Novel multifunctional oligopeptide

Abstract

This invention provides novel peptides and compositions for the treatment of various conditions, including inflammation. [Solution] A compound of formula (I)AQB, where Q represents a specific structural fragment, and A and B are peptide components of the amino acid sequence [W-Lys-X 1 -Ser-UX 2 -Y] n -W-Lys-X 1 -Ser-UX 2 -Y can be represented by the dashed line, n, W, X in the formula. 1 , U, X 2 Compounds in which Y is a specific amino acid are disclosed. Compounds are disclosed which are useful in pharmaceuticals containing these compounds as pharmaceutical excipients, adhesives, and film-forming materials, and / or in the treatment of inflammatory conditions, including wounds, burns, and mucosal disorders such as anorectal diseases, inflammatory bowel diseases, gynecological diseases, and dental diseases.

Description

[Technical Field]

[0001] This invention relates to novel peptides as pharmaceutically active ingredients or otherwise, the use of such peptides in human pharmaceuticals, and pharmaceutical compositions comprising them. Specifically, this invention relates to the use of such peptides and compositions in the treatment of various conditions, including inflammation. [Background technology]

[0002] Inflammation is typically characterized as a local tissue response to the invasion of, for example, microorganisms, specific antigens, damaging cells, or physical and / or chemical factors. The inflammatory response is usually a protective mechanism that destroys, weakens, or isolates both the harmful substance and the damaged tissue, initiating tissue healing.

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

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

[0005] Typically, a series of complex events lead to inflammatory changes such as increased blood flow due to local vasodilation resulting in redness and heat, extravasation of leukocytes and plasma often resulting in local swelling, activation of sensory nerves (causing pain in some tissues), and loss of function. These inflammatory changes are triggered by a cascade of cellular and biochemical events involving cells such as neutrophils, monocytes, macrophages, and lymphocytes, along with inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

[0006] In particular, inflammation plays a crucial role in the wound healing process. Therefore, wounds and burns can be classified as conditions associated with inflammation. The conventional view in this field is that anti-inflammatory drugs should not be directly applied to open wounds because they are detrimental to the progression of wound healing.

[0007] Fibrosis is defined as the excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM), such as collagen and fibronectin), within and around inflamed or damaged tissue. While collagen deposition is typically a reversible part of wound healing, in cases of severe tissue damage or when the wound healing response itself becomes unregulated, it can often develop into an increasingly irreversible fibrotic response. Furthermore, fibrosis is known to be a major cause of morbidity and death in many chronic inflammatory diseases, as well as in 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. In addition, fibrosis can influence the pathogenesis of many progressive myopathies, metastases, and graft rejection.

[0008] Mussel adhesion proteins (MAPs), also known as Mytilus edulis foot proteins (MEFPs), are proteins secreted by marine mollusks such as Mytilus edulis, Mytilus coruscus, and Perna viridis. Eleven distinct adhesion protein subtypes have been identified: collagen pre-COL-P, pre-COL-D, and pre-COL-NG; mussel foot matrix proteins PTMP (proximal filamentous matrix protein) and DTMP (distal filamentous matrix protein); and mfp proteins mfp-2 (sometimes called "MEFP-2," and used interchangeably below), mfp-3 / MEFP-3, mfp-4 / MEFP-4, mfp-5 / MEFP-5, mfp-6 / MEFP-6, most preferably mfp-1 / MEFP-1 (e.g., Zhu et al., Advanc). es in Marine Science, 2014, 32, 560-568 and G It is derived from mussels, including ao et al., Journal of Anhui Agr.Sci., 2011, 39, 19860-19862.

[0009] A significant portion of mefp-1 consists of 70-90 tandem repeats of the decapeptide: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (see SEQ ID NO: 1, Waite, Int. J. Adhesion and Adhesives, 1987, 7(9-14)). This decapeptide sequence can be isolated as a low molecular weight derivative of the naturally occurring MAP, or, for example, Yamamot It can be synthesized as described in J.Chem.Soc., Perkin Trans. 1987, 1, 613-618. See also Dalsin et al, J.Am.Chem.Soc., 2003, 125, 4253-4258.

[0010] Decapeptide analogs, particularly Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2), are also disclosed. See, for example, US5,616,311 and WO96 / 39128.

[0011] The use of lysine amino acid residues for preparing multi-antigen peptides is, for example, seen in Tam Proc. Natl. Acad., Sci. USA, 1988, 85, 5409-541. 3. Disclosed in Rao et al., J.Am.Chem.Soc., 1994, 116, 6975-6976, US5,229,490 and WO2010 / 038220.

[0012] The use of peptide-based scaffolds as drug delivery vehicles is disclosed. For example, See Brokx et al, J. Control. Release, 2002, 78, 115-123.

[0013] There is a clear need for new and / or improved drugs that can be used to treat inflammation and inflammation-characterized conditions. [Overview of the project]

[0014] According to a first aspect of the present invention, the compound of formula I AQB I And in the formula, A and B independently determine Z or A 1 -Q 1 -B 1 This represents, Q is, Equation II [ka] This represents a structural fragment of the formula, in which, The wavy line represents the connection point of Q to A and / or B. m represents an integer from 1 to 4. A 1 and B 1 However, independently, Z or A 2 -Q2 -B 2 represents, A 2 and B 2 are, independently, Z or Z-Q 3 -Z represents, Q 1 Q 2 and Q 3 are, independently, the structural fragment of formula III

Chemical formula

[0015] The compounds of the present invention that may be mentioned include: W represents a sequence of one or two amino acids, where the amino acids are selected from one or more of the groups Lys, Ala, and DOPA. X 1 However, it represents Pro, X 2 However, it represents Ser, Pro, or Hyp, The compound includes a sequence of 1 to 5 amino acids (for example, 1 to 4), where the amino acids are selected from one or more of the groups Pro, Hyp, Thr, DOPA, and Tyr.

