Novel short-chain peptide and derivative thereof

Abstract

There is provided a compound of formula I, X-Y (I) wherein: Y comprises a peptide fragment of formula IV, [Ala] m-[Lys-V] n-Lys-V (IV) wherein m represents 0 or 1, n represents the integer 0, 1, 2, 3 or 4, and each V independently represents a sequence of 2 to 4 amino acids wherein the amino acids are selected from one or more of the group consisting of Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr and Ser; and X represents at least one optional substituent selected from the group consisting of: (i) a lipid selected from the group consisting of vitamin A, vitamin E, cholesterol and fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons and / or one or more cyclic rings, said lipids being linear or branched, saturated or unsaturated with between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10-OH groups, or a derivative of any of these lipids; and / or (ii) a non-steroidal anti-inflammatory agent, which compounds may be used in medicine, including as pharmaceutical excipients, adhesives and film-forming materials, and / or may be used in the treatment of conditions characterized by inflammation, including wounds, burns and mucosal disorders such as skin diseases, oral diseases, gynecological diseases and IBD.

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, tissue-damaging inflammation. 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, as well as 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] A key portion of mefp-1 consists of 70 to 90 tandem decapeptide repeats of the following sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 1; see Waite, Int. J. Adhesion and 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 synthesized, for example, as by Yamamoto. J. Chem. Soc., Perkin Trans. , 1987, 1 See also Dalsin et al., 613-618. J. Am. Chem. Soc. , 2003, 125 , 4253-4258.

[0009] Decapeptide analogs are also disclosed, particularly 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.

[0010] Japanese patent application JP 2003238589 A discloses certain dipeptides and tripeptides that act as angiotensin-converting enzyme inhibitors.

[0011] 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.

[0012] There is clearly a need for new and / or improved medicines that can be used to treat inflammation and conditions characterized by inflammation. Detailed Implementation

[0013] According to a first aspect of the present invention, a compound of formula I is provided. XY(I) in: Y represents Z or Z-Lys-Z; Each time it is used, Z independently represents the structural fragment of expression IV. [Ala] m -[Lys - V] n -Lys-V (IV) (SEQ ID No: 3) in: m represents 0 or 1; n represents an integer 0, 1, 2, 3, or 4; Each time it is used, V independently represents a sequence of 2 to 4 amino acids, wherein the amino acids are selected from one or more of the following group: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, and Ser; X represents at least one optional substituent selected from the following: (i) lipids selected from vitamin A, vitamin E, cholesterol, and fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, wherein the lipids are straight-chain or branched, saturated or unsaturated 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; and / or (ii) Nonsteroidal anti-inflammatory drugs (NSAIDs) And the regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the compounds. The conditions are that when X does not exist, Y represents Z, and both m and n represent 0, and V does not represent -Pro-Lys. The compounds, regioisomers, stereoisomers, and salts mentioned herein are collectively referred to as "the compounds of this invention".

[0014] The compounds of the present invention that may be mentioned include these compounds, wherein Y represents Z-Lys-Z, or more preferably Y represents Z.

[0015] Those skilled in the art will understand that when Y represents Z-Lys-Z and X is present, Y is attached to X via the -NH2 group of Y.

[0016] In a particular embodiment, Y is attached to X via the -NH2 of the side chain of the "Lys" group of Y.

[0017] In an alternative implementation, Y is attached to X via a -NH2 residue at the N-terminus of Y.

[0018] In some implementation schemes: When m represents 1, then Z represents: Ala-Lys-Pro-Ser (SEQ ID No: 4); or Ala-Lys-Pro-Ser-Tyr (SEQ ID No: 5).

[0019] Other implementation schemes that may be specifically mentioned include these implementation schemes, in which: The amino acids in V are selected from the following group: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, and Tyr; and m represents 0.

[0020] Preferably, each time it is used: V represents a sequence of 4 amino acids or more preferably 2 amino acids; The amino acids in V are selected from the following groups: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, and Tyr.

[0021] A further preferred approach is to use it each time: V represents a sequence of 4 amino acids or more preferably 2 amino acids; The amino acids in V are selected from the following group: Pro, Hyp, Lys, Tyr, and DOPA.

[0022] A further preferred approach is to use it each time: The amino acid adjacent to Lys in V is selected from Pro or Hyp; The C-terminal amino acid in V is selected from Tyr and DOPA, and especially Lys; and / or At least one other amino acid in the sequence defining V is Hyp.

[0023] Preferred compounds of the present invention include these compounds, wherein Z represents: [Lys-V]n -Lys-V (SEQ ID No: 6) Where n is as defined above, or more preferably 1, such that the compounds of the present invention are isolated peptides as defined by the following formula: Lys-V-Lys-V (SEQ ID No: 7), Or specifically, 0, such that the compounds of the present invention are isolated peptides as defined by the following formula: Lys-V (SEQ ID No: 8), V is defined as above each time it is used.

[0024] In this case, when n is 0 and V represents a sequence of 2 amino acids, the preferred value of Z is defined by the following sequence: Lys-Pro-Lys (SEQ ID No: 9); Lys-Pro-Tyr (SEQ ID No: 10); Lys-Pro-DOPA (SEQ ID No: 11); more preferably Lys-Hyp-Tyr (SEQ ID No: 12); Lys-Hyp-DOPA (SEQ ID No: 13); or more specifically, Lys-Hyp-Lys (SEQ ID No: 14).

[0025] In the alternative, when n is 0 and V represents a 3-amino acid sequence, the C-terminal amino acid in V is Lys, and the preferred value of Z is defined by the following sequence: Lys-Pro-Pro-Lys (SEQ ID No: 15); Lys-Pro-Hyp-Lys (SEQ ID No: 16); Lys-Hyp-Pro-Lys (SEQ ID No: 17); or more specifically, Lys-Hyp-Hyp-Lys (SEQ ID No: 18).

[0026] Additionally, when n is 0 and V represents a 4-amino acid sequence, the C-terminal amino acid sequence in V contains Pro-Lys or more preferably Hyp-Lys, and the preferred value of Z is defined by the following sequence: Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 19); Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 20); Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 21); Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 22); Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 23); Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 24); or more specifically Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 25); or Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 26).

[0027] When n is 1, V preferably represents a sequence of 2 amino acids each time it is used, and the preferred value of Z is defined by the following sequence: Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID No: 27); Lys-Hyp-Tyr-Lys-Pro-Lys (SEQ ID No: 28); Lys-Hyp-Tyr-Lys-Pro-Tyr (SEQ ID No: 29); Lys-Hyp-Tyr-Lys-Pro-DOPA (SEQ ID No: 30); Lys-Hyp-DOPA-Lys-Hyp-Tyr (SEQ ID No: 31); Lys-Hyp-DOPA-Lys-Pro-Lys (SEQ ID No: 32); Lys-Hyp-DOPA-Lys-Pro-Tyr (SEQ ID No: 33); Lys-Hyp-DOPA-Lys-Pro-DOPA (SEQ ID No: 34); Lys-Pro-Lys-Lys-Hyp-Tyr (SEQ ID No: 35); Lys-Pro-Lys-Lys-Hyp-DOPA (SEQ ID No: 36); Lys-Pro-Lys-Lys-Pro-Tyr (SEQ ID No: 37); Lys-Pro-Lys-Lys-Pro-DOPA (SEQ ID No: 38); Lys-Pro-Tyr-Lys-Hyp-Tyr (SEQ ID No: 39); Lys-Pro-Tyr-Lys-Hyp-DOPA (SEQ ID No: 40); Lys-Pro-Tyr-Lys-Pro-Lys (SEQ ID No: 41); Lys-Pro-Tyr-Lys-Pro-DOPA (SEQ ID No: 42); Lys-Pro-DOPA-Lys-Hyp-Tyr (SEQ ID No: 43); Lys-Pro-DOPA-Lys-Hyp-DOPA (SEQ ID No: 44); Lys-Pro-DOPA-Lys-Pro-Lys (SEQ ID No: 45); Lys-Pro-DOPA-Lys-Pro-Tyr (SEQ ID No: 46); or preferably, Lys-Hyp-Tyr-Lys-Hyp-Tyr (SEQ ID No: 47); Lys-Hyp-DOPA-Lys-Hyp-DOPA (SEQ ID No: 48); Lys-Pro-Lys-Lys-Pro-Lys (SEQ ID No: 49); Lys-Pro-Tyr-Lys-Pro-Tyr (SEQ ID No: 50); Lys-Pro-DOPA-Lys-Pro-DOPA (SEQ ID No: 51); or more preferably, Lys-Hyp-Lys-Lys-Hyp-Tyr (SEQ ID No: 52); Lys-Hyp-Lys-Lys-Hyp-DOPA (SEQ ID No: 53); Lys-Hyp-Lys-Lys-Pro-Lys (SEQ ID No: 54); Lys-Hyp-Lys-Lys-Pro-Tyr (SEQ ID No: 55); Lys-Hyp-Lys-Lys-Pro-DOPA (SEQ ID No: 56); or even more preferably, Lys-Hyp-Tyr-Lys-Hyp-Lys (SEQ ID No: 57); Lys-Hyp-DOPA-Lys-Hyp-Lys (SEQ ID No: 58); Lys-Pro-Lys-Lys-Hyp-Lys (SEQ ID No: 59); Lys-Pro-Tyr-Lys-Hyp-Lys (SEQ ID No: 60); Lys-Pro-DOPA-Lys-Hyp-Lys (SEQ ID No: 61); or Lys-Hyp-Lys-Lys-Hyp-Lys (SEQ ID No: 62).

[0028] Preferred compounds of the present invention include those compounds in which, when Y is defined by Z-Lys-Z, the two peptide sequences defined by Z are identical and are defined by the following formula: Lys-V-Lys-V (SEQ ID No: 7), Or more specifically, it is defined by the following formula: Lys-V (SEQ ID No: 8), V is defined as above each time it is used.

[0029] In this case, V preferably represents a sequence of 2 amino acids, such that the preferred value of Z is defined by the following sequence: (Lys-Pro-Lys)2-Lys (SEQ ID No: 63); (Lys-Pro-Tyr)2-Lys (SEQ ID No: 64); (Lys-Pro-DOPA)2-Lys (SEQ ID No: 65); more preferably (Lys-Hyp-Tyr)2-Lys (SEQ ID No: 66); (Lys-Hyp-DOPA)2-Lys (SEQ ID No: 67); or more specifically (Lys-Hyp-Lys)2-Lys (SEQ ID No: 68).

