New peptide

Abstract

To provide new short chain oligopeptides, the use of such peptides in human medicine, and pharmaceutical compositions comprising them. Specifically, the invention provides for the use of these peptides and compositions in the treatment of, for example, inflammation.SOLUTION: Disclosed are peptide compounds having a specific amino acid sequence, and positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the peptide compounds. These compounds are particularly useful in the treatment of conditions characterized by inflammation, including wounds, burns, and disorders of the mucous membranes, such as anorectal disease, inflammatory bowel disease, gynecological disease, and dental disease.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel short oligopeptides, 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, for example, in the treatment of inflammation.

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

[0003] Inflammation can result from physical trauma, infection, some chronic diseases (e.g., autoimmune diseases such as psoriasis and rheumatoid arthritis), and / or a chemical and / or physiological reaction to an external stimulus (e.g., part of an allergic response). 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, often resulting in local swelling, leukocyte migration to the inflamed area, and pain.

[0004] Many pathologies / disorders are characterized by and / or caused by abnormal tissue damage inflammation.These pathologies are typically characterized by the activation of immune defense mechanisms, resulting in more harmful effects than beneficial effects for 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, including 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 (resulting in 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-related pathologies.The conventional thinking in the art is that anti-inflammatory drugs should not be applied directly to open wounds, because it is harmful 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. Collagen deposition is typically a reversible part of wound healing, but 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, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus. Fibrosis may also influence the pathogenesis of many progressive myopathies, metastasis, and graft rejection.

[0008] Mussel adhesive proteins (MAPs), also known as Mytilus edulis foot proteins (mefps), are proteins secreted by marine shellfish such as Mytilus edulis, Mytilus coruscus, and Perna viridis. Eleven identified individual adhesive protein subtypes have been derived from mussels, including 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 used interchangeably hereafter), 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,32,560(2014) and Gao et al, Journal of Anhui Agr. Sci., 39, 19860 (2011)).

[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, 7, 9 (1987)). This decapeptide sequence can be isolated as a low molecular weight derivative of naturally occurring MAP or synthesized by, for example, Yamamoto et al. It can be synthesized as described in J. Chem. Soc., Perkin Trans. 1, 613 (1987). See also Dalsin et al., J. Am. Chem. Soc., 125, 4253 (2003).

[0010] Analogs of the decapeptide have also been disclosed, particularly Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2). See, e.g., US 5,616,311 and WO 96 / 39128.

[0011] 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

[0012] According to a first aspect of the present invention there is provided an (isolated) peptide compound of the following amino acid sequence: GW-Lys-X 1 -Ser-UX 2 -YZQ (SEQ ID NO: 3) (In the formula, G represents an optional N-terminal 3,4-dihydrocinnamic acid group; W represents Ala or Ser or is absent (in which case Lys is the N-terminal amino acid), U represents Tyr, DOPA, or a single bond (i.e., absent); X 1 and X 2 represents, independently, Pro, Hyp, or DiHyp, Y represents a single bond (i.e., absent) or a sequence of 1 to 5 amino acids; wherein the amino acids are selected from one or more of the group: Pro, Hyp, diHyp, Thr, DOPA, and Tyr; Z represents Pro, Hyp, diHyp, Thr, DOPA, or Tyr; Q represents Lys or is absent (in which case Z represents the C-terminal amino acid), and positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of said peptide compounds, provided that when G is absent, W represents Ala or is absent, and Q represents Lys, then Z represents Pro, Hyp, diHyp, or Thr (i.e., Z does not represent DOPA or Tyr), These compounds, regioisomers, stereoisomers, and salts are hereinafter collectively referred to as "compounds of the invention."

[0013] Among the compounds of the invention that may be mentioned are: G does not exist, X 1 represents Pro, X 2 represents Pro or Hyp, Y represents a single bond (i.e., absent) or a sequence of 1 to 5 amino acids; wherein the amino acids are selected from one or more of the group: Pro, Hyp, Thr, DOPA, and Tyr; and / or Included are compounds in which Z represents Pro, Hyp, Thr, DOPA, or Tyr.

[0014] Preferred compounds of the present invention include U represents DOPA, or more preferably Tyr; X 1 represents Hyp, or more preferably Pro, X 2 represents diHyp, or more preferably Hyp, Y represents a sequence of 1 to 4, e.g., 3, 1, or preferably 2, amino acids, The amino acid sequence is selected from the group of Pro, Hyp, Thr, DOPA, and Tyr; Compounds are included.

[0015] Compounds of the invention that may be mentioned include those in which W represents Ser.

[0016] However, more preferred compounds of the invention include those in which W is absent, or more preferably, W represents Ala.

[0017] Preferred compounds of the invention also include those in which Q represents Lys.

[0018] More preferably, compounds of the invention include those in which Z represents DOPA or Tyr, more preferably Pro, or especially Hyp.

[0019] More preferred compounds of the invention include those in which when Q represents Lys, Z represents DOPA or Tyr, more preferably Pro, or especially Hyp.

[0020] Further preferred compounds of the present invention include those in which the amino acids in the sequence defined by Y are selected from Pro, preferably DOPA, more preferably Hyp, Thr, and Tyr.

[0021] Particularly preferred compounds of the invention include those in which, in the sequence defined by Y, the amino acid DOPA, preferably Thr, or more preferably Tyr, is linked to Z and the amino acid Pro, or more preferably Hyp or Thr, is linked to X. 2 The present invention includes compounds that link to the

[0022] Preferred values ​​for Y include, when it is a three-membered amino acid sequence, -Hyp-Thr-Tyr, or more preferably -Hyp-Thr-DOPA-, and when it is a two-membered amino acid sequence, -Thr-Tyr-, or more preferably -Thr-DOPA-, or -Pro-Thr-, or more preferably -Hyp-Thr-.

[0023] Among the compounds of the invention that may be mentioned are those having the amino acid sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), and The compound Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7) is included.

[0024] Preferred compounds of the invention include those having the amino acid sequence: Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10), The compound includes Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11).

[0025] More preferred compounds of the present invention include those having the amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12), The compound Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13), more preferably the compound having the amino acid sequence: Compounds defined by the amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14), and in particular and compounds defined by Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15).

[0026] Further compounds of the invention that may be mentioned include compounds in which Q is absent, such as those having the amino acid sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 16), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 17), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 18), Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 19), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 21), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 22), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 23), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 24), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 25), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 26), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 27), and in particular the amino acid sequence: and compounds defined by Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 20).

[0027] Further compounds of the invention where G is N-terminal 3,4-dihydrocinnamic acid include those having the amino acid sequence: The compound defined by 3,4-dihydrocinnamic acid-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence 28), and more preferably the amino acid sequence: Included are compounds defined by 3,4-dihydrocinnamic acid-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 29).

[0028] Further preferred compounds of the invention that may be mentioned include those in which W is Ala and Q is Lys, such as those having the amino acid sequence: Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 30), Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 31), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 32), The compound Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 33), and in particular the amino acid sequence: Included are compounds defined by Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 34).

[0029] Further compounds of the invention that may be mentioned include compounds in which Q is absent, such as those having the amino acid sequence: 3,4-Dihydrocinnamic acid-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 35), 3,4-Dihydrocinnamic acid-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 36), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 37), Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (SEQ ID NO: 38), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 39), Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 40), and The compound Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 41) is included.

[0030] As described below, it is understood that certain compounds of the invention, including, for example, compounds where Q is Lys, and / or compounds where W is Ser and / or Z is Pro or particularly Hyp, and in particular compounds of the invention comprising the amino acid sequences of SEQ ID NOs: 4 to 15, and SEQ ID NOs: 28 to 34, are resistant to metabolism.

[0031] Nevertheless, those skilled in the art will appreciate that metabolic products of the compounds of the invention that may be formed following administration are included within the scope of the invention.

[0032] In particular, compounds of the invention lacking Q, including compounds having the amino acid sequences of SEQ ID NOs: 16 to 27, and SEQ ID NOs: 35 to 41, respectively, may be formed as metabolites of corresponding compounds of the invention containing Lys at the C-terminus, which may be cleaved after administration from other compounds of the invention, including compounds having the amino acid sequences of SEQ ID NOs: 4 to 15 and SEQ ID NOs: 28 to 34.

[0033] However, compounds of the invention having the amino acid sequences of SEQ ID NO:16-SEQ ID NO:27 and SEQ ID NO:35-SEQ ID NO:41 are also themselves compounds of the invention and can be made, formulated, and administered to patients in exactly the same manner as other compounds of the invention described herein and / or exemplified below.

[0034] For the avoidance of doubt, 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. The optional 3,4-dihydrocinnamic acid residue that may be attached to W at the N-terminus is essentially a DOPA residue, but does not have an -NH2 group (either Ala, Ser, or Lys) at the 2 or alpha carbon position relative to the carboxylic acid attached at the N-terminus.

[0035] The compounds of the present invention, whether in salt form or not, include positional isomers within the amino acid residues 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).