[0016] Preferred compounds of the present invention that may be mentioned are Q, Q1 2 and Q 3 One or more of these represent a Lys, or more appropriately, a Lys fragment.

[0017] Each time they are used, Q, Q 1 Q 2 and Q 3 Each of these can be bonded to 0, 1, or 2 Z groups.

[0018] In this regard, preferred compounds of the present invention include those in which either A or B represents Z and the other represents A. 1 -Q 1 -B 1 It represents, or more preferably, both A and B represent Z, or both are A 1 -Q 1 -B 1 This represents Q 1 Preferably, the compound includes a Lys fragment, where Z is defined as described above.

[0019] A more preferred compound of the present invention is A 1 and B 1 One of them represents Z, and the other represents A 2 -Q 2 -B 2 It represents, or comfort, A 1 and B 1 Both represent Z, or both represent A 2 -Q 2 -B 2 This represents Q 2 Preferably, the compound includes a Lys fragment, where Z is defined as described above.

[0020] Further preferred compounds of the present invention also include A 2 and B 2 One of them represents Z, and the other represents ZQ. 3 -Z represents, or comfort, A 2 and B 2 Both represent Z, or both represent ZQ 3 -Z represents, and in each case, Q 3 Preferably, the compound includes a Lys fragment, where Z is defined as described above.

[0021] A more preferred compound of the present invention is A 2 and B 2 The compound contains both of which represent Z.

[0022] The peptide components of the compounds of the present invention that may be mentioned include compounds in which n is 0, 1, or 4, or more preferably 0.

[0023] The preferred compounds of the present invention include X 1 However, it represents Hyp, or more preferably Pro, X 2 The first part of the molecule represents Hyp, W represents HCA, HCA-Ala-, preferably Ala or Lys-Ala, or more preferably DOPA or DOPA-Ala--, and / or Y represents a sequence of 5, preferably 3, or more preferably 4 amino acids, the amino acids being selected from one or more of the groups Lys, Ala, Hyp, Thr, DOPA, and Tyr.

[0024] More preferably, the compound of the present invention also contains Y, -Pro-Y1-Y 2 -Lys- or, more preferably, -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 - Represents a sequence of four amino acids selected from the group of Lys, Y 1 and Y 2 Each of these independently includes Pro, or more preferably, selected from the group consisting of Ala, Hyp, Thr, DOPA, and Tyr.

[0025] A more preferred compound of the present invention has an amino acid sequence defined by Y, -Pro-Thr-DOPA-Lys-, -Pro-Thr-Tyr-Lys-, -Thr-Tyr-Pro-Lys-, and -Thr-DOPA-Pro-Lys-, more, -Hyp-Thr-Tyr-, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Tyr-Hyp-, -Thr-DOPA-Hyp-Lys-, and This includes elements selected from the -Thr-Ala-Hyp-Lys- group.

[0026] When Y represents a sequence of two amino acids, preferred compounds of the present invention include those in which the amino acid sequence defined by Y is selected from the group -Hyp-Thr-, -Thr-Tyr-, -Pro-Thr-, and -Thr-DOPA-.

[0027] Other preferred compounds of the present invention that may be mentioned include those whose amino acid sequence defined by Y is selected from the group consisting of -Thr-Tyr-Lys-, -Tyr-Pro-Lys-, -DOPA-Pro-Lys-, -Hyp-Thr-Tyr-, -Hyp-Thr-Tyr-Hyp-Lys-, and more preferably -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

[0028] Compounds of the present invention that may be mentioned include those in which U represents Tyr and / or W represents Ala.

[0029] In this regard, further compounds of the present invention that may be mentioned include those in which Z is Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA---(SEQ ID NO: 6), Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-- (SEQ ID NO: 7), and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 8) This includes items selected from the group.

[0030] The compounds of the present invention that may be mentioned include: U represents Tyr, and / or This includes W, which represents Lys-Ala-.

[0031] In this regard, further compounds of the present invention that may be mentioned include those in which Z is Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr---(SEQ ID NO: 9), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 10) more, This includes substances selected from the group Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 11).

[0032] Further compounds of the present invention that may be mentioned include: U represents Tyr, and / or W may represent HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-.

[0033] In this regard, the compounds of the present invention that can be mentioned include those in which Z is HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 13), HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 14) HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 15) Selected from the group, more preferably Z is DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 16) DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 17) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(Sequence ID 18), and DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 19) This includes items selected from the group.

[0034] Compounds of the present invention that may be mentioned include those in which U represents DOPA.

[0035] In this regard, the compounds of the present invention that can be mentioned include those in which Z is Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 20) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 21) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 22) Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 23) Selected from the group, more preferably Z is Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(SEQ ID NO: 24), and Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-H yp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(SEQ ID NO: 25) This includes items selected from the group.

[0036] Further compounds of the present invention that may be mentioned include: U represents DOPA and / or W may represent HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-.

[0037] Therefore, among the specific compounds of the present invention that may be mentioned, Z is HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 26) HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 27) HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 28) HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 29) Selected from the group, more preferably Z is DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 30) DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 31) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 33), and This includes those selected from the group DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 34).

[0038] The compounds of the present invention that may be mentioned include: Both A and B represent Z, On the other hand, or preferably both Z groups, Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 15) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys--(SEQ ID NO: 18), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 20) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 22) HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 26) DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 31) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32) This represents, or more preferably, one or both Z groups Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), Or, more preferably, one or both Z groups Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 2), or This represents Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(sequence number 1), This includes instances where Q represents a Lys fragment.