[0030] However, the preferred compounds of the present invention comprise a linear peptide sequence defined by Z.

[0031] The compounds of the present invention that may be mentioned include these compounds, wherein X is absent, such that the compounds of the present invention are isolated peptide compounds consisting substantially of any one of the above peptide sequences, or regioisomers, stereoisomers, or pharmaceutically or cosmetically acceptable salts of said compounds.

[0032] When X is present, it can represent one or more lipids, in which case the one or more lipids can be selected from palmitic acid, stearic acid, oleic acid, octadecanoic acid, docosahexaenoic acid and leukotriene B4 (LTB4) or derivatives of any of these.

[0033] Further preferred compounds of the present invention include those compounds in which one or more lipids comprise polyunsaturated fatty acids or derivatives thereof. In such embodiments, the derivative may be a specialized pro-resolving mediator (SPM).

[0034] Further preferred compounds of the present invention include those compounds in which one or more lipids comprise derivatives of fatty acids, such as glycerolipids, glycerophospholipids, sphingolipids, or glycolipids.

[0035] Further preferred compounds of the present invention include those compounds wherein the one or more lipids comprise 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 (DPPS). In such embodiments, the derivative may be phosphatidylethanolamine, or more preferably, 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE).

[0036] Further preferred compounds of the present invention include those compounds in which one or more lipids comprise stearic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-distearate-sn-glycerol-3-phosphate-l-serine.

[0037] Further preferred compounds of the present invention include those compounds in which one or more lipids comprise oleic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-dioleoyl-sn-glycerol-3-phosphate-L-serine.

[0038] Further preferred compounds of the present invention include those compounds wherein one or more lipids comprise hexadecanoic acid ethanol (PEA).

[0039] Further preferred compounds of the present invention include those compounds wherein the one or more lipids are selected from vitamin E, vitamin A, and cholesterol, or derivatives of any of these. In such embodiments, the cholesterol derivative may be cholesterol-acetic acid.

[0040] Further preferred compounds of the invention include those compounds wherein the one or more lipids are selected from vitamin E and cholesterol or derivatives of any of these. In such embodiments, the cholesterol derivative may be cholesterol-acetic acid.

[0041] Further preferred compounds of the present invention include those wherein the lipids are fatty acids as defined above, said fatty acids may contain 1 to 5 -OH groups, such as 1 to 2 -OH groups. In other embodiments, the fatty acids may have 1 to 10 cyclic rings, such as 1 to 8 cyclic rings.

[0042] The compounds of the present invention that may be mentioned include these compounds, wherein X represents at least one lipid as defined above.

[0043] When X is present, it can further represent one or more “nonsteroidal anti-inflammatory drugs” (NSAIDs), and those skilled in the art will understand that the term includes one or more members of a class of drugs used to relieve pain, inflammation, and / or fever (and in some cases, to reduce blood clots). The phrase “nonsteroidal” will be well understood to exclude other pain relievers and, in particular, corticosteroids from this definition.

[0044] NSAIDs typically work by inhibiting the activity of cyclooxygenases (COX), including COX-1 and COX-2, which are known to be involved in the synthesis of key inflammatory mediators (such as prostaglandins) and mediators involved in hemostasis (such as thromboxanes).

[0045] NSAIDs that may be mentioned include those belonging to the following structural categories, and in particular those derived from carboxylic acids, including: Salicylic acid, or "salicylates", includes salicylic acid itself and its salts, disalicylic acid esters, diflunisal, and especially aspirin (acetylsalicylic acid) and 5-aminosalicylic acid (mesarazine). Acetic acid, including indomethacin, acemetacin, fenacs (such as diclofenac, fenclofenac, acetylclofenac and bromofenac), ketorolac, etodoxacin, sulphurin, fentiate, olmetin and nabumetone; Propionic acid, also known as "2-arylpropionic acid derivatives" or "profens", includes ibuprofen, naproxen, dextro-ibuprofen, fenprofen, ketoprofen, dextro-ketoprofen, flurbiprofen, oxapazine, loxoprofen, perbiprofen, zaltoprofen, fenbuprofen, carbofen, and thiaprofen acid; Enolic acids, also known as oxicams, include meloxicam, piroxicam, lornoxicam, itoxicam, tenoxicam, and drolixicam, as well as phenylbutazone (Bute); and Anthranilic acid, also known as "fenamate", includes mefenamic acid, meclofenamic acid, flufenamic acid, tofenamic acid, etofenamate, and clofenamic acid.

[0046] Other NSAIDs that may be mentioned include pyrazolone derivatives, including oxyprofen, isopropylantipyrine, aminopyrine, antipyrine, and analginum / metamizole, as well as nefopam. Other analgesic compounds that can be used in place of NSAIDs and / or in addition to NSAIDs include phenacetin and acetaminophen.

[0047] NSAIDs that may also be mentioned, but are less preferred, include selective COX-2 inhibitors or “coxibs”, such as celecoxib, rofecoxib, vardicoxib, parecoxib, phenicoxib, etoricoxib, and fenicoxib; sulfonylureas such as nimesulide; and clonisin, lecithin, and H-harbazoside.

[0048] Preferred NSAIDs include aspirin, salicylic acid, celecoxib, and mesalazine.

[0049] Optional lipid and / or NSAID substituents defined by X may be covalently bonded to the amino acid sequence of the peptide in the compounds of the present invention via the following bonds: an amide bond formed between the corresponding carboxylic acid residue of X and one or more free NH2 residues present in one or more amino acids of the peptide (including at the N-terminus of the peptide sequence); and / or an ester bond formed between the corresponding -OH residue of X and one or more free carboxylic acid residues present in one or more amino acids of the peptide (including at the C-terminus of the peptide sequence); and / or a sulfonamide bond formed between the corresponding -sulfonic acid group or derivative (such as sulfonyl chloride) group of X and one or more -NH2 residues of the peptide (including at the N-terminus of the peptide sequence).

[0050] Those skilled in the art will understand that the X group, which can be covalently bonded to the Z amino acid sequence via an amide bond, includes: salicylates (such as aspirin, salicylic acid and suitable salts, diflunisal, disalicylate, 5-aminosalicylic acid), propionic acid derivatives (such as ibuprofen, dextro-ibuprofen, naproxen, fenofoprofen, ketoprofen, dextro-ketoprofen, flurbiprofen, oxapazine, loxoprofen, perbiprofen, zaltoprofen), acetic acid derivatives (such as indomethacin, tomatine, sulphurin, etodoxacin, ketoroxyfen, diclofenac, aceclofenac, bromofenac), anthranilic acid derivatives (such as mefenamic acid, meclofenamic acid, flufenamic acid, tofenamic acid), selective COX-2 inhibitors (coxibices) (such as phenicoxib), and others (such as clonisin, levofloxacin).

[0051] Those skilled in the art will understand that the X group, which can be covalently bonded to the amino acid sequence of Z via an ester bond (optionally wherein the ester bond is formed by the -OH group of X, resulting from the acetate modification of X), includes: enolic acid (oxacin) derivatives (such as piroxicam, meloxicam, tenoxacin, lornoxicam) and others (such as H-harbazoside).

[0052] Technicians will understand that the X group that can be covalently bonded to the Z amino acid sequence via sulfonamide bonds includes: selective COX-2 inhibitors (coxib-like compounds) (such as celecoxib, vardicoxib).

[0053] The compounds of the present invention that may be mentioned include these compounds, wherein X represents: At least one lipid as defined above; and / or At least one nonsteroidal anti-inflammatory drug as defined above.

[0054] Preferably, in the compounds of the present invention, the total number of optional substituents defined by X does not exceed 8, more preferably not more than 4, such as 3, 2 or 1.

[0055] Preferred compounds of the present invention include these compounds, wherein X represents two lipids as defined above or more preferably one lipid as defined above.

[0056] Preferred compounds of the present invention include these compounds, wherein each present X group represents a lipid or an NSAID, preferably the same lipid (such as palmitic acid or a derivative thereof) or the same NSAID (such as mesalazine or preferably salicylic acid or aspirin).

