Novel multifunctional oligopeptides

Abstract

Compounds of formula (I), AQB(I), are provided, wherein Q represents a structural fragment of formula (II), the wavy line and m have the meanings given herein, and A and B have the meanings given herein, but which have the amino acid sequence [(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), wherein n, m, T, W, X 1 , U, X 2 and Y have the meanings given in the specification, and the compounds are useful in medicaments, including pharmaceutical excipients, adhesives, and film-forming materials, and / or in the treatment of conditions characterized by inflammation, including wounds, burns, and disorders of the mucous membranes, such as anorectal disorders, inflammatory bowel diseases, gynecological disorders, and dental disorders. [Formula 1] TIFF2026506026000025.tif75166

Description

[Technical Field]

[0001] The present invention relates to novel peptides, as active pharmaceutical ingredients or otherwise, the use of such peptides in human medicine, and pharmaceutical compositions containing them. In particular, the invention relates to the use of these peptides and compositions in the treatment of various pathologies, including inflammation. [Background technology]

[0002] Inflammation is typically characterized as a localized tissue response to, for example, microbial invasion, certain antigens, damaged cells, or physical and / or chemical agents. The inflammatory response is usually a protective mechanism that destroys, weakens, or sequesters both harmful substances and injured tissue, and initiates tissue healing.

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

[0004] Many pathological conditions / disorders are characterized by and / or caused by abnormal tissue-damaging inflammation. Such pathological conditions are typically characterized by the activation of immune defense mechanisms, resulting in effects that are more harmful than beneficial to the host, and are generally associated with varying degrees of tissue redness or hyperemia, 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 due to local vascular dilation resulting in redness and heat, extravasation of leukocytes and plasma often resulting in local swelling, activation of sensory nerves (leading to pain in some tissues), and loss of function. These inflammatory changes are caused by a cascade of cellular and biochemical events involving cells such as neutrophils, monocytes, macrophages, and lymphocytes, along with inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

[0006] In particular, inflammation plays an important role in the wound healing process. Therefore, wounds and burns can be classified as inflammation-associated pathologies. Conventional thinking in the art is that anti-inflammatory drugs should not be applied directly to open wounds because they are 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 injured tissues. While collagen deposition is typically a reversible part of wound healing, when tissue injury is severe or the wound healing response itself becomes dysregulated, it can often develop into an increasingly irreversible fibrotic response. Furthermore, fibrosis is known to be a major cause of morbidity and mortality in many chronic inflammatory diseases, as well as end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure. It is also a pathological feature of many chronic autoimmune diseases, such as scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus. Fibrosis may also contribute to the pathogenesis of many progressive myopathies, metastasis, and graft rejection.

[0008] Mussel adhesive protein (MAP), also known as Mytilus edulis foot protein (mefp), is a protein secreted by marine shellfish such as Mytilus edulis, Mytilus coruscus, and Perna viridis. The 11 identified distinct adhesive protein subtypes are collagens pre-COL-P, pre-COL-D, and pre-COL-NG, mussel foot matrix proteins PTMP (proximal thread matrix protein) and DTMP (distal thread matrix protein), and mfp proteins mfp-2 (sometimes referred to as "mefp-2" and hereafter used interchangeably), 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] The majority of mefp-1 consists of 70-90 tandem repeats of the decapeptide 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 synthesized as described, for example, 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 have also been disclosed, particularly Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 78). See, e.g., U.S. Patent No. 5,616,311 and WO 96 / 39128.

[0011] The use of lysine amino acid residues to prepare multi-antigen peptides has been disclosed, for example, in Tam Proc. Natl. Acad., Sci. USA, 1988, 85, 5409-5413, Rao et al., J. Am. Chem. Soc., 1994, 116, 6975-6976, U.S. Pat. No. 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 a clear need for new and / or improved drugs that can be used to treat inflammation and conditions characterized by inflammation. Summary of the Invention

[0014] According to a first aspect of the present invention, there is provided a compound of formula I, AQB(I) During the ceremony, A and B are independently Z or A 1 -Q 1 -B 1 represents Q represents a structural fragment of formula (II),

[0015] [ka] During the ceremony, the wavy line represents the point of attachment of Q to A and / or B; R,

[0016] [ka] is selected from the group consisting of In the formula, R is

[0017] [ka] where one wavy line represents the point of attachment to the remainder of the Q fragment and the other wavy line represents Z or A. 1 -Q 1 -B 1 represents the point of attachment to In the formula, R is

[0018] [ka] where one wavy line represents the point of attachment to the remainder of the Q fragment and the other wavy line represents the point of attachment to 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 are independently Z or A 2 -Q 2 -B 2 represents A 2 and B 2 may be independently Z or ZQ 3 represents -Z, Q 1 , Q 2 , and Q 3 independently represent a structural fragment of formula III;

[0019] [ka] During the ceremony, The wavy line next to the NH group is Q 1 , Q 2 , and Q 3 From A 1 and / or B 1, A 2 and / or B 2 , and the point of attachment to Z, The wavy line next to the carbonyl group is Q 1 , Q 2 , and Q 3 From, Q, Q 1 , and Q 2 represent the attachment points to n4 to n6 independently represent an integer selected from 1 to 10; m4 to m6 independently represent an integer selected from 0 to 5; p4 to p6 independently represent 0 or 1; y represents 0 or 1; Each occurrence of Z independently 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), During the ceremony, Z is attached to the remainder of the molecule via the N-terminus or C-terminus, as appropriate; Every time it is used, n represents 0 or an integer selected from 1 to 4; W independently represents one or two amino acid sequences, the amino acids being selected from one or more of the group of Ser, Lys, Ala, DOPA, and 3,4-dihydrocinnamic acid (HCA) residues, provided that the HCA residue, if present, is located at the N-terminus of the peptide sequence Z; each occurrence of m independently represents 0 or 1; X 1 each occurrence independently represents Pro or Hyp; each occurrence of T independently represents Ser or pSer; each occurrence of U independently represents Tyr, pTyr, DOPA, Hyp, diHyp, or Pro; X 2 each occurrence independently represents Thr, Ser, Pro, Hyp, or diHyp; each occurrence of Y independently represents 1 to 5 (e.g., 1 to 4) amino acid sequences, wherein the amino acids are selected from one or more of the group: Lys, Ala, Pro, Hyp, Thr, pThr, DOPA, and Tyr; L independently represents at least one optional lipid substituent, the lipid being selected from the group consisting of 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, being straight or branched, saturated or unsaturated, having 1 to 10 carbon-carbon double bonds, and / or being substituted with 1 to 10 -OH groups, or a derivative of any of these lipids; X 3 represents a sequence of two to four amino acids, wherein the amino acids are selected from one or more of the group: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, and Tyr; Optionally, a compound in which the N-terminal amino acid residue of the Z component is covalently attached to a non-steroidal anti-inflammatory drug (NSAID) or montelukast to form an amide bond with a carboxylic acid group in the NSAID or montelukast; and regioisomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of said compounds, These compounds, regioisomers, stereoisomers, and salts are hereinafter collectively referred to as "compounds of the invention."

[0020] Those skilled in the art will be able to determine whether peptide Z is attached to the remainder of the molecule via the N-terminus or the C-terminus. For the avoidance of doubt, Z is attached to the remainder of the molecule by forming an amide bond.

[0021] Therefore, when Z is bonded to formula (II), formula (III), or R is

[0022] [ka] When Z is attached to R when Z is attached via the C-terminus.

[0023] Alternatively, R

[0024] [ka] When Z is attached to R, Z is attached via the N-terminus.

[0025] As used herein, "diHyp" refers to trans-2,3-cis-3,4-dihydroxyproline.

[0026] Compounds of the invention that may be mentioned include those in which Z is [(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 Ala-Lys-Pro (SEQ ID NO: 2), or represents Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID NO: 3), Compounds are included in which the N-terminal amino acid residue of the Z moiety is optionally covalently attached to montelukast to form an amide bond with a carboxylic acid group in the montelukast.

[0027] Every time it is used, Q, Q 1 , Q 2 , and Q 3 may each be attached to 0, 1, 2, or 3 Z groups.

[0028] In this regard, preferred compounds of the invention include those in which one of A or B represents Z and the other represents A. 1 -Q 1 -B 1 or more preferably, both A and B represent Z, or both represent A 1 -Q 1 -B 1 The compound includes compounds which represent:

[0029] Further preferred compounds of the present invention include A 1 and B 1 One of them represents Z and the other represents A 2 -Q 2 -B 2 or more preferably, A 1 and B 1 Both represent Z or both represent A 2 -Q 2 -B 2 Also included are compounds which represent:

[0030] Further preferred compounds of the present invention include A 2 and B 2 One of them represents Z and the other represents ZQ 3 -Z, or more preferably, A 2 and B 2 Both represent Z, or both represent ZQ 3Also included are compounds in which -Z is present.

[0031] More preferred compounds of the present invention include: A 1 and B 1 both represent Z, or A 2 and B 2 and Z are both included.

[0032] In some embodiments, p1 through p6 each represent 0. In particular, in such embodiments, m1 through m6 each represent 0.

[0033] In some embodiments, x represents 0. Particularly in such embodiments, each y independently represents 0.

[0034] In some embodiments, x represents 1. In particular, in such embodiments, each y independently represents 0.

[0035] In some embodiments, p1 through p3 each represent 1. In such embodiments, m1 through m3 independently represent 1 through 5.

[0036] In particular, in such embodiments, p4 to p6 each represent 1 and m4 to m6 each represent 1 to 5.

[0037] In some embodiments, R is

[0038] [ka] Represents.

[0039] In an alternative embodiment, R is

[0040] [ka] Represents.

[0041] 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.

[0042] Peptide moieties of the compounds of the invention that may be mentioned include those in which n is 0, 1 or 4, or more preferably in which n is 1, or in particular in which n is 0.

[0043] Compounds of the invention that may be mentioned include compounds in which the N-terminal amino acid residue of the Z moiety is covalently attached to an NSAID or montelukast.

[0044] Those skilled in the art will appreciate that the term "nonsteroidal anti-inflammatory drug" (NSAID) includes one or more members of a class of drugs that help reduce pain, inflammation, and / or fever (as well as, in some cases, reduce blood clots). It is well understood that the term "nonsteroidal" excludes other pain relievers, particularly corticosteroids, from this definition.

[0045] NSAIDs typically act by inhibiting the activity of cyclooxygenase (COX) enzymes, including COX-1 and COX-2, enzymes known to be involved in the synthesis of important inflammatory mediators such as prostaglandins and mediators involved in hemostasis, such as thromboxanes.

[0046] NSAIDs that may be mentioned include those that fall into the following structural classes, and in particular those derived from carboxylic acids, including: Salicylic acid or "salicylates", such as salicylic acid itself and its salts, salsalate, diflunisal, and especially aspirin (acetylsalicylic acid); and 5-aminosalicylic acid (mesalazine); Acetic acids, such as indomethacin, acemetacin, "phenacs" (such as diclofenac, fenclofenac, aceclofenac, and bromfenac), ketorolac, etodolac, sulindac, fentiazac, and olmetine and nabumetone; Propionic acid, also known as "2-arylpropionic acid derivatives" or "profens", such as ibuprofen, naproxen, dexibuprofen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, perbiprofen, zaltoprofen, fenbufen, carprofen, and tiaprofenic acid; Enolic acids, also known as "oxicams", such as meloxicam, piroxicam, lornoxicam, isoxicam, tenoxicam, and droxicam, and phenylbutazone (Bute); and Anthranilic acids, also known as "fenamates," such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etofenamate, and clofenamic acid.

[0047] Other NSAIDs that may be mentioned include pyrazolone derivatives such as oxyphenbutazone, propyphenazone, aminophenazone, antipyrine, and analginam (metamizole), as well as nefopam. Other analgesic compounds that may be used instead of and / or in addition to NSAIDs include phenacetin and paracetamol (acetaminophen).

[0048] Less preferred NSAIDs that may also be mentioned include selective COX-2 inhibitors or "coxibs," such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, and firocoxib; sulfonanilides, such as nimesulide; and clonixin, licofelone, and H-harpagide.

[0049] Preferred NSAIDs include aspirin, salicylic acid, celecoxib, and mesalazine.

[0050] Preferably, the N-terminal amino acid residue of Z is covalently attached to montelukast.

[0051] The optional NSAID substituents may be covalently attached to the N-terminal amino acid residue of the Z moiety via an amide bond formed between the respective carboxylic acid residue of the NSAID and the N-terminal -NH2 residue of Z.

[0052] Those skilled in the art will appreciate that specific NSAIDs that may be covalently attached 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, etc.), propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, perbiprofen, zaltoprofen, etc.), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac, etc.), anthranilic acid derivatives (such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etc.), selective COX-2 inhibitors (coxibs) (such as lumiracoxib), and others (such as clonixin, licofelone, etc.).

[0053] Among the compounds of the invention that may be mentioned are those in which W represents one or two amino acid sequences, the amino acids being selected from one or more of the group Ser, Lys, Ala and DOPA, X 1 represents Pro, X 2 represents Ser, Pro, or Hyp; Included are compounds in which Y represents a sequence of 1 to 5 (e.g., 1 to 4) amino acids, and the amino acids are selected from one or more of the group: Lys, Ala, Pro, Hyp, Thr, DOPA, and Tyr.

[0054] Preferred compounds of the present invention include X1 represents Hyp, or more preferably Pro, X 2 represents Hyp, W represents HCA-, HCA-Ala-, preferably Ala- or Lys-Ala-, or more preferably DOPA or DOPA-Ala-; and / or Included are compounds in which Y represents a sequence of five, preferably three, or more preferably four amino acids, and the amino acids are selected from one or more of the group: Lys, Ala, Hyp, Thr, DOPA, and Tyr.

[0055] More preferably, the compounds of the present invention include those in which Y is -Pro-Y 1 -Y 2 -Lys-, or more preferably -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 -Lys-, Y represents a sequence of four amino acids selected from the group 1 and Y 2 are each independently selected from the group of Pro, or more preferably Ala, Hyp, Thr, DOPA, and Tyr.

[0056] Further preferred compounds of the invention include those in which the amino acid sequence defined by Y is: -Pro-Thr-DOPA-Lys-, -Pro-Thr-Tyr-Lys-, -Thr-Tyr-Pro-Lys-, and -Thr-DOPA-Pro-Lys-, and more preferably -Thr-Tyr-Hyp-, -Thr-DOPA-Hyp-, -Tyr-Hyp-Lys-, -Tyr-Pro-Lys-, -Hyp-Thr-DOPA-, -Hyp-pThr-DOPA-, -Hyp-Thr-Tyr-, -DOPA-Hyp-Lys-, -Hyp-Thr-Tyr-, -Hyp-Thr-Tyr-Hyp, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-DOPA-Hyp-, -Hyp-Thr-Ala-Lys-, -Hyp-pThr-DOPA-Hyp-, -Thr-Tyr-Hyp-, -Thr-Tyr-Lys-Hyp-, -Thr-DOPA-Lys-Hyp-, -Thr-DOPA-Hyp-Lys-, and -Thr-Ala-Hyp-Lys-.

[0057] When Y represents two amino acid sequences, preferred compounds of the invention include those in which the amino acid sequence defined by Y is selected from the group of -DOPA-Lys-, -Tyr-Lys-, -Thr-Lys-, and -Tyr-Pro-.

[0058] Other preferred compounds of the invention that may be mentioned include those in which the amino acid sequence defined by Y is -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-, - Included are compounds selected from the group 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 from the group -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

[0059] Among the compounds of the invention that may be mentioned are: U represents Tyr, and / or Compounds are included where W represents Ala.

[0060] In this regard, further compounds of the invention that may be mentioned are those in which Z is Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); 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); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 8); Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 179); Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 180); Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 181); Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 182); 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-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID NO: 18); Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID NO: 19); 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-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); Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 93); 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-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 173); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 174); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 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 (SEQ ID NO: 176); and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 177).

[0061] Among the compounds of the invention that may be mentioned are: U represents Tyr, and / or Compounds in which W represents Lys-Ala- are included.

[0062] In this regard, further compounds of the invention that may be mentioned are those in which Z is 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-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 100); Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 101); Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 183); Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 184); and Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 185).

[0063] Among the compounds of the invention that may be mentioned are: U represents Tyr, and / or Compounds are included where W is absent.

[0064] In this regard, further compounds of the invention that may be mentioned are those in which Z is 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-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-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-Tyr-Hyp-Thr-Lys (SEQ ID NO: 122); 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).

[0065] Further compounds of the invention that may be mentioned include: U represents Tyr, and / or Included are compounds in which W represents HCA, HCA-Ala-, or, more preferably, DOPA or DOPA-Ala-.

[0066] In this regard, mention may be made of compounds of the invention in which Z is 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-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-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-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID NO: 161); and The compounds include those selected from the group consisting of HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 162).

[0067] Further compounds of the invention that may be mentioned include: U represents Tyr, and / or Compounds are included where W represents Ser.

[0068] In this regard, mention may be made of compounds of the invention in which Z is 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).

[0069] Compounds of the invention that may be mentioned include those in which U represents DOPA.

[0070] In this regard, mention may be made of compounds of the invention in which Z is Ala-Lys-Pro-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 186); Ala-Lys-Hyp-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 187); 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); 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-Pro-Ser-DOPA-Hyp-Thr (SEQ ID NO: 121); Lys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID NO: 123); 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-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); 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-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); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 172); 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-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-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 178).

[0071] Further compounds of the invention that may be mentioned include: U represents DOPA, and / or Included are compounds in which W represents HCA, HCA-Ala-, or, more preferably, DOPA or DOPA-Ala-.

[0072] Thus, particular compounds of the invention that may be mentioned include those in which Z is 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-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); 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-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID NO: 159); and The compounds include those selected from the group consisting of HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 160).

[0073] Further compounds of the invention that may be mentioned include: Compounds are included where U represents Hyp.

[0074] Thus, particular compounds of the invention that may be mentioned include those in which Z is Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 12); and The compounds include those selected from the group consisting of Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID NO: 16).

[0075] Further compounds of the invention that may be mentioned include those in which U represents Pro.

[0076] Thus, particular compounds of the invention that may be mentioned include those in which Z is Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 15); Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID NO: 17); Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (SEQ ID NO: 59); and The compounds include those selected from the group consisting of Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 60).

[0077] Further compounds of the invention that may be mentioned include those in which U represents pTyr.