[0036] 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 comparison, 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 the Hyp used in the compounds of the present invention is preferably 4-hydroxy-L-proline. Similarly, a corresponding definition may be applied to diHyp, in which the two hydroxy groups can 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.

[0037] The compound of the present invention may be in the form of salt.The salts that can 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 can be formed by conventional means, for example, by reacting the compound of the present invention with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or the medium using standard techniques (for example, by vacuum, lyophilization or filtration).Salts can also be prepared by exchanging the counterion of the active ingredient in the form of salt with another counterion, for example, by using a suitable ion exchange resin.

[0038] 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.

[0039] 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 regard, those skilled in the art will be particularly familiar with the methods and procedures for preparing the compounds of the present invention. Comprehensive Organic Synthesis” by BMT Reference may be made to "Heterocyclic Chemistry" by J. A. Joule, K. Mills and G. F. Smith, "The Chemistry of Heterocyclic Compounds ... th,3 rdedition, published by Chapman&Hall, "Comprehensive Heterocyclic Chemistry II" by ARKatritzky, CWRees and EFVS criven, Pergamon Press, 1996, and "Science o f Synthesis” Volumes 9-17(Hetarenes and R elated Ring Systems), Georg Thieme Verlag, 2006.

[0040] 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.

[0041] 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.

[0042] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and as described below. For example, protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need and type of protecting groups, as well as the sequence for achieving the synthesis. The use of protecting groups is discussed in the context of "Protective Groups in Orthogonal Synthesis." This is fully described in "Primitive Chemistry: A Novel Approach to Organic Synthesis," 5th edition, T.W. Greene & P. ​​G.M. Wutz, Wiley-Interscience (2014), the contents of which are incorporated herein by reference.

[0043] The compounds of the present invention are useful because they have pharmacological activity.Therefore, the compounds of the present invention are useful as human and animal medicines.Therefore, they are indicated as pharmaceuticals (and / or veterinary medicine), but can also be used as cosmetics and / or as part of medical devices.

[0044] While the compounds of the invention may have pharmacological activity themselves, certain pharmaceutically acceptable (e.g., "protected") derivatives of the compounds of the invention exist or may be prepared, which may have no such activity but can be orally administered and subsequently metabolized or chemically converted in the body to form the compounds of the invention. Such compounds (which may have 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 invention.

[0045] As used herein, reference to a prodrug will include a compound that forms an experimentally detectable amount 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.

[0046] The compounds of the present invention are particularly useful in the treatment of inflammation.

[0047] "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 specifically skin), regardless of cause, and also includes all such inflammatory disorders or conditions and / or disorders or conditions characterized by inflammation (e.g., as a symptom).

[0048] 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.

[0049] 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.Another inflammatory condition that may be mentioned is chronic obstructive pulmonary disease (COPD).Another inflammatory condition that may be mentioned is inflammatory bowel disease, including Crohn's disease and especially ulcerative colitis.Other inflammatory conditions that may be mentioned are gynecological diseases such as cervicitis, vaginitis, and colpitis. Diseases affecting the gastrointestinal tract, such as gastric ulcer formation (e.g., gastritis, gastric ulcers, gastric cancer, and other gastric mucosal diseases), as well as gastroesophageal reflux disease (GERD), constipation, and inflammation associated with gastritis, cancer, and infections (e.g., viral infections such as the cold or flu).

[0050] 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.

[0051] More specifically, compound can be used for treating certain pathologies characterized by inflammation and / or associated with inflammation.Such pathologies can include wounds (including abrasions (scratches), incisions (including surgical incisions), lacerations, punctures, avulsions, contusions and scars), burns (including inflammation caused by post-burn surgery, such as skin grafting), and other pathologies such as hemorrhoids.Wounds can be acute or chronic, and / or can be caused by one or more inflammatory disorders as defined herein.

[0052] Skin or mucosal wounds can result from internal or external physical injury to the membrane surface, or can be caused by (ie, be a symptom of) an underlying physiological disorder.

[0053] Physical (e.g., "open") wounds can 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 can be superficial (damage to the epidermis and / or dermis only) or full-thickness wounds (damage below the epidermis and / or dermis). In severe cases, subcutaneous and / or submucosal tissues, such as muscles, bones, joints, and even internal organs, may be damaged.

[0054] The compounds of the present invention can be used to alleviate pain (including pain) associated with inflammation and / or wounds. Specifically, the compounds of the present invention can be used to alleviate procedural pain and / or non-procedural pain. Those skilled in the art will understand that the term "procedural pain" (i.e., surgical pain) refers to acute pain associated with medical investigation and treatment carried out 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 scars), and is not the result of a specific medical intervention.

[0055] Not only can the compounds of the invention be used to treat inflammation, pain (including soreness), and / or pruritus (itching) associated with the wound itself and the healing process, but they can also be used to prevent exudation of fluid from the wound, the risk of infection, and physiological responses resulting from inflammation and / or the wound healing process, such as scarring and melanin pigmentation.

[0056] 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.

[0057] The compounds of the present invention can also be useful for suppressing the production of melanin pigmentation, which may or may not be caused by inflammation and / or wound healing.The compounds of the present invention can also be useful for suppressing the pigmentation caused by skin diseases such as melanoma, freckles, melanin pigmentation, butterfly rash and other pigmentation-related disorders, as well as skin cancers including melanoma, and sun exposure or acne.

[0058] Wounds can also occur as a result of disease or injury (e.g., inflammation). Such wounds can include blisters and / or ulcers of the skin and mucous membranes. These are common conditions that are often long-lasting and difficult to treat. Skin tissue can often be 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.

[0059] 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.

[0060] 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.

[0061] Acne is a chronic inflammatory skin disease of the follicular (pilosebaceous) system, the development of which is closely related to factors such as excessive sebum, obstruction of the pilosebaceous ducts (including closed and open comedones), bacterial infection, and inflammatory reactions. It tends to occur at a young age and is characterized by polymorphic skin lesions on the face. Therefore, the term acne includes both ordinary acne and acne rosacea (i.e., red nose).

[0062] Eczema is an intensely itchy inflammatory reaction of the skin caused by various 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 hypertrophy. The skin lesions are often itchy and easily recur.

[0063] Dermatitis is a common skin disorder characterized by roughness, redness, itchiness, eczema, and dryness. The small lumps, intractable 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). Seborrheic dermatitis (seborrheic eczema) and all forms of steroid-dependent dermatitis (including photosensitive seborrhea, 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-addicted dermatitis (FCAD) or facial corticosteroid-dependent dermatitis (FCDD) (e.g., Xiao ... et al, J. Dermatol., 42, 697 (2015) and Lu et al, Clin. Exp. Dermatol., 35, 618 (2009)).

[0064] 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 of itchy eyes, even when the compound of the present invention is administered nasally (i.e., to the nasal mucous membrane).

[0065] Hemorrhoids are swellings caused by large inflammations of the hemorrhoidal blood vessels found in or around the rectum and anus. Symptoms include bleeding (i.e., wounds) after passing stool, prolapsed hemorrhoids, mucus secretion, 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.

[0066] 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.

[0067] The compounds of the present invention may have a positive effect on the relief of 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.

[0068] Other inflammatory conditions that may be mentioned include: (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 injuries, 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. (b) For example, fractures, pyogenic infections of bones and joints, inflammation due to rheumatic bone disease, and pyogenic osteomyelitis (acute, chronic, localized, sclerotic, post-traumatic), septic arthritis, bone tumors (osteoma, osteoid osteoma, 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 orthopedic inflammation associated with rheumatoid arthritis. (c) Nerve inflammation such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, and intercostal neuritis. (d) Inflammation of subcutaneous and submucosal soft tissues, such as myositis, dendritis, tendonitis, cystitis, lymphadenitis, cryptitis, tonsillitis, synovitis, and fasciitis, as well as inflammation of soft tissues caused by injury, contusion, or tear of muscle, ligament, fascia, tendon, synovium, fat, joint capsule, and lymphatic tissue. (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. (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. (g) Inflammation of the eye and surrounding area, such as conjunctivitis, keratitis (e.g., acute superficial 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), and optic neuritis. (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, and dental ulcers. (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.

[0069] The compounds of the present invention can also be used to treat certain specific diseases of the digestive system, such as GERD, which can 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 between 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 in the distal esophagus to intestinal columnar epithelium), and / or esophageal adenocarcinoma (a form of cancer).

[0070] The compounds of the present invention can also be used to treat certain special diseases of the respiratory system, such as pulmonary cystic fibrosis, common interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, cor pulmonale, pulmonary embolism, etc. A special disease state that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0071] 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 will experience 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.

[0072] The compounds of the invention are useful in treating 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 mycoses, cryptococcosis, lung abscess, anaphylactic pneumonia (Leoffer's syndrome), and / or pulmonary fibrosis. It is particularly useful in the treatment of pulmonary eosinophilia (eosinophilic syndrome), extrinsic allergic alveolitis, pulmonary eosinophilia (hypereosinophilia), obstructive emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis (acidosis), acute lung injury, interstitial lung disease, empyema, pulmonary fibroma, and cor pulmonale.

