel matrix materials include cellulose derivatives, carbomer and alginate, tragacanth gum, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulose polysaccharides, sugars (such as glucose), glycerol, propylene glycol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and especially hyaluronic acid); Detergents (for the detergents, suitable matrix materials include cellulose derivatives, glycerol, non-cellulose polysaccharides, polyethylene glycol and propylene glycol of different molecular weights); Paste or ointment (for the paste or ointment, suitable paste base materials include glycerin, petrolatum, paraffin, polyethylene glycol of different molecular weights, etc.); Creams or foams (for said creams or foams, suitable excipients (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycol of varying molecular weights, sodium lauryl sulfate, sodium fatty alcohol polyoxyethylene ether sulfonate, corn gluten flour, and acrylamide); Powdered aerosols (for said powdered aerosols, suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol, and polysorbate, such as dry powder inhalers); and / or Liquids for oral, inhalation, or facial use, such as mouthwash, water (aerosol) sprays (for said liquids, suitable excipients include viscosity modifiers such as hyaluronic acid, sugars (such as glucose and lactose), emulsifiers, buffers, alcohols, water, preservatives, sweeteners, flavorings, etc.). Injectable solutions or suspensions (which may be aqueous or other forms, and for which suitable excipients include solvents and cosolvents, solubilizers, wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers and / or pH adjusters, fillers, protectants and tension modifiers) may be mentioned. Specific injectable solutions or suspensions may include dermal fillers (i.e., injectable fillers or soft tissue fillers), particularly when the compounds of the present invention are combined with hyaluronic acid.

[0187] Oral tablets (for oral tablets, suitable excipients include binders such as syrup, gum arabic, gelatin, sorbitol, astragalus gum, cellulose, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants such as sodium lauryl sulfate).

[0188] Depending on the circumstances, such formulations may also include humectants such as glycerol, glycerin, polyethylene glycol, trehalose, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic / caprylic triglycerides, etc.; and / or antioxidants such as vitamins and glutathione; and / or pH adjusters such as acids, bases, and pH buffers. In addition, surfactants / emulsifiers may be included, such as cetyl alcohol, fatty acids (e.g., stearic acid), sodium lauryl sulfate, sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerol esters (e.g., glyceryl monostearate), polyethoxylated alcohols, polyvinyl alcohol, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, and polyethylene glycol glyceride. Lauryl dimethylamine oxide, bile salts (e.g., sodium deoxycholate, sodium cholate), lipids (e.g., fatty acids, glycerol lipids, glycerophospholipids, sphingolipids, sterols, prenol, saccharolipids, polyketides), phospholipids, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), glycolipids, polysorbates, etc.; preservatives, such as phenoxyethanol, ethylhexylglycerin, etc.; and thickeners, such as acryloyl dimethyl taurate / VP copolymer. Particularly, especially in cream formulations, stearic acid, glyceryl monostearate, hexadecyl alcohol, sorbitan stearate, cetyl alcohol, caprylic / capric glyceride, etc., may be included.

[0189] The compounds of the present invention, and formulations comprising them (e.g., pharmaceuticals) (e.g., aqueous solutions, gels, creams, ointments, lotions, foams, pastes, and / or dry powders as described above), can be further combined with suitable matrix materials to prepare dressings or therapeutic patches for application on biological surfaces, such as skin or mucous membranes. Thus, such formulations can be used to impregnate matrix materials, such as gauze, nonwoven fabrics, or silk paper. Alternatively, therapeutic patches can be, for example, adhesive bandages, face masks, eye masks, hand masks, foot masks, etc.

[0190] Vaseline can be used to apply such dressings to wounds, but we have also found that PEG-based ointments (e.g., PEG 400) can be combined with matrix materials to prepare dressings without the use of Vaseline.

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

[0192] The compounds of this invention can be administered by inhalation as suspensions, dry powders, or solutions. Suitable inhalation devices include pressurized metered-dose inhalers (pMDIs) (which can be manually or respiratory-actuated and can be used with or without a standard spacer device), dry powder inhalers (DPIs) (which can be single-dose, multi-dose, and power-assisted), and soft mist inhalers (SMIs) or nebulizers (whereby aerosolized medications in the form of a fine mist are delivered at a slower rate than when a nebulizer is delivered using, for example, a pMDI).

[0193] In pMDI, the compounds of the present invention can be administered as a pressurized suspension of micronized particles distributed in a propellant (e.g., an HFA along with excipients such as mannitol, lactose, sorbitol, etc.) or as an ethanol solution to deliver one or more doses between about 20 μL and about 100 μL per actuation. Actuation can be achieved manually (e.g., by pressing) or by inhalation (breath actuation), which involves a spring-driven flow triggering system.

[0194] In a DPI (Digital Inhalation Product), the compounds of the present invention can be administered as micronized drug particles (between about 1 μm and about 5 μm in size) within a capsule (alone or blended with a larger particle size inactive excipient (e.g., mannitol)), which can be pre-loaded or manually loaded into the device. Inhalation from a DPI can depolymerize the drug particles and disperse them within the airway.

[0195] In SMI, the compound of the present invention can be stored as a solution in a cartridge loaded into the device. A spring releases the dose into a micro-pump, such that when a button is pressed, the dose is released, thereby releasing a jet of the drug solution.

[0196] The compounds of the present invention can also be administered in the form of a fine mist of atomized solution using various nebulizers. Nebulizers may include breath-enhanced jet nebulizers (where an airflow moves through the jet with the assistance of a compressor, thereby atomizing the drug solution); breath-actuated jet nebulizers (where, after inhalation by a patient, an airflow moves through a tube with the assistance of a compressor, thereby atomizing the drug solution); ultrasonic nebulizers (where piezoelectric crystal vibration causes atomization by heating); and vibrating screen nebulizers (where a piezoelectric crystal vibrates a screen to cause atomization to obtain very fine droplets, while the temperature of the solution does not change significantly during atomization).

[0197] According to another aspect of the invention, a method for preparing a pharmaceutical composition / formulation as defined herein is provided, the method comprising combining a compound of the invention as defined above with one or more pharmaceutically acceptable excipients as defined above.

[0198] The compounds of the present invention can also be combined with one or more growth factors in treatment, said growth factors being selected from platelet-type 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 factor (IL-1, IL-3), erythropoietin (EPO), and colony-stimulating factor (CSF).

[0199] According to another aspect of the invention, a composition (e.g., a pharmaceutical) is provided comprising the compound of the invention and one or more pharmaceutically acceptable excipients, such as adjuvants, diluents, or carriers. Preferred formulations are suitable for topical application, for example, to mucous membranes (including oral and / or nasal mucosa, lungs, anorectal region, and / or colon) or more preferably to the skin, and therefore comprise topically acceptable adjuvants, diluents, or carriers.

[0200] Therefore, further provided are pharmaceutical compositions comprising the compounds of the present invention that are suitable for, adapted to and / or packaged for, and presented for topical application (e.g., to mucous membranes, including oral and / or nasal mucous membranes, lungs, anorectal regions and / or colon, or preferably to the skin), and the use of such formulations in treating disorders comprising inflammation, inflammatory disorders and / or conditions characterized by inflammation (e.g., as symptoms) by means of direct topical application of said formulations (e.g., to mucous membranes, including oral and / or nasal mucous membranes, lungs, anorectal regions and / or colon, or preferably to the skin).

[0201] Regarding this aspect of the invention, for the avoidance of doubt, topical formulations containing compounds of the invention can be used for any and all conditions described herein, including (as mentioned, defined, or described above) in the treatment of any and all inflammatory disorders and / or in the treatment of any and all conditions characterized by inflammation. Similarly, any and all topical formulations containing compounds of the invention mentioned herein include any and all of those mentioned, defined, or described herein. Any and all of the relevant disclosure herein, in connection with this aspect of the invention, is hereby incorporated by reference.

[0202] Topical formulations containing the compounds of the present invention (e.g., liquid-based or solution-based formulations, e.g., aqueous) can be particularly used for wound healing and can relieve pain (including aches) and, in particular, pruritus / itching associated with the wound itself and the wound healing process. Such topical formulations containing the compounds of the present invention can be particularly used to prevent and / or inhibit fluid exudation from the wound, especially during the acute inflammatory phase, such as during the first 48 hours after a burn or wound. This prevents the risk of infection and other physiological reactions. Such topical formulations containing the compounds of the present invention can also be particularly used to prevent and / or inhibit scar formation and melanin deposition (see above), whether or not related to the wound or other aspects.

[0203] The compounds of this invention can be applied continuously or intermittently. The method of application can also be determined by the timing and frequency of application, but in the case of therapeutic treatment of inflammation, it also depends on the severity of the condition.

[0204] Depending on the impairment, the patient to be treated, and the route of administration, the compounds of the present invention can be administered to patients in need at different therapeutically effective doses.

[0205] Similarly, the amount of the compounds of the present invention in the preparation will depend on the severity of the condition and the patient to be treated, but can be determined by a person skilled in the art.

[0206] In any case, medical practitioners or other skilled personnel will be able to routinely determine the actual dose most suitable for an individual patient based on the severity of the condition and the route of administration. The doses mentioned herein are general examples; of course, there may be individual cases where a higher or lower dose range should be used, and such cases are within the scope of this invention.

[0207] The dosage can be administered between once and four times daily (e.g., three times).

[0208] In all cases, the appropriate concentration of the compounds of the present invention in aqueous products, calculated as free (non-salt) compounds, can be from about 0.01 (e.g., about 0.1) to about 15.0 mg / mL.

[0209] In all cases, the appropriate topical dose of the compounds of the present invention, calculated as free (non-salt) compounds, is from about 0.05 μg to about 50 μg / cm³. 2 Treatment area, such as about 0.1 μg (e.g., about 0.5 μg) to about 20 μg / cm². 2 Treatment area, ranging from approximately 1 µg to approximately 10 µg / cm² 2 Treatment area, such as approximately 5 µg / cm² 2 Within the range of the processing area.

[0210] Appropriate doses of the compounds of the invention for nasal administration (e.g., by inhalation) are in the range of about 0.01 µg to about 2000 mg, for example, between about 0.1 µg and about 500 mg, or between 1 µg and about 100 mg. Specific doses for nasal administration that may be mentioned include doses between about 10 µg and about 1 mg, particularly about 0.1 mg (i.e., about 100 µg). Nasal administration of about 0.1 mg / day of the compounds of the invention has been found to be particularly effective in the treatment of conditions associated with inflammation of the nasal passages and mucous membranes (such as rhinitis (e.g., allergic rhinitis)) and / or conditions associated with sinus surgery.

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

[0212] We prefer that the pH value of the formulation containing the compound of the present invention is in the range of about 1.0 to about 9.0 (e.g., about 3.0 to about 8.0).

[0213] In any case, within the context of this invention, the dosage administered to mammals, particularly humans, should be sufficient to produce a therapeutic response in mammals within a reasonable timeframe (as described above). Those skilled in the art will recognize that the exact dosage and composition, as well as the selection of the most appropriate delivery method, will also be particularly influenced by: the pharmacological properties of the formulation, the nature and severity of the condition being treated, the recipient's physical condition and mental acuity, the age, condition, weight, sex, and response of the patient to be treated, the stage / severity of the disease, and genetic differences between patients.

[0214] The compounds of this invention can be used in human and animal medicine. In this respect, and as stated above, the compounds of this invention that possess appropriate levels of relevant pharmacological (or biological) activity can be used in human and / or animal medicine.

[0215] Some compounds of the present invention, particularly those of Formula I, may have adhesive properties in addition to the above-described biological activities and / or have adhesive properties in lieu of the above-described biological activities.

[0216] These adhesion properties stem from the fact that the relevant W and / or U groups can cross-link to form a three-dimensional network.

[0217] The compounds of this invention can adhere to a variety of substrates, including inorganic substrates (such as glass, metal, etc.) and organic substrates (such as biological tissues).

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

[0219] The compounds of this invention can form a film on the surfaces of various skin and mucous membrane wounds, such as burns, scalds, ulcers, frostbite, and bedsores, to aid in recovery. These compounds can also be used in surgical procedures, such as for the closure of surgical incisions, adhesion of fractured bone, adhesion of mucous membranes, and coatings for human implants such as artificial bone, cartilage scaffolds, periosteum, artificial joints, dental implants, occlusive stents, spinal fusion devices, spinal spacers, and organ patches.

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

[0221] As discussed above, naturally occurring MAPs are known for their adhesive properties. However, it should be remembered that such adhesive properties may stem from the fact that they are high-molecular-weight linear peptides that can exist in multiple conformations, enabling intermolecular and intramolecular reactions / crosslinking of DOPA residues in the molecule and thus achieving adhesion. In contrast, the compounds of the present invention as defined above are not linear peptides or proteins, but rather, for example, low-molecular-weight residues with multiple branches, and surprisingly, properties similar to those of naturally occurring MAPs (both adhesive and biological properties) have been observed.