[0078] Thus, particular compounds of the invention that may be mentioned include those in which Z is Lys-Hyp-Ser-pTyr-Hyp-DOPA (SEQ ID NO: 110); Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID NO: 111); Lys-Pro-Ser-pTyr-Hyp-DOPA (SEQ ID NO: 124); and Lys-Pro-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID NO: 125).

[0079] Further compounds of the invention that may be mentioned include those in which Z is Ala-Lys-Pro-Ser (SEQ ID NO: 4); Ala-Lys-Pro (SEQ ID NO: 2); and The compounds include those selected from the group of Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID NO: 3).

[0080] In some embodiments, Z is Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 179); Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 180); Ala-Lys-Pro-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 186); Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 181); Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 182); Ala-Lys-Hyp-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 187); 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); Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID NO: 19); 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).

[0081] Among the compounds of the invention that may be mentioned are: A and B both represent Z; One, or preferably both, Z groups are 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); 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-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 102); Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 103); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 24); Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 27); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 32); Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 36); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 70); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 75); 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-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 155); HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 158); Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 100); Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 101); Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID NO: 126); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 129); Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 131); Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 133); Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 135); Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 168); or Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 170), or Alternatively, more preferably, one, or preferably both, Z groups are: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 78); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 127); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 136); Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 113); Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 114); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 87); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 142); or Included is a compound representing DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 144).

[0082] Among the compounds of the invention that may be mentioned are: A and B both represent Z; One, or preferably both, Z groups are 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); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 8); or Included is a compound representing Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 9).

[0083] In each of the above peptide sequences Z, the N-terminal amino acid residue of the Z moiety can be covalently attached to an NSAID, as defined herein, or montelukast, forming an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0084] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 represents A 1 and B 1 Both represent Z, One, or preferably both, Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 78); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 144); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 127); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 136); or Included is a compound representing Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 113).

[0085] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 represents A 1 and B 1 Both represent Z, One, or preferably both, Z groups are 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); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 8); or Included is a compound representing Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 9).

[0086] In each of the above peptide sequences Z, the N-terminal amino acid residue of the Z moiety can be covalently attached to an NSAID, as defined herein, or montelukast, forming an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0087] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 represents A 1 and B 1 Both are A 2 -Q 2 -B 2 represents A 2 and B 2 Both represent Z, One, or preferably both, Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 78); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 144); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 127); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 136); or Included is a compound representing Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 113).

[0088] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B1 represents A 1 and B 1 Both are A 2 -Q 2 -B 2 represents A 2 and B 2 Both are ZQ 3 represents -Z, One, or preferably both, Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 9); Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 78); Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83); DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 144); Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 127); Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 136); or Included is a compound representing Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 113).

[0089] In each of the above peptide sequences Z, the N-terminal amino acid residue of the Z moiety can be covalently attached to an NSAID, as defined herein, or montelukast, forming an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0090] Further compounds of the invention that may be mentioned include: A and B both represent Z; one, or preferably both, Z groups represent a structural fragment of formula IV, [Lys-X 3 ] n-Lys-X 3 (IV) (SEQ ID NO: 197) n and X 3 is as defined above, and for each peptide sequence Z, includes compounds in which the N-terminal amino acid residue of the Z component can be covalently attached to an NSAID, as defined herein, or montelukast to form an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0091] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 represents A 1 and B 1 Both represent Z, one, or preferably both, Z groups represent a structural fragment of formula IV, [Lys-X 3 ] n -Lys-X 3 (IV) (SEQ ID NO: 197) n and X 3 is as defined above, and for each peptide sequence Z, includes compounds in which the N-terminal amino acid residue of the Z component can be covalently attached to an NSAID, as defined herein, or montelukast to form an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0092] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 represents A 1 and B 1 Both are A 2 -Q 2 -B 2 represents A 2 and B 2 Both represent Z, one, or preferably both, Z groups represent a structural fragment of formula IV, [Lys-X 3 ]n -Lys-X 3 (IV) (SEQ ID NO: 197) n and X 3 is as defined above, and for each peptide sequence Z, includes compounds in which the N-terminal amino acid residue of the Z component can be covalently attached to an NSAID, as defined herein, or montelukast to form an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0093] Further compounds of the invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 represents A 1 and B 1 Both are A 2 -Q 2 -B 2 represents A 2 and B 2 Both are ZQ 3 represents -Z, one, or preferably both, Z groups represent a structural fragment of formula IV, [Lys-X 3 ] n -Lys-X 3 (IV) (SEQ ID NO: 197) n and X 3 is as defined above, and for each peptide sequence Z, includes compounds in which the N-terminal amino acid residue of the Z component can be covalently attached to an NSAID, as defined herein, or montelukast to form an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0094] When one or more Z groups represent a structural fragment of formula IV defined above, each occurrence thereof: X 3 represents three, four, or more preferably two amino acid sequences, X 3 Preferably, the amino acid in is selected from the group Pro, Hyp, Lys, Tyr, and DOPA.

[0095] Furthermore, each time it is used, X adjacent to Lys 3 the amino acids in are selected from Pro and Hyp; X 3 the N-terminal amino acid in is selected from Tyr and DOPA, in particular Lys, 3 Preferably, at least one of the other amino acids in the sequence defining α is Hyp.

[0096] Furthermore, in such cases, n may represent 1, such that Z has the formula: Lys-X 3 -Lys-X 3 (SEQ ID NO: 198) or Or more preferably, n represents 0, such that Z is of the formula: Lys-X 3 (SEQ ID NO: 199), Each time it is used, X 3 is as defined above.

[0097] n is 0 and X 3 represents two amino acid sequences, preferred tripeptide sequences that Z may represent include: Lys-Pro-Lys (SEQ ID NO: 200); Lys-Pro-Tyr (SEQ ID NO: 201); Lys-Pro-DOPA (SEQ ID NO: 202); more preferably Lys-Hyp-Tyr (SEQ ID NO: 203); Lys-Hyp-DOPA (SEQ ID NO: 204); or more specifically, Lys-Hyp-Lys (SEQ ID NO: 205) is included.

[0098] n is 0 and X 3 If represents a three amino acid sequence, then X 3 is Lys, so that preferred tetrapeptide sequences which Z may represent include: Lys-Pro-Pro-Lys (SEQ ID NO: 206); Lys-Pro-Hyp-Lys (SEQ ID NO: 207); Lys-Hyp-Pro-Lys (SEQ ID NO: 208); or more specifically, Lys-Hyp-Hyp-Lys (SEQ ID NO: 209) is included.

[0099] n is 0 and X 3 If represents a four amino acid sequence, then X 3 The C-terminal amino acid sequence in comprises Pro-Lys, or more preferably Hyp-Lys, such that preferred pentapeptide sequences which Z may represent include: Lys-Pro-DOPA-Hyp-Lys (SEQ ID NO: 210); Lys-Pro-DOPA-Pro-Lys (SEQ ID NO: 211); Lys-Hyp-DOPA-Hyp-Lys (SEQ ID NO: 212); Lys-Hyp-DOPA-Pro-Lys (SEQ ID NO: 213); Lys-Pro-Tyr-Pro-Lys (SEQ ID NO: 214); Lys-Hyp-Tyr-Pro-Lys (SEQ ID NO: 215); or more specifically, Lys-Pro-Tyr-Hyp-Lys (SEQ ID NO: 216); or Lys-Hyp-Tyr-Hyp-Lys (SEQ ID NO: 217) is included.

[0100] When n is 1, each time it is used, X 3 preferably represents two amino acid sequences, such that preferred hexapeptide sequences that Z may represent include: Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID NO: 218); Lys-Hyp-Tyr-Lys-Pro-Lys (SEQ ID NO: 219); Lys-Hyp-Tyr-Lys-Pro-Tyr (SEQ ID NO: 220); Lys-Hyp-Tyr-Lys-Pro-DOPA (SEQ ID NO: 221); Lys-Hyp-DOPA-Lys-Hyp-Tyr (SEQ ID NO: 222); Lys-Hyp-DOPA-Lys-Pro-Lys (SEQ ID NO: 223); Lys-Hyp-DOPA-Lys-Pro-Tyr (SEQ ID NO: 224); Lys-Hyp-DOPA-Lys-Pro-DOPA (SEQ ID NO: 225); Lys-Pro-Lys-Lys-Hyp-Tyr (SEQ ID NO: 226); Lys-Pro-Lys-Lys-Hyp-DOPA (SEQ ID NO: 227); Lys-Pro-Lys-Lys-Pro-Tyr (SEQ ID NO: 228); Lys-Pro-Lys-Lys-Pro-DOPA (SEQ ID NO: 229); Lys-Pro-Tyr-Lys-Hyp-Tyr (SEQ ID NO: 230); Lys-Pro-Tyr-Lys-Hyp-DOPA (SEQ ID NO: 231); Lys-Pro-Tyr-Lys-Pro-Lys (SEQ ID NO: 232); Lys-Pro-Tyr-Lys-Pro-DOPA (SEQ ID NO: 233); Lys-Pro-DOPA-Lys-Hyp-Tyr (SEQ ID NO: 234); Lys-Pro-DOPA-Lys-Hyp-DOPA (SEQ ID NO: 235); Lys-Pro-DOPA-Lys-Pro-Lys (SEQ ID NO: 236); Lys-Pro-DOPA-Lys-Pro-Tyr (SEQ ID NO: 237); or preferably, Lys-Hyp-Tyr-Lys-Hyp-Tyr (SEQ ID NO: 238); Lys-Hyp-DOPA-Lys-Hyp-DOPA (SEQ ID NO: 239); Lys-Pro-Lys-Lys-Pro-Lys (SEQ ID NO: 240); Lys-Pro-Tyr-Lys-Pro-Tyr (SEQ ID NO: 241); Lys-Pro-DOPA-Lys-Pro-DOPA (SEQ ID NO: 242); or more preferably, Lys-Hyp-Lys-Lys-Hyp-Tyr (SEQ ID NO: 243); Lys-Hyp-Lys-Lys-Hyp-DOPA (SEQ ID NO: 244); Lys-Hyp-Lys-Lys-Pro-Lys (SEQ ID NO: 245); Lys-Hyp-Lys-Lys-Pro-Tyr (SEQ ID NO: 246); Lys-Hyp-Lys-Lys-Pro-DOPA (SEQ ID NO: 247); or even more preferably, Lys-Hyp-Tyr-Lys-Hyp-Lys (SEQ ID NO: 248); Lys-Hyp-DOPA-Lys-Hyp-Lys (SEQ ID NO: 249); Lys-Pro-Lys-Lys-Hyp-Lys (SEQ ID NO: 250); Lys-Pro-Tyr-Lys-Hyp-Lys (SEQ ID NO: 251); Lys-Pro-DOPA-Lys-Hyp-Lys (SEQ ID NO: 252); or Lys-Hyp-Lys-Lys-Hyp-Lys (SEQ ID NO: 253).

[0101] In each of the peptide sequences represented by SEQ ID NOs: 197-253 (inclusive), the N-terminal amino acid residue of the Z component can be covalently attached to an NSAID, as defined herein, or montelukast, forming an amide bond with a carboxylic acid group in the NSAID or montelukast.

[0102] Preferred compounds of the present invention include those in which the one or more optional lipids defined by L are selected from the group consisting of palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid, and leukotriene B4 (LTB4), or a derivative of any of these.

[0103] Further preferred compounds of the present invention include those in which 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).

[0104] Further preferred compounds of the present invention include those in which the one or more lipids comprise a derivative of a fatty acid, such as a glycerolipid, a glycerophospholipid, a sphingolipid, or a saccharolipid.

[0105] Further preferred compounds of the present invention include those in which the one or more lipids comprise 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).

[0106] Further preferred compounds of the present invention include those in which the one or more lipids comprise stearic acid or a derivative thereof, and in such embodiments, the derivative may be 1,2-distearoyl-sn-glycero-3-phospho-l-serine.

[0107] Further preferred compounds of the invention include those in which 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.

[0108] Further preferred compounds of the present invention include those in which the one or more lipids comprise palmitoylethanolamide (PEA).

[0109] Further preferred compounds of the present invention include those wherein the one or more lipids are selected from the group consisting of vitamin E, vitamin A, and cholesterol, or a derivative of any of these. In such embodiments, the derivative of cholesterol may be cholesterol-acetate.

[0110] Further preferred compounds of the present invention include those in which the lipid is a fatty acid as defined above, which fatty acid may contain 1 to 5 -OH groups, for example 1 to 2 -OH groups. In other embodiments, the fatty acid may have 1 to 10 cyclic rings, for example 1 to 8 cyclic rings.

[0111] Compounds of the invention that may be mentioned include those in which L represents at least one lipid as defined above.

[0112] The optional lipid defined by L may be covalently attached to the amino acid sequence of the peptide in the compound of the invention via an amide bond formed between each carboxylic acid residue of L and one or more free NH residues present in one or more amino acids of the peptide (including those at the N-terminus of the peptide sequence), and / or via an ester bond formed between each -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 those at the C-terminus of the peptide sequence).

[0113] In the compounds of the present invention, taken together, it is preferred that the total number of optional lipids defined by L is 8 or less, more preferably 4 or less, for example 3, 2 or 1.

[0114] Preferred compounds of the present invention include those in which L represents two lipids, or more preferably one lipid, as defined above.

[0115] Preferred compounds of the invention include those in which each L group present represents the same lipid, for example palmitic acid or a derivative thereof.

[0116] For any one of the above specific peptide sequences defined by Z, at least one lipid defined by L (particularly palmitic acid or a derivative thereof) may be covalently bound to the amino acid sequence of the peptide in the compounds of the invention described above, particularly SEQ ID NOs: 127, 136, 205, 209, 217, and 253. In this regard, further compounds of the invention that may be mentioned include those in which Z is Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID NO: 254); Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 255); Palm-Lys-Hyp-Lys (SEQ ID NO: 256); Palm-Lys-Hyp-Hyp-Lys (SEQ ID NO: 257); Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID NO: 258); or Lys-Hyp-Lys(Palm)-Lys-Hyp-Lys(Palm) (SEQ ID NO: 259).

[0117] For the avoidance of doubt, the compounds of the invention as defined above (compounds of formula I) are hereinafter collectively referred to as "compounds of the invention".

[0118] 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, and DOPA represents 3,4-dihydroxyphenylalanine. A 3,4-dihydrocinnamic acid (HCA) residue is essentially a DOPA residue, but lacks an -NH group at the 2-carbon or α-carbon position relative to the carboxylic acid attached to the N-terminal amino acid (Lys or Ala).

[0119] The compounds of the present invention, whether in salt form or not, include positional isomers within the amino acids of the peptide (e.g., diHyp, Hyp, and Tyr moieties), as well as mixtures of such positional isomers. For example, the definition of Tyr includes not only tyrosine (4-hydroxyphenylalanine) but also 2- and 3-hydroxyphenylalanine. The definition of Hyp includes 4-hydroxyproline (4Hyp), 3-hydroxyproline (3Hyp), and 5-hydroxyproline (5Hyp). It is more preferred that the Hyp residue is 4-hydroxyproline. Similarly, the definition of diHyp includes 3,4-dihydroxyproline (3,4diHyp), 3,5-dihydroxyproline (3,5diHyp), and 4,5-dihydroxyproline (4,5diHyp). It is more preferred that the diHyp residue is 3,4-dihydroxyproline (3,4diHyp).

[0120] Furthermore, in addition to the standard central carbon atom of the amino acids of the compounds of the present invention (usually, but not exclusively, in the L-configuration), certain amino acids in the sequence contain an additional chiral carbon atom. All such stereoisomers and mixtures thereof (including racemic mixtures) are included within the scope of the present invention. In this respect, the definition of Hyp includes trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, cis-3-hydroxy-L-proline, trans-5-hydroxy-L-proline, and cis-5-hydroxy-L-proline, although trans-4-hydroxy-L-proline is preferred for Hyp used in the compounds of the present invention. Similarly, a corresponding definition may be applied to diHyp, in which the two hydroxy groups may be cis or trans relative to each other. In any event, 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.

[0121] The compound of the present invention may be in the form of a salt. Salts that may be mentioned include pharmaceutically acceptable salts and / or cosmetically acceptable salts, such as pharmaceutically and / or cosmetically acceptable acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the compound of the present invention with one or more equivalents of an appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization, or filtration). Salts may also be prepared by exchanging the counterion of the component of the present invention in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0122] Preferred salts include, for example, acetate, hydrochloride, bisulfate, maleate, mesylate, tosylate, alkaline earth metal salts such as calcium and magnesium, or alkali metal salts such as sodium and potassium salts. Most preferably, the compounds of the present invention may be in the form of acetate salts.

[0123] The compounds of the present invention can be prepared by conventional techniques, for example by standard amino acid coupling techniques, using standard coupling reagents and solvents, for example as described below. The compounds of the present invention can be synthesized from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled artisan may refer, inter alia, to "Comprehensive Organic Synthesis" by B.M. Trost and I. Fleming, Pergamon Press, 1991. Further references that may be used include "Heterocyclic Chemistry" by J.A. Joule, K. Mills and G.F. Smith, 3 rd edition, published by Chapman & Hall; "Comprehensive Heterocyclic Chemistry II" by A.R. Katrittzky, C.W. Rees and E.F.V. Scriven, Pergamon Press, 1996; and "Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0124] The compounds of the invention can be isolated from their reaction mixtures and, if necessary, purified using conventional techniques such as those known to those skilled in the art. Thus, the processes for preparing the compounds of the invention described herein may comprise, as a final step, the isolation and optional purification of the compounds of the invention.

[0125] It will be appreciated by those skilled in the art that in the processes described above and below, the functional groups of intermediate compounds may need to be protected by protecting groups. Protection and deprotection of functional groups may be carried out before or after the reaction.

[0126] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and described below. For example, protected compounds / intermediates described herein may be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical reaction involved will dictate the need and type of protecting groups, as well as the sequence for achieving synthesis. The use of protecting groups is fully described in 'Protective Groups in Organic Synthesis', 5th edition, T.W. Greene & P. ​​G.M. Wutz, Wiley-Interscience (2014), the contents of which are incorporated herein by reference.

[0127] The compounds of the present invention are useful in human or veterinary medicine, and therefore, although they are indicated as pharmaceuticals (and / or in veterinary medicine), they may also be used in cosmetics and / or as part of medical devices.

[0128] While the compounds of the present invention may also possess pharmacological activity themselves, certain pharmaceutically acceptable (e.g., "protected") derivatives of the compounds of the present invention exist or may be prepared, which may not possess such activity but may be orally administered and subsequently metabolized or chemically converted to form the compounds of the present invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably less 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.

