Novel multifunctional oligopeptides

Abstract

There is provided a compound of formula I, A-Q-BI wherein Q represents a structural fragment of formula II wherein: the wavy line and m have the meanings given in the description, and wherein A and B have the meanings given in the description, but may represent a peptide component having the following amino acid sequence: [(W) m-Lys-X1-T-(U) m-(X2) m-(Y) m] n-(W) m-Lys-X1-T-(U) m-(X2) m-(Y) m (SEQ ID No: 1); wherein n, m, T, W, X1, U, X2 and Y have the meanings given in the description, are useful in medicine, including as pharmaceutical excipients, adhesives and film-forming materials, and / or in the treatment of conditions characterized by inflammation, including wounds, burns and mucosal disorders such as anorectal diseases, inflammatory bowel diseases, gynecological diseases and dental diseases.

Description

Technical Field

[0001] The present invention relates to novel peptides, the use of such peptides as pharmaceutically active ingredients or otherwise in human medicine, 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 conditions including inflammation. Background Art

[0002] Inflammation is typically characterized as a local tissue response to invasion by, for example, microorganisms, certain antigens, damaged cells, or physical and / or chemical agents. The inflammatory response is generally a protective mechanism that serves to destroy, dilute, or isolate harmful agents and damaged tissues, as well as to initiate tissue healing.

[0003] Inflammation may be caused by 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). It may involve a complex series of events in which inflammatory mediators increase blood flow and dilation of local blood vessels, leading to redness and warmth, extravasation of fluid, often leading to local swelling, migration of white blood cells into the inflamed area, and pain.

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

[0005] Typically, a complex series of events leads to inflammatory changes, such as increased blood flow through local vasodilation, resulting in redness and fever, 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 like neutrophils, monocytes, macrophages, and lymphocytes, as well as inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

[0006] In addition, inflammation plays a key role in the wound healing process. Therefore, wounds and burns can be classified as conditions related to inflammation. The conventional wisdom in this field is that anti-inflammatory drugs should not be applied directly to open wounds because this will be detrimental to the progress of wound healing.

[0007] Fibrosis is defined by the excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM), such as collagen and fibronectin) in and around inflamed or damaged tissue. Although collagen deposition is typically a reversible part of wound healing, if tissue damage is severe, or if the wound healing response itself becomes imbalanced, collagen deposition may usually evolve into a gradually irreversible fibrotic reaction. In addition, known fibrosis is the main cause of morbidity and mortality in many chronic inflammatory diseases and end-stage liver disease, nephropathy, idiopathic pulmonary fibrosis (IPF) and heart failure. It is also the 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.

[0008] Mussel adhesion protein (MAP), also known as Mytilus edulis foot protein (mefp), is a protein secreted by marine shellfish species such as Mytilus edulis, Mytilus coruscus, and Perna viridis. Eleven independently identified adhesion protein subtypes have been produced from mussels, including the collagens pre-COL-P, pre-COL-D, and pre-COL-NG; the mussel foot matrix proteins PTMP (proximal silk matrix protein) and DTMP (distal silk matrix protein); and the mfp proteins mfp-2 (sometimes referred to as "mefp-2," used interchangeably hereinafter), mfp-3 / mefp-3, mfp-4 / mefp-4, mfp-5 / mefp-5, mfp-6 / mefp-6, and most preferably, 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, 19860-19862).

[0009] A significant portion of mefp-1 consists of 70 to 90 tandem repeats of the following decapeptide sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 1; see Waite, Int. J. Adhesion and Adhesives, 1987, 7, 9-14). This decapeptide sequence can be isolated as a low molecular weight derivative of naturally occurring MAP or 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.

[0010] Analogs of the decapeptide are also disclosed, notably Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 78). See, for example, US 5,616,311 and WO 96 / 39128.

[0011] 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.

[0012] 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.

[0013] There is clearly a need for new and / or improved pharmaceuticals that can be used to treat inflammation and conditions characterized by inflammation. DETAILED DESCRIPTION

[0014] According to a first aspect of the present invention, there is provided a compound of formula I,

[0015] AQB(I)

[0016] in:

[0017] A and B independently represent Z or A 1 -Q 1 -B 1 ;

[0018] Q represents a structural fragment of formula (II),

[0019]

[0020] in:

[0021] The wavy lines indicate the points of attachment of Q to A and / or B; and

[0022] R is selected from:

[0023]

[0024] Among them, when R represents When one wavy line indicates the point of attachment to the rest of the Q segment, and the other wavy line indicates the point of attachment to Z or A. 1 -Q 1 -B 1 attachment points;

[0025] Among them, when R represents , one wavy line indicates the point of attachment to the rest of the Q segment, and the other wavy line indicates the point of attachment to Z;

[0026] n1 to n3 independently represent 1 to 10;

[0027] m1 to m3 independently represent 0 to 5;

[0028] p1 to p3 independently represent 0 or 1;

[0029] x represents 0 or 1;

[0030] A 1 and B 1 Independently represents Z or A 2 -Q 2 -B 2 ;

[0031] A 2 and B 2 Independently represents Z or ZQ 3 -Z;

[0032] Q 1 , Q 2 and Q 3 independently represents a structural fragment of formula III,

[0033]

[0034] in:

[0035] The wavy lines adjacent to the NH groups represent Q 1 , Q 2 and Q 3 With A 1 and / or B 1、A 2 and / or B 2 and the attachment point of Z;

[0036] The wavy lines adjacent to the carbonyl group represent Q 1 , Q 2 and Q 3 With Q, Q 1 and Q 2 attachment point; and

[0037] n4 to n6 independently represent an integer selected from 1 to 10;

[0038] m4 to m6 independently represent an integer selected from 0 to 5;

[0039] p4 to p6 independently represent 0 or 1;

[0040] y represents 0 or 1;

[0041] Z, in each instance where it is employed, independently represents:

[0042] L-[(W) m -Lys-X 1 -T-(U) m -(X 2 ) m -(Y) m ] n -(W) m -Lys-X 1 -T-(U) m -(X 2 ) m -(Y) m (SEQ ID No: 1); or

[0043] L-Ala-Lys-Pro (SEQ ID No: 2); or

[0044] L-Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID No: 3); or

[0045] L-[Lys - X 3 ] n -Lys-X 3 (SEQ ID No: 196)

[0046] in:

[0047] Z is attached to the remainder of the molecule via the N-terminus or C-terminus, as appropriate; and

[0048] In each case where they are adopted:

[0049] n represents 0 or an integer selected from 1 to 4;

[0050] W independently represents a sequence of 1 or 2 amino acids, wherein the amino acids are selected from one or more of the following groups: Ser, Lys, Ala, DOPA and 3,4-dihydrocinnamic acid (HCA) residues, with the proviso that when present, the HCA residue is located at the N-terminus of the peptide sequence Z;

[0051] In each instance where it is employed, m independently represents 0 or 1;

[0052] In each case where it is adopted, X 1 Independently represents Pro or Hyp;

[0053] T independently represents Ser or pSer in each instance where it is employed;

[0054] U, at each instance where it is employed, independently represents Tyr, pTyr, DOPA, Hyp, diHyp or Pro;

[0055] In each case where it is adopted, X 2 independently represents Thr, Ser, Pro, Hyp, or diHyp;

[0056] In each instance where it is employed, Y independently 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, Thr, pThr, DOPA, and Tyr;

[0057] L independently represents at least one optional lipid substituent selected from vitamin A; vitamin E; cholesterol and a fatty acid containing one or more carboxylic acid groups, 1 to 50 carbons and / or one or more cyclic rings, said lipid being a linear or branched, saturated or unsaturated lipid having between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10 -OH groups, or a derivative of any of these lipids; and

[0058] X 3 represents a sequence of 2 to 4 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA and Tyr,

[0059] wherein, optionally, the amino acid residue at the N-terminus of the Z component is covalently bonded to a nonsteroidal anti-inflammatory drug (NSAID) or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast,

[0060] and regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of said compounds,

[0061] The compounds, regioisomers, stereoisomers and salts are hereinafter collectively referred to as "compounds of the present invention."

[0062] The skilled person will be able to determine whether peptide Z 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 linkage.

[0063] Thus, when Z is attached to Formula (II), Formula (III) or R, when R is When Z is attached via the C-terminus.

[0064] Alternatively, when Z is attached to R, when R is When Z is attached via the N-terminus.

[0065] As used herein, "diHyp" refers to trans-2,3-cis-3,4-dihydroxyproline.

[0066] Compounds according to the invention which may be mentioned include those in which Z represents:

[0067] [(W) m -Lys-X 1 -T-(U) m -(X 2 ) m -(Y) m ] n -(W) m -Lys-X 1 -T-(U) m -(X 2 ) m -(Y) m (SEQ ID No: 1); or

[0068] Ala-Lys-Pro (SEQ ID No: 2); or

[0069] Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID No: 3),

[0070] 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 the montelukast,

[0071] In each case where they are used, Q, Q 1 , Q 2 and Q 3 Each may be attached to zero, one, two, or three Z groups.

[0072] In this regard, preferred compounds of the present invention include those wherein:

[0073] One of A or B represents Z, and the other represents A 1 -Q 1 -B 1 ; or more preferably,

[0074] A and B both represent Z or both represent A 1 -Q 1 -B 1 .

[0075] Further preferred compounds of the present invention include compounds wherein:

[0076] A 1 and B 1 One of them represents Z, and the other represents A 2 -Q 2 -B 2 ; or more preferably,

[0077] A 1 and B 1 Both represent Z or both represent A 2 -Q 2 -B 2 .

[0078] Further preferred compounds of the present invention include compounds wherein:

[0079] A 2 and B 2 One of them represents Z, and the other represents ZQ 3 -Z; or more preferably,

[0080] A 2 and B 2 All represent Z or all represent ZQ 3 -Z.

[0081] More preferred compounds of the present invention include compounds wherein:

[0082] A 1 and B 1 All represent Z; or

[0083] A 2 and B 2 Both represent Z.

[0084] In some embodiments, each of p1 to p6 represents 0. In particular, in such embodiments, each of m1 to m6 represents 0.

[0085] In some embodiments, x represents 0. In particular, in such embodiments, each y independently represents 0.

[0086] In some embodiments, x represents 1. In particular, in such embodiments, each y independently represents 0.

[0087] In some embodiments, each of p1 to p3 represents 1. In such embodiments, m1 to m3 independently represent 1 to 5.

[0088] In particular, in such embodiments, each of p4 to p6 represents 1, and each of m4 to m6 represents 1 to 5.

[0089] In some embodiments, R represents

[0090] In an alternative embodiment, R represents

[0091] In some embodiments, n1 to n3 independently represent an integer from 1 to 5. In particular, in such embodiments, n4 to n6 independently represent an integer from 1 to 5.

[0092] Peptide components of the compounds of the invention that may be mentioned include those compounds wherein n is 0, 1 or 4, or more preferably, n is 1, or in particular, n is 0.

[0093] Compounds of the invention that may be mentioned include those wherein the amino acid residue at the N-terminus of the Z component is covalently bonded to an NSAID or montelukast.

[0094] Those skilled in the art will understand that the term "nonsteroidal anti-inflammatory drug" (NSAID) includes one or more members of a class of drugs used to reduce pain, inflammation and / or fever (and in some cases, reduce blood clots). The phrase "nonsteroidal" will be well understood to exclude other pain relievers and in particular corticosteroids from this definition.

[0095] NSAIDs typically act by inhibiting the activity of cyclooxygenase (COX) enzymes, including COX-1 and COX-2, which are enzymes known to be involved in the synthesis of key inflammatory mediators, such as prostaglandins, as well as mediators involved in hemostasis, such as thromboxanes.

[0096] NSAIDs that may be mentioned include those belonging to the following structural classes, and especially those derived from carboxylic acids, including:

[0097] Salicylic acid or "salicylate" includes salicylic acid itself and its salts, salsalate, diflunisal, and especially aspirin (acetylsalicylic acid); and 5-aminosalicylic acid (mesalamine);

[0098] Acetic acids, including indomethacin, acemetacin, "fenac" (such as diclofenac, fenclofenac, aceclofenac, and bromfenac), ketorolac, etodolac, sulindac, fentiazine, as well as olmetin and nabumetone;

[0099] Propionic acid, also known as "2-arylpropionic acid derivatives" or "profens," including ibuprofen, naproxen, dexibuprofen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, pebiprofen, zaltoprofen, fenbufen, carprofen, and tiaprofenic acid;

[0100] Enolic acids, also known as "oxicams," include meloxicam, piroxicam, lornoxicam, isoxicam, tenoxicam, and droxicam, as well as phenylbutazone (Bute); and

[0101] Anthranilic acid, also known as "fenamates," includes mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etofenamate, and clofenamic acid.

[0102] Other NSAIDs that may be mentioned include pyrazolone derivatives including oxytocin, isopropyl antipyrine, aminopyrine, antipyrine and analginum (metamizole) and nefopam. Other analgesic compounds that may be used instead of and / or in addition to NSAIDs include phenacetin and paracetamol (acetaminophen).

[0103] NSAIDs that may also be mentioned, but are less preferred, include selective COX-2 inhibitors or "coxibs" such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib; sulfonanilides such as nimesulide; and clonixin, levofloxacin and H-harpagine.

[0104] Preferred NSAIDs include aspirin, salicylic acid, celecoxib, and mesalamine.

[0105] It is preferred that the amino acid residue at the N-terminus of Z is covalently bonded to montelukast.

[0106] The optional NSAID substituent may be covalently bonded to the amino acid residue at the N-terminus of the Z component via an amide bond formed between the corresponding carboxylic acid residue of the NSAID and the -NH2 residue at the N-terminus of Z.

[0107] The skilled person will appreciate that specific NSAIDs that may be covalently bonded to the amino acid sequence of Z via an amide bond include: salicylates (such as aspirin, salicylic acid and suitable salts, diflunisal, salsalate, 5-aminosalicylic acid), propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, pebiprofen, zaltoprofen), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac), anthranilic acid derivatives (such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (such as lumiracoxib) and others (such as clonixin, levofloxacin).

[0108] Compounds of the invention that may be mentioned include those among which:

[0109] W represents a sequence of 1 or 2 amino acids, wherein the amino acids are selected from one or more of the following groups: Ser, Lys, Ala and DOPA;

[0110] X 1 Indicates Pro;

[0111] X 2 Indicates Ser, Pro, or Hyp;

[0112] 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, Thr, DOPA, and Tyr.

[0113] Preferred compounds of the present invention include those wherein:

[0114] X 1 means Hyp or more preferably Pro;

[0115] X 2 Indicates Hyp;

[0116] W represents HCA-, HCA-Ala-, preferably Ala- or Lys-Ala- or more preferably DOPA- or DOPA-Ala-; and / or

[0117] Y represents a sequence of 5, preferably 3 or more preferably 4 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Ala, Hyp, Thr, DOPA and Tyr.

[0118] More preferably, the compounds of the present invention also include those compounds, wherein Y represents a sequence of 4 amino acids selected from the group consisting of: -Pro-Y 1 -Y 2 -Lys-, or more preferably -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 -Lys-, where Y 1 and Y 2 Each is independently selected from the group consisting of Pro, or more preferably Ala, Hyp, Thr, DOPA and Tyr.

[0119] Further preferred compounds of the present invention include those compounds, wherein the amino acid sequence defined by Y is selected from the group consisting of:

[0120] -Pro-Thr-DOPA-Lys-;

[0121] -Pro-Thr-Tyr-Lys-;

[0122] -Thr-Tyr-Pro-Lys-; and

[0123] -Thr-DOPA-Pro-Lys-; and more preferably,

[0124] -Thr-Tyr-Hyp-;

[0125] -Thr-DOPA-Hyp-;

[0126] -Tyr-Hyp-Lys-;

[0127] -Tyr-Pro-Lys-;

[0128] -Hyp-Thr-DOPA-;

[0129] -Hyp-pThr-DOPA-;

[0130] -Hyp-Thr-Tyr-;

[0131] -DOPA-Hyp-Lys-;

[0132] -Hyp-Thr-Tyr-Lys-;

[0133] -Hyp-Thr-Tyr-Hyp;

[0134] -Hyp-Thr-DOPA-Lys-;

[0135] -Hyp-Thr-DOPA-Hyp-;

[0136] -Hyp-Thr-Ala-Lys-;

[0137] -Hyp-pThr-DOPA-Hyp-;

[0138] -Thr-Tyr-Hyp-Lys-;

[0139] -Thr-Tyr-Lys-Hyp-;

[0140] -Thr-DOPA-Lys-Hyp-;

[0141] -Thr-DOPA-Hyp-Lys-; and

[0142] -Thr-Ala-Hyp-Lys-.

[0143] 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 -DOPA-Lys-, -Tyr-Lys-, -Thr-Lys- and -Tyr-Pro-.

[0144] Other preferred compounds of the present invention that may be mentioned include those compounds, wherein the amino acid sequence defined by Y is selected from the group consisting of: -DOPA-, -Tyr, -Hyp-, -Thr-, -Hyp-Thr-, -Thr-Tyr-, -Pro-Thr-, -Thr-DOPA, -Thr-Tyr-Lys-, -Tyr-Pro-Lys, -DOPA-Pro-Lys-, -Hyp-Thr-Tyr-, -Hyp-Thr-Tyr -Hyp-Lys-, -Hyp-Thr-DOPA-Hyp-Lys-, -Hyp-Thr-DOPA-Lys-DOPA-, -Hyp-Thr-Tyr-Lys-DOPA-, -Thr-DOPA-Hyp-Lys-DOPA-, -Thr-Tyr-Hyp-Lys-DOPA-, and more preferably the following group: -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

[0145] Compounds of the invention that may be mentioned include those among which:

[0146] U represents Tyr; and / or

[0147] W stands for Ala.