[0073] Particular mucosal disorders and diseases in which the compounds of the invention are found to be useful include anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, anal fissures, anal itching, anal sinusitis, warts and rectal prolapse; inflammatory bowel diseases including Crohn's disease, especially ulcerative colitis; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as paradentitis.

[0074] The compounds of the present invention may further have antioxidant effects by increasing SOD (superoxide dismutase) production and reducing lipid oxidation, and therefore the compounds of the present invention may be considered to have antioxidant properties.

[0075] The compounds of the present invention may also have antipyretic properties, allowing for the treatment of fever and / or alleviating its symptoms, for example, by reducing the body temperature of a subject (which results in a reduction in fever). Thus, the compounds of the present invention and formulations containing them may be considered to be antipyretics.

[0076] According to a further aspect of the present invention, there is provided a method for treating inflammation, an inflammatory disorder, and / or a disorder / condition characterized by inflammation (e.g., as a symptom), which method comprises administering a compound of the present invention, or a salt thereof, to a patient in need of such treatment.

[0077] 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.

[0078] The compounds of the present invention may further have antiviral properties that may allow for the treatment of viral infections or viral diseases by interfering with viral replication within the host, as opposed to treating any viral infection or any symptoms of a viral infection, such as pain and / or inflammation. Such antiviral properties may also allow for the prevention of the onset of such infections or diseases, the protection of cells within the host from (e.g., further) viral infections, the prevention or arrest of the spread of viral infections or diseases (within a single host or from one host to new hosts), or the prevention of viral reactivation after latency in the host.

[0079] According to a further aspect of the present invention there is provided a method for treating a viral infection which comprises administering to a patient in need of such treatment a compound of the present invention, or a salt thereof.

[0080] Viral infections that may be mentioned include adenoviridae (e.g., adenovirus), papillomaviridae (e.g., human papillomavirus), polyomaviridae (e.g., BK virus, JC virus), herpesviridae (e.g., herpes simplex type 1, herpes simplex type 2, varicella-zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus type 8), poxviridae (e.g., smallpox), hepadnaviridae (e.g., B Hepatitis 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 viruses), retroviridae (e.g., human immunodeficiency virus, HIV), togaviridae (e.g., rubella virus), arenaviridae (e.g., Lassa virus), bunyaviridae (e.g., hantavirus, Crimean-Congo hemorrhagic fever virus, hantavirus), filoviridae (e.g., Ebola virus, Marburg virus, Ravn virus), orthomyxoviridae (e.g., influenza A viruses (e.g., H1N1 and H3N2 viruses) Viruses not assigned to a family, such as influenza viruses, influenza B viruses, or influenza C viruses, 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), and hepatitis D virus, are also included.

[0081] Viruses that may be mentioned more particularly include herpes simplex type 1 and herpes simplex type 2, human papillomavirus, influenza virus, and parainfluenza virus.

[0082] The compounds of the present invention may further have antibacterial and / or bacteriostatic properties that 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 the 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.

[0083] 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 bacterial reactivation after latency in the host.

[0084] According to a further aspect of the present invention there is provided a method for treating a bacterial infection which comprises administering to a patient in need of such treatment a compound of the present invention, or a salt thereof.

[0085] The compounds of the present invention may further have anti-cancer properties that 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 the prevention of the onset of such diseases, for example, by treating inflammation and thereby preventing such onset.

[0086] According to another aspect of the present invention, there is provided a method for treating cancer, comprising administering a compound of the present invention, or a salt thereof, to a patient in need of such treatment.

[0087] 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.

[0088] "Patient" includes reptilian, avian, and preferably mammalian (especially human) patients.

[0089] According to the present invention, the compounds of the present invention are administered in the form of a pharmaceutical preparation 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, intradermally, transdermally, intranasally, pulmonary (e.g., trachea or bronchus), preferably topically, or by any other parenteral route.

[0090] 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 colds and influenza).

[0091] Pulmonary administration is particularly useful when the condition being treated is COPD or IPF. Topical administration forms can be enhanced by, for example, using powder aerosols or aqueous mist using suitable atomizing techniques or devices such as nebulizers to create a spray containing the active ingredient.

[0092] 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.

[0093] Administration to the lower gastrointestinal tract can also be achieved by parenteral, particularly oral delivery, by using standard delayed-release or sustained-release coating technology known to those skilled in the art.Particularly, 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 is first administered orally or parenterally.

[0094] The compounds of the invention may alternatively be administered by direct systemic parenteral administration, which may be useful in methods for treating inflammatory and / or fibrotic disorders or conditions in one or more organs of a patient.

[0095] 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.

[0096] The 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 tissue.Therefore, the preparations 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, the fibrotic conditions of internal organs (for example, acute and / or severe) that can be treated by the preparations of the present invention include fibrosis of the cardiovascular system, including the liver, kidney, lung, heart and vascular system, pancreas, spleen, central nervous system (neurofibrosis), bone marrow fibrosis, eye, vagina, cervix, etc.

[0097] 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 life-threatening.

[0098] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of internal organs (i.e., one or more conditions that require, or may develop into, immediate medical intervention), characterized by inflammation (e.g., as a symptom), such as acute visceral injury in one or more internal organs (including any of the organs mentioned above). 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 also inhibit the progression of morbidity and / or mortality associated with such conditions.

[0099] Thus, acute inflammatory conditions that may be mentioned include conditions such as peritonitis, pancreatitis, colitis, proctitis, gastritis, duodenitis, pharyngitis, GERD, periodontitis, and stomatitis. Specific acute inflammatory conditions that may be mentioned include acute injury to one or more internal organs (including any of those previously mentioned), 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.

[0100] Such conditions can be caused by internal or external trauma (eg, an injury or burn), or by infection, for example, by a virus, bacteria, or fungus.

[0101] For example, inflammation, injury, and / or failure of multiple organs can be caused by extensive and / or traumatic external injuries, 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%, including at least about 20%, such as at least about 15%, of the patient's body area. External (and internal) burns can be caused by exposure to heat, chemicals, etc.

[0102] Acute inflammatory and / or fibrotic conditions may also result from sepsis or septic shock, which may be caused by viral, bacterial, or fungal infections. Additionally, acute lung injury, ARDS, and particularly SARS, can be caused by viruses, such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2).

[0103] Therefore, furthermore, 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 a number of factors, including inflammation.

[0104] 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) another, further medical condition, including (and indeed preferably) those mentioned above, which conditions may interact and / or overlap with each other in some way.

[0105] For this reason, the following is provided: 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 for 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.

[0106] When the compounds of the present invention / salts thereof are administered directly and parenterally, they may be administered intravenously, intraarterially, intravascularly, perivascularly, intramuscularly, cutaneously, and / or subcutaneously, for example, by direct injection, or by any other parenteral route, in the form of the compounds of the present invention or their salts, in the form of a pharmaceutically acceptable dosage form.

[0107] Thus, pharmaceutically acceptable formulations for use in such administration may include a compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, which may be selected with due consideration of the intended route of direct parenteral administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active 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 active ingredient.

[0108] Thus, formulations of the invention 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 a lyophilized powder that can be reconstituted with a vehicle, such as an aqueous vehicle, prior to use (e.g., injection).

[0109] The formulations of the present invention may also 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.

[0110] The formulations of the present invention are preferably buffered to a physiologically acceptable pH value (e.g., a pH between about 4.5 and about 9.5, e.g., about 6 and about 9, e.g., about 6.5 and about 8.5) using buffers and / or pH adjusting agents as described herein by standard techniques, and / or may further comprise a tonicity modifying agent (e.g., sodium chloride).

[0111] 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 oral and / or nasal mucosa, lung, anorectal and / or colon), or more preferably, skin), in a suitable (e.g., pharmaceutically and topically acceptable) vehicle, and / or a commercially available formulation, suitable for application to the skin and / or suitable mucosal surface, but may also include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, or pulmonary delivery.

[0112] Administration by intradermal injection (e.g., intradermal) is particularly useful for administering active ingredients in the form of a solution or suspension (e.g., a dermal filler) to the dermis, which is particularly useful as a means of administration for the melanin pigmentation therapies described above.

[0113] 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 be free of adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also provide immediate or modified release of the active ingredient.

[0114] Suitable pharmaceutical formulations are commercially available or can be found in the literature, for example in Remington T he Science and Practice of Pharmacy,22 nd edition, Pharmaceutical Press (2012), and M artindale-The Complete Drug Reference,38 th Edition, Pharmaceutical Press (2014), as well as documents referenced therein, the relevant disclosures of all of which documents 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.

[0115] The compounds of the invention may be in the form of an aqueous formulation (e.g., solution), such as an emulsion, suspension, and / or solution (e.g., an (optionally) buffered aqueous formulation (e.g., solution), such as a saline-containing formulation (e.g., solution), a phosphate-containing formulation (e.g., solution), an acetate-containing formulation (e.g., solution), or a borate-containing formulation (e.g., solution), or a lyophilized powder.