[0057] In this regard, the compounds of the present invention that may be mentioned include: Palm-Lys-Pro-Lys (SEQ ID No: 69); Palm-Lys-Pro-Tyr (SEQ ID No: 70); Palm-Lys-Pro-DOPA (SEQ ID No: 71); more preferably Palm-Lys-Hyp-Tyr (SEQ ID No: 72) Palm-Lys-Hyp-DOPA (SEQ ID No: 73); or more specifically Palm-Lys-Hyp-Lys (SEQ ID No: 74), as well as: Palm-Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 75); Palm-Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 76); Palm-Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 77); Palm-Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 78); Palm-Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 79); Palm-Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 80); Preferably Palm-Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 81); or more specifically Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 82), as well as: Lys-Hyp-Tyr-Lys(Palm)-Hyp-Tyr (SEQ ID No: 83); Palm-Lys-Hyp-Tyr-Lys-Hyp-Tyr (SEQ ID No: 84); Palm-Lys-Hyp-Tyr-Lys(Palm)-Hyp-Tyr (SEQ ID No: 85); Lys-Hyp-Tyr-Lys(Palm)-Hyp-DOPA (SEQ ID No: 86); Palm-Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID No: 87); Palm-Lys-Hyp-Tyr-Lys(Palm)-Hyp-DOPA (SEQ ID No: 88); Lys-Pro-Lys-Lys-Pro-Lys(Palm) (SEQ ID No: 89); Lys-Pro-Lys-Lys-Pro(Palm)-Lys (SEQ ID No: 90); Lys-Pro-Lys(Palm)-Lys-Pro-Lys (SEQ ID No: 91); Palm-Lys-Pro-Lys-Lys-Pro-Lys (SEQ ID No: 92); Lys-Pro-Lys-Lys(Palm)-Pro-Lys(Palm) (SEQ ID No: 93); Palm-Lys-Pro-Lys-Lys-Pro-Lys(Palm) (SEQ ID No: 94); Lys-Pro-Lys(Palm)-Lys(Palm)-Pro-Lys (SEQ ID No: 95); Palm-Lys-Pro-Lys-Lys(Palm)-Pro-Lys (SEQ ID No: 96); Palm-Lys-Pro-Lys(Palm)-Lys-Pro-Lys (SEQ ID No: 97); Lys-Pro-Lys(Palm)-Lys(Palm)-Pro-Lys(Palm) (SEQ ID No: 98); Palm-Lys-Pro-Lys-Lys(Palm)-Pro-Lys(Palm) (SEQ ID No: 99); Palm-Lys-Pro-Lys(Palm)-Lys-Pro-Lys(Palm) (SEQ ID No: 100); Palm-Lys-Pro-Lys(Palm)-Lys(Palm)-Pro-Lys(Palm) (SEQ ID No: 101); or more preferably Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 102), and: (Palm-Lys-Pro-Lys)2-Lys (SEQ ID No: 103); (Palm-Lys-Pro-Tyr)2-Lys (SEQ ID No: 104); (Palm-Lys-Pro-DOPA)2-Lys (SEQ ID No: 105); more preferably (Palm-Lys-Hyp-Tyr)2-Lys (SEQ ID No: 106); (Palm-Lys-Hyp-DOPA)2-Lys (SEQ ID No: 107); or more specifically (Palm-Lys-Hyp-Lys)2-Lys (SEQ ID No: 108), as well as: ASP-Lys-Pro-Lys (SEQ ID No: 109); ASP-Lys-Pro-Tyr (SEQ ID No: 110); ASP-Lys-Pro-DOPA (SEQ ID No: 111); preferably ASP-Lys-Hyp-DOPA (SEQ ID No: 112); or ASP-Lys-Hyp-Lys (SEQ ID No: 113); or more specifically ASP-Lys-Hyp-Tyr (SEQ ID No: 114), as well as: SA-Lys-Pro-Lys (SEQ ID No: 115); SA-Lys-Pro-Tyr (SEQ ID No: 116); SA-Lys-Pro-DOPA (SEQ ID No: 117); more preferably SA-Lys-Hyp-DOPA (SEQ ID No: 118); SA-Lys-Hyp-Tyr (SEQ ID No: 119); or more specifically SA-Lys-Hyp-Lys (SEQ ID No: 120), as well as ASP-Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 121); ASP-Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 122); ASP-Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 123); ASP-Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 124); ASP-Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 125); ASP-Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 126); ASP-Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 127); ASP-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 128); SA-Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 129); SA-Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 130); SA-Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 131); SA-Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 132); SA-Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 133); SA-Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 134); SA-Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 135); or more particularly SA-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 136), and: (ASP-Lys-Pro-Lys)2-Lys (SEQ ID No: 137); (ASP-Lys-Pro-Tyr)2-Lys (SEQ ID No: 138); (ASP-Lys-Pro-DOPA)2-Lys (SEQ ID No: 139); (ASP-Lys-Hyp-Tyr)2-Lys (SEQ ID No: 140); (ASP-Lys-Hyp-DOPA)2-Lys (SEQ ID No: 141); (ASP-Lys-Hyp-Lys)2-Lys (SEQ ID No: 142); (SA-Lys-Pro-Lys)2-Lys (SEQ ID No: 143); (SA-Lys-Pro-Tyr)2-Lys (SEQ ID No: 144); (SA-Lys-Pro-DOPA)2-Lys (SEQ ID No: 145); (SA-Lys-Hyp-Tyr)2-Lys (SEQ ID No: 146); (SA-Lys-Hyp-DOPA)2-Lys (SEQ ID No: 147); and (SA-Lys-Hyp-Lys)2-Lys (SEQ ID No: 148).

[0058] The particularly preferred compounds of the present invention include the following: SA-Lys-Hyp-Lys (SEQ ID No: 120); Palm-Lys-Hyp-Lys (SEQ ID No: 74); SA-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 136); Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 82); Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 149); ASP-Lys-Hyp-Lys (SEQ ID No: 113); ASP-Lys-Hyp-Tyr (SEQ ID No: 114); Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 102); and (Palm-Lys-Hyp-Lys)2-Lys (SEQ ID No: 108) And more particularly the compounds in the embodiments described below.

[0059] 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, PEA represents hexadecanoic acid, ASP represents aspirin, and SA represents salicylic acid.

[0060] As used in this article, Pro represents proline, 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, and DOPA represents 3,4-dihydroxyphenylalanine.

[0061] To avoid ambiguity, the compounds of the present invention as defined above are collectively referred to as "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 trans-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 counterion of the compound of this invention in salt form with another counterion, for example using a suitable ion exchange resin.

[0065] Preferred salts include, for example, acetates, hydrochlorides, trifluoroacetic acid, 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 agents 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“, ARKatritzky, CW Rees and EFV Scriven, Pergamon Press, 1996 and “ Science of Synthesis ”, Volume 9-17 (Hetarenes and Related Ring Systems), Georg ThiemeVerlag, 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, TWGreene and PGM 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 form experimentally detectable amounts of the compounds of the present invention within a predetermined time after administration. All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[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 ulcers (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 (e.g., viral and / or bacterial infections), or allergic / atopic conditions (e.g., 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 skin lesions), pathological alopecia (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, or 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, the compounds of the present invention are found to be particularly useful for inflammatory skin conditions or diseases including viral skin diseases (such as herpes zoster), bacterial skin diseases, fungal skin diseases, animal-induced skin diseases, sexually transmitted skin diseases, allergy-related skin diseases, autoimmune skin diseases, neutrophilic dermatitis, erythematous papular and squamous skin diseases, connective tissue diseases, bullous skin diseases, pigmented skin diseases, skin appendage disorders, hereditary skin diseases, skin diseases associated with nutritional and metabolic disorders, skin tumors, psoriasis, acne, eczema, and dermatitis (especially allergic / atopic dermatitis and neurodermatitis), and the compounds of the present invention are particularly useful 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 following 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 inside 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 inflammation of the airways). 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 a variety of 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) that affect the mucosal surface (such as those in the oral cavity, nasopharynx, ear, throat, 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 diseases of the respiratory system, 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 can be used to treat 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). 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 fibrosis, and cor pulmonale. The compounds of this invention are particularly useful for treating fibrotic conditions.

[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, eczema, hyperpigmentation, scarring (fibrosis), alopecia, seborrheic alopecia, cicatricial alopecia, and paronychia; Oral diseases, including periodontitis, gingivitis, oral 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 for treating inflammation, inflammatory disorders, and / or disorders / conditions characterized by inflammation (e.g., as a symptom) is provided, 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 that, contrary to the treatment of any symptoms (e.g., pain and / or inflammation) of any viral infection or disease, 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 (e.g., 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, such as those contrary to the treatment of any symptoms (e.g., pain and / or inflammation) of any bacterial infection or disease, which allow 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 that, in contrast to the treatment of any symptoms of cancer (e.g., pain and / or inflammation), allow for the treatment of cancer in its essence, i.e., by interfering with the cancer itself. 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, 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 morbidity and mortality associated therewith. 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 (e.g., 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, gonococcal, 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 consider that the primary condition in question simultaneously causes (and indeed preferably) one or more additional 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 deficiencies such as common variant immunodeficiency, selective immunoglobulin deficiency (e.g., IgA deficiency), transient hypogammaglobulinemia of the newborn, and X-linked agammaglobulinemia; cellular immune deficiencies such as chronic mucocutaneous candidiasis, Digeorg syndrome, and X-linked lymphoproliferative syndrome; combined humoral and cellular immune deficiencies such as ataxia-telangiectasia, hypergammaglobulinemia E syndrome, severe combined immunodeficiency, and Wescott-Aldrich syndrome; phagocytic immune deficiencies such as Chédiak-Higashi syndrome, chronic granulomatous disease, periodic neutropenia, and leukocyte adhesion deficiency; and complement deficiencies 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 challenges, and musculoskeletal disorders / 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, grief, anger, sadness / anger); cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, attachment, self-criticism, self-loathing, unrealistic perfectionism, anxiety, panic attacks, and feelings of being unable to control); 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; visceral organ diseases such as chronic kidney disease, nephrotic syndrome, chronic hepatitis, and liver failure; systemic lupus erythematosus; alcohol poisoning 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, uterotonicumab, and vedolizumab; and especially corticosteroids, such as naturally occurring corticosteroids including cortisol (hydrocortisone), aldosterone, and corticosterone. 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. Acetate), hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tecortisone and tecortisone neovalerate, prednisolone, methylprednisolone, prednisone, chlorprednisolone, chlorprednisolone alcohol, difluprednisolone ester, fluhydrocortisone, 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, fluhydrocortisone, flunisolone and fluocinolone acetonide.(β) Methamphetamine-type drugs (Group C), such as beclomethasone, betamethasone, 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; and progesterone-type drugs, such as fluoroprogesterone, flumethasone, medroxyprogesterone 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 a further 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 the treatment of 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 these. 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 further 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 morbidity and / or death in patients associated with or potentially associated with radiation-induced disorders characterized by inflammation and / or trauma (e.g., ionizing radiation-induced disorders), 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 for 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 alopecia, 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 present invention is the non-therapeutic use of the compounds of the present invention in anti-aging, for example by promoting skin integrity in a manner that gives the skin a more youthful appearance.

[0164] Another aspect of the present invention is a cosmetic composition comprising the compounds of the present 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 can be administered locally 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 via any other parenteral route, preferably topically, or via any other parenteral route, in the form of a pharmaceutical formulation 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] 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.

[0173] The compounds of the present invention are preferably administered by intradermal injection, inhalation or topical application (e.g. to the skin or mucous membrane surface (e.g., oral mucosa, ocular mucosa, nasal mucosa, vaginal mucosa, rectal mucosa, colonic mucosa, esophageal mucosa), to the throat or to the periodontium, gums and / or teeth).

[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 (e.g., 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 (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 appropriate (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), such as formulations 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 are preferably in the form of liquid, gel, cream, emulsion, serum, or powder. The compounds of the present invention may also be in the form of soap (solid or liquid), shampoo, conditioner, sanitary napkin, tampons, suppositories, capsules, or tablets.