[0222] Such crosslinking can be achieved by a variety of chemical means (e.g., iodine vapor, glutaraldehyde, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC / NHS), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) or other water-soluble condensing agents) or 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 have, they can in any case (and / or may further) be combined with an active pharmaceutical ingredient in a combination therapy (as described below), or function as a pharmaceutically acceptable excipient (e.g., adjuvant, diluent or carrier) or a part thereof, as part of a medical device and / or as part of a drug-medical device combination.

[0224] Certain compounds of the present invention can therefore be described as novel multifunctional excipients that can be used in a variety of applications in the pharmaceutical field. In this respect, such compounds of the present invention include those that can be used as adhesives and / or as film-forming agents (as described above), and furthermore, such compounds of the present invention and / or different compounds of the present invention can alternatively and / or additionally be used as delayed-release polymers, as adhesives, as suspending agents, as gelling agents, as coating agents, as diluents, or as carriers of active ingredients (pharmaceuticals) of various solubilities.

[0225] The compounds of this invention, particularly suitable for use as pharmaceutical excipients, are suitable for large-scale production and may not pose significant toxicity risks, and therefore can be described and listed as “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration (FDA).

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

[0227] According to another aspect of the invention, a pharmaceutical formulation is provided comprising an active pharmaceutical ingredient mixed with a pharmaceutically acceptable excipient system (such as a pharmaceutically acceptable adjuvant, diluent, or carrier system), the excipient system comprising one or more compounds of the invention.

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

[0229] When used as part of or as a component of a medical device or a pharmaceutical-medical device combination, those skilled in the art will understand that the relevant compounds of the present invention will be used in human or animal medicine, optionally in combination with an active pharmaceutical ingredient, in a manner that affects the structure and / or one or more functions of the human or animal body, and will achieve its primary intended purpose without the need for chemical action in or on said human or animal body (optionally in a manner that does not depend on the metabolism of the compounds of the present invention to achieve any of its primary intended purpose).

[0230] In this respect, the compounds of the present invention can be combined with a variety of known pharmaceutically active ingredients, and can be combined in this way regardless of whether the compounds of the present invention are used: In combination therapy, it can be used as a standalone pharmaceutically active ingredient. As a medical device or as part thereof; As a drug-medical device combination or as a medical device component of a drug-medical device combination; or As a pharmaceutically acceptable excipient.

[0231] Such patients may also be (and / or may already be) receiving therapy based on the administration of one or more of these other known pharmaceutically active ingredients, which we mean by receiving a prescription dose of one or more of the active ingredients mentioned herein before, in addition to and / or after treatment with the compounds of the present invention.

[0232] Pharmaceutically active agents that can be co-administered with the compounds of the present invention include any agent or drug capable of producing a physiological effect (whether therapeutic or preventive against a particular disease state or symptom) in a living subject (including, in particular, mammals and especially, human subjects (patients)).

[0233] Furthermore, the compounds of the present invention (such as those that can be crosslinked as described above) can be used as pharmaceutical excipients and can be mixed with such pharmaceutically active ingredients before or after the crosslinking and / or at least partial crosslinking described above to form a stable pharmaceutical composition, wherein the compounds of the present invention act as excipients, such as carriers. When used in this manner, it can be found that the compounds of the present invention can actively 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] Pharmaceutically active agents that can be used with the compounds of the present invention may be selected, for example, from anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antibacterial agents, antiviral agents (e.g., protease inhibitors), anesthetics and wound healing agents (e.g., growth factors).

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

[0236] Non-limiting examples of anti-inflammatory drugs that may be used include those used in the treatment of the following conditions: rheumatic diseases and / or arthritis (such as diclofenac, betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodoxic acid, meclofenamic acid, salicylates, methylprednisolone, and piroxicam); osteoarthritis (such as sulindac, meloxicam, fenoprofen, etodoxic acid, and nabumetone); inflammation and its symptoms, such as fever, pain, itching, and / or swelling (such as meclofenamic acid, indomethacin, aspirin, ketorolac, fluomethoate, clotiprednisolone, hydrocortisone, fluomethoate, bromofenac, prednisolone acetate, indomethacin, and ibuprofen); allergic reactions and their symptoms (such as pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, lodoxamide, piriformide, oxymetazoline, ketotifen, naphazoline, and emetic fumarate). Olopatadine, azelastine, tranilastine, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudoephedrine, fexofenadine, terfenadine, loratadine, and alexis; respiratory diseases, including asthma and / or COPD (such as budesonide, ciroxonide, nedolome, dexamethasone, ambroxol, and proxetine); skin diseases (such as mometasone, triamcinolone, desonide, sulfacetamide, talolimer, allantoin, and triamcinolone); mastocytosis (such as cromoglycine); gout (such as diclofenac and febuxostat); conjunctivitis (such as hydroxybenzylazole, pranoprofen, and zinc sulfate); eye diseases (such as dextran 70, terfenadine / triiodothyronine, and eye extracts), known or commercially available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.

[0237] Anti-inflammatory drugs that may be mentioned include endogenous (and / or exogenous) lipid-based pro-remission, anti-inflammatory molecules or mediators, such as lipoxygenin, remissionin, and protectin. Pro-inflammatory agents that may be mentioned include prostaglandins (e.g., latanoprost, prostacyclin E1, and prostacyclin E2) and leukotrienes (e.g., leukotriene B4).

[0238] Non-limiting examples of antibacterial drugs that may be used include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampin, fenofibrate, gentamicin, cetirizine, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, clindamycin, metronidazole, azithromycin, sulfamidone, sulfamethoxazole, acetaminophen, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, cephalexin, moxifloxacin, any known or commercially available pharmaceutically acceptable salt of the foregoing drugs, and any combination of the foregoing compounds and / or salts.

[0239] Non-restricted examples of antiviral drugs that may be used include tobramycin, ribavirin, acyclovir, morpholine guanidine, foscarnet, ganciclovir, idoxuridine, trifluuridine, brivudine, vidarabine, entecavir, telbivudine, foscarnet, zidovudine, norinosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, nevirapine, deraviridine, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, ampranavir, lopinavir, ritonavir, atazanavir, fosamprenavir, and tipranavir. Darunavir, terabhivir, boceprevir, cimetvir, asunaprevir, raltegravir, elvitegravir, dulutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviro, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir dipivoxil, fomivirsin, prodafiloyl, imiquimod, sinecatechin, interferon-α2b (recombinant, human), any known or commercially available pharmaceutically acceptable salts of the foregoing drugs, and any combination of the foregoing compounds and / or salts.

[0240] Non-limiting examples of anesthetic agents that may be used include articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, promocaine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, and any known or commercially available pharmaceutically acceptable salts of the foregoing drugs, as well as any combination of the foregoing compounds and / or salts.

[0241] Non-limiting examples of wound healing agents that may be used include basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, human; yeast), rhEFG (I), acidic 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, carraghenate, aminoiodide peptide, and any known or commercially available pharmaceutically acceptable salts of the foregoing drugs, as well as any combination of the foregoing compounds and / or salts.

[0242] Such pharmaceutically active ingredients include those that can be applied topically to the skin or mucous membranes, for example, together with the compounds of the present invention. In this regard, preferred active ingredients from the above list include cyclosporine, chondroitin, clotipreno, flumethonone, bromofenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, emetine fumarate, olopatadine, azelastine, tranilastine, levocabastine, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, alexis, dexamethasone, ambroxol, sulfacetamide, tacrolimus, allantoin, triamcinolone, cromoglycine, naldrolone Miconazole, Diclofenac, Hydroxybenzazole, Pranoprofen, Zinc Sulfate, Dextran 70, Thyroxine / Isothrolone, Ophthalmic Aminopeptide, Chloramphenicol, Ofloxacin, Levofloxacin, Tobramycin, Norfloxacin, Ciprofloxacin, Lomefloxacin, Lincomycin, Fluconazole, Enoxacin, Furazolidone, Nitrofurazone, Rifampin, Nomicin, Gentamicin, Cetirizine Chloride, Neomycin, Roxithromycin, Silver Sulfadiazine, Clarithromycin, Sulfamethoxazole, Chloramphenicol, Tobramycin, Ribavirin, Acyclovir, Moroxydine, Foscarnet, Ganciclovir, Interferon-α 2b (recombinant, human), articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, promocaine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, human; yeast), rhEFG (I), acidic fibroblast growth factor (recombinant, human), granulocyte-macrophage stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, vitamin A-like substances, calf blood deproteinized extract, carrageenan, aminoiodide peptide, and any known or commercially available pharmaceutically acceptable salts of the foregoing drugs, and any combination of the foregoing compounds and / or salts.

[0243] Other pharmaceutically active ingredients that can be co-administered with the compounds of the present invention include those that can be administered to treat one or more of the gastrointestinal disorders mentioned above.

[0244] Non-restrictive examples of gastrointestinal drugs include oxalazine, sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, live Bacillus species (such as Clostridium butyricum, Bacillus licheniformis, Bacillus cereus), probiotics (such as Bifidobacterium), tegafur, nifuratel, amoxicillin, ampicillin, nystatin, allicin, cefadroxil, dacronin, carmoflurane, fluorouracil, mosapride, thrombin, pantoprazole, cimetidine, cisapride, and ethylenediamine diacetamide. diacetamine, nimostatin, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azasetron, lentinan, bismuth salts combined with, for example, magnesium salts (e.g., aluminates, potassium citrate), magnesium trisilicate, bicarbonate, vitamin U, aluminum hydroxide, belladonna extract, famotidine and calcium carbonate, magnesium hydroxide, aluminum magnesium carbonate, proton pump inhibitors (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, or esomeprazole), glycine, trypsin, allantoin, aluminum hydroxide, L-glutamine guanylate, rebampette, rotundine, quxipite, lafutidine, thymoprotein, hericium The following are listed as pharmaceutically acceptable salts: erinaceus, esolamide maleate, nizatidine, L-glutamine and sodium azulene sulfonate (guanidinium sodium), ranitidine, bismuth citrate, lactobacillus, bisacordine, dimethicone, Clostridium butyricum, loperamide hydrochloride, dibazol, secnidazole, zinc acephate, montmorillonite, tegafur / gemeracil / oteracil, famotidine, oteracil, desoxyfluorouridine, capecitabine, and any of the aforementioned drugs that are known or commercially available.

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

[0246] Anti-inflammatory agents that can be used in combination with the compounds of the present invention in the treatment of inflammation include therapeutic agents that can be used to treat inflammation and / or diseases characterized by inflammation as one of their symptoms (including those described above). Depending on the condition to be treated, such anti-inflammatory agents may include NSAIDs (e.g., aspirin), aminosalicylates (e.g., 5-aminosalicylic acid (mesalazine)), leukotriene receptor antagonists (e.g., montelukast, prolucast, and zafirlucast), corticosteroids, analgesics, and certain enzymes (such as trypsin), for example, as described below. The compounds of the present invention may also be combined with leukotrienes (e.g., cysteyl leukotrienes 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 (generally used to treat inflammation) and trypsin (for treating mucosal inflammation associated with, for example, viral infections).

[0248] The compounds of the present invention can also be combined with other therapeutic agents, which are known to produce inflammation as a side effect when applied.

[0249] The conjugates of the present invention can also be combined with stem cells (e.g., totipotent stem cells, pluripotent stem cells (such as embryonic or induced pluripotent stem cells), pluripotent stem cells (such as mesenchymal stem cells), oligopotent stem cells (such as hematopoietic stem cells), or unipotent stem cells (such as muscle stem cells)).

[0250] Other known pharmaceutically active ingredients can also be used in combination with the compounds of the present invention in various ways.

[0251] For example, the compounds of the present invention can be “combined” with the said (or other) pharmaceutically active ingredients (or “therapeutic agents”) for administration together in the same (e.g., pharmaceutical) formulation, or individually (simultaneously or sequentially) in different (e.g., pharmaceutical) formulations.

[0252] Therefore, such combination products provide for the combined administration of the compound of the present invention with the said (or other) therapeutic agents, and can therefore be presented as individual formulations, wherein at least one of these formulations contains the compound of the present invention and at least one contains the said (or other) therapeutic agent, or can be presented (i.e., formulated) as a combination formulation (i.e., presented as a single formulation containing the compound of the present invention and the said (or other) therapeutic agent).

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

[0254] In another aspect of the invention, a method is provided for preparing a combination formulation (1) as defined above, the method comprising combining the compound of the invention, other pharmaceutically active ingredients and at least one (e.g., pharmaceutically acceptable) excipient.

[0255] In another aspect of the invention, a method is provided for preparing a kit (2) as defined above, the method comprising combining components (A) and (B). As used herein, references to combining are intended to make the two components suitable for combined administration with each other.

