TW202502805A - New multi-functional oligopeptides - Google Patents

Abstract

There is provided a compound of Formula I, Lt-Q<SP>a</SP>-Db (I) wherein: Q<SP>a</SP> represents Z or A-Q-B, and Q is a structural fragment of Formula II, wherein: the squiggly lines, R and m have meanings given in the description, and wherein A and B have meanings given in the description, but may represent a peptide component of Formula (IV), [(W)r-Lys-X1-T-U-X2-Y]n-(W)r-Lys-X1-T-U-X2-Y (IV) (SEQ ID No: 1) in which n, r, T, W, X1, U, X2 and Y have meanings given in the description, each L independently represents a lipid as defined in the description, and D represents one or more optional montelukast moieties, which compounds are useful in medicine, including as pharmaceutical excipients, adhesives and film-forming materials and/or are useful in the treatment of conditions characterised by inflammation, including wounds, burns, and disorders of the mucosa, such as anorectal diseases, inflammatory bowel diseases, gynecological diseases and dental diseases.

Description

New multifunctional oligopeptide

The present invention relates to novel peptides, the use of such peptides as pharmaceutically active ingredients or otherwise in human medicines and pharmaceutical compositions comprising the peptides. In particular, the present invention relates to the use of these peptides and compositions in the treatment of various diseases including inflammation.

Inflammation is typically characterized by a local tissue response to invasion by, for example, microorganisms, certain antigens, damaged cells, or physical and/or chemical factors. The inflammatory response is generally a protective mechanism for destroying, diluting, or isolating harmful agents and damaged tissues, and for initiating tissue healing.

Inflammation may result from physical trauma, infection, some chronic diseases (e.g., psoriasis and autoimmune diseases such as rheumatoid arthritis), and/or a chemical and/or physiological response to external stimuli (e.g., as part of an allergic reaction). A complex series of events may be involved in which inflammatory mediators increase blood flow and dilation of local blood vessels, resulting in redness and heat, fluid secretion, often local swelling, migration of white blood cells into the inflamed area, and pain.

Many disorders/conditions are characterized by and/or result from abnormal tissue damaging inflammation. Such disorders are typically characterized by activation of immune defense mechanisms resulting in effects that are more harmful than beneficial to the host and are usually associated with varying degrees of tissue redness or redness, 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.

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 leukocytes and plasma, often leading to local swelling, activation of sensory nerves (causing pain in some tissues), and loss of function. These inflammatory changes are triggered by a cascade of cellular and biochemical events involving cells, such as neutrophils, monocytes, macrophages, and lymphocytes; and inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

In addition, inflammation plays a key role in the wound healing process. Therefore, wounds and burns can be classified as inflammation-related conditions. The traditional concept in this field is that anti-inflammatory drugs should not be administered directly to open wounds because this will be detrimental to the progress of wound healing.

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 injury is severe, or if the wound healing response itself becomes dysregulated. Furthermore, fibrosis is known to be a major cause of morbidity and mortality 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 affect the pathogenesis of many progressive muscle diseases, metastasis, and transplant rejection.

Mussel adhesion protein (MAP), also known as Mytilus edulis foot protein (MEFP), is a protein secreted by marine mussel species such as Mytilus edulis, Mytilus coruscus , and Perna viridis . Eleven unique adhesion protein isoforms have been identified from mussels, including the collagens pre-COL-P, pre-COL-D, and pre-COL-NG; the mussel foot matrix proteins PTMP (proximal filament matrix protein) and DTMP (distal filament matrix protein); and the mfp proteins mfp-2 (sometimes referred to as "mefp-2", used interchangeably below), mfp-3/mefp-3, mfp-4/mefp-4, mfp-5/mefp-5, mfp-6/mefp-6, and optimally mfp-1/mefp-1 (see, e.g., Zhu et al., Advances in Marine Science , 2014 , 32 , 560-568 and Gao et al., Journal of Anhui Agr. Sci. , 2011 , 39 , 560-568). 19860-19862).

An important part of mefp-1 consists of 70 to 90 tandem repeats of the following decapeptide: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 61; 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 can be synthesized, for example, as described by Yamamoto in J. Chem. Soc., Perkin Trans. , 1987 , 1 , 613-618. See also Dalsin et al., J. Am. Chem. Soc. , 2003 , 125 , 4253-4258.

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

Japanese patent application JP 2003238589 A discloses certain dipeptides and tripeptides as angiotensin converting enzyme inhibitors.

The use of lysine amino acid residues for preparing multiple antigenic peptides has been disclosed in, for example, Tam Proc. Natl. Acad., Sci. USA , 1988 , 85 , 5409-5413, Rao et al., J. Am. Chem. Soc. , 1994 , 116 , 6975-6976, US 5,229,490 and WO 2010/038220. See also international patent application WO 2021/110064 A1.

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

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, for example, in MS Ferreira. Cosmetics. 2000 , 7 , 91. See also Kamysz et al., which discloses palmitoyl tripeptide as an antimicrobial agent.

There is a clear need for new and/or improved pharmaceuticals that can be used to treat inflammation and conditions characterized by inflammation.

According to the first aspect of the present invention, there is provided a compound of formula I, L _t -Q ^a -D _b (I) wherein: Q ^a represents Z or AQB; Q is a structural fragment of formula II, (II) Where: The wavy lines represent the points of attachment of Q to A and/or B; R is selected from: , and Among them, when R represents wherein one wavy line represents the point of attachment to the remainder of the Q fragment and the other wavy line represents the point of attachment to the Z group; m represents an integer from 1 to 4; A and B independently represent Z or A ¹ -Q ¹ -B ¹ ; A ¹ and B ¹ independently represent Z or A ² -Q ² -B ² ; A ² and B ² independently represent Z or ZQ ³ -Z; Q ¹ , Q ² and Q ³ independently represent a structural fragment of Formula III, (III) wherein: the wavy lines adjacent to the NH groups represent the points of attachment of Q ¹ , Q ² and Q ³ to A ¹ and/or B ¹ , A ² and/or B ² and Z, respectively; the wavy lines adjacent to the C═O groups represent the points of attachment of Q ¹ , Q ² and Q ³ to Q, Q ¹ and Q ^2, respectively; m is as defined above; Each L independently represents one or more lipids selected from vitamin A, vitamin E, cholesterol and fatty acids, the fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons and/or one or more cyclic rings, the lipids being linear or branched, saturated or having between 1 and 10 carbon-carbon double bonds but unsaturated and/or substituted with between 1 and 10 -OH groups, or derivatives of any of these lipids; t represents an integer selected from 1 to 32; D represents montelukast; b represents an integer selected from 0 to 16; in each case where it is used above, Z represents a structural fragment of formula IV, [(W) _r -Lys-X ¹ -TUX ² -Y] _n -(W) _r -Lys-X ¹ -TUX ² -Y (IV) (SEQ ID No: 1) wherein: n represents an integer selected from 0 to 4; in each case where it is used, r independently represents 0 or 1; in each case where it is used, W independently represents a sequence of 1 or 2 amino acids, the amino acids being selected from one or more of the following groups: Ser, Lys, Ala, DOPA and 3,4-dihydrocinnamic acid (HCA) residue, provided that when present, the HCA residue is located at the N-terminus of Z; ^X1 independently represents Pro, Hyp or diHyp; T independently represents Ser or pSer; U independently represents Tyr, pTyr, DOPA, Hyp or Pro; ^X2 independently represents Thr, Ser, Pro, Hyp or diHyp; Y independently represents a sequence of 1 to 5 (e.g. 1 to 4) amino acids selected from one or more of the following groups: Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, said sequence optionally terminated by dopamine (or more appropriately, a "dopamine fragment"); if present, each D is covalently bonded to Z via an amide bond between its corresponding carboxylic acid residue and one or more _NH2 residues of Z; and each L residue is covalently bonded to Z via an amide bond between the corresponding carboxylic acid residue of L and one or more _NH2 residues of Z and/or via an ester bond between the corresponding -OH residue of L and one or more carboxylic acid residues of Z, As well as positional isomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of the compounds, the compounds, positional isomers, stereoisomers and salts are hereinafter collectively referred to as "compounds of the present invention".

The skilled person will be able to determine whether the Z peptide is attached to the rest of the molecule via the N or C terminus. For the avoidance of doubt, Z is attached to the rest of the molecule via formation of an amide bond.

Therefore, when Z is attached to R, when R is , Z is attached via the N terminus.

Preferred compounds of the present invention include those wherein the lipid is selected from palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid and leukotriene B4 (LTB4) or a derivative of any of these lipids.

Further preferred compounds of the present invention also include these compounds, wherein the lipid is a polyunsaturated fatty acid or a derivative thereof. In this specific example, the derivative can be a specialized pro-resolving mediator (SPM).

Further preferred compounds of the present invention also include those compounds wherein the lipid is a derivative of fatty acids, such as glycerolipids, glycerophospholipids, sphingolipids or glycolipids.

Further preferred compounds of the present invention also include these compounds, wherein the lipid is palmitic acid or a derivative thereof. In this specific example, the derivative may be phosphatidylserine or more preferably, the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine, and most preferably, the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS). In this specific example, the derivative may be phosphatidylethanolamine or more preferably, the derivative is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

Further preferred compounds of the present invention also include these compounds, wherein the lipid is stearic acid or a derivative thereof. In this specific example, the derivative can be 1,2-distearoyl-sn-glycero-3-phospho-l-serine.

Further preferred compounds of the present invention also include these compounds, wherein the lipid is oleic acid or a derivative thereof. In this specific example, the derivative can be 1,2-dioleyl-sn-glycero-3-phospho-L-serine.

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

Further preferred compounds of the present invention also include these compounds, wherein the lipid is selected from vitamin E, vitamin A and cholesterol or a derivative of any one of these lipids. In this specific example, the derivative of cholesterol can be cholesterol-acetic acid.

Further preferred compounds of the present invention also include those compounds wherein the lipid is a fatty acid containing 1 to 50 carbons and/or one or more cyclic rings, a lipid or derivative thereof that is linear or branched, saturated or has between 1 and 10 carbon-carbon double bonds, is unsaturated, and/or is substituted with between 1 and 10 -OH groups. In such embodiments, the fatty acid may have 6 to 24 carbons, such as 6 to 18 carbons. In other embodiments, the fatty acid may have 1 to 6 carbon-carbon double bonds, such as 1 to 5 carbon-carbon double bonds. In other embodiments, the fatty acid may have 1 to 5 -OH groups, such as 1 to 2 -OH groups. In other embodiments, the fatty acid can have 1 to 10 cyclic rings, such as 1 to 8 cyclic rings.

Further preferred compounds of the present invention also include those compounds, wherein: t represents an integer selected from 1 to 8; or more preferably t represents an integer selected from 1 to 4. Further preferred compounds of the present invention also include those compounds, wherein: b represents an integer selected from 0 to 4; or more preferably b represents 1. As used herein, the terms "dopamine" and "dopamine fragment" refer to the structural fragment of Formula I, The wavy line indicates the point of attachment to Y.

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

As used herein, Pro represents proline, Ala represents alanine, Ser represents serine, Tyr represents tyrosine, Hyp represents hydroxyproline (including 3-hydroxyproline (3Hyp) and 4-hydroxyproline (4Hyp)), diHyp represents dihydroxyproline (including 3,4-dihydroxyproline (3,4diHyp), trans-2,3 -cis-3,4-dihydroxyproline, 3,5-dihydroxyproline (3,5diHyp) and 4,5-dihydroxyproline (4,5diHyp)), Thr represents threonine, Lys represents lysine, Ala represents alanine, DOPA represents 3,4-dihydroxyphenylalanine, Orn represents ornithine, and Chol-Ac represents cholesterol-acetic acid: (It can form an amide bond by attaching to any free amine group, including the N-terminus of the amino acid sequence Z), and Dap stands for diaminopropionic acid. The 3,4-dihydrocinnamic acid (HCA) residue is essentially a DOPA residue, but without the _-NH2 group at the 2- or α-carbon position relative to the carboxylic acid attached to the N-terminal amino acid (Lys or Ala).

In each case where they are employed, Q, Q ¹ , Q ² and Q ³ may each be covalently bonded to zero, one or two Z groups via an amide bond between the corresponding carboxylic acid residue of Z and one or more NH ₂ residues of Q, Q ¹ , Q ² and Q ³ .

In this regard, preferred compounds of the invention include those wherein: one of A or B represents Z and the other represents A ¹ -Q ¹ -B ¹ ; or more preferably, A and B both represent Z or both represent A ¹ -Q ¹ -B ¹ , wherein in each case Q ¹ preferably represents a Lys fragment and Z is as defined above.

Further preferred compounds of the present invention also include those compounds wherein: one of ^A1 and ^B1 represents Z and the other represents ^A2 - ^Q2 - ^B2 ; or more preferably, ^A1 and ^B1 both represent Z or both represent ^A2 - ^Q2 - ^B2 , wherein in each case, ^Q2 preferably represents a Lys fragment and Z is as defined above.

Further preferred compounds of the present invention also include those compounds wherein: one of ^A2 and ^B2 represents Z and the other represents ^ZQ3 -Z; or more preferably, ^A2 and ^B2 both represent Z or both represent ^ZQ3 -Z, wherein in each case, ^Q3 preferably represents a Lys fragment and Z is as defined above.

More preferred compounds of the present invention include those compounds wherein: ^A1 and ^B1 both represent Z; or ^A2 and ^B2 both represent Z.

Further preferred compounds of the invention include those compounds, wherein m represents 1, 3 or more preferably 4, such that one or more of Q, ^Q1 , ^Q2 and ^Q3 represents Lys or more appropriately, a "Lys fragment" as defined above as a "structural fragment of formula II and III" (as the case may be).

Particularly preferred compounds of the present invention include those compounds wherein: ^Qa represents Z; wherein n is 0, 1 or 4, preferably n is 1 or more preferably n is 0.

Compounds according to the invention that may be mentioned include those compounds in which the amino acid residue at the N-terminus of the Z component is optionally covalently bonded to montelukast.

Other compounds of the invention which may be mentioned include those compounds, wherein: R represents t represents an integer selected from 1 to 4; and/or b is 0 or 1.

Compounds of the invention that may be mentioned include those in which: in each case where it is employed, W represents a sequence of 1 or 2 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Ala, DOPA and HCA; T represents Ser; U represents Tyr or DOPA; ^X2 represents Ser, Pro, Hyp or diHyp; Y represents a sequence of 1 to 5 (e.g., 1 to 4) amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Ala, Pro, Hyp, diHyp, Thr, DOPA and Tyr.

Compounds of the invention that may be mentioned include those compounds in which: 1 or 2 amino acids in W represent Ser; T represents pSer; U represents pTyr, Hyp or Pro; ^X2 represents Thr; 1 to 5 (e.g. 1 to 4) amino acids in Y are pThr; Y is optionally terminated by dopamine.

Preferred compounds of the present invention include those compounds wherein: ^X1 represents Hyp or, preferably, Pro; T represents Ser; U represents Tyr or DOPA; ^X2 represents Hyp; if present, W represents HCA-, HCA-Ala-, Lys-Ala-, DOPA-, DOPA-Ala- or, preferably, Ala; and/or Y represents a sequence of 5, preferably 3, more preferably 2 or most preferably 4 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Hyp, Thr, DOPA and Tyr, the sequence optionally being terminated by a dopamine fragment.

Preferred compounds of the present invention also include those compounds, wherein Y represents a sequence of four amino acids selected from the following group: -Pro- ^Y1 - ^Y2 -Lys- or more preferably, -Hyp- ^Y1 - ^Y2 -Lys- and -Thr- ^Y1 - ^Y2 -Lys-, wherein ^Y1 and ^Y2 are each independently selected from the following group: Pro, Ala or more preferably Hyp, Thr, DOPA and Tyr, and the sequence is optionally terminated by a dopamine fragment.

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

Further preferred compounds of the present invention include those compounds wherein the amino acid sequence defined by Y is selected from the following group: -Thr-Tyr-Hyp-; -Thr-DOPA-Hyp-; -Hyp-Thr-DOPA-; -Hyp-pThr-DOPA-; -Hyp-Thr-Tyr-; -Hyp-Thr-Tyr-Hyp; -Hyp-Thr-DOPA-Hyp-; -Hyp-pThr-DOPA-Hyp-; -Thr-Tyr-Lys-Hyp-; -Thr-DOPA-Lys-Hyp-; preferably, -Pro-Thr-DOPA-Lys-; -Pro-Thr-Tyr-Lys-; -Thr-Tyr-Pro-Lys-; -Thr-DOPA-Pro-Lys-； -Tyr-Hyp-Lys-； -Tyr-Pro-Lys-； -DOPA-Hyp-Lys-； -Hyp-Thr-Ala-Lys-； -Thr-Ala-Hyp-Lys-； -Thr-Tyr-Lys； -Thr-Lys-；and more preferably, -Hyp-Thr-Tyr-Lys-； -Hyp-Thr-DOPA-Lys-； -Thr-Tyr-Hyp-Lys-； -Thr-DOPA-Hyp-Lys-； -DOPA-Lys-；and -Tyr-Lys-, each of which is optionally terminated by a dopamine fragment.

Compounds according to the invention which may be mentioned include those compounds, in which W represents Ala.

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

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

More preferred compounds of the present invention that may be mentioned include those compounds, wherein Z is selected from the following group: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 11); and Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 12). Compounds of the present invention that may be mentioned include those compounds, wherein W is absent.

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

Preferred compounds of the present invention that may be mentioned include those compounds, wherein Z is selected from the following group: Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91); Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 93); Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100); Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97); Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); and Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92).

More preferred compounds of the present invention that may be mentioned include those compounds, wherein Z is selected from the following group: Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16); and Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19).

Compounds of the invention that may be mentioned include those compounds wherein the amino acid residue at the N-terminus of the Z component is optionally covalently bonded to montelukast to form an amide linkage with the carboxylic acid group in montelukast.

Further provided is a (optionally isolated) peptide compound Z (i.e. a compound equivalent to a compound of formula I as defined above, but in which L and D are absent and ^Qa represents Z as defined above), wherein: r and n both represent O; ^X1 represents Hyp or preferably Pro; T represents pSer or preferably Ser; U represents DOPA or preferably Tyr; ^X2 represents Hyp; and Y represents a sequence of 1 to 5, preferably 3, more preferably 4 or most preferably 2 amino acids, wherein the amino acids are selected from one or more of the following group: Lys, Hyp, Thr, DOPA and Tyr, the sequence optionally being terminated by a dopamine fragment, as well as positional isomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

Preferred peptide compounds Z include those of the following sequences: Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 86); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 88); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 89); Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID No: 90); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19); Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92); Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 93) Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 95); Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 96); Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97); Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID No: 98); Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99); Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID No: 101); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 102); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID No: 103); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 104); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID No: 105); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 106); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID No: 107); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 108); and Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16), As well as positional isomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

Preferred peptides can be selected from the following group: Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91); Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 93); Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100); Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94); Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97); Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87); and Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92), and positional isomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

Particularly preferred peptide compounds can be selected from the following groups: Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16); and Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19), as well as positional isomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of such peptide compounds.

For the avoidance of doubt, the compounds of the present invention as defined above are hereinafter collectively referred to as "compounds of the present invention".

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

In addition, in addition to the standard central carbon atom of the amino acids in the compounds of the present invention (usually but not exclusively in the L-configuration), some of the 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 regard, the definition of Hyp includes trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, cis-3-hydroxy-L-proline, trans-5-hydroxy-L-proline and cis-5-hydroxy-L-proline, however, we prefer that the Hyp used in the compounds of the present invention is 4-hydroxy-L-proline. Analogously, a corresponding definition may apply to diHyp, wherein the two hydroxyl groups may also be cis or trans relative to each other. In any case, the individual enantiomers of the compounds of formula I which may form part of the compounds of the invention are included within the scope of the invention.

The compounds of the present invention may be in the form of a salt. 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 may be formed by conventional means, for example by reacting the compounds of the present invention with one or more equivalents of a suitable acid or base, as required, in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or the medium using standard techniques (e.g., in a vacuum, by freeze drying or by filtration). Salts may also be prepared by exchanging the counter ion of the compounds of the present invention in salt form with another counter ion, for example using a suitable ion exchange resin.

Preferred salts include, for example, acetates, hydrochlorides, hydrosulfates, maleates, methanesulfonates, toluenesulfonates, alkaline earth metal salts (such as calcium and magnesium salts) or alkaline metal salts (such as sodium and potassium salts). Optimally, the compounds of the present invention may be in the form of acetates.