[0187] 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, for example, dry powder inhalers); Liquids for oral or inhalation use, such as 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), and specific injectable solutions or suspensions that may be mentioned include dermal fillers (i.e., injectable fillers or soft tissue fillers), particularly when the compounds of the present invention are combined with hyaluronic acid; and / or Oral tablets (where 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, glycolipids, 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, pharmaceutical compositions comprising the compounds of the present invention are further provided that are suitable for, adapted for and / or packaged 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 a day (e.g., three times). For example, the dosage can be administered once, twice, three or four times a day.

[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, from approximately 0.1 μg (e.g., approximately 0.5 μg) to approximately 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] Certain compounds of the present invention, particularly those of Formula I, may additionally and / or replace those having the above-mentioned biological activities and adhesive properties.

[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 films on various skin and mucous membrane wound surfaces (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 pharmaceutical 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, disalicylate, 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 fenamirine, diphenhydramine, naphazoline, antazoline, prednisolone, lodusamide, pirimethasone, oxymetazoline, ketotifen, naphazoline, and fumarate). Mestin, olopatadine, azelastine, tranilastine, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudoephedrine, fexofenadine, terfenadine, loratadine, and alexis; respiratory diseases, including asthma and / or COPD (such as budesonide, cistanchedesone, nedolometh, dexamethasone, ambroxol, and proxtromethorphan); 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-regression, anti-inflammatory molecules or mediators, such as lipoxygenin, regressors, and protectants. 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, fluocinolone, 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 acetonide, cromoglycine, nedolyl 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, ethylenediamine diacetamide, nimustine, famotidine, and thiophanate-methyl. 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, sodium L-glutamine guanylate, rebampette, rotundine, quxipite, lafutidine, thymoprotein, Hericium erinaceus 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 this 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 (or with 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 compounds of the present invention with (or other) therapeutic agents, and can thus be presented as single formulations wherein at least one of these formulations contains the compounds of the present invention and at least one contains (or other) therapeutic agents, or can be presented (i.e., formulated) as combination formulations (i.e., presented as a single formulation comprising the compounds of the present invention and (or other) therapeutic agents).

[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 box 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 a further 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 will mean making the two components suitable for combined application with each other.

[0256] Therefore, regarding the method for preparing the kit as defined above, the two components comprising the kit can be "joined" 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 set box is further provided, the set box comprising: (I) One of components (A) and (B) as defined herein; and (II) Instructions for use of this component in combination with another of the two components.

[0258] A further provision of the present invention provides a compound, optionally in the form of a formulation (e.g., a drug) mixed with a pharmaceutically acceptable inactive excipient (e.g., an adjuvant, diluent, or carrier), for use with other pharmaceutically active ingredients; optionally in the form of a formulation (e.g., a drug) mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, for use in methods of treating the relevant conditions and / or disorders disclosed herein.

[0259] Further, another pharmaceutically active ingredient is provided, optionally in the form of a formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier (e.g., a drug), for use with the compounds of the present invention; optionally in the form of a formulation mixed with a pharmaceutically acceptable inactive excipient (e.g., an adjuvant, diluent, or carrier) (e.g., a drug), for use in methods of treating the relevant conditions and / or disorders disclosed herein.

[0260] Regarding the aforementioned kit, although the compounds of the present invention may be provided in the form of a formulation (e.g., a pharmaceutical) mixed with one or more other pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers), they are not provided together 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 preferable that the (other) pharmaceutically active ingredients of the kit are provided in the form of a pharmaceutical formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0261] To provide repeated dosing, the kits described herein may contain more than one appropriate amount / dosage of the compound of the present invention (e.g., a formulation containing it), and / or more than one appropriate amount / dosage of other pharmaceutically active ingredients (e.g., a formulation containing it). If there are more than one formulation containing an amount / dosage of any of the aforementioned substances, or more than one amount / dosage 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.

[0262] 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.

[0263] Therefore, regarding the combination product according to the invention, the term "combined administration with..." includes the administration of two components of the combination product (the compound of the invention and other pharmaceutically active ingredients) together or in sufficiently close proximity in time (optionally repeatedly) to enable the patient to receive a beneficial effect during the treatment of the relevant condition, said beneficial effect being greater than if a formulation containing the compound of the invention or (e.g., containing) another agent were administered 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.

[0264] Furthermore, in the case of the kit according to the invention, the term "in combination with" includes that one or the other of the two components may be applied before, after, and / or simultaneously with the other component (optionally repeatedly). When used in this context, the terms "simultaneous application" and "simultaneous application with" include the application 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.

[0265] 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.

[0266] Wherever the word “about” is used herein (e.g., in the context of the concentration and / or dosage, molecular weight, or pH of an 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%.

[0267] 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.

[0268] 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 used to treat any of the conditions mentioned above, including inflammation, inflammatory disorders (including fibrotic conditions), or disorders characterized by inflammation as a symptom (including wounds), or otherwise.

[0269] The invention is illustrated by the following embodiments with reference to the accompanying drawings, but these embodiments are in no way limiting of the invention. A reduction in swelling was observed in in vivo experiments after administration of the compounds of the invention. Furthermore, pain and itching relief were observed in human patients after administration of the compounds of the invention. Attached Figure Description

[0270] Figures 1 to 5 The degree of swelling obtained in the mouse model experiments of Examples 13 to 17 is shown respectively.

[0271] Example Example 1 SA-Lys-Hyp-Lys (SEQ ID No: 120) Fmoc-Lys(Boc)-Wang resin (9.10 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0272] 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.

[0273] 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).

[0274] 2. Deprotection: A 20% piperidine solution (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) was added to DMF (DBLK, 200 mL) as the deprotection solution, and the reaction was carried out for 20 minutes. Then, the solution was removed by vacuum filtration, and the gel was washed six times with DMF.

[0275] 3. Coupling: Fmoc-4-Hyp(tBu)-OH (3.69 g, 9 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium (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.

[0276] Repeat the above coupling steps to couple an equal amount (in moles) of the remaining amino acids: Fmoc-Lys(Boc)-OH and salicylic acid.

[0277] After coupling with salicylic acid, 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.

[0278] 100.0 mL (i.e., 10 mL / g 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 1000 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 to yield 1.51 g of the crude title compound.

[0279] 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 of 5%–90% of solvent A concentration over 50 minutes; flow rate 1.0 mL / min; sample volume: 10 µL).

[0280] The target peak was eluted at 27.212 minutes and had the expected molecular weight with a purity of 84.833%.

[0281] MS: m / z 507.6 1.5 g of the crude product was then dissolved in 30 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 type (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 of 50%–80% 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 50%–75% solvent A concentration over 25 min).

[0282] 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. The column was then washed with 3.2% ammonium acetate in pure water for approximately 20 minutes at a flow rate of 60 mL / min, followed by a further 10 minutes of washing with pure water. Elution was then performed using the following gradient (solvent A: 0.1% HAc in MeCN, solvent B: 0.1% HAc in water, linear gradient of 50%–80% of 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 1.08 g of purified title compound.

[0283] Example 2 Palm-Lys-Hyp-Lys (SEQ ID No: 74) The title compound was prepared using essentially the same method as described in Example 1 above, except that an equal amount (in moles) of palmitic acid was used instead of salicylic acid in the final coupling step.

[0284] MS: m / z 625.9 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.92 g). Analysis showed that the target peak was eluted at 29.667 min with the expected molecular weight (MS: m / ). z 625.9 The purity is 80.927%.

[0285] The 1.9 g crude product was then purified as described in Example 1 above to obtain 1.38 g of pure title compound after freeze-drying.

[0286] Example 3 SA-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 136) The title compound was prepared using essentially the same method as described in Example 1 above, wherein appropriate amino acids (Fmoc-Lys(Boc)-OH, Fmoc-Hyp(tBu)-OH and Fmoc-Tyr(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0287] MS: m / z 783.9 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.41 g). Analysis showed that the target peak was eluted at 30.746 min with the expected molecular weight (MS: m / ). z 783.9 The purity is 73.882%.

[0288] The 2.4 g crude product was then purified as described in Example 1 above to obtain 1.52 g of pure title compound after freeze-drying.

[0289] Example 4 Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 82) The title compound was prepared using essentially the same method as described in Example 3 above, except that an equal amount (in moles) of palmitic acid was used instead of salicylic acid in the final coupling step.

[0290] MS: m / z 902.2 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.81 g). Analysis showed the target peak was eluted at 31.871 min with the expected molecular weight (MS: m / ). z 902.2 The purity is 75.211%.

[0291] The 2.8 g crude product was then purified as described in Example 1 above, and freeze-dried to give 1.97 g of pure title compound.

[0292] Example 5 Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 149) The title compound was prepared using essentially the same method as described in Example 1 above, wherein appropriate amino acids (Fmoc-Lys(Boc)-OH and Fmoc-Hyp(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0293] MS: m / z 739.0 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.55 g). Analysis showed that the target peak was eluted at 35.877 min with the expected molecular weight (MS: m / ). z 739.0 The purity is 77.192%.

[0294] The 2.5 g crude product was then purified as described in Example 1 above to obtain 1.47 g of pure title compound after freeze-drying.

[0295] Example 6 ASP-Lys-Hyp-Lys(SEQ ID No: 113) The title compound was prepared using essentially the same method as described in Example 1 above, except that an equal amount (in moles) of aspirin (acetylsalicylic acid) was used instead of salicylic acid in the final coupling step.

[0296] MS: m / z 549.6 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.72 g). Analysis showed that the target peak was eluted at 28.121 min with the expected molecular weight (MS: m / ). z 549.6 The purity is 81.112%.

[0297] The 1.7 g crude product was then purified as described in Example 1 above to obtain 1.23 g of pure title compound after freeze-drying.

[0298] Example 7 ASP-Lys-Hyp-Tyr (SEQ ID No: 114) The title compound was prepared using essentially the same method as described in Example 6 above, except that an equal amount (in moles) of Fmoc-Tyr(tBu)-Wang resin was used instead of Fmoc-Lys(Boc)-Wang resin at the beginning.

[0299] MS: m / z 584.6 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.82 g). Analysis showed that the target peak was eluted at 34.267 min with the expected molecular weight (MS: m / ). z 584.6 The purity is 80.018%.

[0300] The 1.8 g crude product was then purified as described in Example 1 above to obtain 1.32 g of pure title compound after freeze-drying.

[0301] Example 8 Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 102) Fmoc-Lys(Dde)-Wang resin (9.97 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0302] 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.