[0148] In this respect, further compounds according to the invention which may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0149] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 83);

[0150] Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5);

[0151] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6);

[0152] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7);

[0153] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8);

[0154] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 179);

[0155] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 180);

[0156] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 181);

[0157] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 182);

[0158] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 13);

[0159] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 14);

[0160] Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID no.18);

[0161] Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys(SEQ ID no.19);

[0162] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID no.23);

[0163] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.24);

[0164] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID no.25);

[0165] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID no.26);

[0166] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.27);

[0167] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp(SEQ ID no.28);

[0168] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID no.29);

[0169] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp(SEQ ID no.30);

[0170] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.31);

[0171] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.32);

[0172] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.33);

[0173] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID no.34);

[0174] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.35);

[0175] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.36);

[0176] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID no.37);

[0177] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.38);

[0178] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID no.39);

[0179] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.40);

[0180] Ala-Lys-Pro-Ser-Tyr-Hyp(SEQ ID no.6);

[0181] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp(SEQ ID no.61);

[0182] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA(SEQ ID no.62);

[0183] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp(SEQ ID no.63);

[0184] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp-Lys(SEQ ID no.64);

[0185] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Lys (SEQ ID no.65);

[0186] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr(SEQ ID no.66);

[0187] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp(SEQ ID no.67);

[0188] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp-Lys (SEQ ID no.68);

[0189] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Lys (SEQ ID no.69);

[0190] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID no.70);

[0191] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp(SEQ ID no.71);

[0192] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.72);

[0193] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.73);

[0194] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID no.74);

[0195] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.75);

[0196] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID no.76);

[0197] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no.77);

[0198] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no.78);

[0199] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID no.79);

[0200] Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (SEQ ID no.80);

[0201] Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID no.81);

[0202] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID no.82);

[0203] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.83);

[0204] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID no.84);

[0205] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID no.85);

[0206] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-DOPA-Lys(SEQ ID no.86);

[0207] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID no.8);

[0208] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no.9);

[0209] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID no.87);

[0210] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp(SEQ ID no.88);

[0211] Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no.89);

[0212] Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no.90);

[0213] Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (SEQ ID no.91);

[0214] Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (SEQ ID no.92);

[0215] Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys(SEQ ID no.93);

[0216] Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys(SEQ ID no.171);

[0217] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys (SEQ ID no.173);

[0218] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.174);

[0219] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-D OPA-Lys (SEQ ID no. 175);

[0220] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-A la-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Al a-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 176); and

[0221] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-D OPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 177).

[0222] Compounds of the invention that may be mentioned include those among which:

[0223] U represents Tyr; and / or

[0224] W represents Lys-Ala-.

[0225] In this respect, further compounds according to the invention which may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0226] Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 96);

[0227] Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 97);

[0228] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 100);

[0229] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 101);

[0230] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 183);

[0231] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 184); and

[0232] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 185).

[0233] Compounds of the invention that may be mentioned include those among which:

[0234] U represents Tyr; and / or

[0235] W does not exist.

[0236] In this respect, further compounds according to the invention which may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0237] Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 102);

[0238] Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 103);

[0239] Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 104);

[0240] Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 105);

[0241] Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID no.106);

[0242] Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID no.107);

[0243] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID no.108);

[0244] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys(SEQ ID no.109);

[0245] Lys-Hyp-Ser-Tyr-Hyp-DOPA(SEQ ID no.112);

[0246] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no.113);

[0247] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no.114);

[0248] Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID no.118);

[0249] Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID no.119);

[0250] Lys-Pro-Ser-Tyr-Hyp-Thr(SEQ ID no.120);

[0251] Lys-Pro-Ser-Tyr-Hyp-Thr-Lys(SEQ ID no.122);

[0252] Lys-Pro-Ser-Tyr-Hyp-DOPA(SEQ ID no.126);

[0253] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no.127);

[0254] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp(SEQ ID no.128);

[0255] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 129);

[0256] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 130);

[0257] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 131);

[0258] Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 132);

[0259] Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 133);

[0260] Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 134);

[0261] Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 135); and

[0262] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136).

[0263] Other compounds of the invention that may be mentioned include those among which:

[0264] U represents Tyr; and / or

[0265] W represents HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-.

[0266] In this respect, compounds of the invention that may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0267] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 141);

[0268] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 142);

[0269] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.143);

[0270] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.144);

[0271] DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID no.147);

[0272] DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID no.148);

[0273] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.153);

[0274] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.154);

[0275] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.155);

[0276] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.156);

[0277] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID no.157);

[0278] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.158);

[0279] HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID no.161); and

[0280] HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID no.162).

[0281] Other compounds of the invention that may be mentioned include those among which:

[0282] U represents Tyr; and / or

[0283] W stands for Ser.

[0284] In this respect, compounds of the invention that may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0285] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 163);

[0286] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 164);

[0287] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 165);

[0288] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 166);

[0289] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 167);

[0290] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 168);

[0291] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 169); and

[0292] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 170).

[0293] Other compounds of the invention that may be mentioned include those in which U represents DOPA.

[0294] In this respect, compounds of the invention that may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0295] Ala-Lys-Pro-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys(SEQ ID no.186);

[0296] Ala-Lys-Hyp-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys(SEQ ID no.187);

[0297] Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.10);

[0298] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.11);

[0299] Lys-Pro-Ser-DOPA-Hyp-DOPA(SEQ ID no.115);

[0300] Lys-Pro-Ser-DOPA-Hyp-DOPA-Lys(SEQ ID no.116);

[0301] Lys-Pro-Ser-DOPA-Hyp-Tyr-Lys(SEQ ID no.117);

[0302] Lys-Pro-Ser-DOPA-Hyp-Thr(SEQ ID no.121);

[0303] Lys-Pro-Ser-DOPA-Hyp-Thr-Lys(SEQ ID no.123);

[0304] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp(SEQ ID no.20);

[0305] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.11);

[0306] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID no.21);

[0307] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp(SEQ ID no.22);

[0308] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.41);

[0309] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID no.42);

[0310] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID no.43);

[0311] Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys(SEQ ID no.44);

[0312] Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys(SEQ ID no.45);

[0313] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp(SEQ ID no.46);

[0314] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.47);

[0315] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID no.48);

[0316] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID no.49);

[0317] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.50);

[0318] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID no.51);

[0319] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp(SEQ ID no.52);

[0320] Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no.53);

[0321] Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no.54);

[0322] Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys (SEQ ID no.55);

[0323] Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys (SEQ ID no.56);

[0324] Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys (SEQ ID no.57);

[0325] Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys (SEQ ID no.58);

[0326] Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no.94);

[0327] Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no.95);

[0328] Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no.98);

[0329] Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no.99);

[0330] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Th r-DOPA-Lys (SEQ ID no.172); and

[0331] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Th r-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 178).

[0332] Other compounds of the invention that may be mentioned include those among which:

[0333] U for DOPA; and / or

[0334] W represents HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-.

[0335] Specific compounds of the present invention that may be mentioned therefore include those compounds, wherein Z is selected from the group consisting of:

[0336] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 137);

[0337] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 138);

[0338] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 139);

[0339] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 140);

[0340] DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 145);

[0341] DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 146);

[0342] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 149);

[0343] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 150);

[0344] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 151);

[0345] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 152);

[0346] HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 159); and

[0347] HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 160).

[0348] Other compounds of the invention that may be mentioned include those among which:

[0349] U stands for Hyp.

[0350] Specific compounds of the present invention that may be mentioned therefore include those compounds, wherein Z is selected from the group consisting of:

[0351] Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 12); and

[0352] Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID no. 16).

[0353] Other compounds of the invention that may be mentioned include those among which:

[0354] U stands for Pro.

[0355] Specific compounds of the present invention that may be mentioned therefore include those compounds, wherein Z is selected from the group consisting of:

[0356] Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 15);

[0357] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID no. 17);

[0358] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (SEQ ID no. 59); and

[0359] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 60).

[0360] Other compounds of the invention that may be mentioned include those among which:

[0361] U represents pTyr.

[0362] Specific compounds of the present invention that may be mentioned therefore include those compounds, wherein Z is selected from the group consisting of:

[0363] Lys-Hyp-Ser-pTyr-Hyp-DOPA (SEQ ID no. 110);

[0364] Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 111);

[0365] Lys-Pro-Ser-pTyr-Hyp-DOPA (SEQ ID no. 124); and

[0366] Lys-Pro-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 125).

[0367] Other compounds of the invention that may be mentioned are those, wherein Z is selected from the group consisting of:

[0368] Ala-Lys-Pro-Ser(SEQ ID no.4);

[0369] Ala-Lys-Pro (SEQ ID no. 2); and

[0370] Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID no. 3).

[0371] In some embodiments, Z is selected from the group consisting of:

[0372] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys(SEQ ID no.179);

[0373] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys(SEQ ID no.180);

[0374] Ala-Lys-Pro-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys(SEQ ID no.186);

[0375] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys(SEQ ID no.181);

[0376] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys(SEQ ID no.182);

[0377] Ala-Lys-Hyp-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys(SEQ ID no.187);

[0378] Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.10);

[0379] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.11);

[0380] Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.12);

[0381] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.13);

[0382] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.14);

[0383] Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys(SEQ ID no.15);

[0384] Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID no.16);

[0385] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID no.17);

[0386] Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no.18);

[0387] Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys(SEQ ID no.19);

[0388] Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID no.102);

[0389] Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID no.103);

[0390] Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no.104);

[0391] Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no.105);

[0392] Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID no.106);

[0393] Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID no.107);

[0394] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID no.108);

[0395] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no.109);

[0396] Lys-Hyp-Ser-pTyr-Hyp-DOPA(SEQ ID no.110);

[0397] Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no.111);

[0398] Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID no. 112);

[0399] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113);

[0400] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 114);

[0401] Lys-Pro-Ser-DOPA-Hyp-DOPA (SEQ ID no. 115);

[0402] Lys-Pro-Ser-DOPA-Hyp-DOPA-Lys (SEQ ID no. 116);

[0403] Lys-Pro-Ser-DOPA-Hyp-Tyr-Lys (SEQ ID no. 117);

[0404] Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID no. 118);

[0405] Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID no. 119);

[0406] Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 120);

[0407] Lys-Pro-Ser-DOPA-Hyp-Thr (SEQ ID no. 121);

[0408] Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID no. 122); and

[0409] Lys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID no. 123).

[0410] Compounds of the invention that may be mentioned include those among which:

[0411] A and B both represent Z;

[0412] One or preferably two Z groups represent:

[0413] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.13);

[0414] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no.14);

[0415] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID no.108);

[0416] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no.109);

[0417] Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID no.102);

[0418] Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID no.103);

[0419] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.24);

[0420] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no.27);

[0421] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.32);

[0422] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.36);

[0423] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID no.70);

[0424] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.75);

[0425] DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID no.147);

[0426] DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 148);

[0427] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 155);

[0428] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 158);

[0429] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 100);

[0430] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 101);

[0431] Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID no. 126);

[0432] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 129);

[0433] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 131);

[0434] Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 133);

[0435] Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 135);

[0436] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 168); or

[0437] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 170),

[0438] Or more preferably, one or preferably two Z groups represent:

[0439] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0440] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9);

[0441] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78);

[0442] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0443] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127);

[0444] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136);

[0445] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113);

[0446] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 114);

[0447] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 87);

[0448] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 142); or

[0449] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144).

[0450] Compounds of the invention that may be mentioned include those among which:

[0451] A and B both represent Z;

[0452] One or preferably two Z groups represent:

[0453] Ala-Lys-Pro (SEQ ID no. 2);

[0454] Ala-Lys-Pro-Ser(SEQ ID no.4);

[0455] Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5);

[0456] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6);

[0457] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7);

[0458] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8); or

[0459] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9).

[0460] In each of the above peptide sequences Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0461] Other compounds of the invention that may be mentioned include those among which:

[0462] A and B both represent A 1 -Q 1 -B 1 ;

[0463] A 1 and B 1 All represent Z;

[0464] One or preferably two Z groups represent:

[0465] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0466] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9);

[0467] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78);

[0468] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0469] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144);

[0470] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127);

[0471] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136); or

[0472] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113).

[0473] Other compounds of the invention that may be mentioned include those among which:

[0474] A and B both represent A 1 -Q 1 -B 1 ;

[0475] A 1 and B 1 All represent Z;

[0476] One or preferably two Z groups represent:

[0477] Ala-Lys-Pro (SEQ ID no. 2);

[0478] Ala-Lys-Pro-Ser(SEQ ID no.4);

[0479] Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5);

[0480] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6);

[0481] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7);

[0482] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8); or

[0483] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9).

[0484] In each of the above peptide sequences Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0485] Other compounds of the invention that may be mentioned include those among which:

[0486] A and B both represent A 1 -Q 1 -B 1 ;

[0487] A 1 and B 1 Both represent A 2 -Q 2 -B 2 ;

[0488] A 2 and B 2 All represent Z;

[0489] One or preferably two Z groups represent:

[0490] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0491] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9);

[0492] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78);

[0493] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0494] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144);

[0495] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127);

[0496] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136); or

[0497] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113).

[0498] Other compounds of the invention that may be mentioned include those among which:

[0499] A and B both represent A 1 -Q 1 -B 1 ;

[0500] A 1 and B 1 Both represent A 2 -Q 2 -B 2 ;

[0501] A 2 and B 2 Both represent ZQ 3 -Z;

[0502] One or preferably two Z groups represent:

[0503] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0504] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9);

[0505] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78);

[0506] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83);

[0507] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144);

[0508] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127);

[0509] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136); or

[0510] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113).

[0511] In each of the above peptide sequences Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0512] Other compounds of the invention that may be mentioned include those among which:

[0513] A and B both represent Z;

[0514] One or preferably two Z groups represent a structural fragment of formula IV,

[0515] [Lys - X 3 ] n -Lys-X 3 (IV) (SEQ ID No: 197)

[0516] where n and X 3 As defined above, and wherein for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0517] Other compounds of the invention that may be mentioned include those among which:

[0518] A and B both represent A 1 -Q 1 -B 1 ;

[0519] A 1 and B 1 All represent Z;

[0520] One or preferably two Z groups represent a structural fragment of formula IV,

[0521] [Lys - X 3 ] n -Lys-X 3 (IV) (SEQ ID No: 197)

[0522] where n and X 3As defined above, and wherein for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0523] Other compounds of the invention that may be mentioned include those among which:

[0524] A and B both represent A 1 -Q 1 -B 1 ;

[0525] A 1 and B 1 Both represent A 2 -Q 2 -B 2 ;

[0526] A 2 and B 2 All represent Z;

[0527] One or preferably two Z groups represent a structural fragment of formula IV,

[0528] [Lys - X 3 ] n -Lys-X 3 (IV) (SEQ ID No: 197)

[0529] where n and X 3 As defined above, and wherein for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0530] Other compounds of the invention that may be mentioned include those among which:

[0531] A and B both represent A 1 -Q 1 -B 1 ;

[0532] A 1 and B 1 Both represent A 2 -Q 2 -B 2 ;

[0533] A 2 and B 2 Both represent ZQ 3 -Z;

[0534] One or preferably two Z groups represent a structural fragment of formula IV,

[0535] [Lys - X 3 ] n -Lys-X 3 (IV) (SEQ ID No: 197)

[0536] where n and X 3 As defined above, and wherein for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to the NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0537] When one or more Z groups represent a structural fragment of formula IV as defined above, it is preferred that, in each case where it is employed:

[0538] X 3 represents a sequence of 3, 4 or more preferably 2 amino acids;

[0539] X 3 The amino acids are selected from Pro, Hyp, Lys, Tyr and DOPA.

[0540] It is further preferred that, in each case where it is employed:

[0541] X 3 The amino acid adjacent to Lys is selected from Pro and Hyp;

[0542] X 3 wherein the N-terminal amino acid is selected from Tyr and DOPA, and in particular Lys;

[0543] In the definition of X 3 At least one other amino acid in the sequence is Hyp.

[0544] Furthermore, in such cases, n may represent 1, so that Z is defined by:

[0545] Lys-X 3 -Lys-X 3 (SEQ ID No: 198)

[0546] Or more preferably, n represents 0, so that Z is defined by the following formula:

[0547] Lys-X 3 (SEQ ID No: 199)

[0548] where, in each case where it is adopted, X 3 As defined above.

[0549] When n is 0 and X 3 When representing a sequence of two amino acids, preferred tripeptide sequences that Z can represent include:

[0550] Lys-Pro-Lys (SEQ ID No: 200);

[0551] Lys-Pro-Tyr (SEQ ID No: 201);

[0552] Lys-Pro-DOPA (SEQ ID No: 202); more preferably

[0553] Lys-Hyp-Tyr (SEQ ID No: 203);

[0554] Lys-Hyp-DOPA (SEQ ID No: 204); or more preferably,

[0555] Lys-Hyp-Lys (SEQ ID No: 205).

[0556] When n is 0 and X 3 When representing a sequence of 3 amino acids, X 3 Where the C-terminal amino acid is Lys, preferred tetrapeptide sequences such that Z may represent include:

[0557] Lys-Pro-Pro-Lys (SEQ ID No: 206);

[0558] Lys-Pro-Hyp-Lys (SEQ ID No: 207);

[0559] Lys-Hyp-Pro-Lys (SEQ ID No: 208); or more preferably,

[0560] Lys-Hyp-Hyp-Lys (SEQ ID No: 209).

[0561] When n is 0 and X 3 When representing a sequence of 4 amino acids, X 3 The C-terminal amino acid sequence in contains Pro-Lys or more preferably Hyp-Lys, so that preferred pentapeptide sequences that Z may represent include:

[0562] Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 210);

[0563] Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 211);

[0564] Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 212);

[0565] Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 213);

[0566] Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 214);

[0567] Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 215); or more preferably

[0568] Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 216); or

[0569] Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 217).