[0256] Therefore, regarding the method for preparing a kit as defined above, the two components comprising the kit can be "combined" with each other: (i) provided individually (i.e., independently of each other), the individual formulations being subsequently put together for combined use in combination therapy; or (ii) Packaged and presented together as individual components of a “combination pack” for use in combination therapy.

[0257] Therefore, a complete kit is further provided, the complete kit comprising: (I) One of components (A) and (B) as defined herein; and (II) Instructions for using the component in combination with another of the two components.

[0258] Regarding the aforementioned kits, although the compounds of the present invention may be provided as formulations (e.g., pharmaceutical preparations) mixed with one or more other pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers), they are not provided with such other pharmaceutically acceptable excipients when the purpose of providing the compounds of the present invention is primarily to function as a medical device or excipient. In any case, it is preferred that the (other) pharmaceutically active ingredients of the kit be provided as pharmaceutical preparations mixed with pharmaceutically acceptable adjuvants, diluents, or carriers.

[0259] To provide repeated dosing, the kits described herein may contain more than one appropriate amount / dose of the compound of the present invention (e.g., a formulation containing it), and / or more than one appropriate amount / dose of other pharmaceutically active ingredients (e.g., a formulation containing it). If there are more than one formulation containing an amount / dose of any of the aforementioned substances, they may be the same or different in terms of the dosage of any compound, one or more chemical compositions, and / or one or more physical forms.

[0260] Regarding the kits described herein, “in combination with” includes the sequential, separate and / or simultaneous administration of the corresponding components during the treatment of the relevant condition.

[0261] Therefore, regarding the combination product according to the invention, the term "in combination with" includes administering the two components of the combination product (the compound of the invention and other pharmaceutically active ingredients) together or at sufficiently close temporal proximity (optionally repeatedly) to enable the patient to obtain a beneficial effect during the treatment of the relevant condition, said beneficial effect being greater than the beneficial effect of administering the compound of the invention or another agent (e.g., a formulation containing another agent) alone (optionally repeatedly) in the absence of the other component during the same treatment. The determination of whether the combination provides a greater beneficial effect with respect to a particular condition and during the treatment of that condition will depend on the condition to be treated or prevented, but can be routinely performed by those skilled in the art.

[0262] Furthermore, in the context of the kit according to the invention, the term "in combination with" includes the possibility that one or the other of the two components may be administered before, after, and / or simultaneously with the other component (optionally repeatedly). When used in this context, the terms "simultaneous administration" and "simultaneous administration with" include the administration of individual amounts / doses of the relevant compounds and other pharmaceutically active ingredients of the invention within 48 hours (e.g., 24 hours) of each other.

[0263] Regarding the above-mentioned combination formulations and kits, it is preferred that the other pharmaceutically active ingredient is an anti-inflammatory agent, or an agent known to cause inflammation as a side effect, as described above.

[0264] Wherever the word “about” is used herein (e.g., in the context of amounts such as the concentration and / or dosage, molecular weight, or pH of the active ingredient and / or the compounds of the invention), it should be appreciated that such variables are approximate and can therefore vary by ±10%, for example ±5%, preferably ±2% (e.g., ±1%), relative to the numbers specified herein. In this respect, the term “about 10%” means, for example, ±10% near the number 10, i.e., between 9% and 11%.

[0265] The advantages of the compounds of this invention lie in their diverse applications, including: As a bioactive agent, it is used for a variety of conditions characterized by inflammation, whether the condition is an inflammatory disease of an organ as described above, or is related to or characterized by inflammation (e.g., wounds or burns), and / or for surgical and / or cosmetic applications. In combination with active pharmaceutical ingredients, in combination therapy, or as part of the following by exhibiting a more inert function: o Pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers). o Medical devices, and / or o The medical device component of a drug-medical device combination.

[0266] The compounds, uses, and methods described herein may also have the following advantages: in treating the conditions mentioned above, they may be more convenient and effective for physicians and / or patients, less toxic, have a wider range of activity, be more potent, produce fewer side effects, or have other useful pharmacological properties, whether for treating any of the conditions mentioned above (including inflammation, inflammatory disorders, or disorders characterized by inflammation as a symptom, including wounds) or otherwise. Attached Figure Description

[0267] Figure 1 The results of ear swelling in mouse models treated with xylene and test compounds A, B, and C are shown.

[0268] Figure 2 The results of ear swelling in mouse models treated with xylene and test compounds D, E, F, G, and H are shown.

[0269] Figure 3The results of ear swelling in mouse models treated with xylene, test compounds E, I, J, and palmitic acid + DMSO are shown.

[0270] Figure 4 The results of ear swelling in a mouse model treated with xylene and test compound E are shown.

[0271] Figure 5 The results of radiation-induced oral mucositis scores in a hamster model treated with test compound E are shown.

[0272] Figure 6 The results of mechanical pain thresholds in an SD rat model treated with test compound E and lidocaine are shown.

[0273] Figure 7 The results of 5-FU-induced oral mucositis scores in an SD rat model treated with the test compound E are shown.

[0274] Figure 8 The results are shown for subjects with rosacea treated with the test compound E.

[0275] Figure 9 The results show the severity of esophagitis in a GERD rat model treated with test compounds K, L, and M.

[0276] Example 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.

[0277] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. The DCM was then removed by vacuum filtration.

[0278] resin N,N Wash 3 times with dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0279] 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 carried out for 20 minutes. The solution was then removed by vacuum filtration, and the column was washed six times with DMF.

[0280] Fmoc-Tyr(tBu)-OH (4.14 g, 9 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylamineonium 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 with a small amount of resin; the yellow color of the solution and the appearance of a colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0281] Repeat the above coupling steps to couple the same amount (in mol) of the remaining amino acids: 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.

[0282] 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 then dried under vacuum for approximately 2 hours.

[0283] 130.0 mL (i.e., 10 mL / g of dry resin) of lysis buffer was added to submerge the peptide-containing compound bound to the resin. The lysis buffer consisted of 95% trifluoroacetic acid (TFA, Macklin, Shanghai, China), 2.5% water, and 2.5% triisopropylsilane (Tis, Macklin, Shanghai, China). After approximately 2 hours of lysis, 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 / ml filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours, yielding 4.51 g of the crude title compound.

[0284] First, the crude product was analyzed as a 1 mg / mL sample in pure water using a Shimadzu LCMS-8050 system (Shimadzu, 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 from 5% to 90% of solvent A concentration over 50 minutes; flow rate 1.0 mL / min; sample volume: 10 µL).

[0285] The target peak was eluted at 35.232 minutes and had the expected molecular weight ( MS: m / z 1421.7 The purity is 64.564%.

[0286] 4.5 g of the crude product was then dissolved in 90 mL of pure water and purified using an NP7010C semi-preparative apparatus (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China). The preparative column was a Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50 * 250 mm, 100 Å column; detection: UV at 220 nm). An appropriate elution gradient was calculated from the LCMS detection procedure (solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient from 50% to 80% of solvent A concentration over 30 min; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) (column as described above, except the linear gradient is from 50% to 75% of solvent A concentration over 25 min).

[0287] Fractions with a purity higher than 90% were then mixed together for anion exchange. This was performed using an NP7010C semi-preparative apparatus (preparative column model: Dubhe-C18, as described above). The fractions were diluted once with pure water and loaded directly onto the column, followed by washing the column with 3.2% ammonium acetate in pure water for approximately 20 minutes at a flow rate of 60 mL / min, then washing with pure water for another 10 minutes, and then eluting with the following gradient (solvent A: 0.1% HAc in MeCN, solvent B: 0.1% HAc in water, linear gradient from 50%–80% solvent A concentration 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 described above). Fractions with a purity higher than 95% were mixed and lyophilized to give 1.64 g of purified title compound.

[0288] 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 method as described in Example 1 above, except that the same amount (in moles) of stearic acid was used instead of palmitic acid in the final coupling step.

[0289] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.37 g). Analysis showed that the target peak was eluted at 36.231 min, with the expected molecular weight ( MS: m / z 1449.8 The purity is 60.287%.

[0290] The 4.3 g crude product was then purified as described in Example 1 above to obtain 1.52 g of pure title compound after freeze-drying.

[0291] 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 above, except that the coupling steps were performed in the same amounts (in moles) in the following order: Fmoc-4-Hyp(tBu)-OH, Fmoc-DOPA (acetone condensation)-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.

[0292] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.56 g). Analysis showed that the target peak was eluted at 30.746 min, with the expected molecular weight ( MS: m / z 1437.7 The purity is 65.128%.

[0293] The 4.5 g crude product was then purified as described in Example 1 above to obtain 1.57 g of pure title compound after freeze-drying.

[0294] Example 4 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-Dopamine (SEQ ID No: 109) The title compound was synthesized using Fmoc-Lys(Boc)-Wang resin with Lys as the first amino acid, employing almost the same method as 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 method as described in Example 1 above.

[0295] After coupling palmitic acid to the resin, the resin was washed three times each with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL). The resin was then dried under vacuum for approximately 2 hours.

[0296] 120.0 mL (i.e., 10 mL / g dry resin) of lysis buffer, consisting of 2% trifluoroacetic acid (TFA) in DCM, was added to submerge the peptide-containing compound bound to the resin. After approximately 2 hours of lysis, 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 a 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 / ml final solution) of saturated citric acid (Aladdin, Shanghai, China) in aqueous solution, and the precipitate was collected by filtration. The precipitate was then added to 120 mL (i.e., 10 mL / g solid) of lysis buffer to dissolve the peptide-containing solid, the lysis buffer containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis). Side chains were deprotected during lysis. After approximately 2 hours of lysis, the solution was precipitated with 1200 mL (i.e., 10 mL / ml filtrate) of diethyl ether, and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours. Finally, 4.25 g of the crude title compound was obtained.

[0297] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.38 g). Analysis showed that the target peak was eluted at 32.173 min, with the expected molecular weight ( MS: m / z 1556.9 The purity is 55.395%.

[0298] The 4.3 g crude product was then purified as described in Example 1 above to obtain 1.39 g of pure title compound after freeze-drying.

[0299] 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 method as described in Example 1 above, except that the same amount (in moles) of oleic acid was used instead of palmitic acid in the final coupling step.

[0300] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.41 g). Analysis showed that the target peak was eluted at 35.877 min, with the expected molecular weight ( MS: m / z 1447.8 The purity is 61.737%.

[0301] The 4.4 g crude product was then purified as described in Example 1 above to obtain 1.55 g of pure title compound after freeze-drying.

[0302] Example 6 Olei-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 13) The title compound was prepared using essentially the same method as described in Example 5 above, except that the same amount (in moles) of Fmoc-DOPA (acetone condensate)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling step.

[0303] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.53 g). Analysis showed that the target peak was eluted at 35.124 min, with the expected molecular weight ( MS: m / z 1479.8 The purity is 62.522%.

[0304] The 4.5 g crude product was then purified as described in Example 1 above to obtain 1.52 g of pure title compound after freeze-drying.

[0305] 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 method as described in Example 1 above, except that the same amount (in moles) of docosahexaenoic acid was used instead of palmitic acid in the final coupling step.

[0306] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.47 g). Analysis showed that the target peak was eluted at 35.877 min, with the expected molecular weight ( MS: m / z 1493.8 The purity is 63.228%.

[0307] The 4.4 g crude product was then purified as described in Example 1 above to obtain 1.57 g of pure title compound after freeze-drying.

[0308] Example 8 (Compound E) Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 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 the relevant peptide-coupled sequence.

[0309] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 3.59 g). Analysis showed that the target peak was eluted at 29.947 min, with the expected molecular weight ( MS: m / z 1136.4 The purity is 70.223%.

[0310] The 3.5 g crude product was then purified as described in Example 1 above to obtain 1.21 g of pure title compound after freeze-drying.

[0311] Example 9 Olei-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 15) The title compound was synthesized using essentially the same procedure as described in Example 6 above, except that appropriate amino acids and fatty acids were used in the relevant peptide coupling sequence.

[0312] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 3.65 g). Analysis showed that the target peak was eluted at 30.093 min, with the expected molecular weight ( MS: m / z 1178.6 The purity is 71.943%.

[0313] The 3.6 g crude product was then purified as described in Example 1 above to obtain 1.25 g of pure title compound after freeze-drying.

[0314] 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 method as described in Example 1 above, except that the same amount (in moles) of Fmoc-DPPS-OH was used instead 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 DPPS. The resin was washed three times with DMF (200 mL each time). A 20% piperidine solution (200 mL) in DMF was added as the deprotection solution and reacted for 20 minutes, and then removed under vacuum. The remaining steps were then performed according to essentially the same method as described in Example 1.