[0303] 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).

[0304] 2. Deprotection: A 5% hydrazine hydrate (Merck KGaA, Darmstadt, Germany) solution was added to DMF (200 mL) as the 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.

[0305] 3. Coupling: Palmitic acid (2.31 g, 9 mmol; Merck KGaA, Darmstadt, Germany) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium (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.

[0306] After coupling the side chain palmitic acid, the amino acid is then coupled to the resin.

[0307] 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).

[0308] 2. Deprotection: A 20% piperidine solution (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) was added to DMF (DBLK, 200 mL) as the deprotection solution, and the reaction was carried out for 20 minutes. Then, the solution was removed by vacuum filtration, and the gel was washed six times with DMF.

[0309] 3. Coupling: Fmoc-4-Hyp(tBu)-OH (3.69 g, 9 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium (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.

[0310] Repeat the above coupling steps to couple equal amounts (in moles) of the following amino acids: Fmoc-Lys(Boc)-OH and subsequently Fmoc-Lys(Dde)-OH.

[0311] 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.

[0312] After coupling palmitic acid to the side chain of the unprotected lysine residue, the further coupling steps are repeated using essentially the same method as described above to couple equal amounts (in moles) of the following amino acids: Fmoc-4-Hyp(tBu)-OH and subsequently Boc-Lys(Boc)-OH.

[0313] 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.

[0314] MS: m / z 1233.8 The procedure was repeated essentially the same as in Example 1 to obtain another batch of crude title compound (yield 3.96 g). Analysis showed that the target peak was eluted at 31.981 min, with the expected molecular weight ( MS: m / z 1233.8 The purity is 62.294%.

[0315] The 3.9 g crude product was then purified as described in Example 1 above, and freeze-dried to give 2.19 g of pure title compound.

[0316] Example 9 (Palm-Lys-Hyp-Lys)2-Lys (SEQ ID No: 108) Fmoc-Lys(Fmoc)-Wang resin (10.23 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0317] 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.

[0318] The title compound was then prepared using essentially the same method as described in Example 2 above, except that the first amino acid coupled to the resin was Fmoc-Lys(Boc)-OH, followed by Fmoc-Hyp(tBu)-OH, Fmoc-Lys(Boc)-OH and palmitic acid, and the amounts of the amino acid, palmitic acid and condensing agents (TBTU and DIPEA) were doubled (in moles).

[0319] MS: m / z 1362.0 The procedure was repeated essentially the same as in Example 1 to obtain another batch of crude title compound (yield 4.23 g). Analysis showed that the target peak was eluted at 31.981 min, with the expected molecular weight ( MS: m / z 1362.0 The purity is 58.298%.

[0320] The 4.2 g crude product was then purified as described in Example 1 above to obtain 2.03 g of pure title compound after freeze-drying.

[0321] Example 10 Lys-Hyp-Lys (SEQ ID No: 14) The title compound was prepared using essentially the same method as described in Example 1 above, except that Boc-Lys(Boc)-OH was used instead of Fmoc-Lys(Boc)-OH in the final coupling step, and salicylic acid was not coupled.

[0322] MS: m / z 387.5 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.21 g). Analysis showed that the target peak was eluted at 5.084 min with the expected molecular weight (MS: m / ). z 387.5 The purity is 86.279%.

[0323] The 1.2 g crude product was then purified as described in Example 1 above to obtain 0.86 g of pure title compound after freeze-drying.

[0324] Example 11 Lys-Hyp-Hyp-Lys (SEQ ID No: 18) The title compound was prepared using substantially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH and Fmoc-Hyp(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0325] MS: m / z 500.6 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.58 g). Analysis showed that the target peak was eluted at 8.084 min with the expected molecular weight (MS: m / ). z 500.6 The purity is 82.291%.

[0326] The crude product was then purified as described in Example 1 above to obtain 1.03 g of pure title compound after freeze-drying.

[0327] Example 12 Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 26) The title compound was prepared using essentially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH, Fmoc-Hyp(tBu)-OH and Fmoc-Tyr(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0328] MS: m / z 663.8 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.13 g). Analysis showed that the target peak was eluted at 8.084 min with the expected molecular weight (MS: m / ). z 663.8 The purity is 78.028%.

[0329] The 2.1 g crude product was then purified as described in Example 1 above, and freeze-dried to give 1.27 g of pure title compound.

[0330] Example 13 Lys-Pro-Pro-Lys (SEQ ID No: 15) The title compound was prepared using substantially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH and Fmoc-Pro-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0331] MS: m / z 468.8 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.79 g). Analysis showed that the target peak was eluted at 7.395 min with the expected molecular weight (MS: m / ). z 468.8 The purity is 85.396%.

[0332] The 1.7 g crude product was then purified as described in Example 1 above to obtain 0.92 g of pure title compound after freeze-drying.

[0333] Example 14 Lys-Pro-Hyp-Lys (SEQ ID No: 16) The title compound was prepared using substantially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH, Fmoc-Pro-OH and Fmoc-Hyp(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0334] MS: m / z 484.6 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.61 g). Analysis showed that the target peak was eluted at 7.958 min with the expected molecular weight (MS: m / ). z 484.6 The purity is 89.177%.

[0335] The 1.6 g crude product was then purified as described in Example 1 above to obtain 0.97 g of pure title compound after freeze-drying.

[0336] Example 15 Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 20) The title compound was prepared using essentially the same method as described in Example 10 above, wherein the appropriate amino acids (Boc-Lys(Boc)-OH, Fmoc-Pro-OH and Fmoc-DOPA(acetone)-OH) were used in the relevant peptide conjugation in an appropriate order.

[0337] MS: m / z 647.8 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.23 g). Analysis showed that the target peak was eluted at 8.107 min with the expected molecular weight (MS: m / ).z 647.8 The purity is 80.824%.

[0338] The 2.2 g crude product was then purified as described in Example 1 above, and freeze-dried to give 1.37 g of pure title compound.

[0339] Example 16 Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 21) The title compound was prepared using essentially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH, Fmoc-Hyp(tBu)-OH and Fmoc-DOPA(acetone)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0340] MS: m / z 679.8 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.33 g). Analysis showed that the target peak was eluted at 8.357 min with the expected molecular weight (MS: m / ). z 679.8 The purity is 78.968%.

[0341] The 2.3 g crude product was then purified as described in Example 1 above to obtain 1.36 g of pure title compound after freeze-drying.

[0342] Example 17 Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 22); The title compound was prepared using essentially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH, Fmoc-Hyp(tBu)-OH, Fmoc-DOPA(acetone)-OH and Fmoc-Pro-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0343] MS: m / z 663.8 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.33 g). Analysis showed that the target peak was eluted at 8.389 min with the expected molecular weight (MS: m / ). z 663.8 The purity is 79.667%.

[0344] The 2.3 g crude product was then purified as described in Example 1 above to obtain 1.36 g of pure title compound after freeze-drying.

[0345] Example 18 Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 23) The title compound was prepared using substantially the same method as described in Example 10 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH, Fmoc-Pro-OH and Fmoc-Tyr(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0346] MS: m / z 631.8 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 2.19 g). Analysis showed the target peak was eluted at 8.731 min with the expected molecular weight (MS: m / ). z 631.8 The purity is 79.598%.

[0347] The 2.1 g crude product was then purified as described in Example 1 above to obtain 1.26 g of pure title compound after freeze-drying.

[0348] Example 19 Lys-Pro-Tyr (SEQ ID No: 10) The title compound was prepared using essentially the same method as described in Example 10 above, except that an equal amount (in moles) of Fmoc-Tyr(tBu)-Wang resin was used instead of Fmoc-Lys(Boc)-Wang resin at the beginning, and appropriate amino acids (Boc-Lys(Boc)-OH and Fmoc-Pro-OH) were used in the relevant peptide coupling sequence in the appropriate order.

[0349] MS: m / z 406.5 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.43 g). Analysis showed that the target peak was eluted at 15.224 min with the expected molecular weight (MS: m / ). z 406.5 The purity is 90.554%.

[0350] The 1.4 g crude product was then purified as described in Example 1 above to obtain 0.87 g of pure title compound after freeze-drying.

[0351] Example 20 Lys-Pro-DOPA (SEQ ID No: 11); The title compound was prepared using essentially the same method as described in Example 10 above, except that an equal amount (in moles) of Fmoc-DOPA (acetone condensate)-Wang resin was used instead of Fmoc-Lys(Boc)-Wang resin at the beginning, and appropriate amino acids (Boc-Lys(Boc)-OH and Fmoc-Pro-OH) were used in the relevant peptide coupling sequence in the appropriate order.

[0352] MS: m / z 422.5 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.36 g). Analysis showed the target peak was eluted at 18.827 min with the expected molecular weight (MS: m / ). z 422.5 The purity is 88.938%.

[0353] The 1.3 g crude product was then purified as described in Example 1 above to obtain 0.86 g of pure title compound after freeze-drying.

[0354] Example 21 Lys-Hyp-Tyr (SEQ ID No: 12); The title compound was prepared using substantially the same method as described in Example 19 above, wherein appropriate amino acids (Boc-Lys(Boc)-OH and Fmoc-Hyp(tBu)-OH) were used in the relevant peptide-coupled sequences in an appropriate order.

[0355] MS: m / z 422.5 Repeating essentially the same procedure yielded another batch of crude title compounds (yield 1.39 g). Analysis showed that the target peak was eluted at 18.231 min with the expected molecular weight (MS: m / ). z 422.5 The purity is 89.129%.

[0356] The 1.3 g crude product was then purified as described in Example 1 above to obtain 0.89 g of pure title compound after freeze-drying.

[0357] Example 22 Mouse model of ear swelling Test compound: Compound A: Palm-Lys-Hyp-Lys (SEQ ID No: 74) Compound B: Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 82) Before the experiment, 20 healthy male BALB / c mice aged 6 to 8 weeks (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China) with an average weight of 18-25 g were housed and cared for for about 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 1, these mice were randomly divided into 4 groups (5 mice in each group).

[0358] Table 1 The left ear of each mouse served as an autologous control. The right ear of each mouse was treated differently: 20 μl of xylene (Shanghai Aladdin Bio-Chem Technology Co., LTD) was applied to both the inner and outer sides of the right ear of each mouse. Swelling began in the ear 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.