[0116] The active ingredient may additionally and / or alternatively be combined with suitable excipients to prepare: gel formulations (for which suitable gel matrix materials include cellulose derivatives, carbomers and alginates, tragacanth gum, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulose polysaccharides, sugars such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and, in particular, hyaluronic acid); lotions (suitable matrix materials for which 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 glycol of various molecular weights, sodium dodecyl sulfate, sodium fatty alcohol polyoxyethylene ether sulfonate, corn gluten powder, and acrylamide); powder aerosols (suitable excipients for which include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol, and polysorbates, e.g., dry powder inhalants); and / or Oral or inhaled liquids, for example, water (aerosol) sprays (suitable excipients for these include viscosity adjusting agents such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohol, water, preservatives, sweeteners, flavors, etc.). Injectable solutions or suspensions (which may be aqueous or other, suitable excipients of which include solvents and co-solvents, solubilizing agents, wetting agents, suspending agents, emulsifying agents, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers and / or pH adjusting agents, bulking agents, protectants, and tonicity modifiers). Particular injectable solutions or suspensions that may be mentioned include dermal fillers (i.e., injectable fillers or soft tissue fillers).

[0117] Moisturizing agents such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (for example, sodium salt and potassium salt), octanoic acid / capric acid triglyceride, 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.In addition, hexadecanol (cetyl alcohol), fatty acids (for example, stearic acid), sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (for example, sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (glyceryl monostearate, etc.), polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (for example, polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, Polyoxylglycerides, lauryldimethylamine oxide, bile salts (e.g., sodium deoxycholate, sodium cholate), phospholipids, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), sugar esters, surfactants / emulsifiers such as polysorbates, preservatives such as phenoxyethanol and ethylhexylglycerin, and thickeners such as acryloyldimethyltaurate / VP copolymer may also be included. In particular, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, octanoic / capric glycerides, etc. may be included, especially in cream formulations.

[0118] The compounds of the present invention and (e.g., pharmaceutical) formulations containing 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. Thus, such formulations can be used to impregnate matrix materials such as gauze, nonwoven fabrics, or silk paper. Alternatively, the therapeutic patch can be, for example, a Band-Aid®, a face mask, an eye mask, a hand mask, a foot mask, etc.

[0119] Although petrolatum may be used for use in applying such dressings to wounds, we 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.

[0120] The compounds of the present invention can be administered for inhalation by 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 standard spacer devices; dry powder inhalers (DPIs), which can be single-dose or multi-dose power-assisted; and soft mist inhalers (SMIs) or nebulizers, which deliver aerosolized medicine in a fine mist at a slower rate than the spray delivered, for example, using pMDIs.

[0121] In pMDIs, the compounds of the invention may be administered as a pressurized suspension of micronized particles dispersed in a propellant (e.g., with an excipient such as HFA, mannitol, lactose, sorbitol, etc.) or as an ethanol solution 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.

[0122] 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-sized inert excipients (e.g., mannitol), in capsules that may be preloaded or manually filled into the device. Inhalation from a DPI may break down the drug particles and allow them to disperse in the respiratory tract.

[0123] 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.

[0124] Various nebulizers can also be used to administer the compounds of the present invention in the form of a fine mist of aerosolized solution, including exhalation-enhanced jet nebulizers (with the aid of a compressor, airflow moves through a jet, aerosolizing the medicinal solution), exhalation-activated jet nebulizers (with the aid of a compressor, airflow moves through a tube, aerosolizing the medicinal solution after the patient inhales), 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).

[0125] 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.

[0126] 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).

[0127] 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.

[0128] Thus, there is further provided a pharmaceutical composition comprising a compound of the invention presented in a manner suitable, adapted, and / or packaged for topical administration (e.g., to the oral and / or nasal mucosa, lungs, 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 mucosa, including the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin).

[0129] For the avoidance of doubt, with regard to this aspect of the present invention, topical formulations comprising the compounds of the present invention can 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, the topical formulations comprising the compounds of the present invention that may be mentioned include any and all of those mentioned, defined, or described above.Any and all of the relevant disclosures herein are incorporated herein by reference in connection with this aspect of the present invention.

[0130] Topical formulations (e.g., liquid or (e.g., aqueous) solution-based) containing the compounds of the present invention may be particularly useful in wound healing and may alleviate pain (including soreness) and pruritus / itch, particularly associated with the wound itself and the wound healing process. Such topical formulations containing the compounds of the present invention may be particularly useful in preventing and / or suppressing exudation of fluid from the wound, especially during the acute inflammatory phase, e.g., the first 48 hours, after a burn or wound. This prevents the risk of infection and other physiological reactions. Such topical formulations containing the compounds of the present invention may also be particularly useful in preventing and / or suppressing scarring and melanin pigmentation (see above), whether or not associated with a wound.

[0131] The administration of the active ingredient can be continuous or intermittent. The mode of administration can 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.

[0132] 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.

[0133] Similarly, the amount of active ingredient in the formulation will depend on the severity of the condition being treated and the patient, but may be determined by one skilled in the art.

[0134] In any event, a practitioner 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 mentioned herein are exemplary of the average case, and there can, of course, be individual instances in which higher or lower dosage ranges are merited, and these are within the scope of this invention.

[0135] The dose can be administered one to four (eg, three) times daily.

[0136] 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.

[0137] 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 2 within the therapeutic range of

[0138] 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 rhinitis (e.g., allergic rhinitis).

[0139] 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, from about 0.1 μg to about 500 mg, or from 1 μg to about 100 mg. Particular doses for pulmonary administration that may be mentioned include doses from about 10 μg to about 10 mg, in particular doses from about 0.6 mg (i.e., 60 μg) to 6 mg (e.g., for use in the treatment of COPD or IPF).

[0140] 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).

[0141] In any case, the dose administered to a mammal, particularly a human, in the context of the present invention must be sufficient to bring about 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, among other things, 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.

[0142] In the uses and methods described herein, the compounds of the present invention may be combined with one or more active ingredients (other anti-inflammatory agents) useful in the treatment of inflammation and / or inflammatory disorders. Accordingly, such patients may also (and / or already) be undergoing a therapy based on the administration of one or more of such other active ingredients, by which is meant receiving prescribed doses of one or more of the active ingredients mentioned herein before, in addition to, and / or after treatment with the compounds of the present invention.

[0143] The anti-inflammatory agent that can be used in combination with the compound of the present invention in the treatment of inflammation includes the therapeutic agent that is useful for treating inflammation and / or the disease characterized by inflammation as one of its symptoms.Depending on the pathological condition to be treated, such anti-inflammatory agent can also include NSAIDs (for example, aspirin), leukotriene receptor antagonists (for example, montelukast), corticosteroids, analgesics, and certain enzymes, such as trypsin, as described below.The compound of the present invention can also be combined with leukotriene B4 (LTB4).

[0144] In this context, the compounds of the invention may also be combined with one or more mussel adhesive proteins (MAPs) for use in treating inflammation, including any adhesive protein that may be derived from a mussel species such as Mytilus edulis (blue mussel), including full-length proteins including all subtypes that are or may be derived from mussels, such as collagens pre-COL-P, pre-COL-D, and pre-COL-NG, mussel foot matrix proteins PTMP and DTMP, and more preferably mfps or mefps (such as mefp-2, mefp-3, mefp-4, mefp-5, mefp-6, and especially mefp-1), including mixtures or combinations of any of these proteins, such as mefps. Naturally occurring MAP can be prepared, for example, by mixed adsorption chromatography (see China Patent No. 2007 / 10179491.0), by carboxymethyl ion exchange chromatography (see China Patent No. 2007 / 10179492.5), and / or by salting out and dialysis (see China Patent No. 2009 / 10087567.6). Commercial sources of MAP include USUN Bio Co. (China, MAP Me Manufacturers of MAPs include BD Biosciences (USA), Kollodis (South Korea), and Biopolymer (Sweden). Alternatively, MAPs may be produced using known recombinant DNA methods.

[0145] Derivatives (e.g., pharmaceutically acceptable derivatives) of MAPs may be combined with the compounds of the invention, including, for example, compounds having molecular weights ranging from about 500 Da to about 2,000 Da (e.g., about 1,500, such as about 1,200, including about 800 Da). Such derivatives may also include other compounds containing amino acid sequences that are the same as or are (e.g., minor) variants (as defined above) of sequences identified in naturally occurring MAPs, which can be synthesized by chemical and / or biological processes (e.g., chemical modification of naturally occurring MAPs or direct synthesis).

[0146] For example, as discussed herein above, the isolated decapeptide compounds of the sequences: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (mefp-1 decapeptide, SEQ ID NO: 1) and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2) are pharmaceutically acceptable low molecular weight derivatives of MAP that can be combined with the compounds of the present invention.

[0147] Other preferred agents that can be combined with the compounds of the invention include LTB4 (for treating wounds and burns), NSAIDs (e.g., aspirin), montelukast (for treating inflammation generally), and trypsin (e.g., for treating inflammation of the mucous membranes associated with viral infections).