[0570] When n is 1, in each case where it is used, X 3 Preferably represents a sequence of 2 amino acids, so that preferred hexapeptide sequences that Z can represent include:

[0571] Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID No: 218);

[0572] Lys-Hyp-Tyr-Lys-Pro-Lys (SEQ ID No: 219);

[0573] Lys-Hyp-Tyr-Lys-Pro-Tyr (SEQ ID No: 220);

[0574] Lys-Hyp-Tyr-Lys-Pro-DOPA (SEQ ID No: 221);

[0575] Lys-Hyp-DOPA-Lys-Hyp-Tyr (SEQ ID No: 222);

[0576] Lys-Hyp-DOPA-Lys-Pro-Lys (SEQ ID No: 223);

[0577] Lys-Hyp-DOPA-Lys-Pro-Tyr (SEQ ID No: 224);

[0578] Lys-Hyp-DOPA-Lys-Pro-DOPA (SEQ ID No: 225);

[0579] Lys-Pro-Lys-Lys-Hyp-Tyr (SEQ ID No:226);

[0580] Lys-Pro-Lys-Lys-Hyp-DOPA (SEQ ID No:227);

[0581] Lys-Pro-Lys-Lys-Pro-Tyr (SEQ ID No:228);

[0582] Lys-Pro-Lys-Lys-Pro-DOPA (SEQ ID No:229);

[0583] Lys-Pro-Tyr-Lys-Hyp-Tyr (SEQ ID No:230);

[0584] Lys-Pro-Tyr-Lys-Hyp-DOPA (SEQ ID No:231);

[0585] Lys-Pro-Tyr-Lys-Pro-Lys (SEQ ID No:232);

[0586] Lys-Pro-Tyr-Lys-Pro-DOPA (SEQ ID No:233);

[0587] Lys-Pro-DOPA-Lys-Hyp-Tyr (SEQ ID No:234);

[0588] Lys-Pro-DOPA-Lys-Hyp-DOPA (SEQ ID No:235);

[0589] Lys-Pro-DOPA-Lys-Pro-Lys (SEQ ID No:236);

[0590] Lys-Pro-DOPA-Lys-Pro-Tyr (SEQ ID No:237); or preferably,

[0591] Lys-Hyp-Tyr-Lys-Hyp-Tyr (SEQ ID No:238);

[0592] Lys-Hyp-DOPA-Lys-Hyp-DOPA (SEQ ID No:239);

[0593] Lys-Pro-Lys-Lys-Pro-Lys (SEQ ID No:240);

[0594] Lys-Pro-Tyr-Lys-Pro-Tyr (SEQ ID No: 241);

[0595] Lys-Pro-DOPA-Lys-Pro-DOPA (SEQ ID No: 242); or more preferably,

[0596] Lys-Hyp-Lys-Lys-Hyp-Tyr (SEQ ID No: 243);

[0597] Lys-Hyp-Lys-Lys-Hyp-DOPA (SEQ ID No: 244);

[0598] Lys-Hyp-Lys-Lys-Pro-Lys (SEQ ID No: 245);

[0599] Lys-Hyp-Lys-Lys-Pro-Tyr (SEQ ID No: 246);

[0600] Lys-Hyp-Lys-Lys-Pro-DOPA (SEQ ID No: 247); or even more preferably,

[0601] Lys-Hyp-Tyr-Lys-Hyp-Lys (SEQ ID No: 248);

[0602] Lys-Hyp-DOPA-Lys-Hyp-Lys (SEQ ID No: 249);

[0603] Lys-Pro-Lys-Lys-Hyp-Lys (SEQ ID No: 250);

[0604] Lys-Pro-Tyr-Lys-Hyp-Lys (SEQ ID No: 251);

[0605] Lys-Pro-DOPA-Lys-Hyp-Lys (SEQ ID No: 252); or

[0606] Lys-Hyp-Lys-Lys-Hyp-Lys (SEQ ID No: 253).

[0607] In each of the peptide sequences represented by SEQ ID Nos: 197 to 253 (inclusive), the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID or montelukast as defined herein, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.

[0608] Preferred compounds of the present invention include those wherein the one or more optional lipids defined by L are selected from palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid and leukotriene B4 (LTB4) or derivatives of any of these lipids.

[0609] Further preferred compounds of the present invention also include those compounds wherein the one or more optional lipids comprise a polyunsaturated fatty acid or a derivative thereof. In such embodiments, the derivative may be a specialized pro-resolving mediator (SPM).

[0610] Further preferred compounds of the present invention also include those compounds, wherein the one or more lipids comprise derivatives of fatty acids, such as glycerolipids, glycerophospholipids, sphingolipids or glycolipids.

[0611] Further preferred compounds of the present invention also include these compounds, wherein the one or more lipids include palmitic acid or a derivative thereof. In such embodiments, the derivative may be phosphatidylserine, or more preferably, the derivative is 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS). In such embodiments, the derivative may be phosphatidylethanolamine, or more preferably, the derivative is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0612] Further preferred compounds of the present invention also include those compounds, wherein the one or more lipids comprise stearic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-distearoyl-sn-glycero-3-phospho-l-serine.

[0613] Further preferred compounds of the present invention also include those wherein the one or more lipids comprise oleic acid or a derivative thereof. In such embodiments, the derivative may be 1,2-dioleoyl-sn-glycero-3-phospho-L-serine.

[0614] Further preferred compounds of the present invention also include those compounds, wherein the one or more lipids comprise palmitoylethanolamide (PEA).

[0615] Further preferred compounds of the present invention also include those compounds, wherein the one or more lipids are selected from vitamin E, vitamin A and cholesterol or derivatives of any of these lipids. In such embodiments, the derivative of cholesterol can be cholesterol-acetic acid.

[0616] Further preferred compounds of the present invention also include these compounds, wherein the lipid is a fatty acid as defined above, and the fatty acid can include 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.

[0617] Compounds of the invention that may be mentioned include those in which L represents at least one lipid as defined above.

[0618] The optional lipid defined by L may be covalently bonded to the amino acid sequence of the peptide in the compound of the invention via an amide bond formed between the corresponding carboxylic acid residue of L and one or more free NH2 residues present in one or more amino acids of the peptide (including at the N-terminus of the peptide sequence) and / or via an ester bond formed between the corresponding -OH residue of L and one or more free carboxylic acid residues that may be present in one or more amino acids of the peptide (including at the C-terminus of the peptide sequence).

[0619] Preferably, the total number of optional lipids defined by L in the compounds of the present invention does not exceed 8, more preferably does not exceed 4, such as 3, 2 or 1.

[0620] Preferred compounds of the invention include those wherein L represents 2 lipids as defined above or more preferably 1 lipid as defined above.

[0621] Preferred compounds of the invention include those wherein each L present represents the same lipid, such as palmitic acid or a derivative thereof.

[0622] With respect to any of the above-mentioned specific peptide sequences defined by Z, at least one lipid defined by L (and in particular palmitic acid or a derivative thereof) may be covalently bonded to the amino acid sequence of the peptide in the compound of the invention as described above (in particular SEQ ID Nos: 127, 136, 205, 209, 217 and 253). In this regard, further compounds of the invention that may be mentioned include those compounds, wherein Z is selected from the group consisting of:

[0623] Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 254);

[0624] Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 255);

[0625] Palm-Lys-Hyp-Lys (SEQ ID No: 256);

[0626] Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 257);

[0627] Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 258); or

[0628] Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID No: 259).

[0629] For the avoidance of doubt, the compounds of the present invention (compounds of formula I) as defined above are hereinafter collectively referred to as "compounds of the present invention".

[0630] 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), 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 Dap represents diaminopropionic acid. 3,4-Dihydrocinnamic acid (HCA) residues are essentially DOPA residues, 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).

[0631] The compounds of the present invention, whether in salt form or other forms, include regioisomers within the amino acids of the peptide (e.g., diHyp, Hyp, and Tyr moieties), as well as mixtures of such regioisomers. 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).

[0632] 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), certain amino acids in the sequence contain additional chiral carbon atoms. All such stereoisomers and mixtures thereof (including racemic mixtures) are included within the scope of the present invention. In this 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, it is preferred that the Hyp used in the compounds of the present invention is trans-4-hydroxy-L-proline. Similarly, the corresponding definition can be applied to diHyp, wherein the two hydroxyl groups can also be cis or trans relative to each other. In any case, the individual enantiomers of the compounds of Formula I that may form part of the compounds of the present invention are included within the scope of the present invention.

[0633] The compounds of this invention can be in the form of a salt. Mentionable salts include pharmaceutically acceptable and / or cosmetically acceptable salts, such as pharmaceutically and / or cosmetically acceptable acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by forming in the following manner: the compounds of this invention are reacted with one or more equivalents of appropriate acid or base, optionally in a solvent or in a salt-insoluble medium, followed by removing the solvent or the medium using standard techniques (for example, in a vacuum, by freeze drying or by filtering). Salt can also be prepared in the following manner: the counter ion of the compounds of this invention in salt form is exchanged with another counter ion, for example, using a suitable ion exchange resin.

[0634] Preferred salts include, for example, acetates, hydrochlorides, bisulfates, maleates, methanesulfonates, toluenesulfonates, alkaline earth metal salts (such as calcium and magnesium salts) or alkali metal salts (such as sodium and potassium salts).Most preferably, the compounds of the present invention may be in the form of acetates.

[0635] The compound of the present invention can be prepared by conventional techniques, for example, by standard amino acid coupling techniques, using standard coupling agents and solvents, for example, as described below. The compound of the present invention can be synthesized by available starting materials using appropriate reagents and reaction conditions. In this regard, technical personnel can especially refer to " Comprehensive Organic Synthesis ", BMTrost and I.Fleming, Pergamon Press, 1991. Other references that can be adopted include " Heterocyclic Chemistry ", JA Joule, K.Mills and GF Smith, 3rd edition, published by Chapman & Hall, " Comprehensive Heterocyclic Chemistry II ", A R Katritzky, C W Rees and EF V Scriven, Pergamon Press, 1996 and " Science of Synthesis ", Vol. 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0636] The compounds of the present invention can be isolated from their reaction mixtures and, if desired, 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 comprise isolating and optionally purifying the compounds of the present invention (as a final step).

[0637] 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.

[0638] Blocking group can be applied and removed according to technology well known to those skilled in the art and as described below.For example, standard deprotection techniques can be used to chemically convert protected compound / intermediate as herein described into unprotected compound.Involved chemical type will determine the needs and type of blocking group, and realize the order of synthesis.The use of blocking group is fully described in " Protective Groups in Organic Synthesis ", the 5th edition, TW Greene&P.GM Wutz, Wiley-Interscience (2014), its content is incorporated herein by reference.

[0639] The compounds of the invention can be used as human and animal medicine. They are therefore indicated as pharmaceuticals (and / or in veterinary science), although they can also be used as cosmetics and / or as part of medical devices.

[0640] The compounds of the present invention may also have pharmacological activity, but certain pharmaceutically acceptable (e.g., "protected") derivatives of the compounds of the present invention may exist or be prepared, which may not have such activity, but which may be administered and then metabolized or chemically converted to form the compounds of the present invention. Such compounds (which may have some pharmacological activity, provided that such activity is significantly lower than the activity of the active compound to which they are metabolized / converted) may therefore be described as "prodrugs" of the compounds of the present invention.

[0641] As used herein, reference to a prodrug is intended to include compounds that form a compound 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.

[0642] When the compounds of the present invention are pharmacologically active, they are particularly useful in the treatment of inflammatory diseases.

[0643] The term "treatment of inflammation" includes treatment of inflammation (regardless of cause) in any organ of the body, including soft tissues, joints, nerves, the vascular system, internal organs, especially mucosal surfaces, and particularly the skin, and also includes all such inflammatory disorders or conditions, and / or disorders or conditions characterized by inflammation (e.g., as a symptom).

[0644] Inflammatory disorders and / or conditions can be (and typically are) characterized by activation of immune defense mechanisms that produce effects that do more harm than good to the host. Such conditions are typically associated with varying degrees of tissue redness or redness, swelling, edema, hyperthermia, pain (including aches and pains), fluid exudation, itching (pruritus), cell death and tissue destruction, cell proliferation, and / or loss of function.

[0645] Inflammatory conditions that may be mentioned include arteritis, diabetes, metabolic syndrome, rosacea, asthma and allergies, ankylosing spondylitis, chronic obstructive pulmonary disease, gouty arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, osteoarthritis, pancreatitis, prostatitis, psoriatic arthritis, rheumatoid arthritis, tendinitis, bursitis, Sjögren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis and related cardiovascular disorders. A disease state characterized by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD). Another disease state characterized by inflammation that may be mentioned is inflammatory bowel disease, including Crohn's disease and especially 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 disease (e.g., gastritis, gastric ulcers, stress-induced gastritis, gastric cancer, and other diseases of the stomach lining), 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).

[0646] Inflammatory disorders that may be mentioned more particularly include inflammation of the skin or mucous membranes (including the oral, nasal, ocular, vaginal, cervical and / or anorectal mucosa, more particularly the 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 disorders, such as herpes, drug eruptions, polymorphous light eruption, sunburn, early manifestations of skin cancer (erythematous skin lesions), pathological alopecia (including after skin transplantation), chemical rashes, psoriasis, erythema multiforme, folliculitis, eczema and otitis externa. A disease state that may be mentioned is polymorphous light eruption.

[0647] More particularly, the compounds can be used to treat certain conditions characterized by and / or associated with inflammation. Such conditions can include wounds (including abrasions (scratches), incisions (including surgical incisions), tears, punctures, avulsions, bruises, and scarring) and burns (including inflammation caused by surgical procedures (such as skin grafts) following burns) and other conditions (such as hemorrhoids). Wounds can be acute or chronic and / or can be caused by one or more inflammatory disorders as defined herein.

[0648] Wounds of the skin or mucous membranes may result from internal or external physical damage to the membrane surface, or may be caused by (ie, be a symptom of) an underlying physiological disorder.

[0649] Physical (e.g., "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 rays (sunburn), cold (chilblains or frostbite). Wounds can be superficial (damage to the epidermis and / or dermis only) or full-thickness wounds (damage below the epidermis and / or dermis). In severe cases, subcutaneous and / or submucosal tissues such as muscles, bones, joints, and even internal organs may be damaged.

[0650] The compounds of the present invention can be used to alleviate pain (including soreness) associated with inflammation and / or wounds. In particular, the compounds of the present invention can be used to alleviate procedural pain and / or non-procedural pain. It will be understood by the skilled artisan that the term "procedural pain" (i.e., surgical pain) refers to acute pain associated with medical research and treatment for healthcare purposes. The term "non-procedural" refers to general pain associated with inflammation and / or injury (e.g., pain associated with oral ulcers, burns, and / or scars) and is not the result of a specific medical intervention.

[0651] The compounds of the present invention can be used not only to treat inflammation, pain (including soreness) and / or pruritus (itching) associated with the wound itself and the healing process, but also to prevent the leakage of body fluids from the wound, the risk of infection, and the physiological reactions caused by inflammation and / or the wound healing process (such as scarring and pigmentation).

[0652] Scarring is a result of inflammation and / or wound healing and is a general term for the formation of fibrous tissue as a result of such inflammation / healing.

[0653] 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 disorders associated with melanin pigmentation, such as chloasma, freckles, melanosis, malar rash and other pigmentation disorders, skin cancers associated with melanoma, and pigmentation disorders or skin diseases caused by exposure to sunlight (like acne).

[0654] Wounds can also occur as a result of (e.g., inflammatory) diseases or disorders. Such wounds can include blisters and / or ulcers of the skin and mucous membranes. These are common conditions that are usually long-lasting and difficult to treat. Skin tissue may often be damaged, removed, liquefied, infected, and / or necrotic. Ulcers may cause secondary consequences to health (especially if they are infected), are difficult to cure, and are expensive to treat. They may also cause significant psychological stress and financial losses to the patient, thereby affecting overall well-being and quality of life.

[0655] In alternative embodiments, inflammatory skin conditions or diseases in which the compounds of the invention are found to be particularly useful include psoriasis, acne, eczema and dermatitis, especially allergic dermatitis / atopic dermatitis, and in the treatment of mucosal inflammation such as is characterized by, for example, rhinitis (especially allergic rhinitis), hemorrhoids, chronic obstructive pulmonary disease and ulcerative colitis.

[0656] Psoriasis is a chronic inflammatory skin disease with a tendency to relapse (some patients remain incurable throughout their lifetime). The clinical manifestations of psoriasis mainly include erythema and scaling. It can occur throughout the body, but is more commonly observed on the scalp and limbs.

[0657] Acne is a follicular (pilosebaceous unit) chronic inflammatory skin disease that 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. It tends to occur in adolescence and is characterized by polymorphic skin lesions on the face. Therefore, the term acne includes both common acne and rosacea (i.e., rosacea).

[0658] Eczema is an intensely itchy skin inflammatory reaction caused by a variety of internal and external factors. It has three stages: acute, subacute, and chronic. The acute stage tends to produce exudates, while the chronic stage involves infiltration and hypertrophy. Skin lesions are often pruritic and prone to recurrence.

[0659] Dermatitis is a common skin disorder characterized by roughness, redness, itching, eczema, and dryness. If not treated quickly, the small patches, persistent 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 conditions, as well as all forms of steroid-dependent dermatitis (including photosensitivity seborrheic dermatitis, perioral dermatitis, rosacea-like dermatitis, steroid-rosacea, steroid-induced rosacea, iatrosacea, steroid dermatitis similar to rosacea, topical corticosteroid-induced rosacea-like dermatitis, and more particularly facial corticosteroid addiction dermatitis (FCAD) or facial dermatitis. Facial corticosteroid-dependent dermatitis (FCDD), such as flushing, erythema, telangiectasia, atrophy, papules, and / or pustules in 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).

[0660] 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, which is caused by allergens such as pollen, dust, mold, or certain animal flakes. It has been surprisingly discovered that patients with allergic rhinitis treated with the compounds of the invention experience relief of ocular itching even when the compounds are administered nasally (i.e., to the nasal mucosa).

[0661] Hemorrhoids are swellings caused by inflammation of the hemorrhoidal blood vessels in or around the rectum and anus. Symptoms include bleeding after passing stool (i.e., hurting), hemorrhoidal prolapse, mucus discharge, and itching, pain, redness, and swelling in the anal area. Hemorrhoids are thought to be the result of increased abdominal pressure, such as as a result of constipation or diarrhea.

[0662] Chronic obstructive pulmonary disease (COPD) is the name of a group of lung conditions that cause breathing difficulties. The lung conditions include emphysema (damage to the alveoli) and chronic bronchitis (long-term inflammation of the airways). COPD occurs when the lungs become inflamed, damaged, and narrowed. The damage to the lungs is usually irreversible and causes damage to the air flow 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 high levels of air pollution and occupational exposure to dust, chemicals, and fumes.

[0663] The compounds of the present invention may have a positive effect in alleviating erythema, redness and swelling, edema, blisters and bullous pemphigoid caused by various conditions including those mentioned generally and specifically herein, and may inhibit the exudation of subcutaneous fluid, and inhibit the itching and pain caused by such inflammatory conditions.

[0664] Other inflammatory conditions that may be mentioned include:

[0665] (a) Mucosal inflammation, such as oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis and enterocolitis (including bacillary dysentery, chronic amoebic dysentery, schistosomiasis, nonspecific ulcerative colitis and Crohn's disease), cervicitis and endocervicitis, endometritis, inflammation caused by inhalation injury, etc., and mucosal inflammation associated with cancers and infections (e.g., viral infections such as the common cold or flu) affecting mucosal surfaces (such as those in the mouth, nasopharynx, ear, throat, trachea, gastrointestinal tract, cervix, etc.).

[0666] (b) orthopedic inflammation associated with, for example, fractures, suppurative infections of bones and joints, inflammation caused by rheumatic bone diseases and suppurative osteomyelitis (acute, chronic, localized, sclerotic, post-traumatic), suppurative arthritis; bone tumors (osteoma, osteoid osteoma, chondroma), bone cysts, osteoclastomas, primary bone sarcomas (osteosarcoma, chondrosarcoma, fibrosarcoma of bone, Ewing's sarcoma, non-Hodgkin's lymphoma, myeloma, chordoma), metastatic bone tumors, bone tumor-like lesions (bone cysts, aneurysmal bone cysts, eosinophilic granulomas, fibrous dysplasia); and rheumatoid arthritis.