[0129] As used herein, reference to a prodrug is meant to include compounds that form experimentally detectable amounts of a compound of the invention within a given time period after administration. All prodrugs of the compounds of the invention are included within the scope of the invention.

[0130] The compounds of the present invention, when pharmacologically active, are particularly useful in the treatment of inflammation.

[0131] The term "treatment of inflammation" includes treatment of inflammation in any organ of the body (including soft tissues, joints, nerves, vasculature, internal organs, particularly mucosal surfaces, and especially skin), regardless of cause, and also includes all such inflammatory disorders or conditions and / or disorders or conditions characterized (e.g., as a symptom) by inflammation.

[0132] Inflammatory disorders and / or conditions may be (and typically are) characterized by the activation of immune defense mechanisms, resulting in effects that are more harmful than beneficial to the host. Such conditions are generally associated with varying degrees of tissue redness or hyperemia, swelling, edema, hyperthermia, pain (including soreness), fluid exudation, itching (pruritus), cell death, and tissue destruction, cell proliferation, and / or loss of function.

[0133] 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, tendonitis, bursitis, Sjögren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis, and related cardiovascular disorders. A condition characterized by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD). Another condition characterized by inflammation that may be mentioned is inflammatory bowel disease, including Crohn's disease and, in particular, ulcerative colitis. Other conditions 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 formation (e.g., gastritis, gastric ulcer, stress-induced gastritis, gastric cancer, and other gastric mucosal diseases), as well as inflammation associated with gastroesophageal reflux disease (GERD), constipation, and gastritis, cancer, and infections (e.g., viral infections such as the common cold or influenza).

[0134] Further inflammatory conditions that may be mentioned in particular 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 resulting from infection (such as viral and / or bacterial infection) or allergic / atopic conditions (such as rhinitis (e.g., allergic rhinitis), pharyngitis, periodontitis, gingivitis, xerophthalmia, conjunctivitis (e.g., allergic conjunctivitis), dermatitis, urticaria (hives), and food allergies), as well as other inflammatory conditions such as herpes, drug eruptions, polymorphous light eruption, sunburn, early symptoms of skin cancer (erythematous skin lesions), pathological alopecia (including after skin grafts), chemical rash, psoriasis, erythema multiforme, folliculitis, eczema, and otitis externa. A condition that may be mentioned is polymorphous light eruption.

[0135] More specifically, the compounds may be used to treat certain conditions characterized by and / or associated with inflammation. Such conditions may include wounds (including abrasions (scratches), incisions (including surgical incisions), lacerations, punctures, lacerations, bruises, and scars), burns (including inflammation resulting from post-burn surgery, such as skin grafts), and other conditions such as hemorrhoids. Wounds may be acute or chronic and / or may result from one or more inflammatory disorders as defined herein.

[0136] Skin or mucosal wounds may result from internal or external physical injury to the membrane surface, or may be caused by (ie, be a symptom of) an underlying physiological disorder.

[0137] 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 light (sunburn), cold (chills or frostbite). Wounds may 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.

[0138] The compounds of the present invention may be used to alleviate pain (including soreness) associated with inflammation and / or wounds. Specifically, the compounds of the present invention may be used to alleviate procedural and / or non-procedural pain. Those skilled in the art will appreciate that the term "procedural pain" (i.e., surgical pain) refers to acute pain associated with medical investigations and treatments performed for medical purposes. The term "non-procedural" refers to general pain associated with inflammation and / or wounds (e.g., pain associated with dental ulcers, burns, and / or scarring) and is not the result of a specific medical intervention.

[0139] Not only can the compounds of the invention be used to treat inflammation, pain (including pain), and / or pruritus (itching) associated with the wound itself and the healing process, they may also be used to prevent exudation of fluid from the wound, the risk of infection, and prevent physiological responses resulting from inflammation and / or the wound healing process, such as scarring and melanin pigmentation.

[0140] Scarring is the result of inflammation and / or wound healing and is a general term for the formation of fibrous tissue that is the result of such inflammation / healing.

[0141] The compounds of the present invention may also be useful in suppressing the production of melanin pigmentation, which may or may not result from inflammation and / or wound healing. The compounds of the present invention may also be useful in suppressing disorders associated with melanin pigmentation, such as melasma, freckles, melanin pigmentation, butterfly rash, and other pigmentation, skin cancer including melanoma, and pigmentation caused by sun exposure or skin diseases such as acne.

[0142] Wounds can also occur as a result of (e.g., inflammatory) diseases or disorders. Such wounds may include blisters and / or ulcers of the skin and mucous membranes. These are common conditions that are often long-lasting and difficult to treat. Skin tissue can often become damaged, removed, liquefied, infected, and / or necrotic. Ulcers, especially if infected, can have secondary health consequences, are difficult to heal, and are expensive to treat. They can also cause significant psychological stress and economic loss to patients, affecting both their overall well-being and quality of life.

[0143] Alternatively, inflammatory skin conditions or diseases in which the compounds of the invention find particular utility include the treatment of psoriasis, acne, eczema and dermatitis, particularly allergic / atopic dermatitis, as well as rhinitis, particularly allergic rhinitis, haemorrhoids, chronic obstructive pulmonary disease, and mucositis characterized by ulcerative colitis.

[0144] Psoriasis is a chronic inflammatory skin disease that tends to recur (some patients never recover). Clinical symptoms of psoriasis mainly include erythema and scaling. It can occur all over the body, but is more commonly observed on the scalp and hands and feet.

[0145] Acne is a chronic inflammatory skin disease of the follicular (pilosebaceous unit) whose occurrence is closely related to major factors such as excess sebum, obstruction of the pilosebaceous duct (including closed and open comedones), bacterial infection, and inflammatory reactions. It tends to occur at an early age and is characterized by polymorphic skin lesions on the face. Therefore, the term acne includes ordinary acne and acne rosacea (i.e., red nose).

[0146] Eczema is an intensely itchy inflammatory reaction of the skin caused by a variety of internal and external factors. It has three stages: acute, subacute, and chronic. The acute stage tends to produce exudate, while the chronic stage involves infiltration and swelling. The skin lesions are often itchy and easily recur.

[0147] Dermatitis is a common skin disorder characterized by roughness, redness, itchiness, eczema, and dryness. The small lumps, persistent ulcers, and pigmented patches caused by dermatitis can develop into basal cell carcinoma, squamous cell carcinoma, and malignant melanoma if not treated promptly. Dermatitis can be caused by a variety of internal and external infectious or non-infectious factors, including substances (contact dermatitis) or allergies (allergic / atopic dermatitis). Also included are seborrheic dermatitis (seborrheic eczema), cicatricial alopecia and related disorders, and all forms of steroid-dependent dermatitis (including photosensitive seborrheic dermatitis, perioral dermatitis, rosacea-like dermatitis, steroid rosacea, steroid-induced rosacea, iatrosacea, steroid-dermatitis-like rosacea, topical corticosteroid-induced rosacea-like dermatitis, and more specifically facial corticosteroid addictive dermatitis (FCAD) or facial corticosteroid-dependent dermatitis (FCDD), characterized by flushing, erythema, telangiectasias, atrophy, papules, and / or pustules in the facial area after long-term treatment (including uncontrolled use, abuse, or misuse) with topical corticosteroids, see, for example, Xiao et al., J. Dermatol., 2015, 42, 697-702 and Lu et al., J. Dermatol., 2015, 42, 697-702). al., Clin. Exp. Dermatol., 2009, 35, 618-621).

[0148] Rhinitis is the irritation and inflammation of the mucous membrane inside the nose.The common symptoms of rhinitis include stuffy nose, 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 skin flakes.Surprisingly, it has been found that the patients with allergic rhinitis treated with the compound of the present invention can experience relief from itchy eyes, even when the compound of the present invention is administered nasally (i.e., to the nasal mucous membrane).

[0149] Hemorrhoids are swellings caused by large inflammations of hemorrhoidal blood vessels found in or around the rectum and anus. Symptoms include bleeding (i.e., wounds) after passing stool, prolapsed hemorrhoids, mucus discharge and itching, burning, redness, and swelling in the anal area. Hemorrhoids are thought to be the result of increased abdominal pressure, for example, as a result of constipation or diarrhea.

[0150] Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause difficulty breathing, including emphysema (damage to the alveoli) and chronic bronchitis (long-term airway inflammation). COPD occurs when the lungs become inflamed, damaged, and narrowed. The damage to the lungs is usually irreversible, resulting in impaired airflow 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 smoke.

[0151] The compounds of the present invention may have a positive effect on reducing erythema, redness and swelling, edema, blisters, and bullous pemphigoid caused by various conditions, including those generally and specifically mentioned herein, and may inhibit the exudation of subcutaneous tissue fluid and suppress the itching and pain caused by such inflammatory conditions.

[0152] Other inflammatory conditions that may be mentioned include:

[0153] (a) Mucosal inflammation such as inflammation caused by oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis, and enterocolitis (including bacterial dysentery, chronic amebic dysentery, schistosomiasis, nonspecific ulcerative colitis, and regional enteritis), cervicitis and endocervicitis, endometritis, inhalation injury, and the like, as well as inflammation of the mucosa associated with cancer and infections (e.g., viral infections such as the common cold or influenza) affecting mucosal surfaces such as the oral cavity, nasopharynx, ears, throat, trachea, gastrointestinal tract, and cervix.

[0154] (b) Orthopedic inflammation associated with, for example, fractures, pyogenic infections of bones and joints, inflammation caused by rheumatic bone disease, and pyogenic osteomyelitis (acute osteomyelitis, chronic osteomyelitis, focal osteomyelitis, sclerosing osteomyelitis, post-traumatic osteomyelitis), septic arthritis; bone tumors (osteoma, osteoid, chondroma), bone cysts, osteoclastoma, primary bone sarcomas (osteosarcoma, chondrosarcoma, osteofibrosarcoma, Ewing's sarcoma, non-Hodgkin's lymphoma, myeloma, chordoma), metastatic bone tumors, tumor-like lesions of bone (bone cysts, aneurysmal bone cysts, eosinophilic granuloma, fibrous dysplasia); and rheumatoid arthritis.

[0155] (c) Nerve inflammation such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, and intercostal neuritis.

[0156] (d) Inflammation of subcutaneous and submucosal soft tissues, such as myositis, dendritis, tendonitis, cystitis, lymphadenitis, cryptitis, tonsillitis, synovitis, fasciitis, and soft tissue inflammation caused by injury, contusion, or tear of muscle, ligament, fascia, tendon, synovium, fat, joint capsule, and lymphatic tissue.

[0157] (e) Vascular inflammation such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatoid vasculitis, as well as vascular inflammation associated with vascular cancer caused by allergic leukocytoclastic vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatoid vasculitis.

[0158] (f) Inflammation of internal organs such as the heart, stomach, intestines, lungs, liver, spleen, kidneys, pancreas, bladder, ovaries, and prostate, including, but not limited to, pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, splenitis, nephritis, pancreatitis, cystitis, oophoritis, prostatitis, and gastric ulcers.

[0159] (g) Inflammation of the eye and peripheral area, such as conjunctivitis, keratitis (e.g., acute epithelial keratitis, nummular keratitis, interstitial keratitis, disciform keratitis, neurotrophic keratitis, mucoplaque keratitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, acanthamoeba keratitis, Onchocerca volvulus keratitis, superficial punctate keratitis, ulcerative keratitis, lagophthalmos keratitis, photokeratitis, and acute hyperemia during contact lens wear), optic neuritis, retinal maculopathy, and retinopathy.

[0160] (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, and dental ulcers.

[0161] (i) Rheumatoid inflammation such as rheumatoid 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, Sjogren's syndrome, spondyloarthropathy, systemic lupus erythematosus, and tendonitis.

[0162] The compounds of the invention may also be used (eg, by systemic and local administration) to differentiate and regenerate bone marrow cells and in aplastic anemia.

[0163] The compounds of the invention may also be used in the treatment of renal disease, including end-stage renal disease and its complications, including uremic pruritus.

[0164] The compounds of the present invention may also be used to treat certain specific disorders of the digestive system, such as gastroesophageal reflux disease (GERD), which may be characterized by sour taste in the mouth, reflux, heartburn, painful swallowing and / or sore throat, increased salivation (heartburn), nausea, chest pain, and coughing. GERD can cause damage to the esophagus, including reflux esophagitis (i.e., inflammation of the esophageal epithelium that can lead to 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 epithelial cells from squamous epithelium to intestinal columnar epithelium in the distal esophagus), and / or esophageal adenocarcinoma (a form of cancer)).

[0165] The compounds of the present invention may also be used in the treatment of certain specific diseases of the respiratory system, such as cystic fibrosis, common interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, cor pulmonale, pulmonary embolism, etc. A particular disease state that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0166] IPF is a diffuse and fatal pulmonary interstitial disease with pathological characteristics including alveolar epithelial damage, extensive proliferation of pulmonary fibroblasts, and excessive deposition of extracellular matrix, which ultimately leads to irreversible lung tissue damage.In the later stage of the disease, the subject with IPF experiences respiratory failure and death.It has been found that the compound of the present invention can be useful in treating IPF and / or alleviating the symptoms associated with this disease.

[0167] The compounds of the invention may be used to treat the following pulmonary and / or fibrotic conditions (whether or not otherwise described herein): pulmonary fibrosis, renal fibrosis, hepatic fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, severe asthma, bronchiectasis, upper respiratory tract infections (including colds and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasmal pneumonia, reckettsia, radiation pneumonitis, pneumococcal (including staphylococcus, streptococcus, and gram-negative bacillus) pneumonia, pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis, and nocardiosis), pulmonary mycosis, cryptococcosis, lung abscess, anaphylactic pneumonia, extrinsic allergic alveolitis, pulmonary eosinophilia (Loeffler's syndrome), and / or pulmonary eosinophilia (Loeffler's syndrome). It is particularly useful in the treatment of pulmonary eosinophilia (eosinophilia syndrome), extrinsic allergic alveolitis, pulmonary eosinophilia (eosinophilia), obstructive emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis / acidosis, acute lung injury, interstitial lung disease, empyema, pulmonary fibroma, and cor pulmonale.

[0168] Particular mucosal disorders and diseases for which the compounds of the invention are useful include, for example, anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, fissures, anal itching, anal sinusitis, warts, and rectal prolapse; inflammatory bowel diseases including Crohn's disease and especially ulcerative colitis; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as periodontitis.

[0169] The compounds of the present invention may further have antioxidant effects by increasing SOD (superoxide dismutase) production and reducing lipid oxidation, and therefore may be considered to have antioxidant properties.

[0170] The compounds of the present invention may also possess antipyretic properties, allowing for the treatment of fever and / or alleviating its symptoms, for example, by reducing the body temperature of a subject, resulting in a reduction in fever. Thus, the compounds of the present invention and formulations containing them may be considered to be antipyretics.

[0171] According to a further aspect of the present invention, there is provided a method for treating inflammation, inflammatory disorders, and / or disorders / conditions characterised by inflammation (e.g., as a symptom), which method comprises administering a compound of the invention, or a salt thereof, to a patient in need of such treatment.

[0172] For the avoidance of doubt, in the context of the present invention, the terms "treatment", "therapy" and "treatment" include therapeutic or palliative treatment of patients in need of treatment as well as prophylactic treatment and / or diagnosis of patients susceptible to inflammation and / or inflammatory disorders.

[0173] The compounds of the invention may further possess antiviral properties which may allow for the treatment of the viral infection itself, i.e., the treatment of a viral infection or disease by interfering with viral replication within the host, as opposed to treating any viral infection or any symptom of a viral infection, such as pain and / or inflammation. Such antiviral properties may also allow for the prevention of the onset of such infection or disease, the protection of cells within the host from (e.g., further) viral infection, the prevention or arrest of the spread of viral infection or disease (within a single host or from one host to new hosts), or the prevention of viral reactivation after latency in the host.

[0174] According to a further aspect of the present invention there is provided a method for treating a viral infection which comprises administering a compound of the present invention, or a salt thereof, to a patient in need of such treatment.

[0175] 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 virus type 1; herpes simplex virus type 2; varicella-zoster virus; Epstein-Barr virus; human cytomegalovirus; human herpesvirus type 8), poxviridae (e.g., smallpox), hepadnaviridae (e.g., hepatitis B virus). , parvoviridae (e.g., parvovirus B19), astroviridae (e.g., human astrovirus), caliciviridae (e.g., norovirus; Norwalk virus), picornaviridae (e.g., coxsackievirus, hepatitis A virus; poliovirus; rhinovirus), coronaviridae (e.g., severe acute respiratory syndrome virus), flaviviridae (e.g., hepatitis C virus; yellow fever virus; dengue virus; West Nile virus; tick-borne encephalitis virus), retroviridae (e.g., human immunodeficiency virus; human immunodeficiency virus, HIV), togaviridae (e.g., rubella virus), arenaviridae (e.g., Lassa virus), bunyaviridae (e.g., hantavirus; Crimean-Congo hemorrhagic fever virus; hantavirus), filoviridae (e.g., Ebola virus; Marburg virus; Ravn virus), orthomyxoviridae (e.g., influenza viruses, including influenza A virus (e.g., H1N1 and H3N2 viruses), influenza B virus, or influenza C virus), paramyxoviridae (e.g., measles virus; mumps virus; parainfluenza virus; respiratory syncytial virus), rhabdoviridae (e.g., rabies virus), hepeviridae (e.g., hepatitis E virus), reoviridae (e.g., rotavirus; orbivirus; coltivirus;Bannavirus), as well as viruses not assigned to a family, such as hepatitis D virus;

[0176] Viruses that may be mentioned more particularly include herpes simplex type 1 and herpes simplex type 2, human papillomavirus, influenza virus and parainfluenza virus.

[0177] The compounds of the present invention may further possess antibacterial and / or bacteriostatic properties which may allow for the treatment of the bacterial infection itself, i.e., the treatment of a bacterial infection or disease by interfering with the growth or proliferation of bacteria within the host, as opposed to treating any symptoms of any bacterial infection or disease, such as pain and / or inflammation. Thus, the compounds of the present invention may be considered to be bactericidal and / or preferably bacteriostatic agents.

[0178] Such antibacterial properties may also enable the prevention of the onset of such infection or disease, the protection of cells within a host from (e.g., further) bacterial infection, the prevention or arrest of the spread of bacterial infection or disease (within a single host or from one host to new hosts), or the prevention of reactivation of bacteria after latency in the host.

[0179] According to a further aspect of the present invention there is provided a method for treating a bacterial infection which comprises administering a compound of the present invention, or a salt thereof, to a patient in need of such treatment.