The compounds of the present invention can be prepared by conventional techniques, such as by standard amino acid coupling techniques, using standard coupling reagents and solvents, such as described below. The compounds of the present invention can be synthesized by available starting materials using appropriate reagents and reaction conditions. In this regard, technicians can refer to " Comprehensive Organic Synthesis ", BM Trost and I. Fleming, Pergamon Press, 1991. Other references that can be adopted include " Heterocyclic Chemistry ", JA Joule, K. Mills and GF Smith, the 3rd edition, published by Chapman & Hall, " Comprehensive Heterocyclic Chemistry II ", AR Katritzky, CW Rees and EFV Scriven, Pergamon Press, 1996 and " Science of Synthesis ", Vol. 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

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. Thus, the methods for preparing the compounds of the present invention as described herein may include isolating and, if necessary, purifying the compounds of the present invention as a final step.

Those skilled in the art will appreciate that, in the methods described above and below, it may be necessary to protect the functional groups of the intermediate compounds by protecting groups. The protection and deprotection of the functional groups can be carried out before or after the reaction.

Protective groups can be applied and removed according to techniques well known to those skilled in the art and as described below. For example, protected compounds/intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will determine the need and type of protecting groups, as well as the order in which the synthesis is achieved. The use of protecting groups is fully described in " Protective Groups in Organic Synthesis ", 5th edition, TWGreene & PGM Wutz, Wiley-Interscience (2014), the contents of which are incorporated herein by reference.

The compounds of the invention can be used as human and animal medicines. Therefore, they are indicated as medicines (and/or in veterinary science), although they can also be used as cosmetics and/or as part of a medical device.

The compounds of the present invention may also thus have pharmacological activity, but certain pharmaceutically acceptable (e.g., "protected") derivatives of the compounds of the present invention may exist or may be prepared, which may not have such activity, but which may be administered and subsequently metabolized or chemically converted to form the compounds of the present invention. Such compounds (which may have certain pharmacological activity, provided that such activity is significantly lower than the activity of the active compound obtained by its metabolism/conversion) may therefore be described as "prodrugs" of the compounds of the present invention.

As used herein, reference to prodrugs will include compounds that form the compounds of the invention in an experimentally detectable amount within a predetermined time after administration. All prodrugs of the compounds of the invention are included within the scope of the invention.

When the compounds of the invention are pharmacologically active, they are particularly useful in the treatment of inflammation.

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 system, visceral organs, especially mucosal surfaces, especially the skin, and also includes all such inflammatory conditions or disorders and/or conditions or disorders characterized by inflammation (e.g. as a symptom).

Inflammatory conditions and/or disorders can be (and typically are) characterized by 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 hyperemia, swelling, edema, hyperthermia, pain (including aching), fluid exudation, itching (pruritus), cell death and tissue destruction, cell proliferation and/or loss of function.

Inflammatory disorders that may be mentioned include arteritis, diabetes, metabolic syndromes, rosacea, asthma and allergies, ankylosing spondylitis, chronic obstructive pulmonary disease, gouty arthritis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), multiple sclerosis, osteoarthritis, pancreatitis, prostatitis, psoriasis arthritis, rheumatoid arthritis, tendinitis, bursitis, Sjogren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis and related cardiovascular conditions. Disease states that may be mentioned that are characterized by inflammation are chronic obstructive pulmonary disease (COPD). Further disease states characterized by inflammation that may be mentioned are inflammatory bowel diseases, including Crohn's disease and in particular ulcerative colitis. Other disease states characterized by inflammation that may be mentioned are gynecological diseases, such as cervicitis, vaginitis (e.g., radiation vaginitis) and colpitis. Diseases affecting the gastrointestinal tract, such as gastric ulcer diseases (e.g., gastritis, gastric ulcers, pressure-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 flu).

Inflammatory disorders that may be mentioned more particularly include inflammation of the skin or mucous membranes (including oral, nasal, ocular, vaginal, cervical and/or anorectal mucosa, more particularly oral or nasal mucosa), such as inflammation caused by infection (such as viral and/or bacterial infection) or allergic/atopic disorders (such as rhinitis (e.g. allergic rhinitis), pharyngitis, periodontitis, gingivitis, dry eyes, conjunctivitis (e.g. Allergic conjunctivitis), dermatitis, urticaria (hives), and food allergies); and other inflammatory conditions such as herpes, drug eruptions, polymorphous light eruptions, sunburn, early manifestations of skin cancer (erythematous dermatoses), pathological hair loss (including after skin transplants), chemical eruptions, psoriasis, erythema multiforme, folliculitis, eczema, and otitis externa. Disease conditions that may be mentioned are polymorphous light eruptions.

More particularly, the compounds of the invention 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, tearing, bruises and scars) and burns (including inflammation caused by surgical procedures (such as skin grafts) after burns) and other conditions (such as hemorrhoids). Wounds can be acute or chronic and/or can be caused by one or more inflammatory conditions as defined herein.

Wounds of the skin or mucosa may result from internal or external physical injury to the membrane surface, or may result from (i.e., be a symptom of) an underlying physiological condition.

Physical (i.e., "open") wounds may be caused by sharp objects (cuts, incisions, punctures) or blunt objects/mechanical forces (lacerations, abrasions, avulsions), physical blows (bruises), heat or chemicals (burns and blisters), ultraviolet light (sunburns), cold (frostbite or frostbite). Wounds may be superficial (damage to the epidermis and/or dermis only) or may be full-thickness wounds (damage below the epidermis and/or dermis). In severe cases, damage may occur to subcutaneous and/or submucosal tissues such as muscle, bone, joints, and even internal organs.

The compounds of the present invention can be used to relieve pain (including latent pain) associated with inflammation and/or wounds. In particular, the compounds of the present invention can be used to relieve procedural pain and/or non-procedural pain. The skilled person will understand that the term "procedural pain" (i.e., surgical pain) refers to acute pain associated with medical research and treatment for health care purposes. The term "non-procedural" refers to general pain associated with inflammation and/or injury (e.g., pain associated with tooth ulcers, burns and/or scars) and is not the result of a specific medical intervention.

The compounds of the present invention can be used not only to treat inflammation, pain (including underlying pain) and/or pruritus (itching) associated with the wound itself and the healing process, but also to prevent leakage of body fluids from the wound, the risk of infection, and physiological reactions (such as scarring and pigmentation) caused by inflammation and/or the wound healing process.

Scarring is the result of inflammation and/or wound healing, and is a general term for the formation of fibrous tissue as a result of this inflammation/healing.

The compounds of the present invention may also be used to inhibit the production of melanin pigmentation, which may or may not be caused by inflammation and/or wound healing. The compounds of the present invention may also be used to inhibit conditions associated with melanin pigmentation, such as melasma, freckles, melanosis, malar rash and other pigmentation disorders, skin cancers with melanoma, and pigmentation disorders or skin diseases caused by exposure to the sun (like acne).

Wounds may also occur as a result of a (e.g. inflammatory) disease or condition. Such wounds may include blisters and/or ulcers of the skin and mucous membranes. These are common conditions that are often long-lasting and difficult to treat. Skin tissue may often be damaged, removed, liquefied, infected and/or necrotic. Ulcers may lead to secondary consequences for health (especially if they become infected), are difficult to heal and expensive to treat. They may also cause significant psychological stress and economic losses to the patient, affecting overall well-being and quality of life.

In alternative embodiments, inflammatory skin disorders or diseases in which the compounds of the present invention are found to be particularly useful include viral skin diseases (such as herpes zoster), bacterial skin diseases, fungal skin diseases, skin diseases caused by animals, sexually transmitted skin diseases, skin diseases associated with allergies, autoimmune skin diseases, neutrophilic dermatoses, erythematous and squamous dermatoses, connective tissue diseases, macrophages, Acne skin diseases, pigmented skin diseases, skin appendage conditions, hereditary skin diseases, skin diseases associated with nutritional and metabolic conditions, skin tumors, psoriasis, acne, eczema and dermatitis (especially allergic/atopic dermatitis and neurodermatitis), as well as in the treatment of inflammation of the mucosa as characterized, for example, by rhinitis (especially allergic rhinitis), hemorrhoids, chronic obstructive pulmonary disease and ulcerative colitis.

Psoriasis is a chronic inflammatory skin disease with a relapsing tendency (some patients never recover throughout their lifetime). The clinical manifestations of psoriasis mainly include erythema and scaling. It can occur all over the body, but is more commonly observed on the scalp and limbs.

Acne is a follicular (pilosebaceous unit) chronic inflammatory skin disease, the occurrence of which is closely related to major factors such as excessive sebum secretion, obstruction of the pilosebaceous ducts (including closed comedones and open comedones), bacterial infection and inflammatory response, which tends to occur in adolescence and is characterized by polymorphic skin lesions on the face. Therefore, the term acne includes common acne and rosacea (i.e., rosacea (copper nose)).

Eczema is an inflammatory reaction of the skin with 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 exudate production, while the chronic phase includes infiltration and hypertrophy. Skin lesions are usually pruritic and tend to recur.

Dermatitis is a common skin disease characterized by roughness, redness, itching, eczema, and dryness. If not treated quickly, the small bumps, stubborn ulcers, and pigmented macules caused by dermatitis may progress to basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Dermatitis may be caused by a variety of internal and external infectious or non-infectious factors, including substances (contact dermatitis) or allergies (allergic/atopic dermatitis). Also included are seborrheic dermatitis (seborrheic eczema), scarring alopecia and related disorders, and all forms of steroid-dependent dermatitis (including photosensitive seborrheic dermatitis; perioral dermatitis; dermatitis rosacea; rosacea, such as steroid-rosacea, steroid-induced rosacea, iatrosacea, steroid dermatitis rosacea-like, topical corticosteroid-induced rosacea, rosacea; and more particularly facial corticosteroid addiction dermatitis (FCAD) or facial corticosteroid dependence dermatitis (FCDD), characterized by flushing, erythema, telangiectasia, atrophy, papules and/or pustules on the facial area following long-term treatment with topical corticosteroids (including uncontrolled use, abuse, or misuse); see, e.g., Xiao et al., J. Dermatol. , 2015 , 42 , 697-702 and Lu et al., Clin. Exp. Dermatol. , 2009 , 35 , 618-621).

Rhinitis is an irritation and inflammation of the mucous membranes lining 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 flakes. It has been unexpectedly discovered that patients with allergic rhinitis treated with the compounds of the invention experience relief of eye itching even when the compounds of the invention are administered nasally (i.e., to the nasal mucosa).

Hemorrhoids are swellings caused by inflammation of the hemorrhoidal blood vessels found in or around the rectum and anus. Symptoms include bleeding after passing a stool (i.e., hurting), prolapsed hemorrhoids, mucus discharge, and itching, pain, redness, and swelling in the anal area. Hemorrhoids are thought to be the result of increased abdominal pressure, for example as a result of constipation or diarrhea.

Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties, including emphysema (damage to the air sacs) 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 results in impairment of the flow of air in and out of the lungs. Symptoms of COPD include shortness of breath, a productive cough, frequent chest infections, and persistent wheezing. The most common cause of the disease is smoking, but other risk factors include severe air pollution and occupational exposure to dust, chemicals, and fumes.

The compounds of the present invention may have an active effect in reducing erythema, redness and swelling, edema, blisters and bullous pemphigoid caused by various conditions including those mentioned generally and specifically herein, and may inhibit the exudation of subcutaneous tissue fluid and inhibit the itching and pain caused by such inflammatory conditions.

Other inflammatory conditions that may be mentioned include: (a) Mucosal inflammations such as oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis and enterocolitis (including bacillary dysentery, chronic amoebic dysentery, schistosomiasis, non-specific ulcerative colitis and regional enteritis), cervicitis and endocervicitis, endometritis, inflammation caused by aspiration injury etc. and mucosal inflammations associated with cancers and infections (e.g. viral infections such as the common cold or flu) affecting mucosal surfaces (such as those in the oral cavity, nasopharynx, ear, larynx, trachea, gastrointestinal tract, cervix etc.). (b) Orthopedic inflammation associated with, for example, fractures, purulent infections of bones and joints, inflammation due to rheumatic bone disease and purulent osteomyelitis (acute, chronic, localized, sclerotic, post-traumatic), purulent arthritis; bone tumors (osteoma, osteoid osteoma, chondroma), bone cysts, osteoclastomas, primary bone sarcomas (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. (c) Neuroinflammation, such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, intercostal neuritis, etc. (d) Subcutaneous and submucosal soft tissue inflammation, such as myositis, ligamentitis, tendinitis, membrane inflammation, bursitis, lymphadenitis, bubonadentitis, tonsillitis, synovitis, fasciitis and soft tissue inflammation caused by injury, contusion or tear of muscle, ligament, fascia, tendon, synovium, fat, joint capsule and lymphatic tissue. (e) Vascular inflammation, such as allergic leukocytic vasculitis, allergic cutaneous vasculitis, polyangiitis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition and rheumatic vasculitis and vascular inflammation associated with vascular cancer caused by allergic leukocytic vasculitis, polyangiitis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition and rheumatic vasculitis. (f) Inflammation of internal organs (such as the heart, stomach, intestines, lungs, liver, spleen, kidneys, pancreas, bladder, ovaries and prostate), including but not limited to pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, splenitis, nephritis, pancreatitis, cystitis (including interstitial cystitis), oophoritis, prostatitis and treatment of gastric ulcers. (g) Inflammation of the eye and surrounding areas, such as conjunctivitis, keratitis (e.g., acute epithelial keratitis, numeral keratitis, stromal keratitis, discoid keratitis, neurotrophic keratitis, viscous keratitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, acanthamebic keratitis, onchocercal keratitis, superficial punctate keratitis, ulcerative keratitis, exposure keratitis, photokeratitis, and acute red eye with contact lens), optic neuritis, retinal maculopathy, retinal lesions, etc. (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, dental ulcers, etc. (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, rheumatic polymyalgia, polymyositis, psoriasis arthritis, scleroderma, Gehrig's syndrome, spondyloarthropathies, systemic lupus erythematosus, tendinitis, etc.

The compounds of the invention may also be used for differentiation and regeneration of bone marrow cells and for regenerative pathological anemia (eg, by systemic and topical administration).

The compounds of the present invention may also be used to treat kidney disease, including end-stage kidney disease and its complications (including uremic pruritus).

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

The compounds of the present invention can also be used to treat certain specific diseases of the respiratory system, such as cystic pulmonary fibrosis, interstitial pneumonia (including common interstitial pneumonia), allergic pneumonitis, asbestosis, emphysema, cor pulmonale, pulmonary embolism, etc. A specific disease state that can be mentioned is idiopathic pulmonary fibrosis (IPF).

IPF is a diffuse and fatal interstitial lung disease, whose pathological features include alveolar epithelial damage, massive proliferation of pulmonary fibroblasts, and excessive deposition of extracellular matrix, which ultimately lead to irreversible lung tissue damage. In the later stages of the disease, individuals with IPF experience respiratory failure and death. It has been found that the compounds of the present invention can be used to treat IPF and/or alleviate symptoms associated with the disease.

The compounds of the invention are also particularly useful for treating the following pulmonary and/or fibrotic disorders (whether or not otherwise mentioned herein): pulmonary fibrosis, renal fibrosis, hepatic fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, severe asthma (status asthmatics), bronchiectasis, upper respiratory tract infections (including the common cold and influenza), allergic respiratory inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, rickettsial pneumonia (reckettsia), radiation pneumonia, pneumococcal (including staphylococcal, streptococcal, and gram-negative bacilli) pneumonia, pulmonary candidiasis (including aspergillosis, white mold disease, histoplasmosis, actinomycosis, and nocardiosis), pulmonary mycoses, cryptococcosis, pulmonary abscesses, allergic pneumonia, extrinsic allergic alveolitis, pulmonary eosinophilia (including Leoffer’s syndrome and pulmonary eosinophilia) eosinophilia), obstructive pulmonary edema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis/acidosis, acute lung injury, interstitial lung disease, abscesses, pulmonary fibrosis, and cor pulmonale.

Specific mucosal conditions and diseases for which the compounds of the invention are useful include, for example, anorectal diseases such as diarrhea, hemorrhoids, abscesses, ulcers, 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 conditions; and dental diseases such as periodontitis.

The compounds of the present invention may further have an antioxidant effect by increasing the production of SOD (superoxide dismutase) and reducing lipid oxidation. Therefore, it can be considered that the compounds of the present invention have antioxidant properties.

The compounds of the invention may also have antipyretic properties, which allow the treatment of fever and/or the alleviation of its symptoms; for example, by lowering the body temperature of an individual, which results in a reduction in fever. Thus, the compounds of the invention and formulations containing them may be considered antipyretics.

The compounds of the invention are particularly useful for treating: ●   Skin diseases, including acne, rosacea, dermatitis, seborrheic dermatitis, neurodermatitis, eczema, melanin hyperpigmentation, scarring (fibrosis), hair loss, seborrheic alopecia, scarring alopecia and groinitis; ●   Oral diseases, including periodontitis, gingivitis, oral mucositis (including radiation-induced mucositis), tooth sensitivity and gingival recession; ●   Gynecological diseases, including vaginitis, vulvitis, genital leukoplakia, cervicitis, genital episiotomy and radiation vaginitis; and/or ●   Inflammatory bowel disease (IBD), including ulcerative colitis, proctitis, radiation proctitis, hemorrhoids and anal sinusitis.

According to a further aspect of the invention, there is provided a method of treating inflammation, an inflammatory condition, and/or a condition/disorder characterized by (e.g., as a symptom of) inflammation, comprising administering to a patient in need of such treatment a compound of the invention or a salt thereof.

For the avoidance of doubt, in the context of the present invention, the terms "treatment", "therapy" and "method of treatment" include curative or palliative treatment of patients in need thereof as well as preventive treatment and/or diagnosis of patients susceptible to inflammation and/or inflammatory conditions.

The compounds of the invention may further have antiviral properties, such as in contrast to the treatment of any symptoms of any viral infection or disease (such as pain and/or inflammation), which allow the treatment of viral infections in nature, i.e., by interfering with the replication of the virus in the host. Such antiviral properties may also allow the prevention of the onset of such infections or diseases, the protection of host cells from (e.g., further) viral infection, the prevention or cessation of the spread of viral infections or diseases (within a single host or from one host to a new host), or the prevention of reactivation of viruses after being latent in a host.

According to another aspect of the present invention, there is provided a method for treating viral infection, the method comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

Viral infections that may be mentioned include those caused by viruses of the following families: Adenoviridae (e.g. adenovirus), Papillomaviridae (e.g. human papillomavirus), Polyomaviridae (e.g. BK virus; JC virus), Herpesviridae (e.g. herpes simplex type 1; herpes simplex type 2; varicella zoster virus; Epstein-Barr virus; human cytomegalovirus; human herpesvirus type 8), Poxviridae (e.g. smallpox), Hepadnaviridae (e.g. hepatitis B virus), Parvoviridae (e.g. parvovirus B19), Astroviridae (e.g. human astrovirus), Caliciviridae (e.g. norovirus; Norwalk virus), Picornaviridae (e.g. coxsackievirus, hepatitis A virus; poliovirus; rhinovirus) , Coronaviridae (e.g., severe acute respiratory syndrome virus), Flaviviridae (e.g., hepatitis C virus; yellow fever virus; dengue virus; West Nile virus; tick-borne encephalitis virus), Retroviridae (e.g., human immunodeficiency virus; HIV), Togaviridae (e.g., rubella virus), Arenaviridae (e.g., Lassa virus), Bunyaviridae (e.g., hantavirus; Crimean-Congo hemorrhagic fever virus; Hantaan virus), virus), Filoviridae (e.g., Ebola virus; Marburg virus; Ravn virus), Orthomyxoviridae (e.g., influenza virus, including influenza A virus (e.g., H1N1 and H3N2 virus), influenza B virus or influenza C virus), Paramyxoviridae (e.g., measles virus; mumps virus; parainfluenza virus, respiratory syncytial virus), Collaviridae (e.g., rabies virus), Hepaciviridae (e.g., hepatitis E virus), Reoviridae (e.g., rotavirus; orivirus; coltivirus; Banna virus), and viruses not assigned to a family (e.g., hepatitis D virus).

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

The compounds of the present invention may further have antibacterial and/or bacteriostatic properties, such as in contrast to the treatment of any symptoms of any bacterial infection or disease (such as pain and/or inflammation), which properties may allow the treatment of bacterial infections in nature, i.e., by interfering with the growth or proliferation of bacteria in the host to treat bacterial infections or bacterial diseases. Therefore, the compounds of the present invention may be considered bactericidal and/or preferred bacteriostatic agents.

Such antibacterial properties may also allow prevention of the onset of such an infection or disease, protection of host cells from (e.g., further) bacterial infection, prevention or cessation of the spread of a bacterial infection or disease (within a single host or from one host to a new host), or prevention of reactivation of bacteria after being latent in a host.