[0315] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 5.77 g). Analysis showed that the target peak was eluted at 48.284 min, with the expected molecular weight ( MS: m / z 1814.2 The purity is 53.933%.

[0316] The 5.7 g crude product was then purified as described in Example 1 above to obtain 1.79 g of pure title compound after freeze-drying.

[0317] Example 11 (Compound O) LTB4-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 8) The title compound was prepared using essentially the same method as described in Example 1 above, except that the same amount (in moles) of LTB4 was used instead of palmitic acid in the final coupling step.

[0318] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.39 g). Analysis showed that the target peak was eluted at 33.877 min, with the expected molecular weight ( MS: m / z 1501.8 The purity is 57.847%.

[0319] The 4.3 g crude product was then purified as described in Example 1 above to obtain 1.38 g of pure title compound after freeze-drying.

[0320] Example 12 (Compound M) Montelukast-Ala-lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm) (SEQ ID No: 2) Fmoc-Lys(Boc)-Wang resin (9.15 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0321] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. The DCM was then removed by vacuum filtration.

[0322] A 200 mL solution of 30% trifluoroacetic acid (TFA, Macklin Biochemical Co. Ltd., Shanghai, China) in DCM was added to the column and reacted with the resin for approximately half an hour to remove the Boc protecting group on the Lys column. The TFA solution in the DCM was then removed by vacuum filtration.

[0323] resin N,N Wash 6 times with dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co Ltd, Shandong, China).

[0324] Palmitic acid (2.31 g, 9 mmol; Macklin Biochemical Co. Ltd., Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylamineonium 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 reacting for 30 minutes, a Kaiser test was performed with a small amount of resin; the yellow color of the solution and the appearance of a colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0325] After coupling palmitic acid to the side chain of the lysine resin, other amino acids were coupled in essentially the same steps 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, the difference being 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 (in moles) as in Example 1.

[0326] After coupling with sodium montelukast, the essentially same procedure was repeated to obtain another batch of crude title compound (yield 5.86 g). Analysis showed that the target peak was eluted at 43.848 min, with the expected molecular weight (MS: m / z 2011.9) and a purity of 52.432%.

[0327] The 5.8 g crude product was then purified as described in Example 1 above to obtain 1.63 g of pure title compound after freeze-drying.

[0328] 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 method as described in Example 10 above, except that the same amount (in moles) of oleic acid was used instead of sodium montelukast in the final coupling step.

[0329] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 4.37 g). Analysis showed that the target peak was eluted at 46.129 min, with the expected molecular weight ( MS: m / z 1686.2 The purity is 51.237%.

[0330] The 4.3 g crude product was then purified as described in Example 1 above to obtain 1.51 g of pure title compound after freeze-drying.

[0331] Example 14 Palm-Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID 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 the relevant peptide-coupled sequence.

[0332] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 3.51 g). Analysis showed that the target peak was eluted at 28.847 min, with the expected molecular weight ( MS: m / z 1152.5 The purity is 68.983%.

[0333] The 3.5 g crude product was then purified as described in Example 1 above to obtain 1.16 g of pure title compound after freeze-drying.

[0334] Example 15 DPPS-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 18) The title compound was synthesized using essentially the same procedure as described in Example 10 above, except that appropriate amino acids were used in the relevant peptide-coupled sequence.

[0335] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 5.03 g). Analysis showed that the target peak was eluted at 43.288 min, with the expected molecular weight ( MS: m / z 1616.0 The purity is 65.039%.

[0336] The 5.0 g crude product was then purified as described in Example 1 above to obtain 2.1 g of pure title compound after freeze-drying.

[0337] Example 16 Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Chol-Ac)-NH2 (SEQ ID No: 110) The title compound was synthesized using essentially the same procedure as described in Example 12 above, except that, compared to Example 12, Fmoc-Lys(Boc)-AM resin (6.98 g, USUN Pharma, Jiangsu, China) was used as the starting material. After deprotecting the side chains of the Fmoc-Lys(Boc)-AM resin, cholesterol-acetic acid (self-synthesized) was linked to the side chains of the Fmoc-Lys-AM resin. Appropriate amino acids were used in the relevant peptide coupling sequence to obtain the title compound, compared to Example 12.

[0338] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 3.84 g). Analysis showed that the target peak was eluted at 37.822 min, with the expected molecular weight ( MS: m / z 1323.7 The purity is 61.438%.

[0339] The 3.8 g crude product was then purified as described in Example 1 above to obtain 1.3 g of pure title compound after freeze-drying.

[0340] Example 17 Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-PEA (SEQ ID No: 111) The title compound was synthesized using Fmoc-Lys(Boc)-CTC resin (7.23 g, USUN Pharma, Jiangsu, China) as a solid support and lysine as the first amino acid.

[0341] 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 above, except that, compared to Example 1, appropriate amino acids were used in the relevant peptide coupling sequence (Boc-Lys(Boc)-OH was used in the final coupling step).

[0342] After coupling Boc-Lys(Boc)-OH to the resin, the resin was washed three times each with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL). The resin was then dried under vacuum for approximately 2 hours.

[0343] 100.0 mL (i.e., 10 mL / g dry resin) of lysis buffer, consisting of 2% trifluoroacetic acid (TFA) in DCM, was added to submerge the peptide-containing compound bound to the resin. After approximately 2 hours of lysis, 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. The reaction was complete after 3 hours. Precipitation of the final solution was carried out by adding 1000 mL (i.e., 10 mL / ml final solution) of saturated citric acid (Aladdin, Shanghai, China) aqueous solution, and the precipitate was collected by filtration. 100 mL (i.e., 10 mL / g solid) of lysis buffer containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to the precipitate to dissolve the peptide-containing solid. The side chains were deprotected during lysis. After approximately 2 hours of lysis, the solution was precipitated with 1000 mL (i.e., 10 mL / ml filtrate) of diethyl ether, and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours. Finally, 3.87 g of the crude title compound was obtained.

[0344] Analysis showed that the target peak was eluted at 30.449 minutes, having the expected molecular weight ( MS: m / z 1179.5 The purity is 58.323%.

[0345] The 3.8 g crude product was then purified as described in Example 1 above to obtain 1.2 g of pure title compound after freeze-drying.

[0346] 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. Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column, and the resin was allowed to soak for approximately half an hour. 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).

[0347] 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.

[0348] Fmoc-Lys(Boc)-OH (8.43 g, 18 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylamineonium 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 30 minutes of reaction, a Kaiser test was performed on a small amount of resin, where the yellow color of the solution and the appearance of a colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0349] The title compound was prepared using essentially the same method as described in Example 8 above, except that the amounts of amino acids, palmitic acid, and condensing agents (TBTU and DIPEA) were doubled (in moles).

[0350] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 6.68 g). Analysis showed that the target peak was eluted at 30.665 min, with the expected molecular weight ( MS: m / z 2383.1 The purity is 57.542%.

[0351] The 6.6 g crude product was then purified as described in Example 1 above to obtain 2.76 g of pure title compound after freeze-drying.

[0352] 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 essentially the same procedure as described in Example 18 above, except that appropriate amino acids were used in the relevant peptide-coupled sequence.

[0353] Repeating essentially the same procedure yielded another batch of crude title compounds (yield 8.53 g). Analysis showed that the target peak was eluted at 32.192 min, with the expected molecular weight ( MS: m / z 2953.7 The purity is 52.821%.

[0354] The 8.5 g crude product was then purified as described in Example 1 above to obtain 3.2 g of pure title compound after freeze-drying.

[0355] 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.

[0356] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for approximately half an hour. The DCM was removed by vacuum filtration.

[0357] Side chain coupling steps: 1. Resin washing: Wash the resin three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0358] 2. Deprotection: A 200 mL solution of 5% hydrazine monohydrate (Merck KGaA, Darmstadt, Germany) in DMF was added as the 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.

[0359] 3. Coupling: Palmitic acid (2.31 g, 9 mmol; Merck KGaA, Darmstadt, Germany) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylamineonium 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 reacting for 30 minutes, a Kaiser test was performed with a small amount of resin; the yellow color of the solution and the appearance of a colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0360] After coupling the side chain palmitic acid, the amino acid is coupled to the resin.

[0361] Amino acid coupling steps: 1. Resin washing: Wash the resin three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0362] 2. Deprotection: A 20% piperidine solution (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) (DBLK, 200 mL) was added to DMF as the deprotection solution, and the reaction was carried out for 20 minutes. The solution was removed by vacuum filtration, and the gel was washed six times with DMF.

[0363] 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-tetramethylamineonium 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 on a small amount of resin; the yellow color of the solution and the appearance of a colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0364] Repeat the above coupling steps to couple the same amount (in mol) of the following amino acids: 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.

[0365] After coupling Fmoc-Lys(Dde)-OH, the protecting group of the Dde side chain is removed, and then palmitic acid is coupled to the side chain using essentially the same method as described above.

[0366] After coupling palmitic acid to the side chain of the deprotected lysine residue, the further coupling steps are repeated using essentially the same method as described above to couple the same amount (in moles) of the following amino acids: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, and then Boc-Lys(Boc)-OH.

[0367] After coupling Boc-Lys(Boc)-OH, the resin was washed three times each 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 then dried under vacuum for approximately 2 hours.

[0368] MS: m / z 2254.9 The procedure was repeated essentially the same as in Example 1 to obtain another batch of crude title compound (yield 6.3 g). Analysis showed that the target peak was eluted at 31.282 min, with the expected molecular weight ( MS: m / z 2254.9 The purity is 50.872%.

[0369] The 6.3 g crude product was then purified as described in Example 1 above to obtain 2.01 g of pure title compound after freeze-drying.

[0370] Example 21 Compound E Cream-1: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound E cream contains a mixture of the following substances listed in Table 1. The components of phase A are mixed, heated to 85ºC, and stirred at 85ºC for 30 minutes. Phase B is added, and the mixture is homogenized for 5 minutes, then stirred until cooled. When the temperature drops to 45ºC, the raw material of phase C is added, and the mixture is homogenized for 1 minute. Phase D is added, and the mixture is homogenized for 3–5 minutes until the system is homogeneous to obtain compound E cream-1.

[0371] Table 1 Example 22 Oral spray containing compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound E oral spray contains a mixture of the following substances listed in Table 2. The components of phase A are mixed, heated to 85ºC, and stirred at 85ºC for 30 minutes. When the temperature drops to 45ºC, the premixed raw materials of phase B are added. The mixture is stirred for 3–5 minutes until phase B is dissolved and the system is homogeneous to obtain compound E oral spray.

[0372] Table 2 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 92.355 A2 glycerin glycerin 5.3 A3 Citric acid (1%) Citric acid 0.77 B1 Sucralose (10%) Sucralose 0.175 B2 Compound E 0.1 B3 Potassium sorbate Potassium sorbate 0.2 B4 Menthol Menthol 0.1 B5 C0-40 PEG-40 hydrogenated castor oil Lucsei 1 100 Example 23 Compound E Facial Spray-1: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound E Facial Spray-1 contains a mixture of the following substances listed in Table 3. The components of phase A are mixed and heated to 85ºC, and stirred at 85ºC for 30 minutes. When the temperature drops to 45ºC, phase B is added. The mixture is stirred for 3–5 minutes until phase B is dissolved and the system is homogeneous to obtain Compound E Facial Spray-1.

[0373] Table 3 Example 24 Compound E Facial Spray-2: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound E Facial Spray-2 contains a mixture of the following substances listed in Table 4. The components of phase A are mixed and heated to 85ºC. The mixture is stirred at 85ºC for 30 minutes. When the temperature drops to 45ºC, phase B is added and stirred for 3–5 minutes until phase B is dissolved and the system is homogeneous, to obtain Compound E Facial Spray-2.

[0374] Table 4 Example 25 Compound E Mouthwash-1: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound E mouthwash contains a mixture of the following substances listed in Table 5. The components of phase A are mixed and heated to 85ºC, and stirred at 85ºC for 30 minutes. When the temperature drops to 45ºC, phase B is added and stirred for 3–5 minutes until phase B dissolves and the system is homogeneous, to obtain Compound E mouthwash-1.

[0375] Table 5 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 contain a mixture of the following substances listed in Tables 6 and 7 below. The components of phase A are mixed, heated to 80ºC, and stirred at 80ºC for 30 minutes. The components of phase B are mixed, heated to 80ºC, and stirred at 80ºC for 30 minutes. The solution of phase B is transferred to the solution of phase A and homogenized for 5 minutes. The sample is allowed to cool until homogeneous to obtain Compound E Cream-1 or its placebo sample.