[0180] The compounds of the present invention may further possess anti-cancer properties which may allow for the treatment of cancer itself, i.e., by interfering with the cancer, as opposed to treating any symptoms of cancer, such as pain and / or inflammation. Such anti-cancer properties may also include preventing the onset of such diseases, for example, by preventing such onset by treating inflammation.

[0181] According to another aspect of the present invention, there is provided a method for treating cancer, which method comprises administering a compound of the present invention, or a salt thereof, to a patient in need of such treatment.

[0182] Specific cancers that may be mentioned include oral cavity cancer, nasopharyngeal cancer, middle ear cancer, conjunctival cancer, throat cancer, tracheal cancer, esophageal cancer, stomach cancer, intestinal cancer, cervical cancer, endometrial cancer, skin cancer caused by oral mucositis, rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophagitis, gastritis, enterocolitis, cervicitis, endometritis, erythematous skin lesions, etc. A specific skin cancer that may be mentioned is basal cell carcinoma.

[0183] Fibrotic conditions of internal organs that may be mentioned include acute and / or severe internal fibrotic conditions characterized by excessive accumulation of fibrous connective tissue (as described above) in and around inflamed or damaged tissues. Therefore, the formulations of the present invention may be useful for treating or preventing fibrosis (as described above) and the morbidity and mortality that may be associated therewith. Therefore, fibrotic conditions of internal organs (e.g., acute and / or severe) that can be treated with the formulations of the present invention include fibrosis of the liver, kidneys, lungs, cardiovascular system including the heart and vascular system, pancreas, spleen, central nervous system (neurofibrosis), bone marrow fibrosis, fibrosis of the eye, vagina, cervix, etc.

[0184] Inflammatory conditions of the internal organs include those that are or may develop into any severe condition (i.e., those requiring intensive medical treatment), and those in which some inflammatory component is evident such that they may be characterized by detectable inflammation, as well as those in which morbidity is evident (or anticipated) and / or is life-threatening.

[0185] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of an internal organ (i.e., one or more conditions that require, or may develop into, a condition requiring immediate medical intervention), such as acute visceral injury, in one or more internal organs (including any of the organs mentioned above) that are characterized by inflammation (e.g., as a symptom). By treating such acute inflammatory disorders, the formulations of the present invention may prevent or inhibit the onset of symptoms (acute or chronic) associated with such conditions, and may inhibit the progression of morbidity and / or mortality associated with such conditions.

[0186] Thus, acute inflammatory conditions that may be mentioned include conditions such as peritonitis, pancreatitis, colitis, proctitis (including radiation proctitis), gastritis, duodenitis, pharyngitis, GERD, periodontitis, and stomatitis. Particular acute inflammatory conditions that may be mentioned include acute injury to one or more internal organs (including any of those mentioned above), such as acute lung injury, airway injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and multi-organ inflammation, injury, and / or failure.

[0187] Such conditions may be caused by internal or external trauma (eg, an injury or burn), or by infection, for example, by a virus, bacteria, or fungus.

[0188] For example, proctitis (including eosinophilic, gonococcal and / or ulcerative proctitis) may be caused by inflammatory bowel disease, infection, radiation (e.g., due to cancer), drugs such as antibiotics, surgery, or allergic conditions such as food intolerances.

[0189] For example, multiple organ inflammation, injury, and / or failure can result from extensive and / or traumatic external injury, including traumatic and / or extensive burns. Traumatic external burns are understood to include second-degree, more specifically third-degree and fourth-degree burns. Extensive external burns are understood to include burns affecting at least about 10%, such as at least about 15%, including at least about 20% of the patient's body area. External (and internal) burns may result from exposure to heat, chemicals, and the like. Acute inflammatory and / or fibrotic conditions may also result from sepsis or septic shock, which may be caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and particularly SARS, may be caused by viruses, such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2).

[0190] Additionally, one or more of the aforementioned (e.g., acute) inflammatory conditions may (and in some cases likely will) result in some form of internal tissue damage and / or dysfunction of associated internal tissues. As such, associated tissues include tissues (e.g., mucosal) such as the respiratory epithelium. Such tissue damage may also result in one or more of the fibrotic conditions described above. For example, SARS disease, caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019, or COVID-19), is known to often cause fibrosis resulting from one or more of many factors, including inflammation.

[0191] In this regard, the compounds of the present invention and their salts find particular utility in the treatment of related inflammatory and / or fibrotic conditions, given that such conditions are often characterized by one or more co-morbidities. A condition "characterized by a co-morbidity" includes when the primary condition in question simultaneously causes (or is caused by) further medical conditions, including (and indeed preferably) those mentioned above, which may interact and / or overlap with one another in some way.

[0192] For this reason, a method for treating at least one inflammatory and / or fibrotic disorder or condition of one or more internal organs in a patient, the method 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; a method for treating two or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs in a patient, the method comprising direct systemic parenteral administration of a compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment; A method of reducing the incidence of morbidity and / or mortality associated with or which may be associated with one or more inflammatory and / or fibrotic disorders or conditions in 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.

[0193] Additionally, the compounds of the present invention may be used in the treatment of conditions characterized by immunosuppression, immune deficiency disorders, in the treatment of patients with compromised immune systems, and / or to restore normal function of a patient's immune system.

[0194] Conditions characterized by immunosuppression (or immunodeficiency disorders) include primary immunodeficiency disorders (PIDDs), which are typically rare congenital disorders that are usually inherited. Thus, PIDD includes humoral immunodeficiency disorders, such as common variable immunodeficiency, selective immunoglobulin deficiency (e.g., IgA deficiency), transient hypogammaglobulinemia of infancy, and X-linked agammaglobulinemia; cellular immunodeficiency disorders, such as chronic mucocutaneous candidiasis, DiGeorge syndrome, and X-linked lymphoproliferative syndrome; combined humoral and cellular immunodeficiency disorders, such as ataxia-telangiectasia, hyperimmunoglobulinemia E syndrome, severe combined immunodeficiency, and Wiskott-Aldrich syndrome; phagocytic immunodeficiencies, such as Chediak-Higashi syndrome, chronic granulomatous disease, cyclic neutropenia, and leukocyte adhesion deficiency; and complement deficiencies, such as complement component 1 (C1) inhibitor deficiency (or hereditary angioedema), C3 deficiency, C4 deficiency, and C5, C6, C7, C8, and / or C9 deficiency.

[0195] However, the immunodeficiency disorder treated in accordance with the present invention is preferably a secondary immunodeficiency disorder (SIDD), which is more common than PIDD and tends to occur later in life, and includes immunodeficiency disorders caused by secondary factors such as aging, malnutrition (e.g., nutritional deficiencies), chronic disorders, one or more chemical agents (e.g., drugs), and / or (e.g., ionizing) radiation.

[0196] For purposes of the present invention, the term "SIDD" may also include physical and / or psychological stress, which may act to impair the patient's immune system.

[0197] Physical stress may be caused by trauma (injury, infection, surgery), strenuous physical work / excessive effort (e.g., overtraining), environmental pollution (pesticides, herbicides, toxins, heavy metals, insufficient light, radiation, noise, electromagnetic fields), disease (viral, bacterial, or fungal agents), fatigue, inadequate oxygen supply, hypoglycemia, hormonal and / or biochemical imbalances, dietary stress (nutritional deficiencies, food allergies and sensitivities, unhealthy eating habits), dehydration, substance abuse, dental problems, and musculoskeletal misalignment / imbalance.

[0198] Mental stress may include various forms of psychological and / or psychosocial stress, such as emotional stress (e.g., negative emotions such as anxiety, fear, frustration, sadness, anger, grief / bereavement, etc.); cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, obsession, self-criticism, self-loathing, unworkable perfectionism, anxiety, panic attacks, 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 partner, siblings, children, extended family, employer, coworkers); lack of social support (e.g., friends and / or isolation); financial stress (e.g., due to unemployment, investments, savings, bankruptcy, home foreclosure, etc.).

[0199] Disorders that can cause immunodeficiency in a patient include cancer; blood disorders such as aplastic anemia, leukemia, multiple myeloma; sickle cell disease, Down's syndrome; infections such as viral infections, including chickenpox, cytomegalovirus, Epstein-Barr virus, HIV, measles, and bacterial infections; diabetes; diseases of the internal organs, such as chronic kidney disease, nephrotic syndrome, chronic hepatitis, liver failure; systemic lupus erythematosus; alcoholism, chronic burns; and surgery, such as removal of the spleen.

[0200] Drugs that may cause immune deficiency in patients include anti-seizure medications such as lamotrigine, phenytoin, valproate; immunosuppressants such as azathioprine, cyclosporine, everolimus, leflunomide, mycophenolate, mofetil, sirolimus, tacrolimus, tofacitinib; biologics such as abatacept, adalimumab, anakinra, basiliximab, certolizumab, daclizumab, etanercept, golimumab, infliximab, ixekizumab, muromonab (OKT3), natalizumab, rifametrin ... Tuximab, secukinumab, tocilizumab, ustekinumab, vedolizumab; and in particular corticosteroids, including naturally occurring corticosteroids, cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, and naturally occurring precursors and intermediates in corticosteroid biosynthesis, 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, hydrocortisone type (group A), such as cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol;Acetonides and related substances (group B), such as amcinonide, budesonide, desonide, fluocinolone cetonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formotruol, fludroxycortide, flunisolide and fluocinolone acetonide, (beta)methasone types (group C), such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halometasone, mometasone and mometasone furoate, alclometasone and alclometasone propionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, difluocortolone (d ifluocortolone), flucloron, flumethasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone, and urobetasol; progesterone-type drugs such as flugestone, fluorometholone, medrysone, and prebedilone acetate, and progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medrogestone, 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;

[0201] However, drugs that may cause immunodeficiency in patients that may be of particular mention include chemotherapy treatments for cancer such as alemtuzumab, busulfan, cyclophosphamide, melphalan, etc.

[0202] Particular SIDDs that may be mentioned include those caused by radiation therapy (ie, radiation-induced immunosuppression) used to treat disorders such as cancer.

[0203] Ionizing radiation not only suppresses the immune system as described above, but can also alter immune system function in irradiated organs in other ways. For example, increased 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 beta (TGF-β), and interferon gamma (IFN-γ), are associated with the release of prostaglandins and free radicals, including reactive oxygen species (ROS) and nitric oxide (NO). Exposure to high doses of radiation, as can occur during accidental exposure (e.g., as a result of a nuclear or radiological disaster), can trigger inflammatory responses and / or wounds that can persist for years and / or disrupt the function of irradiated organs.

[0204] The compounds of the present invention may be used not only to provide an immune restorative effect, but also to simultaneously promote wound recovery and / or healing, which is particularly useful in view of the fact that wounds associated with such conditions are difficult, if not impossible, to treat adequately in view of the radiation-induced immunosuppressive effects and lack of a normal endogenous inflammatory response.

[0205] By providing the aforementioned immune restorative effect, this allows the body's immune system and localized 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 impair the patient's immune system (in the manner that corticosteroids are used to treat inflammation).

[0206] According to a further aspect of the invention there is provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of inflammation and / or a condition characterised by inflammation or wounding in a patient having or vulnerable to a condition characterised by immunosuppression, including the treatment of radiation-induced conditions characterised by inflammation and / or wounding.

[0207] Diseases (including those characterized by inflammation and / or wounds) that are themselves radiation-induced and / or that can result in radiation-induced immunosuppression include those that can occur after accidental exposure to radiation (commonly known as "radiation poisoning") or after intentional and / or targeted exposure to radiation, for example, as a result of (e.g., ionizing) radiation therapy to treat diseases such as cancer.

[0208] Radiation therapy is a type of cancer treatment that uses an external beam of intense energy to kill cancer cells, for example. Radiation therapy most often uses X-rays, but protons or other types of energy can also be used. Radiation therapy may be used as a primary cancer treatment, in neoadjuvant therapy (to shrink cancerous tumors before surgery), in adjuvant therapy (to prevent cancer cell growth after surgery), to relieve symptoms caused by advanced cancer, or a combination of two or more of the above. Radiation therapy may also be used in combination with other treatments, such as chemotherapy.

[0209] Disorders characterized by inflammation and / or wounding of mucous membranes and / or skin that can result from exposure to radiation are often associated with the part of the body that is targeted / irradiated. For example: Radiation-induced dermatitis and mucositis can occur in the skin or mucosa, respectively, in locations that may be close to the irradiated body part. For example, radiation-induced oral mucositis can occur after irradiation of the head or neck. Radiation-induced encephalitis can also occur after irradiation of the head or neck. Radiation pneumonitis and / or radiation esophagitis often result from radiation therapy for lung cancer, breast cancer, lymphoma, thymic tumors, or esophageal cancer.

[0210] Radiation therapy directed at the abdomen, pelvis, or rectum (e.g., to treat cervical, prostate, bladder, or rectal cancer) can cause one or more of radiation enteropathy (or radiation enteritis, including radiation colitis), radiation hepatitis, radiation myelitis, and radiation vaginitis, especially radiation proctitis.

[0211] In particular, radiation proctitis or radiation proctopathy is a condition characterized by damage to the rectum after exposure to radiation during radiation therapy. The inflammation can be acute (acute radiation proctitis and associated radiation colitis) or chronic (e.g., radiation-associated vascular ectasias (RAVE) and chronic radiation proctopathy).

[0212] Initial symptoms of acute radiation proctitis include pelvic pain, diarrhea, and tenesmus, but radiation damage to the rectum often causes urinary incontinence and rectal bleeding, and in severe cases, scars, strictures, and / or fistulas.

[0213] Thus, for example, in the treatment of disorders induced by irradiation for cancer therapy, more particularly irradiation of the lower abdominal region, including disorders such as radiation proctitis, radiation colitis, and radiation-induced dermatitis as defined above, the compounds of the present invention and their salts can be used to treat wounds associated with such disorders and / or promote wound recovery and / or healing, and may provide an immune restorative effect at the same time; and / or It may be used to promote further wound healing without compromising the patient's immune system, while also providing a more direct anti-inflammatory effect.

[0214] According to two further aspects of the invention: Methods for treating radiation-induced pathologies characterized by (i) immunosuppression and (ii) inflammation and / or wounds, and A method is provided for treating inflammation and / or wounds associated with radiation-induced immunodeficiency disorders while simultaneously restoring normal function of the patient's immune system, The method includes administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0215] The above-described methods of treatment and uses are particularly useful when the radiation-induced damage, for example for cancer therapy, results from irradiation of the lower abdominal region as described above.

[0216] Further provided is a method of reducing the incidence of morbidity and / or mortality that may be, or be associated with, radiation (e.g., ionizing radiation) induced damage characterized by inflammation and / or wounding in a patient, comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

[0217] Conditions for which the compounds of the invention are particularly useful include skin inflammation, physiological responses resulting from skin inflammation and / or wound healing processes, e.g., scarring and melanin pigmentation; inflammation and fibrosis of the scalp and hair follicles, including seborrheic dermatitis, cicatricial alopecia, and related conditions; gastritis, gastric ulcers, stress-induced gastritis; GERD; IBD, including Crohn's disease, ulcerative colitis, and / or proctitis, radiation proctitis; arthritis; retinal maculopathy; bone marrow cell differentiation and regeneration, 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.

[0218] In addition, the compounds of the present invention may be used in non-therapeutic cosmetic treatments such as anti-aging.

[0219] Thus, a further aspect of the invention is the non-therapeutic use of the compounds of the invention in anti-aging, for example by promoting skin integrity so that the skin has the appearance of younger skin.

[0220] A further aspect of the present invention is a cosmetic composition comprising a compound of the present invention. Such a composition may provide anti-aging properties.

[0221] "Patient" includes reptilian, avian and preferably mammalian (especially human) patients.

[0222] According to the present invention, the compounds of the present invention are administered in the form of a pharmaceutical formulation comprising the compound in a pharmaceutically acceptable dosage form, preferably locally or systemically, for example orally, intravenously, or intra-arterially (including intravascular and other perivascular devices / dosage forms (e.g., stents)), intramuscularly, cutaneously, subcutaneously, transmucosally (e.g., sublingually or bucally), rectally, intravaginally, transdermally, intranasally, pulmonary (e.g., trachea or bronchus), for example, by direct injection, or by any other parenteral route, preferably topically, or by any other parenteral route.

[0223] Administration by inhalation (eg, intranasal) is particularly useful when the condition being treated is rhinitis or inflammation resulting from a viral infection of the respiratory tract (eg, upper respiratory tract infections such as the common cold and influenza).

[0224] Pulmonary administration is particularly useful when the condition being treated is COPD or IPF. Topical administration forms may be enhanced by creating a spray containing the active ingredient, for example, by using a powder aerosol or by an aqueous mist using appropriate atomization techniques or devices such as a nebulizer.

[0225] Anorectal administration is particularly useful when the condition being treated is hemorrhoids or ulcerative colitis, using an appropriate delivery means such as an injectable foam solution or suppository.

[0226] Administration to the lower gastrointestinal tract can also be achieved by parenteral, particularly oral, delivery using standard delayed-release or sustained-release coating techniques known to those skilled in the art. In particular, separate parts of the upper or lower intestine can be targeted. For example, colonic administration can also be achieved by colon-targeted drug delivery means that are first administered orally or parenterally.

[0227] The compounds of the invention may alternatively be administered by direct systemic parenteral administration, which may be useful in methods of treating one or more of the aforementioned disorders or conditions of one or more internal organs of a patient.

[0228] Internal organs that may be mentioned include the stomach, intestines, pancreas, liver, spleen, bladder, vascular system, ovaries, prostate, preferably the heart and kidneys, more preferably the lungs.

[0229] Standard delayed-release or sustained-release techniques known to those skilled in the art may be used for administration means other than oral, for example, subcutaneous or intramuscular depot formation techniques, or via alternative means of parenteral administration.

[0230] Thus, pharmaceutically acceptable formulations for use in 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 compounds and may have no adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also provide immediate or modified release of the compound of the invention.

[0231] Thus, formulations for injection may 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 alternatively, a lyophilized powder that can be reconstituted with a vehicle, such as an aqueous vehicle, prior to use (e.g., injection).

[0232] Formulations for injection may include other suitable excipients known to those skilled in the art, such as solvents (e.g., water), cosolvents, solubilizing agents (e.g., cyclodextrins), wetting agents, suspending agents, emulsifying agents, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, bulking agents, and / or protectants.