[0148] 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.

[0149] When the compounds of the invention are "combined" with other therapeutic agents in this manner, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0150] Such combination products provide for the administration of a compound of the invention in combination with another therapeutic agent, and therefore may be presented as separate formulations (at least one of which contains a compound of the invention and at least one of which contains the other therapeutic agent) or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing a compound of the invention and the other therapeutic agent).

[0151] Thus, there is further provided (1) a pharmaceutical formulation comprising a compound of the present invention, another anti-inflammatory agent, or an agent known to cause inflammation as a side effect, and a pharmaceutically acceptable excipient (e.g., adjuvant, diluent, or carrier) (this formulation is hereinafter referred to as a "combination preparation"), and (2) a kit of parts comprising components: (A) a pharmaceutical formulation comprising a compound of the present invention in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier, and (B) a pharmaceutical formulation comprising another anti-inflammatory agent, or an agent known to cause inflammation as a side effect, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier, wherein components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0152] In a further aspect of the present invention, there is provided a process for preparing a combination preparation as defined above, which comprises associating a compound of the present invention, another anti-inflammatory agent, or an agent known to cause inflammation as a side effect, with at least one (e.g., pharmaceutically acceptable) excipient.

[0153] In a further aspect of the present invention, there is provided a process for preparing a kit-of-parts as defined herein above, comprising associating components (A) and (B). As used herein, reference to associating means making the two components suitable for administration in combination with each other.

[0154] Thus, with respect to the process for preparing a kit-of-parts as defined above, by "associating" two components with one another, the inventors include that the two components of the kit-of-parts may either (i) be provided as separate formulations (i.e., independently of one another) which may then be used in conjunction with one another in a combination treatment, or (ii) be packaged and provided together as separate components of a "combination package" for use in conjunction with one another in a combination treatment.

[0155] Accordingly, there is further provided a kit of parts comprising (I) one of components (A) and (B) as defined herein, together with (II) instructions for using that component in combination with the other of the two components.

[0156] The kits of parts described herein may contain two or more formulations containing suitable amounts / doses of a compound of the invention and / or two or more formulations containing suitable amounts / doses of another anti-inflammatory agent to provide for repeated administration. When two or more formulations (containing any of the active compounds) are present, such formulations may be the same or different with respect to the dosage, chemical composition, and / or physical form of any of the compounds.

[0157] With respect to the kits of parts described herein, by "administration in combination with," we include sequential, separate, and / or simultaneous administration of respective formulations comprising a compound of the invention and another anti-inflammatory agent over the course of treatment of the relevant condition.

[0158] 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 anti-inflammatory agent) either together or sufficiently closely in time (optionally repeatedly) so as to permit a greater beneficial effect to the patient over the course of treatment of the relevant conditions than would occur if, over the same course of treatment, either a formulation comprising the compound of the invention or a formulation comprising the other agent were administered alone (optionally repeatedly) without the other component. Determining whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over the 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.

[0159] 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 formulations 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 individual doses of the relevant compound of the invention and the other anti-inflammatory agent within 48 hours (e.g., 24 hours) of each other.

[0160] In a further aspect of the present invention, there is provided a process for preparing a combination preparation as defined above, which comprises associating a compound of the present invention as defined above or a salt thereof, another anti-inflammatory agent, or an agent known to cause inflammation as a side effect, with at least one (e.g., pharmaceutically acceptable) excipient.

[0161] Certain compounds of the present invention may possess adhesive properties in addition to and / or instead of possessing the aforementioned biological activities.

[0162] Such compounds of the present invention are capable of adhering to a number of substrates, including inorganic substrates such as glass, metals, etc., and organic substrates such as biological tissue.

[0163] 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.

[0164] Such compounds of the present invention can form films on various skin and mucosal wound surfaces, such as burns, scalds, ulcers, frostbite, and bedsores, to aid in healing. Such compounds of the present invention can also be used in surgery, for example, for closing surgical incisions, bonding fractured bones, bonding mucous membranes, and coating human body implants, such as artificial bones, cartilage brackets, periosteum, artificial joints, dental implants, occlusion stents, spinal fixation devices, spinal spacers, and organ patches.

[0165] According to a further aspect of the present invention there is provided a compound of the present invention or a salt thereof as an adhesive or film-forming material.

[0166] Whenever the term "about" is used herein in the context of quantities such as concentration and / or dosage of an active ingredient, molecular weight, or pH, it will be understood that such variables are approximate and thus may vary from the numerical values ​​specified herein by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%). In this regard, the term "about 10%" means, for example, ±10% of the numerical value 10, i.e., 9% to 11%.

[0167] The compounds of the present invention have the advantage that they can be used in a variety of conditions characterized by inflammation, whether the condition itself is an organic inflammatory disease or is associated with or characterized by inflammation (e.g., wounds, burns, or viral infections).

[0168] The compounds of the invention may also have the advantage of exhibiting improved resistance to metabolism in vivo compared to compounds described in the prior art, including those defined by SEQ ID NO: 1 and / or SEQ ID NO: 2. The compounds of the invention may exhibit improved resistance to metabolism by chymotrypsin (a digestive enzyme that breaks down proteins) and / or elastase (an enzyme that breaks down elastin, which together with collagen determines the mechanical properties of connective tissue).

[0169] The compounds, uses and methods described herein may also have advantages over similar compounds or methods (treatments) known in the prior art in treating the above-mentioned conditions, whether for use in treating inflammation, inflammatory disorders, or disorders characterized by inflammation as a symptom (including wounds), or other methods, 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 methods (treatments).

[0170] The invention is illustrated by the following examples, in which Figure 1 shows the Evans Blue content in rectal and anal tissues, indicating the vascular permeability of the test compounds. [Brief explanation of the drawings]

[0171] [Figure 1] The Evans Blue content in rectal and anal tissues is shown, indicating the vascular permeability of the test compound. [Example]

[0172] Example 1 Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15) Fmoc-Lys-Boc-Wang resin (9.15g, GLS180322-413 01, GL Biochem, Shanghai, China) was packed into a glass reaction column.

[0173] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemi The resin was allowed to soak for approximately 30 minutes. DCM was then removed by vacuum filtration.

[0174] The resin was dissolved in N,N-dimethylformamide (DMF, 200 mL; Shandong Sh The mixture was washed three times with Itaifeng Fertilizer Industry Co Ltd (Shandong, China).

[0175] A 20% piperidine solution (200 mL) in DMF 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. Fmoc-4-Hyp(tBu)-OH (GLS 21303; GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GLS 170805-00705, GL Biochem, Shanghai, China) was 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) was added. After 30 minutes, a color reaction was detected on the resin, indicating the reaction was complete. The solvent was removed by vacuum filtration.

[0176] The above coupling steps were repeated to couple the remaining amino acids in the same amounts (by mole): Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH.

[0177] A 91.5 mL (i.e., 10 mL per gram of resin) solution of 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to soak the resin-bound peptide compound. The side chains were also deprotected during cleavage. After cleavage, the solid support was removed by filtration, and the filtrate was concentrated under reduced pressure. The cleaved peptide was precipitated with diethyl ether and lyophilized to give the crude title compound.

[0178] 1 mg of the crude product was dissolved in 1 mL of a 1:3 mixture of acetonitrile and water and detected using a P3000A HPLC pump and an LC3000 semi-preparative instrument (preparative column model: GS-120-10-C18-AP 30 mm; Beijing Chuangxin Tonggheng Science & Technology Co., Ltd., Beijing, China). A suitable gradient was calculated for elution, and the target peak was detected by LCMS at 11:035 min (analytical column model: GS-120-5-C18-BIO, 4.6 × 250 mm, detection: UV at 220 nm, solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, flow rate: 1.0 mL / min, volume: 10 μL).

[0179] The crude compound was desalted using anion exchange resin, analyzed and lyophilized. After purification, the purified peptide was obtained.

[0180] The above synthesis was repeated except that after coupling of Fmoc-Ala-OH to the resin, a deprotection step was carried out to remove the Fmoc group and the resin was washed three times with DMF (200 mL).

[0181] A 20% piperidine solution (200 mL) in DMF was added as a deprotection solution and allowed to react for 20 minutes. The resin was then washed three times with the following solvents: DMF (200 mL), DCM (200 mL), and methanol (200 mL; Xilong Scientific Co., Ltd., Guangdong, China). The resin was then dried under vacuum for approximately 2 hours.

[0182] 85.0 mL (i.e., 10 mL per gram of dry resin) of the lysate was added to soak the peptide-containing compound bound to the resin. 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 850 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 give 3.66 g of crude title compound.

[0183] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system. The analytical column was an Angilent 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).

[0184] The target peak eluted at 9.537 min with the expected molecular weight and a purity of 77.256%.