According to another aspect of the present invention, there is provided a method for treating bacterial infection, the method comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

As disclosed herein, the compounds of the invention may further have anti-cancer properties, such as those that may allow for the treatment of cancer per se, i.e., by interfering with it, as opposed to the treatment of any symptoms of cancer, such as pain and/or inflammation. Such anti-cancer properties may also include the prevention of attacks of the disease, for example, by treating inflammation and thereby preventing such attacks.

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

Specific cancers that may be mentioned include oral cancer, nasopharyngeal cancer, middle ear cancer, conjunctival cancer, laryngeal cancer, tracheal cancer, esophageal cancer, gastric cancer, intestinal cancer, cervical cancer, endometrial cancer, skin cancer, etc. caused by oral mucositis (including severe oral mucositis), rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophageal cancer, gastric cancer, intestinal cancer, cervical cancer, endometrial cancer, skin cancer, etc. A specific skin cancer that may be mentioned is basal cell carcinoma.

Fibrous disorders of internal organs that may be mentioned include acute and/or severe internal fibrotic disorders characterized by excessive accumulation of fibrous connective tissue (as described above) in and around inflamed or damaged tissue. Thus, the formulations of the present invention may be used to treat or prevent fibrosis (as described above) and the morbidity and mortality associated therewith. Thus, (e.g., acute and/or severe) fibrotic disorders of internal organs that may be treated with the formulations of the present invention include fibrosis of the liver, kidney, lung, cardiovascular system (including heart and vascular system), pancreas, spleen, central nervous system (neurofibrosis), bone marrow fibrosis, eyes, vagina, cervix, etc.

Inflammatory disorders of internal organs include any severe disorder (i.e., a disorder requiring intensive medical treatment) or any disorder that may develop into a severe disorder and in which an inflammatory component is significant (because it is characterized by detectable inflammation) and in which disease is overt (or expected) and/or life-threatening.

Inflammatory disorders that may be mentioned include one or more acute conditions or disorders of an internal organ (i.e., one or more disorders that require immediate medical intervention or one or more disorders that may develop into disorders that require immediate medical intervention), characterized by inflammation (e.g., as a symptom) in one or more internal organs (including any of the organs mentioned above), such as acute internal injury. By treating such acute inflammatory conditions, the formulations of the present invention may prevent or arrest the development of symptoms (acute or chronic) associated with such disorders, and may also arrest the progression of morbidity and/or mortality associated with such disorders.

Acute inflammatory conditions that may be mentioned therefore include conditions such as peritonitis, pancreatitis, colitis, proctitis (including radiation proctitis), gastritis, duodenitis, pharyngitis, GERD, periodontitis and stomatitis. Specific acute inflammatory conditions that may be mentioned include acute damage to one or more internal organs (including any of those mentioned above), such as acute lung injury, inhalation injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS) and multi-organ inflammation, damage and/or failure.

Such conditions may result from internal or external trauma (e.g., injury or burns) or from infection, such as by viruses, bacteria, or fungi.

For example, proctitis (which includes eosinophilic, gonococcal, and/or ulcerative proctitis) may be caused by inflammatory bowel disease, infection, radiation (e.g., for cancer), medications (such as antibiotics), surgery, or allergic conditions (such as food intolerances).

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

Acute inflammatory and/or fibrotic disorders may also be caused by sepsis or septic shock, which may be caused by viral, bacterial or fungal infections. In addition, acute lung injury, ARDS and, in particular, SARS may be caused by viruses, such as coronaviruses, including the novel SARS coronavirus type 2 (SARS-CoV-2).

Thus, in addition, one or more of the aforementioned (e.g., acute) inflammatory conditions may (and indeed in some cases will likely) lead to some form of internal tissue damage and/or functional pathology of relevant internal tissues. Thus, relevant tissues include (e.g., mucosal) tissues, such as the respiratory epithelium. Such tissue damage may also result in 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 lead to fibrosis in many cases, which is caused by one or more of a variety of factors, including inflammation.

In this regard, the compounds of the present invention and their salts are particularly useful in the treatment of related inflammatory and/or fibrotic disorders, based on the fact that such disorders are often characterized by one or more comorbidities. By a disorder "characterized by a comorbidity," we mean that the primary disorder in question simultaneously leads to (or is caused by) one or more other medical disorders, including (and indeed preferably) those described above, which disorders may affect each other and/or overlap with each other in some way.

Thus, provided are: ●   a method for treating at least one inflammatory and/or fibrotic condition or disorder of one or more internal organs of a patient, the method comprising direct systemic parenteral administration of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment; ●   a method for treating two or more inflammatory and/or fibrotic conditions or disorders of one or more internal organs of a patient, the method comprising direct systemic parenteral administration of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment; and ●   a method for reducing the incidence of morbidity and/or mortality associated or potentially associated with one or more inflammatory and/or fibrotic conditions or disorders of one or more internal organs of a patient, the method comprising direct systemic parenteral administration of a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

Additionally, the compounds of the invention may be used to treat conditions characterized by immunosuppression, immunodeficiency conditions, for treating patients with compromised immune systems and/or for restoring normal function of a patient's immune system.

Disorders characterized by immunosuppression (or immunodeficiency conditions) include primary immunodeficiency disorders (PIDDs), which are typically rare congenital conditions that are usually inherited. Thus, PIDDs include humoral immunodeficiency conditions such as common variable immunodeficiency, selective immunoglobulin deficiency (e.g., IgA deficiency), transient agammaglobulinemia of the newborn, X-linked agammaglobulinemia; cellular immunodeficiency conditions such as chronic mucocutaneous candidiasis, DiGeorge syndrome, X-linked lymphoproliferative syndrome; combined humoral and cellular immunodeficiency conditions such as ataxia-telangiectasia, hyperimmunoglobulinemia E syndrome, severe combined immunodeficiency, Wiskott-Aldrich syndrome; phagocytic immunodeficiency conditions such as Chédiak-Higashi syndrome, and leukocytic dyschromatosis. syndrome), chronic granulomatous disease, cyclic neutropenia, leukocyte adhesion defects; and complement deficiencies, such as complement component 1 (C1) inhibitor deficiency (or hereditary angioedema), C3 deficiency, C4 deficiency, and deficiencies of C5, C6, C7, C8, and/or C9.

However, we prefer that the immunodeficiency condition treated according to the present invention is a secondary immunodeficiency condition (SIDD), which is more common than PIDD and tends to develop later in life. SIDD includes immunodeficiency conditions caused by secondary factors such as old age, malnutrition (e.g., undernutrition), chronic conditions, one or more chemical agents (e.g., drugs) and/or (e.g., ionizing) radiation.

For purposes of the present invention, the term "SIDD" may also include physical stress and/or mental stress, which may compromise the patient's immune system.

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

Mental stress can include many forms of psychological and/or psychosocial stress, such as emotional stress (e.g., negative emotions such as resentment, fear, frustration, sadness, anger, grief/sadness); cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, attachment, self-criticism, self-loathing, unrealistic perfectionism, anxiety, panic attacks, feelings of being out of control); perceived stress (of beliefs, roles, attitudes, values, meaning, and/or purpose); death/loss of a loved one; relationship difficulties (with partner, siblings, children, extended family, employer, co-workers); lack of social support (e.g., friends and/or isolation); financial stress (e.g., due to job loss, investments, savings, bankruptcy, home foreclosure, etc.).

Conditions that may cause a patient to become immunocompromised include cancer; blood conditions, such as regenerative anemia, leukemia, multiple myeloma; sickle cell disease; Down syndrome; infections, such as viral infections (including varicella, cytomegalovirus, Estein-Barr virus, HIV, measles) and bacterial infections; diabetes; diseases of internal organs, such as chronic kidney disease, nephrotic syndrome, chronic hepatitis, liver failure; systemic lupus erythematosus; alcoholism, chronic burns; and surgery, such as spleen removal.

Drugs that may cause immunodeficiency in patients include anti-epileptic 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, anakinra, basiliximab, and selegiline. tocilizumab, daclizumab, etanercept, golimumab, infliximab, ixekizumab, muromonab (OKT3), natalizumab, rituximab, sukinuzumab, tocilizumab, ustekinumab, vedolizumab; in particular corticosteroids, such as naturally occurring corticosteroids, including corticosteroids (hydrocortisone), aldosterone, corticosteroids cortisol, pregnenolone, progesterone; and naturally occurring precursors and intermediates in the biosynthesis of corticosteroids; and other derivatives of naturally occurring corticosteroids, such as 11-deoxycorticol, 21-deoxycorticol, 11-dehydrocorticone, 11-deoxycorticone, 18-hydroxy-11-deoxycorticone, 18-hydroxycorticone, 21-deoxycortisol, 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, hydrocortisone acepropionate, and hydrocortisone acetate. aceponate), hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortolone and tixocortolone pivalate, prednisolone, methylprednisolone, prednisone, chlorprednisolone, chlorprednisolone, diflupredniate, fluocinolone, fluperone, fluprednisolone, loteprednol, prednicarbate and triamcinolone; acetonide compounds and related substances (Group B), such as amcinonide, budesonide, desonide, fluocinolone aceton ... cetonide), fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocort, fluhydrocortolone, fluocinolone acetonide; those of the (beta)methasone type (Group C), such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halometasone, mometasone and mometasone furoate, alclomethasone and alclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoxymethasone, diflorasone, difluprednate, difluocortolone, fluclorolone, flumethasone, fluocortidine, fluprednisone and fluprednisone acetate, fluticasone, fluticasone furoate and fluticasone propionate, methylprednisolone, paramethasone, prednisone, rimexolone, and ulbetasol; those of the progesterone type, such as flugestrol, fluorometholone, methylprednisolone, and prebediolone acetate acetate); and progesterone derivatives (progestogens), such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate and segesterone acetate; and other corticosteroids, such as cortivazole and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one. Specific corticosteroids that may be mentioned include cortisone, prednisone, prednisolone, methylprednisolone and dexamethasone.

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

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

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, which may occur during accidental exposure (e.g., due to a nuclear or radiological disaster), may result in inflammatory responses and/or trauma that may persist for years thereafter and/or damage the function of the irradiated organs.

The compounds of the present invention can be used not only to provide an immune restorative effect, but can also simultaneously promote wound recovery and/or healing. This is particularly useful in view of the fact that the wounds associated with this condition are difficult, if not impossible, to treat properly due to radiation-induced immunosuppression and the absence of a normal endogenous inflammatory response.

By providing the above-mentioned immune restorative effects, this enables the body's immune system and local inflammatory responses to become more effective, and in this regard, the compounds of the present invention can also be used to provide an anti-inflammatory effect while promoting further healing of the wound, but in a manner that does not further damage the patient's immune system (i.e., the way corticosteroids would when used to treat inflammation).

According to a further aspect of the invention, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating inflammation and/or a condition characterized by inflammation or trauma in a patient suffering from or susceptible to a condition characterized by immunosuppression, including the treatment of radiation-induced conditions characterized by inflammation and/or trauma.

Diseases that are radiation-induced per se and/or that may result from radiation-induced immunosuppression (including those characterized by inflammation and/or trauma) include those that may arise following accidental exposure to radiation (often referred to as "radiation poisoning") or following deliberate and/or targeted exposure to radiation (e.g., as a result of (e.g., ionizing) radiation therapy for the treatment of diseases such as cancer).

Radiation therapy is a type of cancer treatment that uses external beams of intense energy to kill cancer cells. Radiation therapy most often uses X-rays, but protons or other types of energy may also be used. Radiation therapy may be used as a primary cancer treatment, in neoadjuvant therapy (to shrink cancerous tumors before surgery), in adjuvant therapy (to prevent cancer cells from multiplying after surgery), to reduce symptoms caused by advanced cancer, or a combination of two or more of the above. Radiation therapy may also be used in combination with other treatments, such as chemotherapy.

Conditions characterized by inflammation and/or trauma of the mucous membranes and/or skin that may result from exposure to radiation are usually related to the part of the body that was targeted/irradiated. For example: ●   Radiation-induced dermatitis and mucositis may occur in the skin or mucous membranes, respectively, at locations that may be close to the part of the body that was irradiated. For example, radiation-induced oral mucositis may occur after radiation exposure to the head or neck; ●   Radiation-induced encephalitis may also occur after radiation exposure to the head or neck; and ●   Radiation pneumonitis and/or radiation esophagitis are usually caused by radiation therapy of lung cancer, breast cancer, lymphoma, thymic tumor, or esophageal cancer with radiation.

Radiation therapy to the abdomen, pelvis, or rectum (for example, to treat cervical, prostate, bladder, or rectal cancer) may cause one or more of radiation enteropathy (or radiation enteritis, which includes radiation colitis and radiation enterocolitis), radiation hepatitis, radiation myelitis, radiation vaginitis, and especially radiation proctitis.

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

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 in severe cases, trauma, strictures, and/or cysts.

Thus, in the treatment of conditions caused by radiation exposure (more particularly radiation exposure to the lower abdominal area) used, for example, in cancer therapy, including conditions such as radiation proctitis, radiation colitis and radiation-induced dermatitis as defined above, the compounds of the present invention and their salts may be used to: ●   provide an immune restorative effect while treating trauma associated with such conditions and/or promoting the recovery and/or healing of said trauma; and/or ●   provide a more direct anti-inflammatory effect without further compromising the patient's immune system while being useful in promoting further healing of the trauma.

According to two further aspects of the invention, there are provided: ●   A method for treating a radiation-induced disorder characterized by (i) immunosuppression and (ii) inflammation and/or trauma; and ●   A method for treating inflammation and/or trauma associated with a radiation-induced immunodeficiency condition in a patient while restoring the normal function of the immune system, said method comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The treatment methods and uses described above are particularly useful when the condition induced by radiation exposure for example in cancer therapy is caused by radiation exposure to the lower abdominal area as described above.

Further provided is a method of reducing the incidence of radiation-related morbidity and/or mortality characterized by inflammation and/or trauma (e.g., ionizing radiation-induced conditions) in a patient, the method comprising administering to a patient in need of such treatment a compound of the invention or a pharmaceutically acceptable salt thereof.

Conditions for which the compounds of the invention may be particularly useful include skin inflammation, physiological responses resulting from skin inflammation and/or wound healing processes, such as scarring and pigmentation; scalp and hair follicle inflammation and fibrosis, including seborrheic dermatitis, conditions characterized by pathological hair loss (including scarring alopecia and related conditions such as seborrheic alopecia and fibrotic alopecia); gastritis, gastric ulcers, and pressure-induced gastritis; GERD; I BD, including Crohn's disease, ulcerative colitis and/or proctitis, radiation-induced proctitis; arthritis; retinoic maculopathy (retinoic macular degeneration); myeloid cell differentiation and regeneration and regenerative anemia; stress; and IPF, ALI/ARDS, uremic pruritus, COPD, asthma, bronchitis (including chronic bronchitis), vasculitis, pancreatitis, multi-organ damage, and/or viral infections.

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

Thus, a further aspect of the invention is the non-therapeutic use of the compounds of the invention in anti-aging, for example by promoting skin integrity in such a way that the skin has the appearance of younger skin.

Another aspect of the present invention is a cosmetic composition comprising the compounds of the present invention. Such a composition may provide anti-aging properties.

“Patient” includes reptilian patients, avian patients and preferably mammalian (especially human) patients.

According to the present invention, the compounds of the present invention are preferably administered topically or systemically, for example orally, intravenously or intraarterially (including via intravascular and other perivascular devices/dosage forms (e.g., stents)), intramuscularly, dermally, subcutaneously, transmucosally (e.g., sublingually or transbuccally), rectally, intravaginally, intradermally, transdermally, nasally, transpulmonary (e.g., tracheal or bronchial), for example by direct injection or by any other parenteral route, preferably topically or by any other parenteral route, in the form of a pharmaceutical preparation comprising said one or more compounds in one or more pharmaceutically acceptable dosage forms.

Administration by inhalation (e.g., nasal) is particularly useful when the condition to be treated is rhinitis or inflammation caused by viral infections of the respiratory tract (e.g., upper respiratory tract infections such as the common cold and flu).

Pulmonary administration is particularly useful when the condition to be treated is COPD or IPF.Topical administration forms may be enhanced by producing a spray containing the active ingredient, for example by using a powder aerosol or with the aid of an aqueous mist using appropriate atomization techniques or equipment such as a nebulizer.

Anorectal administration is particularly useful when the condition to be treated is hemorrhoids or ulcerative colitis, using appropriate delivery means, such as foam solutions or suppositories to be injected.

Administration to the lower gastrointestinal tract can also be achieved by parenteral, particularly oral, delivery, with the aid of standard delayed or extended release coating techniques known to those skilled in the art. In particular, different parts of the upper or lower intestine can be targeted. For example, colonic administration can also be achieved with drug delivery means that are initially administered orally or parenterally and are targeted to the colon.

In an alternative embodiment, the compounds of the invention may be administered by direct systemic parenteral administration. Such administration may be used in a method of treating one or more of the above-mentioned conditions or disorders in one or more internal organs of a patient.

The compounds of the invention are preferably administered by intradermal injection, by inhalation or by topical administration (e.g., to the skin or mucosal surfaces (e.g., oral mucosa, ocular mucosa, nasal mucosa, vaginal mucosa, rectal mucosa, colonic mucosa, esophageal mucosa), throat or peri-dental, gum and/or teeth).

Internal organs that may be mentioned include the stomach, intestines, pancreas, liver, spleen, bladder, vascular system, ovaries, prostate, preferably heart and kidneys, and more preferably lungs.

Standard delayed or extended release technologies known to those skilled in the art may be used for administration routes other than oral, such as subcutaneous or intramuscular depot formation techniques or alternative routes of administration via parenteral administration.

Therefore, pharmaceutically acceptable formulations for the above-mentioned routes of administration may include a compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due consideration of 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 have no harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate release or modified release of the compounds of the present invention.

Thus, 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 saline-containing formulations (e.g., solutions), phosphate-containing formulations (e.g., solutions), acetate-containing formulations (e.g., solutions) or borate-containing formulations (e.g., solutions), or lyophilized powders that can be reconstituted with a vehicle (e.g., an aqueous vehicle) prior to use (e.g., injection)).

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, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, swelling agents and/or preservatives.

Formulations for injection are preferably buffered by standard techniques to a physiologically acceptable pH (e.g., a pH between about 4.5 and about 9.5, e.g., between about 6 and about 9, such as between about 6.5 and about 8.5) using a buffer and/or pH adjuster as described herein and/or may further comprise a tonicity adjuster (e.g., sodium chloride).

Although the above preferred delivery methods of the compounds of the present invention include topical application to the site of inflammation (e.g., mucosa (including oral mucosa and/or nasal mucosa, lungs, anorectal area and/or colon) or preferably skin) in a suitable (e.g., pharmaceutically acceptable and topically acceptable) vehicle and/or commercially available formulation suitable for application to the skin and/or appropriate mucosal surfaces, it may also include oral, intravenous, dermal or subcutaneous, nasal, intramuscular, intraperitoneal or pulmonary delivery.

Administration by injection is particularly useful for administering the compounds of the invention as a solution, suspension, for example, into the dermis (eg, intradermal injection), a joint cavity, or the eye.

Administration by intradermal injection (e.g., intradermally) is particularly useful for administering 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 melanin therapy as described above or for use of the compounds of the invention in treating, for example, wrinkles.

Administration by injection is particularly useful for filling (e.g., surgical sites in the nasal cavity, anal fistulas, spaces between the gums and tooth roots or nasal sinuses). This is particularly useful for shaping support and/or lubrication.

The compounds of the invention will generally be administered in the form of one or more pharmaceutical formulations, for example, mixed with (e.g., pharmaceutically acceptable) adjuvants, diluents or carriers, which may be selected with due consideration of the intended route of administration (e.g., topical application to 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 compounds and may have no harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate or modified release of the compounds of the invention.

Suitable pharmaceutical formulations may be commercially available or prepared in other ways according to the techniques described in the literature, such as Remington The Science and Practice of Pharmacy , 22nd edition, Pharmaceutical Press (2012) and Martindale - The Complete Drug Reference, 38th edition, Pharmaceutical Press (2014) and the documents mentioned therein, the relevant disclosures of all of which are hereby incorporated by reference. In other aspects, the preparation of suitable formulations containing the compounds of the present invention can be achieved non-inventively by a skilled person using conventional techniques.

The compounds of the present invention may be in the form of an aqueous formulation such as an emulsion, suspension and/or solution (e.g., an optionally buffered aqueous formulation (e.g., solution), such as a saline-containing formulation (e.g., solution), a phosphate-containing formulation (e.g., solution), an acetate-containing formulation (e.g., solution) or a borate-containing formulation (e.g., solution)) or a lyophilized powder.