[0667] (c) Neuroinflammation, such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, intercostal neuritis, etc.

[0668] (d) Subcutaneous and submucosal soft tissue inflammations, such as myositis, ligamentitis, tendinitis, panniculitis, bursitis, lymphadenitis, bubonadentitis, tonsillitis, synovitis, fasciitis, and soft tissue inflammations caused by injury, contusion or tear of muscles, ligaments, fascia, tendons, synovium, fat, joint capsules and lymphatic tissue.

[0669] (e) Vascular inflammation, such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis, and vascular inflammation associated with vascular cancer caused by allergic leukocytoclastic vasculitis, polyarteritis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis.

[0670] (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 the treatment of pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, splenitis, nephritis, pancreatitis, cystitis, oophoritis, prostatitis and gastric ulcer.

[0671] (g) Inflammation of the eye and surrounding areas, such as conjunctivitis, keratitis (e.g., acute epithelial keratitis, nummular keratitis, interstitial keratitis, disciform keratitis, neurotrophic keratitis, lenticular keratitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, acanthamoebic keratitis, onchocercal keratitis, superficial punctate keratitis, ulcerative keratitis, exposure keratitis, photokeratitis, and acute red eye caused by contact lenses), optic neuritis, maculopathy, retinopathy, etc.

[0672] (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, oral ulcers, etc.

[0673] (i) Inflammation associated with rheumatic diseases, such as rheumatic vasculitis, rheumatoid arthritis, rheumatic bone disease, ankylosing spondylitis, bursitis, Crohn's disease, gout, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, osteoporosis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, scleroderma, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, tendinitis, etc.

[0674] The compounds of the present invention may also be used for differentiation and regeneration of bone marrow cells and for aplastic anemia (eg, by systemic and topical administration).

[0675] The compounds of the present invention may also be used to treat renal disease, including end-stage renal disease and its complications (including uremic pruritus).

[0676] The compounds of the present invention may also be used to treat certain specific diseases of the digestive system, such as gastroesophageal reflux disease (GERD), which can be characterized by a sour taste in the mouth, regurgitation, heartburn, dysphagia 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 stricture (i.e., persistent narrowing of the esophagus caused by reflux-induced inflammation), Barrett's esophagus (i.e., intestinal metaplasia (i.e., a change in the epithelial cells of the distal esophagus from squamous to columnar epithelium)), and / or esophageal adenocarcinoma (a form of cancer).

[0677] The compounds of the present invention may also be used to treat certain specific diseases of the respiratory system, such as cystic fibrosis, common interstitial pneumonia, hypersensitivity pneumonitis, asbestosis, emphysema, cor pulmonale, pulmonary embolism, etc. A specific disease state that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0678] IPF is a diffuse and fatal interstitial lung disease characterized by excessive deposition of alveolar epithelial cells, proliferation of pulmonary fibroblasts, and extracellular matrix, which ultimately lead to irreversible lung tissue damage. In the later stages of the disease, subjects with IPF experience respiratory failure and death. It has been found that the compounds of this invention can be used to treat IPF and / or alleviate the symptoms associated with the disease.

[0679] The compounds of the present 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, status asthmaticus, bronchiectasis, upper respiratory tract infections (including the common cold and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, rickettsia pneumonia (reckettsia), radiation pneumonia, pneumococcal (including staphylococcal, Streptococcus and Gram-negative bacilli) pneumonia, pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis, and nocardiosis), pulmonary fungal disease, cryptococcosis, lung abscess, hypersensitivity pneumonitis, extrinsic allergic alveolitis, pulmonary eosinophilia (including Leoffer's syndrome and hypereosinophilia), obstructive pulmonary emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis / acidosis, acute lung injury, interstitial lung disease, empyema, pulmonary fibrosis, and cor pulmonale.

[0680] Specific mucosal disorders and diseases for which the compounds of the present invention are useful include, for example, anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, fissures, pruritus anus, sinusitis, warts, and rectal prolapse; inflammatory bowel diseases, including Crohn's disease, particularly ulcerative colitis; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as periodontitis.

[0681] 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 is believed that the compounds of the present invention have antioxidant properties.

[0682] The compounds of the present invention may also have antipyretic properties that allow for the treatment of fever and / or alleviation of its symptoms; for example, by lowering the subject's body temperature, which results in a reduction in fever. Thus, the compounds of the present invention and formulations containing them may be considered antipyretics.

[0683] According to another aspect of the present invention, there is provided a method of treating inflammation, inflammatory disorders, and / or disorders / conditions characterized by inflammation (e.g., as a symptom), comprising administering to a patient in need of such treatment a compound of the present invention or a salt thereof.

[0684] For the avoidance of doubt, in the context of the present invention, the terms "treatment", "therapy" and "method of treatment" include therapeutic or palliative treatment of a patient in need thereof as well as prophylactic treatment and / or diagnosis of a patient susceptible to inflammation and / or inflammatory disorders.

[0685] The compounds of the present 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), the antiviral properties allow for the treatment of viral infections in nature, i.e., the treatment of viral infections or viral diseases by interfering with viral replication within the host. Such antiviral properties may also allow for the prevention of the onset of such infections or diseases, 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 they have become latent in a host.

[0686] According to another aspect of the present invention, there is provided a method of 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.

[0687] 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), 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; Raven 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), Rhabdoviridae (e.g., rabies virus), Hepaciviridae (e.g., hepatitis E virus), Reoviridae (e.g., rotavirus; orbivirus; coltivirus; Banna virus), and viruses not assigned to a family (such as hepatitis D virus).

[0688] Viruses that may be mentioned more particularly include herpes simplex virus type 1 and type 2, human papillomavirus, influenza virus and parainfluenza virus.

[0689] The compounds of the present invention may further have antibacterial and / or bacteriostatic properties, such as, as opposed to the treatment of any symptoms of any bacterial infection or disease (such as pain and / or inflammation), said properties may allow the bacterial infection to be treated in essence, i.e., by interfering with the growth or proliferation of bacteria in the host to treat the bacterial infection or bacterial disease. Thus, the compounds of the present invention may be considered bactericides and / or preferably bacteriostatics.

[0690] Such antibacterial properties may also allow for prevention of the onset of such infection or disease, protection of host cells from (e.g., further) bacterial infection, prevention or cessation of the spread of bacterial infection or disease (within a single host or from one host to a new host), or prevention of reactivation of bacteria after they have become latent in a host.

[0691] According to a further aspect of the present invention, there is provided a method of treating a bacterial infection, the method comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0692] As disclosed herein, the compounds of the present invention may further have anti-cancer properties, such as, as opposed to treating any symptoms of cancer (such as pain and / or inflammation), which may allow for the treatment of cancer in itself, i.e., treating cancer by interfering with it. Such anti-cancer properties may also include preventing the onset of the disease, for example, by treating inflammation and thereby preventing such an onset.

[0693] According to another aspect of the present invention, there is provided a method for treating cancer, which comprises administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0694] 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, rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophageal cancer, gastric cancer, intestinal cancer, cervical cancer, endometrial cancer, skin cancer, etc. Specific skin cancer that may be mentioned is basal cell carcinoma.

[0695] Fibrotic conditions of internal organs that may be mentioned include acute and / or severe internal fibrotic conditions, which are 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 conditions of internal organs that may be treated with the formulations of the present invention include fibrosis of the liver, kidneys, lungs, cardiovascular system (including the heart and vascular system), pancreas, spleen, central nervous system (neurofibrosis), myelofibrosis, eyes, vagina, cervix, etc.

[0696] Inflammatory disorders of an internal organ include any serious disorder (i.e., a disorder requiring intensive medical treatment) or any disorder that may progress to a serious disorder, and in which an inflammatory component is evident (because it can be characterized by detectable inflammation), and further in which the morbidity is overt (or anticipated) and / or life-threatening.

[0697] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of an internal organ (i.e., one or more conditions requiring immediate medical intervention or one or more conditions that may develop into a condition requiring 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 disorders, the formulations of the present invention can prevent or arrest the development of symptoms (acute or chronic) associated with such conditions, and can also arrest the progression of morbidity and / or mortality associated with such conditions.

[0698] 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 injury to one or more internal organs (including any of those mentioned above), for example acute lung injury, inhalation injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and multi-organ inflammation, injury and / or failure.

[0699] Such conditions may result from internal or external trauma (eg, injury or burns), or from infection, eg, by a virus, bacteria, or fungus.

[0700] For example, proctitis (which includes eosinophilic, gonococcal, and / or ulcerative proctitis) may be caused by inflammatory bowel disease, infection, radiation (eg, for cancer), medications (such as antibiotics), surgery, or allergic conditions (such as food intolerances).

[0701] For example, multiple organ inflammation, damage and / or failure may be caused by 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 be caused by exposure to heat, chemicals, etc.

[0702] Acute inflammatory and / or fibrotic conditions 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 particularly SARS may be caused by viruses, such as coronaviruses, including novel SARS coronavirus type 2 (SARS-CoV-2).

[0703] Thus, in addition, one or more of the aforementioned (e.g., acute) inflammatory conditions may (indeed, in some cases, will likely) lead to some form of internal tissue damage and / or dysfunction of related internal tissues. Thus, related tissues include (e.g., mucosal) tissues, such as respiratory epithelium. Such tissue damage may also result in one or more of the fibrotic conditions mentioned above. For example, it is known that in many cases, SARS disease caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19) can lead to fibrosis, which is caused by one or more of a variety of factors, including inflammation.

[0704] In this regard, the compounds of the present invention and their salts are particularly useful in treating 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) 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.

[0705] Therefore, it provides:

[0706] A method of treating at least one inflammatory and / or fibrotic disorder or condition of one or more internal organs in a patient, said 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;

[0707] a method of treating two or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs in a patient comprising direct systemic parenteral administration of a compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment; and

[0708] A method of reducing the incidence of morbidity and / or mortality associated or potentially associated with one or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs in a patient, said 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.

[0709] Additionally, the compounds of the present invention may be used to treat conditions characterized by immunosuppression, immunodeficiency disorders, for treating patients with compromised immune systems, and / or for restoring normal function of a patient's immune system.

[0710] Conditions characterized by immunosuppression (or immunodeficiency disorders) include primary immunodeficiency disorders (PIDDs), which are typically rare congenital disorders that are usually inherited. Thus, PIDDs include humoral immune deficiency disorders such as common variable immunodeficiency, selective immunoglobulin deficiency (e.g., IgA deficiency), transient hypogammaglobulinemia of the newborn, X-linked agammaglobulinemia; cellular immune deficiency disorders such as chronic mucocutaneous candidiasis, DiGeorge syndrome, X-linked lymphoproliferative syndrome; combined humoral and cellular immune deficiency disorders such as ataxia-telangiectasia, hyperimmunoglobulinemia E syndrome, severe combined immunodeficiency, Wiskott-Aldrich syndrome; phagocytic immune deficiencies such as Chédiak-Higashi 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 C5, C6, C7, C8, and / or C9 deficiency.

[0711] However, we prefer that the immunodeficiency disorder treated according to the present invention is a secondary immunodeficiency disorder (SIDD), which is more common than PIDD and tends to develop later in life. SIDD includes immunodeficiency disorders caused by secondary factors such as old age, malnutrition (e.g., undernutrition), chronic disorders, one or more chemical agents (e.g., drugs) and / or (e.g., ionizing) radiation.

[0712] For the 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.

[0713] Physical stress may be caused by trauma (injury, infection, surgery), strenuous physical exertion / overexertion (e.g., overtraining), environmental contaminants (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 challenges, and musculoskeletal disorders / imbalances.

[0714] Mental stress can include various forms of psychological and / or psychosocial stress, such as emotional stress (e.g., negative emotions such as resentment, fear, frustration, grief, anger, sadness / grief); cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, attachment, self-criticism, self-loathing, unrealistic perfectionism, anxiety, panic attacks, a general feeling of being out of control); perceptual stress (beliefs, roles, attitudes, values, meaning and / or purpose); death / loss of a loved one; relationship difficulties (with a partner, siblings, children, extended family, employer, coworkers); lack of social support (e.g., friends and / or isolation); financial stress (e.g., due to job loss, investments, savings, bankruptcy, home foreclosure, etc.).

[0715] Disorders that may cause immunodeficiency in patients include cancer; blood disorders such as aplastic anemia, leukemia, multiple myeloma; sickle cell disease; Down syndrome; infections such as viral infections (including chickenpox, cytomegalovirus, Epstein-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.

[0716] Drugs that may cause immunodeficiency in patients include antiepileptic drugs such as lamotrigine, phenytoin, and valproic acid; immunosuppressants such as azathioprine, cyclosporine, everolimus, leflunomide, mycophenolate mofetil, sirolimus, tacrolimus, and tofacitinib; biologics such as abatacept, adalimumab, anakinra, basiliximab, certolizumab pegol, daclizumab, etanercept, golimumab, infliximab, ixekizumab, muromonab (OKT3), natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and vedolizumab; and, in particular, corticosteroids, such as naturally occurring corticosteroids, including cortisol (hydrocortisone), aldosterone, and corticosterone. , cortisone, pregnenolone, progesterone; and naturally occurring precursors and intermediates in the biosynthesis of corticosteroids; and other derivatives of naturally occurring corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone and 18-hydroxyprogesterone; and synthetic corticosteroids, including those of the hydrocortisone type (Group A), such as cortisone acetate, hydrocortisone acepromate (hydrocortisone acetate), aceponate), hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, chloropredniol, difluprednate, fludrocortisone, fluocinolone, fluperone, fluprednisolone, loteprednol, prednicarbate and triamcinolone; acetonide compounds and related substances (Group B) such as amcinonide, budesonide, desonide, fluocinolone cetonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, flurandrenolide, flunisolide and fluocinolone acetonide;(β) Those of the methasone type (Group C), such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halometasone, mometasone and mometasone furoate, alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, difluocortolone, fluclorololone, flumethasone, fluocortidine, fluprednidone and fluprednidone acetate, fluticasone, fluticasone furoate and fluticasone propionate, methylprednisone, paramethasone, prednidone, rimexolone and ulbetasol; those of the progesterone type, such as flugestrol, fluorometholone, medrysone and acetoxypregnenolone acetate); and progesterone derivatives (progestogens), such as chlormadinone acetate, cyproterone acetate, medrogestone acetate, medroxyprogesterone acetate, megestrol acetate and segesterone acetate; and other corticosteroids, such as cortivazol 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. ;

[0717] However, drugs that may cause immunodeficiency in patients may be specifically mentioned including cancer chemotherapy treatments such as alemtuzumab, busulfan, cyclophosphamide, and melphalan.

[0718] Specific SIDDs that may be mentioned include those caused by radiation therapy used to treat disorders such as cancer (ie, radiation-induced immunosuppression).

[0719] Ionizing radiation not only suppresses the immune system in the manner described above, but can also alter the function of the immune system in irradiated organs in other ways. For example, elevated levels of inflammatory mediators (such as NF-κB and SMAD2 / 3) and cytokines (such as IL-1, IL-2, IL-6, IL-8, IL-33, tumor necrosis factor (TNF-α), transforming growth factor β (TGF-β), and interferon γ (IFN-γ)) are associated with the release of prostaglandins and free radicals (including reactive oxygen species (ROS) and nitric oxide (NO)). Exposure to high doses of radiation that may occur during accidental exposure (e.g., due to a nuclear or radiological disaster) can result in inflammatory responses and / or trauma that may persist for years thereafter and / or damage the function of the irradiated organs.

[0720] 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 wounds associated with such conditions are difficult (if not impossible) to treat appropriately due to radiation-induced immunosuppression and the absence of a normal endogenous inflammatory response.

[0721] By providing the above-mentioned immunorestorative effects, this allows the body's immune system and local inflammatory response 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 wound healing, but in a manner that does not further damage the patient's immune system (i.e., the manner in which corticosteroids would act when used to treat inflammation).

[0722] According to a further aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for 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.

[0723] Diseases that are themselves radiation-induced 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 (commonly referred to as "radiation poisoning") or following intentional and / or targeted exposure to radiation (e.g., due to (e.g., ionizing) radiation therapy to treat diseases such as cancer).

[0724] Radiation therapy is a type of cancer treatment that uses an external high-energy beam to kill cancer cells. Radiation therapy most commonly uses X-rays, but protons or other types of energy can also be used. Radiation therapy can be used as a primary cancer treatment, for neoadjuvant therapy (shrinking cancerous tumors before surgery), adjuvant therapy (preventing cancer cell proliferation after surgery), to alleviate symptoms caused by advanced cancer, or a combination of two or more of the above. Radiation therapy can also be used in combination with other treatments (such as chemotherapy).

[0725] Disorders characterized by inflammation and / or trauma of the mucous membranes and / or skin, which may result from exposure to radiation, are usually associated with the part of the body that was targeted / irradiated. For example:

[0726] Radiation-induced dermatitis and mucositis may occur in the skin or mucous membranes, respectively, which may be close to the irradiated body part. For example, radiation-induced oral mucositis may occur after irradiation of the head or neck;

[0727] Radiation-induced encephalitis may also occur after irradiation of the head or neck; and

[0728] Radiation pneumonitis and / or radiation esophagitis are usually caused by radiation therapy for lung cancer, breast cancer, lymphoma, thymic tumors, or esophageal cancer.

[0729] Radiation therapy to the abdomen, pelvis, or rectum (e.g., to treat cervical, prostate, bladder, or rectal cancer) may cause one or more of radiation enteropathy (or radiation enteritis, including radiation colitis), radiation hepatitis, radiation myelitis, radiation vaginitis, and particularly radiation proctitis.

[0730] 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 the related radiation colitis) or chronic (e.g., radiation-related vasodilation (RAVE) and chronic radiation proctopathy).

[0731] Initial symptoms of acute radiation proctitis include pelvic pain, diarrhea, and tenesmus, but radiation damage to the rectum often causes incontinence and rectal bleeding, and in severe cases, leads to trauma, strictures, and / or fistulas.

[0732] Thus, in the treatment of disorders caused by irradiation (more particularly irradiation of the lower abdominal area) for example cancer therapy (including disorders such as radiation proctitis, radiation colitis and radiation-induced dermatitis as defined above), the compounds of the invention and their salts can be used:

[0733] Providing an immune restorative effect while treating trauma associated with such a disorder and / or promoting recovery and / or healing of said trauma; and / or

[0734] ● Provides a more direct anti-inflammatory effect without further damaging the patient's immune system, and can be used to promote further wound healing.