[0376] Table 6 Mutually Material quantity(%) A1 Tefose 63 10.0 A2 Stearyl alcohol 1.5 A3 cetyl alcohol 1.5 A4 Liquid paraffin 10.0 A5 Methylparaben 0.1 B1 pure water 76.8 B2 Compound E 0.1 100 Table 7 Mutually Material quantity(%) A1 Tefose 63 10.0 A2 Stearyl alcohol 1.5 A3 cetyl alcohol 1.5 A4 Liquid paraffin 10.0 A5 Methylparaben 0.1 B1 pure water 76.9 100 Example 27 Compound E Hair Care Serum: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound E hair serum and its placebo sample each contain the substances listed in Tables 8 and 9 below. The components of phase A are mixed, heated to 80ºC, and stirred at 80ºC for 30 minutes. The sample is allowed to cool until homogeneous to obtain Compound E hair serum or its placebo sample.

[0377] Table 8 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 99.89 A2 benzalkonium chloride benzalkonium chloride 0.01 A3 Compound E 0.1 100 Table 9 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 99.99 A2 benzalkonium chloride benzalkonium chloride 0.01 100 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 contain a mixture of the following substances listed in Tables 10 and 11 below. The components of phase A are mixed, heated to 80ºC, and stirred at 80ºC for 30 minutes. The sample is allowed to cool until homogeneous to obtain compound E mouthwash-2 or its placebo sample.

[0378] Table 10 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 99.89 A2 cetylpyridinium chloride cetylpyridinium chloride 0.05 A3 Menthol Menthol 0.01 A4 Sucralose Sucralose 0.02 A5 Compound E 0.03 100 Table 11 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 99.92 A2 cetylpyridinium chloride cetylpyridinium chloride 0.05 A3 Menthol Menthol 0.01 A4 Sucralose Sucralose 0.02 100 Example 29 Compound E foam: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Formula-1: Compound E foam formula-1 contains a mixture of the following substances listed in Table 12 below. Mix the components of phase A and stir for 30 minutes until the system is homogeneous to obtain Compound E foam formula-1.

[0379] Table 12 Mutually Material quantity(%) A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 glycerin 5.0 A4 amphoteric alcohol 1.0 A5 pure water 90.4 A6 Compound E 0.1 100 Formula-2: Compound E foam formula-2 contains a mixture of the following substances listed in Table 13 below. Mix the components of phase A and stir for 30 minutes until the system is homogeneous. While stirring, add sodium hydroxide to adjust the pH of the solution to 6.5-7.0 to obtain compound E foam formula-2.

[0380] Table 13 Mutually Material quantity(%) A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 glycerin 5.0 A4 amphoteric alcohol 1.0 A5 pure water 90.4 A6 Compound E 0.1 B1 Sodium hydroxide 100 Formula-3: Compound E foam formula-3 contains a mixture of the following substances listed in Table 14 below. The procedure for preparing compound E foam formula-3 is the same as that described for formula-2.

[0381] Table 14 Mutually Material quantity(%) A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 glycerin 5.0 A4 amphoteric alcohol 1.0 A5 Glucosamine 1.5 A6 Maluca Honey 1.0 A7 pure water 87.9 A8 Compound E 0.1 B1 Sodium hydroxide 100 Example 30 Compound E gel: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) The preparation of compound E gel involves a mixture of the following substances listed in Table 15. The components of phase A are mixed, heated to 80ºC, and stirred at 80ºC for 30 minutes. The sample is allowed to cool until homogeneous to obtain compound E gel.

[0382] Table 15 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 81.23 A2 Propylene glycol Propylene glycol 13.40 A3 glycerin glycerin 2.60 A4 Carbomer 940 KABOMUER 0.67 A5 Carbomer 941 KABOMUER 0.13 A6 Triethanolamine Triethanolamine 0.80 A7 4-Hydroxyacetophenone Hydroxyacetophenone 0.50 A8 1,2-Hexanediol Hexanediol 0.50 A9 Sodium hyaluronate (1.5 M Da) Sodium hyaluronate 0.07 A10 Compound E 0.10 100 Example 31 Mouse model of ear swelling 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) Before the experiment, 25 healthy male BALB / c mice (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China), aged 6 to 8 weeks and with an average weight of 18-25 g, were housed and cared for for approximately one week. The housing conditions were 25ºC-27ºC, 74% humidity, a 12-hour dark-light cycle, and free access to food and water. As shown in Table 16 below, these mice were randomly divided into 5 groups (5 mice per group).

[0383] Table 16 Group Drug concentration Apply medication to the right ear Total dose (μg / mouse) Model / xylene / Dex cream (dexamethasone) 0.75 mg / g Xylene + Dex cream 0.03 Compound A 1.5 mg / ml Xylene + Compound A 60 Compound B 1.5 mg / ml Xylene + Compound B 60 Compound C 1.5 mg / ml Xylene + Compound C 60 The left ear of each mouse was used as an autologous control, and the right ear of each mouse was treated differently: 20 μl of xylene (Shanghai Aladdin Bio-Chem Technology Co., LTD, Shanghai, China) was applied to both the inner and outer sides of the right ear of each mouse. Swelling of the ear began after approximately 4 minutes. Then, 40 μl of the drug was applied to the right ear of each group. The mice were then returned to their cages.

[0384] Purchase dexamethasone acetate cream (0.75 mg / g, China Resources Group) from a local pharmacy. Compound AC was synthesized by Chinese Peptide Company as described above. Dissolve 15 mg of each compound (powder) in 10 ml of physiological saline to prepare a 1.5 mg / ml solution. The resulting solutions were then applied to mice accordingly.

[0385] Mice were euthanized by cervical dislocation after 40 minutes. The left and right ears were removed. A piece of each ear was harvested from the same site using an 8 mm diameter skin pouch (Electron Microscopy Sciences, P.O. Box 550, 1560 Hatfield Industrial Road, Pennsylvania, 19440). Weights were recorded and used to calculate the swelling rate, as shown in Table 17 below. Figure 1 As shown in the image.

[0386] Swelling rate (%) = (Right ear weight - Left ear weight) / Left ear weight × 100% Table 17 The results showed that all three compounds significantly reduced xylene-induced ear swelling in a mouse model. Their effects were slightly weaker than those of dexamethasone.

[0387] Example 32 Mouse model of ear swelling 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 procedures and results recording were the same as those described in Example 31 above. Xylene induced ear swelling in mice. As shown in Table 18 below, 35 mice were divided into 7 groups, and the results are shown in Table 19 below. Figure 2 As shown in the image.

[0388] Table 18 Group Drug concentration Apply medication to the right ear Total dose (μg / mouse) Model / xylene / Dex cream (dexamethasone) 0.75 mg / g Xylene + Dex cream 0.03 Compound D 1.5 mg / ml Xylene + Compound D 60 Compound E 1.5 mg / ml Xylene + Compound E 60 Compound F 1.5 mg / ml Xylene + compound F 60 Compound G 1.5 mg / ml Xylene + Compound G 60 Compound H 1.5 mg / ml Xylene + compound H 60 Table 19 The results showed that all five compounds effectively reduced the swelling rate in mouse models treated with xylene, but not to the extent that dexamethasone treatment could reduce the swelling rate.

[0389] Example 33 Mouse model of ear swelling 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 procedures and results recording were the same as described in Example 31 above. Xylene induced ear swelling in mice. As shown in Table 20 below, 35 mice were divided into 7 groups, and the results are shown in Table 21 below. Figure 3 As shown in the image.

[0390] Table 20 Group Drug concentration Apply medication to the right ear Model / physiological saline Dex cream (dexamethasone) 0.75 mg / g Xylene + Dex cream Compound E 1 mg / ml Xylene + Compound E Compound I 1 mg / ml Xylene + Compound I Compound J 1 mg / ml Xylene + Compound J Palmitic acid + DMSO 0.3 mg / ml Xylene + Palmitic acid + DMSO Table 21 Group Model Dex Compound E Compound I Compound J Palmitic acid + DMSO Swelling rate (%) 82.09 38.56 46.86 54.29 64.67 49.88 SD (%) 13.62 18.09 11.96 3.91 9.23 11.71 Example 34 Mouse model of ear swelling Test compound: Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) The experimental procedures and results recording were the same as described in Example 31 above. Mouse ear swelling was induced by xylene. As shown in Table 22 below, the mice were divided into 8 groups, and the results are shown in Table 23 below. Figure 4 As shown in the image.

[0391] Table 22 Group Drug concentration Apply medication to the right ear Model / physiological saline Dex 0.75 mg / g Dexamethasone cream Compound E 0.1 mg / ml Compound E Compound E 0.3 mg / ml Compound E Compound E 1.0 mg / ml Compound E Compound E 1.5 mg / ml Compound E Compound E 3.0 mg / ml Compound E Compound E 10 mg / ml Compound E Table 23 Group Swelling rate (%) SD Model 79.49 16.42 Dex 32.75 9.80 Compound E (0.1 mg / ml) 68.30 5.42 Compound E (0.3 mg / ml) 64.10 6.54 Compound E (1.0 mg / ml) 50.77 24.08 Compound E (1.5 mg / ml) 43.85 9.26 Compound E (3.0 mg / ml) 34.95 22.30 Compound E (10 mg / ml) 46.04 10.70 The results showed that compound E was effective as an anti-inflammatory agent in a mouse ear swelling model and provides guidance for future clinical anti-inflammatory use. Compound E also exhibited good dose-dependent anti-inflammatory effects.

[0392] Example 35 Pain relief from radiation-induced oral mucositis Two patients were undergoing radiation therapy to the head and neck. Both patients had experienced severe stomatitis, diagnosed as grade 4 (the most severe level), and oral mucosal ulcers. The patients also experienced high levels of pain and difficulty eating. They were advised to use a 1 mg / ml x 5 ml compound E solution as a mouthwash three times daily. After 5 days, both patients reported very positive feedback. One patient's pain VAS score decreased from 8 to 1, and the other's from 7 to 3. The latter patient also reported a significant reduction in mucus in his mouth caused by infection and inflammatory exudate. Therefore, compound E has been shown to be effective in treating stomatitis.

[0393] Example 36 Relief of itching in neurodermatitis A 28-year-old male presented with a skin lesion on his left elbow accompanied by persistent itching and scaling. He had been diagnosed with neurodermatitis a year prior. He had previously used corticosteroids to treat the lesion, but the effects were temporary. The itching worsened when he experienced stress. He tried a 3 mg / ml compound E solution spray. After one application to the lesion, the itching completely subsided within approximately 30 minutes. The patient reported that the itching stopped the day after application.

[0394] Example 37 Radiation mucositis in golden hamster model Prior to the experiment, 32 healthy male LVG Syrian golden hamsters (Beijing Chairs River Experimental Animal Technology Co., Ltd.), aged 6 to 8 weeks and with an average weight of 93-101 g, were housed and cared for for approximately one week. Housing conditions included 25ºC-27ºC, 74% humidity, a 12-hour dark-light cycle, and free access to food and water. As shown in Table 24 below, the hamsters were randomly divided into 4 groups (8 hamsters per group).

[0395] Table 24 After anesthesia, the animal's left cheek pouch was pulled out and secured 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 waking the animals, they were returned to their cages. Photographs were taken and evaluated every two days. Evaluation was performed according to the Sonis scoring system (0 - pouch is completely healthy, with no erythema or vasodilation; 1 - erythema and vasodilation, but the mucosa is intact; 2 - severe erythema with superficial mucosal erosion; 3 - formation of mucosal ulcers, with a cumulative size of approximately 25% of the pouch surface area; 4 - ulcers, with a cumulative size of approximately 50% of the pouch surface area; 5 - continuous ulcers involving almost the entire surface area of ​​the pouch mucosa). Results are shown in Table 25 below. Figure 5 As shown in the image.

[0396] Table 25 Group days Model low dose of compound E Compound E, moderate dose High dose of compound E Before 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 Day 7 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 Day 9 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 Day 11 0.75±0.46 0.5±0.53 0.5±0.53 0.38±0.52 Day 13 1.50±0.53 1.38±0.52 1.38±0.52 1.38±0.52 Day 15 2.50±0.53 2.13±0.35 2.13±0.64 2.38±0.52 Day 17 3.25±0.46 3.13±0.35 3.13±0.35 3.13±0.35 Day 19 4.00±0.00 3.38±0.74 3.63±0.52 3.13±0.35** Day 21 3.75±0.46 3.00±0.53* 3.00±0.00** 2.63±0.74** Day 23 3.25±0.46 2.75±0.46* 2.63±0.52* 2.25±0.46** Day 25 2.88±0.64 2.13±0.35* 1.88±0.35** 1.63±0.52** Day 27 2.50±0.93 1.75±0.46* 1.50±0.76* 1.00±0.53** Day 29 2.00±0.93 1.00±0.53** 0.88±0.83** 0.50±0.53** Note: Data in the table are expressed as mean ± standard deviation (mean ± SD). Eight animals were used for statistical analysis in each group. * P < 0.05, ** P < 0.01 indicates the comparison results between each treatment group and the model control group.