[0233] Formulations for injection are preferably buffered to a physiologically acceptable pH value (e.g., a pH of about 4.5 to about 9.5, e.g., about 6 to about 9, e.g., about 6.5 to about 8.5) using buffers and / or pH adjusting agents as described herein by standard techniques, and / or may further comprise a tonicity adjusting agent (e.g., sodium chloride).

[0234] Notwithstanding the above, preferred modes of delivery of the compounds of the present invention include local delivery to the site of inflammation (e.g., mucosa including the oral and / or nasal mucosa, lung, anorectal and / or colon, or more preferably the skin) in a suitable (e.g., pharmaceutically and topically acceptable) vehicle suitable for application to the skin and / or suitable mucosal surfaces, and / or in a commercially available formulation, but may also include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, or pulmonary delivery.

[0235] Administration by injection is particularly useful for administering the compounds of the invention in the form of a solution, for example as a suspension, into the dermis (eg, intradermal injection), joint cavity, or eye.

[0236] Administration by intradermal injection (e.g., intradermal) is particularly useful for administering the compounds of the invention to the dermis in the form of a solution or suspension (e.g., dermal filler), which is particularly useful as a means of administration for melanin pigmentation therapy as described above, or for use of the compounds of the invention in, for example, the treatment of wrinkles.

[0237] Administration by injection is particularly useful, for example, for filling surgical sites in the nasal cavity, anal fistulas, spaces between the gums and the roots of teeth or sinuses. It is particularly useful for shaping and / or lubricating supports.

[0238] The compounds of the present invention will generally be administered in the form of one or more, e.g., pharmaceutical formulations, mixed with (e.g., pharmaceutically acceptable) adjuvants, diluents, or carriers, which may be selected with due consideration of the intended route of administration (e.g., topical administration to relevant mucous membranes (including the lungs) or preferably to the skin) and standard pharmaceutical or other (e.g., cosmetic) practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also provide immediate or modified release of the compounds of the present invention.

[0239] Suitable pharmaceutical formulations are commercially available or can be found in the literature, for example, Remington The Science and Practice of Pharmacy, 22 nd edition,Pharmaceutical Press(2012), and Martindale-The Complete Drug Reference,38 th Edition, Pharmaceutical Press (2014), as well as the documents referenced therein, the relevant disclosures of all of which are incorporated herein by reference. Otherwise, the preparation of suitable formulations containing the compounds of the present invention can be achieved in ways not of the present invention by those skilled in the art using conventional techniques.

[0240] The compounds of the invention may be in the form of aqueous formulations such as emulsions, suspensions and / or solutions (e.g., (optionally) buffered aqueous formulations (e.g., solutions) such as saline-containing formulations (e.g., solutions), phosphate-containing formulations (e.g., solutions), acetate-containing formulations (e.g., solutions), or borate-containing formulations (e.g., solutions)), or as lyophilized powders.

[0241] The compounds of the invention can also and / or alternatively be prepared in combination with suitable excipients: Gel formulations (for which suitable gel matrix materials include cellulose derivatives, carbomers and alginates, tragacanth gum, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulose polysaccharides, sugars such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, especially hyaluronic acid); Lotions (for which suitable matrix materials include cellulose derivatives, glycerin, non-cellulose polysaccharides, polyethylene glycols of different molecular weights, and propanediol); Pastes or ointments (for which suitable paste matrix materials include glycerin, petrolatum, paraffin, polyethylene glycols of different molecular weights, etc.); Creams or foams (for which suitable excipients (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycols of various molecular weights, sodium dodecyl sulfate, sodium fatty alcohol polyoxyethylene ether sulfonate, corn gluten powder, and acrylamide); powder aerosols (suitable excipients for this include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol, and polysorbates, e.g., dry powder inhalants); and / or Oral or inhalable liquids, for example water (aerosol) sprays (suitable excipients for this include viscosity regulators such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohol, water, preservatives, sweeteners, flavors, etc.); injectable solutions or suspensions (whether aqueous or otherwise, for which suitable excipients include solvents and cosolvents, solubilizers, wetting agents, suspending agents, emulsifiers, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers and / or pH adjusters, bulking agents, protectants, and tonicity adjusters), especially when the compounds of the invention are combined with hyaluronic acid; particular injectable solutions or suspensions that may be mentioned include dermal fillers (e.g., injectable fillers or soft tissue fillers).

[0242] Moisturizing agents such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and salts (e.g., sodium and potassium salts), octanoic / capric triglyceride, and the like; and / or antioxidants such as vitamins and glutathione; and / or pH adjusters such as acids, bases, and pH buffers may also be included in such formulations as needed. Further, surfactants / emulsifiers such as hexadecanol (cetyl alcohol), fatty acids (e.g., stearic acid), sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (e.g., glyceryl monostearate), polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, polyoxylglycerides, lauryl dimethyl ethers, Other additives that may be included include: hydroxylamine oxide, bile salts (e.g., sodium deoxycholate, sodium cholate), lipids (e.g., fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenol, glycolipids, polyketides), phospholipids, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), sugar esters, polysorbates, etc.; preservatives such as phenoxyethanol, ethylhexylglycerin, etc.; and thickeners such as acryloyldimethyltaurate / VP copolymer. Specifically, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, octanoic / capric glycerides, etc. may be included, particularly in cream formulations.

[0243] The compounds of the present invention and (e.g., pharmaceutical) formulations comprising them (e.g., solutions, gels, creams, ointments, lotions, foams, pastes, and / or dry powders as described above) can be further combined with a suitable matrix material to prepare bandages or therapeutic patches for application to biological surfaces such as skin or mucosal surfaces. To this end, such formulations may be used to impregnate matrix materials such as gauze, nonwoven fabrics, or silk paper. Alternatively, the therapeutic patch may be, for example, a band-aid, facial mask, eye mask, hand mask, foot mask, etc.

[0244] Although petrolatum may be used for use in applying such dressings to wounds, the inventors have also found that a PEG (e.g., PEG 400) based ointment can be combined with a matrix material to prepare a dressing without the need for petrolatum.

[0245] The compounds of the invention may also be used in combination with a solid support, such as a nasal dressing (e.g., to stop nosebleeds), a skin scaffold (e.g., in wound healing) or an artificial bone (e.g., for bone grafts / transplants).

[0246] The compounds of the present invention may be administered for inhalation via suspension, dry powder, or solution. Suitable inhalation devices include pressurized metered-dose inhalers (pMDIs), which can be manually or breath-activated and can be used with or without a standard spacer device; dry powder inhalers (DPIs), which can be single-dose, multi-dose, or power-assisted; and soft mist inhalers (SMIs) or nebulizers, which deliver aerosolized medication in a fine mist at a slower rate than the spray delivered using, for example, a pMDI.

[0247] In pMDIs, the compounds of the invention may be administered as a pressurized suspension of micronized particles dispersed in a propellant (e.g., with excipients such as HFA, mannitol, lactose, sorbitol, etc.) or as a solution in ethanol to deliver one or more metered doses of about 20 to about 100 μL with each actuation. Actuation can be by hand (e.g., pushing) or by inhalation (breath actuation) and involves a spring-driven float trigger system.

[0248] In DPIs, the compounds of the invention may be administered in the form of micronized drug particles (between about 1 and about 5 μm in size), either alone or mixed with larger particle size inert excipients (e.g., mannitol) in capsules that may be pre-loaded or manually loaded into the device. Inhalation from a DPI allows the drug particles to break down and disperse in the respiratory tract.

[0249] In an SMI, the compound of the invention can be stored as a solution in a cartridge that is loaded into the device. A spring can release the dose into a micropump so that the dose is released when a button is pressed, releasing a jet of drug solution.

[0250] Various nebulizers can also be used to administer the compounds of the present invention in the form of a fine mist of aerosolized solution. Nebulizers can include exhalation-enhanced jet nebulizers (with the aid of a compressor, airflow moves through a jet, aerosolizing the medicinal solution), exhalation-activated jet nebulizers (after the patient inhales, with the aid of a compressor, airflow moves through a tube, aerosolizing the medicinal solution), ultrasonic nebulizers (piezoelectric crystals vibrate and heat to cause aerosolization, resulting in nebulization), and vibrating mesh nebulizers (piezoelectric crystals vibrate mesh plates to cause aerosolization, generating very fine droplets without significantly changing the temperature of the solution during nebulization).

[0251] 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, which process comprises bringing into association a compound of the invention as defined above with one or more pharmaceutically acceptable excipients as defined above.

[0252] The compounds of the present invention may also be combined in treatment with one or more growth factors selected from platelet-type growth factors (including platelet-derived growth factor, PDGF), osteosarcoma-derived growth factor (ODGF), epidermal growth factor (EGF), transforming growth factors (TGFα and TGFβ), fibroblast growth factors (αFGF, βFGF), insulin-like growth factors (IGF-I, IGF-II), nerve growth factor (NGF), interleukin-type growth factors (IL-1, IL-1, IL-3), erythropoietin (EPO), and colony stimulating factors (CSF).

[0253] According to a further aspect of the present invention, there is provided a (e.g., pharmaceutical) composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, such as an adjuvant, diluent, or carrier. Preferred formulations are suitable for topical application, for example, to mucosa (including the oral and / or nasal mucosa, lung, anorectal and / or colon), or more preferably, to the skin, and therefore include a topically acceptable adjuvant, diluent, or carrier.

[0254] Thus, there is further provided a pharmaceutical composition comprising a compound of the invention presented in a package suitable for, adapted for, and / or packaged for topical administration (e.g., to the oral and / or nasal mucosa, the lungs, the mucosa including the anorectal region and / or colon, or preferably to the skin), and the use of such a formulation in the treatment of disorders including inflammation, inflammatory disorders, and / or conditions (e.g., as a symptom) characterized by inflammation by direct topical administration of the formulation (e.g., to the oral and / or nasal mucosa, the lungs, the mucosa including the anorectal region and / or colon, or preferably to the skin).

[0255] For the avoidance of doubt, with respect to this aspect of the invention, topical formulations comprising the compounds of the invention may be used in any and all conditions described herein, including the treatment of inflammation, in the treatment of any and all inflammatory disorders, and / or in the treatment of any and all conditions characterized by inflammation as mentioned, defined, or described herein above. Similarly, references to topical formulations comprising the compounds of the invention include any and all of those mentioned, defined, or described above. Any and all of the relevant disclosures herein are incorporated by reference in connection with this aspect of the invention.

[0256] Topical (e.g., liquid or (e.g., aqueous) solution-based) formulations comprising the compounds of the present invention may be particularly useful in wound healing and may relieve pain (including aching) and itching / itchiness, particularly associated with the wound itself and the wound healing process. Such topical formulations comprising the compounds of the present invention may be particularly useful in preventing and / or inhibiting exudation of fluid from a wound after a burn or wound, particularly during the acute inflammatory phase, e.g., the first 48 hours. This prevents the risk of infection and other physiological reactions. Such topical formulations comprising the compounds of the present invention may also be particularly useful in preventing and / or inhibiting scarring and melanin pigmentation (see above), whether or not associated with a wound.

[0257] The administration of the compounds of the present invention may be continuous or intermittent. The mode of administration may also be determined by the timing and frequency of administration, and in the case of therapeutic treatment of inflammation, by the severity of the condition.

[0258] Depending on the disorder and patient being treated, as well as the route of administration, the compounds of the present invention may be administered to a patient in need of treatment in different therapeutically effective doses.

[0259] Similarly, the amount of the compound of the present invention will depend on the severity of the condition and the patient being treated, but may be determined by one skilled in the art.

[0260] In any event, a medical professional or other skilled artisan can routinely determine the actual dosage that will be most suitable for an individual patient, depending on the severity of the condition and the route of administration. The dosages set forth herein are exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and these are within the scope of this invention.

[0261] The dose can be administered one to four (eg, three) times daily.

[0262] Suitable concentrations of the compounds of the invention in the aqueous solution product can be from about 0.01 (eg, about 0.1) to about 15.0 mg / mL, in all cases calculated as the free (non-salt) peptide.

[0263] A suitable topical dose of the compounds of the invention is about 5 μg / cm, in all cases calculated as the free (non-salt) compound. 2 Approximately 1 to 10 μg / cm of the treatment area 2 ) treatment area, about 0.1 (e.g., about 0.5) to about 20 μg / cm 2 Approximately 0.05 to approximately 50 μg / cm of treatment area 2 within the therapeutic range of

[0264] Suitable doses of the compounds of the present invention for nasal administration (e.g., by inhalation) range from about 0.01 μg to about 2000 mg, for example, from about 0.1 μg to about 500 mg, or from 1 μg to about 100 mg. Specific doses for nasal administration that may be mentioned include doses of about 10 μg to about 1 mg, particularly about 0.1 mg (i.e., about 100 μg). Nasal administration of about 0.1 mg of the compounds of the present invention per day has been found to be particularly effective in treating conditions associated with inflammation of the nasal cavity and mucous membranes, such as conditions associated with rhinitis (e.g., allergic rhinitis) and / or rhinosinus surgery.

[0265] Suitable doses of the compounds of the invention for pulmonary administration (e.g., by inhalation) range from about 0.01 μg to about 2000 mg, for example, between about 0.1 μg and about 500 mg, or 1 μg to about 100 mg. Specific doses for pulmonary administration that may be mentioned include doses of about 10 μg to about 10 mg, in particular about 0.6 mg (i.e., 60 μg) to 6 mg (e.g., for use in the treatment of COPD or IPF).

[0266] The pH value of a formulation containing the compound of the present invention is preferably within the range of about 1.0 to about 9.0 (for example, about 3.0 to about 8.0).

[0267] In any event, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable time frame (as described above). Those skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by, inter alia, the pharmacological properties of the formulation, the nature and severity of the condition being treated, the physical and mental state of the recipient, and the age, condition, weight, sex and response of the patient being treated, the stage / severity of the disease, and genetic differences between patients.

[0268] The compounds of the present invention are therefore useful in human or veterinary medicine. In this regard, compounds of the present invention that possess an appropriate degree of relevant pharmacological (or biological) activity per se, as described above, can be used as human and / or veterinary medicine.

[0269] Certain compounds of the present invention, particularly compounds of formula I, may possess adhesive properties in addition to and / or instead of possessing the aforementioned biological activities.

[0270] These adhesive properties result from the fact that associated W and / or U groups can crosslink with each other to form a three-dimensional network.

[0271] Such compounds of the present invention may adhere to a number of substrates, including inorganic substrates such as glass, metals, etc., and organic substrates such as biological tissue.

[0272] In comparison, such compounds of the present invention may also be used as wound surface repair products, wound surface protection products, medical biological adhesive products, medical coating products, industrial coating products (e.g., in corrosion prevention in ships, electronic equipment, pipelines, etc.), biochemical reagents, medical products, sterilization products, culture vessels for cell culture, etc.

[0273] Such compounds of the present invention may form films on various skin and mucosal wound surfaces, such as burns, scalds, ulcers, frostbite, and bedsores, to aid in healing. Such compounds of the present invention may also be used in surgery, for example, for closing surgical incisions, bonding fractured bones, bonding mucous membranes, and coating human implants, such as artificial bones, cartilage brackets, periosteum, artificial joints, dental implants, occlusion stents, spinal fixation devices, spinal spacers, and organ patches.

[0274] According to a further aspect of the present invention there is provided a compound of formula I as an adhesive or film-forming material.

[0275] As mentioned above, naturally occurring MAPs are known for their adhesive properties, but it should be remembered that such adhesive properties may result from the fact that they are high molecular weight linear peptides that can exist in multiple conformations, allowing for intermolecular reaction / crosslinking of DOPA residues within the molecule and thereby adhesion. Conversely, it is surprising to the applicant that the compounds of the present invention as defined above are not linear polypeptides or proteins, but instead are, for example, multiply branched low molecular weight residues, and have similar properties (adhesive or biological) as naturally occurring MAPs.

[0276] Such cross-linking may be achieved by a variety of chemicals (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-methylmorpholinium chloride (DMTMM), or other water-soluble condensing agents) or enzymatic means (e.g., tyrosinase, or as described below).

[0277] Regardless of the level of pharmacological activity that the compounds of the present invention may possess, they may in any event be combined (and / or further combined) with active pharmaceutical ingredients in combination therapy (described below) or by performing a function as or part of a pharmaceutically acceptable excipient (e.g., adjuvant, diluent, or carrier), as part of a medical device, and / or as part of a drug-medical device combination.

[0278] Therefore, certain compounds of the present invention may be described as novel multifunctional excipients that can be used for a variety of applications in the pharmaceutical field. In this regard, such compounds of the present invention include compounds that can be used as adhesives and / or film-forming agents (as described above). Furthermore, such compounds of the present invention and / or different compounds of the present invention may alternatively and / or additionally be used as release-retarding polymers, binders, suspending agents, gelling agents, coating agents, diluents, or carriers for active ingredients (drugs) of various solubilities.

[0279] Compounds of the invention that are particularly useful as pharmaceutical excipients may be adapted to large-scale production, may exist without presenting significant toxicity risks, and may be described and listed as "Generally Recognized as Safe" (GRAS) by the US Food & Drug Administration (FDA).

[0280] Such compounds of the invention may also be used as excipients in veterinary medicine and in cosmetics.

[0281] According to a further aspect of the present invention, there is provided a pharmaceutical formulation comprising an active pharmaceutical ingredient mixed with a pharmaceutically acceptable excipient system (such as a pharmaceutically acceptable adjuvant, diluent or carrier system), which excipient system comprises one of more compounds of the present invention.

[0282] Additionally, the compounds of the present invention may be combined with active pharmaceutical ingredients and thus used as part of a drug-medical device combination, which includes one or more active pharmaceutical ingredients and one or more compounds of the present invention, which constitute the medical device component of the combination.

[0283] Those skilled in the art will understand that the related compounds of the present invention, when used as or as part of a medical device or a medical device portion of a drug-medical device combination, are used in human or veterinary medicine, optionally in combination with an active pharmaceutical ingredient (API) in a manner that affects the structure and / or one or more functions of the human or animal body, and achieves its primary intended purpose without exerting a chemical action in or on said human or animal body (optionally in a manner that does not rely on the compound of the present invention being metabolized to achieve any of its primary intended purposes).

[0284] In this regard, the compounds of the present invention may be combined with many known active pharmaceutical ingredients, whether or not a compound of the present invention is used, as follows: As a separate active pharmaceutical ingredient in combination therapy, As or as part of a medical device, as a drug-medical device combination or as part of a medical device; or As a pharmaceutically acceptable excipient.