[0359] Purchase dexamethasone acetate cream (0.75 mg / g, China Resources Group) from a local pharmacy. Compounds A and B were synthesized by Chinese Peptide Company as described above. Dissolve 10 mg of each compound (powder) in 10 ml of physiological saline to prepare a 1.0 mg / ml solution. The resulting solutions were then applied to mice accordingly.

[0360] 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 leather bag (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 2 below. Figure 1 As shown in the figure, the swelling percentage (%) = (right ear weight - left ear weight) / left ear weight × 100%.

[0361] Table 2 The results showed that both compounds could significantly reduce xylene-induced ear swelling in a mouse model, especially compound A, which had a corresponding effect with dexamethasone.

[0362] Example 23 Mouse model of ear swelling Test compound: Compound A: Palm-Lys-Hyp-Lys (SEQ ID No: 74) Compound C: (Palm-Lys-Hyp-Lys)2-Lys (SEQ ID No: 108) The experimental procedures and results recording were the same as those described in Example 22 above. Xylene induced ear swelling in mice. As shown in Table 3 below, 40 mice were divided into 8 groups.

[0363] Table 3 PL-429 (also known as Naturalpenetrant 2020) represents a known penetrant containing water, butylene glycol, glycerin, hydrolyzed chitin, betaine, polylysine, hydroxypropyl cyclodextrin, inositol, and tetrahydropiperine.

[0364] The groups “Compound AL”, “Compound AM” and “Compound AH” refer to low, medium and high doses of Compound A, respectively, as indicated in Table 3 above.

[0365] The results are shown in Table 4 below. Figure 2 As shown in the image.

[0366] Table 4 The results showed that both compounds C and A effectively reduced the swelling rate in xylene-treated mouse models; however, compound A did not achieve the same level of reduction as dexamethasone treatment, and its effectiveness was dose-dependent. Furthermore, the results for both compounds C and A indicate that PL-429 showed some improvement in drug efficacy.

[0367] Example 24 Mouse model of ear swelling Test compound: Compound D: Aspirin-Lys-Hyp-Lys (SEQ ID No: 113) aspirin The experimental procedure and results recording were the same as those described in Example 22 above. Xylene induced ear swelling in mice. As shown in Table 5 below, 20 mice were divided into 4 groups.

[0368] Table 5 Aspirin and compound D have the same molar concentration.

[0369] The results are shown in Table 6 below. Figure 3 As shown in the image.

[0370] Table 6 The results showed that compound D effectively reduced the swelling rate in xylene-treated mouse models, and its effectiveness exceeded that of dexamethasone treatment. Aspirin itself had some effect on reducing the swelling rate in xylene-treated mouse models, but its effectiveness was far less than that of its tripeptide conjugate, compound D.

[0371] Example 25 Mouse model of ear swelling Test compound: Compound E: Salicylic acid-Lys-Hyp-Lys (SEQ ID No: 120) Compound F: Salicylic acid-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 136) salicylic acid The experimental procedure and results recording were the same as those described in Example 22 above. Xylene induced ear swelling in mice. As shown in Table 7 below, 25 mice were divided into 5 groups.

[0372] Table 7 Salicylic acid and compound E have the same molar concentration.

[0373] The results are shown in Table 8 below. Figure 4 As shown in the image.

[0374] Table 8 The results showed that compounds E and F effectively reduced the swelling rate in xylene-treated mouse models, with compound E showing better efficacy, approaching the level seen in dexamethasone-treated models. Salicylic acid itself had some effect on reducing the swelling rate in xylene-treated mouse models, but its efficacy was far less than that of its conjugates, compounds E and F.

[0375] Example 26 Mouse model of ear swelling The experimental procedures and results recording were the same as those described in Example 22 above. Xylene induced ear swelling in mice. As shown in Table 9 below, 40 mice were divided into 8 groups.

[0376] Table 9 Groups “Compound C-1” through “Compound C-6” refer to compounds in different doses, as indicated in Table 9 above.

[0377] The results are shown in Table 10 below. Figure 5 As shown in the image.

[0378] Table 10 The results showed that different concentrations of compound C effectively reduced the swelling rate in xylene-treated mouse models; however, none of the concentrations of compound C achieved the same level of effectiveness as dexamethasone treatment, indicating that the efficacy was dose-dependent.

[0379] Example 27 Mouse model of ear swelling Test compound: Compound G: Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 149) Compound H: ASP-Lys-Hyp-Tyr (SEQ ID No: 114) Compound I: Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 102) Compound J: Lys-Hyp-Lys (SEQ ID No: 14) Compound K: Lys-Hyp-Hyp-Lys (SEQ ID No: 18) Compound L: Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 26) Compound M: Lys-Pro-Tyr (SEQ ID No: 10) Prior to the experiment, 45 healthy male BALB / c mice aged 6 to 8 weeks (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China), 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 11, these mice were randomly divided into 9 groups (5 mice per group).

[0380] Table 11 The results are shown in Table 12 below.

[0381] The left ear of each mouse served as an autologous control. 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 began in the ear after approximately 4 minutes. After 20 minutes, 40 μl of the drug was applied to the right ear of each group. The mice were then returned to their cages.

[0382] Purchase dexamethasone acetate cream (0.75 mg / g, China Resources Group) from a local pharmacy. Compound GL was synthesized by Chinese Peptide Company as described above. Dissolve 10 mg of each compound (powder) in 10 ml of physiological saline to prepare a 1 mg / ml solution. The resulting solutions were then applied to mice accordingly.

[0383] Two hours after xylene administration, mice were euthanized by cervical dislocation. The left and right ears were removed. A piece of each ear was harvested from the same site using an 8mm diameter leather bag (Electron Microscopy Sciences, P.O. Box 550, 1560 Hatfield Industrial Road, Pennsylvania, 19440). The weight was recorded and used to calculate the swelling percentage, shown in Table 12 below, where swelling percentage (%) = (right ear weight - left ear weight) / left ear weight × 100%.

[0384] Table 12 The results showed that all tested compounds significantly reduced xylene-induced ear swelling in a mouse model, and the efficacy of most compounds was comparable to that of dexamethasone treatment.

[0385] Example 28 Mouse model of ear swelling Test compound: Compound N: Lys-Pro-DOPA (SEQ ID No: 11); Compound O: Lys-Hyp-Tyr (SEQ ID No: 12); Compound P: Lys-Pro-Pro-Lys (SEQ ID No: 15); Compound Q: Lys-Pro-Hyp-Lys (SEQ ID No: 16); Compound R: Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 20); Compound S: Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 21); Compound T: Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 22); Compound U: Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 23) The experimental procedures and results recording were the same as those described in Example 27 above. Xylene induced ear swelling in mice. As shown in Table 13 below, 40 mice were divided into 8 groups.

[0386] Table 13 The results are shown in Table 14 below.

[0387] Table 14 The results showed that all tested compounds could significantly reduce the swelling rate in a mouse model treated with xylene, indicating that all peptides had anti-inflammatory effects.

[0388] Example 29 Anti-inflammatory test of keratinocytes Test compound: Compound G: Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 149) Compound H: ASP-Lys-Hyp-Tyr (SEQ ID No: 114) Compound I: Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 102) Compound J: Lys-Hyp-Lys (SEQ ID No: 14) Compound K: Lys-Hyp-Hyp-Lys (SEQ ID No: 18) Compound L: Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 26) Cell viability assay methods: HaCat keratinocytes were used at a rate of 2 × 10⁻⁶. 5Cells were seeded at a density of 10 cells / well in 12-well plates and cultured in DMEM (Gibco, USA) containing 10% heat-inactivated fetal bovine serum (FBS; Gibco) and 1% penicillin and streptomycin (P / S; Gibco). Cells were incubated at 37ºC in a 5% CO2 incubator for 24 h. The medium was then replaced with fresh DMEM containing 1% P / S and various concentrations of peptides. Distilled water and dexamethasone (20 μg / mL) were added to the cells as negative and positive controls, respectively. Cells were incubated for 1 h. After 1 h of incubation, 10 ng / mL of lipopolysaccharide (LPS) was added, and the cells were incubated for another 24 h. Cells were then washed twice with phosphate-buffered saline (PBS), and cell viability was assessed at 570 nm using a microplate reader (Molecular Devices Filter Max F5; San Francisco, California, USA) via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The levels of TNF-α, IL-1α, IL-6, and IL-8 in the culture supernatant were then determined using an ELISA kit according to the manufacturer's instructions.

[0389] The results are shown in Table 15 below.

[0390] Table 15 Based on cell viability studies, the concentration of the peptide used for the anti-inflammatory test was selected as 1 μg / ml. The results are shown in Table 16.

[0391] Table 16 The results showed that all tested peptides inhibited cytokine secretion to some extent. In some cases, the anti-inflammatory effects of the tested peptides were even greater than those of dexamethasone.

[0392] Example 29 Sebum control Test compound: Compound E: SA-Lys-Hyp-Lys (SEQ ID No: 120) Compound A: Palm-Lys-Hyp-Lys (SEQ ID No: 74) Compound B: Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 82) Compound G: Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 149) Compound C: (Palm-Lys-Hyp-Lys)2-Lys (SEQ ID No: 108) Compound J: Lys-Hyp-Lys (SEQ ID No: 14) Compound K: Lys-Hyp-Hyp-Lys (SEQ ID No: 18) Compound L: Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 26) SZ95 sebaceous gland cells (3 × 10⁻⁶) 4 Cells were seeded at 100 μM / well in 12-well plates and incubated overnight. They were then treated for 48 hours with either 100 μM linoleic acid plus peptides or 100 μM linoleic acid plus retinoic acid (positive control). Cells treated with the medium served as controls. At the end of treatment, cells were washed with phosphate-buffered saline (PBS) and fixed in 4% formaldehyde for 5 minutes. The fixed cells were stained in the dark for 15 minutes with Oil Red O solution (a mixture of 1% Oil Red O (Sigma) and dH2O in a 6:4 (vol / vol) ratio), followed by washing with PBS. The stained cells were visualized by fluorescence microscopy. Lipid fluorescence intensity calculation: Image analysis was performed using ImageJ software, with the model group (M) as 100%, and the relative fluorescence intensity of each group was calculated.