[0185] MS: m / z 1183.1 Next, 3.6 g of the crude product was dissolved in 40 mL of purified water and purified using an LC3000 semi-preparative system. Next, 3.6 g of the crude product was dissolved in 40 mL of purified water and purified using an LC3000 semi-preparative system. The preparative column model was a Dubhe-C18 model (Hanbon Sci. & Tech. Co., Ltd., Jiangsu, China) (50 × 250 mm column, UV detection: 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, 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 (the same column as above, except a linear gradient from 5% to 30% solvent A concentration in 25 min was used).

[0186] Next, the 98% pure fractions were mixed together for the anion exchange step. This was achieved using an LC3000 semi-preparative system (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 0.37% ammonium acetate in pure water for approximately 20 minutes at a flow rate of 60 mL / min, followed by elution with the following gradient: Solvent A: 0.1% HAc in MeCN; Solvent B: 0.1% HAc in water; a linear gradient of solvent A concentration from 5% to 20% over 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). The 98% pure fractions were mixed and lyophilized to yield 2.03 g of purified title compound.

[0187] Example 2 Croton oil-induced anal swelling model in rats A gel containing 0.5 g of the peptide Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15; see Example 1 above) was made, which also consisted of the following components: methylcellulose (2.2 g; Shandong Guangda Technology Development Co., Ltd., ShanDong, China), glycerin (11 g) and propanediol 11 g (both Sinopharm Chemical Reagent Co. Ltd.), and purified water (75.3 g).

[0188] Methylcellulose and water were mixed together and stirred until a homogeneous colloidal suspension was formed. Next, the peptide powder, glycerin, and propanediol were added to the methylcellulose / water mixture, and the resulting mixture was rapidly stirred for 5 minutes to obtain the final product.

[0189] Six- to eight-week-old SD rats, half male and half female, with an average weight of 180–220 g were provided by Changzhou Cvens Experimental Animal Co. Ltd. (Changzhou, Jiangsu Province, China). Before any experiments were performed, the rats were housed under standardized conditions (constant temperature or 22 ± 2°C, 12-hour alternating light and dark cycles) for approximately 1 week and fed standard mouse chow containing water.

[0190] Thirty-two rats were randomly divided into four groups, with eight rats in each group.

[0191] Rats were anesthetized by inhalation of isoflurane (China Pharmaceutical Group Chemical Reagents Co., Ltd.). The perianal skin was disinfected using a cotton ball soaked in 75% alcohol. 0.16 mL of a croton oil mixture (1 part distilled water, 4 parts pyridine (Nanjing Chemical Reagent Co., Ltd.), 5 parts ether (China Pharmaceutical Group Chemical Reagents Co., Ltd.), and 10 parts 6% croton oil (Shanghai Yuanye Biotechnology Co., Ltd.)) was slowly dripped onto a cotton swab and inserted 0.5 cm into the rat's anus.

[0192] The rats were lifted and held head-up for 10 seconds, then the cotton swab was removed and the croton oil mixture was applied evenly to the surrounding skin. A blank control group received the same volume of olive oil.

[0193] One hour after modeling, rats in each group were treated as follows: Control group - given normal saline ("control") Model group - treated with blank gel containing no active ingredient ("Model") Positive control - MaYinglong hemorrhoid ointment (MaYinglong Pharmaceutical Group Co., Ltd., "Mayinglong") Peptide gel (as mentioned above, "peptide")

[0194] 200 μL of test substance was aspirated into a 1 mL syringe (with the needle removed). The syringe was inserted into the anal canal, and approximately 160 mL of each test substance was pushed in to a depth of approximately 1.5 cm. The remaining drug was applied to the skin around the anus. The skin around the anus was pressed firmly for approximately 1 minute to prevent the drug from expelling.

[0195] On the morning of day 4, 1% Evans Blue (EB) was injected into the tail vein 30 minutes after drug administration (200 μL / 100 g). After another 30 minutes, the rats were sacrificed by cervical dislocation.

[0196] The rat was placed supine on a dissection plate and the abdomen was opened. The anorectal tissue (15 mm in length) was isolated and weighed, and the EB dye present in the tissue was extracted using 1 mL of formamide.

[0197] All samples were transferred to a 55°C water bath or heating block. EBs were extracted from the tissues by incubation for 24 hours. The formamide / EB mixture was centrifuged to pellet any remaining tissue fragments. Absorbance was measured at 610 nm using 500 μL of formamide as a blank.

[0198] The content of EB in the rectal and anal tissues was calculated using the amount of extravasated EB (in ng) per mg of tissue to assess vascular permeability. The results are shown in Figure 1, which demonstrate that the test peptide can reduce the inflammatory swelling caused by the application of croton oil.

[0199] Example 3 Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) The title compound was prepared using essentially the same process as the latter described in Example 1 above, except that Fmoc-DOPA(acetonide)-OH was used instead of Fmoc-Tyr(tBu)-OH in the relevant amino acid coupling step, yielding 3.73 g of crude title compound.

[0200] Analysis showed that the target peak eluted at 9.297 min with the expected molecular weight (MS: m / z 1199.1). The purity was 74.493%.

[0201] 3.7 g of the crude product was then purified as described in Example 1 above to give 2.01 g of pure title compound after lyophilization.

[0202] Example 4 3,4-Dihydroxyhydrocinnamic acid-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 29) The title compound was prepared using essentially the same process as the latter described in Example 1 above, except for the final coupling with 3,4-dihydroxyhydrocinnamic acid, to give 4.05 g of crude title compound.

[0203] Analysis showed that the target peak eluted at 9.716 min with the expected molecular weight (MS: m / z 1347.1). The purity was 79.183%.

[0204] 4.0 g of the crude product was then purified as described in Example 1 above to give 2.67 g of pure title compound after lyophilization.

[0205] Example 5 Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 34) The title compound was prepared using essentially the same process as the latter described in Example 1 above, except that Fmoc-DOPA(acetonide)-OH and Fmoc-4-Hyp(tBu)-OH were used instead of Fmoc-Tyr(tBu)-OH and Fmoc-Pro-OH, respectively, in the relevant amino acid coupling step, yielding 3.79 g of crude title compound.

[0206] Analysis showed that the target peak eluted at 9.177 min with the expected molecular weight (MS: m / z 1215.7). The purity was 75.365%.

[0207] 3.7 g of the crude product was then purified as described in Example 1 above to give 2.09 g of pure title compound after lyophilization.

[0208] Example 6 Synthesis of other peptides The following peptides were synthesized following essentially the same process as described in Example 1 above, except that the appropriate amino acids were used in the appropriate peptide coupling sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4, MS: m / z 1241.3), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5, MS: m / z 1225.3), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6, MS:m / z 1128.2), Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7, MS:m / z 1112.2), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8, MS: m / z 1215.3), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9, MS: m / z 1199.3), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10, MS: m / z 1215.3), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11, MS: m / z 1199.3), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12, MS: m / z 1312.4), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13, MS:m / z 1296.4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 16, MS: m / z 1113.1), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 17, MS: m / z 1097.1), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 18, MS:m / z 1000), Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 19, MS:m / z 984), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 20, MS: m / z 1087.1), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 21, MS: m / z 1071.1), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 22, MS: m / z 1087.1), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 23, MS: m / z 1071.1), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 24, MS: m / z 1184.2), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 25, MS: m / z 1168.2), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 26, MS:m / z 1071.1), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 27, MS: m / z 1055.1), and Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 30, MS:m / z 1215.3).

[0209] The following peptides are synthesized following essentially the same process as described in Example 1 above, except that the appropriate amino acids are used in the appropriate peptide coupling sequence: 3,4-Dihydrocinnamic acid-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 28), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 32), and Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 33).

[0210] Example 7 Cream Formulation I Cream-based formulations containing each of the peptides Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7) (see Example 6 above) were made as follows using the following excipients, all supplied by Sinopharm Chemical Reagent Co. Ltd, Shanghai, China:

[0211] Sorbitan stearate (0.6 g), polysorbate-80 (1 g), silicone oil (0.5 g), hexadecanol (2 g), octanoic / decanoic glyceride (5 g), liquid paraffin (2 g), monostearate glyceride (2 g), and petrolatum (5 g) were mixed together and stirred, and the mixture was heated to 85°C until completely dissolved.

[0212] Methylcellulose (0.5 g), glycerin (4 g), trehalose (0.5 g), and 64.97 g of purified water were mixed together, stirred, and heated to 85° C. to form a homogeneous colloidal suspension.

[0213] 30 mg of each of the four peptides was dissolved in 1 g of purified water.

[0214] The copolymer / water mixture was added to the sorbitan stearate-containing mixture, which was then rapidly stirred for 5 minutes using an emulsifier. After the resulting emulsion was cooled to 55°C, polyethylene glycol 200 (4 g), phenoxy alcohol (0.3 g), and ethylhexylglycerin (0.1 g) were added to the mixture with constant stirring until a uniform suspension was obtained. Subsequently, a solution containing Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4) was mixed in.

[0215] The resulting mixture was allowed to cool to room temperature to give the final product.

[0216] This procedure was repeated for the other three peptides. Additionally, cream-based formulations containing 100 mg each of Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11) (see Example 6 above) were made using essentially the same procedure as described above.