The compounds of the present invention may be further and/or in the alternative combined with suitable excipients to prepare: ●   Gel formulations (for which suitable gel matrix materials include cellulose derivatives, carbomers and alginates, 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); ●  Lotion (for the lotion, suitable base materials include cellulose derivatives, glycerin, non-cellulose polysaccharides, polyethylene glycols of different molecular weights and propylene glycol); ●   Paste or ointment (for the paste or ointment, suitable paste base materials include glycerin, vaseline, paraffin, polyethylene glycols of different molecular weights, etc.); ●   Cream or foam (for the cream or foam, suitable excipients (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycols of different molecular weights, sodium lauryl sulfate, sodium polyoxyethylene fatty alcohol ether sulfonate, corn gluten powder and acrylamide); ●  Powder aerosols (for the powder aerosols, suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol and polysorbate, such as dry powder inhalers); and/or ●   Liquids for oral use, inhalation or facial use, such as mouthwash, water (aerosol) spray (for the liquids, suitable excipients include viscosity regulators such as hyaluronic acid, sugars (such as glucose and lactose), emulsifiers, buffers, alcohol, water, preservatives, sweeteners, flavorings, etc.); ●  Injectable solutions or suspensions (the injectable solutions or suspensions may be aqueous or otherwise, and suitable excipients for the injectable solutions or suspensions include solvents and co-solvents, solubilizers, wetting agents, suspending aids, emulsifiers, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers and/or pH adjusters, fillers, protectants and tonicity adjusters), 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 invention are combined with hyaluronic acid. ●   Oral tablets (for oral tablets, suitable formulations include binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol or silicon dioxide; and surfactants such as sodium lauryl sulfate).

Such formulations may also include moisturizers such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, mineral oils, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic/caprylic triglycerides, etc., as appropriate; 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 (cetyl alcohol), fatty acids (e.g., stearic acid), sodium lauryl sulfate (sodium lauryl sulfate), sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (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, polyoxylglyceride, Lauryl dimethylamine oxide, bile salts (e.g., sodium deoxycholate, sodium cholate), lipids (e.g., fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids, polyketides), phospholipids, N,N-dimethyldodecylamine-N-oxide, cetyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), sugar esters, polysorbates, etc.; preservatives such as phenoxyethanol, ethylhexylglycerin, etc.; and thickeners such as acryloyl dimethyl taurate/VP copolymer. In particular, especially in cream formulations, stearic acid, glyceryl monostearate, cetyl alcohol, sorbitan stearate, cetyl alcohol, caprylic/capric glycerides, etc. may be included.

The compounds of the present invention and (e.g., medicament) formulations containing them (e.g., aqueous solutions, gels, creams, ointments, lotions, foams, pastes and/or dry powders as described above) can be further combined with appropriate base materials to prepare dressings or therapeutic patches for application on biological surfaces (e.g., skin or mucosal surfaces). Therefore, such formulations can be used to impregnate base materials such as gauze, nonwoven fabrics or silk paper. Alternatively, the therapeutic patch can be, for example, an OK bandage, a facial mask, an eye mask, a hand mask, a foot mask, etc.

Petroleum jelly can be used to apply such a dressing to the wound, but we have also found that a PEG (e.g., PEG 400) based ointment can be combined with a base material to prepare a dressing without the need for petroleum jelly.

The compounds of the invention may also be used in combination with a solid support such as a nasal dressing (e.g., for stopping nosebleeds), a dermal scaffold (e.g., for wound healing), or an artificial bone (e.g., in the context of bone transplantation/implantation).

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

In a pMDI, the compounds of the invention may be administered as a pressurized suspension of micronized particles distributed in a propellant (e.g., HFA together with an excipient such as mannitol, lactose, sorbitol, etc.) or as an ethanol solution to facilitate delivery of one or more metered doses of between about 20 μL and about 100 μL per actuation. Actuation may be achieved manually (e.g., by compression) or by inhalation (breath actuation), involving a flow trigger system driven by a spring.

In a DPI, the compounds of the invention can be administered as micronized drug particles (between about 1 μm and about 5 μm in size) in capsules (either alone or blended with a larger particle size inactive excipient (e.g., mannitol)) that can be preloaded or manually loaded into the device. Inhalation from the DPI can deagglomerate the drug particles and disperse them within the respiratory tract.

In an SMI, the compounds of the invention may be stored as a solution in a cartridge that is loaded into the device. A spring may release a dose into a micropump so that the dose is released when a button is pressed, thereby releasing a jet of drug solution.

The compounds of the present invention may also be administered in the form of a fine spray of an aerosolized solution using various sprayers. Nebulizers may include breath-enhanced nebulizers (in which air flow is moved through the nebulizer with the aid of a compressor to aerosolize the drug solution); breath-actuated nebulizers (in which, after the patient inhales, air flow is moved through a tube with the aid of a compressor to aerosolize the drug solution); ultrasonic nebulizers (in which piezoelectric crystals vibrate to induce aerosolization by heating to induce atomization); and vibrating mesh nebulizers (in which piezoelectric crystals vibrate a mesh plate to induce aerosolization to obtain very fine droplets without significant changes in the temperature of the solution during atomization).

According to a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition/formulation as defined herein, said process comprising combining a compound of the invention as defined above with one or more pharmaceutically acceptable excipients as defined above.

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

According to another aspect of the present invention, a (e.g., pharmaceutical) composition is provided, which comprises a compound of the present invention and one or more pharmaceutically acceptable excipients, such as adjuvants, diluents or carriers. Preferred formulations are suitable for topical application, for example, to mucosa (including oral mucosa and/or nasal mucosa, lungs, anorectal region and/or colon) or more preferably to the skin, and therefore comprise an externally acceptable adjuvant, diluent or carrier.

Thus, further provided are pharmaceutical compositions comprising a compound of the invention adapted, adapted and/or packaged and presented for topical administration (e.g., to mucosa, including oral and/or nasal mucosa, lungs, anorectal area and/or colon or preferably to the skin), and the use of such formulations in the treatment of conditions comprising inflammation, inflammatory conditions and/or disorders characterized by inflammation (e.g., as a symptom) by direct topical administration of the formulations (e.g., to mucosa, including oral and/or nasal mucosa, lungs, anorectal area and/or colon or preferably to the skin).

With respect to this aspect of the invention, for the avoidance of doubt, topical formulations comprising the compounds of the invention may be used in any and all conditions described herein, including (as mentioned, defined or described above) in the treatment of any and all inflammatory conditions and/or in the treatment of inflammation in the treatment of any and all conditions characterized by inflammation. Similarly, topical formulations comprising the compounds of the invention that may be mentioned include any and all of those mentioned, defined or described herein. Any and all of the relevant disclosures herein are hereby incorporated by reference in conjunction with this aspect of the invention.

Topical (e.g., liquid-based or (e.g., aqueous) solution-based formulations comprising the compounds of the present invention may be particularly useful for wound healing and may reduce pain (including underlying pain) associated with the wound itself and the wound healing process and particularly pruritus/itching. Such topical formulations comprising the compounds of the present invention may be particularly useful for preventing and/or inhibiting the leakage of body fluids from wounds, particularly during the acute inflammatory phase, such as during the first 48 hours after suffering a burn or wound. This prevents the risk of infection and other physiological reactions. Such topical formulations comprising the compounds of the present invention may also be particularly useful for preventing and/or inhibiting scarring and melanin deposition (see above), whether associated with wounds or otherwise.

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

Depending on the condition and patient to be treated and the route of administration, the compounds of the present invention may be administered to a patient in need thereof in varying therapeutically effective doses.

Similarly, the amount of a compound of the invention in a formulation will depend on the severity of the condition and the patient being treated, but can be determined by the skilled artisan.

In any case, a medical practitioner or other skilled person will be able to routinely determine the actual dosage that is most suitable for an individual patient based on the severity of the condition and the route of administration. The dosages mentioned herein are illustrative of general situations; there may, of course, be individual situations where a higher or lower dosage range should be used, and such situations are within the scope of the present invention.

The dose may be administered between once and four times daily (e.g., three times).

Suitable concentrations of the compounds of the invention in aqueous solutions may be from about 0.01 (eg, about 0.1) to about 15.0 mg/mL, calculated in all cases as the free (non-salt) compound.

Suitable topical dosage amounts of the compounds of the invention, calculated in all cases as free (non-salt) compound, range from about 0.05 μg to about 50 μg/ ^cm2 treatment area, such as from about 0.1 μg (e.g., about 0.5 μg) to about 20 μg/ ^cm2 treatment area, including from about 1 μg to about 10 μg/ ^cm2 treatment area, such as about 5 μg/ ^cm2 treatment area.

Suitable dosages 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 to about 500 mg or between 1 μg to about 100 mg. Specific dosages that may be mentioned for nasal administration include dosages between about 10 μg to about 1 mg, in particular about 0.1 mg (i.e., about 100 μg). It has been found that nasal administration of about 0.1 mg/day of the compounds of the invention is particularly effective in the treatment of conditions associated with inflammation of the nasal passages and mucosa, such as rhinitis (e.g., allergic rhinitis) and/or conditions associated with sinus surgery.

Suitable dosages 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 to about 500 mg or between 1 μg to about 100 mg. Specific dosages for pulmonary administration that may be mentioned include between about 10 μg to about 10 mg, in particular dosages of about 0.6 mg (i.e., 60 μg) to 6 mg (e.g., for the treatment of COPD or IPF).

We prefer that formulations containing compounds of the invention have a pH in the range of about 1.0 to about 9.0 (e.g., about 3.0 to about 8.0).

In any case, in the context of the present invention, the dose administered to a mammal, particularly a human, should be sufficient to produce a therapeutic response in the mammal within a reasonable time frame (as described above). Those skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be affected by, among other things, the pharmacological properties of the formulation, the nature and severity of the condition being treated and the physical condition and mental acuity of the recipient, as well as the age, condition, weight, sex and stage/severity of the response and disease of the patient to be treated, as well as genetic differences between patients.

The compounds of the present invention can be used in human and animal medicine. In this regard, and as mentioned above, the compounds of the present invention which themselves have an appropriate degree of relevant pharmacological (or biological) activity can be used as human and/or animal medicine.

Certain compounds of the present invention, particularly compounds of Formula I, may have adhesion properties in addition to and/or instead of having the above-mentioned biological activities.

These adhesive properties originate from the fact that the associated W and/or U groups are able to cross-link with each other to form a three-dimensional network.

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

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 (for example, in the anti-corrosion of ships, electronic equipment, pipelines, etc.), biochemical reagents, medical products, sterilization products, culture vessels for cell culture, etc.

The compounds of the present invention can form films on various skin and mucosal wound surfaces (such as burns, scalds, ulcers, frostbite and bedsores) to help recovery. The compounds of the present invention can also be used in surgery, such as for the closure of surgical incisions, the adhesion of fractured bones, the adhesion of mucosa, and the coating of human implants such as artificial bones, cartilage scaffolds, periosteum, artificial joints, dental implants, occlusion stents, spinal fusion devices, spinal spacers and organ patches.

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

As discussed above, naturally occurring MAP is known for its adhesive properties, but it should be remembered that such adhesive properties may result from the fact that it is a high molecular weight linear peptide that can exist in multiple conformations, enabling intermolecular and intramolecular reactions/crosslinking of the DOPA residues in the molecule and thereby enabling adhesion. In contrast, the compounds of the present invention as defined above are not linear polypeptides or proteins, but are, for example, multi-branched, lower molecular weight residues, and the applicants were surprised to observe similar properties (whether adhesive or biological) to those of naturally occurring MAP.

Such cross-linking can be carried out by a variety of chemical (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).

Regardless of the level of pharmacological activity that the compounds of the invention may possess, they may in any case (and/or may further) function in combination with an active pharmaceutical ingredient in a combination therapy (as described below) or by being a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent or carrier) or a portion thereof, as a part of a medical device and/or as a part of a drug-medical device combination.

Certain compounds of the invention may therefore be described as novel multifunctional excipients that can be used in a variety of applications in the pharmaceutical field. In this regard, such compounds of the invention include those that can be used as adhesives and/or as film formers (as described above), and furthermore, such compounds of the invention and/or different compounds of the invention may 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 for active ingredients (drugs) of various solubilities.

The compounds of the invention, which are particularly useful as drug formulations, may be adapted for large-scale production and may not present significant toxicity risks and may therefore be described and listed as "Generally Recognized as Safe" (GRAS) by the U.S. Food and Drug Administration (FDA).

The compounds of the present invention can also be used as excipients in veterinary science and in cosmetics.

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

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

When used as a medical device or as a medical device portion of a drug-medical device combination, the skilled artisan will understand that the relevant compounds of the present invention will be used in human or animal medicines, optionally in combination with active pharmaceutical ingredients, 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 to exert a chemical effect in or on the human or animal body (optionally in a manner that is not dependent on the metabolism of the compounds of the present invention in order to achieve any of its primary intended purpose).

In this regard, the compounds of the invention may be combined with a variety of known pharmaceutically active ingredients, and whether or not the compounds of the invention are employed, they may be combined as follows: ●   as an individual pharmaceutically active ingredient itself in a combination therapy; ●   as a medical device or as a part thereof; ●   as a drug-medical device combination or as a medical device part of a drug-medical device combination; or ●   as a pharmaceutically acceptable formulation.

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

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

In addition, the compounds of the invention (such as those that can be cross-linked as described above) can be used as drug excipients and can be mixed with such pharmaceutically active ingredients before or after cross-linking and/or at least partial cross-linking as described above to form a stable pharmaceutical composition in which the compounds of the invention act as excipients, such as carriers. When used in this manner, it can be found that the compounds of the invention can actively affect the physical, chemical and/or biological properties of such active ingredients, including their physical and/or chemical stability and/or their metabolism after administration.

Pharmaceutically active agents that can be used together with the compounds of the present invention can be selected, for example, from anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and/or antiprotozoal agents, antiviral agents (e.g., protease inhibitors), anesthetics and wound healing drugs (e.g., growth factors).

The biologically active agent can, for example, be selected from anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and/or antiprotozoal agents, antiviral agents (e.g., protease inhibitors), anesthetic agents, and wound healing drugs (e.g., growth factors).

Non-limiting examples of anti-inflammatory drugs that may be used also include those used in the treatment of rheumatic disease and/or arthritis (such as diclofenac (cataflam), betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodolac, meclofenamic acid, disalicylates, meprenolide, and piroxicam); osteoarthritis (such as sulindac, meloxicam, fenoprofen, etoricoxib, and nabumetone); Inflammation and its symptoms, such as fever, pain, itching and/or swelling (such as mefenamic acid, indomethacin, aspirin, ketorolac, flumetholone, loteprednol, hydrocortisone, flumetholone, bromfenac, prednisolone acetate, indomethacin and ibuprofen); allergic reactions and their symptoms (such as pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, lodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, rich emetastine malate, olopatadine, azelastine, tranilast, levocarbastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudoephedrine, fexofenadine, terfenadine, loratadine, and Alexis; respiratory diseases, including asthma and/or COPD (such as budesonide, ciclesonide, nedocromil, dexamethasone, ambroxol, and pramelastin); skin diseases (such as mometasone, triamcinolone, desonide, sulfacetamide, talolimide, allantoin and triamcinolone); mastocytosis (such as cromolyn); gout (such as diclofenac and febuxostat); conjunctivitis (such as oxybenzone, pranoprofen and zinc sulfate); eye diseases (such as dextran 70, trosin/triiodothyronine and eye extracts), any of the foregoing known or commercially available pharmaceutically acceptable salts, and combinations of any of the foregoing compounds and/or salts.

Anti-inflammatory drugs that may be mentioned include endogenous (and/or exogenous) lipid-based pro-resolving, anti-inflammatory molecules or mediators, such as lipoxins, resolvins and protectins. Proinflammatory agents that may be mentioned include prostaglandins (e.g., latanoprost, prostacyclin E1 and prostacyclin E2) and leukotrienes (e.g., leukotriene B4).

Non-limiting examples of antibacterial drugs that can be used include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, gentamicin, cetirizine, neomycin, roxithromycin, silver sulfadiazine, Clarithromycin, clindamycin, metronidazole, azithromycin, mafenide, sulfamethoxazole, acetaminophen, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin/clavulanic acid, trimethoprim/sulfamethoxazole, cefoperazone, moxifloxacin, any known or commercially available pharmaceutically acceptable salts of the foregoing drugs, and any combination of the foregoing compounds and/or salts.

Non-limiting examples of antiviral drugs that can be used include tobramycin ribavirin, acyclovir, morphine guanidine, foscarnet, ganciclovir, iodoxuridine, trifluridine, brivudine, vidarabine, entecavir, telbivudine, foscarnet, zidovudine, desoxyinosine, zacitabine, stavudine, lamivudine, abacavir, , emtricitabine, nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir , darunavir, telaprevir, boceprevir, simiprevir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir, fomivir, podafilox, imiquimod, sinecatechin, interferon-alpha 2b (recombinant, human), any known or commercially available pharmaceutically acceptable salts of the foregoing, and combinations of any of the foregoing compounds and/or salts.

Non-limiting examples of anesthetics that may be used also include articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, and any known or commercially available pharmaceutically acceptable salts of the foregoing and combinations of any of the foregoing compounds and/or salts.

Non-limiting examples of wound healing drugs that can be used also 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, subtilisin, lohexidine, silver nitrate, triethanolamine, ethacridin, vitamin A, calf blood deproteinized extract, carraghenate, amiotide, and any known or commercially available pharmaceutically acceptable salts of the foregoing drugs and combinations of any of the foregoing compounds and/or salts.

Such pharmaceutically active ingredients include those that can be administered topically to the skin or mucosal surfaces, for example, together with the compounds of the invention. In this regard, preferred active ingredients from the above list include cyclosporine, chondroitin, loteprednol, flumetholone, bromfenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, ipecac fumarate, olopatadine, azelastine, tranilast, levocetirizine, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, alexis, dexamethasone, ambroxol), sulfacetyl, tacrolimus, allantoin, triamcinolone, cromoglycine, nedocrolate, Rice, diclofenac, oxazolidinone, pranoprofen, zinc sulfate, dextran 70, thyroxine/liothyronine, oculopeptide, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofuran, rifampicin, nomicin, gentamicin, cetirizine, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, sulfamethoxazole, chloramphenicol, tobramycin ribavirin, acyclovir, morphine, foscarnet, ganciclovir, interferon-α 2b (recombinant, human), articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, alkaline 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, subtilisin, lohexidine, silver nitrate, triethanolamine, ethacridine, vitamin A, calf blood deproteinized extract, carrageenan ester, aminoiodine, and any known or commercially available pharmaceutically acceptable salts of the foregoing drugs and combinations of any of the foregoing compounds and/or salts.

Other pharmaceutically active ingredients that may be co-administered with the compounds of the invention include those that may be administered to treat one or more of the gastrointestinal conditions mentioned above.

Non-limiting examples of gastrointestinal medications include oxalazine (olsalazine), sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, axetil), levofloxacin, mesalazine, solanum, sulfobenzidine, azathioprine, sulfasalazine, live Bacillus species (such as Clostridium butyricum, Bacillus licheniformis, Bacillus cereus), probiotics (such as Bifidobacterium), tegafur, nifuratel, amoxicillin, ampicillin, nystatin, allicin, cefoperazone, daclonin, carmofur, fluorouracil, mosapride, carbosulfan sodium, thrombin, pantoprazole, cimetidine, cisapride, ethylenediamine diacetamine), nimustine, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azastrone, lentinan, bismuth salts in combination with, for example, magnesium salts (e.g., aluminum salts, potassium citrate), magnesium trisilicate, bicarbonate, vitamin U, aluminum hydroxide, solanum extract, famotidine and calcium carbonate, magnesium hydroxide, aluminum magnesium carbonate, Proton pump inhibitors (for example, omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, or esomeprazole), glycine, trypsin, allantoin aluminum hydroxide, L-glutamine amide sodium peramide, rebampette, rotundine, quxipite, lafutidine, thymic protein, hericium erinaceus, erinaceus), esogladine maleate, nisatidine, L-glutamine amide and sodium azulene sulfonate (sodium guanyl), ranitidine, bismuth citrate, lactobacillus, bisacordine, dimethicone, live Clostridium butyricum, loperamide hydrochloride, dibazole, secnidazole, acetyl phosphamide zinc, montmorillonite, tegafur/gimeracil/oteracil, famotidine, oteracil, doxifluridine, capecitabine, and any known or commercially available pharmaceutically acceptable salts of the foregoing.

Pharmaceutically active ingredients that may be mentioned for use in combination with the compounds of the invention include active ingredients useful for the treatment of inflammation and/or inflammatory conditions (other anti-inflammatory agents).

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

Other preferred agents that may be combined with the compounds of the invention include LTB4 (used to treat wounds and burns), NSAIDs (e.g., aspirin) or montelukast (generally used to treat inflammation), and trypsin (used to treat mucosal inflammation associated with, for example, viral infections).