[0393] Table 17 The results showed that all peptides could reduce sebum secretion from SZ95 sebaceous gland cells. The efficacy was comparable to or even stronger than that of the positive control. These results indicate that all peptides can be used as anti-acne agents, especially for sebum control.

[0394] Example 30 Itching relief A 10-year-old girl experienced an allergic rhinitis attack. She had a runny nose, watery eyes, and itchy eyes. She used a nasal spray containing 0.5 mg / ml of compound J in saline solution three times a day for three days. Approximately one minute after application, the runny nose and itchy eyes were relieved. After three days, all of the patient's rhinitis symptoms disappeared. The patient experienced no irritation during the treatment period.

[0395] Example 31 Skin abrasion A 20-year-old male suffered a chafing to his left knee while playing soccer. The patient presented with abrasions, swelling, and some minor bleeding on his knee. He used a spray containing compound H at a concentration of 0.5 mg / ml in 10% glycerin and saline solution. Pain immediately subsided after application. The spray was applied four times a day, at two-hour intervals, on the day of injury. The swelling completely disappeared. The patient continued using the spray three times daily for one week. The wound was completely healed after one week.

[0396] Example 32 Pain relief from radiation-induced oral mucositis Two patients were undergoing radiation therapy to the head and neck. Both patients experienced severe oral mucositis, 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 A 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 decreased from 8 to 2.

[0397] Example 33 Relief of itching in neurodermatitis A 35-year-old man presented with a skin lesion on his left calf accompanied by persistent itching and scaling. He had been diagnosed with neurodermatitis three years 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 solution spray of Compound A. 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.

Claims

1. A compound of formula I, XY(I) in: Y represents Z or Z-Lys-Z; Each time it is used, Z independently represents the structural fragment of expression IV. [Ala] m -[Lys - V] n -Lys-V (IV)(SEQ ID No: 3) in: m represents 0 or 1; n represents an integer 0, 1, 2, 3, or 4; Each time it is used, V independently represents a sequence of 2 to 4 amino acids, wherein the amino acids are selected from one or more of the following group: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, and Ser. X represents at least one optional substituent selected from the following: (i) lipids selected from vitamin A, vitamin E, cholesterol, and fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, wherein the lipids are straight-chain or branched, saturated or unsaturated 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; and / or (ii) Nonsteroidal anti-inflammatory drugs (NSAIDs) And the regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the compounds. The condition is that when X does not exist, Y represents Z, and both m and n represent 0, and V does not represent -Pro-Lys.

2. The compound according to claim 1, wherein the amino acid in V is selected from the group consisting of Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, and Tyr.

3. The compound according to any one of the preceding claims, wherein the amino acid in V is selected from the group consisting of Pro, Hyp, Lys, Tyr and DOPA.

4. The compound according to any one of the preceding claims, wherein the amino acid adjacent to Lys in V is selected from the group consisting of Pro and Hyp.

5. The compound according to any one of the preceding claims, wherein V represents a sequence of two amino acids.

6. The compound according to claim 5, wherein the C-terminal amino acid is selected from Lys, Tyr and DOPA.

7. The compound of claim 6, wherein Z comprises the following sequence: Lys-Pro-Lys (SEQ ID No: 9); Lys-Pro-Tyr (SEQ ID No: 10); Lys-Pro-DOPA (SEQ ID No: 11); Lys-Hyp-Tyr (SEQ ID No: 12); Lys-Hyp-DOPA (SEQ ID No: 13); or Lys-Hyp-Lys (SEQ ID No: 14).

8. The compound according to claim 6 or claim 7, wherein Z comprises the following sequence: Lys-Pro-Tyr (SEQ ID No: 10); Lys-Pro-DOPA (SEQ ID No: 11); Lys-Hyp-Tyr (SEQ ID No: 12); Lys-Hyp-DOPA (SEQ ID No: 13); or Lys-Hyp-Lys (SEQ ID No: 14).

9. The compound of claim 6, wherein Z comprises the following sequence: Lys-Hyp-Tyr (SEQ ID No: 12); Lys-Hyp-Lys (SEQ ID No: 14); or Lys-Hyp-Hyp-Lys (SEQ ID No: 18).

10. The compound according to any one of claims 1 to 9, wherein V represents a sequence of 3 or 4 amino acids.

11. The compound according to claim 10, wherein the C-terminal amino acid in V is Lys.

12. The compound of claim 11, wherein at least one other amino acid in the sequence defining V is Hyp.

13. The compound according to any one of claims 10 to 12, wherein Z comprises the following sequence: Lys-Pro-Pro-Lys (SEQ ID No: 15); Lys-Pro-Hyp-Lys (SEQ ID No: 16); Lys-Hyp-Pro-Lys (SEQ ID No: 17); Lys-Hyp-Hyp-Lys (SEQ ID No: 18); Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 19); Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 20); Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 21); Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 22); Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 23); Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 24); Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 25); or Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 26).

14. The compound according to any one of the preceding claims, wherein m represents 0.

15. The compound according to any one of the preceding claims, wherein n represents 0, such that Z is defined by the formula Lys-V.

16. The compound according to any one of claims 1 to 14, wherein n represents 1, such that Z is defined by the formula Lys-V-Lys-V.

17. The compound according to claim 16, wherein V represents a sequence of two amino acids.

18. The compound according to claim 16 or claim 17, wherein Z comprises the following sequence: Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID No: 27); Lys-Hyp-Tyr-Lys-Pro-Lys (SEQ ID No: 28); Lys-Hyp-Tyr-Lys-Pro-Tyr(SEQ ID No: 29); Lys-Hyp-Tyr-Lys-Pro-DOPA(SEQ ID No: 30); Lys-Hyp-DOPA-Lys-Hyp-Tyr(SEQ ID No: 31); Lys-Hyp-DOPA-Lys-Pro-Lys(SEQ ID No: 32); Lys-Hyp-DOPA-Lys-Pro-Tyr(SEQ ID No: 33); Lys-Hyp-DOPA-Lys-Pro-DOPA(SEQ ID No: 34); Lys-Pro-Lys-Lys-Hyp-Tyr(SEQ ID No: 35); Lys-Pro-Lys-Lys-Hyp-DOPA(SEQ ID No: 36); Lys-Pro-Lys-Lys-Pro-Tyr(SEQ ID No: 37); Lys-Pro-Lys-Lys-Pro-DOPA(SEQ ID No: 38); Lys-Pro-Tyr-Lys-Hyp-Tyr(SEQ ID No: 39); Lys-Pro-Tyr-Lys-Hyp-DOPA(SEQ ID No: 40); Lys-Pro-Tyr-Lys-Pro-Lys(SEQ ID No: 41); Lys-Pro-Tyr-Lys-Pro-DOPA(SEQ ID No: 42); Lys-Pro-DOPA-Lys-Hyp-Tyr(SEQ ID No: 43); Lys-Pro-DOPA-Lys-Hyp-DOPA(SEQ ID No: 44); Lys-Pro-DOPA-Lys-Pro-Lys(SEQ ID No: 45); Lys-Pro-DOPA-Lys-Pro-Tyr(SEQ ID No: 46); Lys-Hyp-Tyr-Lys-Hyp-Tyr(SEQ ID No: 47); Lys-Hyp-DOPA-Lys-Hyp-DOPA(SEQ ID No: 48); Lys-Pro-Lys-Lys-Pro-Lys(SEQ ID No: 49); Lys-Pro-Tyr-Lys-Pro-Tyr(SEQ ID No: 50); Lys-Pro-DOPA-Lys-Pro-DOPA(SEQ ID No: 51); Lys-Hyp-Lys-Lys-Hyp-Tyr(SEQ ID No: 52); Lys-Hyp-Lys-Lys-Hyp-DOPA(SEQ ID No: 53); Lys-Hyp-Lys-Lys-Pro-Lys (SEQ ID No: 54); Lys-Hyp-Lys-Lys-Pro-Tyr (SEQ ID No: 55); Lys-Hyp-Lys-Lys-Pro-DOPA (SEQ ID No: 56); Lys-Hyp-Tyr-Lys-Hyp-Lys (SEQ ID No: 57); Lys-Hyp-DOPA-Lys-Hyp-Lys (SEQ ID No: 58); Lys-Pro-Lys-Lys-Hyp-Lys (SEQ ID No: 59); Lys-Pro-Tyr-Lys-Hyp-Lys (SEQ ID No: 60); Lys-Pro-DOPA-Lys-Hyp-Lys (SEQ ID No: 61); or Lys-Hyp-Lys-Lys-Hyp-Lys (SEQ ID No: 62).

19. The compound according to any one of the preceding claims, wherein Y represents Z.

20. The compound according to any one of claims 1 to 18, wherein Y represents Z-Lys-Z.

21. The compound of claim 20, wherein the peptide sequence Z is identical and defined by the formula Lys-V, wherein V represents a sequence of 2 amino acids.

22. The compound according to claim 20 or claim 21, wherein the compound is: (Lys-Pro-Lys)2-Lys (SEQ ID No: 63); (Lys-Pro-Tyr)2-Lys (SEQ ID No: 64); (Lys-Pro-DOPA)2-Lys (SEQ ID No: 65); (Lys-Hyp-Tyr)2-Lys (SEQ ID No: 66); (Lys-Hyp-DOPA)2-Lys (SEQ ID No: 67); or (Lys-Hyp-Lys)2-Lys (SEQ ID No: 68).

23. The compound according to any one of the preceding claims, wherein X is absent.

24. The compound according to any one of claims 1 to 22, wherein X represents at least one lipid as defined in claim 1.

25. The compound according to any one of claims 1 to 22 or 24, wherein X represents a lipid selected from derivatives of fatty acids as defined in claim 1.

26. The compound according to any one of claims 1 to 22, 24 or 25, wherein the lipid is selected from palmitic acid, stearic acid, oleic acid, octadecanoic acid, docosahexaenoic acid and leukotriene B4 (LTB4) or derivatives thereof.