[0397] Based on the Sonis scoring system and SOM duration in radiation-induced hamster mucositis, compound E showed improvement in mucositis. Compound E demonstrated good dose-dependency in this model. Therefore, compound E suggests that it may alleviate symptoms associated with mucositis in clinical practice.

[0398] Example 38 Pain relief in Sprague Dawley (SD) rats Prior to the experiment, 48 healthy male SD rats (BeijingChairs River Experimental Animal Technology Co., Ltd.) aged 7 to 8 weeks with an average weight of 180-220 g were housed and cared for for approximately one week. Housing conditions included 25ºC-27ºC, 74% humidity, a 12-hour dark-light cycle, and free access to food and water. As shown in Table 26 below, these rats were randomly divided into 6 groups (n=8 rats per group), and the results were presented in... Figure 6 As shown in the image.

[0399] Table 26 All animals were pre-trained to allow rats to adapt to external stimuli. Oral mucosal ulcers were then induced using acetic acid (Sigma-Aldrich). Mechanical pain threshold measurements were performed on the ulcerated areas of rats using Von Frey filaments (Danmic Aesthesio) (0.008 g, 0.04 g, 0.02 g, 0.04 g, 0.07 g, 0.16 g, 0.4 g, 0.6 g, 1.0 g, 1.4 g, 2.0 g, 4.0 g). Each level of stimulation was administered five times consecutively, with a 15-second interval between tests, until three or more positive responses were observed at a given level of stimulation. The values ​​were recorded as the mechanical pain threshold. To prevent damage to the rat mucosa and to avoid affecting subsequent tests, the maximum detection intensity of von Frey was set to 4.0 g.

[0400] Compound E showed relief of acetic acid-induced pain in SD rats, exhibiting pain-relieving effects comparable to lidocaine. Compound E demonstrated good dose-dependency in this model. Therefore, compound E has been shown to alleviate symptoms associated with oral mucosal ulcers in patients.

[0401] Example 39 5-FU-induced oral mucositis in SD rats Prior to the experiment, 40 healthy male SD rats aged 7 to 8 weeks with an average weight of 180-220 g (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China) were housed and cared for for approximately one week. Housing conditions included 25ºC-27ºC, 74% humidity, a 12-hour dark-light cycle, and free access to food and water. As shown in Table 27 below, the rats were randomly divided into 5 groups (n=8 per group).

[0402] Table 27 Three days prior to the injection of the test compound, rats were administered an intraperitoneal injection of 5-FU (MCE, China) at a dose of 50 mg / kg and a volume of 2 ml / kg. One day prior to the injection of the test compound, rats were administered an intraperitoneal injection of additional 5-FU, followed by inhalation of 2.5% isoflurane (Sigma-Aldrich) to anesthetize the animals.

[0403] The animals were placed in a right supine position, and the rats' maxilla and mandible 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 5 μL of 80% acetic acid (Sigma-Aldrich) was dripped onto the filter paper. After maintaining contact for 20 seconds, the filter paper was removed, and any remaining fluid on the buccal mucosa was wiped away with a cotton swab. The sham surgery group underwent the same procedure, but 5 μL of saline was dripped onto the filter paper.

[0404] After 24 h of acetic acid treatment, ulcer scores were assessed in all animals except the sham group, and animals were regrouped accordingly. Animals were treated according to the study protocol described in Table 27 and assessed daily using the following criteria: 0 - normal mucosal appearance, no erythema or hyperemia; 1 - erythema or hyperemia of the oral mucosa, but the mucosa is intact; 2 - extensive erythema of the oral mucosa with punctate diffuse ulcers; 3 - patchy ulcers of the oral mucosa, covering an area less than 1 / 4 of the buccal mucosa (+); 4 - oral mucosal ulcers, covering an area less than 1 / 2 of the buccal mucosa (++); 5 - buccal mucosal ulcers, covering more than half of the area (+++).

[0405] result( Figure 7 Compound E showed that it improved 5-FU and acetic acid-induced mucositis scores in SD rats and accelerated the healing of mucosal ulcers. Compound E demonstrated a favorable dose-dependent effect in this model. Therefore, compound E has been shown to alleviate symptoms associated with mucositis in clinical practice.

[0406] Example 40 Wound healing effect - Cell scratch assay in HaCaT In 96-well plates, when cell confluence reached 40%-60%, the following substances were added: 200 μL of medium containing 10% PBS (Sigma) was added to each well of the control group; 200 μL of medium containing 10% DMSO was added to each well of the positive control group; 200 μL of medium containing the corresponding concentration of the sample was added to each well of the sample group; and 200 μL of cell culture medium was added to the zero group (no cell seeding). After application, the 96-well plates were incubated in an incubator (37ºC, 5% CO2). After 24 hours of cell incubation, the supernatant was discarded, and MTT working solution (0.5 mg / mL) was added. The 96-well plates were incubated in the dark at 37ºC 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.

[0407] The results showed that compound E was non-cytotoxic at its effective dose.

[0408] Cells were suspended using 200 μL pipettes in 24-well plates covered with cells and labeled “damaged.” Cells were washed three times with PBS to remove scratched cells. Treatment with compound E at concentrations of 0.001%, 0.004%, and 0.008% (m / V) significantly increased the cell healing rate of immortalized human skin keratinocytes (HaCaT) (ATCC) (p<0.01), indicating that compound E is effective in cell repair. Therefore, compound E has been shown to effectively promote cell healing in vitro, corresponding to in vivo results, and compound E can effectively promote healing in clinical practice.

[0409] Example 41 Non-immunosuppressive effect - In vitro peripheral blood mononuclear cell (PBMC) study PBMCs were resuscitated and stained with Celltrace. The T cell concentration was adjusted to 0.1 M (50 μL) per well using 1640 complete medium. 50 μL of LPS (Sigma-Aldrich) was added to the cells four times. 100 µL of blank medium / different concentrations of compound E or dexamethasone / medium containing 0.4% DMSO + the highest concentration were added to the respective wells. The LPS group was incubated for 24 hours. Cell supernatant was collected to detect the secretion of relevant inflammatory factors. Cell proliferation and viability were assessed using flow cytometry.

[0410] The results showed that, under these experimental conditions, compound E did not have immunosuppressive effects. Compared with dexamethasone, compound E does not cause immunosuppression and is therefore safer for clinical use by reducing the risk of infection.

[0411] Example 42 In vitro anti-inflammatory effects in keratinocytes Culture medium was added to the blank control group; culture medium containing LPS (Sigma-Aldrich) was added to the model control group; culture medium containing LPS and dexamethasone was added to the positive control group; and culture medium containing LPS and a certain concentration of compound E was added to the sample group. Each group was exposed for 24 hours. After incubation, cell supernatants were collected and stored at -80ºC. The levels of IL-1α, IL-6, IL-8, and TNF-α were measured according to the ELISA kit (R&D Systems) instructions.

[0412] The results showed that compound E effectively reduced inflammatory factors in keratinocytes, and therefore indicated that compound E could be used to alleviate inflammation associated with clinical skin diseases.

[0413] Example 43 In vitro anti-inflammatory effects in macrophages Culture medium was added to the blank control group; culture medium containing LPS (Sigma-Aldrich) was added to the model control group; culture medium containing LPS and dexamethasone was added to the positive control group; and culture medium containing LPS and a certain concentration of compound E was added to the sample group. Each group was exposed for 24 hours. After incubation, cell supernatants were collected and stored at -80ºC. The levels of IL-6, TNF-α, and NO were measured according to the ELISA kit (R&D Systems) instructions.

[0414] The results showed that compound E effectively reduced inflammatory factors in macrophages, and therefore indicated that compound E could be used to alleviate inflammation associated with clinical diseases.

[0415] Example 44 In vitro oil control of sebaceous gland cells Two mL of cell culture medium was added to the blank control group; two mL of cell culture medium containing linoleic acid (MCE, China) was added to the model group; two mL of cell culture medium containing linoleic acid and retinoic acid was added to the positive control group; and two mL of cell culture medium containing linoleic acid and the test concentration sample was added to the sample group. All groups were incubated in a CO2 incubator for 48 hours. After incubation, the supernatant was discarded, and 1 mL of PBS was added dropwise to wash the cell layer. 500 μL of paraformaldehyde was added for fixation at room temperature for 5 minutes. The cell layer was washed twice with 1 mL of PBS, and 500 μL of Nile Red dye was added. The cells were incubated in the dark at 37ºC for 15 minutes. The cell layer was washed twice with 1 mL of PBS, and the cells were observed and photographed under an inverted phase-contrast fluorescence microscope.

[0416] The results showed that compound E was effective in controlling the sebum content of sebaceous gland cells. Therefore, compound E has been shown to effectively reduce sebum secretion in the skin of patients using it clinically.

[0417] Example 45 Acute oral toxicity in mice from the Institute for Cancer Research (ICR) Animals (Beijing Chairs River Experimental Animal Technology Co., Ltd.) were divided into male and female cages, with 5 animals in each cage. Before the experiment, the animals were fasted overnight, but drinking water was not restricted. Using a maximum-limit experiment, the animals were weighed and administered the toxin via tube feeding at a volume of 2 mL / 100 g and a dose of 5000 mg / kg body weight. Animals were poisoned once every 24 hours. After poisoning, the animals were fasted for 3-4 hours. Following poisoning, the animals were observed for any abnormalities daily, and autopsies were performed on any animals that died during the observation period. The animals were euthanized at the end of the observation period. Abnormalities in tissues and organs were observed visually, and histopathological examination was performed when necessary. The results are shown in Table 28 below.

[0418] Table 28 The results showed that compound E had an LD50 greater than 5000 mg / kg in ICR mice and was classified as non-toxic according to the acute oral toxicity grading. Therefore, compound E has been shown to be safe in ICR mice at very high doses, and based on previous animal data, compound E also demonstrates good safety in a clinical setting.

[0419] Example 46 Acute transdermal toxicity in SD rats The animals (Beijing Chairs River Experimental Animal Technology Co., Ltd.) were divided into male and female cages, with 5 animals in each cage. The testing area was approximately 30-40 cm. 2 Before the experiment, animals were acclimatized to the laboratory environment for 3 days to ensure they were healthy and free of skin damage. Approximately 24 hours before the experiment, the fur on the back of the animals in the area to be contaminated was trimmed. Care was taken to avoid skin damage during fur removal. The experiment used a maximum-limit test with a toxic dose of 2180 mg / kg. After weighing the animals, the test substance was moistened with water and applied evenly to the contaminated area of ​​the animal's back skin. The skin was covered with a thin film and secured with non-irritating adhesive tape. The skin was sealed and kept under wraps for 24 hours without contact. After poisoning, residual test substance was removed with warm water. Animals were observed daily for any abnormalities after poisoning, and autopsies were performed on dead animals during the observation period. Animals were euthanized after the observation period. Abnormalities in tissues were observed visually, and histopathological examination was performed if necessary. The observation period was 14 days. During the observation period, the weight of the active subjects was recorded on days 0, 1, 7, and 14 (D0-14). The results are shown in Table 29 below.

[0420] Table 29 The results showed that the LD50 of compound E in SD rats was greater than or equal to 2180 mg / kg, indicating mild toxicity. Therefore, compound E has been shown to be safe in SD rats at very high doses, and based on previous animal data, compound E has a good safety profile for clinical use.

[0421] Example 47 Compound E's effects on human acne Compound E was administered to adult subjects for 28 consecutive days under normal conditions, according to the product instructions, to evaluate whether the product demonstrated efficacy in reducing acne, controlling oil production, moisturizing, repairing, and soothing, and whether it was gentle (non-irritating) and suitable for sensitive skin. A total of 32 adult Chinese men and women with sensitive skin were included, comprising 7 men and 25 women, aged 19 to 43 years (mean age 27.91 ± 6.82), all meeting the inclusion and exclusion criteria. Compound E was applied twice daily in fingertip units for a total of 28 days. The dosage of the cream was based on fingertip units (FTUs), where one fingertip unit was the amount of cream (approximately 0.5 g) squeezed from a 5 mm open tube from the index finger to the first interphalangeal joint.

[0422] Images were captured using VISIA 7 for IPP analysis of skin color, redness areas, and porphyrins. Images were captured using Antera 3D (Miravex Limited, Ireland) for acne volume analysis. Skin hydration was measured using Corneometer® CM825 (Courage+Khazaka electronic GmbH, Germany). Transepidermal water loss was measured using Tewameter®™ HEX 5 (Courage+Khazaka electronic GmbH, Germany). Skin sebum was measured using Sebumeter SM 815 (Courage+Khazaka electronic GmbH, Germany). Dermatologist evaluation and self-assessment were performed.

[0423] The results are shown in Tables 30 and 31 below.