[0039] Further compounds of the present invention that may be mentioned include: Both A and B are A 1 -Q 1 -B 1 This represents, A 1 and B 1 Both represent Z, On the other hand, or preferably both Z groups, Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 11), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 13), DOPA - Ala - Lys - Pro - Ser - Tyr - Hyp - Thr - Tyr - Hyp - Lys---(SEQ ID NO: 18), Ala - Lys - Pro - Ser - DOPA - Hyp - Thr - DOPA - Hyp - Lys---(SEQ ID NO: 20), Ala - Lys - Pro - Ser - DOPA - Hyp - Hyp - Thr - DOPA - Lys---(SEQ ID NO: 21), Lys - Ala - Lys - Hyp - Ser - Tyr - Hyp - Hyp - Thr - DOPA---(SEQ ID NO: 10), HCA - Lys - Pro - Ser - DOPA - Hyp - Thr - Ala - Hyp - Lys---(SEQ ID NO: 28), DOPA - Lys - Pro - Ser - DOPA - Hyp - Thr - Ala - Hyp - Lys---(SEQ ID NO: 30), DOPA - Ala - Lys - Pro - Ser - DOPA - Hyp - Thr - DOPA - Hyp - Lys---(SEQ ID NO: 32), represent, or more preferably, one or preferably both of the Z groups are Ala - Lys - Pro - Ser - Tyr - Hyp - Hyp - Thr - Tyr - Lys---(SEQ ID NO: 2), or Ala - Lys - Pro - Ser - Tyr - Hyp - Hyp - Thr - DOPA - Lys---(SEQ ID NO: 1), and Q 1 includes those in which it represents a Lys fragment.

[0040] Further compounds of the invention that may be mentioned include both A and B are A 1 -Q 1 -B 1 represent, and both A 1 and B 1 are both A 2 -Q 2 -B 2 represent, both A 2 and B 2 are both Z,<e000403>one or preferably both of the Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(SEQ ID NO: 5), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 18), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(SEQ ID NO: 21), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(SEQ ID NO: 32), which represent, or more preferably, one or preferably both of the Z groups are DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 19), or even more preferably, one or preferably both of the Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 2), or Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(SEQ ID NO: 1), and Q 1 and Q 2 both representing Lys are included. <000041​​​​​​​​​​​​​​​​​​​​​​​​​2 and B 2 Both are Z- 3 -Represents Z, On the other hand, or preferably both Z groups, Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 2), or This represents Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(sequence number 1), Q 1 Q 2 and Q 3 All of these include elements that represent Lys fragments.

[0042] In a further aspect of the present invention, the amino acid sequence [Ala-Lys-X 1 -Ser-UX 2 -Y] p -Ala-Lys-X 1 -Ser-UX 1 -YG (Sequence ID 35) an (isolated) peptide compound, in which, p represents an integer from 1 to 4, There may be cases where G is absent (in which case Y is the C-terminal amino acid), or where G represents DOPA or dopamine (or more precisely, a "dopamine fragment"). X 1 , U, X 2 And Y is as previously defined, a peptide compound, Furthermore, positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the compound are provided. These compounds, positional isomers, stereoisomers, and salts are hereinafter referred to as "the long-chain compounds of the present invention."

[0043] As used herein, the terms dopamine and dopamine fragment refer to formula IV [ka] This refers to a structural fragment, and in the formula, the wavy line represents the connection point to Y.

[0044] The preferred values ​​of p in the straight-chain compounds of the present invention are in ascending order of priority: 2, 3, 1, and 4.

[0045] The preferred values ​​for U, X, and Y described for the compounds of the present invention are also preferred for the straight-chain compounds of the present invention.

[0046] The specific straight-chain compounds of the present invention that may be mentioned are those that do not contain G.

[0047] In this regard, certain straight-chain peptide compounds have an amino acid sequence Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID NO: 36), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 37), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 38) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 39), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 40), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 41), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-L ys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 42), and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 43) It includes the following.

[0048] To avoid misunderstanding, whether it is the compound of formula I or the straight-chain peptide compound of sequence number 35, the compounds of the present invention described above will collectively be referred to as "compounds of the present invention" below.

[0049] As used herein, Pro represents proline, Ala represents alanine, Ser represents serine, Tyr represents tyrosine, Hyp represents hydroxyproline (including 3-hydroxyproline (3Hyp) and 4-hydroxyproline (4Hyp)), diHyp represents dihydroxyproline (including 3,4-dihydroxyproline (3,4diHyp), 3,5-dihydroxyproline (3,5diHyp), and 4,5-dihydroxyproline (4,5diHyp)), Thr represents threonine, Lys represents lysine, Ala represents alanine, and DOPA represents 3,4-dihydroxyphenylalanine. A 3,4-dihydrocinnamic acid (HCA) residue is essentially a DOPA residue, but without the -NH2 group at the 2-carbon or α-carbon position relative to the carboxylic acid attached to the N-terminal amino acid (Lys or Ala).

[0050] The compounds of the present invention, whether in salt form or not, include positional isomers within the amino acids of a peptide (e.g., diHyp, Hyp, and Tyr portions), 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 preferable 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 preferable that the diHyp residue is 3,4-dihydroxyproline (3,4diHyp).

[0051] Furthermore, in addition to the standard central carbon atoms of the amino acids in the compounds of the present invention (which are not exclusive but usually in the L configuration), certain amino acids in the sequence contain additional chiral carbon atoms. All such stereoisomers and mixtures thereof (including racemic mixtures) are within the scope of the present invention. By 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, but the Hyp used in the compounds of the present invention is preferably 4-hydroxy-L-proline. Similarly, the corresponding definition may be applied to diHyp, where the two hydroxyl groups can be cis or trans relative to each other. In any case, individual enantiomers of the compounds of formula I (and the isolated peptide sequences of SEQ ID NOs. 4-26) that can form part of the compounds of the present invention are within the scope of the present invention.