The compounds of the invention may also be combined with other therapeutic agents that are known to produce inflammation as a side effect when administered.

The conjugates of the present invention may also be combined with stem cells (e.g., totipotent (all-potent) stem cells, multipotent 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)).

Other known pharmaceutically active ingredients can also be administered in combination with the compounds of the present invention in a variety of ways.

For example, the compounds of the invention may be "combined" with the (or with other) pharmaceutically active ingredients (or "therapeutic agents") for administration together in the same (e.g., drug) formulation or for separate (simultaneous or sequential) administration in different (e.g., drug) formulations.

Thus, such combination products provide for the combined administration of a compound of the invention and said (or with other) therapeutic agents, and thus may be presented as separate formulations, wherein at least one of these formulations comprises a compound of the invention and at least one comprises said (or other) therapeutic agent, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation comprising a compound of the invention and said (or other) therapeutic agent).

Thus, further provided are: (1) a (e.g., drug) formulation comprising a compound of the invention; another pharmaceutically active ingredient; and, optionally, a pharmaceutically acceptable inactive excipient (e.g., an adjuvant, a diluent, or a carrier), the formulation being hereinafter referred to as a "combination preparation"; and (2) a kit of parts comprising the following components: (A) a compound of the invention, optionally in the form of a (e.g., drug) formulation mixed with a pharmaceutically acceptable inactive excipient (e.g., an adjuvant, a diluent, or a carrier); and (B) another pharmaceutically active ingredient, optionally in the form of a (e.g., drug) formulation mixed with a pharmaceutically acceptable adjuvant, a diluent, or a carrier, the components (A) and (B) Each is provided in a form suitable for administration in conjunction with each other.

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

In a further aspect of the invention, there is provided a method for preparing a kit of parts (2) as defined above, the method comprising combining components (A) and (B). As used herein, reference to combining will mean that the two components are suitable for administration in combination with each other.

Thus, with respect to methods for preparing a kit of parts as defined above, bringing two components "into combination" with one another includes that the two components of the kit of parts may be: (i) provided individually (i.e., separate from one another), the individual formulations being subsequently brought together for use in combination with one another in a combination therapy; or (ii) packaged and presented together as the individual components of a "combination pack" for use in combination with one another in a combination therapy.

Thus, there is further provided a kit comprising: (I) one of components (A) and (B) as defined herein; and (II) instructions for use of said component in combination with the other of said two components.

Regarding the above kits, although the compounds of the present invention may be provided in the form of a (e.g., drug) formulation mixed with one or more additional pharmaceutically acceptable excipients (e.g., adjuvants, diluents or carriers), when the compounds of the present invention are provided for the purpose of primarily exerting their function as a medical device or excipient, they are not provided together with such additional pharmaceutically acceptable excipients. In any case, it is preferred that the (other) pharmaceutically active ingredients of the kit are provided in the form of a drug formulation mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

In order to provide repeated administration, the kits described herein may contain more than one appropriate amount/dose of the compounds of the present invention (e.g., formulations containing it) and/or more than one appropriate amount/dose of other pharmaceutically active ingredients (e.g., formulations containing it). If there are more than one formulation containing a certain amount/dose of any of the foregoing substances or more than one certain amount/dose of any of the foregoing substances, they may be the same or different in terms of the dosage of any of the compounds, one or more chemical compositions, and/or one or more physical forms.

With respect to the kit of parts as described herein, "administered in combination with" includes administering the corresponding components sequentially, separately and/or simultaneously during the treatment of the relevant disease.

Thus, with respect to the combination products according to the present invention, the term "administered in conjunction with..." includes administering the two components of the combination product (the compound of the present invention and the other pharmaceutically active ingredient) together or sufficiently close in time (repeatedly as necessary) to enable the patient to obtain a beneficial effect in the treatment of the relevant disorder, which is greater than the beneficial effect of individually administering (repeatedly as necessary) the compound of the present invention or the other agent (e.g., a formulation containing the other agent) in the absence of the other component in the same treatment. The determination of whether the combination provides a greater beneficial effect with respect to a particular disorder and in the treatment of a particular disorder will depend on the disorder to be treated or prevented, but can be routinely achieved by a skilled person.

In addition, in the context of a kit according to the present invention, the term "in combination with" includes that one or the other of the two components can be administered before, after and/or simultaneously with the other component (repeated administration as needed). When used in this context, the terms "simultaneous administration" and "administered simultaneously with" include administering individual amounts/doses of the relevant compounds of the present invention and other pharmaceutically active ingredients within 48 hours (e.g., 24 hours) of each other.

With regard to the above-mentioned combination preparations and kits, preferably, the other pharmaceutically active ingredient is an anti-inflammatory agent or an agent known to cause inflammation as a side effect as described above.

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

The compounds of the invention are advantageous in that they have a wide variety of uses, including: ●   As biologically active agents for a variety of conditions characterized by inflammation, whether such conditions are organ inflammatory diseases per se as described above or are associated with or characterized by inflammation (e.g., wounds or burns) and/or for surgical applications and/or cosmetic applications ●   In combination with active drug ingredients, either in combination therapy or by performing a more inert function as or as a part of: o   A pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), o   A medical device and/or o   The medical device portion of a drug-medical device combination.

The compounds, uses and methods described herein may also have the following advantages: in the treatment of the above-mentioned conditions, they may be more convenient for physicians and/or patients, more effective, less toxic, have a broader range of activity, be more potent, produce fewer side effects, or it/they may have other useful pharmacological properties, whether for the treatment of any of the above-mentioned conditions (including inflammation, inflammatory conditions or conditions characterized by inflammation as a symptom (including wounds)) or in other aspects.

Embodiment Embodiment 1 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys （ SEQ ID No: 3 ）

Fmoc-Lys(Boc)-Wang resin (9.32 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

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

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

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

Fmoc-Tyr(tBu)-OH (4.14 g, 9 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 2.89 g, 9 mmol; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N -diisopropylethylamine (DIPEA, 2.33 g, 9 mmol; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, Kaiser test was performed with very little resin, and the yellow color of the solution and colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

The above coupling steps were repeated to couple the same amount (by mol) of the remaining amino acids: Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH and palmitic acid.

After coupling of palmitic acid, the resin was washed three times with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL; Xilong Scientific Co., Ltd., Guangdong, China). The resin was dried under vacuum for about 2 hours.

130.0 mL (i.e., 10 mL/gram of dry resin) of lysis solution consisting of 95% trifluoroacetic acid (TFA, Macklin, Shanghai, China), 2.5% water, and 2.5% triisopropylsilane (Tis, Macklin, Shanghai, China) was added to submerge the peptide-containing compound bound to the resin. After about 2 hours of lysis, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1300 mL (i.e., 10 mL/ml of filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was vacuum dried for about 2 hours to produce 4.51 g of the crude title compound.

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

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

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

The fractions with a purity higher than 90% were then pooled together for the anion exchange step. This was achieved using a NP7010C semi-preparative apparatus (preparative column model: Dubhe-C18 model, as above). The fractions were diluted once with pure water and loaded directly onto the column, after which the column was washed with 3.2% ammonium acetate in pure water for about 20 minutes at a flow rate of 60 mL/min followed by pure water for another 10 minutes and then eluted with the following gradient (solvent A: 0.1% HAc in MeCN, solvent B: 0.1% HAc in water, linear gradient from 50%-80% solvent A concentration in 30 minutes; flow rate 60.0 mL/min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). Fractions with purity greater than 95% were pooled and freeze-dried to give 1.64 g of the purified title compound. Example 2 Stea-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys ( SEQ ID No: 4 )

The title compound was prepared using essentially the same procedure as described above in Example 1, except that the same amount (by mole) of stearic acid was used instead of palmitic acid in the final coupling step.

Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 4.37 g). Analysis showed the target peak eluted at 36.231 minutes with the expected molecular weight ( MS : m/z 1449.8 ) and a purity of 60.287%.

4.3 g of the crude product was then purified as described in Example 1 above to give 1.52 g of the pure title compound after freeze drying. Example 3 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys ( SEQ ID No: 10 )

The title compound was prepared using essentially the same procedure as described above in Example 1, except that the coupling step was performed in the following order with the same amounts (by mol): Fmoc-4-Hyp(tBu)-OH, Fmoc-DOPA(acetone)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and palmitic acid.

Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 4.56 g). Analysis showed the target peak eluted at 30.746 minutes with the expected molecular weight ( MS : m/z 1437.7 ) and a purity of 65.128%.

4.5 g of the crude product was then purified as described in Example 1 above to give 1.57 g of the pure title compound after freeze drying. Example 4 Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys- dopamine ( SEQ ID No: 109 )

The title compound was synthesized using Fmoc-Lys(Boc)-Wang resin using almost the same method as described above in Example 1, with Lys as the first amino acid. Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH and palmitic acid were coupled using the same method as described above in Example 1.

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

120.0 mL (i.e., 10 mL/g of dry resin) of lysis solution consisting of 2% trifluoroacetic acid (TFA) in DCM was added to submerge the peptide-containing compound bound to the resin. After about 2 hours of lysis, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was then concentrated by rotary distillation under reduced pressure. After all the solvents were removed, DMF (100 mL) was added to the flask to dissolve the solids, and dopamine hydrochloride (1.71 g, 9 mmol; Aladdin, Shanghai, China), TBTU (2.89 g), and DIPEA (2.33 g) were added to the reaction solution. After 30 minutes of reaction, the reaction was complete. The final solution was precipitated by adding 1200 mL (i.e., 10 mL/ml of the final solution) of saturated citric acid (Aladdin, Shanghai, China) in aqueous solution, and the precipitate was collected by filtration. The precipitate was then added to 120 mL (i.e., 10 mL/gram of solid) of lysis buffer to dissolve the peptide-containing solid, which contained 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis). The side chains were deprotected during cleavage. After about 2 hours of cleavage, the solution was precipitated with 1200 mL (i.e., 10 mL/ml of filtrate) of diethyl ether, and the precipitate was collected by filtration. The precipitate was dried by vacuum drying for about 2 hours. Finally, 4.25 g of the crude title compound was obtained.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 4.38 g). Analysis showed the target peak eluted at 32.173 minutes with the expected molecular weight ( MS : m/z 1556.9 ) and a purity of 55.395%.

4.3 g of the crude product was then purified as described in Example 1 above to give 1.39 g of the pure title compound after freeze drying. Example 5 Olei-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys ( SEQ ID No: 5 )

The title compound was prepared using essentially the same procedure as described above in Example 1, except that the same amount (by mole) of oleic acid was used instead of palmitic acid in the final coupling step.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 4.41 g). Analysis showed the target peak eluted at 35.877 minutes with the expected molecular weight ( MS : m/z 1447.8 ) and a purity of 61.737%.

4.4 g of the crude product was then purified as described in Example 1 above to give 1.55 g of the pure title compound after freeze drying. Example 6 Olei-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys ( SEQ ID No: 13 )

The title compound was prepared using essentially the same method as described in Example 5 above, except that the same amount (by mol) of Fmoc-DOPA(acetone)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling steps.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 4.53 g). Analysis showed the target peak eluted at 35.124 minutes with the expected molecular weight ( MS : m/z 1479.8 ) and a purity of 62.522%.

4.5 g of the crude product was then purified as described in Example 1 above to give 1.52 g of the pure title compound after freeze drying. Example 7 DHA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys ( SEQ ID No: 6 )

The title compound was prepared using essentially the same procedure as described above in Example 1, except that the same amount (by mole) of docosahexaenoic acid was used instead of palmitic acid in the final coupling step.

Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 4.47 g). Analysis showed the target peak eluted at 35.877 minutes with the expected molecular weight ( MS : m/z 1493.8 ) and a purity of 63.228%.

4.4 g of the crude product was then purified as described in Example 1 above to give 1.57 g of the pure title compound after freeze drying. Example 8 (Compound E ) Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys ( SEQ ID No: 17 )

The title compound was synthesized using essentially the same procedure as described above in Example 1, except that the appropriate amino acids were used in the relevant peptide coupling sequences.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 3.59 g). Analysis showed the target peak eluted at 29.947 minutes with the expected molecular weight ( MS : m/z 1136.4 ) and a purity of 70.223%.

3.5 g of the crude product was then purified as described in Example 1 above to give 1.21 g of the pure title compound after freeze drying. Example 9 Olei-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys ( SEQ ID No: 15 )

The title compound was synthesized using essentially the same procedure as described above in Example 6, except that the appropriate amino acids and fatty acids were used in the relevant peptide coupling sequences.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 3.65 g). Analysis showed the target peak eluted at 30.093 minutes with the expected molecular weight ( MS : m/z 1178.6 ) and a purity of 71.943%.

3.6 g of the crude product was then purified as described above in Example 1 to give 1.25 g of the pure title compound after freeze drying. Example 10 (Compound N ) DPPS-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys ( SEQ ID No: 7 )

The title compound was prepared using substantially the same method as described in Example 1 above, except that the same amount (by mol) of Fmoc-DPPS-OH was used instead of palmitic acid in the final coupling step. After coupling Fmoc-DPPS-OH to the resin, a deprotection step was performed to remove the Fmoc protection of DPPS. The resin was washed with DMF 3 times (200 mL each time). A 20% piperidine solution (200 mL) in DMF was added as a deprotection solution and reacted for 20 minutes, and then removed by vacuum. The remaining steps were then performed according to substantially the same method as described in Example 1.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 5.77 g). Analysis showed the target peak eluted at 48.284 minutes with the expected molecular weight ( MS : m/z 1814.2 ) and a purity of 53.933%.

5.7 g of the crude product was then purified as described above in Example 1 to give 1.79 g of the pure title compound after freeze drying. Example 11 (Compound O ) LTB4-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys ( SEQ ID No: 8 )

The title compound was prepared using essentially the same procedure as described above in Example 1, except that the same amount (by mole) of LTB4 was used instead of palmitic acid in the final coupling step.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 4.39 g). Analysis showed the target peak eluted at 33.877 minutes with the expected molecular weight ( MS : m/z 1501.8 ) and a purity of 57.847%.

4.3 g of the crude product was then purified as described in Example 1 above to give 1.38 g of the pure title compound after freeze drying. Example 12 (Compound M ) Montelukast -Ala-lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Palm) ( SEQ ID No: 2 )

Fmoc-Lys(Boc)-Wang resin (9.15 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

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

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

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

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

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

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

5.8 g of the crude product was then purified as described in Example 1 above to give 1.63 g of the pure title compound after freeze drying. Example 13 Olei-Ala-lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm) ( SEQ ID No: 2 )

The title compound was prepared using essentially the same procedure as described above in Example 10, except that the same amount (by mole) of oleic acid was used instead of montelukast sodium in the final coupling step.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 4.37 g). Analysis showed the target peak eluted at 46.129 minutes with the expected molecular weight ( MS : m/z 1686.2 ) and a purity of 51.237%.

4.3 g of the crude product was then purified as described in Example 1 above to give 1.51 g of the pure title compound after freeze drying. Example 14 Palm-Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys ( SEQ ID No: 20 )

The title compound was synthesized using essentially the same procedure as described above in Example 8, except that the appropriate amino acids were used in the relevant peptide coupling sequences.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 3.51 g). Analysis showed the target peak eluted at 28.847 minutes with the expected molecular weight ( MS : m/z 1152.5 ) and a purity of 68.983%.

3.5 g of the crude product was then purified as described in Example 1 above to give 1.16 g of the pure title compound after freeze drying. Example 15 DPPS-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys ( SEQ ID No: 18 )

The title compound was synthesized using essentially the same procedure as described above in Example 10, except that the appropriate amino acids were used in the relevant peptide coupling sequences.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 5.03 g). Analysis showed the target peak eluted at 43.288 minutes with the expected molecular weight ( MS : m/z 1616.0 ) and a purity of 65.039%.

5.0 g of the crude product was then purified as described in Example 1 above to give 2.1 g of the pure title compound after freeze drying. Example 16 Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Chol-Ac)-NH ₂ ( SEQ ID No: 110 )

The title compound was synthesized using essentially the same procedure as described in Example 12 above, except that Fmoc-Lys(Boc)-AM resin (6.98 g, USUN pharma, Jiangsu, China) was used as the starting material compared to Example 12. After the side chain of the Fmoc-Lys(Boc)-AM resin was deprotected, cholesterol-acetic acid (self-synthesized) was linked to the side chain of the Fmoc-Lys-AM resin. Compared to Example 12, appropriate amino acids were used in the relevant peptide coupling sequence to obtain the title compound.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 3.84 g). Analysis showed the target peak eluted at 37.822 minutes with the expected molecular weight ( MS : m/z 1323.7 ) and a purity of 61.438%.

3.8 g of the crude product was then purified as described in Example 1 above to give 1.3 g of the pure title compound after freeze drying. Example 17 Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-PEA ( SEQ ID No: 111 )

The title compound was synthesized using Fmoc-Lys(Boc)-CTC resin (7.23 g, USUN pharma, Jiangsu, China) as a solid support and lysine as the first amino acid.

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

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

100.0 mL (i.e., 10 mL/gram of dry resin) of lysis solution consisting of 2% trifluoroacetic acid (TFA) in DCM was added to submerge the peptide-containing compound bound to the resin. After about 2 hours of lysis, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was concentrated by rotary distillation under reduced pressure. After all solvents were removed, PEA (1.8 g, CAS: 544-31-0; Macklin, Shanghai, China) was added, and then pyridine (100 mL) was added to the flask to dissolve the solid, and then phosphorus oxychloride (0.3 ml, Adamas-beta Co. Ltd., Shanghai, China) was added to the reaction solution. After 3 hours of reaction, the reaction was complete. The final solution was precipitated by adding 1000 mL (i.e., 10 mL/ml final solution) of saturated citric acid (Aladdin, Shanghai, China) aqueous solution, and the precipitate was collected by filtration. 100 mL (i.e., 10 mL/gram solid) of lysis buffer containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to the precipitate to dissolve the peptide-containing solid. The side chains were deprotected during cleavage. After about 2 hours of cleavage, the solution was precipitated with 1000 mL (i.e., 10 mL/ml filter buffer) of diethyl ether, and the precipitate was collected by filtration. The precipitate was dried by vacuum drying for about 2 hours. Finally, 3.87 g of the crude title compound was obtained.

Analysis showed that the target peak eluted at 30.449 minutes with the expected molecular weight ( MS : m/z 1179.5 ) and a purity of 58.323%.

3.8 g of the crude product was then purified as described in Example 1 above to give 1.2 g of the pure title compound after freeze drying. Example 18 (Compound K ) (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys) ₂ -Lys ( SEQ ID No: 113 )

Fmoc-Lys(Fmoc)-Wang resin (10.23 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column. Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. DCM was removed by vacuum filtration. The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

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

Fmoc-Lys(Boc)-OH (8.43 g, 18 mmol; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 5.78 g, 18 mmol; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 4.66 g, 18 mmol; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, some of the resin was subjected to the Kaiser test, where the yellow color of the solution as well as the colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

The title compound was prepared using essentially the same procedure as described above in Example 8, except that the amounts of amino acid, palmitic acid and condensing agents (TBTU and DIPEA) were doubled (by mol).

Essentially the same procedure was repeated to give another batch of crude title compound (yield 6.68 g). Analysis showed the target peak eluted at 30.665 minutes with the expected molecular weight ( MS : m/z 2383.1 ) and a purity of 57.542%.

6.6 g of the crude product was then purified as described in Example 1 above to give 2.76 g of the pure title compound after freeze drying. Example 19 (Compound P ) (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys) ₂ -Lys ( SEQ ID No: 114 )

The title compound was synthesized using essentially the same procedure as described above in Example 18, except that the appropriate amino acids were used in the relevant peptide coupling sequences.

Essentially the same procedure was repeated to give another batch of crude title compound (yield 8.53 g). Analysis showed the target peak eluted at 32.192 minutes with the expected molecular weight ( MS : m/z 2953.7 ) and a purity of 52.821%.

8.5 g of the crude product was then purified as described above in Example 1 to give 3.2 g of the pure title compound after freeze drying. Example 20 (Compound L ) Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm)-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm) ( SEQ ID No: 115 )

Fmoc-Lys(Dde)-Wang resin (9.97 g, 3 mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

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

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

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

The above coupling steps were repeated to couple the same amount (by mol) of the following amino acids: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and then Fmoc-Lys(Dde)-OH.