[0735] According to two further aspects of the present invention, there are provided:

[0736] A method of treating a radiation-induced condition characterized by (i) immunosuppression and (ii) inflammation and / or trauma; and

[0737] A method of treating inflammation and / or trauma associated with radiation-induced immunodeficiency disorders in a patient while restoring normal function of the immune system,

[0738] The method comprises administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0739] The methods of treatment and uses described above are particularly useful when the disorder induced by radiation, for example for cancer therapy, is caused by irradiation of the lower abdominal region as described above.

[0740] Further provided is a method of reducing the incidence of morbidity and / or mortality in a patient associated with or potentially associated with a radiation (e.g., ionizing radiation)-induced disorder characterized by inflammation and / or trauma, comprising administering to a patient in need of such treatment a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0741] Conditions for which the compounds of the present invention may be particularly useful include skin inflammation, physiological responses resulting from skin inflammation and / or wound healing processes, such as scarring and hyperpigmentation; scalp and hair follicle inflammation and fibrosis, including seborrheic dermatitis, cicatricial alopecia, and related conditions; gastritis, gastric ulcers, and stress-induced gastritis; GERD; IBD, including Crohn's disease, ulcerative colitis and / or proctitis, radiation proctitis; arthritis; maculopathy; myeloid cell differentiation and aplastic anemia; stress; and IPF, ALI / ARDS, uremic pruritus, COPD, asthma, bronchitis (including chronic bronchitis), vasculitis, pancreatitis, multi-organ injury, and / or viral infection.

[0742] Additionally, the compounds of the present invention may be used in non-therapeutic cosmetic treatments, such as anti-aging.

[0743] Therefore, another aspect of the invention is the non-therapeutic use of the compounds of the invention in anti-aging, for example by promoting skin integrity in such a way that the skin has a younger skin appearance.

[0744] Another aspect of the present invention is a cosmetic composition comprising a compound of the present invention. Such a composition may provide anti-aging properties.

[0745] "Patient" includes reptilian patients, avian patients and preferably mammalian (particularly human) patients.

[0746] According to the present invention, the compounds of the 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, cutaneously, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, intravaginally, intradermally, transdermally, nasally, pulmonary (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 one or more of said compounds in one or more pharmaceutically acceptable dosage forms.

[0747] Administration by inhalation (eg, nasal) is particularly useful when the condition to be treated is rhinitis or inflammation caused by a viral infection of the airways (eg, upper respiratory tract infections such as the common cold and flu).

[0748] Pulmonary administration is particularly useful when the condition to be treated is COPD or IPF.Topical administration forms may be enhanced by generating a spray comprising the active ingredient, for example by using a powder aerosol or with water mist using appropriate atomisation techniques or equipment such as a nebuliser.

[0749] Anorectal administration is particularly useful when the condition to be treated is hemorrhoids or ulcerative colitis, using appropriate delivery means, such as foam solutions to be injected or suppositories.

[0750] 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 by initially orally or parenterally administered drug delivery methods that target the colon.

[0751] 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 disorders or conditions of one or more internal organs of a patient.

[0752] Internal organs that may be mentioned include the stomach, intestines, pancreas, liver, spleen, bladder, vascular system, ovaries, prostate, preferably the heart and kidneys, and more preferably the lungs.

[0753] Standard delayed-release or extended-release technologies known to those skilled in the art may be used for modes of administration other than oral, such as subcutaneous or intramuscular depot formation technologies or via alternative modes of parenteral administration.

[0754] Thus, pharmaceutically acceptable formulations for the above-mentioned routes of administration may comprise a compound of the 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 be free of 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.

[0755] Thus, the formulation for injection can be in the form of an aqueous formulation, such as a suspension and / or, more preferably, a 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 that can be reconstituted with a vehicle (e.g., an aqueous vehicle) prior to use (e.g., injection)).

[0756] 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., cyclodextrins), wetting agents, suspending agents, emulsifiers, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, swelling agents and / or protective agents.

[0757] Formulations for injection are preferably buffered to a physiologically acceptable pH value (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) by standard techniques using buffers and / or pH adjusting agents as described herein, and / or may further comprise a tonicity adjusting agent (such as sodium chloride).

[0758] While the above-described preferred modes of delivery of the compounds of the invention include topical application to the site of inflammation (e.g., mucosa (including oral and / or nasal mucosa, lungs, anorectal area and / or colon), or more preferably skin) in an appropriate (e.g., pharmaceutically acceptable and topically acceptable) vehicle and / or commercially available formulation suitable for application to the skin and / or appropriate mucosal surfaces, oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal or pulmonary delivery may also be included.

[0759] Administration by injection is particularly useful for administering the compounds of the invention as a solution or suspension, for example, into the dermis (eg, intradermal injection), into a joint cavity, or into the eye.

[0760] Administration by intradermal injection (e.g., intradermal) is particularly useful for administering a compound 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 a compound of the invention in treating, for example, wrinkles.

[0761] 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 sinuses). This is particularly useful for shaping support and / or lubrication.

[0762] The compounds of the present 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 regard to 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 be free of 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 present invention.

[0763] 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 skilled person can non-inventively achieve the preparation of suitable formulations comprising the compounds of the invention using conventional techniques.

[0764] The compounds of the invention can 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.

[0765] The compounds of the invention may further and / or in the alternative be combined with suitable excipients to prepare:

[0766] Gel formulations (for which suitable gel matrix materials include cellulose derivatives, carbomers and alginates, tragacanth, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulosic polysaccharides, sugars such as glucose, glycerol, propylene glycol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and in particular hyaluronic acid);

[0767] Lotions (for which suitable base materials include cellulose derivatives, glycerol, non-cellulose polysaccharides, polyethylene glycols of varying molecular weights, and propylene glycol);

[0768] Paste or ointment (for the paste or ointment, suitable paste base materials include glycerol, vaseline, paraffin, polyethylene glycol of different molecular weights, etc.);

[0769] Creams or foams (for which suitable excipients (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycols of varying molecular weights, sodium lauryl sulfate, sodium fatty alcohol polyoxyethylene ether sulfonate, corn gluten powder, and acrylamide);

[0770] powder aerosols (for which suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol and polysorbates, such as dry powder inhalers); and / or

[0771] liquids for oral use or for inhalation, e.g., aqueous (aerosol) sprays (for which suitable excipients include viscosity modifiers such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohols, water, preservatives, sweeteners, flavorings, etc.);

[0772] 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 agents, emulsifiers, thickeners, 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.

[0773] Such formulations may also include moisturizers such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic / 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 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 (such as glyceryl monostearate), polyethoxylated alcohols, polyvinyl alcohol, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, polyoxylglycerides, Lauryldimethylamine 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 acryloyldimethyltaurate / 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.

[0774] The compounds of this invention and (for example, medicine) preparation (for example, aqueous solution as described above, gel, emulsifiable paste, ointment, lotion, foam, paste and / or dry powder) comprising them can be further combined with suitable host material to prepare dressing or therapeutic patch for application on biological surface (such as skin or mucosal surface).Therefore, this type of preparation can be for impregnating host material, such as gauze, nonwoven fabric or silk paper.Alternately, therapeutic patch can be for example band-aid, facial mask, eye mask, hand film, foot film etc.

[0775] Petrolatum may be employed for applying such dressings to wounds, but we have also found that a PEG (eg, PEG 400) based ointment can be combined with a matrix material to prepare a dressing without the use of petrolatum.

[0776] The compounds of the invention may also be used in combination with a solid support such as a nasal dressing (eg, to stop nose bleeding), a dermal scaffold (eg, for wound healing), or an artificial bone (eg, in the case of bone transplantation / implantation).

[0777] The compounds of the present invention can be administered by inhalation of a suspension, dry powder or solution. Suitable inhalation devices include pressurized metered dose inhalers (pMDIs) (which can be manually actuated or breath-actuated and can be used with or without a standard spacer device), dry powder inhalers (DPIs) (which can be single-dose, multi-dose and power-assisted), and soft mist inhalers (SMIs) or nebulizers (which deliver aerosol medication in the form of a fine mist at a slower rate than a spray delivered using, for example, a pMDI).

[0778] In a pMDI, the compounds of the invention can be administered as a pressurized suspension of micronized particles distributed in a propellant (e.g., HFA with excipients such as mannitol, lactose, sorbitol, etc.) or as an ethanol solution so that each actuation delivers one or more metered doses of between about 20 μL and about 100 μL. Actuation can be achieved manually (e.g., by pressing) or by inhalation (breath actuation), involving a flow trigger system driven by a spring.

[0779] In DPIs, the compounds of the invention can be administered in the form of micronized drug particles (between about 1 μm and about 5 μm in size) within a capsule, either alone or blended with larger particle size inactive excipients (e.g., mannitol), which can be preloaded or manually loaded into the device. Inhalation from the DPI can disaggregate the drug particles and disperse them within the airways.

[0780] In an SMI, the compound 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 the micropump so that the dose is released when a button is pressed, thereby releasing a jet of drug solution.

[0781] Various nebulizers can also be used to administer the compounds of the present invention in the form of a fine mist of an aerosolized solution. Nebulizers can include breath-enhanced jet nebulizers (wherein, with the assistance of a compressor, a stream of air is moved through the nebulizer, thereby aerosolizing the drug solution); breath-actuated jet nebulizers (wherein, after the patient inhales, with the assistance of a compressor, a stream of air is moved through a tube, thereby aerosolizing the drug solution); ultrasonic nebulizers (wherein, piezoelectric crystal vibrations cause aerosolization by heating, thereby causing atomization); vibrating mesh nebulizers (wherein, a piezoelectric crystal vibrates a mesh plate to cause aerosolization to obtain very fine droplets, without a significant change in the temperature of the solution during atomization).

[0782] According to a further aspect of the present 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.

[0783] The compounds of the present invention may also be combined in therapy with one or more growth factors selected from the group consisting of 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).

[0784] According to another aspect of the present invention, there is provided a (e.g., pharmaceutical) composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients, such as an adjuvant, diluent, or carrier. Preferred formulations are suitable for topical application to, for example, mucous membranes (including oral and / or nasal mucosa, lungs, anorectal region, and / or colon) or more preferably skin, and therefore comprise an externally acceptable adjuvant, diluent, or carrier.

[0785] Thus, further provided are pharmaceutical compositions comprising a compound of the invention that are suitable, adapted and / or packaged and presented for topical administration (e.g., to mucous membranes, including the oral and / or nasal mucosa, the lungs, the anorectal area and / or the colon, or preferably to the skin), and the use of such formulations in the treatment of disorders comprising inflammation, inflammatory disorders and / or conditions characterized by inflammation (e.g., as a symptom) by direct topical administration of the formulations (e.g., to mucous membranes, including the oral and / or nasal mucosa, the lungs, the anorectal area and / or the colon, or preferably to the skin).

[0786] With respect to this aspect of the invention, for the avoidance of doubt, topical formulations comprising the compounds of this invention may be used for any and all conditions described herein, including (as mentioned, defined or described above) in the treatment of any and all inflammatory disorders and / or in the treatment of any and all conditions characterized by inflammation. Similarly, topical formulations comprising the compounds of this 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.

[0787] Topical (e.g., liquid-based or (e.g., aqueous) solution-based) formulations comprising a compound of the invention may be particularly useful for wound healing and may reduce pain (including soreness) and, in particular, pruritus / itching, associated with the wound itself and the wound healing process. Such topical formulations comprising a compound of the invention may be particularly useful for preventing and / or inhibiting the leakage of body fluids from wounds, particularly during the acute inflammatory phase, for example, during the first 48 hours after incurring a burn or wound. This prevents the risk of infection and other physiological reactions. Such topical formulations comprising a compound of the invention may also be particularly useful for preventing and / or inhibiting scarring and melaninization (see above), whether wound-related or otherwise.

[0788] 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 also depends on the severity of the condition.

[0789] Depending on the disorder and patient to be treated, as well as the route of administration, the compounds of the invention may be administered to a patient in need thereof at varying therapeutically effective doses.

[0790] 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.

[0791] In any case, a medical practitioner or other technical staff 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 the general case; there may, of course, be individual circumstances in which a higher or lower dosage range should be used, and such circumstances are within the scope of the present invention.

[0792] The dose may be administered between once and four times (eg, three times) per day.

[0793] Suitable concentrations of the compounds of the invention in aqueous solution products 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.

[0794] In all cases, suitable topical dosages of the compounds of the present invention are in the range of about 0.05 μg to about 50 μg / cm2 calculated as the free (non-salt) compound. 2 Treatment area, such as about 0.1 μg (e.g., about 0.5 μg) to about 20 μg / cm 2 Treatment area, including about 1 μg to about 10 μg / cm 2 Treatment area, such as about 5 μg / cm 2 within the scope of the treatment area.

[0795] Suitable doses of the compounds of the invention for nasal administration (e.g., by inhalation) are in the range of about 0.01 μg to about 2000 mg, for example, between about 0.1 μg to about 500 mg, or between 1 μg to about 100 mg. Specific doses that may be mentioned for nasal administration include doses 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 mucous membranes, such as rhinitis (e.g., allergic rhinitis), and / or conditions associated with sinus surgery.

[0796] 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 about 0.6 mg (i.e., 60 μg) to 6 mg (e.g., for the treatment of COPD or IPF).

[0797] We prefer that formulations comprising 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).

[0798] 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 (as described above) in the mammal within a reasonable timeframe. Those skilled in the art will recognize that the selection of the exact dose and composition, as well as 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 response of the patient to be treated, and the stage / severity of the disease, as well as genetic differences between patients.

[0799] The compounds of the present invention may be used in human and animal medicine. In this regard, and as mentioned above, the compounds of the present invention which themselves possess an appropriate degree of relevant pharmacological (or biological) activity may be used as human and / or animal medicine.

[0800] Certain compounds of the present invention, in particular compounds of formula I, may, in addition to and / or instead of possessing the above-mentioned biological activities, possess adhesive properties.

[0801] These adhesive properties result from the fact that the associated W and / or U groups are able to crosslink with each other to form a three-dimensional network.

[0802] Such compounds of the present invention can adhere to a variety of substrates, including inorganic substrates (such as glass, metal, etc.) as well as organic substrates (such as biological tissue).

[0803] 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 prevention of corrosion of ships, electronic equipment, pipelines, etc.), biochemical reagents, medical products, sterilization products, culture vessels for cell culture, etc.

[0804] Such 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. Such compounds of the present invention can also be used in surgical operations, for example, for the closure of surgical incisions, adhesion of fractured bones, adhesion of mucous membranes, and coatings of human implants such as artificial bones, cartilage scaffolds, periosteum, artificial joints, dental implants, blocking stents, spinal fusion devices, spinal spacers and organ patches.

[0805] According to another aspect of the present invention, there is provided a compound of formula I as an adhesive or film-forming material.

[0806] As discussed above, naturally occurring MAP is known for its adhesive properties, but it should be remembered that such adhesive properties may be due to the fact that it is a high molecular weight linear peptide that can exist in multiple conformations, enabling inter- and intramolecular reactions / crosslinking of the DOPA residues in the molecule and thus 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 surprisingly, the applicant observed similar properties (whether adhesive or biological) to those of naturally occurring MAP.

[0807] Such cross-linking can be performed 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).

[0808] Regardless of the level of pharmacological activity that the compounds of the invention may possess, they can in any case (and / or can further) be combined with an active pharmaceutical ingredient in a combination therapy (as described below), or function by being a pharmaceutically acceptable excipient (e.g., adjuvant, diluent or carrier) or a part thereof, as part of a medical device and / or as part of a drug-medical device combination.

[0809] Certain compounds of the present invention can therefore be described as novel multifunctional excipients that can be used in a variety of applications in the pharmaceutical field. In this regard, such compounds of the present invention include those that can be used as adhesives and / or as film formers (as described above), and furthermore, such compounds of the present invention and / or different compounds of the present invention can alternatively and / or additionally be used as delayed-release polymers, as binders, as suspending agents, as gelling agents, as coating agents, as diluents or as carriers for active ingredients (drugs) of various solubility.

[0810] Compounds of the invention that are particularly useful as pharmaceutical excipients may be amenable to large-scale production and may not present significant toxicity risks and therefore may be described and listed as "Generally Recognized as Safe" (GRAS) by the U.S. Food and Drug Administration (FDA).

[0811] The compounds according to the invention can also be used as excipients in veterinary science and in cosmetics.

[0812] According to a further aspect of the present invention, there is provided a pharmaceutical formulation comprising an active pharmaceutical ingredient in admixture with a pharmaceutically acceptable excipient system (such as a pharmaceutically acceptable adjuvant, diluent or carrier system) comprising one or more compounds of the present invention.

[0813] Furthermore, the compounds of the present invention may be combined with active pharmaceutical ingredients and, thus, may be used as part of a drug-medical device combination comprising one or more active pharmaceutical ingredients and one or more compounds of the present invention, wherein the one or more compounds of the present invention constitute the medical device component of the combination.

[0814] When used as a medical device or as a portion of 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 medicine, optionally in combination with an active pharmaceutical ingredient, in a manner that affects the structure and / or one or more functions of the human or animal body, and will achieve its primary intended purpose without exerting a chemical effect in or on said human or animal body (optionally in a manner that is independent of the metabolism of the compounds of the present invention in order to achieve any of its primary intended purpose).

[0815] In this regard, the compounds of the present invention may be combined with a variety of known pharmaceutically active ingredients, and such combinations may be made whether or not the compounds of the present invention are employed:

[0816] as the sole pharmaceutically active ingredient itself in a combination therapy;

[0817] As a medical device or as a part thereof;

[0818] as a drug-medical device combination or as the medical device portion of a drug-medical device combination; or

[0819] ●As a pharmaceutically acceptable excipient.

[0820] Such patients may also be (and / or may already be) receiving a therapy based on the administration of one or more such other known pharmaceutically active ingredients, by which we mean receiving prescribed doses of one or more of the active ingredients mentioned herein before, in addition to and / or after treatment with the compounds of the invention.

[0821] Pharmaceutically active agents that can be co-administered with the compounds of the present invention include any agent or drug that is capable of producing a physiological effect in a living subject, including particularly mammals and especially human subjects (patients), whether in a therapeutic or preventative capacity for a particular disease state or condition.

[0822] In addition, the compounds of the present invention (such as those that can be cross-linked as described above) can be used as pharmaceutical 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 present invention act as an excipient, such as a carrier. When used in this manner, it can be found that the compounds of the present invention can affect the physical, chemical and / or biological properties of such active ingredients in an active manner, including their physical and / or chemical stability and / or their metabolism after administration.

[0823] Pharmaceutically active agents that can be used with the compounds of the present invention can, for example, be selected from anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial and / or antiprotozoal agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing drugs (e.g., growth factors).

[0824] The bioactive agent can, for example, be selected from anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial and / or antiprotozoal agents, antiviral agents (eg, protease inhibitors), anesthetics, and wound healing drugs (eg, growth factors).