[0052] The compounds of the present invention may also be in the form of salts. Salts that may be mentioned include pharmaceutically acceptable salts and / or cosmetically acceptable salts, such as pharmaceutically acceptable acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the compound of the present invention with one equivalent or more of a suitable acid or base in optionally a solvent or a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying or filtration). Salts may also be prepared, for example, by exchanging the counterions of the components of the present invention in salt form with other counterions using a suitable ion exchange resin.

[0053] Preferred salts include, for example, acetates, hydrochlorides, bisulfates, maleates, mesylates, tosylates, 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 acetates.

[0054] 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 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 know, among other things, Comprehensive Organic Synthesis”by BMT You may also refer to Rost and I. Fleming, Pergamon Press, 1991. Further references that may be used include "Heterocyclic Chemistry" by J.A. Joule, K. Mills and G.F.M. th,3 rd edition, published by Chapman&Hall, “Comprehensive Heterocyclic Chemistry II” by ARKatritzky,CWRees and EFVSc Riven, Pergamon Press, 1996, and “Science of Synthesis”, Volumes 9-17(Hetarenes and R This includes (Elated Ring Systems), Georg Thieme Verlag, 2006.

[0055] The compounds of the present invention can be isolated from their reaction mixtures and, if necessary, purified using prior art, such as that known to those skilled in the art. Therefore, the preparation process of the compounds of the present invention described herein may include, as a final step, isolation and optionally purification of the compounds of the present invention.

[0056] Those skilled in the art will understand that in the processes described above and below, the functional groups of the intermediate compound may need to be protected by protecting groups. Protection and deprotection of the functional groups may be carried out before or after the reaction.

[0057] Protecting groups are well known to those skilled in the art and can be applied and removed according to techniques such as those described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will determine the need and type of protecting group, as well as the sequence for achieving the synthesis. The use of protecting groups is well described in "Protective Groups in Organic Synthesis," 5th edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (2014), the contents of which are incorporated herein by reference.

[0058] Therefore, the compounds of the present invention are useful as pharmaceuticals for human or animal use. Thus, they are indicated as pharmaceuticals (and / or in veterinary medicine), but can also be used as part of cosmetics and / or medical devices.

[0059] The compounds (and isolated peptide sequences) of the present invention may also possess pharmacological activity on their own, but certain pharmaceutically acceptable (e.g., “protected”) derivatives of the compounds of the present invention may also be prepared, which may not possess such activity, but can be administered and subsequently metabolized or chemically converted to form the compounds of the present invention. Thus, such compounds (which may possess some pharmacological activity, provided that such activity is recognizably lower than the activity of the active compound to which they are metabolized / converted) may be described as “prodrugs” of the compounds of the present invention.

[0060] As used herein, a reference to a prodrug will include a compound that forms an experimentally detectable amount of the compound of the present invention within a predetermined time after administration. All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0061] If the compounds of the present invention possess pharmacological activity, they are particularly useful in the treatment of inflammation.

[0062] The term “treatment of inflammation” includes the treatment of inflammation in any organ of the body, regardless of its cause (including soft tissues, joints, nerves, vascular system, internal organs, mucous membrane surfaces in particular, and specifically the skin), and also includes all such inflammatory disorders or conditions, and / or disorders or conditions characterized by inflammation (e.g., as symptoms).

[0063] Inflammatory disorders and / or conditions may (and typically) be characterized by the activation of immune defense mechanisms that produce effects that are more detrimental than beneficial to the host. Such conditions are generally associated with varying degrees of tissue redness or congestion, swelling, edema, hyperthermia, pain (including numbness), fluid exudation, itching (pruritus), cell death, and tissue destruction, cell proliferation, and / or loss of function.

[0064] Inflammatory conditions that may be mentioned include arteritis, diabetes, metabolic syndrome, rosacea, asthma and allergies, ankylosing spondylitis, chronic obstructive pulmonary disease, gouty arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, osteoarthritis, pancreatitis, prostatitis, psoriatic arthritis, rheumatoid arthritis, tendinitis, bursitis, Sjögren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis, and related cardiovascular disorders. A condition characterized by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD). Further conditions characterized by inflammation that may be mentioned are inflammatory bowel disease, including Crohn's disease and, in particular, ulcerative colitis. Other medical conditions characterized by inflammation that may be mentioned include gynecological disorders such as cervicitis, vaginitis (radiation 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 inflammation associated with gastroesophageal reflux disease (GERD), constipation, gastritis, cancer, and infections (e.g., viral infections such as the common cold or influenza).

[0065] Further inflammatory conditions that may be specifically mentioned include inflammation of the skin or mucous membranes (including the mucous membranes of the oral cavity, nose, eyes, vagina, cervix, and / or anorectum, more specifically including the mucous membranes of the oral cavity or nose), such as inflammation resulting from infection (such as viral and / or bacterial infections) or allergic / atopic conditions (such as rhinitis (e.g., allergic rhinitis), pharyngitis, periodontitis, gingivitis, xerosis, conjunctivitis (e.g., allergic conjunctivitis), dermatitis, urticaria (hives), and food allergies), as well as other inflammatory conditions such as herpes, drug eruptions, photoerectomy, sunburn, early signs of skin cancer (erythematous skin lesions), pathological alopecia (including post-skin grafting), chemical rashes, psoriasis, erythema multiforme, folliculitis, eczema, and otitis externa. Photoerectomy is a condition that may be specifically mentioned.