[0285] Such patients may also (and / or already) be undergoing therapy based on the administration of one or more of such other known pharmaceutically active ingredients, meaning that they have received 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 present invention.

[0286] Pharmaceutically active agents that may be co-administered with the compounds of the invention include any drug or agent that is capable of producing some physiological effect (whether therapeutic or prophylactic for a particular disease state or condition) in a living subject, including particularly mammalian and especially human subjects (patients).

[0287] Additionally, compounds of the present invention, such as those that can be crosslinked as described above, may be used as pharmaceutical excipients and may be mixed with such active pharmaceutical ingredients before or after crosslinking and / or at least partial crosslinking, as described above, to form stable pharmaceutical compositions in which the compounds of the present invention act as excipients, such as carriers. When used in this manner, it may be found that the compounds of the present invention can positively affect the physical, chemical, and / or biological properties of such active ingredients, including their physical and / or chemical stability and / or their metabolism after administration.

[0288] Pharmaceutically active agents that may be used in conjunction with the compounds of the present invention may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial and / or antiprotozoal agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing agents (growth factors).

[0289] The bioactive agent may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial and / or antiprotozoal agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing agents (growth factors).

[0290] Non-limiting examples of anti-inflammatory drugs that can be used include drugs for treating rheumatic diseases and / or arthritis (such as cataflam, betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodolac, meclofenamate, salsalate, methylprednisolone, piroxicam, etc.); osteoarthritis (such as sulindac, meloxicam, fenoprofen, etoricoxib, nabumetone, etc.); inflammation and its symptoms, such as fever, pain, itching, and / or swelling (such as methadone, ... fenamic acid, indomethacin, aspirin, ketorolac, fluorometholone, loteprednol, hydrocortisone, fluorometholone, bromfenac, prednisolone acetate, indomethacin, and ibuprofen; allergies and their symptoms (pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, lodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, emestine fumarate, oncolytic acid, steroids ... Lopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudoephedrine, fexofenadine, terfenadine, loratadine, Alexis, etc.); respiratory diseases including asthma and / or COPD (budesonide, ciclesonide, nedocromil, dexamethasone, ambroxol, pranlukast, etc.); skin diseases (mometasone, triamcinolone, desonide, sulfacetamide, Also included are those used to treat mastocytosis (such as tacrolimus, allantoin, triamcinolone, etc.); mastocytosis (such as cromolyn, etc.); gout (such as diclofenac, febuxostat, etc.); conjunctivitis (such as hydrobenzol, pranoprofen, zinc sulfate, etc.); ophthalmic diseases (such as dextran 70, thyroxine / liothyronine, and ophthalmic extracts), known or commercially available pharmaceutically acceptable salts of any of the foregoing, and any combination of the above compounds and / or salts.

[0291] Anti-inflammatory drugs that may be mentioned include endogenous (and / or exogenous) lipid-based proresolving, anti-inflammatory molecules or mediators such as lipoxins, resolvins, and protectins. Anti-inflammatory agents that may be mentioned include prostaglandins (e.g., latanoprost, prostaglandin E1, and prostaglandin E2) and leukotrienes (e.g., leukotriene B4).

[0292] Non-limiting examples of antibacterial agents that may be used include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomycin, gentamicin, cetylpyridinium, 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, as well as any combination of the foregoing compounds and / or salts.

[0293] Non-limiting examples of antiviral agents that may be used include tobramycin, ribavirin, acyclovir, moroxydine, 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 Also included are fluticasone, simeprevir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir pivoxil, fomivirsen, podofilox, imiquimod, sinecatechins, interferon alpha 2b (recombinant, human), known or commercially available pharmaceutically acceptable salts of any of the foregoing, and any combination of the foregoing compounds and / or salts.

[0294] Non-limiting examples of anesthetics that may be used include articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, dyclonine, tetracaine, bupivacaine, and known or commercially available pharmaceutically acceptable salts of any of the foregoing, as well as any combination of the foregoing compounds and / or salts.

[0295] Non-limiting examples of wound healing agents that may be used include basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, human; yeast), rhEFG(I), acidic fibroblast growth factor (recombinant, human), granulocyte-macrophage stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, retinoids, calf blood deproteinized extract, carrageenates, amiotide, and known or commercially available pharmaceutically acceptable salts of any of the foregoing, as well as any combination of the foregoing compounds and / or salts.

[0296] Such active pharmaceutical ingredients include those that may be administered topically, in conjunction with a compound of the invention, for example, to the skin or mucosal surfaces.In this respect, preferred active ingredients from the above list include cyclosporine, chondroitin, loteprednol, fluorometholone, bromfenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, emestine fumarate, olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, alexis, dexamethasone, ambroxol, sulphonamide, sulphonate, sulphonylurea ... Facetamide, tacrolimus, allantoin, triamcinolone, cromolyn, nedocromil, diclofenac, hydrobenzol, pranoprofen, zinc sulfate, dextran 70, thyroxine / liothyronine, ophthalmic extract, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomycin, gentamicin, cetylpyridinium , neomycin, roxithromycin, silver sulfadiazine, clarithromycin, sulfamethoxazole, chloramphenicol, tobramycin, ribavirin, acyclovir, moroxydine, foscarnet, ganciclovir, interferon-α2b (recombinant, human), articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, dyclonine, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human; recombinant Also included are erythrocyte 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, deproteinized calf blood extract, carrageenates, amiotide, and known or commercially available pharmaceutically acceptable salts of any of the foregoing, as well as any combination of the foregoing compounds and / or salts.

[0297] Other active pharmaceutical ingredients that may be co-administered with the compounds of the invention include those that may be administered to treat one of the gastrointestinal disorders mentioned above.

[0298] Non-limiting examples of gastrointestinal medications include oxalazine (olsalazine), sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, live bacillus (such as Clostridium butyricum, licheniformis, cereus), probiotics (such as Bifidobacterium), tegafur, nifuratel, amoxicillin, ampicillin, nystatin, allicin, Cefadroxil, dyclonine, carmofur, fluorouracil, mosapride, sodium carbosulfan, thrombin, pantoprazole, cimetidine, cisapride, ethylenediaminediacetamide, nimustine, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azasetron, lentinan, bismuth salts (e.g., aluminates, potassium citrate) and magnesium salts (e.g., magnesium trisilicate, bicarbonate, vitamin U, aluminum hydroxide). Um, belladonna extract, famotidine and calcium carbonate in combination, magnesium hydroxide, hydrotalcite, proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, or esomeprazole), glycine, trypsin, allantoin, aluminum hydroxide, sodium L-glutamine guarenate, levampet, rotundin, cuxipit, lafutidine, thymus protein, erythritol erinaceus, yl maleate Included are sogladine, nizatidine, L-glutamine and sodium azulene sulfonate (sodium gualenate), ranitidine, bismuth citrate, lactobacillin, bisaccordin, dimethylsiloxane, live clostridium butyricum, loperamide hydrochloride, dibazole, secnidazole, zinc acetate, montmorillonite, tegafur / gimeracil / oteracil, famotidine, oteracil, doxifluridine, capecitabine, or known or commercially available pharmaceutically acceptable salts of any of the foregoing.

[0299] Pharmaceutical active ingredients that may be mentioned for use in combination with the compounds of the present invention include active ingredients useful in the treatment of inflammation and / or inflammatory disorders (other anti-inflammatory agents).

[0300] Anti-inflammatory agents that can be used in combination with the compounds of the present invention to treat 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 being treated, such anti-inflammatory agents may include, for example, NSAIDs (e.g., aspirin), aminosalysates (e.g., 5-aminosalicylic acid (mesalazine)), leukotriene receptor antagonists (e.g., montelukast, pranlukast, and zafirlukast), corticosteroids, analgesics, and certain enzymes such as trypsin, as described below. The compounds of the present invention may also be combined with leukotrienes (e.g., cysteinyl leukotrienes and leukotriene B4).

[0301] Other preferred agents that can be combined with the compounds of the invention include LTB4 (to treat wounds and burns), NSAIDs (e.g., aspirin), or montelukast (to treat inflammation generally), and trypsin (e.g., to treat inflammation of the mucous membranes associated with viral infections).

[0302] The compounds of the present invention may also be combined with other therapeutic agents that are known to cause inflammation as a side effect when administered.

[0303] The conjugates of the invention may also be combined with stem cells (e.g., totipotent, omnipotent, pluripotent (such as embryonic or induced pluripotent stem cells), multipotent (such as mesenchymal stem cells), oligopotent (such as hematopoietic stem cells), or unipotent (such as muscle stem cells)).

[0304] Other known active pharmaceutical ingredients can also be administered in combination with the compounds of the present invention in a number of ways.

[0305] For example, the compounds of the present invention may be "combined" with the pharmaceutically active ingredient (or 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.

[0306] As such, such combination products provide for administration of a compound of the invention in combination with a therapeutic agent (or other therapeutic agent), and thus may be presented as separate formulations (at least one of which contains a compound of the invention and at least one of which contains a therapeutic agent (or other therapeutic agent)) or as a combined preparation (i.e., formulation) (i.e., a single formulation containing a compound of the invention and a therapeutic agent (or other therapeutic agent)).

[0307] For this reason, (1) (e.g., pharmaceutical) formulations comprising a compound of the invention, another active pharmaceutical ingredient, and, optionally, a pharmaceutically acceptable inert excipient (e.g., an adjuvant, diluent, or carrier) (the formulations are hereinafter referred to as "combination preparations"); and (2) A kit of parts comprising: (A) a compound of the present invention in the form of a (e.g., pharmaceutical) formulation, optionally mixed with a pharmaceutically acceptable inert excipient (e.g., an adjuvant, diluent, or carrier); and (B) optionally another active pharmaceutical ingredient in the form of a (e.g., pharmaceutical) formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier; Further provided is a kit of parts, in which components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0308] In a further aspect of the present invention, there is provided a process for the preparation of a combination preparation (1) as defined herein above, comprising bringing into association a compound of the present invention, another active pharmaceutical ingredient, a therapeutic agent, with at least one (e.g., pharmaceutically acceptable) excipient.

[0309] In a further aspect of the present invention, there is provided a process for preparing the kit of parts (2) as defined herein above, comprising associating components (A) and (B). As used herein, reference to associating means making the two components suitable for administration together.

[0310] Thus, in the context of the process for the preparation of a kit of parts as defined herein above, "associating" two components with each other means that the two components of the kit of parts are (i) provided separately (i.e., independently of each other) and then combined for use in combination with each other in a combination therapy; or (ii) may be packaged and presented together as separate components of a "combination pack" for use in combination with each other in combination therapy.

[0311] For this reason, it is a parts kit, (I) one of components (A) or (B) as defined herein, (II) A kit of parts is further provided that includes the component together with instructions for use in combination with the other of the two components.

[0312] In relation to the above kit of parts, the compound 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), but when the compound of the present invention is provided primarily for the purpose of performing its function as a medical device or excipient, it may not be provided together with such additional pharmaceutically acceptable excipients. In any case, it is preferred that the (other) active pharmaceutical ingredient of the kit of parts is provided in the form of a pharmaceutical formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0313] The kits of parts described herein may contain two or more suitable amounts / doses of (e.g., formulations containing) a compound of the invention, and / or two or more suitable amounts / doses of (e.g., formulations containing) another active pharmaceutical ingredient, to provide for multiple administrations. When more than one formulation containing any of the above amounts / doses or any of the above amounts / doses is present, they may be the same or may differ in terms of the dosage of any compound, chemical composition, and / or physical form.

[0314] With respect to kits of parts described herein, "administration in combination with" includes sequential, separate and / or simultaneous administration of each component over the course of treatment of the relevant condition.

[0315] Thus, with respect to a combination product according to the invention, the term "administration in combination with" includes administration of the two components of the combination product (a compound of the invention and another pharmaceutically active ingredient) together, or sufficiently closely in time (optionally repeatedly), to allow a greater beneficial effect to the patient over the course of treatment of the relevant condition than if either the compound of the invention, or the other agent, were administered alone (optionally repeatedly) without the other component over the course of treatment of the relevant condition. The determination of whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over a course of treatment, will depend on the condition being treated or prevented, but can be routinely accomplished by one of ordinary skill in the art.

[0316] Furthermore, in the context of the kit-of-parts according to the invention, the term "in combination with" includes that one or the other of the two components may be administered before, after, and / or simultaneously (optionally repeatedly) with the administration of the other component. When used in this context, the terms "co-administered" and "administered simultaneously with" include administration of the individual amounts / doses of the compound of the invention and the other active pharmaceutical ingredient(s) involved within 48 hours (e.g., 24 hours) of each other.

[0317] With regard to the above combined preparations and kits of parts, the other active pharmaceutical ingredient is preferably an anti-inflammatory agent or an agent known to cause inflammation as a side effect, as described above.

[0318] Whenever the term "about" is used herein in the context of a quantity, such as, for example, the concentration and / or dosage of an active ingredient, molecular weight, or pH, it is understood that such a variable is an approximation and may therefore vary by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%) from the numerical value specified herein. In this regard, the term "about 10%" means, for example, ±10% of the numerical value 10, i.e., 9% to 11%.

[0319] The compounds of the present invention have a wide variety of uses, including: as biologically active agents in various pathological conditions characterized by inflammation, whether the condition itself is an organic inflammatory disease or not, whether associated with or characterized by inflammation (e.g. wounds or burns), and / or in the aforementioned surgical and / or cosmetic applications; and / or In combination therapy, or a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), Medical devices, and / or - It has the advantage of having use in combination with the active pharmaceutical ingredient by performing a more inert function, either as the medical device part of the drug-medical device combination, or as part of it.

[0320] The compounds, uses, and methods described herein, whether for use in the treatment of any of the aforementioned conditions, including inflammation, inflammatory disorders, or disorders characterized by inflammation as a symptom (including wounds), or otherwise, may have advantages over similar compounds or methods (treatments) known in the prior art in that they may be more convenient for the physician and / or patient, more effective, less toxic, have a broad spectrum of activity, be more potent, cause fewer side effects, or have other useful pharmacological properties over similar compounds or methods (treatments) in the treatment of the above-mentioned conditions. [Brief explanation of the drawings]

[0321] [Figure 1] 1 shows the swelling levels obtained in the mouse model experiments of Examples 21 and 22, respectively. [Figure 2] 1 shows the swelling levels obtained in the mouse model experiments of Examples 21 and 22, respectively. [Example]

[0322] As used herein, "N-(acid-PEG3)-N-bis(PEG3-amine)" refers to the following structure having CAS number 2183440-35-7:

[0323] [ka] The following fragment (as appropriate):

[0324] [ka]

[0325] The names "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)" are used interchangeably with "N-(acid-PEG3)-N-bis(PEG3-amine)".

[0326] In the following examples, peptide When is attached to two amines in N-(acid-PEG3)-N-bis (PEG3-amine), this is N-(acid-PEG3)-N-bis( peptide The compound is designated as -NH-PEG3), where the amino acid fragment adjacent to the "NH" is the amino acid attached to the amine.

[0327] Examples in which the peptide is attached at only one of the amines are named in a similar manner.

[0328] As used herein, "tri(amino-PEG3-amido)-amine" refers to the following structure having CAS number 2523025-40-1:

[0329] [ka]

[0330] Example 1 N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N-(PEG3 acid) (SEQ ID NO: 188) N-Bis(Fmoc-NH-PEG3)-N-(PEG3-acid)-Wang resin (13.5 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0331] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for approximately 30 minutes. The DCM was then removed by vacuum filtration.

[0332] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0333] A solution of 20% piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) in DMF (DBLK, 200 mL) was added as a deprotection solution and allowed to react for 20 minutes. The solution was then removed by vacuum filtration, and the column was washed six times with DMF.

[0334] Fmoc-Lys(Boc)-OH (8.44 g; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium 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). A Kaiser test was performed on a small amount of resin after 30 minutes of reaction; the yellow color of the solution and colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0335] The above coupling steps were repeated to couple the remaining amino acids in the same amounts (by mole): 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.

[0336] In another procedure, after coupling Fmoc-Ala-OH to the resin, a deprotection step was performed to remove the Fmoc protection of alanine. The resin was washed three times with DMF (200 mL each time). 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and allowed to react for 20 minutes. Next, the resin was washed three times each with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China). The resin was dried in vacuo for approximately 2 hours.

[0337] The resin-bound peptide-containing compound was soaked in 190.0 mL (i.e., 10 mL per gram of dry resin) of a solution consisting of 95% trifluoroacetic acid (TFA, Macklin, Shanghai, China), 2.5% water, and 2.5% triisopropylsilane (Tis, Macklin, Shanghai, China). After approximately 2 hours of cleavage, 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 per ml of filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours to yield 8.58 g of crude title compound.

[0338] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan). The analytical column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient from 5% to 90% solvent A concentration in 50 min; flow rate: 1.0 mL / min; sample volume: 10 μL).

[0339] The target peak eluted at 10.378 min with the expected molecular weight and a purity of 71.382%.

[0340] MS: m / z 2934.6

[0341] Next, 8.5 g of the crude product was dissolved in 90 mL of purified water and purified using an NP7010C semi-preparative system (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China). The preparative column model was a Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50*250 mm, 100 Å column; detection: UV at 220 nm). The appropriate gradient for elution was calculated from the LCMS detection step (Solvent A: 0.1% TFA in MeCN, Solvent B: 0.1% TFA in water, a linear gradient from 5% to 20% solvent A concentration in 30 min; flow rate: 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) using the same column as above, except that a linear gradient from 5% to 30% solvent A concentration in 25 min was used.

[0342] Fractions with purity greater than 90% were then mixed together for the anion exchange step. This was achieved using an NP7010C semi-preparative apparatus (preparative column model: Dubhe-C18 model (described above)). The fractions were diluted once with pure water and loaded directly onto the column. The column was then washed with 3.2% ammonium acetate in pure water for approximately 20 minutes, followed by another 10 minutes with pure water at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN; solvent B: 0.1% hAc in water, linear gradient from 5% to 20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as described above). Fractions with purity greater than 95% were combined and lyophilized to yield 3.78 g of purified title compound.

[0343] Example 2 N-bis{[N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG)-N-(PEG3 acid)]-NH-PEG}-N-(PEG3 acid) (SEQ ID NO: 189) The method was the same as that described in Example 1, starting with N-Bis(Fmoc-NH-PEG3)-N-(PEG3 acid) and continuing with 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, with the amounts of amino acids, TBTU, and DIPEA doubled (molarly), except that the N-Bis(Fmoc-amido-PEG3)-N-PEG3 acid coupling step was not doubled compared to Example 1.