[0825] Non-limiting examples of anti-inflammatory drugs that can be used also include those used in the treatment of rheumatic diseases and / or arthritis (such as diclofenac, betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodolac, meclofenamic acid, salsalate, methylprednisolone, 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, fluorometholone, loteprednol, hydrocortisone, fluorometholone, bromfenac, prednisolone acetate, indomethacin, and ibuprofen); allergic reactions and their symptoms (such as pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, lodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, emetofemidine fumarate); and / or benzodiazepines (such as dapoxetine, bupropion, olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudoephedrine, fexofenadine, terfenadine, loratadine, and Alexis); respiratory diseases, including asthma and / or COPD (such as budesonide, ciclesonide, nedocerolamide, dexamethasone, ambroxol, and pranlukast); skin diseases (such as mometasone, triamcinolone, desonide, sulfacetamide, taloxlimab, allantoin, and triamcinolone); mastocytosis (such as cromolyn); gout (such as diclofenac and febuxostat); conjunctivitis (such as hydroxybenzoate, pranoprofen, and zinc sulfate); eye diseases (such as dextran 70, trosin / triiodothyronine, and eye extracts), known or commercially available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.

[0826] 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).

[0827] Non-limiting examples of antibacterial drugs that can be used also include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, metronidazole, gentamicin, cetylpyridinium chloride, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, clindamycin, metronidazole, azithromycin, mafenide, sulfamethoxazole, paracetamol, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, cephalexin, moxifloxacin, known or commercially available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.

[0828] Non-limiting examples of antiviral drugs that can be used include tobramycin ribavirin, acyclovir, morphine, foscarnet, ganciclovir, idoxuridine, trifluridine, brivudine, vidarabine, entecavir, telbivudine, foscarnet, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir, darunavir, telaprevir, boceprevir, and sirolimus. ), simeprevir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir dipivoxil, fomivirson, podafilox, imiquimod, sinecatechin, interferon-α2b (recombinant, human), known or commercially available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.

[0829] Non-limiting examples of anesthetics that can be used also include articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, and known or commercially available pharmaceutically acceptable salts of any of the foregoing, as well as combinations of any of the foregoing compounds and / or salts.

[0830] Non-limiting examples of wound recovery 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, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, retinoids, calf blood deproteinized extract, carraghenate, aminoiodine, and known or commercially available pharmaceutically acceptable salts of any of the foregoing drugs, as well as combinations of any of the foregoing compounds and / or salts.

[0831] Such pharmaceutically active ingredients include those that can be applied topically, for example, to the skin or mucosal surfaces, together with the compounds of the invention. In this regard, preferred active ingredients from the above list include cyclosporine, chondroitin, loteprednol, fluorometholone, bromfenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, emetine fumarate, olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, alexis, dexamethasone, ambroxol), sulfacetamide, Tacrolimus, allantoin, triamcinolone acetonide, cromoglycine, nedocromil, diclofenac, hydroxybenzone, pranoprofen, zinc sulfate, dextran 70, thyroxine / liothyronine, ophthalmic peptide, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, gentamicin, cetylpyridinium chloride, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, Sulfadiazine, chloramphenicol, tobramycin, ribavirin, acyclovir, morphine, foscarnet, ganciclovir, interferon-α2b (recombinant, human), articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, yeast), rhEFG(I), acidic fibroblast growth factor (recombinant, human), granulocyte macrophage stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, retinoids, calf blood deproteinized extract, carrageenate, aminoiodine, and known or commercially available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.

[0832] Other pharmaceutically active ingredients that may be co-administered with the compounds of the present invention include those that may be administered to treat one or more of the gastrointestinal disorders mentioned above.

[0833] Non-limiting examples of gastrointestinal medications include oxalazine (olsalazine), sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, live Bacillus species (such as Clostridium butyricum, Bacillus licheniformis, Bacillus cereus), probiotics (such as Bifidobacterium), tegafur, nifuratel, amoxicillin, ampicillin, nystatin, allicin, cefadroxil, dyclonine, carmofur, fluorouracil, mosapride, carbosulfan sodium, thrombin, pantoprazole, cimetidine, cisapride, ethylenediamine diethylamide, and dapoxetine. diacetamine), nimustine, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azasetron, lentinan, bismuth salts (e.g., aluminates, potassium citrate) in combination with, for example, magnesium salts, magnesium trisilicate, bicarbonate, vitamin U, aluminum hydroxide, belladonna extract, famotidine and calcium carbonate, magnesium hydroxide, hydrotalcite, proton pump inhibitors (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, or esomeprazole), glycine, trypsin, allantoin, aluminum hydroxide, L-glutamine sodium guarenate, rebampette, rotundine, quxipite, lafutidine, thymus protein, hericium erinaceus erinaceus), erisogladin maleate, nizatidine, L-glutamine and sodium azulenesulfonate (sodium guanate), ranitidine, bismuth citrate, lactobacillus, bisacordine, dimethicone, live Clostridium butyricum, loperamide hydrochloride, dibazole, secnidazole, acephate zinc, montmorillonite, tegafur / gimeracil / oteracil, famotidine, oteracil, doxifluridine, capecitabine, and any known or commercially available pharmaceutically acceptable salts of the foregoing drugs.

[0834] Pharmaceutically active ingredients that may be mentioned for use in combination with the compounds of the present invention include active ingredients useful for the treatment of inflammation and / or inflammatory disorders (other anti-inflammatory agents).

[0835] 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 their 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 zafirlukast), 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., cysteinyl leukotrienes and leukotriene B4).

[0836] Other preferred agents that can be combined with the compounds of the invention include LTB4 (used in the treatment of 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).

[0837] The compounds of the present invention may also be combined with other therapeutic agents that are known to produce inflammation as a side effect when administered.

[0838] The conjugates of the present invention can 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)).

[0839] Other known pharmaceutically active ingredients can also be administered in combination with the compounds of the present invention in various ways.

[0840] For example, the compounds of the invention can be "combined" with (or with other) pharmaceutically active ingredients (or "therapeutic agents") for administration together in the same (e.g., pharmaceutical) formulation, or for separate (simultaneous or sequential) administration in different (e.g., pharmaceutical) formulations.

[0841] Such combination products therefore provide for the combined administration of a compound of the invention and (or with other) therapeutic agents, and therefore may be presented as separate formulations, wherein at least one of these formulations comprises a compound of the invention and at least one comprises the (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 (or other) therapeutic agent).

[0842] Therefore, it is further provided that:

[0843] (1) a (e.g., pharmaceutical) formulation comprising a compound of the invention; another pharmaceutically active ingredient; and optionally, a pharmaceutically acceptable inactive excipient (e.g., adjuvant, diluent, or carrier), hereinafter referred to as a "combination preparation"; and

[0844] (2) A kit comprising the following components:

[0845] (A) a compound of the invention, optionally in the form of a (e.g., pharmaceutical) formulation in admixture with a pharmaceutically acceptable inactive excipient (e.g., adjuvant, diluent, or carrier); and

[0846] (B) another pharmaceutically active ingredient, optionally in the form of a (e.g., pharmaceutical) formulation in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier,

[0847] The components (A) and (B) are each provided in a form suitable for administration in conjunction with one another.

[0848] In a further aspect of the invention, there is provided a process for preparing a combined preparation (1) as defined above, said process comprising combining a compound of the invention, other pharmaceutically active ingredients and at least one (eg pharmaceutically acceptable) excipient.

[0849] In a further aspect of the invention, there is provided a method for preparing a kit of parts (2) as defined above, said method comprising combining components (A) and (B). As used herein, reference to combining shall mean making the two components suitable for administration in conjunction with each other.

[0850] Thus, with respect to the method for preparing a kit of parts as defined above, "associating" two components with one another comprises two components of the kit of parts which may:

[0851] (i) are provided separately (i.e., independently of each other), the separate formulations being subsequently brought together for use in conjunction with each other in a combination therapy; or

[0852] (ii) The separate components are packaged and presented together as a "combination pack" for use in conjunction with each other in a combination therapy.

[0853] Therefore, a kit is further provided, comprising:

[0854] (I) one of components (A) and (B) as defined herein; and

[0855] (II) instructions for using the component in combination with the other of the two components.

[0856] With respect to the above-mentioned kits, although the compounds of the present invention may be provided in the form of a (e.g., pharmaceutical) formulation mixed with one or more additional pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers), when the compounds of the present invention are provided primarily for 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 be provided in the form of a pharmaceutical formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0857] To provide for repeated administration, the kits described herein may contain more than one appropriate amount / dose of a compound of the invention (e.g., a formulation comprising it), and / or more than one appropriate amount / dose of other pharmaceutically active ingredients (e.g., a formulation comprising it). If there is 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 dose, one or more chemical compositions, and / or one or more physical forms of any of the compounds.

[0858] With respect to a kit of parts as described herein, "administered in combination with" includes sequential, separate and / or simultaneous administration of the respective components during the treatment of the relevant conditions.

[0859] Thus, with respect to a combination product according to the invention, the term "administered in conjunction with" includes that the two components of the combination product (the compound of the invention and the other pharmaceutically active ingredient) are administered together or sufficiently close in time (optionally repeatedly) to enable the patient to experience a beneficial effect during the treatment of the relevant condition that is greater than if the formulation comprising the compound of the invention or (e.g., comprising) another agent were administered (optionally repeatedly) alone in the absence of the other component during the same treatment. The determination of whether a combination provides a greater beneficial effect with respect to and during the treatment of a particular condition will depend on the condition to be treated or prevented, but can be routinely accomplished by the skilled person.

[0860] In addition, in the case of a kit of parts 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 administration of the other component (optionally repeated administration). When used in this context, the terms "simultaneous administration" and "administered simultaneously with" include administering separate amounts / doses of the relevant compound of the present invention and the other pharmaceutically active ingredient within 48 hours (e.g., 24 hours) of each other.

[0861] With regard to the above-mentioned combination preparations and kits, it is preferred that the other pharmaceutically active ingredient is an anti-inflammatory agent, or an agent known to cause inflammation as a side effect as described above.

[0862] Wherever the word "about" is used herein (e.g., in the context of amounts such as concentration and / or dosage of active ingredient and / or compound of the invention, molecular weight, or pH), it will 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%.

[0863] The compounds of the present invention are advantageous in that they have a wide variety of uses, including:

[0864] as bioactive agents for various conditions characterized by inflammation, whether such conditions are inflammatory diseases of an organ per se as described above or are associated with or characterized by inflammation (e.g. wounds or burns), and / or for surgical and / or cosmetic applications; and / or

[0865] In combination with an active pharmaceutical ingredient, in a combination therapy, or by performing a more inert function as or as part of:

[0866] o a pharmaceutically acceptable excipient (e.g., adjuvant, diluent, or carrier),

[0867] oMedical devices, and / or

[0868] oThe medical device portion of a drug-medical device combination.

[0869] The compounds, uses and methods described herein may also have the following advantages: in treating the above-mentioned conditions, they may be more convenient for the physician and / or patient, more effective, less toxic, have a broader spectrum 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 disorders or disorders characterized by inflammation as a symptom (including wounds) or otherwise, compared to similar compounds or methods (treatments) known in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0870] Figure 1 and Figure 2 The degrees of swelling obtained in the mouse model experiments of Examples 21 and 22 are shown, respectively.

[0871] Example

[0872] As used herein, "N-(acid-PEG3)-N-bis(PEG3-amine)" refers to the following structure having CAS number 2183440-35-7:

[0873] or

[0874] The following snippets (as appropriate):

[0875]

[0876] The terms “N-bis(amine-PEG3)-N-(acid-PEG3)”, “N-bis(PEG3-amine)-N-(PEG3-acid)”, “N-bis(PEG3-amine)-N-PEG3-acid” and “N-bis(amine-PEG3)-N-(PEG3-acid)” can be used interchangeably with “N-(acid-PEG3)-N-bis(PEG3-amine)”.

[0877] In the following examples, when the peptide is bound to both amines in N-(acid-PEG3)-N-bis(PEG3-amine), this is indicated in the name of the compound as follows: N-(acid-PEG3)-N-bis(peptide-NH-PEG3), where the amino acid segment adjacent to the "NH" is the amino acid bound to the amines.

[0878] Examples in which the peptide is conjugated to only one amine are named in a similar manner.

[0879] As used herein, "tris(amino-PEG3-amide)-amine" refers to the following structure having CAS number 2523025-40-1:

[0880]

[0881] Example 1

[0882] N-Bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N-(PEG3 acid) (SEQ ID No:188)

[0883] N-bis(Fmoc-NH-PEG3)-N-(PEG3-acid)-Wang resin (13.5 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0884] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. The DCM was then removed by vacuum filtration.

[0885] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0886] A 20% piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) solution in DMF (DBLK, 200 mL) 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.

[0887] Fmoc-Lys(Boc)-OH (8.44 g; GL Biochem, Shanghai, China) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 5.78 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, 4.66 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, the Kaiser test was performed with very little resin, and the yellow color of the solution and the colorless gel indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0888] The above coupling steps were repeated to couple the same amounts (in mol) of the remaining amino acids: Fmoc-4-Hyp(tBu)-OH, Fmoc-DOPA(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH.

[0889] In a separate procedure, after Fmoc-Ala-OH is coupled to the resin, a deprotection step is performed to remove the Fmoc protection of alanine. The resin is washed 3 times with DMF (200 mL each time). A 20% piperidine solution (200 mL) in DMF is added as a deprotection solution and reacted for 20 minutes. The resin is then 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 is dried under vacuum for approximately 2 hours.

[0890] 190.0 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 resin-bound peptide compound. After approximately 2 hours of lysis, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1700 mL (i.e., 10 mL / ml filtrate) of ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours to yield 8.58 g of the crude title compound.

[0891] First, the crude product was 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, with a linear gradient from 5% to 90% solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL).

[0892] The target peak eluted at 10.378 minutes and had the expected molecular weight with a purity of 71.382%.

[0893] MS: m / z 2934.6

[0894] Then 8.5 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, 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 5% to 20% solvent A concentration over 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 that the linear gradient was from 5% to 30% solvent A concentration over 25 minutes).

[0895] The fractions with a purity higher than 90% were then mixed together to carry out anion exchange steps. This was achieved using NP7010C semi-preparative equipment (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 at a flow rate of 60 mL / min for approximately 20 minutes followed by another 10 minutes of pure water washing, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN, solvent B: 0.1% hAc in water, a linear gradient of 5%-20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fractions with a purity higher than 95% were mixed and freeze-dried to obtain 3.78 g of purified title compound.

[0896] Example 2

[0897] N-Bis{[N-Bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N-(PEG3 acid)]-NH-PEG3}-N-(PEG3 acid) (SEQ ID No: 189)

[0898] The method was the same as described in Example 1, starting with N-bis(Fmoc-NH-PEG3)-N-(PEG3 acid), followed by Fmoc-Lys(boc)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Dopa(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH and Fmoc-Ala-OH, and compared to Example 1, except that the N-bis(Fmoc-amido-PEG3)-N-PEG3 acid coupling step was not doubled, the amounts of amino acids, TBTU and DIPEA were doubled (by mol).

[0899] MS: m / z 6404.3

[0900] Essentially the same procedure was repeated to give another batch of crude title compound (yield 17.25 g). Analysis showed the desired peak eluting at 11.732 minutes with the expected molecular weight (MS: m / z 6404.3). The purity was 50.281%.

[0901] 17 g of the crude product was then purified as described above in Example 1 to give 5.73 g of the pure title compound after freeze drying.

[0902] Example 3

[0903] N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N-(PEG3 amide) (SEQ ID No:190)

[0904] Compared with Example 1, the method was the same as described in Example 1 except that N-bis(Fmoc-NH-PEG3)-N-(PEG3 acid)-AM resin (12.9 g, GLBiochem, Shanghai, China) was used as the starting material.

[0905] MS: m / z 2949.6

[0906] Essentially the same procedure was repeated to give another batch of crude title compound (yield 7.36 g). Analysis showed the desired peak eluting at 10.246 minutes with the expected molecular weight (MS: m / z 2949.6). The purity was 71.377%.

[0907] 7 g of the crude product was then purified as described above in Example 1 to give 3.67 g of the pure title compound after freeze drying.

[0908] Example 4

[0909] N-bis{[N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG5)-N-(PEG5 acid)]-N H-PEG3}-N-(PEG3 acid)(SEQ ID No: 191)

[0910] The method was the same as described in Example 1, starting with N-bis(Fmoc-NH-PEG5)-N-(PEG5 acid), followed by Fmoc-Lys(boc)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Dopa(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH and Fmoc-Ala-OH, and compared to Example 1, except that the N-bis(Fmoc-amido-PEG5)-N-PEG5 acid coupling step was not doubled, the amounts of amino acids, TBTU and DIPEA were doubled (by mol).

[0911] MS: m / z 6668.3

[0912] Essentially the same procedure was repeated to give another batch of crude title compound (yield 18.17 g). Analysis showed the desired peak eluting at 12.072 minutes with the expected molecular weight (MS: m / z 6668.3). The purity was 51.392%.

[0913] 18 g of the crude product was then purified as described above in Example 1 to give 5.96 g of the pure title compound after freeze drying.

[0914] Example 5

[0915] N-bis(montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N- (PEG3 acid)(SEQ IDNo:192)

[0916] Compared to Example 1, the method was the same as described in Example 1, except that a further coupling step with montelukast sodium was performed after the attachment of Fmoc-Ala-OH and deprotection.

[0917] MS: m / z 4071.0

[0918] Essentially the same procedure was repeated to give another batch of crude title compound (yield 10.19 g). Analysis showed the desired peak eluting at 32.847 minutes with the expected molecular weight (MS: m / z 4071.0). The purity was 47.93%.

[0919] 10 g of the crude product was then purified as described above in Example 1 to give 2.95 g of the pure title compound after freeze drying.

[0920] Example 6

[0921] N-Bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3 acid)-Lys-Pro-Ser- Tyr-Hyp-DOPA-Lys(SEQ ID No:193)

[0922] Fmoc-Lys(Boc)-Wang resin (9.15 g; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0923] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. The DCM was then removed by vacuum filtration.

[0924] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0925] A 20% piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) solution in DMF (DBLK, 200 mL) 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.

[0926] Fmoc-DOPA (acetonide) -OH (4.14 g; GL Biochem, Shanghai, China) and 2- (1H-benzotriazole-1-yl) -1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N, N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, a Kaiser test was performed with a small amount of resin. The yellow color of the solution and the colorless gel indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0927] The above coupling steps were repeated to couple the same amounts (by mol) of the remaining amino acids: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH and N-bis(Fmoc-NH-PEG3)-N-(PEG3 acid).