[0066] More specifically, the compounds can be used to treat certain conditions characterized by and / or associated with inflammation. Such conditions may include wounds (including abrasions (scratches), incisions (including surgical incisions), lacerations, punctures, avulsions, bruises, and scars), burns (including inflammation resulting from post-burn surgery such as skin grafts), and other conditions such as hemorrhoids. Wounds may be acute or chronic and / or result from one or more inflammatory disorders as defined herein.

[0067] Wounds of the skin or mucous membranes may result from physical injury inside or outside the membrane surface, or they may be caused by (i.e., symptoms of) an underlying physiological disorder.

[0068] Physical (e.g., “open”) wounds can be caused by sharp objects (cuts, incisions, punctures) or blunt / mechanical forces (lacerations, abrasions, avulsions), physical blows (bruises), heat or chemicals (burns and blisters), ultraviolet radiation (sunburn), or cold (chilblains or frostbite). Wounds can be superficial (damage to the epidermis and / or dermis only) or full-thickness (damage to the epidermis and / or below the dermis). In severe cases, subcutaneous and / or submucosal tissues such as muscles, bones, joints, and even internal organs may be damaged.

[0069] The compounds of the present invention can be used to alleviate pain (including numbness) 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 investigations and treatments performed for medical purposes. The term “non-procedural” refers to general pain associated with inflammation and / or wounds (e.g., pain associated with dental ulcers, burns, and / or scars) that is not the result of a specific medical intervention.

[0070] The compounds of the present invention can be used not only to treat inflammation, pain (including numbness), and / or pruritus (itching) associated with the wound itself and the healing process, but also to prevent the exudation of bodily fluids from the wound, the risk of infection, and physiological reactions resulting from inflammation and / or the wound healing process, such as scarring and melanin pigmentation.

[0071] A scar is the result of inflammation and / or wound healing, and is a general term for the formation of fibrous tissue that is a consequence of such inflammation / healing.

[0072] The compounds of the present invention may also be useful in suppressing the production of melanin pigmentation that may or may not be caused by inflammation and / or wound healing. The compounds of the present invention may also be useful in suppressing melanin pigmentation-related disorders such as melasma, freckles, melanin deposition, butterfly rash, and other pigmentation, skin cancer with melanoma, and pigmentation caused by sun exposure or skin diseases such as acne.

[0073] Wounds can also arise as a result of disease or disorder (e.g., inflammation). Such wounds may include blisters, as well as / 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 costly to treat. They can also cause significant psychological stress and financial loss to the patient, potentially affecting both overall well-being and quality of life.

[0074] Alternatively, inflammatory skin conditions or diseases in which the compounds of the present invention find particular utility include the treatment of psoriasis, acne, eczema and dermatitis, particularly allergic / atopic dermatitis, as well as rhinitis, particularly allergic rhinitis, hemorrhoids, chronic obstructive pulmonary disease, and mucositis characterized by ulcerative colitis.

[0075] Psoriasis is a chronic inflammatory skin disease that tends to recur (some patients never recover). Clinical symptoms of psoriasis primarily include erythema and scaling, which can occur anywhere on the body but are more commonly seen on the scalp and hands and feet.

[0076] Acne is a follicular (hair follicle-sebaceous gland) chronic inflammatory skin disease whose development is closely related to major factors such as excessive sebum, obstruction of the hair follicle-sebaceous gland ducts (including closed and open comedones), bacterial infection, and inflammatory response. It tends to develop in adolescence and is characterized by pleomorphic skin lesions on the face. Therefore, the term acne includes both common acne and rosacea (i.e., red nose).

[0077] Eczema is an inflammatory skin reaction characterized by intense itching, triggered by various internal and external factors. It has three stages: acute, subacute, and chronic. The acute phase tends to produce exudate, while the chronic phase involves infiltration and hypertrophy. Skin lesions are itchy and frequently recur.

[0078] Dermatitis is a common skin condition characterized by roughness, redness, itching, eczema, and dryness. Small nodules, refractory ulcers, and pigmented spots caused by dermatitis can develop into basal cell carcinoma, squamous cell carcinoma, and malignant melanoma if left untreated. 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). This also includes seborrheic dermatitis (seborrheic eczema) and all forms of steroid-dependent dermatitis (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) characterized by flushing, erythema, telangiectasia, atrophy, papules, and / or pustules of the facial area after long-term treatment with topical corticosteroids (including uncontrolled use, abuse, or misuse) (see, e.g., Xiao et al, J. Dermatol., 2015, 42, 697-702 and Lu et al, Clin. Exp. Dermatol., 2009, 35, 618-621).

[0079] Rhinitis is irritation and inflammation of the mucous membrane inside the nose. Common symptoms of rhinitis include nasal congestion, runny nose, sneezing, and postnasal drip. The most common type of rhinitis is allergic rhinitis, caused by allergens such as pollen, dust, mold, or flakes of skin from certain animals. Surprisingly, it has been found that patients with allergic rhinitis treated with the compounds of the present invention experienced relief of itchy eyes, even when the compounds of the present invention were administered intranasally (i.e., into the nasal mucosa).

[0080] Hemorrhoids are swellings caused by large inflammation of hemorrhoidal blood vessels found inside or around the rectum and anus. Symptoms include bleeding after stool passage (i.e., sores), hemorrhoid prolapse, mucus discharge and itching, burning, redness, and swelling in the anal area. Hemorrhoids are thought to be a result of increased abdominal pressure, for example, as a consequence of constipation or diarrhea.

[0081] Chronic obstructive pulmonary disease (COPD) is the name given to 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 and results in impaired airflow in and out of the lungs. Symptoms of COPD include shortness of breath, a wet cough, frequent chest infections, and persistent wheezing. The most common cause of this disease is smoking, but other risk factors include high levels of air pollution, as well as occupational exposure to dust, chemicals, and smoke.