27. The compound according to any one of claims 24 to 26, wherein the lipid is palmitic acid or a derivative thereof.

28. The compound according to any one of claims 24 to 27, wherein the compound is selected from: Palm-Lys-Pro-Lys (SEQ ID No: 69); Palm-Lys-Pro-Tyr (SEQ ID No: 70); Palm-Lys-Pro-DOPA (SEQ ID No: 71); Palm-Lys-Hyp-Tyr (SEQ ID No: 72); Palm-Lys-Hyp-DOPA (SEQ ID No: 73); Palm-Lys-Hyp-Lys (SEQ ID No: 74); Palm-Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 75); Palm-Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 76); Palm-Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 77); Palm-Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 78); Palm-Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 79); Palm-Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 80); Palm-Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 81); Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 82); Lys-Hyp-Tyr-Lys(-Palm)-Hyp-Tyr (SEQ ID No: 83); Palm-Lys-Hyp-Tyr-Lys-Hyp-Tyr (SEQ ID No: 84); Palm-Lys-Hyp-Tyr-Lys(-Palm)-Hyp-Tyr (SEQ ID No: 85); Lys-Hyp-Tyr-Lys(-Palm)-Hyp-DOPA (SEQ ID No: 86); Palm-Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID No: 87); Palm-Lys-Hyp-Tyr-Lys(-Palm)-Hyp-DOPA (SEQ ID No: 88); Lys-Pro-Lys-Lys-Pro-Lys(-Palm) (SEQ ID No: 89); Lys-Pro-Lys-Lys-Pro(-Palm)-Lys (SEQ ID No: 90); Lys-Pro-Lys(-Palm)-Lys-Pro-Lys (SEQ ID No: 91); Palm-Lys-Pro-Lys-Lys-Pro-Lys (SEQ ID No: 92); Lys-Pro-Lys-Lys(-Palm)-Pro-Lys(-Palm) (SEQ ID No: 93); Palm-Lys-Pro-Lys-Lys-Pro-Lys(-Palm) (SEQ ID No: 94); Lys-Pro-Lys(-Palm)-Lys(-Palm)-Pro-Lys (SEQ ID No: 95); Palm-Lys-Pro-Lys-Lys(-Palm)-Pro-Lys (SEQ ID No: 96); Palm-Lys-Pro-Lys(-Palm)-Lys-Pro-Lys (SEQ ID No: 97); Lys-Pro-Lys(-Palm)-Lys(-Palm)-Pro-Lys(-Palm) (SEQ ID No: 98); Palm-Lys-Pro-Lys-Lys(-Palm)-Pro-Lys(-Palm) (SEQ ID No: 99); Palm-Lys-Pro-Lys(-Palm)-Lys-Pro-Lys(-Palm) (SEQ ID No: 100); Palm-Lys-Pro-Lys(-Palm)-Lys(-Palm)-Pro-Lys(-Palm) (SEQ ID No: 101); Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 102); (Palm-Lys-Pro-Lys)2-Lys (SEQ ID No: 103); (Palm-Lys-Pro-Tyr)2-Lys (SED ID No: 104); (Palm-Lys-Pro-DOPA)2-Lys (SEQ ID No: 105); (Palm-Lys-Hyp-Tyr)2-Lys (SEQ ID No: 106); (Palm-Lys-Hyp-DOPA)2-Lys (SEQ ID No: 107); or (Palm-Lys-Hyp-Lys)2-Lys (SEQ ID No: 108).

29. The compound according to any one of claims 1 to 22, wherein X represents at least one nonsteroidal anti-inflammatory drug.

30. The compound according to any one of claims 1 to 22 or 24 to 29, wherein X represents at least one lipid and at least one nonsteroidal anti-inflammatory drug as defined in claim 1.

31. The compound according to claim 29 or claim 30, wherein the nonsteroidal anti-inflammatory drug is selected from aspirin, salicylic acid, celecoxib, and mesalazine.

32. The compound according to claim 31, wherein the nonsteroidal anti-inflammatory drug is aspirin or salicylic acid.

33. The compound according to any one of claims 29 to 32, wherein the compound is selected from: ASP-Lys-Pro-Lys (SEQ ID No: 109); ASP-Lys-Pro-Tyr (SEQ ID No: 110); ASP-Lys-Pro-DOPA (SEQ ID No: 111); ASP-Lys-Hyp-DOPA (SEQ ID No: 112); ASP-Lys-Hyp-Lys (SEQ ID No: 113); ASP-Lys-Hyp-Tyr (SEQ ID No: 114); SA-Lys-Pro-Lys (SEQ ID No: 115); SA-Lys-Pro-Tyr (SEQ ID No: 116); SA-Lys-Pro-DOPA (SEQ ID No: 117); SA-Lys-Hyp-DOPA (SEQ ID No: 118); SA-Lys-Hyp-Tyr (SEQ ID No: 119); SA-Lys-Hyp-Lys (SEQ ID No: 120); ASP-Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 121); ASP-Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 122); ASP-Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 123); ASP-Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 124); ASP-Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 125); ASP-Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 126); ASP-Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 127); ASP-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 128); SA-Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 129); SA-Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 130); SA-Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 131); SA-Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 132); SA-Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 133); SA-Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 134); SA-Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 135); SA-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 136); (ASP-Lys-Pro-Lys)2-Lys (SEQ ID No: 137); (ASP-Lys-Pro-Tyr)2-Lys (SEQ ID No: 138); (ASP-Lys-Pro-DOPA)2-Lys (SEQ ID No: 139); (ASP-Lys-Hyp-Tyr)2-Lys (SEQ ID No: 140); (ASP-Lys-Hyp-DOPA)2-Lys (SEQ ID No: 141); (ASP-Lys-Hyp-Lys)2-Lys (SEQ ID No: 142); (SA-Lys-Pro-Lys)2-Lys (SEQ ID No: 143); (SA-Lys-Pro-Tyr)2-Lys (SEQ ID No: 144); (SA-Lys-Pro-DOPA)2-Lys (SEQ ID No: 145); (SA-Lys-Hyp-Tyr)2-Lys (SEQ ID No: 146); (SA-Lys-Hyp-DOPA)2-Lys (SEQ ID No: 147); or (SA-Lys-Hyp-Lys)2-Lys (SEQ ID No: 148).

34. The compound according to any one of the preceding claims, the compound being used in human or animal medicine.

35. The compound according to any one of claims 1 to 33, wherein the compound is used as a drug.

36. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 33.

37. The pharmaceutical formulation of claim 36, wherein the pharmaceutical formulation further comprises a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

38. The pharmaceutical formulation according to claim 36 or claim 32, wherein the pharmaceutical formulation is adapted for 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.

39. The pharmaceutical preparation according to any one of claims 36 to 38, wherein the pharmaceutical preparation is in the form of a liquid, gel, cream, emulsion, serum, powder, suppository, capsule or tablet.

40. The pharmaceutical preparation according to any one of claims 36 to 39, wherein the pharmaceutical preparation further comprises one or another pharmaceutically active ingredient.

41. A kit box comprising the following components: (A) The compound according to any one of claims 1 to 33 or the pharmaceutical preparation according to any one of claims 29 to 33; and (B) A pharmaceutical formulation 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.

42. The pharmaceutical preparation according to claim 40 or the kit according to claim 41, 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.

43. The pharmaceutical preparation or kit according to claim 42, wherein the pharmaceutically active ingredient is an anti-inflammatory agent.

44. The compound according to any one of claims 1 to 33, the formulation according to any one of claims 36 to 40, 42 or 43, or the kit according to any one of claims 41 to 43, wherein the compound, the formulation or the kit is used to treat inflammation, inflammatory disorders and / or disorders characterized by inflammation.

45. Use of the compound according to any one of claims 1 to 33, the formulation according to any one of claims 36 to 40, 42 or 43, or the kit according to any one of claims 41 to 43 for the manufacture of an agent for the treatment of inflammation, inflammatory disorders and / or disorders characterized by inflammation.

46. ​​A method for treating inflammation, inflammatory disorders, and / or disorders characterized by inflammation, the method comprising administering to a patient requiring such treatment a compound according to claims 1 to 33, a formulation according to any one of claims 36 to 40, 42, or 43, or a kit according to any one of claims 41 to 43.

47. The compound, formulation, or kit for the said use according to claim 44, the use according to claim 45, or the method according to claim 46, wherein the inflammatory disorder is a skin disease or causes a skin disease such as acne, rosacea, dermatitis, eczema, hyperpigmentation, scarring (fibrosis), alopecia, seborrheic alopecia, cicatricial alopecia, and paronychia.

48. The compound, formulation, or kit for the said use according to claim 44, the use according to claim 45, or the method according to claim 46, wherein the inflammatory disorder is an oral disease or causes an oral disease, including periodontitis, gingivitis, oral mucositis, tooth sensitivity, or gingival recession.

49. The compound, formulation, or kit for the said use according to claim 44, the use according to claim 45, or the method according to claim 46, wherein the inflammatory disorder is a gynecological disease or causes a gynecological disease, including vaginitis, vulvitis, leukoplakia of the external genitalia, cervicitis, episiotomy, or radiation vaginitis.

50. The compound, formulation, or kit for the said use as claimed in claim 44, the use as claimed in claim 45, or the method as claimed in claim 46, wherein the inflammatory disorder is inflammatory bowel disease or causes inflammatory bowel disease, including ulcerative colitis, proctitis, radiation proctitis, hemorrhoids, or anal cryptitis.

51. The compound, formulation, or kit, use, or method (as the case may be) for the said use according to any one of claims 34 to 50, wherein the one or more compounds or salts thereof are applied topically as an external formulation.

52. The compound, formulation, or kit, use, or method for the said purpose according to claim 51, wherein the relevant condition is treated by direct topical application to the skin.

53. The compound, formulation, or kit, use, or method for the stated purpose according to claim 51, wherein the relevant condition is treated by direct topical application to a mucosal surface, including oral mucosa, ocular mucosa, nasal mucosa, vaginal mucosa, rectal mucosa, or colonic mucosa.

54. The compound, formulation, or kit, use, or method for the stated purpose according to claim 51, wherein the relevant condition is treated by direct topical application to the esophagus, throat, periodontium, gums, and / or teeth.

55. The compound, formulation, or kit, use, or method (as the case may be) for the said use according to any one of claims 34 to 50, wherein the one or more compounds are administered via intradermal or inhalation delivery.

56. The compound, formulation, or kit, use, or method (as the case may be) for the said use according to any one of claims 40 to 55, wherein the compound according to any one of claims 1 to 34 acts as an excipient, a medical device component of a medical device, or a pharmaceutical-medical device combination.

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