[0928] After coupling N-bis(Fmoc-NH-PEG3)-N-(PEG3 acid) to the resin, a deprotection step was performed to remove the Fmoc protection of N-bis(amino-PEG3)-N-(PEG3 acid). The resin was washed three times with DMF (200 mL each time). A 20% piperidine solution (200 mL) in DMF was added as a deprotection solution and allowed to react for 20 minutes. The resin was then washed six times with DMF.

[0929] Then, another coupling step was performed starting with Fmoc-Lys(Boc)-OH, followed by Fmoc-DOPA(acetonide)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH and Fmoc-Lys(Boc)-OH, and in this coupling step the amounts of amino acids, TBTU and DIPEA were doubled (by mol) compared to the previous coupling step.

[0930] In a separate procedure, after Fmoc-Lys(Boc)-OH was coupled to the resin, a deprotection step was performed to remove the Fmoc protection on lysine. The resin was washed 3 times with DMF (200 mL each time). A 20% piperidine solution (200 mL) in DMF was added as a deprotection solution and reacted for 20 minutes. The resin was then 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 approximately 2 hours.

[0931] 180.0 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 resin-bound peptide compound. After approximately 2 hours of lysis, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1600 mL (i.e., 10 mL / ml filtrate) of ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours to yield 7.23 g of the crude title compound.

[0932] First, the crude product was 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, with a linear gradient from 5% to 90% solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL).

[0933] The target peak eluted at 15.232 minutes and had the expected molecular weight with a purity of 64.322%.

[0934] MS: m / z 3259.8

[0935] Then 7.2 g of the crude product was dissolved in 70 mL of pure water and purified using a NP7010C semi-preparative apparatus (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China). The preparative column model was Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50*250 mm, 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 5% to 20% solvent A concentration over 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 that the linear gradient was from 5% to 30% solvent A concentration over 25 minutes).

[0936] The fractions with a purity higher than 90% were then mixed together to carry out anion exchange steps. This was achieved using NP7010C semi-preparative equipment (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 approximately 20 minutes at a flow rate of 60 mL / min, followed by another 10 minutes of pure water washing, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN, solvent B: 0.1% hAc in water, a linear gradient of 5%-20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fractions with a purity higher than 95% were mixed and freeze-dried to obtain 2.55 g of purified title compound.

[0937] Example 7

[0938] N-(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(Lys-Hyp-Ser-Tyr-Hyp-DOPA- Lys-NH-PEG3)-(PEG3 acid)-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys(SEQ ID No:194)

[0939] Fmoc-Lys(Boc)-Wang resin (9.15 g; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0940] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. The DCM was then removed by vacuum filtration.

[0941] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0942] A 20% piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) solution in DMF (DBLK, 200 mL) 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.

[0943] Fmoc-DOPA (acetonide) -OH (4.14 g; GL Biochem, Shanghai, China) and 2- (1H-benzotriazole-1-yl) -1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N, N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China). After 30 minutes of reaction, a Kaiser test was performed with a small amount of resin. The yellow color of the solution and the colorless gel indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0944] The above coupling steps were repeated to couple the same amounts (by mol) of the remaining amino acids: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH and N-(Fmoc-NH-PEG3)-N-(Dde-NH-PEG3)-(PEG3 acid).

[0945] After coupling N-(Fmoc-NH-PEG3)-N-(Dde-NH-PEG3)-(PEG3 acid) to the resin, a deprotection step was performed to remove the Fmoc protection of N-bis(amino-PEG3)-N-(PEG3 acid). The resin was washed three times with DMF (200 mL each time). A 20% piperidine solution (200 mL) in DMF was added as a deprotection solution and reacted for 20 minutes. The resin was then washed six times with DMF.

[0946] Then, another coupling step was performed starting with Fmoc-Lys(Boc)-OH, followed by Fmoc-Tyr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH and Fmoc-Lys(Boc)-OH with the same amounts (by mol) of amino acids, TBTU and DIPEA compared to the previous coupling step.

[0947] After Fmoc-Lys(Boc)-OH is coupled to the resin, a deprotection step is performed to remove the Dde protection of N-bis(amino-PEG3)-N-(PEG3 acid). The resin is washed 3 times with DMF (200 mL each time). A 5% hydrazine hydrate solution (200 mL) in DMF is added as a deprotection solution and the reaction is continued for 20 minutes. The resin is then washed six times with DMF.

[0948] Then, additional coupling steps were performed starting with Fmoc-Lys(Boc)-OH, followed by Fmoc-DOPA(acetonide)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-4-Hyp(tBu)-OH and Fmoc-Lys(Boc)-OH with the same amounts (in mol) of amino acids, TBTU and DIPEA compared to the previous coupling steps.

[0949] In a separate procedure, after Fmoc-Lys(Boc)-OH was coupled to the resin, a deprotection step was performed to remove the Fmoc protection on lysine. The resin was washed 3 times with DMF (200 mL each time). A 20% piperidine solution (200 mL) in DMF was added as a deprotection solution and reacted for 20 minutes. The resin was then 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 approximately 2 hours.

[0950] 180.0 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 resin-bound peptide compound. After approximately 2 hours of lysis, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1600 mL (i.e., 10 mL / ml filtrate) of ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours to yield 7.15 g of the crude title compound.

[0951] First, the crude product was 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, with a linear gradient from 5% to 90% solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL).

[0952] The target peak eluted at 15.322 minutes and had the expected molecular weight with a purity of 61.453%.

[0953] MS: m / z 3259.8

[0954] Then 7.1 g of the crude product was dissolved in 70 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, 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 5% to 20% solvent A concentration over 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 that the linear gradient was from 5% to 30% solvent A concentration over 25 minutes).

[0955] The fractions with a purity higher than 90% were then mixed together to carry out anion exchange steps. This was achieved using NP7010C semi-preparative equipment (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 at a flow rate of 60 mL / min for approximately 20 minutes followed by another 10 minutes of pure water washing, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN, solvent B: 0.1% hAc in water, a linear gradient of 5%-20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fractions with a purity higher than 95% were mixed and freeze-dried to obtain 2.49 g of purified title compound.

[0956] Example 8

[0957] Tris(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3-amide)-amine (SEQ ID No: 195)

[0958] The title compound was synthesized using Fmoc-Lys(Boc)-CTC resin as the solid support and lysine as the first amino acid.

[0959] Fmoc-Lys(Boc)-CTC resin (7.35 g, USUN pharma, Jiangsu, China) was loaded into a glass reaction column.

[0960] Dichloromethane (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for about half an hour. The DCM was then removed by vacuum filtration.

[0961] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co Ltd, Shandong, China).

[0962] 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 resin in the column was washed six times with DMF.

[0963] Fmoc-DOPA (acetonide) -OH (4.14 g; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU, 2.89 g; 00705, GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd, Jiangsu, China). After 30 minutes of reaction, a Kaiser test was performed with a small amount of resin. The yellow color of the solution and the colorless gel indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0964] The above coupling steps were repeated to couple the same amount (in mol) of the remaining amino acids: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH and Boc-Lys(Boc)-OH.

[0965] After coupling Boc-Lys(Boc)-OH to the resin, the resin was washed three times with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time). The resin was then dried under vacuum for about 2 hours.

[0966] 120.0mL (i.e., 10mL / gram of dry resin) lysate is added to immerse the peptide compound bound to the resin, and the lysate is composed of 2% trifluoroacetic acid (TFA) in DCM. After about 2 hours of cleavage, the solid support is removed by filtration and the filtrate is collected under reduced pressure. The filtrate is then concentrated by rotary distillation under reduced pressure. After removing all solvents, tris (amino-PEG3-amide) -amine (0.38g, CAS: 2523025-40-1; GL Biochem, Shanghai, China) is added, and then pyridine (100mL) is added to the flask to dissolve the solid, and then phosphorus oxychloride (0.3ml, Adamas-beta Co. Ltd., Shanghai, China) is added to the reaction solution. After reacting for 3 hours, the reaction is complete. The final solution is precipitated by adding 1200mL (i.e., 10mL / ml of the final solution) saturated citric acid (Aladdin, Shanghai, China) aqueous solution, and the precipitate is collected by filtration. Then add 120mL (that is, 10mL / gram solid) lysate to dissolve the peptide-containing solid, and the lysate comprises 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (Tis). By side chain deprotection during the cracking period. After about 2 hours of cracking, the solution is precipitated with 1200mL (that is, 10mL / ml filtrate) ether, and the precipitate is collected by filtration. The precipitate is passed through vacuum drying for about 2 hours. Finally, 7.11g of thick title compound are obtained.

[0967] First, the crude product was 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, with a linear gradient from 5% to 90% solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL).

[0968] The target peak eluted at 17.123 minutes and had the expected molecular weight with a purity of 55.284%.

[0969] MS: m / z 3444.1

[0970] Then 7.1 g of the crude product was dissolved in 70 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, 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 5% to 20% solvent A concentration over 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 that the linear gradient was from 5% to 30% solvent A concentration over 25 minutes).

[0971] The fractions with a purity higher than 90% were then mixed together to carry out anion exchange steps. This was achieved using NP7010C semi-preparative equipment (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 at a flow rate of 60 mL / min for approximately 20 minutes followed by another 10 minutes of pure water washing, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN, solvent B: 0.1% hAc in water, a linear gradient of 5%-20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fractions with a purity higher than 95% were mixed and freeze-dried to obtain 2.04 g of purified title compound.

[0972] Example 9

[0973] N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(PEG3-acid)]-NH- PEG3}-N-(P EG3-acid) (SEQ ID No: 260)

[0974] The title compound was prepared using essentially the same procedures as described above in Example 2, except that the appropriate amino acids were used in the relevant peptide coupling sequences.

[0975] MS: m / z 5199.1

[0976] Substantially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 14.12 g). Analysis showed the desired peak eluting at 10.792 minutes with the expected molecular weight (MS: m / z 5199.1). The purity was 53.223%.

[0977] 14.1 g of the crude product was then purified as described above in Example 1 to give 3.92 g of the pure title compound after freeze drying.

[0978] Example 10

[0979] N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3-acid)]-NH- PEG3}-N-(PEG3-acid)(SEQ ID No: 261)

[0980] The title compound was prepared using essentially the same procedure as described above in Example 9, except that the same amount (by mole) of Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling steps.

[0981] MS: m / z 5263.1

[0982] Substantially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 14.25 g). Analysis showed the desired peak eluting at 10.543 minutes with the expected molecular weight (MS: m / z 5263.1). The purity was 55.833%.

[0983] 14.2 g of the crude product was then purified as described above in Example 1 to give 4.01 g of the pure title compound after freeze drying.

[0984] Example 11

[0985] N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(PEG3-acid)]-NH- PEG3}-N-(PEG3-acid)(SEQ ID No: 262)

[0986] The title compound was prepared using essentially the same procedure as described in Example 9 above, except that after the last amino acid, Fmoc-Lys(Boc)-OH, was coupled to the resin, a further coupling step was performed to couple palmitic acid to the resin. Palmitic acid was used in the same amount (by mole) as the other amino acids.

[0987] After coupling of palmitic acid, 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 then dried under vacuum for about 2 hours.

[0988] MS: m / z 6152.7

[0989] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 15.83 g). Analysis showed the target peak eluting at 39.857 minutes with the expected molecular weight (MS: m / z 6152.7). The purity was 50.202%.

[0990] 15.8 g of the crude product was then purified as described above in Example 1 to give 4.78 g of the pure title compound after freeze drying.

[0991] Example 12

[0992] N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3-acid)]- NH-PEG 3}-N-(PEG3-acid)(SEQ IDNo: 263)

[0993] The title compound was prepared using essentially the same procedure as described above in Example 11, except that the same amount (by mole) of Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling steps.

[0994] MS: m / z 6216.7

[0995] Essentially the same procedure was repeated to give another batch of crude title compound (yield 15.71 g). Analysis showed the desired peak eluting at 38.788 minutes with the expected molecular weight (MS: m / z 6216.7). The purity was 50.482%.

[0996] 15.7 g of the crude product was then purified as described above in Example 1 to give 4.52 g of the pure title compound after freeze drying.

[0997] Example 13

[0998] N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(PEG3-acid) (SEQ ID No: 264)

[0999] The title compound was prepared using essentially the same method as described in Example 1 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences. After the last amino acid, Fmoc-Lys(Boc)-OH, was coupled to the resin, a further coupling step was performed to couple palmitic acid to the resin. Palmitic acid was used in the same amount (by mol) as the other amino acids.

[1000] After coupling of palmitic acid, 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 then dried under vacuum for about 2 hours.

[1001] MS: m / z 2808.6

[1002] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 7.81 g). Analysis showed the target peak eluting at 35.839 minutes with the expected molecular weight (MS: m / z 2808.6). The purity was 65.748%.

[1003] 7.8 g of the crude product was then purified as described above in Example 1 to give 3.55 g of the pure title compound after freeze drying.

[1004] Example 14

[1005] N-Bis(Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3-acid) (SEQ ID No: 265)

[1006] The title compound was prepared using essentially the same procedure as described above in Example 13, except that the same amount (by mole) of Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling steps.

[1007] MS: m / z 2840.6

[1008] Substantially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 7.74 g). Analysis showed the target peak eluting at 36.221 minutes with the expected molecular weight (MS: m / z 2840.6). The purity was 53.211%.

[1009] 7.7 g of the crude product was then purified as described above in Example 1 to give 3.29 g of the pure title compound after freeze drying.

[1010] Example 15

[1011] N-Bis(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(PEG3-acid) (SEQ ID No: 266)

[1012] The title compound was prepared using essentially the same procedures as described above in Example 1, except that the appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.

[1013] MS: m / z 2331.7

[1014] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 7.05 g). Analysis showed the target peak eluting at 9.882 minutes with the expected molecular weight (MS: m / z 2331.7). The purity was 68.473%.

[1015] 7.0 g of the crude product was then purified as described above in Example 1 to give 3.57 g of the pure title compound after freeze drying.

[1016] Example 16

[1017] N-bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3-acid) (SEQ ID No: 267)

[1018] The title compound was prepared using essentially the same procedure as described above in Example 15, except that the same amount (by mole) of Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling steps.

[1019] MS: m / z 2363.7

[1020] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 6.91 g). Analysis showed the target peak eluting at 9.988 minutes with the expected molecular weight (MS: m / z 2363.7). The purity was 65.832%.

[1021] 6.9 g of the crude product was then purified as described above in Example 1 to give 3.56 g of the pure title compound after freeze drying.

[1022] Example 17

[1023] N-Bis(Palm-Lys-Hyp-Lys-NH-PEG3)-N-(PEG3-acid) (SEQ ID No: 268)

[1024] The title compound was prepared using essentially the same procedures as described above in Example 13, except that the appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.

[1025] MS: m / z 1787.5

[1026] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 5.28 g). Analysis showed the target peak eluting at 29.812 minutes with the expected molecular weight (MS: m / z 1787.5). The purity was 70.928%.

[1027] 5.2 g of the crude product was then purified as described above in Example 1 to give 2.98 g of the pure title compound after freeze-drying.

[1028] Example 18

[1029] N-bis(Lys-Hyp-Lys-NH-PEG3)-N-(PEG3-acid) (SEQ ID No: 269)

[1030] The title compound was prepared using essentially the same procedures as described above in Example 1, except that the appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.

[1031] MS: m / z 1310.6

[1032] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 4.65 g). Analysis showed the target peak eluting at 9.883 minutes with the expected molecular weight (MS: m / z 1310.6). The purity was 75.291%.

[1033] 4.6 g of the crude product was then purified as described above in Example 1 to give 2.57 g of the pure title compound after freeze-drying.

[1034] Example 19

[1035] N-bis{[N-bis(Palm-Lys-Hyp-Lys-NH-PEG3)-N-(PEG3-acid)]-NH-PEG3}-N-(PEG3- Acid)(SEQ ID No:270)

[1036] The title compound was prepared using essentially the same procedures as described above in Example 11, except that the appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.

[1037] MS: m / z 4110.6

[1038] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 12.52 g). Analysis showed the target peak eluting at 41.282 minutes with the expected molecular weight (MS: m / z 4110.6). The purity was 41.938%.

[1039] 12.5 g of the crude product was then purified as described above in Example 1 to give 4.34 g of the pure title compound after freeze drying.

[1040] Example 20

[1041] N-bis{[N-bis(Lys-Hyp-Lys-NH-PEG3)-N-(PEG3-acid)]-NH-PEG3}-N-(PEG3-acid) (SEQ ID No:271)

[1042] The title compound was prepared using essentially the same procedures as described above in Example 2, except that the appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.

[1043] MS: m / z 3157.0

[1044] After drying the resin, essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 9.38 g). Analysis showed the target peak eluting at 13.123 minutes with the expected molecular weight (MS: m / z 3157.0). The purity was 43.126%.

[1045] 9.3 g of the crude product was then purified as described above in Example 1 to give 3.27 g of the pure title compound after freeze drying.

[1046] Example 21

[1047] Ear swelling mouse model

[1048] Test compound:

[1049] Compound A: N-bis{[N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N-(PEG3 acid)]-NH-PEG3}-N-(PEG3 acid) (SEQ ID No: 189), which is equal to:

[1050] (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid)

[1051] Compound G: ((Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)4-Lys)2-Lys

[1052] Twenty healthy male BALB / c mice (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China), aged 6 to 8 weeks and weighing an average of 18-25 g, were housed and cared for approximately one week prior to the experiment. They were housed at 25-27°C, 74% humidity, and a 12-h dark-light cycle, with free access to food and water. The mice were randomly divided into four groups (five mice per group) as described in Table 1.

[1053] Table 1

[1054]

[1055]

[1056] The left ear of each mouse served as an autologous control. The right ear of each mouse was treated differently: 20 μl of xylene (Shanghai Aladdin Bio-Chem Technology Co., LTD, Shanghai, China) was applied to both the inside and outside of the right ear of each mouse. After approximately 4 minutes, the ear began to swell. 40 μl of the drug was then applied to the right ear of each group. The mice were returned to their cages.

[1057] Dexamethasone acetate cream (0.75 mg / g, China Resources Group) was purchased from a local pharmacy. Compounds A and G were synthesized by Chinese Peptide Company as described above. 15 mg of each compound (powder) was dissolved in 10 ml of normal saline to make a 1.5 mg / ml solution. The resulting solution was applied to mice accordingly.

[1058] After 40 min, the mice were sacrificed by cervical dislocation. The left and right ears were excised. An 8 mm diameter skin pouch (Electron Microscopy Sciences, P.O. Box 550, 1560 Hatfield Industrial Road, Pennsylvania 19440) was used to remove a piece of ear from the same location on both ears. The weight was recorded and used to calculate the degree of swelling, which is reported in Tables 2 and 3. Figure 1 Shown in.