[0082] The compounds of the present invention may have a positive effect in alleviating erythema, redness and swelling, edema, blisters, and bullous pemphigoid caused by various pathological conditions, including those commonly and specifically mentioned herein, by inhibiting the exudation of subcutaneous fluid and suppressing itching and pain caused by such inflammatory conditions.

[0083] Other inflammatory conditions that may be mentioned include: (a) 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 endometritis, endometritis, inhalation injury, etc., as well as inflammation of the mucosa associated with cancer, and inflammation of the mucosa such as infections (e.g., viral infections such as the common cold or influenza) that affect the mucosal surface of the oral cavity, nasopharynx, ears, throat, trachea, gastrointestinal tract, cervix, etc.

[0084] (b) For example, fractures, suppurative infections of bone and joints, inflammation due to rheumatic bone disease, and suppurative osteomyelitis (acute, chronic, localized, sclerosing, post-traumatic), suppurative arthritis, bone tumors (osteoma, osteoid osteoma, chondroma), bone cysts, osteoclastoma, primary osteosarcoma (osteosarcoma, chondrosarcoma, osteofibrosarcoma, Ewing's sarcoma, non-Hodgkin lymphoma, myeloma, chordoma), metastatic bone tumors, neoplastic lesions of bone (bone cysts, aneurysmal bone cysts, eosinophilic granulomas, fibrous dysplasias), and orthopedic inflammation associated with rheumatoid arthritis.

[0085] (c) Neuroinflammation such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, and intercostal neuritis.

[0086] (d) Inflammation of subcutaneous and submucosal soft tissues, such as myositis, ligamentitis, tendinitis, cystitis, lymphadenitis, fodderitis, tonsillitis, synovitis, and fasciitis, as well as inflammation of soft tissues caused by injury, bruising, or tearing of muscles, ligaments, fascia, tendons, synovial membrane, fat, joint capsules, and lymphatic tissues.

[0087] (e) Vascular inflammation such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic 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 rheumatic vasculitis.

[0088] (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, spleenitis, nephritis, pancreatitis, cystitis, oophoritis, prostatitis, and gastric ulcers.

[0089] (g) Inflammation of the eye and surrounding areas, such as conjunctivitis, keratitis (e.g., acute superficial keratitis, nummular keratitis, interstitial keratitis, discoid keratitis, neurotrophic keratitis, mucosal maculitis, herpetic keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, rotifera keratitis, punctate superficial keratitis, ulcerative keratitis, lagophthalmos, actinic keratitis, and acute conjunctivitis during contact lens wear), and optic neuritis.

[0090] (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, and odontogenic ulcers.

[0091] (i) Rheumatoid arthritis, rheumatoid arthritis, rheumatic bone disease, ankylosing spondylitis, bursitis, Crohn's disease, gout, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, osteoporosis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, scleroderma, Sjögren's syndrome, spondyloarthritis, systemic lupus erythematosus, tendinitis, and other rheumatoid arthritis-related inflammations.

[0092] The compounds of the present invention can also be used to treat certain specific diseases of the digestive system, such as gastroesophageal reflux disease (GERD), which may be characterized by sourness in the mouth, reflux, heartburn, dysphagia and / or sore throat, increased salivation (heartburn), nausea, chest pain, and cough. GERD can cause injuries to the esophagus, including reflux esophagitis (i.e., inflammation of the esophageal epithelium that can cause ulcers at or around the junction of the stomach and esophagus), esophageal stricture (i.e., persistent narrowing of the esophagus caused by reflux-induced inflammation), Barrett's esophagus (i.e., intestinal metaplasia (i.e., changes in epithelial cells from squamous epithelium to intestinal columnar epithelium in the distal esophagus), and / or esophageal adenocarcinoma (a form of cancer)).

[0093] The compounds of the present invention can also be used to treat certain specific respiratory diseases such as cystic fibrosis, typical interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, cor pulmonale, and pulmonary embolism. One specific disease condition that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0094] IPF is a diffuse and fatal interstitial lung disease characterized by pathological features including alveolar epithelial damage, widespread proliferation of lung fibroblasts, and excessive deposition of extracellular matrix, ultimately leading to irreversible lung tissue damage. In the later stages of the disease, subjects with IPF experience respiratory failure and death. The compounds of the present invention have been found to be useful in the treatment of IPF and / or in the alleviation of symptoms associated with this disease.

[0095] The compounds of the present invention are effective in treating the following pulmonary and / or fibrotic conditions (whether otherwise stated herein): pulmonary fibrosis, renal fibrosis, hepatic fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, severe asthma, bronchiectasis, upper respiratory tract infections including the common cold and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, reckettsia, radioactive pneumonia, pneumococcal pneumonia (including staphylococcus, streptococcus, and gram-negative bacilli), pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis, and nocardiosis), pulmonary mycosis, cryptococcosis, lung abscess, anaphylactic pneumonia, exogenous allergic alveolitis, and pulmonary eosinophilia (Loeffler's syndrome). It is particularly useful in the treatment of pulmonary eosinophilia (and eosinophilia syndrome), exogenous allergic alveolitis, pulmonary eosinophilia (eosinophilia), obstructive emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalinity / acidosis, acute lung injury, interstitial lung disease, empyema, pulmonary fibroma, and cor pulmonale.

[0096] Specific mucosal disorders and diseases for which the compounds of the present invention are deemed useful include anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, anal fissures, anal itching, anal sinusitis, warts, and rectal prolapse; Crohn's disease and inflammatory bowel diseases, particularly ulcerative colitis; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as paraodontitis.

[0097] The compounds of the present invention may further possess antioxidant effects by increasing SOD (superoxide dismutase) production and reducing lipid oxidation. Therefore, the compounds of the present invention can be considered to have antioxidant properties.