[0424] Table 30 Table 31 efficacy indicators Compound E, relative to baseline Whiteheads Statistical differences were observed on days 3, 7, and 28. Blackheads Statistical differences were observed on days 3, 7, and 28. papules Statistical differences were observed on days 3, 7, and 28. abscess There was a statistically significant difference on day 28. nodules There was a statistically significant difference between days 7 and 28. Acne size Statistical differences were observed on days 3, 7, and 28. Red skin There were statistically significant differences in the reddened areas on days 3, 7, and 28. Porphyrin No statistical difference skin oil content There was a statistically significant difference on day 28. Skin stratum corneum moisture content There was a statistically significant difference between days 7 and 28. Transdermal moisture loss rate There was a statistically significant difference on day 28. In a study of 32 Chinese male and female participants with sensitive skin, results showed that, under evaluation conditions, the product had anti-acne, oil-controlling, moisturizing, repairing, and soothing effects, and was gentle (non-irritating) and suitable for sensitive skin. Therefore, compound E has been shown to effectively reduce acne and provide significant skin benefits for patients using it.

[0425] Example 48 The efficacy of compound E in treating human gingivitis (ongoing) The purpose of this clinical study was to test the efficacy of compound E as a novel raw material for gingival protective peptide mouthwash and for controlling gingivitis. This study included seventy participants aged 18 to 60 years with gingivitis, with an estimated total of ≥60 participants completing the entire study (≥30 per group).

[0426] Inclusion criteria were: 1) good overall health and no systemic diseases; 2) age 18 to 60 years, male or female; 3) more than 20 intact teeth, no large-area restoration of the gingival margin, no untreated cavities, severe gingival recession, and severe periodontal disease; 4) modified Quigley-Hein plaque index ≥ 1.5; 5) Loe-Silness gingival index ≥ 2.0 and bleeding index ≥ 2.0.

[0427] Clinical evaluation criteria and methods: 1) Plaque Index (PI): 0 = No plaque; 1 = A single spot of plaque at the cervical margin of the tooth; 2 = A thin, continuous band of plaque (up to 1 mm wide) at the cervical margin; 3 = A band of plaque wider than 1 mm but covering less than 1 / 3 of the crown; 4 = Plaque covering at least 1 / 3 but less than 2 / 3 of the crown; 5 = Plaque covering 2 / 3 or more of the crown.

[0428] 2) Gingival Index (GI): 0 = normal gingiva; 1 = mild inflammation, slight color change, slight edema, no bleeding on probe; 2 = moderate inflammation, glazing gingiva, redness, edema, hyperplasia or bleeding on probe; 3 = severe inflammation, significant redness, edema, spontaneous bleeding tendency.

[0429] 3) Bleeding index: 0 = gums look healthy, with no inflammation or bleeding; 1 = color changes due to inflammation, no bleeding during probing; 2 = bleeding after probing; 3 = bleeding after probing that spreads to the marginal gums; 4 = bleeding that fills and overflows the gingival sulcus; 5 = spontaneous bleeding.

[0430] The test product is a mouthwash composed 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 is the same formulation without compound E. The mouthwash has a pH of 6.0.

[0431] All participants were provided with soft-bristled toothbrushes and toothpaste, and randomly assigned to either the test product group or the placebo group. After baseline data collection, participants were instructed to use the specified toothpaste and toothbrush twice daily (once in the morning and once after dinner), applying toothpaste to the entire length of the brush head and brushing for 3 minutes. They were then instructed to rinse thoroughly with 10 ml of mouthwash 30 seconds after brushing, spitting out the mouthwash, and to avoid eating or drinking for 30 minutes. Efficacy was evaluated after 1 month. Plaque index, gingival index (GI), and bleeding index were assessed by a dentist. Efficacy is expressed as the mean index score for each group.

[0432] The results showed that after one month of treatment, the plaque index, gingival index (GI), and bleeding index of the compound E group were all lower than those of the placebo group (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).

[0433] Therefore, compound E has been shown to be effective in relieving gingivitis and has significant benefits for patients using it.

[0434] Example 49 The efficacy of compound E on seborrheic dermatitis of the scalp. The test product was prepared as described in Example 27 above. This study included 66 healthy subjects aged 25 to 60 years, and the estimated number of subjects who completed the entire study was ≥ 60, i.e., ≥ 30 per group.

[0435] The inclusion criteria were: 1) hair length ≥ 3cm, 2) no severe hair loss, hair roots covering at least 70% of the scalp, 3) dandruff level ≥ 3 points, and 4) subjective feeling of scalp itching and redness.

[0436] Participants were randomly assigned to either the test group or the placebo group. After a two-week washout period, participants began using the test product, Compound E hair serum, or the placebo while washing their hair every two days with the provided shampoo. The test product was applied evenly to the scalp using a scalp applicator on dry hair, once daily, at a dose of 3 ml. If using the product after shampooing, hair must be dried before application.

[0437] Efficacy was evaluated after 28 days. The evaluation included measurements by laboratory technicians of scalp oil content (Sebumeter SM815, Courage+Khazaka electronic GmbH, Germany), stratum corneum moisture content (Corneometer CM825, Courage+Khazaka electronic GmbH, Germany), and transdermal water transfer loss rate (Tewameter, Courage+Khazaka electronic GmbH, Germany). Overall scalp condition, itching, dandruff, dryness, and redness were assessed by a dermatologist.

[0438] The results showed that compound E can effectively control scalp oil secretion, increase scalp moisture content, and repair the scalp skin barrier. It can also relieve itching, reduce the severity of dandruff, and reduce scalp dryness and redness (Table 32 below).

[0439] Table 32 parameter rate of change Significant difference compared to D0 Improvement in subjects (improvement rate %) Skin hydration 28.56% Significant 30 (100%) Transdermal water loss -15.35% Significant 30 (100%) skin sebum -28.26% Significant 30 (100%) Therefore, compound E has been shown to be effective in relieving symptoms associated with seborrheic dermatitis and to provide significant benefits to patients using it.

[0440] Example 50 Rosacea treatment A 31-year-old woman was diagnosed with rosacea. She had small pink or red bumps on her face. She experienced redness around her mouth (blushing) and felt warmth, heat, itching, or pain. She may have experienced a burning or stinging sensation when using water or skincare products. She used Compound E cream (as described in Example 26) twice daily for 7 days. The redness and itching subsided, and the bumps disappeared. Figure 8 ).

[0441] Example 51 Gastroesophageal reflux disease (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) Twenty SPF-grade male Wistar rats weighing 280-350 g were provided by Zhejiang Charles River Experimental Animal Technology Co., Ltd., certificate number: 20211103Aaz0600000356.

[0442] Before surgery and experimentation, the rats were fed and cared for for approximately one week. The temperature was 25ºC-27ºC, the humidity was 74%, and there was a 12-hour light-dark cycle with free access to food and water.

[0443] Rats were randomly divided into 5 groups of 4 rats each. The groups were: sham group, model group, and groups containing compounds K, L, and M. Rats were anesthetized with 2% isoflurane inhalation and placed in a supine position. The surgical area was shaved with a clipper, and the skin was disinfected with povidone-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. The connective tissue between the liver and stomach was separated and cut. The vascular bundle between the spleen and the gastric fundus was ligated and severed to completely release the gastric fundus. The gastric fundus was slightly rotated to the left to expose the left side of the gastroesophageal junction. A 5 mm longitudinal incision was made in the muscle along the distal esophagus using sharp scissors to expose the gastroesophageal junction.

[0444] Gently separate the dorsal side of the esophagus from the blood vessels behind it. Insert a small cotton swab between the esophagus and the blood vessels. Using sharp surgical scissors, make two 5 mm longitudinal incisions at the gastroesophageal junction and at the proximal duodenum near the pylorus. For the duodenal incisions, avoid the blood vessels and place them at the edge of the mesentery. Use interrupted 8-0 Prolene sutures to precisely anastomose the incisions mucosa to mucosa. Suture 3-4 stitches on the dorsal side and 2-3 stitches on the anterior side. Wash the abdominal cavity with saline and close the abdominal wall and skin. Perform surgery on each rat except those in the sham surgery group. After anesthesia and laparotomy, separate the lower esophagus, duodenum, and gastric fundus in the sham surgery group without making an incision.

[0445] Rats were fasted and deprived of water for 30 hours post-surgery. Glucose solution (8 ml / animal) was administered via tail vein infusion for two consecutive days. Rats were also given 50,000 IU of penicillin intramuscularly once daily for three consecutive days to prevent infection. One week post-surgery, different interventions were administered to rats via tube feeding according to Table 33 below.

[0446] Table 33 Compounds K, L, and M (GL Biochem, Shanghai, China) were completely suspended in 10 ml of 0.5% CMC-Na (sodium carboxymethyl cellulose, Chemical Reagent Co., Ltd. China) solution to obtain three test solutions with a concentration of 50 mg / ml.

[0447] Intervention was administered once daily for two weeks. Body weight was measured every three days. Two weeks after intervention, the animal was euthanized and the thoracic cavity opened. The esophagus was dissected and longitudinally incised to expose the anastomosis site. The severity of esophagitis was assessed according to the scoring criteria in Table 34 below.

[0448] Table 34 The results of the severity of esophagitis are in Figure 9 The results showed that montelukast and pranlukast can reduce the severity of esophagitis in a rat model of GERD.

[0449] Example 52 PK Study: Instrument-Assisted Transdermal Administration Test sample: Compound E: Dissolve 1 mg of compound E in 1 ml of physiological saline to prepare a 1 mg / ml solution.

[0450] Compound E + PL429: PL429 (Guangzhou Jizhou Trading Co., Ltd) is a transdermal enhancer. Add 0.5% PL429 to the above solution.

[0451] Twenty-seven SPF-grade male SD rats weighing 250-300 g were provided by Zhejiang Charles River Experimental Animal Technology Co., Ltd. and were housed and cared for for approximately one week prior to the experiment. The housing temperature was 25ºC-27ºC, with 74% humidity and a 12-hour dark-light cycle, and free access to food and water. As described in Table 35 below, the rats were randomly divided into three groups of nine rats each (three sample collection points per group).

[0452] Table 35 The instrument used is a high-pressure transdermal nutritional supplementation instrument (Guangzhou Tuonasi Beauty Instrument Co., Ltd, China).

[0453] Shave the hair from the application site (skin on the left side of the spine), covering an area of ​​4.0 cm. 2 The application area is 3 cm. 2 Mark it. Apply to intact skin (without any damage).

[0454] Sample preparation: At each time point, approximately 200 µL of whole blood was collected from the carotid artery of each group of animals and injected into EP tubes containing EDTA-K anticoagulant. Immediately, the tubes were manually shaken and placed on wet ice. The samples were centrifuged at 1800 g, 4ºC for 10 minutes. Plasma was separated over 2 hours and stored at -80ºC. Simultaneously, skin tissue from the application site was collected. Before collecting tissue samples, the site was washed with physiological saline and allowed to dry. After collection, the samples were stored at -80ºC for further analysis.

[0455] The results are shown in Table 36 below.

[0456] Table 36 The results showed that after topical application to the skin, a significant amount of compound E remained in the skin tissue. Neither the transdermal enhancer nor the instrument significantly increased plasma exposure. However, the instrument could increase the local concentration. This demonstrates the beneficial properties of topical application of compound E.

[0457] Example 53 Skin pigmentation: Instrument-assisted transdermal application - 1 Test sample: Compound E: Dissolve 1 mg of compound E in 1 ml of physiological saline to prepare a 1 mg / ml solution.

[0458] instrument: Dermashine pro (Huons Meditech, Republic of Korea) is an automated mesotherapy injector that uses vacuum pressure. It has been used to replenish moisture and nutrients to the skin.

[0459] Following a beach trip, a 56-year-old woman developed pigmentation on her cheeks. During her time at the beach, the subject was exposed to sunlight, causing her skin to redden. Pigmentation appeared a few days later. The subject visited a beauty salon for treatment. Compound E was injected into the entire face using Dermashine. The solution was filtered through a 0.22 µm Minisart® high-flow filter (Sartorius, Germany). A total of 3 ml of solution was injected. Treatment was repeated after 2 weeks. One week after the second injection, the pigmentation had disappeared, and skin dullness and roughness had significantly improved.

[0460] Example 54 Skin pigmentation: Instrument-assisted transdermal application - 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.

[0461] A 32-year-old woman developed hyperpigmentation on both cheeks after giving birth to a baby girl. Six months postpartum, she sought treatment for her face. The subject visited a beauty salon and was recommended a non-invasive treatment using the solution mentioned above. A high-pressure transdermal nutrient supplementation device (Guangzhou Tuonasi Beauty Instrument Co., Ltd., China) was used to enhance solution absorption. Treatments were performed weekly. After two months, her skin became firm and flawless.