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

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

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

MS : m/z 2254.9

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

6.3 g of the crude product was then purified as described in Example 1 above to give 2.01 g of the pure title compound after freeze drying. Example 21 Compound E Cream -1 : Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys ( SEQ ID No: 17 )

Compound E cream contains a mixture of the following substances in Table 1 below. The ingredients of phase A are mixed, heated to 85°C, and stirred at 85°C for 30 minutes. Phase B is added, the mixture is homogenized for 5 minutes, and then stirred until cooled. When the temperature drops to 45°C, the raw materials of phase C are added, and the mixture is homogenized for 1 minute. Phase D is added, and the mixture is homogenized for 3-5 minutes until the system is uniform to obtain Compound E cream-1.

surface 1 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 71.95 A2 Glycerin Glycerin 1.7 A3 1,3-Butanediol Butanediol 3 A4 Betaine Betaine 0.2 A5 EDTA-2NA Disodium EDTA 0.05 A6 AVC Ammonium acryloyl dimethyl taurate/VP copolymer 0.4 A7 HA(150W) Sodium hyaluronate 0.08 B1 A165 Glyceryl stearate 0.4 PEG-100 stearate B2 olive800 Ceteareth-6 Oleate 1.47 B3 RH-201-2 Dimethicone 2.57 B4 DC200/100 Dimethicone 2.53 B5 DC200/350 Dimethicone 1.3 B6 BUTYROSPERMUM PARKII (Shea butter) Avocado (Shea) Butter 0.25 B7 L70 Tocopherol 0.1 HELIANTHUS ANNUUS (Sunflower) Seed Oil B8 Phytosteryl Isostearate Phytosteryl Isostearate 0.1 Phytosterols B9 ININ Isononyl isononanoate 4.3 B10 Lanolin Lanolin 1 B11 CHE Cetyl ethylhexanoate 4 C1 Compound E 0.1 Pure water AQUA 1 C2 BHC Butanediol 1 1,2-Hexanediol Octanoyl hydroxamic acid C3 PL-429 Tetrahydropiperonine 0.5 Inositol Hydroxypropyl cyclodextrin Polylysine Betaine Hydrolyzed chitosan Glycerin Butanediol AQUA D1 SKG-19 Dimethicone 2 Dimethicone/vinyl dimethicone crosslinked polymer 100 Embodiment twenty two Compound E Oral spray: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E oral spray contains a mixture of the following substances in Table 2 below. The ingredients of phase A are mixed, heated to 85°C, and stirred at 85°C for 30 minutes. When the temperature drops to 45°C, the premixed raw materials of phase B are added. The mixture is stirred for 3-5 minutes until phase B is dissolved and the system is uniform to obtain compound E oral spray.

surface 2 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 92.355 A2 Glycerin Glycerin 5.3 A3 Citric acid (1%) Citric acid 0.77 B1 Sucralose (10%) Sucralose 0.175 B2 Compound E 0.1 B3 Potassium sorbate Potassium sorbate 0.2 B4 Menthol Menthol 0.1 B5 C0-40 PEG-40 Hydrogenated Castor Oil Lucsei 1 100 Embodiment twenty three Compound E Facial Spray -1 : Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E facial spray-1 contains a mixture of the following substances in Table 3 below. The ingredients of phase A are mixed and heated to 85°C and stirred at 85°C for 30 minutes. When the temperature drops to 45°C, phase B is added. The mixture is stirred for 3-5 minutes until phase B is dissolved and the system is uniform to obtain compound E facial spray-1.

surface 3 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 98.6 A2 PL-429 Tetrahydropiperonine 0.5 Inositol Hydroxypropyl cyclodextrin Polylysine Betaine Hydrolyzed chitosan Glycerin Butanediol AQUA A3 PHL 1,2-Hexanediol 0.8 1,3-Propanediol Octanoyl hydroxamic acid B Compound E 0.1 100 Embodiment twenty four Compound E Facial Spray - 2 : Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E Facial Spray-2 contains a mixture of the following substances in Table 4 below. The ingredients of phase A are mixed and heated to 85°C. The mixture is stirred at 85°C for 30 minutes. When the temperature drops to 45°C, phase B is added and stirred for 3-5 minutes until phase B is dissolved and the system is uniform to obtain compound E facial spray-2.

surface 4 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 92.1 A2 Betaine Betaine 0.2 A3 Glycerin Glycerin 1.8 A4 E-20 METHYL GLUCETH-20 0.5 A5 PEG-32 PEG-32 0.5 B1 SymCalmin Pentylene glycol 0.1 Butanediol Hydroxyphenylpropionamide benzoic acid Ascorbyl palmitate B2 PL-429 Tetrahydropiperonine 0.5 Inositol Hydroxypropyl cyclodextrin Polylysine Betaine Hydrolyzed chitosan Glycerin Butanediol AQUA B3 PHL 1,2-Hexanediol 0.8 1,3-Propanediol Octanoyl hydroxamic acid B4 rose water ROSA RUGOSA FLOWER WATER 3.4 B5 Compound E 0.1 100 Embodiment 25 Compound E Mouthwash -1 : Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E mouthwash contains a mixture of the following substances in Table 5. The ingredients of phase A are mixed, heated to 85°C, and stirred at 85°C for 30 minutes. When the temperature drops to 45°C, phase B is added and stirred for 3-5 minutes until phase B is dissolved and the system is uniform to obtain compound E mouthwash-1.

surface 5 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 90.84 A2 Sorbitol (70%) Sorbitol 6.0 A3 Citric acid (1%) Citric acid 0.5 B1 NB371 Rosemary (ROSMARINUS OFFICINALIS/ROSEMARY) leaf water 2.0 B3 Sucralose (10%) Sucralose 0.03 B4 Compound E 0.1 B5 Menthol Menthol 0.03 C0-40 PEG-40 Hydrogenated Castor Oil Lucsei 0.3 B6 Potassium sorbate Potassium sorbate 0.2 100 Embodiment 26 Compound E Cream -2 : Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E cream-2 and its placebo sample contain a mixture of the following substances in Tables 6 and 7 below, respectively. The ingredients of phase A are mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The ingredients of phase B are mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The solution of phase B is transferred to the solution of phase A and homogenized for 5 minutes. The sample is allowed to cool until the system is uniform to obtain compound E cream-1 or its placebo sample.

surface 6 Mutually Material quantity( % ） A1 Tefose 63 10.0 A2 Stearyl alcohol 1.5 A3 Cetearyl alcohol 1.5 A4 Liquid wax 10.0 A5 Methyl 4-hydroxybenzoate 0.1 B1 Pure water 76.8 B2 Compound E 0.1 100

surface 7 Mutually Material quantity( % ） A1 Tefose 63 10.0 A2 Stearyl alcohol 1.5 A3 Cetearyl alcohol 1.5 A4 Liquid wax 10.0 A5 Methyl 4-hydroxybenzoate 0.1 B1 Pure water 76.9 100 Embodiment 27 Compound E Hair Essence: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E hair serum and its placebo sample contain the following substances in Tables 8 and 9 below, respectively. The ingredients of phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was allowed to cool until the system was uniform to obtain Compound E hair serum or its placebo sample.

surface 8 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 99.89 A2 Benzyl ammonium chloride Benzyl ammonium chloride 0.01 A3 Compound E 0.1 100

surface 9 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 99.99 A2 Benzyl ammonium chloride Benzyl ammonium chloride 0.01 100 Embodiment 28 Compound E Mouthwash -2 : Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Compound E mouthwash-2 and its placebo sample respectively contain a mixture of the following substances in Tables 10 and 11 below. The ingredients of phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was allowed to cool until the system was uniform to obtain Compound E mouthwash-2 or its placebo sample.

surface 10 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 99.89 A2 Cetylpyridinium chloride Cetylpyridinium chloride 0.05 A3 Menthol Menthol 0.01 A4 Sucralose Sucralose 0.02 A5 Compound E 0.03 100

surface 11 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 99.92 A2 Cetylpyridinium chloride Cetylpyridinium chloride 0.05 A3 Menthol Menthol 0.01 A4 Sucralose Sucralose 0.02 100 Embodiment 29 Compound E Foam: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Formulation-1: Compound E Foam Formulation-1 contains a mixture of the following substances in the following Table 12. The ingredients of Phase A were mixed and stirred for 30 minutes until the system was uniform to obtain Compound E Foam Formulation-1.

surface 12 Mutually Material quantity( % ） A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 Glycerin 5.0 A4 Benzyl alcohol 1.0 A5 Pure water 90.4 A6 Compound E 0.1 100

Formula-2: Compound E foam formula-2 contains a mixture of the following substances in Table 13 below. The ingredients of phase A were mixed and stirred for 30 minutes until the system was uniform. Sodium hydroxide was added while stirring to adjust the pH of the solution to 6.5-7.0 to obtain compound E foam formula-2.

surface 13 Mutually Material quantity( % ） A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 Glycerin 5.0 A4 Benzyl alcohol 1.0 A5 Pure water 90.4 A6 Compound E 0.1 B1 Sodium hydroxide 100

Formulation-3: Compound E Foam Formulation-3 contained a mixture of the following materials in Table 14 below. The procedure for preparing Compound E Foam Formulation-3 was the same as that described for Formulation-2.

surface 14 Mutually Material quantity( % ） A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 Glycerin 5.0 A4 Benzyl alcohol 1.0 A5 Glucosamine 1.5 A6 Maluca honey 1.0 A7 Pure water 87.9 A8 Compound E 0.1 B1 Sodium hydroxide 100 Embodiment 30 Compound E Gel: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys （ SEQ ID No: 17 ）

Preparation of Compound E Gel A mixture containing the following substances in Table 15 below was prepared. The ingredients of Phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was allowed to cool until the system was homogeneous to obtain Compound E Gel.

surface 15 Mutually Brand Name INCI Name quantity( % ） A1 Pure water AQUA 81.23 A2 Propylene glycol Propylene glycol 13.40 A3 Glycerin Glycerin 2.60 A4 Carbomer 940 KABOMUER 0.67 A5 Carbomer 941 KABOMUER 0.13 A6 Triethanolamine Triethanolamine 0.80 A7 4-Hydroxyacetophenone Hydroxyacetophenone 0.50 A8 1,2-Hexanediol Hexanediol 0.50 A9 Sodium hyaluronate (1.5 M Da) Sodium hyaluronate 0.07 A10 Compound E 0.10 100 Embodiment 31 Mouse model of ear swelling

Test compounds: Compound A: Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 3) Compound B: Stea-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 4) Compound C: Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 10)

Twenty-five healthy male BALB/c mice (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China) aged 6 to 8 weeks with an average body weight of 18-25 g were housed and cared for approximately 1 week before the experiment. The housing conditions were 25ºC-27ºC, 74% humidity, 12 h dark-light cycle, and free access to food and water. These mice were randomly divided into 5 groups (5 mice per group) as described in Table 16 below.

surface 16 Group Drug concentration Administer medication in the right ear Total dose ( μg/ Mouse Model / Xylene / Dex Cream (dexamethasone) 0.75mg/g Xylene + Dex cream 0.03 Compound A 1.5mg/ml Xylene + Compound A 60 Compound B 1.5mg/ml Xylene + Compound B 60 Compound C 1.5mg/ml Xylene + Compound C 60

The left ear of each mouse was used as a self-control, and the right ear of each mouse was treated with different treatments: 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. After about 4 min, the ear began to swell. Then 40 μl of the drug was applied to the right ear of each group. The mice were returned to their cages.

Dexamethasone acetate cream (0.75 mg/g, China resources group) was purchased from a local pharmacy. Compounds A-C were synthesized by Chinese Peptide Company as described above. 15 mg of each compound (powder) was dissolved in 10 ml of saline to make a 1.5 mg/ml solution. The resulting solution was applied to mice accordingly.

After 40 min, mice were sacrificed by cervical dislocation. The left and right ears were cut off. A piece of ear was removed from the same part of both ears using a skin pouch with a diameter of 8 mm (Electron Microscopy Sciences, P.O. Box 550, 1560 Industrial Road, Hatfield, Pennsylvania 19440). The weight was recorded and used to calculate the swelling rate, which is shown in Table 17 below and in Figure 1.

Swelling rate (%) = (right ear weight - left ear weight) / left ear weight × 100%

surface 17 Group Model DEX Compound A Compound B Compound C Swelling rate (%) 81.03 33.33 45.29 53.59 45.70 SD(%) 25.08 21.83 17.88 13.52 20.32

The results showed that these three compounds can significantly reduce ear swelling in the xylene-induced mouse model. The effect is slightly weaker than that of dexamethasone. Example 32 Ear swelling mouse model

Test compounds: Compound D: DHA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 6) Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound F: Olei-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 5) Compound G: Olei-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 13) Compound H: DPPS-Ala-Lys-Pro-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 112)

The experimental procedure and result recording were the same as those described in Example 31 above. Ear swelling was induced in mice by xylene. 35 mice were divided into 7 groups as described in Table 18 below, and the results are shown in Table 19 below and FIG. 2 .

surface 18 Group Drug concentration Administer medication in the right ear Total dose ( μg/ Mouse Model / Xylene / Dex Cream (dexamethasone) 0.75mg/g Xylene + Dex cream 0.03 Compound D 1.5mg/ml Xylene + Compound D 60 Compound E 1.5mg/ml Xylene + Compound E 60 Compound F 1.5mg/ml Xylene + Compound F 60 Compound G 1.5mg/ml Xylene + Compound G 60 Compound H 1.5mg/ml Xylene + Compound H 60

surface 19 Group Model Dex Compound D Compound E Compound F Compound G Compound H Swelling rate (%) 94.11 42.74 69.49 51.92 72.79 69.56 62.98 SD(%) 21.82 12.37 11.24 12.21 9.99 18.14 31.49

The results showed that the five compounds were effective in reducing the swelling rate in the mouse model treated with xylene, but not to the extent of the mouse model treated with dexamethasone. Example 33 Ear swelling mouse model

Test compounds: Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17) Compound I: Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16) Compound J: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2) Palmitic acid + DMSO

The experimental procedure and result recording were the same as those described in Example 31 above. Ear swelling was induced in mice by xylene. 35 mice were divided into 7 groups as described in Table 20 below, and the results are shown in Table 21 below and FIG3 .

surface 20 Group Drug concentration Administer medication in the right ear Model / Physiological saline Dex Cream (dexamethasone) 0.75mg/g Xylene + Dex cream Compound E 1 mg/ml Xylene + Compound E Compound I 1 mg/ml Xylene + Compound I Compound J 1 mg/ml Xylene + Compound J Palmitic acid + DMSO 0.3mg/ml Xylene + Palmitic acid + DMSO

surface twenty one Group Model Dex Compound E Compound I Compound J Palmitic acid + DMSO Swelling rate (%) 82.09 38.56 46.86 54.29 64.67 49.88 SD(%) 13.62 18.09 11.96 3.91 9.23 11.71 Embodiment 34 Mouse model of ear swelling

Test compound: Compound E: Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17)

The experimental procedure and result recording were the same as those described in Example 31 above. Ear swelling was induced in mice by xylene. The mice were divided into 8 groups as described in Table 22 below, and the results are shown in Table 23 below and Figure 4.

surface twenty two Group Drug concentration Administer medication in the right ear Model / Physiological saline Dex 0.75mg/g Dexamethasone cream Compound E 0.1mg/ml Compound E Compound E 0.3mg/ml Compound E Compound E 1.0mg/ml Compound E Compound E 1.5mg/ml Compound E Compound E 3.0mg/ml Compound E Compound E 10 mg/ml Compound E

surface twenty three Group Swelling rate ( % ） SD Model 79.49 16.42 Dex 32.75 9.80 Compound E (0.1 mg/ml) 68.30 5.42 Compound E (0.3 mg/ml) 64.10 6.54 Compound E (1.0 mg/ml) 50.77 24.08 Compound E (1.5 mg/ml) 43.85 9.26 Compound E (3.0 mg/ml) 34.95 22.30 Compound E (10 mg/ml) 46.04 10.70

The results showed that compound E was effective as an anti-inflammatory agent in the mouse ear swelling model and provided guidance for future clinical anti-inflammatory use. Compound E also had good dose dependence in anti-inflammatory properties. Example 35 Pain relief of radiation-induced oral mucositis

Two patients were being treated with radiation therapy to the head and neck. Both patients experienced severe oral mucositis, diagnosed as grade 4 (the most severe grade) and oral mucosal ulcers. The patients also experienced severe pain and difficulty eating. The patients were advised to use 1 mg/ml x 5 ml of Compound E solution as a mouthwash three times a day. After 5 days, both patients reported very positive feedback. The pain VAS score of one patient decreased from 8 to 1, and that of the other patient decreased from 7 to 3. The latter patient also reported a significant reduction in mucus in his mouth caused by infection and inflammatory exudates. Therefore, Compound E has been shown to be effective for the treatment of oral mucositis. Example 36 Relief of itching in neurodermatitis

A 28-year-old male presented with skin lesions with persistent itching and scaling on his left elbow. Neurodermatitis was diagnosed one year ago. The patient had previously used corticosteroids to treat the lesions, but the effect was short-lived. The itching became more severe when he felt stressed. The patient tried 3 mg/ml of Compound E solution spray. After one spray on the lesions, the itching symptoms were completely relieved after about 30 min. The patient reported that the itching symptoms stopped the day after administration. Example 37 Radiation mucositis in golden hamster model

Thirty-two healthy male LVG Syrian golden hamsters (Beijing Chairs river Experimental Animal Technology Co., Ltd) aged 6 to 8 weeks with an average body weight of 93-101 g were housed and cared for about 1 week before the experiment. Housing conditions: 25ºC-27ºC, 74% humidity, 12 h dark-light cycle, free access to food and water. The hamsters were randomly divided into 4 groups (8 hamsters per group) as described in Table 24 below.

surface twenty four Group Test samples Dosage （ mg/ animal) Concentration （ mg/mL ） Volume （ mL/ animal) Administration Model Placebo - - 0.2 Topical oral administration Twice a day Compound E (low dose) Compound E 0.02 0.1 0.2 Compound E (medium dose) Compound E 0.06 0.3 0.2 Compound E (high dose) Compound E 0.2 1 0.2

After anesthesia, the animals' left buccal bursa was pulled out and fixed on a self-made fixation device and exposed to radiation. The rest of the body was shielded by 3.5 mm thick lead. The radiation dose was 40 Gy (Precision X-ray Inc., X-RAD 320). After awakening the animals, they were returned to the cage. Photographs were taken and evaluated every two days. The evaluation was performed according to the Sonis scoring criteria (0 - the capsule is completely healthy, without erythema or vasodilation; 1 - erythema and vasodilation, but the mucosa is intact; 2 - severe erythema with superficial mucosal erosion; 3 - formation of mucosal ulcers, the cumulative size of which is approximately 25% of the surface area of the bag; 4 - ulcers, the cumulative size of which is approximately 50% of the surface area of the bag; 5 - continuous ulcers, involving almost the entire surface area of the capsule mucosa). The results are shown in Table 25 below and Figure 5.

Table 25 Group Days Model Compound E low dose Compound E Medium Dose Compound E High Dose Before 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 Day 7 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 Day 9 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 Day 11 0.75±0.46 0.5±0.53 0.5±0.53 0.38±0.52 Day 13 1.50±0.53 1.38±0.52 1.38±0.52 1.38±0.52 Day 15 2.50±0.53 2.13±0.35 2.13±0.64 2.38±0.52 Day 17 3.25±0.46 3.13±0.35 3.13±0.35 3.13±0.35 Day 19 4.00±0.00 3.38±0.74 3.63±0.52 3.13±0.35** Day 21 3.75±0.46 3.00±0.53* 3.00±0.00** 2.63±0.74** Day 23 3.25±0.46 2.75±0.46* 2.63±0.52* 2.25±0.46** Day 25 2.88±0.64 2.13±0.35* 1.88±0.35** 1.63±0.52** Day 27 2.50±0.93 1.75±0.46* 1.50±0.76* 1.00±0.53** Day 29 2.00±0.93 1.00±0.53** 0.88±0.83** 0.50±0.53** Note: The data in the table are expressed as mean ± standard deviation (mean ± SD), and 8 animals in each group were used for statistical analysis. * P < 0.05, ** P < 0.01 represent the comparison results between each treatment group and the model control group.

According to the Sonis scoring standard and SOM duration of radiation-induced mucositis in hamsters, compound E showed improvement in mucositis. Compound E showed good dose dependence in this model. Therefore, it was shown that compound E can alleviate patient symptoms associated with mucositis in clinical practice. Example 38 Pain relief in Sprague Dawley ( SD ) rats

Before the experiment, 48 healthy male SD rats (Beijing Chairs river Experimental Animal Technology Co., Ltd) aged 7 to 8 weeks with an average body weight of 180-220 g were housed and cared for about 1 week. Housing conditions: 25ºC-27ºC, 74% humidity, 12 h dark-light cycle, free access to food and water. These rats were randomly divided into 6 groups (8 rats per group) as described in Table 26 below, and the results are shown in Figure 6.

surface 26 Group Dosage （ mg/ animal) Concentration （ mg/mL ） Volume （ µL ） Administration Normal control - - 20 Local administration of medication to the affected area Model comparison - - 20 Compound E 0.003/0.02/0.3 0.3/1/3 20 Lidocaine 0.2 10 20

All animals were pre-trained to allow rats to adapt to external stimuli. Oral mucosal ulcers were then induced with acetic acid (Sigma-Aldrich). Von Frey filaments (Danmic Aesthesio) (0.008 g, 0.04 g, 0.02 g, 0.04 g, 0.07 g, 0.16 g, 0.4 g, 0.6 g, 1.0 g, 1.4 g, 2.0 g, 4.0 g) were used to stimulate the ulcer area of the rats for mechanical pain threshold measurement. Each level of stimulation was given 5 times in a row with a 15-second interval between each test until there were 3 or more positive responses at a certain level of stimulation. The value was recorded as the mechanical pain threshold. To prevent damage to the rat mucosa and affect subsequent testing, the maximum von Frey test intensity was set to 4.0 g.