[0344] MS: m / z 6404.3

[0345] Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 17.25 g). Analysis showed that the target peak eluted at 11.732 minutes with the expected molecular weight (MS: m / z 6404.3). The purity was 50.281%.

[0346] 17 g of the crude product was then purified as described in Example 1 above to give 5.73 g of pure title compound after lyophilization.

[0347] Example 3 N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3)-N-(PEG3 amide) (SEQ ID NO: 190) The method was the same as that described in Example 1, except that, compared with Example 1, N-bis(Fmoc-NH-PEG)-N-(PEG acid)-AM resin (12.9 g, GL Biochem, Shanghai, China) was used as the starting material.

[0348] MS: m / z 2949.6

[0349] Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 7.36 g). Analysis showed that the target peak eluted at 10.246 minutes with the expected molecular weight (MS: m / z 2949.6). The purity was 71.377%.

[0350] 7 g of the crude product was then purified as described in Example 1 above to give 3.67 g of pure title compound after lyophilization.

[0351] Example 4 N-bis{[N-bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG)-N-(PEG5 acid)]-NH-PEG}-N-(PEG3 acid) (SEQ ID NO: 191) The method was the same as that described in Example 1, starting with N-Bis(Fmoc-NH-PEG5)-N-(PEG5 acid) and continuing with 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, with the amounts of amino acids, TBTU, and DIPEA doubled (molarly), except that the N-Bis(Fmoc-amido-PEG5)-N-PEG5 acid coupling step was not doubled compared to Example 1.

[0352] MS: m / z 6668.3

[0353] Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 18.17 g). Analysis showed that the target peak eluted at 12.072 minutes with the expected molecular weight (MS: m / z 6668.3). The purity was 51.392%.

[0354] 18 g of the crude product was then purified as described in Example 1 above to give 5.96 g of pure title compound after lyophilization.

[0355] Example 5 N-Bis(montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG)-N-(PEG acid) (SEQ ID NO: 192) The method was the same as that described in Example 1, except that, compared to Example 1, an additional coupling step with montelukast sodium was performed after Fmoc-Ala-OH was attached and deprotected.

[0356] MS: m / z 4071.0

[0357] Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 10.19 g). Analysis showed that the target peak eluted at 32.847 minutes with the expected molecular weight (MS: m / z 4071.0). The purity was 47.93%.

[0358] 10 g of the crude product was then purified as described in Example 1 above to give 2.95 g of pure title compound after lyophilization.

[0359] Example 6 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) Fmoc-Lys(Boc)-Wang resin (9.15 g; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0360] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for approximately 30 minutes. The DCM was then removed by vacuum filtration.

[0361] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0362] A solution of 20% piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) in DMF (DBLK, 200 mL) was added as a deprotection solution and allowed to react for 20 minutes. The solution was then removed by vacuum filtration, and the column was washed six times with DMF.

[0363] Fmoc-DOPA(acetonide)-OH (4.14 g; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co., Ltd., Jiangsu, China). A Kaiser test was performed on a small amount of resin after 30 minutes of reaction; the yellow color of the solution and colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0364] The above coupling steps were repeated to couple the remaining amino acids in equal amounts: 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-PEG)-N-(PEG acid).

[0365] 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). 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. The resin was then washed six times with DMF.

[0366] Another coupling step was then 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, in which the amounts (molar) of amino acid, TBTU, and DIPEA were doubled compared to the previous coupling step.

[0367] In another procedure, after coupling Fmoc-Lys(Boc)-OH to the resin, a deprotection step was performed to remove the Fmoc protection of lysine. The resin was washed three times with DMF (200 mL each time). 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and allowed to react for 20 minutes. Next, the resin was washed three times each with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China). The resin was dried under vacuum for approximately 2 hours.

[0368] The resin-bound peptide-containing compound was soaked in 180.0 mL (i.e., 10 mL per gram of dry resin) of a solution consisting of 95% trifluoroacetic acid (TFA, Macklin, Shanghai, China), 2.5% water, and 2.5% triisopropylsilane (Tis, Macklin, Shanghai, China). After approximately 2 hours of cleavage, 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 per ml of filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours to yield 7.23 g of crude title compound.

[0369] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan). The analytical column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient from 5% to 90% solvent A concentration in 50 min; flow rate: 1.0 mL / min; sample volume: 10 μL).

[0370] The target peak eluted at 15.232 min with the expected molecular weight and a purity of 64.322%.

[0371] MS: m / z 3259.8

[0372] Next, 7.2 g of the crude product was dissolved in 70 mL of purified water and purified using an NP7010C semi-preparative system (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China). The preparative column model was a Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50*250 mm, 100 Å column; detection: UV at 220 nm). The appropriate gradient for elution was calculated from the LCMS detection step (Solvent A: 0.1% TFA in MeCN, Solvent B: 0.1% TFA in water, a linear gradient from 5% to 20% solvent A concentration in 30 min; flow rate: 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) using the same column as above, except that a linear gradient from 5% to 30% solvent A concentration in 25 min was used.

[0373] Fractions with purity greater than 90% were then mixed together for the anion exchange step. This was achieved using an NP7010C semi-preparative apparatus (preparative column model: Dubhe-C18 model (described above)). The fractions were diluted once with pure water and loaded directly onto the column. The column was then washed with 3.2% ammonium acetate in pure water for approximately 20 minutes, followed by another 10 minutes with pure water at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN; solvent B: 0.1% hAc in water, linear gradient from 5% to 20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as described above). Fractions with purity greater than 95% were combined and lyophilized to yield 2.55 g of purified title compound.

[0374] Example 7 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) Fmoc-Lys(Boc)-Wang resin (9.15 g; GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0375] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for approximately 30 minutes. The DCM was then removed by vacuum filtration.

[0376] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0377] A solution of 20% piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) in DMF (DBLK, 200 mL) was added as a deprotection solution and allowed to react for 20 minutes. The solution was then removed by vacuum filtration, and the column was washed six times with DMF.

[0378] Fmoc-DOPA(acetonide)-OH (4.14 g; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co., Ltd., Jiangsu, China). A Kaiser test was performed on a small amount of resin after 30 minutes of reaction; the yellow color of the solution and colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0379] The above coupling steps were repeated to couple the remaining amino acids in equal amounts: 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).

[0380] 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). 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. The resin was then washed six times with DMF.

[0381] Another coupling step was then 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 (in moles) of amino acids, TBTU, and DIPEA compared to the previous coupling step.

[0382] After coupling Fmoc-Lys(Boc)-OH to the resin, a deprotection step was performed to remove the Dde protection of N-bis(amino-PEG3)-N-(PEG3 acid). The resin was washed three times with DMF (200 mL each time). 200 mL of 5% hydrazine hydrate solution in DMF was added as a deprotection solution and reacted for 20 minutes. The resin was then washed six times with DMF.

[0383] Then, other 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 moles) of amino acid, TBTU, and DIPEA compared to the previous coupling step.

[0384] In another procedure, after coupling Fmoc-Lys(Boc)-OH to the resin, a deprotection step was performed to remove the Fmoc protection of lysine. The resin was washed three times with DMF (200 mL each time). 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and allowed to react for 20 minutes. Next, the resin was washed three times each with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China). The resin was dried under vacuum for approximately 2 hours.

[0385] The resin-bound peptide-containing compound was soaked in 180.0 mL (i.e., 10 mL per gram of dry resin) of a solution consisting of 95% trifluoroacetic acid (TFA, Macklin, Shanghai, China), 2.5% water, and 2.5% triisopropylsilane (Tis, Macklin, Shanghai, China). After approximately 2 hours of cleavage, 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 per ml of filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China), and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours to yield 7.15 g of crude title compound.

[0386] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan). The analytical column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient from 5% to 90% solvent A concentration in 50 min; flow rate: 1.0 mL / min; sample volume: 10 μL).

[0387] The target peak eluted at 15.322 min with the expected molecular weight and a purity of 61.453%.

[0388] MS: m / z 3259.8

[0389] Next, 7.1 g of the crude product was dissolved in 70 mL of purified water and purified using an NP7010C semi-preparative system (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China). The preparative column model was a Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50*250 mm, 100 Å column; detection: UV at 220 nm). The appropriate gradient for elution was calculated from the LCMS detection step (Solvent A: 0.1% TFA in MeCN, Solvent B: 0.1% TFA in water, a linear gradient from 5% to 20% solvent A concentration in 30 min; flow rate: 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) using the same column as above, except that a linear gradient from 5% to 30% solvent A concentration in 25 min was used.

[0390] Fractions with purity greater than 90% were then mixed together for the anion exchange step. This was achieved using an NP7010C semi-preparative apparatus (preparative column model: Dubhe-C18 model (described above)). The fractions were diluted once with pure water and loaded directly onto the column. The column was then washed with 3.2% ammonium acetate in pure water for approximately 20 minutes, followed by another 10 minutes with pure water at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN; solvent B: 0.1% hAc in water, linear gradient from 5% to 20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as described above). Fractions with purity greater than 95% were combined and lyophilized to yield 2.49 g of purified title compound.

[0391] Example 8 Tri(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3-amido)-amine (SEQ ID NO: 195) The title compound was synthesized from lysine as the first amino acid using Fmoc-Lys(Boc)-CTC resin as the solid support.

[0392] Fmoc-Lys(Boc)-CTC resin (7.35 g, USUN pharma, Jiangsu, China) was loaded into a glass reaction column.

[0393] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and the resin was allowed to soak for approximately 30 minutes. The DCM was then removed by vacuum filtration.

[0394] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co Ltd, Shandong, China).

[0395] 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 min.

[0396] The solution was then removed by vacuum filtration and the resin in the column was washed six times with DMF.

[0397] Fmoc-DOPA(acetonide)-OH (4.14 g; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium 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). A Kaiser test was performed on a small amount of resin after 30 minutes of reaction; the yellow color of the solution and colorless gel indicated the completion of the reaction. The solvent was removed by vacuum filtration.

[0398] The above coupling steps were repeated to couple the remaining amino acids in the same amounts: Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, and Boc-Lys(Boc)-OH.

[0399] After coupling of Boc-Lys(Boc)-OH to the resin, the resin was washed three times with each of the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time), and then dried under vacuum for about 2 hours.

[0400] A solution of 120.0 mL (i.e., 10 mL per gram of dry resin) containing 2% trifluoroacetic acid (TFA) in DCM was added to soak the resin-bound peptide-containing compound. After approximately 2 hours of cleavage, the solid support was removed by filtration, and the filtrate was collected under reduced pressure. The filtrate was then concentrated by rotary evaporation under reduced pressure. After removing all solvent, tri(amino-PEG3-amido)-amine (0.38 g, CAS: 2523025-40-1; GL Biochem, Shanghai, China) was added, followed by pyridine (100 mL) to dissolve the solid. After that, phosphorus oxychloride (0.3 mL, Adamas-beta Co. Ltd., Shanghai, China) was added to the reaction solution. After 3 hours of reaction, the reaction was complete. The final solution was precipitated by adding 1200 mL (i.e., 10 mL per 1 mL of final solution) of saturated aqueous citric acid (Aladdin, Shanghai, China), and the precipitate was collected by filtration. Next, 120 mL (i.e., 10 mL per gram of solid) of a solution containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to the precipitate to dissolve the peptide-containing solid. The side chains were deprotected during cleavage. After approximately 2 hours of cleavage, the solution was precipitated with 1200 mL (i.e., 10 mL per 1 mL of filtrate) of diethyl ether, and the precipitate was collected by filtration. The precipitate was dried under vacuum for approximately 2 hours. Finally, 7.11 g of crude title compound was obtained.

[0401] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan). The analytical column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient from 5% to 90% solvent A concentration in 50 min; flow rate: 1.0 mL / min; sample volume: 10 μL).

[0402] The target peak eluted at 17.123 min with the expected molecular weight and a purity of 55.284%.

[0403] MS: m / z 3444.1

[0404] Next, 7.1 g of the crude product was dissolved in 70 mL of purified water and purified using an NP7010C semi-preparative system (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China). The preparative column model was a Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50*250 mm, 100 Å column; detection: UV at 220 nm). The appropriate gradient for elution was calculated from the LCMS detection step (Solvent A: 0.1% TFA in MeCN, Solvent B: 0.1% TFA in water, a linear gradient from 5% to 20% solvent A concentration in 30 min; flow rate: 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) using the same column as above, except that a linear gradient from 5% to 30% solvent A concentration in 25 min was used.

[0405] Fractions with purity greater than 90% were then mixed together for the anion exchange step. This was achieved using an NP7010C semi-preparative apparatus (preparative column model: Dubhe-C18 model (described above)). The fractions were diluted once with pure water and loaded directly onto the column. The column was then washed with 3.2% ammonium acetate in pure water for approximately 20 minutes, followed by another 10 minutes with pure water at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% hAc in MeCN; solvent B: 0.1% hAc in water, linear gradient from 5% to 20% solvent A concentration in 30 minutes; flow rate 60.0 mL / min). Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as described above). Fractions with purity greater than 95% were combined and lyophilized to yield 2.04 g of purified title compound.

[0406] Example 9 N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG)-N-(PEG-oic acid)]-NH-PEG}-N-(PEG-oic acid) (SEQ ID NO: 260) The title compound was prepared using essentially the same process as described in Example 2 above, except that the appropriate amino acids were used in the correct peptide coupling order.

[0407] MS: m / z 5199.1

[0408] Essentially the same procedure described in Example 1 was repeated to obtain another batch of crude title compound (yield 14.12 g). Analysis showed that the target peak eluted at 10.792 minutes with the expected molecular weight (MS: m / z 5199.1). The purity was 53.223%.

[0409] 14.1 g of the crude product was then purified as described in Example 1 above to give 3.92 g of pure title compound after lyophilization.

[0410] Example 10 N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG)-N-(PEG-oic acid)]-NH-PEG}-N-(PEG-oic acid) (SEQ ID NO: 261) The title compound was prepared using essentially the same process as described in Example 9 above, except that Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling step.

[0411] MS: m / z 5263.1

[0412] Essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 14.25 g). Analysis showed that the target peak eluted at 10.543 minutes with the expected molecular weight (MS: m / z 5263.1). The purity was 55.833%.

[0413] 14.2 g of the crude product was then purified as described in Example 1 above to give 4.01 g of pure title compound after lyophilization.

[0414] Example 11 N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG)-N-(PEG-oic acid)]-NH-PEG}-N-(PEG-oic acid) (SEQ ID NO: 262) The title compound was prepared using essentially the same process as described in Example 9 above, except that after the final amino acid, Fmoc-Lys(Boc)-OH, was coupled onto the resin, an additional coupling step was performed to couple palmitic acid to the resin. Palmitic acid was used in the same amount (in moles) as the other amino acids.

[0415] After coupling of palmitic acid, the resin was directly washed three times with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China). The resin was then dried under vacuum for approximately 2 hours.

[0416] MS: m / z 6152.7

[0417] 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 that the target peak eluted at 39.857 minutes with the expected molecular weight (MS: m / z 6152.7). The purity was 50.202%.

[0418] 15.8 g of the crude product was then purified as described in Example 1 above to give 4.78 g of pure title compound after lyophilization.

[0419] Example 12 N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG)-N-(PEG-oic acid)]-NH-PEG}-N-(PEG-oic acid) (SEQ ID NO: 263) The title compound was prepared using essentially the same process as described in Example 11 above, except that Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling step.

[0420] MS: m / z 6216.7

[0421] Essentially the same procedure was repeated to obtain another batch of crude title compound (yield 15.71 g). Analysis showed that the target peak eluted at 38.788 minutes with the expected molecular weight (MS: m / z 6216.7). The purity was 50.482%. 15.7 g of crude product was then purified as described in Example 1 above to yield 4.52 g of pure title compound after lyophilization.

[0422] Example 13 N-Bis(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG)-N-(PEG-acid) (SEQ ID NO: 264) The title compound was prepared using essentially the same process as described in Example 1 above, except that the appropriate amino acids were used, where appropriate, in the correct peptide coupling order. After the final amino acid, Fmoc-Lys(Boc)-OH, was coupled onto the resin, an additional coupling step was performed to couple palmitic acid to the resin. Palmitic acid was used in the same amount (molar) as the other amino acids.

[0423] After coupling of palmitic acid, the resin was directly washed three times with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China). The resin was then dried under vacuum for approximately 2 hours.

[0424] MS: m / z 2808.6

[0425] 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 that the target peak eluted at 35.839 minutes with the expected molecular weight (MS: m / z 2808.6). The purity was 65.748%.

[0426] 7.8 g of the crude product was then purified as described in Example 1 above to give 3.55 g of pure title compound after lyophilization.

[0427] Example 14 N-Bis(Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG)-N-(PEG-acid) (SEQ ID NO: 265) The title compound was prepared using essentially the same process as described in Example 13 above, except that Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling step.

[0428] MS: m / z 2840.6

[0429] Essentially the same procedure as described in Example 1 was repeated to obtain another batch of crude title compound (yield 7.74 g). Analysis showed that the target peak eluted at 36.221 minutes with the expected molecular weight (MS: m / z 2840.6). The purity was 53.211%.

[0430] 7.7 g of the crude product was then purified as described in Example 1 above to give 3.29 g of pure title compound after lyophilization.

[0431] Example 15 N-bis(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG)-N-(PEG-acid) (SEQ ID NO: 266) The title compound was prepared using essentially the same process as described in Example 1 above, except that the appropriate amino acids were used where appropriate in the correct peptide coupling order.

[0432] MS: m / z 2331.7

[0433] 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 that the target peak eluted at 9.882 minutes with the expected molecular weight (MS: m / z 2331.7). The purity was 68.473%.

[0434] 7.0 g of the crude product was then purified as described in Example 1 above to give 3.57 g of pure title compound after lyophilization.

[0435] Example 16 N-bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG)-N-(PEG-acid) (SEQ ID NO: 267) The title compound was prepared using essentially the same process as described in Example 15 above, except that Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the corresponding coupling step.

[0436] MS: m / z 2363.7

[0437] 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 that the target peak eluted at 9.988 minutes with the expected molecular weight (MS: m / z 2363.7). The purity was 65.832%.

[0438] 6.9 g of the crude product was then purified as described in Example 1 above to give 3.56 g of pure title compound after lyophilization.

[0439] Example 17 N-Bis(Palm-Lys-Hyp-Lys-NH-PEG)-N-(PEG-acid) (SEQ ID NO: 268) The title compound was prepared using essentially the same process as described in Example 13 above, except that the appropriate amino acids were used where appropriate in the correct peptide coupling order.