[1059] Swelling (%) = (right ear weight - left ear weight) / left ear weight × 100%

[1060] Table 2

[1061] Group Model DEX Compound A Compound G Swelling degree (%) 63.22 46.79 36.74 47.89 SD (%) 9.05 12.93 21.29 16.99

[1062] The results showed that both compounds could significantly reduce ear swelling in the xylene-induced mouse model, especially compound A, which was more effective than dexamethasone.

[1063] Example 22

[1064] Ear swelling mouse model

[1065] Test compound:

[1066] Compound B: N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3 acid)]-NH-PEG3}-N-(PEG3 acid) (SEQ ID No: 263), which is equal to:

[1067] (Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid)

[1068] Compound C: N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(PEG3 acid)]-NH-PEG3}-N-(PEG3 acid) (SEQ ID No: 262), which is equal to:

[1069] (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid)

[1070] Compound D: N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3)-N-(PEG3 acid)]-NH-PEG3}-N-(PEG3 acid) SEQ ID No: 261), which is equal to:

[1071] (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid)

[1072] Compound E: N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3)-N-(PEG3 acid)]-NH-PEG3}-N-(PEG3 acid) (SEQ ID No: 260), which is equal to:

[1073] (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid)

[1074] The experimental procedures and results were the same as those described in Example 1. Xylene induced ear swelling in mice. 40 mice were divided into 8 groups as described in Table 3.

[1075] Table 3

[1076]

[1077]

[1078] The results are shown in Table 4 and Figure 2 Shown in.

[1079] Table 4

[1080] Group Model Dex Compound B Compound C Compound D Compound E Swelling degree (%) 72.18 39.62 43.41 39.42 39.52 52.42 SD (%) 15.48 8.24 19.39 13.81 14.03 8.85

[1081] The results showed that compounds B, C and D were all effective in reducing swelling in the xylene-treated mouse model, which was comparable to the effect of dexamethasone. Compound E was also effective, but not as effective as the other compounds.

[1082] Example 23

[1083] Pain relief in radiation-induced oral mucositis

[1084] A patient is receiving head radiation therapy. The patient experienced severe oral mucositis, diagnosed as greedy grade 4 (the most serious grade) and oral mucosal ulcers. The patient also experienced high levels of pain and difficulty eating. The patient was advised to use 1.5mg / ml x 5ml Compound A solution as a mouthwash three times a day. After 7 days, the patient reported very positive feedback. The pain VAS score dropped from 8 to 1.

[1085] Example 24

[1086] Itch relief for neurodermatitis

[1087] A 33-year-old woman presented with skin lesions on her back with persistent itching and scaling. She had been diagnosed with neurodermatitis two years prior. The patient had previously used glucocorticoids to treat the lesions, but the effect was short-lived. The itching became more severe when she felt stressed. The patient tried a 3mg / ml spray of Compound A solution. After one spray on the lesions, the itching symptoms were completely relieved after about 60 minutes. The patient reported that the itching symptoms stopped the next day after application.

Claims

1. A compound of formula I, AQB (I) in: A and B independently represent Z or A 1 -Q 1 -B 1 ; Q represents a structural fragment of formula (II), in: The wavy lines indicate the points of attachment of Q to A and / or B; and R is selected from: Among them, when R represents When one wavy line indicates the point of attachment to the rest of the Q segment, and the other wavy line indicates the point of attachment to Z or A. 1 -Q 1 -B 1 attachment points; Among them, when R represents , one wavy line indicates the point of attachment to the rest of the Q segment, and the other wavy line indicates the point of attachment to Z; n1 to n3 independently represent 1 to 10; m1 to m3 independently represent 0 to 5; p1 to p3 independently represent 0 or 1; x represents 0 or 1; A 1 and B 1 Independently represents Z or A 2 -Q 2 -B 2 ; A 2 and B 2 Independently represents Z or ZQ 3 -Z; Q 1 , Q 2 and Q 3 independently represents a structural fragment of formula III, in: The wavy lines adjacent to the NH groups represent Q 1 , Q 2 and Q 3 With A 1 and / or B 1 、A 2 and / or B 2 and the attachment point of Z; The wavy lines adjacent to the carbonyl group represent Q 1 , Q 2 and Q 3 With Q, Q 1 and Q 2 attachment point; and n4 to n6 independently represent 1 to 10; m4 to m6 independently represent 0 to 5; p4 to p6 independently represent 0 or 1; y represents 0 or 1; Z, in each instance where it is employed, independently represents: L-[(W) m -Lys-X 1 -T-(U) m -(X 2 ) m -(Y) m ] n -(W) m -Lys-X 1 -T-(U) m -(X 2 ) m -(Y) m (SEQ ID No: 1); or L-Ala-Lys-Pro (SEQ ID No: 2); or L-Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID No: 3); or L-[Lys - X 3 ] n -Lys-X 3 (SEQ ID No:196) in: Z is attached to the rest of the molecule via the N- or C-terminus, as appropriate; and In each case where they are adopted: n represents 0 or an integer from 1 to 4; W independently represents a sequence of 1 or 2 amino acids, wherein the amino acids are selected from one or more of the following groups: Ser, Lys, Ala, DOPA and 3,4-dihydrocinnamic acid (HCA) residues, with the proviso that when present, the HCA residue is located at the N-terminus of the peptide sequence Z; In each instance where it is employed, m independently represents 0 or 1; In each case where it is adopted, X 1 Independently represents Pro or Hyp; T independently represents Ser or pSer in each instance where it is employed; U, at each instance where it is employed, independently represents Tyr, pTyr, DOPA, Hyp or Pro; In each case where it is adopted, X 2 independently represents Thr, Ser, Pro, Hyp, or diHyp; In each instance where it is employed, Y independently 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, Thr, pThr, DOPA, and Tyr; L independently represents at least one optional lipid substituent selected from vitamin A, vitamin E, cholesterol, and fatty acids containing one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, said lipid being a linear or branched, saturated or unsaturated lipid having between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10 -OH groups, or a derivative of any of these lipids; and X 3 represents a sequence of 2 to 4 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA and Tyr, wherein, optionally, the amino acid residue at the N-terminus of the Z component is covalently bonded to a nonsteroidal anti-inflammatory drug or montelukast, forming an amide linkage with the carboxylic acid group in the nonsteroidal anti-inflammatory drug or montelukast, and regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the compounds.

2. The compound according to claim 1, wherein A and B both represent Z or both represent A 1 -Q 1 -B 1 .

3. A compound according to any one of the preceding claims, wherein A 1 and B 1 Both represent Z or both represent A 2 -Q 2 -B 2 .

4. A compound according to any one of the preceding claims, wherein A 2 and B 2 Both represent Z or both represent ZQ 3 -Z.

5. A compound according to any one of the preceding claims, wherein: p1 to p6 represent 0; and m1 to m6 represent 0.

6. A compound according to any one of the preceding claims, wherein x and y represent 0. 7 . The compound according to claim 1 , wherein p1 to p6 represent 1. 8 . The compound according to claim 1 , wherein m1 to m6 independently represent 1 to 6.

9. A compound according to any one of the preceding claims, wherein R represents 10. A compound according to any one of claims 1 to 4 and 6 to 8, wherein R represents 11. A compound according to any one of the preceding claims, wherein n1 to n6 independently represent 1 to 5.

12. The compound according to any one of the preceding claims, wherein the amino acid residue at the N-terminus of the Z component is covalently bonded to montelukast.

13. A compound according to any one of the preceding claims, wherein n is 0.

14. A compound according to any one of the preceding claims, wherein T is Ser.

15. A compound according to any one of the preceding claims, wherein X 1 Indicates Pro.

16. A compound according to any one of the preceding claims, wherein X 2 Indicates Hyp.

17. The compound according to any one of the preceding claims, wherein W is selected from the group consisting of Ser, HCA, HCA-Ala-, Ala, DOPA, Lys-Ala and DOPA-Ala.

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

19. A compound according to any one of the preceding claims, wherein W represents Ala or Lys-Ala-.

20. The compound according to any one of the preceding claims, wherein Z is selected from the group consisting of: Ala-Lys-Pro (SEQ ID no. 2); Ala-Lys-Pro-Ser(SEQ ID no.4); Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5); Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7); and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8), And optionally, the amino acid residue at the N-terminus of the Z component is covalently bonded to montelukast, forming an amide linkage with the carboxylic acid group in montelukast.

21. The compound of claim 19, wherein Z is selected from the group consisting of: Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 10); Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11); Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 12); Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 13); Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 14); Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 15); Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID no. 16); Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID no. 17); Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 18); and Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 19).

22. The compound of claim 19, wherein Z is selected from the group consisting of: Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID no. 20); Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11); Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 21); Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 22); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 23); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 24); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 25); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 26); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 27); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 28); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 29); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 30); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 31); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 32); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 33); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID no.34); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.35); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.36); Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID no.37); Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.38); Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp(SEQ ID no.39); Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.40); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.41); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID no.42); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID no.43); Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys(SEQ ID no.44); Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys(SEQ ID no.45); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp(SEQ ID no.46); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.47); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID no.48); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID no.49); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.50); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID no.51); Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp(SEQ ID no.52); Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys(SEQ ID no.53); Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no.54); Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys(SEQ ID no.55); Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys (SEQ ID no.56); Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys(SEQ ID no.57); Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys (SEQ ID no.58); Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro(SEQ ID no.59); Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no.60); Ala-Lys-Pro-Ser-Tyr-Hyp(SEQ ID no.6); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp(SEQ ID no.61); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA(SEQ ID no.62); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp(SEQ ID no.63); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp-Lys(SEQ ID no.64); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Lys (SEQ ID no.65); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr(SEQ ID no.66); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp(SEQ ID no.67); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp-Lys (SEQ ID no.68); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Lys (SEQ ID no.69); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID no.70); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp(SEQ ID no.71); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.72); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.73); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID no.74); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.75); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp(SEQ ID no.76); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no.77); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no.78); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID no.79); Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (SEQ ID no.80); Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID no.81); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp(SEQ ID no.82); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.83); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID no.84); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp(SEQ ID no.85); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-DOPA-Lys (SEQ ID no. 86); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 87); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 88); Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no. 89); Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no. 90); Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (SEQ ID no. 91); Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (SEQ ID no. 92); and Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 93).

23. The compound of claim 19, wherein Z is selected from the group consisting of: Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no. 94); Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no. 95); Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 96); Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 97); Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no. 98); Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no. 99); Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 100); and Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.101).

24. A compound according to any one of claims 1 to 18, wherein with respect to (W) m m is 0; and n is 0.

25. The compound according to claim 24, wherein Z is selected from the group consisting of: Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID no.102); Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID no.103); Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID no.104); Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys(SEQ ID no.105); Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys(SEQ ID no.106); Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys(SEQ ID no.107); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys(SEQ ID no.108); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys(SEQ ID no.109); Lys-Hyp-Ser-pTyr-Hyp-DOPA(SEQ ID no.110); Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys(SEQ ID no.111); Lys-Hyp-Ser-Tyr-Hyp-DOPA(SEQ ID no.112); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys(SEQ ID no.113); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys(SEQ ID no.114); Lys-Pro-Ser-DOPA-Hyp-DOPA(SEQ ID no.115); Lys-Pro-Ser-DOPA-Hyp-DOPA-Lys(SEQ ID no.116); Lys-Pro-Ser-DOPA-Hyp-Tyr-Lys(SEQ ID no.117); Lys-Hyp-Ser-Tyr-Hyp-Tyr(SEQ ID no.118); Lys-Pro-Ser-Tyr-Hyp-Tyr(SEQ ID no.119); Lys-Pro-Ser-Tyr-Hyp-Thr(SEQ ID no.120); Lys-Pro-Ser-DOPA-Hyp-Thr(SEQ ID no.121); Lys-Pro-Ser-Tyr-Hyp-Thr-Lys(SEQ ID no.122); and Lys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID no. 123).

26. The compound of claim 24, wherein Z is selected from the group consisting of: Lys-Pro-Ser-pTyr-Hyp-DOPA (SEQ ID no. 124); Lys-Pro-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 125); Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID no. 126); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 128); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 129); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 130); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 131); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 132); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 133); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 134); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 135); and Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136).

27. A compound according to any one of claims 1 to 18, wherein W represents HCA, HCA-Ala-, DOPA, or DOPA-Ala-.

28. The compound according to claim 27, wherein Z is selected from the group consisting of: DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no.137): DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 138); DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 139); DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.140); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.141); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.142); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.143); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.144); DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID no.145); DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID no.146); DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID no.147); DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID no.148); HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.149); HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.150); HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID no.151); HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID no.152); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.153); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID no.154); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.155); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 156); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 157); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 158); HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 159); HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 160); HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 161); and HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 162).

29. A compound according to any one of claims 1 to 18, wherein W represents Ser.

30. The compound of claim 29, wherein Z is selected from the group consisting of: Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 163); Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 164); Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 165); Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 166); Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 167); Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 168); Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 169); and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 170).

31. The compound of any one of claims 1 to 19, wherein n is 1 or 4.

32. The compound of claim 31 , wherein Z is selected from the group consisting of: Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys(SEQ ID no.171); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.172); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys (SEQ ID no.173); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.174); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP A-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.175); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Al a-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID no.176); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOP and Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-H yp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID no.178).

33. The compound according to any one 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, Ala, Hyp, Thr, DOPA and Tyr.

34. The compound according to claim 10, wherein Y represents an amino acid sequence selected from the group consisting of: -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 -Lys-, where Y 1 and Y 2 Each is independently selected from the group consisting of Ala, Hyp, Thr, DOPA and Tyr.

35. A compound according to claim 33 or claim 34, wherein the amino acid sequence defined by Y is selected from the group consisting of -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys- and -Thr-Ala-Hyp-Lys-.

36. The compound according to any one of claims 1 to 32, wherein the amino acid sequence defined by Y is selected from the group consisting of -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

37. A compound according to any one of the preceding claims, wherein U represents Tyr or pTyr.

38. The compound according to any one of the preceding claims 1 to 19, wherein L represents at least one lipid according to claim 1.

39. The compound according to claim 38, wherein L represents a lipid selected from the derivatives of fatty acids as defined in claim 1.

40. The compound of claim 38, 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.

41. The compound of any one of claims 38 to 40, wherein the lipid is palmitic acid or a derivative thereof.

42. A compound according to any preceding claim for use in human or animal medicine.

43. A compound according to any one of claims 1 to 41 for use as a medicament.

44. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 41.

45. The pharmaceutical formulation of claim 44, further comprising a pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier.

46. ​​A pharmaceutical formulation according to claim 44 or claim 45, suitable, adapted 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.

47. The pharmaceutical formulation according to any one of claims 44 to 46, which is in the form of a gel, spray, cream, ointment or dry powder.

48. The pharmaceutical formulation according to any one of claims 44 to 47, further comprising one or more additional pharmaceutically active ingredients.

49. A kit of parts, comprising the following components: (A) a compound according to any one of claims 1 to 41 or a pharmaceutical formulation according to any one of claims 44 to 48; and (B) a pharmaceutical formulation comprising one or more additional pharmaceutically active ingredients in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, The components (A) and (B) are each provided in a form suitable for administration in conjunction with one another.

50. The pharmaceutical formulation according to claim 48 or the kit of parts according to claim 49, 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.

51. The pharmaceutical formulation or kit of parts according to claim 50, wherein the pharmaceutically active ingredient is an anti-inflammatory agent.

52. A compound according to any one of claims 1 to 41, a formulation according to any one of claims 44 to 48, 50 or 51, or a kit of parts according to any one of claims 49 to 51 for use in treating inflammation, an inflammatory disorder, and / or a disorder characterized by inflammation.

53. Use of a compound according to any one of claims 1 to 41, a formulation according to any one of claims 44 to 48, 50 or 51, or a kit of parts according to any one of claims 49 to 51 for the manufacture of a medicament for treating inflammation, an inflammatory disorder, and / or a disorder characterized by inflammation.

54. A method of treating inflammation, an inflammatory disorder, and / or a disorder characterized by inflammation, comprising administering to a patient in need of such treatment a compound according to any one of claims 1 to 41, a formulation according to any one of claims 44 to 48, 50 or 51, or a kit of parts according to any one of claims 49 to 51.

55. The compound, formulation or kit for use according to claim 52, the use according to claim 53, or the method according to claim 54, wherein the disorder characterized by inflammation is a wound or burn or results in a wound or burn.

56. The compound, formulation or kit for use, use or method according to claim 55, wherein the disorder causing wounds is hemorrhoids or ulcerative colitis.

57. The compound, formulation or kit for use, use or method (as the case may be) according to any one of claims 42 to 56, wherein the one or more compounds or salts thereof are administered topically in the form of a topical formulation.

58. A compound, formulation or kit for use, use or method according to claim 57, wherein the relevant condition is treated by topical application directly to the skin.

59. The compound, formulation or kit for use, use or method according to claim 57, wherein the relevant condition is treated by direct topical administration to a mucosal surface.

60. The compound, formulation or kit for use, use or method (as the case may be) according to any one of claims 41 to 59, wherein the compound(s) are administered orally, intravenously, cutaneously or subcutaneously, nasally, intramuscularly, intraperitoneally, pulmonary or anorectally.

61. The compound, formulation or kit for use, use or method (as the case may be) according to any one of claims 48 to 60, wherein the compound according to any one of claims 1 to 41 serves as an excipient, a medical device, or a medical device component of a drug-medical device combination.

62. The compound, formulation or kit for use, use or method (as the case may be) according to any one of claims 45 to 61, wherein the compound is as defined in any one of claims 1 to 41, wherein W is as defined in claim 27 and / or U is as defined in claim 18, and the compound is cross-linked before or after administration to a subject.

63. The compound according to claim 62, which is used as an adhesive or film-forming material.

64. The compound for use according to claim 63, wherein the use is as a wound surface repair product, a wound surface protection product, a medical bioadhesive product, a medical coating product, an industrial coating product, a biochemical reagent, a medical product, a sterilized product or a culture vessel for cell culture.

65. A compound for use according to claim 63 or claim 64, wherein a film is formed on the surface of a skin or mucosal wound to aid recovery.

66. The compound for use according to any one of claims 63 to 65, wherein the use is for closure of surgical incisions, adhesion of fractured bones, adhesion of mucous membranes or coating of human implants.

67. A pharmaceutical formulation comprising a compound according to claim 63 and a pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier.

68. The pharmaceutical formulation of claim 67, which is suitable, adapted 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.

69. The pharmaceutical formulation of claim 67 or claim 68, which is in the form of a gel, spray, cream, ointment or dry powder.

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