Compound E was shown to relieve acetic acid-induced pain in SD rats and showed a pain-relieving effect comparable to that of lidocaine. Compound E showed good dose dependence in this model. Therefore, it has been shown that Compound E can alleviate the symptoms associated with oral mucosal ulcers in patients. Example 39 5-FU- induced oral mucositis in SD rats

Before the experiment, 40 healthy male SD rats (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China) aged 7 to 8 weeks with an average body weight of 180-220 g were housed and cared for about 1 week. Housing conditions: 25ºC-27ºC, 74% humidity, 12 h dark-light cycle, free access to food and water. The rats were randomly divided into 5 groups (8 rats in each group) as described in Table 27 below.

surface 27 Group Dosage ( mg/ animal) Concentration ( mg/mL ） Volume ( µL ） Administration Normal control - - 20 Apply the medication topically to the affected area. Twice daily Model comparison - - 20 Compound E 0.006/0.02/0.06 0.3/1/3 20

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

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

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

The results (Figure 7) show that compound E improved 5-FU and acetic acid-induced mucositis scores in SD rats and accelerated the recovery of ulcers in the mucosa. Compound E showed good dose dependence in this model. Therefore, it has been shown that compound E can reduce patient symptoms associated with mucositis in clinical practice. Example 40 Wound healing effect - cell scratch assay in HaCaT

In a 96-well plate, when the cell placement rate reached 40%-60%, the following substances were added: 200 μL of medium containing 10% PBS (Sigma) was added to each well in the control group; 200 μL of medium containing 10% DMSO was added to each well in the positive control group; 200 μL of medium containing the corresponding concentration sample was added to each well of the sample group; and 200 μL of cell culture medium was added to the zero group without cell inoculation. After administration, the 96-well plate was placed in an incubator (37ºC, 5% CO ₂ ) for culture. After the cells were incubated for 24 hours, the supernatant was discarded and MTT working solution (0.5 mg/mL) was added. Incubate the 96-well plate at 37ºC in the dark for 2 hours. After incubation, discard the supernatant and add 100 μL of DMSO to each well. Read the OD value at 490 nm.

The results showed that compound E exhibited no cytotoxicity at its effective dose.

A 200 μL pipette gun was used to suspend a 24-well plate covered with cells and marked as "injury". The cells were washed three times with PBS to remove the punctured cells. After treatment with compound E at concentrations of 0.001%, 0.004%, and 0.008% (m/V), the cell healing rate of human skin immortalized keratinocytes (HaCaT) (ATCC) increased significantly (p < 0.01), indicating that compound E is effective in cell repair. Therefore, it has been shown that compound E effectively promotes cell healing in vitro, which corresponds to the in vivo results, and compound E can effectively promote healing in clinical practice. Example 41 No immunosuppressive effect - in vitro peripheral blood mononuclear cell ( PBMC ) study

PBMCs were revived and stained with Celltrace. T cell concentration was adjusted to 0.1 M per well (50 μL) using 1640 complete medium. 50 ul of LPS (Sigma-Aldrich) was added to the cells four times. 100 μL of blank medium/different concentrations of compound E or dexamethasone/medium containing 0.4% DMSO + highest concentration was added to the corresponding wells. The LPS group was incubated for 24 hours. Cell supernatants were collected to detect the secretion of relevant inflammatory factors. Cell proliferation and viability were detected using flow cytometry.

The results show that under this experimental condition, compound E does not have an immunosuppressive effect. Compared with dexamethasone, compound E does not cause immunosuppressive effects and is therefore safer for clinical use by reducing the risk of infection. Example 42 In vitro anti-inflammatory effect in keratinocytes

The medium was added to the blank control group; the medium containing LPS (Sigma-Aldrich) was added to the model control group; the medium containing LPS and dexamethasone was added to the positive control group; and the medium containing LPS and a certain concentration of compound E was added to the sample group. Each group was exposed for 24 hours. After incubation, the cell supernatant was collected and stored in a -80ºC ultra-low temperature freezer. The levels of IL-1 α, IL-6, IL-8, and TNF-α were measured according to the instructions of the ELISA kit (R&D Systems).

The results showed that compound E effectively reduced inflammatory factors in keratinocytes, and thus indicated that compound E can be used to reduce inflammation associated with clinical skin diseases. Example 43 In vitro anti-inflammatory effect in macrophages

The medium was added to the blank control group; the medium containing LPS (Sigma-Aldrich) was added to the added model control group; the medium containing LPS and dexamethasone was added to the positive control group; and the medium containing LPS and a certain concentration of compound E was added to the sample group. Each group was exposed for 24 hours. After incubation, the cell supernatant was collected and stored in a -80ºC ultra-low temperature freezer. The levels of IL-6, TNF-α, and NO were measured according to the instructions of the ELISA kit (R&D Systems).

The results showed that compound E effectively reduced inflammatory factors in macrophages, and thus indicated that compound E can be used to reduce inflammation associated with clinical diseases. Example 44 In vitro oil control of sebaceous gland cells

2 mL of cell culture medium was added to the blank control group; 2 mL of cell culture medium containing linoleic acid (MCE, China) was added to the model group; 2 mL of cell culture medium containing linoleic acid and retinoic acid was added to the positive control group; and 2 mL of cell culture medium containing linoleic acid and the test concentration sample was added to the sample group. Each group was incubated in a CO2 incubator for 48 hours. After incubation, the supernatant was discarded, 1 mL of PBS was added dropwise to wash the cell layer, 500 μL of paraformaldehyde was added to fix at room temperature for 5 minutes, the cell layer was washed twice with 1 mL of PBS, 500 μL of Nile Red dye was added, and incubated at 37ºC in the dark for 15 minutes. The cell layer was washed twice with 1 mL of PBS, and the cells were observed under an inverted phase contrast fluorescence microscope and photographs were recorded.

The results show that Compound E is effective in controlling the oil content of sebaceous gland cells. Therefore, Compound E has been shown to be effective in reducing oil secretion in the skin of patients for clinical use. Example 45 Acute oral toxicity in mice of Institute for Cancer Research ( ICR )

Animals (Beijing Chairs River Experimental Animal Technology Co., Ltd) were divided into two cages of males and females, with 5 animals in each cage. Before the experiment, animals were fasted overnight, and there was no restriction on drinking water. Using the maximum limit experiment, animals were weighed, and toxins were administered by tube feeding with a capacity of 2 mL/100 g and a dose of 5000 mg/kg body weight. Animals were poisoned once within 24 hours. After poisoning, animals were fasted for 3 h-4 h. After poisoning, animals were observed for abnormal conditions every day, and dead animals were autopsied during the observation period, and animals were euthanized at the end of the observation period. Abnormalities of tissues and organs were observed with the naked eye, and histopathological examinations were performed when necessary. The results are shown in Table 28 below.

surface 28 Compound E exist ICR Toxicity data in mice gender Dosage （ mg/kg ） weight( g ） Toxicity manifestations mortality rate Autopsy abnormalities D0 D1 D7 D14 F 5000 19.1 19.7 25.2 33.3 - 0 - M 5000 19.4 20.1 26.3 35.6 - 0 -

The results showed that the LD50 of compound E in ICR mice was greater than 5000 mg/kg, and it was non-toxic according to the acute oral toxicity classification. Therefore, compound E has been shown to be safe in ICR mice at very high doses, and based on previous animal data, compound E also has good safety in clinical settings. Example 46 Acute percutaneous toxicity in SD rats

The animals (Beijing Chairs River Experimental Animal Technology Co., Ltd) were divided into two cages of males and females, with 5 animals in each cage. The test area was approximately 30-40 ^cm2 . Before the experiment, the animals were adapted to the experimental animal room environment for 3 days to ensure that the animals were healthy and had no skin damage. About 24 hours before the experiment, the fur on the back of the animal's trunk in the area to be contaminated was cut off. When removing the fur, ensure that the skin is not damaged. The experiment adopted a maximum limit test with a toxic dose of 2180 mg/kg; after the animals were weighed, the test substance was moistened with water and evenly applied to the contaminated area of the animal's back skin. The skin was covered with a film and fixed with a non-irritating tape. The skin was sealed and covered for 24 hours without contact. After poisoning, the residual test substance was removed with warm water. After poisoning, the animals were observed for abnormal conditions every day, and dead animals were autopsied during the observation period, and animals were euthanized after the observation period. The tissues were observed for abnormalities with the naked eye, and if necessary, tissue pathology was performed. The observation period was 14 days. During the observation period, the weight of the active subjects was recorded at 0 days, 1 day, 7 days and 14 days (D0-14). The results are shown in Table 29 below.

surface 29 Acute dermal toxicity results gender Dosage weight( g ） Toxicity manifestations mortality rate Autopsy abnormalities D0 D1 D7 D14 F 2180 mg/kg 203.8 204.7 210.2 216.6 - 0 - M 2810 mg/kg 206.6 207.5 214.1 219.9 - 0 -

The results showed that the LD50 of compound E in SD rats was greater than or equal to 2180 mg/kg, indicating mild toxicity. Therefore, it has been shown that compound E is safe in SD rats at very high doses, and based on previous animal data, compound E has good safety in clinical use. Example 47 Efficacy of compound E in human acne

Compound E was applied to adult individuals under normal conditions for 28 consecutive days according to the instructions to evaluate whether the product showed acne reduction, oil control, moisturizing, repairing and soothing effects, and whether it was mild (non-irritating) and suitable for sensitive skin. A total of 32 Chinese adult men and women with sensitive skin were used, including 7 men and 25 women, aged 19 to 43 years (mean age 27.91 ± 6.82), and all met the inclusion and exclusion criteria. Fingertip units of compound E were applied twice a day for a total of 28 days. The dosage of the cream is based on fingertip units (FTU), and 1 fingertip unit refers to the amount of cream squeezed from the index finger to the first interphalangeal joint from a 5 mm opening tube (approximately 0.5 g).

Images were taken with VISIA 7 to analyze skin color, redness area, and porphyrins using IPP. Images were taken with Antera 3D (Miravex Limited, Ireland) to analyze acne volume. Skin hydration was measured with Corneometer® CM825 (Courage+Khazaka electronic GmbH, Germany). Transepidermal water loss was measured with Tewameter ®TM HEX 5 (Courage+Khazaka electronic GmbH, Germany). Skin sebum was measured with Sebumeter SM 815 (Courage+Khazaka electronic GmbH, Germany). Dermatologist assessment and self-assessment were performed.

The results are shown in Table 30 and Table 31 below.

surface 30 Project Variation value Rate of change D3 D7 D28 D3 D7 D28 Whiteheads -2.75 -3.75 -5.44 -29.83% -40.68% -58.98% Blackheads -0.91 -0.94 -0.94 -96.67% -100.00% -100.00% Non-inflammatory lesions -3.66 -4.69 -6.38 -36.00% -46.15% -62.77% Papules -0.25 -0.25 -0.28 -88.89% -88.89% -100.00% Pustules -0.16 -0.47 -0.88 -12.50% -37.50% -70.00% Nodules -0.38 -0.63 -0.78 -38.71% -64.52% -80.65% Inflammatory lesions -0.78 -1.34 -1.94 -31.25% -53.75% -77.50% Non-inflammatory and inflammatory lesions -4.44 -6.03 -8.31 -35.06% -47.65% -65.68% Overall healthy appearance 0.00 -0.03 -0.53 0.00% -1.00% -17.00% PIH-PIE -0.05 -0.08 -0.42 -1.46% -2.43% -13.11% Redness 0.00 -0.13 -0.72 0.00% -4.00% -23.00%

surface 31 Efficacy indicators Compound E , relative to the baseline Whiteheads There are statistical differences on days 3, 7, and 28 Blackheads There are statistical differences on days 3, 7, and 28 Papules There are statistical differences on days 3, 7, and 28 Abscess Statistically significant difference on day 28 Nodules There is a statistical difference on the 7th and 28th days Acne volume There are statistical differences on days 3, 7, and 28 Redness of the skin There was a statistical difference in the redness area on days 3, 7, and 28. Porphyrin No statistical difference Skin oil content Statistically significant difference on day 28 Water content of the stratum corneum of the skin There is a statistical difference on the 7th and 28th days Transdermal water loss rate Statistically significant difference on day 28

In 32 Chinese male and female subjects with sensitive skin, the results showed that under the evaluation conditions, the product had anti-acne, oil control, moisturizing, repairing and soothing effects, and was mild (non-irritating) and suitable for sensitive skin. Therefore, it has been shown that compound E can effectively reduce acne and has significant skin benefits for patients using it. Example 48 Human gingivitis efficacy of compound E (in progress)

The aim of the clinical study was to test the efficacy of Compound E as a novel raw material for gingival protective peptide mouthwash and control of gingivitis. Seventy individuals aged 18 to 60 years with gingivitis were included in this study, and the estimated number of individuals who completed the entire study was ≥ 60, i.e. ≥ 30 per group.

Inclusion criteria were: 1) good general health and no systemic diseases; 2) aged 18 to 60 years, male or female; 3) with more than 20 complete teeth, no major gingival restorations, no untreated cavities and severe gingival recession, and severe periodontal disease; 4) modified Quigley-Hein plaque index ≥ 1.5; 5) Loe-Silness gingival index ≥ 2.0, and bleeding index ≥ 2.0.

Clinical evaluation criteria and methods: 1) Plaque index (PI): 0 = no plaque; 1 = isolated spots of plaque on the cervical margin of the tooth; 2 = thin, continuous band of plaque (up to 1 mm wide) on the cervical margin; 3 = plaque band wider than 1 mm but covering less than 1/3 of the crown; 4 = plaque covering at least 1/3 but less than 2/3 of the crown; 5 = plaque covering 2/3 or more of the crown. 2) Gum Index (GI): 0 = normal gingiva; 1 = mild inflammation, slight color change, slight edema, no bleeding on probing; 2 = moderate inflammation, glazing gingiva, redness, edema, hyperplasia or bleeding on probing; 3 = severe inflammation, marked redness, edema, spontaneous bleeding tendency. 3) Bleeding Index: 0 = gingiva appears healthy, no inflammation and bleeding; 1 = inflammatory color change, no bleeding on probing; 2 = spotting after probing; 3 = bleeding extending to the marginal gingiva after probing; 4 = bleeding fills and overflows the gingival groove; 5 = spontaneous bleeding.

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

All subjects were provided with a soft toothbrush, toothpaste, and randomly assigned to the test product group or the placebo group. After baseline data collection, subjects were instructed to use the designated toothpaste and toothbrush twice a day (once in the morning and once in the evening after meals) to apply toothpaste to the entire length of the brush head and brush their teeth for 3 minutes. They were then instructed to use 10 ml of mouthwash for 30 seconds after brushing, rinse thoroughly and spit out the mouthwash, and avoid eating or drinking for 30 minutes. Efficacy was evaluated after 1 month. Plaque index, gingival index (GI), and bleeding index were evaluated by dentists. Efficacy was expressed as the mean index score for each group.

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

Thus, it has been shown that compound E is effective in reducing gingivitis and has significant benefits for patients using it. Example 49 Efficacy of compound E on scalp seborrheic dermatitis

The test product was prepared as described above in Example 27. 66 healthy individuals aged 25 to 60 years were included in this study, and the estimated number of individuals who completed the entire study was ≥ 60, i.e. ≥ 30 per group.

Inclusion criteria were: 1) hair length ≥ 3 cm, 2) no severe hair loss, hair roots covering at least 70% of the scalp, 3) dandruff level ≥ 3 points, and 4) self-perceived scalp itching and redness.

The test subjects were randomly divided into a test group and a placebo group. After a 2-week wash-out period, when the subjects washed their hair every two days using the provided shampoo, they began to use the test product, Compound E Hair Serum, or placebo. The test product was evenly applied to the scalp using a scalp applicator in a dry hair state, once a day, 3 ml each time. If the product is used after washing the hair, the hair must be dried before use.

Efficacy was assessed after 28 days. Assessments included measurement of scalp skin oil content (Sebumeter SM815, Courage+Khazaka electronic GmbH, Germany), stratum corneum water content (Corneometer CM825, Courage+Khazaka electronic GmbH, Germany), and transdermal water transfer loss (Tewameter, Courage+Khazaka electronic GmbH, Germany) by laboratory technicians. Overall scalp condition, itching, dandruff, dryness, and redness were assessed by dermatologists.

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

surface 32 Parameters Rate of change Significant difference compared with D0 Improved individuals (improvement rate %) Skin hydration 28.56% Significant 30 (100%) Transepidermal water loss -15.35% Significant 30 (100%) Skin sebum -28.26% Significant 30 (100%)

Thus, Compound E has been shown to be effective in relieving symptoms associated with seborrheic dermatitis and has significant benefits for patients using it. Example 50 Treatment of rosacea

A 31-year-old female was diagnosed with rosacea. The patient had small pink or red bumps on her face. She developed redness (blushing) around her mouth, and she felt warmth, heat, itching, or pain. She may feel burning or stinging when using water or skin care products. She used Compound E cream (as described in Example 26) twice a day for 7 days. The redness and itching were relieved, and the mass disappeared (Figure 8). Example 51 Gastroesophageal Reflux ( GERD ) in Rats

Test compounds: Compound K: (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys) ₂ -Lys (SEQ ID No: 113) Compound L: Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm)-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys(Palm) (SEQ ID No: 115) Compound M: Montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Palm) (SEQ ID No: 2)

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

Before surgery, rats were housed and cared for approximately 1 week prior to the experiment. The housing temperature was 25ºC-27ºC, with a humidity of 74%, 12-hour cycles of light and dark, and free access to food and water.

Rats were randomly divided into 5 groups, with 4 rats in each group. The groups were as follows: sham group, model group, compound K, L, and M groups. Rats were anesthetized with 2% isoflurane inhalation and placed in a supine position. The surgical area was shaved with a hair clipper, and the skin was disinfected with iodine. A 2 cm incision was made along the midline of the abdomen 0.5 cm below the xiphoid process to open the abdominal cavity and expose the surgical field. The connective tissue was separated and cut between the liver and the stomach. The vascular bundle between the spleen and the gastric fundus was ligated and cut to completely release the gastric fundus. The gastric fundus was slightly turned to the left to expose the left side of the gastroesophageal junction to the field of view. A 5 mm longitudinal incision was made in the muscle along the distal end of the esophagus using a pair of sharp scissors to expose the gastroesophageal junction.

The dorsal side of the esophagus was gently separated from the blood vessels behind the esophagus. A small cotton tip was inserted between the esophagus and the blood vessels. Two 5 mm longitudinal incisions were made with sharp surgical scissors at the gastroesophageal junction and the proximal duodenum adjacent to the pylorus. For the incision on the duodenum, the blood vessels were avoided and placed at the anterior mesenteric edge. The incisions were anastomosed with interrupted 8-0 Prolene sutures with precise mucosa-to-mucosa apposition. 3-4 sutures were made on the dorsal side and 2-3 sutures were made on the anterior side. The abdominal cavity was lavaged with saline, and the abdominal wall and skin were closed. Surgery was performed on each rat except for the rats in the sham surgery group. After anesthesia and laparotomy, the lower esophagus, duodenum, and gastric fundus were isolated in the sham surgery group without incision.