[0440] MS: m / z 1787.5

[0441] 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 that the target peak eluted at 29.812 minutes with the expected molecular weight (MS: m / z 1787.5). The purity was 70.928%.

[0442] 5.2 g of the crude product was then purified as described in Example 1 above to give 2.98 g of pure title compound after lyophilization.

[0443] Example 18 N-bis(Lys-Hyp-Lys-NH-PEG)-N-(PEG-acid) (SEQ ID NO: 269) The title compound was prepared using essentially the same process as described in Example 1 above, except that the appropriate amino acids were used where appropriate in the correct peptide coupling order.

[0444] MS: m / z 1310.6

[0445] 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 that the target peak eluted at 9.883 minutes with the expected molecular weight (MS: m / z 1310.6). The purity was 75.291%.

[0446] 4.6 g of the crude product was then purified as described in Example 1 above to give 2.57 g of pure title compound after lyophilization.

[0447] Example 19 N-bis{[N-bis(Palm-Lys-Hyp-Lys-NH-PEG)-N-(PEG-acid)]-NH-PEG}-N-(PEG-acid) (SEQ ID NO: 270) The title compound was prepared using essentially the same process as described in Example 11 above, except that the appropriate amino acids were used where appropriate in the correct peptide coupling order.

[0448] MS: m / z 4110.6

[0449] 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 that the target peak eluted at 41.282 minutes with the expected molecular weight (MS: m / z 4110.6). The purity was 41.938%.

[0450] 12.5 g of the crude product was then purified as described in Example 1 above to give 4.34 g of pure title compound after lyophilization.

[0451] Example 20 N-bis{[N-bis(Lys-Hyp-Lys-NH-PEG)-N-(PEG-acid)]-NH-PEG}-N-(PEG-acid) (SEQ ID NO: 271) The title compound was prepared using essentially the same process as described in Example 2 above, except that the appropriate amino acids were used where appropriate in the correct peptide coupling order.

[0452] MS: m / z 3157.0

[0453] 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 that the target peak eluted at 13.123 minutes with the expected molecular weight (MS: m / z 3157.0). The purity was 43.126%.

[0454] 9.3 g of the crude product was then purified as described in Example 1 above to give 3.27 g of pure title compound after lyophilization.

[0455] Example 21 Ear swelling mouse model Test Compound: Compound A: N-bis{[N-Bis(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG)-N-(PEG acid)]-NH-PEG}-N-(PEG acid) (SEQ ID NO: 189), which is equivalent to (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)-(N-bis(PEG-amine)-N(PEG-acid))-N-bis(PEG-amine)-N-(PEG-acid). Compound G:((Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)4-Lys)2-Lys Twenty healthy male BALB / c mice (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd., Hangzhou, China), 6-8 weeks old and weighing an average of 18-25 g, were housed and cared for for approximately one week prior to the experiment. The mice were housed at 25-27°C, 74% humidity, and had a 12-hour light-dark cycle. Food and water were available ad libitum. The mice were randomly divided into four groups (five mice per group) as shown in Table 1.

[0456] [Table 1]

[0457] The left ear of each mouse was used as a control. The right ear of each mouse was treated with a different treatment agent: 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 about 4 minutes, the ear began to swell. Next, in each group, 40 μl of the drug was applied to the right ear. The mice were returned to their cages.

[0458] Dexamethasone acetate cream (0.75 mg / g, China Resources Group) was purchased from a local drug store. 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 saline to prepare a 1.5 mg / ml solution. The resulting solution was applied to mice as appropriate.

[0459] Mice were sacrificed by cervical dislocation 40 minutes later. Both ears were amputated. Ear sections were harvested from the same location on both ears using 8 mm diameter skin pouches (Electron Microscopy Sciences, PO Box 550, 1560 Industry Road, Hatfield, PA 19440). Weights were recorded and used to calculate swelling, which is shown in Table 2 and Figure 1. Swelling (%) = (right ear weight - left ear weight) / left ear weight × 100%

[0460] [Table 2]

[0461] The results showed that both compounds were able to significantly reduce xylene-induced ear swelling in a mouse model, with compound A in particular having a better effect than dexamethasone.

[0462] Example 22 Ear swelling mouse model Test Compound: Compound B: N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG)-N-(PEG acid)]-NH-PEG}-N-(PEG acid) (SEQ ID NO: 263), which is Equivalent to (Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid) Compound C: N-bis{[N-bis(Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG)-N-(PEG acid)]-NH-PEG}-N-(PEG acid) (SEQ ID NO: 262), which is Equivalent to (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid) Compound D: N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG)-N-(PEG acid)]-NH-PEG}-N-(PEG acid) (SEQ ID NO: 261), which is Equivalent to (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid) Compound E: N-bis{[N-bis(Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG)-N-(PEG acid)]-NH-PEG}-N-(PEG acid) (SEQ ID NO: 260), which is Equivalent to (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys)4-(N-bis(PEG3-amine)-N-(PEG3-acid))2-N-bis(PEG3-amine)-N-(PEG3-acid)

[0463] The experimental procedures and results recording were the same as those described in Example 1 above. Ear swelling was induced in mice by xylene. Forty mice were divided into eight groups as described in Table 3.

[0464] [Table 3]

[0465] The results are shown in Table 4 and FIG.

[0466] [Table 4]

[0467] The results showed that compounds B, C, and D were effective in reducing swelling in xylene-treated mouse models, with efficacy comparable to that of dexamethasone. Compound E was also effective, but not as effective as the other compounds.

[0468] Example 23 Pain relief in radiation-induced oral mucositis One patient had undergone radiotherapy to the head. The patient experienced severe oral mucositis and was diagnosed with grade 4 (the most severe level) and oral mucosal ulcers. The patient also experienced high levels of pain and difficulty eating. The patient was advised to use 1.5 mg / ml x 5 ml of Compound A solution as a mouthwash three times a day. After 7 days, the patient reported very positive feedback. The pain VAS score was reduced from 8 to 1.

[0469] Example 24 Relief of itching in neurodermatitis A 33-year-old woman presented with persistent itchy, scaly skin lesions on her back. She had been diagnosed with neurodermatitis two years prior. The patient had previously used glucocorticoids to treat the lesions, but the effects were temporary. The itching worsened when she was stressed. The patient tried spraying a 3 mg / ml solution of Compound A. After a single spray on the lesions, the itching symptoms were completely relieved approximately 60 minutes later. The patient reported that the itching symptoms stopped during the day following administration.

Claims

1. A compound of formula I, A-Q-B(I) During the ceremony, A and B are independently Z or A １ -Q １ -B １ represents Q represents a structural fragment of formula (II), 【Chemistry 1】 During the ceremony, the wavy line represents the point of attachment of Q to A and / or B; R is, 【Chemistry 2】 is selected from the group consisting of In the formula, R is 【Transformation 3】 where one wavy line represents the point of attachment to the remainder of the Q fragment and the other wavy line represents Z or A １ -Q １ -B １ represents the point of attachment to In the formula, R is 【Chemistry 4】 where one wavy line represents the point of attachment to the remainder of the Q fragment and the other wavy line represents the point of attachment to 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 are independently Z or A ２ -Q ２ -B ２ represents A ２ and B ２ are independently Z or Z-Q ３ represents -Z, Q １ , Q ２ , and Q ３ independently represent a structural fragment of formula III, 【Transformation 5】 During the ceremony, The wavy line adjacent to the NH group is Q １ , Q ２ , and Q ３ From A １ and / or B １ , A ２ and / or B ２ , and the point of attachment to Z, The wavy line adjacent to the carbonyl group is Q １ , Q ２ , and Q ３ From Q, Q １ , and Q ２ represent the attachment points to 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; Each occurrence of Z 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), During the ceremony, Z is attached to the remainder of the molecule via the N-terminus or C-terminus, as appropriate; Every time it is used, n represents 0 or an integer of 1 to 4; W independently represents one or two amino acid sequences, said amino acids being selected from one or more of the group of Ser, Lys, Ala, DOPA, and 3,4-dihydrocinnamic acid (HCA) residues, with the proviso that, if present, said HCA residue is located at the N-terminus of peptide sequence Z; each occurrence of m independently represents 0 or 1; X １ each occurrence independently represents Pro or Hyp; each occurrence of T independently represents Ser or pSer; each occurrence of U independently represents Tyr, pTyr, DOPA, Hyp, or Pro; X ２ each occurrence independently represents Thr, Ser, Pro, Hyp, or diHyp; each occurrence of Y independently represents a sequence of 1 to 5 (e.g., 1 to 4) amino acids, the amino acids being selected from one or more of the group: Lys, Ala, Pro, Hyp, Thr, pThr, DOPA, and Tyr; L independently represents at least one optional lipid substituent, the lipid being selected from the group consisting of 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, being straight or branched, saturated or unsaturated, having 1 to 10 carbon-carbon double bonds, and / or being substituted by 1 to 10 —OH groups, or a derivative of any of these lipids; X ３ represents a sequence of two to four amino acids, said amino acids being selected from one or more of the group: Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA, and Tyr; Optionally, a compound wherein the N-terminal amino acid residue of the Z moiety is covalently attached to the nonsteroidal anti-inflammatory drug or montelukast to form an amide bond with a carboxylic acid group in said nonsteroidal anti-inflammatory drug or montelukast; and positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of said compounds.

2. Both A and B represent Z, or both represent A １ -Q １ -B １ 2. The compound of claim 1, wherein

3. A １ and B １ Both represent Z or both represent A ２ -Q ２ -B ２ 3. The compound according to claim 1 or 2, wherein

4. A ２ and B ２ Both represent Z or both represent Z-Q ３ A compound according to any one of claims 1 to 3, which represents -Z.

5. p1 to p6 represent 0, The compound according to any one of claims 1 to 4, wherein m1 to m6 represent 0.

6. A compound according to any one of claims 1 to 5, wherein x and y represent 0.

7. 7. The compound according to any one of claims 1 to 4 and 6, wherein p1 to p6 represent 1.

8. The compound according to any one of claims 1 to 4, 6 and 7, wherein m1 to m6 independently represent 1 to 6.

9. R is, 【Transformation 6】 The compound according to any one of claims 1 to 8, wherein

10. R is, 【Transformation 7】 The compound according to any one of claims 1 to 4 and 6 to 8, wherein

11. The compound according to any one of claims 1 to 10, wherein n1 to n6 independently represent 1 to 5.

12. 12. The compound of any one of claims 1 to 11, wherein the amino acid residue at the N-terminus of the Z moiety is covalently attached to montelukast.

13. The compound according to any one of claims 1 to 12, wherein n is 0.

14. The compound of any one of claims 1 to 13, wherein T is Ser.

15. X １ A compound according to any one of claims 1 to 14, wherein represents Pro.

16. X ２ A compound according to any one of claims 1 to 15, wherein represents Hyp.

17. 17. The compound of any one of claims 1 to 16, wherein W is selected from the group of Ser, HCA, HCA-Ala-, Ala, DOPA, Lys-Ala, and DOPA-Ala.

18. 18. A compound according to any one of claims 1 to 17, wherein U represents Tyr or DOPA.

19. A compound according to any one of claims 1 to 18, wherein W represents Ala or Lys-Ala-.

20. Z is, 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), 20. The compound of any one of claims 1 to 19, wherein optionally, the amino acid residue at the N-terminus of the Z moiety is covalently attached to montelukast to form an amide bond with a carboxylic acid group in montelukast.

21. Z is, 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 20. The compound of claim 19, selected from the group Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID NO: 19).

22. Z is, 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 20. The compound of claim 19, selected from the group of Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 93).

23. Z is, 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 20. The compound of claim 19, selected from the group of Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 101).

24. (W) ｍ The compound according to any one of claims 1 to 18, wherein m is 0 and n is 0 for

25. Z is, Lys-Pro-pSer-Tyr-Hyp-DOPA (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 25. The compound of claim 24, selected from the group of Lys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID NO: 123).

26. Z is, 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 25. The compound of claim 24, selected from the group of Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID NO: 136).

27. 19. The compound of any one of claims 1 to 18, wherein W represents HCA, HCA-Ala-, DOPA, or DOPA-Ala-.

28. Z is, 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 28. The compound of claim 27, selected from the group of 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. Z is, 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 30. The compound of claim 29, selected from the group of Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 170).

31. The compound according to any one of claims 1 to 19, wherein n is 1 or 4.

32. Z is, 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-DOPA-Lys (SEQ ID NO: 173), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-H yp-Thr-DOPA-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-DOPA-Lys-Ala- Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 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 (SEQ ID NO: 176), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hy p-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 177), and 32. The compound of claim 31 , wherein the compound is selected from the group consisting of 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-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. 33. The compound of any one of claims 1 to 32, wherein Y represents a sequence of four amino acids, the amino acids being selected from one or more of the group: Lys, Ala, Hyp, Thr, DOPA, and Tyr.

34. Y is -Hyp-Y １ -Y ２ -Lys- and -Thr-Y １ -Y ２ -Lys-, Y represents an amino acid sequence selected from the group １ and Y ２ 11. The compound of claim 10, wherein each is independently selected from the group of Ala, Hyp, Thr, DOPA, and Tyr.

35. 35. The compound of claim 33 or 34, wherein the amino acid sequence defined by Y is selected from the group 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. 33. The compound of any one of claims 1 to 32, wherein the amino acid sequence defined by Y is selected from the group of -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

37. 37. A compound according to any one of claims 1 to 36, wherein U represents Tyr or pTyr.

38. 20. The compound according to any one of claims 1 to 19, wherein L represents at least one lipid as defined in claim 1.

39. 39. The compound of claim 38, wherein L represents a lipid selected from derivatives of fatty acids as defined in claim 1.

40. 39. The compound of claim 38, wherein the lipid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid, and leukotriene B4 (LTB4), or a derivative of any of these.

41. 41. The compound according to any one of claims 38 to 40, wherein the lipid is palmitic acid or a derivative thereof.

42. A compound according to any one of claims 1 to 41 for use in human or veterinary 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 as defined in any one of claims 1 to 41.

45. 45. The pharmaceutical formulation of claim 44, further comprising a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

46. 46. ​​A pharmaceutical formulation according to claim 44 or 45, which is suitable, adapted and / or packaged and presented for topical administration, and wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier is a topical adjuvant, diluent or carrier.

47. 47. The pharmaceutical formulation of any one of claims 44 to 46, in the form of a gel, spray, cream, ointment, or dry powder.

48. 48. A pharmaceutical formulation according to any one of claims 44 to 47, further comprising an active pharmaceutical ingredient or a further active pharmaceutical ingredient.

49. 1. A kit of parts comprising: (A) a compound as defined in any one of claims 1 to 41 or a pharmaceutical formulation as defined in any one of claims 44 to 48; (B) a pharmaceutical formulation comprising the active pharmaceutical ingredient or a further active pharmaceutical ingredient mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier; A kit of parts in which components (A) and (B) are each provided in a form suitable for administration in combination with the other.

50. 50. The pharmaceutical formulation of claim 48 or the kit of parts of claim 49, wherein the active pharmaceutical ingredient is an anti-inflammatory agent, a pro-inflammatory agent, an antibiotic, an antibacterial and / or antiprotozoal agent, an antiviral agent, an anesthetic agent, and / or a wound healing agent.

51. 51. The pharmaceutical formulation or kit-of-parts of claim 50, wherein the active pharmaceutical 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 the treatment of inflammation, an inflammatory disorder and / or a disorder characterised by inflammation.

53. Use of a compound as defined in any one of claims 1 to 41, a formulation as defined in any one of claims 44 to 48, 50 or 51, or a kit of parts as defined in any one of claims 49 to 51, for the manufacture of a medicament for the treatment of inflammation, an inflammatory disorder and / or a disorder characterised by inflammation.

54. A method for the treatment of inflammation, inflammatory disorders and / or disorders characterised by inflammation, comprising administering to a patient in need of such treatment a compound as defined in any one of claims 1 to 41, a formulation as defined in any one of claims 44 to 48, 50 or 51, or a kit of parts as defined in any one of claims 49 to 51.

55. 55. The compound, formulation or kit-of-parts 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 or results in a wound or burn.

56. 56. The compound, formulation or kit-of-parts, use or method for use according to claim 55, wherein the wound-leading disorder is hemorrhoids or ulcerative colitis.

57. 57. The compound, formulation, or kit-of-parts, use, or method for use according to any one of claims 42 to 56 (optionally), wherein the compound or salt thereof is administered topically in the form of a topical formulation.

58. 58. The compound, formulation or kit-of-parts, use or method for use according to claim 57, wherein the associated condition is treated by direct topical administration to the skin.

59. 58. The compound, formulation, or kit-of-parts, use, or method for use according to claim 57, wherein the associated pathology is treated by direct topical administration to a mucosal surface.

60. 60. The compound, formulation, or kit-of-parts, use, or method for use according to any one of claims 41 to 59 (as appropriate), wherein the compound is administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, pulmonary, or anorectal delivery.

61. 61. A compound, formulation or kit of parts, use or method for use according to any one of claims 48 to 60 (as appropriate), wherein the compound as defined in any one of claims 1 to 41 functions as an excipient, as a medical device or as a medical device component of a drug-medical device combination.

62. 62. A compound, formulation or kit-of-parts, use or method for use according to any one of claims 45 to 61 (as appropriate), wherein the compound is as defined in any one of claims 1 to 41, W is as defined in claim 27, and / or U is as defined in claim 18, and is crosslinked before or after administration to a subject.

63. 63. A compound according to claim 62 for use as an adhesive or as a film-forming material.

64. 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 biological adhesive product, a medical coating product, an industrial coating product, a biochemical reagent, a medical product, a sterilization product, or as a culture vessel for cell culture.

65. 65. A compound for use according to claim 63 or 64, wherein a film is formed on the surface of a skin or mucosal wound to aid in healing.

66. 66. A compound for use according to any one of claims 63 to 65, wherein said use is in the closure of surgical incisions, in the adhesion of fractured bones, in the adhesion of mucous membranes, or in the coating of body implants.

67. 64. A pharmaceutical formulation comprising a compound as defined in claim 63 and a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

68. 68. The pharmaceutical formulation of claim 67, which is suitable, adapted and / or packaged and presented for topical administration, and wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier is a topical adjuvant, diluent or carrier.

69. 69. The pharmaceutical formulation of claim 67 or 68, in the form of a gel, spray, cream, ointment, or dry powder.

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