[0098] The compounds of the present invention may also have antipyretic properties that enable the treatment of fever and / or alleviate its symptoms, for example, by reducing the body temperature of the subject (which results in a reduction of fever). Therefore, the compounds of the present invention and formulations containing them may be considered antipyretics.

[0099] A further aspect of the present invention provides a method for treating inflammation, inflammatory disorders, and / or disorders / conditions characterized by inflammation (for example, as a symptom), comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0100] To avoid misunderstanding, in the context of this invention, the terms “treatment,” “therapy,” and “treatment” include therapeutic or palliative treatment for patients in need of treatment, as well as prophylactic treatment and / or diagnosis for patients susceptible to inflammation and / or inflammatory disorders.

[0101] The compounds of the present invention may further possess antiviral properties that enable the treatment of viral infection or viral disease by interfering with viral replication within a 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 enable the prevention of the development of such infection or disease, protection of cells within a host from (e.g., further) viral infection, prevention or cessation of the spread of viral infection or disease (within a single host or from one host to a new host), or prevention of viral reactivation after a waiting period in a host.

[0102] A further aspect of the present invention provides a method for treating a viral infection, comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0103] Potentially mentioned viral infections 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., For example, hepatitis B virus), parvoviridae (e.g., parvovirus B19), astroviridae (e.g., human astrovirus), caliciviridae (e.g., norovirus, Norwalk virus), picoraviridae (e.g., coxsackievirus, hepatitis A virus, poliovirus, rhinovirus), coronaviridae (e.g., acute respiratory syndrome virus), flaviviridae (e.g., hepatitis C virus, yellow fever virus, dengue virus, West Nile virus) Russus (tick-borne encephalitis virus), retroviridae (e.g., human immunodeficiency virus, HIV), togaviridae (e.g., rubella virus), arenaviridae (e.g., Lassa virus), bunyaviridae (e.g., hantavirus, Crimean-Congo hemorrhagic fever virus, Hantan virus), filoviridae (e.g., Ebola virus, Marburg virus, Ravn virus), orthomyxoviridae (e.g., influenza A virus (e.g., H1N1 and H3N2 viruses)). This category includes influenza viruses (including influenza B virus or influenza C virus), paramyxoviridae (e.g., measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus), rhabdoviridae (e.g., rabies virus), hepeviridae (e.g., hepatitis E virus), reoviridae (e.g., rotavirus, orbivirus, cortivirus, vannavirus), and viruses not assigned to a family such as hepatitis D virus.

[0104] More specifically, viruses that may be mentioned include herpes simplex virus type 1 and type 2, human papillomavirus, influenza virus, and parainfluenza virus.

[0105] The compounds of the present invention may further possess antibacterial and / or bacteriostatic properties that enable the treatment of bacterial infections or diseases by inhibiting the growth or proliferation of bacteria within the host, in contrast to the treatment of any symptoms of any bacterial infection or disease, such as pain and / or inflammation. Therefore, the compounds of the present invention can be considered as bactericides and / or preferably bacteriostatic agents.

[0106] Such antimicrobial properties may also enable the prevention of the development of such infections or diseases, the protection of cells in the host from (e.g., further) bacterial infections, the prevention or cessation of the spread of bacterial infections or diseases (within a single host or from one host to a new host), or the prevention of bacterial reactivation after a waiting period in the host.

[0107] A further aspect of the present invention provides a method for treating a bacterial infection, comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0108] The compounds of the present invention may further possess anticancer properties that enable the treatment of cancer itself, i.e., by interfering with cancer, as opposed to treating any symptoms of cancer, such as pain and / or inflammation. Such anticancer properties may also include the prevention of the development of such diseases, for example, by treating inflammation and thereby preventing such development.

[0109] According to another aspect of the present invention, a method for treating cancer is provided, comprising administering a compound of the present invention or a salt thereof to a patient in need of such treatment.

[0110] Specific cancers that may be mentioned include oral cancer, nasopharyngeal cancer, middle ear cancer, conjunctival cancer, throat cancer, tracheal cancer, esophageal cancer, stomach cancer, intestinal cancer, cervical cancer, endometrial cancer, oral mucositis, rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophagitis, gastritis, enterocolitis, cervixitis, endometritis, and skin cancers caused by erythematous skin lesions, etc. One specific skin cancer that may be mentioned is basal cell carcinoma.

[0111] "Patients" include reptiles, birds, and preferably mammals (especially humans).

[0112] According to the present invention, the compounds of the present invention are administered in the form of pharmaceuticals comprising compounds in pharmaceutically acceptable dosage forms, preferably topically or systemically, for example, orally, intravenously, or intra-arterial (including intravascular and other perivascular devices / dosage forms (e.g., stents)), intramuscularly, cutaneously, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, intravaginally, intradermally, transdermally, transnasally, pulmonaryly (e.g., trachea or bronchi), preferably topically, or by any other parenteral route.

[0113] Administration by inhalation (e.g., intranasal) is particularly useful when the condition being treated is inflammation resulting from rhinitis or a viral infection of the respiratory tract (e.g., upper respiratory tract infections such as the common cold and influenza).

[0114] Lung administration is particularly useful when the condition being treated is COPD or IPF. Topical administration can be enhanced by creating a spray containing the active ingredient, for example, by using a powder aerosol or by using an aqueous mist with appropriate atomization technology or equipment such as a nebulizer.

[0115] Anorectal administration, using appropriate delivery methods such as an injectable foam solution or suppositories, is particularly useful when the condition being treated is hemorrhoids or ulcerative colitis.

[0116] Administration to the lower gastrointestinal tract can also be achieved by parenteral, and especially by oral, delivery using standard delayed-release or sustained-release coating techniques known to those skilled in the art. In particular, distinct portions of the upper or lower intestine may be targeted. For example, colonic administration can also be achieved by colon-targeted drug delivery means that are initially administered orally or parenterally.