[0217] Example 8 Cream Formulation II Cream-based formulations containing each of the peptides Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13) (see Example 6 above), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) (see Example 3 above), and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15) (see Example 1 above) were made as follows using the following excipients, all supplied by Sinopharm Chemical Reagent Co. Ltd, Shanghai, China, unless otherwise specified.

[0218] Stearic acid (2 g), glyceryl monostearate (2 g), and hexadecanol (2 g) were mixed together and stirred, and the mixture was heated to 85° C. until completely dissolved.

[0219] Ammonium acryloyldimethyltaurate / VP copolymer (0.13 g; Clariant Chemical Co., Ltd., Guangzhou, China), purified water (87.02 g), and sodium hydroxide (0.25 g) were mixed together at 85°C and stirred to form a homogeneous colloidal suspension. Next, glycerin (5 g), phenoxyethanol (0.3 g), and 0.1 g of ethylhexylglycerin (both from Shanghai Rayson Chemicals Co., Ltd., Shanghai, China) were added to the mixture with constant stirring.

[0220] 200 mg of each of the four peptides was dissolved in 1 g of purified water.

[0221] The copolymer / water mixture and the sorbitan stearate-containing mixture were combined as described above in Example 7. The resulting emulsion was cooled to 55° C. and then a solution containing Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12) was mixed in. Upon cooling to room temperature, the final product was obtained.

[0222] This procedure was repeated for the other three peptides.

[0223] Example 9 Lotion formulation The peptides Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7), Ser-Lys-Pro-Ser-Tyr-Hyp- Body lotions containing 100 mg each of Hyp-Thr-DOPA-Lys (SEQ ID NO: 8), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11) (see Example 6 above) were made as follows using the following excipients, all supplied by Sinopharm Chemical Reagent Co. Ltd., Shanghai, China:

[0224] Hydroxypropyl methylcellulose (HPMC; cosmetic grade, 0.1 g), hydroxyethyl cellulose (cosmetic grade, 0.1 g), glucose, phenoxy alcohol (0.5 g), and purified water (93.2 g) were mixed together and heated to 85°C with constant stirring until a homogeneous colloidal suspension was obtained. The mixture was then cooled to room temperature.

[0225] 100 mg of each of the eight peptides was dissolved in 1 g of purified water. A solution containing Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4) was added to the colloidal suspension and mixed together until the resulting mixture was homogeneously mixed into the final product.

[0226] This procedure was repeated for the other seven peptides. Additionally, using essentially the same procedure as above, cream-based formulations containing 10 mg each of the peptides Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13) (see Example 6 above), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) (see Example 3 above), and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15) (see Example 1 above) were made.

[0227] Example 10 Gel Formulation I Each of the peptides Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7) (see Example 6 above). A gel-based formulation containing these compounds was prepared essentially in the same manner as described in Example 9, except that HPMC (1 g), hydroxyethyl cellulose (1 g), glucose (5 g), phenoxy alcohol (0.5 g), and purified water (91.45 g) were mixed together and heated to 85° C. with constant stirring, followed by the addition of a solution of 50 mg of Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4) in 1 g of purified water.

[0228] Upon thorough mixing, the final product was obtained and this procedure was repeated for the other three peptides.

[0229] Example 11 Gel Formulation II Gel-based formulations comprising each of the peptides Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11) (see Example 6 above) were prepared using a process similar to that described in Example 10 above, but with the following excipients, all supplied by Sinopharm Chemical Reagent Co. Ltd, Shanghai, China.

[0230] Methylcellulose (cosmetic grade, 2.2 g), glycerol (11 g), propanediol (11 g), and purified water (74.75 g) were mixed together and stirred for 10 hours to obtain a homogeneous colloidal suspension.

[0231] 50 mg of Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8) pre-dissolved in 1 g of purified water was added with mixing to obtain a homogeneous final product.

[0232] This procedure was repeated for the other three peptides.

[0233] Essentially the same procedure was used to make gel formulations containing 150 mg each of the peptides Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13) (see Example 6 above), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) (see Example 3 above), and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15) (see Example 1 above), except that 1 g of carbomer (Sinopharm Chemical Reagent Co. Ltd) was used instead of methylcellulose and 5 g of glycerol was used with 82.85 g of purified water.

[0234] Example 11 Gel Formulation III Skin care gel-based compositions based on the peptides Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7) (see Example 6 above) were made.

[0235] First, sodium hyaluronate (0.2 g; Sinopharm Chemical Reagent Co. Ltd.) was allowed to swell in purified water (98.75 g) for 24 hours.

[0236] 50 mg of Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4) pre-dissolved in 1 g of purified water was added to the sodium hyaluronate gel and mixed thoroughly to obtain the final product. This procedure was repeated for the other three peptides.

[0237] In this case, 0.1 g of sodium hyaluronate was added to 94.88 g of purified water, and then, in each case, a pre-prepared solution containing 20 mg of each peptide in 1 g of purified water was dissolved in butanediol (2 g) and pentanediol (2 g) (both Sinopharm Chemical Reagents). Essentially the same procedure was used to make gel formulations containing 20 mg each of the peptides Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11) (see Example 6 above), except that 20 mg of each of the peptides Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 11) was added with mixing along with PEG-1000 (Promega Inc., San Diego, CA) to obtain the final product.

[0238] Similarly, gel formulations were prepared using Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13) (see Example 6 above), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) (see Example 3 above), and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15) (see Example 1 above), as well as Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 16), Lys-Pro-Ser Eight separate gel products were prepared from the peptides Lys-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 17), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 18), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 19) (see Example 6 above), in each case using 0.4 g of sodium hyaluronate in 96.4 g (first four peptides) or 96.5 g (last four peptides) of purified water, and 2 g of butanediol (alone) was added together with individually pre-prepared solutions containing 200 mg of each of the first four peptides and 100 mg of each of the last four peptides, each dissolved in 1 g of purified water.

[0239] Example 12 Skin Tonic Skin tonics were made by dissolving the following amounts of each of the following peptides in the indicated amount of purified water. (a) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7) (see Example 6 above), 20 mg of each peptide in 99.98 g (b) Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 8), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 9), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 10), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 11) (see Example 6 above), 100 mg of each peptide in 99.9 g (c) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12) and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13) (see Example 6 above), 10 mg of each peptide in 99.99 g (d) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) (see Example 3 above), 10 mg in 99.99 g (e) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15) (see Example 1 above), 10 mg in 99.99 g (f) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 16), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 17), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 18), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 19) (see Example 6 above), 100 mg of each peptide in 99.9 g (g) Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 20), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 21), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 22), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 23) (see Example 6 above), 40 mg of each peptide in 99.96 g (h) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 24), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 25), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 26), and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 27) (see Example 6 above), 60 mg of each peptide in 99.94 g

[0240] In each case, appropriate preservatives and / or moisturizers may be added to the skin tonic to improve skin feel.

[0241] Example 13 Moisturizing spray Moisturizing sprays based on the peptides Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 16), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 17), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 18), and Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 19) (see Example 6 above) were made in the following manner using the following excipients, all supplied by Sinopharm Chemical Reagent Co. Ltd, Shanghai, China.

[0242] The four peptide skin tonics were prepared by first dissolving 10 mg of each peptide in 1 g of purified water, followed by mixing together disodium EDTA (0.02 g), butanediol (1.5 g), arginine (0.02 g), hexanediol (0.5 g), and purified water (96.95 g).

[0243] The peptide solution containing Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 16) was added to the resulting solution to obtain the final product. This procedure was repeated for the other three peptides.

[0244] Example 14 essence Essences based on the peptides Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 20), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 21), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 22), and Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 23) (see Example 6 above) were made in the following manner using the following excipients, all supplied by Sinopharm Chemical Reagent Co. Ltd, Shanghai, China.

[0245] Sodium hyaluronate (0.5 g) and carbomer (0.04 g) were added to 98.36 g of purified water. After 24 hours, a swollen gel was obtained.

[0246] Each of the four peptides (100 mg) was dissolved in 1 g of purified water. The resulting solution containing Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 20) was added to the sodium hyaluronate / carbomer mixture. After thorough mixing, the final product was obtained.

[0247] This procedure was repeated for the other three peptides.

[0248] Example 15 Synthetic peptides as peptide glues Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14) (see Example 3 above) was first dissolved in pure water (as well as aqueous solutions containing acetate buffer and phosphate buffer) at pH 2-8.

[0249] Various peptide mixtures were prepared at concentrations ranging from 100 to 800 mg / g. After the peptides were completely dissolved, the clear solution was used as an adhesive.

Claims

1. A compound consisting of the following amino acid sequence: W-Lys-X １ -Ser-U-X ２ -Y-Z-Q (SEQ ID NO: 3) (In the formula, W represents Ala or is absent; U represents Tyr, DOPA, or a single bond; X １ and X ２ independently represent Pro, Hyp, or diHyp; Y represents a single bond or a sequence of 1 to 5 amino acids, wherein the amino acids are selected from one or more of the group: Pro, Hyp, diHyp, Thr, DOPA, and Tyr; Z represents Pro, Hyp, diHyp, or Thr; Q represents Lys and stereoisomers, and pharmaceutically or cosmetically acceptable salts of said peptide compounds.