After 30 hours of postoperative fasting and water deprivation, rats were given glucose injection via caudal vein infusion, 8 ml/animal, once a day for 2 consecutive days. Rats were given intramuscular injection of 50,000 IU penicillin once a day to prevent infection for 3 consecutive days. One week after surgery, rats were given different interventions by tube feeding according to Table 33 below.

surface 33 Group Intervention Dosage Volume Concentration Fake Physiological saline / 2 ml / Model Physiological saline / 2 ml / Test 1 Compound K 10 mg/kg 2 ml 50 mg/ml Test 2 Compound L 10 mg/kg 2 ml 50 mg/ml Test 3 Compound M 10 mg/kg 2 ml 50 mg/ml

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

The intervention was given once a day for 2 weeks. Body weight was measured every 3 days. After 2 weeks of intervention, the animals were sacrificed and the chest was opened. The esophagus was stripped and longitudinally incised to expose the anastomotic site. The severity of esophagitis was assessed according to the scoring criteria in Table 34 below.

surface 34 Erosion (mm) 1 or less 1 to 2 2 to 3 Greater than 3 Score 1 2 3 4

The results of esophagitis severity are shown in Figure 9, indicating that montelukast and pranlukast can reduce the severity of esophagitis in the rat GERD model. Example 52 PK Study: Device-Assisted Transdermal Administration

Test samples: Compound E: 1 mg of Compound E was dissolved in 1 ml of physiological saline to prepare a 1 mg/ml solution. Compound E + PL429: PL429 (Guangzhou Jizhou Trading Co., Ltd) is a transdermal enhancer. 0.5% PL429 was added to the above solution.

27 SPF male SD rats weighing 250-300 g were provided by Zhejiang Charles River Experimental Animal Technology Co., Ltd. and housed and cared for about 1 week before the experiment. The housing temperature was 25°C-27°C, with a humidity of 74% and a dark-light cycle of 12 h, and free access to food and water. The rats were randomly divided into 3 groups of 9 rats each (3 sample collection points per group) as described in Table 35 below.

surface 35 Group Concentration (mg/mL) Dosage (mg) Dosage (mg/cm ² ) Dosage (mL/g) Sample collection Compound E 1 0.2 0.02 0.2 0.25 h, 0.5 h, 1 h after administration. 3 rats were collected each time. Compound E + PL429 Compound E + Instrument

The instrument used was a high-pressure transdermal nutritional supplement device (Guangzhou Tuonasi Beauty Instrument Co., Ltd, China).

The hair on the injection site (skin on the left back of the spine) was shaved and the area was 4.0 cm ² . The injection area was 3 cm ² and it was marked. The injection was made on intact skin (without any damage).

Sample handling: Approximately 200 µL of whole blood was collected from the carotid artery of each group of animals at each time point and injected into EP tubes containing EDTA-K anticoagulant. Immediately, it was shaken manually and placed in wet ice. The samples were centrifuged at 1800 g, 4ºC for 10 minutes. Within 2 hours, the plasma was separated and stored at -80ºC. At the same time, skin tissues from the administration site were collected. Before collecting tissue samples, the site was cleaned with physiological saline and the water was dried. After collection, the samples were stored at -80ºC for further analysis.

The results are shown in Table 36 below.

surface 36 Compound E concentration in plasma (ng/mL) Group/Time 0.25h 0.5h 1h Compound E 7.37 7.03 0.84 Compound E + PL429 11.60 3.10 4.60 Compound E + Instrument 12.70 8.02 5.30 Compound E concentration in skin (ng/mL) Group/Time 0.25 h 0.5 h 1 h Compound E 19633 20433 28267 Compound E + PL429 18700 20433 19677 Compound E + Instrument 25867 27692 20653

The results show that after topical application to the skin, a large amount of Compound E is retained in the skin tissue. Neither the transdermal enhancer nor the device significantly increases plasma exposure. However, the device can increase local concentrations. This shows the beneficial properties of topical application of Compound E. Example 53 Skin Pigmentation: Device-Assisted Transdermal Administration -1

Test sample: Compound E: Dissolve 1 mg of Compound E in 1 ml of physiological saline to prepare a 1 mg/ml solution.

Device: Dermashine pro (Huons Meditech, Republic of Korea), an automatic mesotherapy injector using vacuum pressure. It has been used to replenish moisture and nutrients to the skin.

A 56-year-old woman presented with pigmentation on her cheeks after a trip to the beach. During her stay at the beach, the subject was exposed to sunlight, which caused the skin to become red. After a few days, pigmentation developed. The subject went to a beauty salon for treatment. The subject was treated by injection of Compound E over the entire face via Dermashine. The solution was filtered through a 0.22 µm Minisart® high flow filter (Sartorius, Germany). A total of 3 ml of solution was injected. After 2 weeks, the treatment was repeated. One week after the second injection, the pigmentation disappeared and the dullness and roughness of the skin improved significantly. Example 54 Skin Pigmentation: Instrument-Assisted Transdermal Administration -2

Test sample: Compound K: (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys) ₂ -Lys (SEQ ID No: 113) was dissolved in physiological saline to prepare a 1 mg/ml solution.

A 32-year-old woman presented with pigmentation on both cheeks after giving birth to a baby girl. Six months after giving birth, she sought treatment for her face. The individual went to a beauty salon and was recommended non-invasive treatment using the solution mentioned above. A high-pressure transdermal nutrient supplement device (Guangzhou Tuonasi Beauty Instrument Co., Ltd, China) was used to enhance the absorption of the solution. Treatments were performed weekly. After two months, the skin became firm and flawless. Example 55 LPS- induced lung injury in rats

Test compounds: Compound N: DPPS-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 7) Compound O: LTB4-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 8) Compound M: Montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Palm) (SEQ ID No: 2)

A total of 67 male SD rats were randomly assigned to a normal control group (10 rats) and a model group (57 rats) according to the animal weight. The animals in the normal control group received intraperitoneal injection and intratracheal aerosol inhalation of sodium chloride injection. The animals in the model group received intraperitoneal injection and intratracheal aerosol inhalation of lipopolysaccharide (LPS) to induce an acute lung injury model (2 mg/kg intraperitoneal injection on day 0, 4 mg/kg intratracheal aerosol inhalation on day 1, approximately 16 hours apart). On day 1, after LPS was aerosolized into the trachea of the animals, the animals in the model group were randomly assigned again according to weight into: vehicle control group; test compound N group (0.5 mg/kg); test compound O group (0.5 mg/kg); test compound M group (0.5 mg/kg); and positive control group (2.5 mg/kg). The normal control group was not regrouped. Both the normal control group and the vehicle control group were given an intravenous injection of 0.9% sodium chloride injection; the test compound N, compound O and compound M groups were given an intravenous injection of the corresponding dose once a day for 1 day; and the animals in the positive control group were given an intraperitoneal injection of dexamethasone sodium phosphate injection once a day for 1 day. On day 2, animals were anesthetized and euthanized, and lung lavage fluid testing and lung weight index testing were performed.

Bronchoalveolar lavage fluid (BALF): The mean values of WBC, Neut, Lymph and Mono in the test compound N, compound O and compound M groups and the positive control group were significantly decreased compared to the corresponding indicators of the animals in the vehicle control group. The maximum decreases in WBC were approximately 62%, 74%, 84% and 87%, respectively, with statistical differences. The maximum decreases in Neut were approximately 73%, 79%, 92% and 93%, respectively, with statistical differences. The maximum decreases in Lymph were approximately 65%, 76%, 82% and 84%, respectively, with statistical differences. The maximum decreases in Mono were approximately 71%, 85%, 88% and 91%, respectively, with statistical differences.

Total protein: The mean values of total protein in the animals in the test compound N, compound O, and compound M groups and the positive control group showed a significant decrease compared to the total protein in the BALF of the animals in the vehicle control group. The maximum decreases in total protein were approximately 68%, 72%, 77%, and 56%, respectively, which were statistically different.

Lung weight index: Compared with the lung weight index of animals in the vehicle control group, the mean lung weight index of animals in the test compound N, compound O and compound M groups and the positive control group showed a significant decrease. The maximum decrease in lung weight index was about 20%, 23%, 25% and 29%, respectively, which was statistically different.

Inflammatory factors: Compared with the serum and BALF inflammatory factors (Ang-2, LTD4) of animals in the vehicle control group, the test compound N, compound O and compound M groups and the positive control group decreased significantly. The maximum decreases in serum Ang-2 were approximately 25%, 31%, 40% and 46%, respectively. The maximum decreases in BALF Ang-2 were approximately 25%, 27%, 37% and 55%, respectively, which were statistically different from the positive control group. The maximum decreases in serum LTD4 indicators were approximately 35%, 32%, 37% and 32%, respectively. The maximum decreases in BALF LTD4 were approximately 5%, 15%, 10% and 25%, respectively.

In summary, under the conditions of this study, once-daily intravenous administration of compounds N, O and M at a dose of 0.5 mg/kg reduced total white blood cell count, neutrophil count, total protein, lung weight index, serum and BALF indices of Ang-2 and LTD4 in rats with acute lung injury model, indicating that the compounds are effective in treating acute lung injury. Example 56 Compound P foam: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys) ₂ -Lys ( SEQ ID No: 114 )

The preparation of Compound P foam contained a mixture of the following materials in Table 37 below.

surface 37 Mutually Material quantity(%) A1 Tween-80 3.0 A2 Hydroxypropyl methylcellulose (HPMC) 0.5 A3 Glycerin 5.0 A4 Benzyl alcohol 1.0 A5 Pure water 90.4 A6 Compound P 0.1 B1 Sodium hydroxide

The ingredients of phase A were mixed and stirred for 30 minutes until the system was homogeneous. While stirring, sodium hydroxide was added to adjust the pH of the solution to 6.5.0 to obtain compound P foam.

This foam is intended to be used as an anti-inflammatory agent for repairing vaginal mucosal damage caused by disease and surgery. Example 57 Compound P Gel: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys) ₂ -Lys ( SEQ ID No: 114 )

The formulation of Compound P gel contained a mixture of the following substances in Table 38 below.

surface 38 Mutually Brand Name INCI name quantity(%) A1 Pure water AQUA 81.23 A2 Propylene glycol Propylene glycol 13.40 A3 Glycerin Glycerin 2.60 A4 Carbomer 940 KABOMUER 0.67 A5 Carbomer 941 KABOMUER 0.13 A6 Triethanolamine Triethanolamine 0.80 A7 4-Hydroxyacetophenone Hydroxyacetophenone 0.50 A8 1,2-Hexanediol Hexanediol 0.50 A9 Sodium hyaluronate (1.5 M Da) Sodium hyaluronate 0.07 A10 Compound P 0.10

The ingredients of Phase A were mixed, heated to 80°C, and stirred at 80°C for 30 minutes. The sample was allowed to cool until the system was homogeneous to obtain Compound P Gel.

This gel is intended to be used as an anti-inflammatory drug to repair colorectal mucosal damage caused by disease and surgery. Example 58 Compound P Tablet: (Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys) ₂ -Lys ( SEQ ID No: 114 )

The preparation of Compound P tablets contained a mixture of the following substances in Table 39 below.

surface 39 Mutually Material quantity(%) A1 β-cyclodextrin 6.0 A2 Mannitol 20.0 A3 Citric acid 3.0 A4 Cross-linked polyvinyl pyrrolidone 7.0 A5 Starch 62.9 A6 Compound P 0.1 B1 50% ethanol Moderate C1 Magnesium stearate 1.0

The ingredients of phase A were sieved through a 100 mesh sieve. The drug adjuvants were added to compound P in order and mixed uniformly. 50% ethanol was used as a wetting agent, the drug adjuvants were added simultaneously, and the mixture was continuously stirred to be uniformly wetted. The wetness of the material was adjusted to prepare a soft material that could be kneaded into a ball by hand and dispersed when lightly pressed. The prepared soft material was sieved through a 20 mesh sieve to obtain wet granules.

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

The dried granules were sieved again, graded by size, mixed with a certain amount of lubricant magnesium stearate, and put into a tablet press for tableting to obtain Compound P tablets.

This tablet is intended for use as an anti-inflammatory and to repair gastrointestinal mucosal damage caused by disease and surgery.

without

[Figure 1] shows the results of ear swelling in a mouse model treated with xylene and test compounds A, B and C.

[Figure 2] shows the results of ear swelling in a mouse model treated with xylene and test compounds D, E, F, G and H.

[Figure 3] shows the results of ear swelling in the mouse model treated with xylene, test compounds E, I, J, and palmitic acid + DMSO.

[Fig. 4] shows the results of ear swelling in a mouse model treated with xylene and test compound E.

[ Fig. 5 ] shows the results of radiation oral mucositis scores in the hamster model treated with test compound E.

[ Fig. 6 ] shows the results of mechanical pain threshold in SD rat model treated with test compound E and lidocaine.

[ Fig. 7 ] shows the results of 5-FU-induced oral mucositis score in SD rat model treated with test compound E.

[Figure 8] shows the results of human subjects with rosacea treated with test compound E.

[ Fig. 9 ] shows the results of the severity of esophagitis in the GERD rat model treated with test compounds K, L and M.

Claims (43)

A compound of formula I, L _t -Q ^a -D _b (I) wherein: Q ^a represents Z or AQB; Q is a structural fragment of formula II, (II) Where: The wavy lines represent the points of attachment of Q to A and/or B; R is selected from: , and Among them, when R represents wherein one wavy line represents the point of attachment to the remainder of the Q fragment and the other wavy line represents the point of attachment to the Z group; m represents an integer from 1 to 4; A and B independently represent Z or A ¹ -Q ¹ -B ¹ ; A ¹ and B ¹ independently represent Z or A ² -Q ² -B ² ; A ² and B ² independently represent Z or ZQ ³ -Z; Q ¹ , Q ² and Q ³ independently represent a structural fragment of Formula III, (III) wherein: the wavy lines adjacent to the NH groups represent the points of attachment of Q ¹ , Q ² and Q ³ to A ¹ and/or B ¹ , A ² and/or B ² and Z, respectively; the wavy lines adjacent to the C═O groups represent the points of attachment of Q ¹ , Q ² and Q ³ to Q, Q ¹ and Q ^2, respectively; m is as defined above; Each L independently represents one or more lipids selected from vitamin A, vitamin E, cholesterol and fatty acids, the fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons and/or one or more cyclic rings, the lipids being linear or branched, saturated or having between 1 and 10 carbon-carbon double bonds but unsaturated and/or substituted with between 1 and 10 -OH groups, or derivatives of any of these lipids; t represents an integer selected from 1 to 32; D represents montelukast; b represents an integer selected from 0 to 16; in each case where it is used above, Z represents a structural fragment of formula IV, [(W) _r -Lys-X ¹ -TUX ² -Y] _n -(W) _r -Lys-X ¹ -TUX ² -Y (IV) (SEQ ID No: 1) wherein: n represents an integer selected from 0 to 4; in each case where it is used, r independently represents 0 or 1; in each case where it is used, W independently represents a sequence of 1 or 2 amino acids, the amino acids being selected from one or more of the following groups: Ser, Lys, Ala, DOPA and 3,4-dihydrocinnamic acid (HCA) residue, provided that when present, the HCA residue is located at the N-terminus of Z; X ¹ independently represents Pro, Hyp or diHyp; T independently represents Ser or pSer; U independently represents Tyr, pTyr, DOPA, Hyp or Pro; X ² independently represents Thr, Ser, Pro, Hyp or diHyp; Y independently represents a sequence of 1 to 5 (e.g. 1 to 4) amino acids selected from one or more of the following groups: Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, said sequence optionally terminated by dopamine (or more appropriately, a "dopamine fragment"); if present, each D is covalently bonded to Z via an amide bond between its corresponding carboxylic acid residue and one or more _NH2 residues of Z; and each L residue is covalently bonded to Z via an amide bond between the corresponding carboxylic acid residue of L and one or more _NH2 residues of Z and/or via an ester bond between the corresponding -OH residue of L and one or more carboxylic acid residues of Z, And positional isomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of the compounds. The compound according to claim 1, wherein the lipid is selected from palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid and leukotriene B4 or a derivative of any one of these lipids. A compound according to claim 2, wherein the lipid is palmitic acid or a derivative thereof. A compound according to claim 3, wherein the derivative is palmitylamide ethanol (PEA). A compound according to claim 3, wherein the derivative is phosphatidylserine. The compound according to claim 3, wherein the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine, phosphatidylethanolamine or 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine. The compound according to claim 3, wherein the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine. A compound according to claim 2, wherein the lipid is stearic acid or a derivative thereof. The compound according to claim 8, wherein the derivative is 1,2-distearyl-sn-glycero-3-phospho-l-serine. A compound according to claim 2, wherein the lipid is oleic acid or a derivative thereof. The compound according to claim 10, wherein the derivative is 1,2-dioleyl-sn-glycero-3-phospho-L-serine. A compound according to claim 1, wherein the lipid is selected from vitamin E, vitamin A and cholesterol or a derivative of any of these lipids. The compound according to claim 12, wherein the derivative of cholesterol is cholesterol-acetic acid. A compound according to any one of the preceding claims, wherein ^Qa represents Z. A compound according to any of the preceding claims, wherein n represents 0. A compound according to any of the preceding claims, wherein W, if present, represents Ala. A compound according to any one of the preceding claims, wherein X ¹ represents Pro. A compound according to any of the preceding claims, wherein T represents Ser. A compound according to any of the preceding claims, wherein U represents Tyr or DOPA. A compound according to any one of the preceding claims, wherein ^X2 represents Hyp. A compound according to any of the preceding claims, wherein Y represents a sequence of 4 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Hyp, Thr, DOPA and Tyr, the sequence optionally being terminated by a dopamine fragment. A compound according to claim 21, wherein the amino acid sequence defined by Y is selected from the following group: -Hyp-Thr-Tyr-Lys-; -Hyp-Thr-DOPA-Lys-; -Thr-Tyr-Hyp-Lys-; -Thr-DOPA-Hyp-Lys-; -DOPA-Lys-; and -Tyr-Lys-, each of which is optionally terminated by a dopamine fragment. The compound according to claim 22, wherein Z is selected from the following group: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 11); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 12); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16); and Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19). A compound according to any of the preceding claims for use in human or animal medicine. A compound according to any one of claims 1 to 23 for use as a medicine. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 25. According to the pharmaceutical formulation of claim 26, the pharmaceutical formulation further comprises a pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation according to claim 26 or claim 27, which is suitable for, adapted for and/or packaged and presented for topical administration, wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier is a topical adjuvant, diluent or carrier. The pharmaceutical formulation according to any one of claims 26 to 28, which is in the form of a gel, a spray, a cream, an ointment or a dry powder. The pharmaceutical formulation according to any one of claims 26 to 29, further comprising one or more additional pharmaceutically active ingredients. A kit of parts comprising the following components: (A) a compound according to any one of claims 1 to 23 or a pharmaceutical formulation according to any one of claims 26 to 30; and (B) a pharmaceutical formulation comprising one or more additional pharmaceutically active ingredients mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein components (A) and (B) are each provided in a form suitable for administration in combination with each other. A pharmaceutical formulation according to claim 30 or a kit of parts according to claim 31, wherein the pharmaceutically active ingredient is an anti-inflammatory agent, a pro-inflammatory agent, an antibiotic, an antibacterial agent and/or an antiprotozoal agent, an antiviral agent, an anesthetic agent and/or a wound healing drug. The pharmaceutical formulation or kit of parts according to claim 32, wherein the pharmaceutically active ingredient is an anti-inflammatory agent. A compound according to any one of claims 1 to 23, a formulation according to any one of claims 26 to 30, 32 or 33, or a kit according to any one of claims 31 to 33, wherein the compound, the formulation or the kit is used to treat inflammation, an inflammatory condition and/or a condition characterized by inflammation. A use of a compound according to any one of claims 1 to 23, a formulation according to any one of claims 26 to 30, 32 or 33, or a kit according to any one of claims 31 to 33 for the manufacture of a medicament for treating inflammation, an inflammatory condition and/or a condition characterized by inflammation. A method for treating inflammation, inflammatory conditions and/or conditions characterized by inflammation, the method comprising administering to a patient in need of such treatment a compound according to any one of claims 1 to 23, a formulation according to any one of claims 26 to 30, 32 or 33, or a kit according to any one of claims 31 to 33. A compound, formulation or kit for use according to claim 34, a use according to claim 35 or a method according to claim 36, wherein the condition characterized by inflammation is a wound or a burn or causes a wound or a burn. The compound, formulation or kit for use, use or method according to claim 37, wherein the condition leading to the wound is hemorrhoids or ulcerative colitis. A compound, formulation or kit of parts, use or method for use according to any one of claims 24 to 38 (as the case may be), wherein the one or more compounds or salts thereof are administered topically in the form of a topical formulation. The compound, formulation or kit, use or method for use according to claim 39, wherein the relevant disease is treated by direct topical administration to the skin. The compound, formulation or kit, use or method for use according to claim 39, wherein the relevant disease is treated by direct topical administration to a mucosal surface. A compound, formulation or kit of parts, use or method for use according to any one of claims 24 to 41, as the case may be, wherein the one or more compounds are administered orally, intravenously, cutaneously or subcutaneously, nasally, intramuscularly, intraperitoneally, pulmonary or anorectally. A compound, formulation or kit of parts, use or method for use according to any one of claims 30 to 42 (as the case may be), wherein the compound according to any one of claims 1 to 23 serves as a dispensing agent, a medical device or a medical device component of a drug-medical device combination.