[0462] 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) Based on animal weight, a total of 67 male SD rats were randomly assigned to a normal control group (n=10) and a model group (n=57). Animals in the normal control group received intraperitoneal injection and endotracheal nebulization of sodium chloride injection. Animals in the model group received intraperitoneal injection and endotracheal nebulization of lipopolysaccharide (LPS) to induce an acute lung injury model (2 mg / kg intraperitoneally on day 0, 4 mg / kg endotracheal nebulization on day 1, approximately 16 hours apart). On day 1, after LPS nebulization into the trachea, the animals in the model group were again randomly assigned by weight to: a mediator 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 a positive control group (2.5 mg / kg). The normal control group was not further reassigned. Animals in the normal control group and the medium control group were given intravenous injection of 0.9% sodium chloride solution. Animals in the test compound N, compound O, and compound M groups were given intravenous injections of the corresponding doses once daily for one day. Animals in the positive control group were given intraperitoneal injection of dexamethasone sodium phosphate solution once daily for one day. On the second day, the animals were anesthetized and euthanized, and lung lavage fluid and lung weight index tests were performed.

[0463] Bronchoalveolar lavage fluid (BALF): Compared with the corresponding indicators in the control group, the mean values ​​of WBC, Neut, Lymph, and Mono in the test compound N, compound O, and compound M groups, as well as the positive control group, were significantly reduced. The maximum decreases in WBC were approximately 62%, 74%, 84%, and 87%, respectively, which were statistically significant. The maximum decreases in Neut were approximately 73%, 79%, 92%, and 93%, respectively, which were statistically significant. The maximum decreases in Lymph were approximately 65%, 76%, 82%, and 84%, respectively, which were statistically significant. The maximum decreases in Mono were approximately 71%, 85%, 88%, and 91%, respectively, which were statistically significant.

[0464] Total protein: Compared with the total protein in the BALF of animals in the vector control group, the mean total protein in the test compound N, compound O, and compound M groups, as well as the positive control group, showed a significant decrease. The maximum decreases in total protein were approximately 68%, 72%, 77%, and 56%, respectively, which were statistically significant.

[0465] Lung weight index: Compared with the lung weight index of animals in the vector control group, the mean lung weight index of animals in the test compound N, compound O, and compound M groups, as well as the positive control group, showed a significant decrease. The maximum decreases in lung weight index were approximately 20%, 23%, 25%, and 29%, respectively, which were statistically significant.

[0466] Inflammatory factors: Compared with the serum and BALF inflammatory factors (Ang-2, LTD4) in the vector control group, the levels of test compound N, compound O, and compound M, as well as the positive control group, were significantly decreased. The maximum decreases in serum Ang-2 were approximately 25%, 31%, 40%, and 46%, respectively. The maximum decreases in BALF Ang-2 were approximately 25%, 27%, 37%, and 55%, respectively, showing statistical differences compared to the positive control group. The maximum decreases in serum LTD4 were approximately 35%, 32%, 37%, and 32%, respectively. The maximum decreases in BALF LTD4 were approximately 5%, 15%, 10%, and 25%, respectively.

[0467] In summary, under the conditions of this study, intravenous administration of the test products of compounds N, O, and M at a dose of 0.5 mg / kg once daily reduced total white blood cell count, neutrophil count, total protein, lung weight index, and serum and BALF markers of Ang-2 and LTD4 in rats with acute lung injury, indicating that the compounds are effective in treating acute lung injury.

[0468] Example 56 Compound P foam: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO) ID No: 114) The preparation of compound P foam involves a mixture of the following substances listed in Table 37.

[0469] Table 37 Mutually Material quantity(%) A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 glycerin 5.0 A4 benzyl alcohol 1.0 A5 pure water 90.4 A6 Compound P 0.1 B1 Sodium hydroxide Mix the components of phase A and stir for 30 minutes until the system is homogeneous. While stirring, add sodium hydroxide to adjust the pH of the solution to 6.5.0 to obtain compound P foam.

[0470] This foam is intended to be used as an anti-inflammatory agent to repair vaginal mucosal damage caused by obstruction and surgery.

[0471] Example 57 Compound P gel: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 1) ID No: 114) The formulation of compound P gel contains a mixture of the following substances listed in Table 38.

[0472] Table 38 Mutually Brand Name INCI Name quantity(%) A1 pure water AQUA 81.23 A2 Propylene glycol Propylene glycol 13.40 A3 glycerin glycerin 2.60 A4 Carbomer 940 KABOMUER 0.67 A5 Carbomer 941 KABOMUER 0.13 A6 Triethanolamine Triethanolamine 0.80 A7 4-Hydroxyacetophenone Hydroxyacetophenone 0.50 A8 1,2-Hexanediol Hexanediol 0.50 A9 Sodium hyaluronate (1.5 M Da) Sodium hyaluronate 0.07 A10 Compound P 0.10 Mix the components of phase A, heat to 80ºC, and stir at 80ºC for 30 minutes. Allow the sample to cool until the system is homogeneous to obtain a gel of compound P.

[0473] This gel is intended to be used as an anti-inflammatory agent to repair colorectal mucosal damage caused by obstruction and surgery.

[0474] Example 58 Compound P tablets: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 1) ID No: 114) The preparation of compound P tablets involves a mixture of the following substances listed in Table 39.

[0475] Table 39 Mutually Material quantity(%) A1 β-Cyclodextrin 6.0 A2 Mannitol 20.0 A3 Citric acid 3.0 A4 Cross-linked polyvinylpyrrolidone 7.0 A5 starch 62.9 A6 Compound P 0.1 B1 50% ethanol Appropriate amount C1 magnesium stearate 1.0 The components of phase A were sieved through a 100-mesh sieve. The adjuvant was added sequentially to compound P and mixed thoroughly. 50% ethanol was used as a wetting agent, and the adjuvant was added simultaneously, with continuous stirring to ensure uniform wetting. The moisture content of the material was adjusted to prepare a soft material that could be formed into balls by hand and dispersed upon gentle pressing. The prepared soft material was sieved through a 20-mesh standard sieve to obtain wet granules.

[0476] The prepared wet granules were evenly spread on a tray with a granule layer thickness of 2 cm to 3 cm. The granules were dried at 55ºC for 1 h, turning them every 15 min to accelerate the drying process, and ensuring uniform drying until the moisture content was below 3%.

[0477] The dried granules are sieved again, graded by size, mixed with a certain amount of lubricant magnesium stearate, and then compressed in a tablet press to obtain tablets of compound P.

[0478] This tablet is intended to be used as an anti-inflammatory drug and to repair gastrointestinal mucosal damage caused by obstruction and surgery.

Claims

1. A compound of formula I, L t -Q a -D b (I) in: Q a Indicates Z or AQB; Q is a structural segment of equation II. (II) in: The wavy line represents the attachment point of Q to A and / or B; R is selected from: , and Where R represents In this case, one wavy line represents the attachment point with the rest of the Q segment, and the other wavy line represents the attachment point with the Z group. m represents an integer from 1 to 4; A and B independently represent Z or A 1 -Q 1 -B 1 ; A 1 and B 1 Independently represent Z or A 2 -Q 2 -B 2 ; A 2 and B 2 Independently represent Z or ZQ 3 -Z; Q 1 Q 2 and Q 3 Independently represent the structural fragment of expression III. (III) in: The wavy lines adjacent to the NH group represent Q. 1 Q 2 and Q 3 With A 1 and / or B 1 A 2 and / or B 2 The attachment point of Z; The wavy lines adjacent to the C=O group represent Q. 1 Q 2 and Q 3 With Q, Q 1 and Q 2 Attachment point; m is as defined above; Each L independently represents one or more lipids selected from vitamin A, vitamin E, cholesterol, and fatty acids, wherein the fatty acids contain one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, and the lipids are straight-chain or branched, saturated or unsaturated lipids having between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10 -OH groups, or derivatives of any of these lipids. 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 above cases where it is used, Z represents the structural fragment of expression 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) in: n represents an integer selected from 0 to 4; In each case where it is used, r independently represents 0 or 1; In each case of its use, 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, when present, the HCA residues are located at the N-terminus of Z. X 1 Independently represent Pro, Hyp, or diHyp; T independently represents Ser or pSer; U independently represents Tyr, pTyr, DOPA, Hyp, or Pro; X 2 Independently represent Thr, Ser, Pro, Hyp, or diHyp; Y independently represents a sequence of 1 to 5 (such as 1 to 4) amino acids selected from one or more of the group consisting of Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, the sequence optionally terminated by dopamine (or more appropriately, "dopamine fragment"). If present, each D is covalently bonded to Z via an amide bond between its corresponding carboxylic acid residue and one or more NH2 residues of Z; and Each L residue is covalently bonded to Z via an amide bond between the corresponding carboxylic acid residue of L and one or more NH2 residues of Z and / or via an ester bond between the corresponding -OH residue of L and one or more carboxylic acid residues of Z. And the regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the compound.

2. The compound according to claim 1, wherein the lipid is selected from palmitic acid, stearic acid, oleic acid, octadecanoic acid, docosahexaenoic acid and leukotriene B4 or derivatives of any one of these lipids.

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 palmitamide ethanol (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-glycerol-3-phosphate-1-serine, phosphatidylethanolamine, or 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine.

7. The compound according to claim 3, wherein the derivative is 1,2-dipalmitoyl-sn-glycerol-3-phosphate-1-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-distearate-sn-glycerol-3-phosphate-1-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-dioleoyl-sn-glycerol-3-phosphate-L-serine.

12. The compound of claim 1, wherein the lipid is selected from vitamin E, vitamin A, and cholesterol, or derivatives of any one of these lipids.

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

14. The compound according to any one of the preceding claims, wherein Q a Z represents the symbol.

15. The compound according to any one of the preceding claims, wherein n represents 0.

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

17. The compound according to any one of the preceding claims, wherein X 1 It stands for Pro.

18. The compound according to any one of the preceding claims, wherein T represents Ser.

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

20. The compound according to any one of the preceding claims, wherein X 2 It represents Hyp.

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

22. The compound of claim 21, wherein the amino acid sequence defined by Y is selected from the group consisting of: -Hyp-Thr-Tyr-Lys-; -Hyp-Thr-DOPA-Lys-; -Thr-Tyr-Hyp-Lys-; -Thr-DOPA-Hyp-Lys-; -DOPA-Lys-; and -Tyr-Lys- Each of these is optionally terminated via a dopamine fragment.

23. The compound according to claim 22, wherein Z is selected from the group consisting of: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 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 (SEQ ID No: 12); 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 (SEQ ID No: 19).

24. The compound according to any one of the preceding claims, wherein the compound is used in human or animal medicine.

25. The compound according to any one of claims 1 to 23, wherein the compound is used as a drug.

26. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 25.

27. The pharmaceutical formulation of claim 26, wherein the pharmaceutical formulation further comprises a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

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

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

30. The pharmaceutical preparation according to any one of claims 26 to 29, wherein the pharmaceutical preparation further comprises one or another pharmaceutically active ingredient.

31. A kit comprising the following components: (A) The compound according to any one of claims 1 to 23 or the pharmaceutical preparation according to any one of claims 26 to 30; and (B) A pharmaceutical preparation comprising one or more pharmaceutically active ingredients mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. The components (A) and (B) are each provided in a form suitable for combined application with each other.

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

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

34. The compound according to any one of claims 1 to 23, the formulation according to any one of claims 26 to 30, 32 or 33, or the kit according to any one of claims 31 to 33, wherein the compound, the formulation, or the kit is used to treat inflammation, inflammatory disorders, and / or disorders characterized by inflammation.

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

36. A method for treating inflammation, inflammatory disorders, and / or disorders characterized by inflammation, the method 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 kit according to any one of claims 31 to 33.

37. The compound, formulation, or kit for the said use according to claim 34, the use according to claim 35, or the method according to claim 36, wherein the inflammatory barrier is a wound or burn or causes a wound or burn.

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

39. The compound, formulation, or kit for the said use according to any one of claims 24 to 38, the use, or method (as the case may be), wherein the one or more compounds or salts thereof are applied topically as an external formulation.

40. The compound, formulation, or kit for the said use according to claim 39, wherein the related condition is treated by direct topical application to the skin.

41. The compound, formulation, or kit for the said use according to claim 39, wherein the related condition is treated by direct topical application to a mucosal surface.

42. The compound, formulation, or kit for the said use according to any one of claims 24 to 41, the use, or method (as the case may be), wherein the one or more of the compound is administered orally, intravenously, through the skin or subcutaneously, via the nose, intramuscularly, intraperitoneally, via the lungs, or via the anus or rectum.

43. The compound, formulation, or kit for the said use according to any one of claims 30 to 42, the use, or the method (as the case may be), wherein the compound according to any one of claims 1 to 23 acts as an excipient, a medical device, or a component of a pharmaceutical-medical device combination.

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