2. X １ 2. The compound of claim 1, wherein represents Hyp or Pro.

3. X １ 3. The compound of claim 2, wherein represents Pro.

4. A compound according to any one of claims 1 to 3, wherein U represents Tyr.

5. X ２ The compound according to any one of claims 1 to 4, wherein represents Pro or Hyp.

6. X ２ The compound according to claim 5, wherein represents Hyp.

7. 7. The compound according to any one of claims 1 to 6, wherein Y represents a sequence of 1 to 4 amino acids.

8. 8. The compound of claim 7, wherein Y represents a single amino acid or a sequence of three amino acids.

9. 8. The compound of claim 7, wherein Y represents an amino acid sequence of 2.

10. The compound of any one of claims 1 to 9, wherein W is absent.

11. A compound according to any one of claims 1 to 9, wherein W represents Ala.

12. 12. The compound of any one of claims 1 to 11, wherein Z represents Pro, Hyp, Thr, DOPA, or Tyr.

13. 13. The compound of claim 12, wherein Z represents Hyp.

14. 14. The compound of any one of claims 1 to 13, wherein Y represents a sequence of 1 to 5 amino acids, said amino acids being selected from one or more of the group: Pro, Hyp, Thr, DOPA, and Tyr.

15. 15. The compound of any one of claims 1 to 14, wherein the amino acids in the sequence defined by Y are selected from DOPA, Hyp, Thr, and Tyr.

16. 16. The compound of claim 15, wherein the amino acid is selected from Thr and Tyr.

17. The compound according to any one of claims 1 to 16, wherein the amino acid linked to Z in the sequence defined by Y is selected from DOPA, Thr, and Tyr.

18. 18. The compound of claim 17, wherein the amino acid linked to Z is Tyr.

19. The compound according to any one of claims 1 to 18, wherein the amino acid linked to X in the sequence defined by Y is selected from Pro, Hyp, and Thr.

20. 20. The compound of claim 19, wherein the amino acid linked to X is Hyp or Thr.

21. 21. The compound of claim 20, wherein the amino acid linked to X is Thr.

22. 22. The compound of any one of claims 1 to 21, wherein the sequence defined by Y is -Hyp-Thr-Try, -Hyp-Thr-DOPA-, -Thr-Tyr-, -Thr-DOPA-, -Pro-Thr-, or -Hyp-Thr-.

23. The compound has the amino acid sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 4), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 5), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 6), Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 7), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 13), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 30), Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 31), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 32), Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 33), or 23. The compound of any one of claims 1 to 22, comprising or consisting of Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 34).

24. The compound has the amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 14), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15), or 24. The compound of claim 23, comprising or consisting of Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 34).

25. A compound according to any one of claims 1 to 24 for use as a medicament.

26. A compound according to any one of claims 1 to 25 for use as a cosmetic.

27. A formulation comprising a compound according to any one of claims 1 to 24 and a pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier.

28. 28. The formulation of claim 27, 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.

29. 29. The formulation of claim 27 or 28, in the form of a gel, spray, cream, ointment, or dry powder.

30. 30. The pharmaceutical formulation of any one of claims 27 to 29, further comprising another anti-inflammatory agent.

31. A kit of parts comprising: (A) a pharmaceutical formulation according to any one of claims 27 to 29; (B) a pharmaceutical formulation comprising another anti-inflammatory agent 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.

32. A compound according to any one of claims 1 to 24, a formulation according to any one of claims 27 to 29 or a kit of parts according to claim 31 for use in the treatment of inflammation, an inflammatory disorder and / or a disorder characterised by inflammation.

33. Use of a compound according to any one of claims 1 to 24, a formulation according to any one of claims 27 to 29, or a kit of parts according to claim 31 for the manufacture of a medicament for the treatment of inflammation, an inflammatory disorder, and / or a disorder characterized by inflammation.

34. 33. The compound for use according to claim 32, wherein the inflammatory disorder is selected from disorders of the mucous membrane, such as allergic rhinitis, conjunctivitis, anorectal disease, inflammatory bowel disease, gynecological disease, gastrointestinal disease, or dental disease.

35. 35. The compound for use according to claim 34, wherein the anorectal disease is selected from diarrhea, hemorrhoids, anal abscess, fistula, anal fissure, anal itching, anal sinusitis, anal warts, radiation proctitis, and rectal prolapse.

36. 35. The compound for use according to claim 34, wherein the gynecological disorder is selected from cervicitis, vaginitis, colpitis, or pelvic pain.

37. 35. The compound for use according to claim 34, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

38. 35. The compound for use according to claim 34, wherein the dental disease is periodontitis.

39. 35. The compound for use according to claim 34, wherein the gastrointestinal disease is stomatitis, gastroesophageal reflux disease, esophageal burns, gastric ulcers, or duodenal ulcers.

40. 33. The compound for use according to claim 32, wherein the disorder characterized by inflammation is or results in a wound or a burn.

41. 41. The compound for use according to claim 40, wherein the disorder resulting in wounds is hemorrhoids or ulcerative colitis.

42. A compound according to any one of claims 1 to 24 for use in the treatment of fibrosis, fibrotic disorders and / or disorders characterised by fibrosis.

43. The inflammatory disorder is a disorder of the mucous membrane, for example, allergic rhinitis, conjunctivitis, Anorectal diseases such as diarrhea, hemorrhoids, anal abscess, fistula, anal fissure, anal itching, anal sinusitis, anal warts, radiation proctitis, and rectal prolapse, inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, Cervicitis, vaginitis, colpitis or pelvic pain Which gynecological diseases, gastrointestinal disorders such as stomatitis, gastroesophageal reflux disease, esophageal burns, gastric or duodenal ulcers, or 33. The formulation of claim 32, selected from dental diseases such as periodontitis.

44. the inflammatory disorder is Mucous membrane disorders, such as allergic rhinitis, conjunctivitis, Anorectal diseases such as diarrhea, hemorrhoids, anal abscess, fistula, anal fissure, anal itching, anal sinusitis, anal warts, radiation proctitis, and rectal prolapse, Inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, Gynecological diseases such as cervicitis, vaginitis, colpitis or pelvic pain, 33. The kit of parts according to claim 32, wherein the treatment is selected from gastrointestinal diseases such as stomatitis, gastroesophageal reflux disease, esophageal burns, gastric or duodenal ulcers, or dental diseases such as periodontitis.

45. 33. The formulation of claim 32, wherein the disorder characterized by inflammation is or causes a wound, such as hemorrhoids or ulcerative colitis, or a burn.

46. 33. The kit of parts of claim 32, wherein the disorder characterized by inflammation is or causes a wound, such as hemorrhoids or ulcerative colitis, or a burn.

47. A formulation according to any one of claims 27 to 29 for use in the treatment of fibrosis, fibrotic disorders and / or disorders characterised by fibrosis.

48. 32. The kit of parts of claim 31 for use in the treatment of fibrosis, fibrotic disorders, and / or disorders characterized by fibrosis.

49. 43. The compound for use according to claim 42, wherein the fibrosis is vaginal or cervical fibrosis.

50. 48. The formulation for use according to claim 47, wherein the fibrosis is vaginal or cervical fibrosis.

51. 49. A kit of parts for use according to claim 48, wherein said fibrosis is vaginal or cervical fibrosis.

52. 50. The compound for use according to any one of claims 25, 26, 34-42 and 49, wherein the compound or salt thereof is administered topically in the form of a topical formulation.

53. 51. The formulation of any one of claims 27 to 29, 43, 45, 47 and 50, wherein the compound or salt thereof is administered topically in the form of a topical formulation.

54. 52. The kit-of-parts of any one of claims 31, 44, 46, 48 and 51, wherein the compound or salt thereof is administered topically in the form of a topical formulation.

55. 53. The compound for use according to claim 52, wherein the associated condition is treated by direct topical administration to the skin.

56. 53. The compound for use according to claim 52, wherein the associated pathology is treated by direct topical administration to a mucosal surface.

57. 54. The formulation of claim 53, wherein the associated condition is treated by direct topical administration to a mucosal surface.

58. 55. The kit of parts of claim 54, wherein the associated pathology is treated by direct topical administration to a mucosal surface.

59. 57. The compound for use according to any one of claims 42, 49, 52, 55 and 56, wherein the compound is administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, pulmonary, or anorectal delivery.

60. 60. The formulation of any one of claims 47, 50, 53 and 57, wherein the compound is administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, pulmonary, or anorectal delivery.

61. 60. The kit-of-parts of any one of claims 48, 51, 54 and 58, wherein the compound is administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, pulmonary, or anorectal delivery.

62. 32. A process for preparing the kit of parts of claim 31, comprising packaging said kit of parts component (A) and said kit of parts component (B) as separate components of a "combination package" for use in combination.

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