[0117] The compounds of the present invention may, alternatively, be administered by direct, systemic parenteral administration. Such administration may be useful in methods for treating inflammatory and / or fibrotic disorders or conditions in one or more organs of a patient.

[0118] The 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.

[0119] Visceral fibrotic conditions that may be mentioned include acute and / or severe internal fibrotic conditions characterized by an excessive accumulation of fibrous connective tissue (as described above) in and around inflamed or damaged tissue. For this reason, the formulations of the present invention may be useful in the treatment or prevention of fibrosis (as described above) and the morbidity and death that may be associated therewith. For this reason, visceral (e.g., acute and / or severe) fibrotic conditions that can be treated with the formulations of the present invention include fibrosis of the liver, kidneys, lungs, cardiovascular system including the heart and vascular system, pancreas, spleen, central nervous system (neurofibrosis), myelofibrosis, eyes, vagina, cervix, and other organs.

[0120] Visceral inflammatory conditions include any severe condition (i.e., a condition requiring intensive medical treatment) or a condition that may develop into one; conditions in which certain inflammatory elements are evident that may be characterized by detectable inflammation; and conditions in which the disease is evident (or anticipated) and / or life-threatening.

[0121] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of one or more viscera (including any of the organs mentioned above) characterized by inflammation (e.g., as a symptom), such as acute visceral injury (i.e., one or more conditions that require immediate medical intervention, or that may develop into a condition requiring immediate medical intervention). By treating such acute inflammatory disorders, the formulations of the present invention may prevent or inhibit the onset of symptoms (acute or chronic) associated with such conditions, and may inhibit the progression of morbidity and / or death associated with such conditions.

[0122] Therefore, 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 lung injury, airway injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and acute injury to one or more organs (including any of those mentioned above), such as inflammation, injury, and / or failure of multiple organs.

[0123] Such conditions can be caused by internal or external trauma (e.g., injury or burns), or by infections such as viruses, bacteria, or fungi.

[0124] For example, proctitis (including eosinophilic, gonococcal, and / or ulcerative proctitis) can be caused by inflammatory bowel disease, infections, radiation (e.g., cancer), drugs such as antibiotics, surgery, or allergic conditions such as food intolerance.

[0125] For example, multi-organ inflammation, injury, and / or failure may result from extensive and / or traumatic external injury, including traumatic and / or extensive burns. Traumatic external burns are understood to include second-degree burns, more specifically third-degree and fourth-degree burns. Extensive external burns are understood to include burns affecting at least about 10% of the patient's body surface area, such as at least about 20% or at least about 15%. External (and internal) burns may result from exposure to heat, chemicals, etc.

[0126] Acute inflammatory and / or fibrotic conditions may also result from sepsis or septic shock, which can be caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and SARS in particular can be caused by viruses such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2).

[0127] Therefore, one or more of the aforementioned (e.g., acute) inflammatory conditions can (in fact, in some cases, likely) result in some form of internal tissue damage and / or dysfunction of associated internal tissues. As such, associated tissues include (e.g., mucosal) tissues such as airway epithelium. Such tissue damage can also lead to 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 result in fibrosis arising from one or more of a number of factors, including inflammation.

[0128] In this regard, the compounds and salts of the present invention find particular utility in the treatment of related inflammatory and / or fibrous conditions, given that such conditions are often characterized by one or more comorbidities. A condition “characterized by comorbidities” includes the fact that the primary condition in question simultaneously causes (or is caused by) another further medical condition, including (in fact preferably) those described above, and these conditions may interact with and / or overlap with each other in some way.

[0129] Therefore, the following is provided: A method for treating at least one inflammatory and / or fibrous disorder or condition of one or more internal organs in a patient, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof directly to a patient in need of such treatment, ● A method for treating two or more inflammatory and / or fibrous disorders or conditions of one or more internal organs of a patient, comprising direct systemic parenteral administration of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. A method for reducing the incidence of morbidity and / or death associated with or potentially associated with one or more inflammatory and / or fibrous disorders or conditions of one or more internal organs in a patient, comprising direct systemic parenteral administration of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0130] When the compounds / salts of the present invention are administered directly and parenterally, they may be administered intravenously, intra-arterially, intravascularly, perivascularly, intramuscularly, skinly, and / or subcutaneously, for example by direct injection, or by any other parenteral route, in the form of the compounds or salts of the present invention, in the form of a pharmaceutically acceptable dosage form.

[0131] Therefore, pharmaceutically acceptable formulations for use in such administration may include the compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, which can be selected in full consideration of the intended direct parenteral administration route and standard pharmacokinetics. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may not have adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate release or release regulation of the compound of the present invention.

[0132] Therefore, the formulation for injection may be an aqueous formulation such as a suspension and / or more preferably a solution (an optional buffered aqueous formulation such as a water-containing formulation (e.g., a solution), a phosphate-containing formulation (e.g., a solution), an acetate-containing formulation (e.g., a solution), or a borate-containing formulation (e.g., a solution), or in the form of a lyophilized powder that can be reconstituted with a vehicle such as an aqueous vehicle before use (e.g., injection).

[0133] The formulation for injection may contain other suitable excipients known to those skilled in the art, such as solvents (e.g., water), co-solvents, solubilizers (e.g., cyclodextrin), wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, volume extenders, and / or protective agents.

[0134] The formulation for injection is preferably buffered to a physiologically acceptable pH value (e.g., about 4.5 to about 9.5, e.g., about 6 to about 9, e.g., about 6.5 to about 8.5 pH) using a buffer and / or pH adjuster as described herein by standard technique, and / or may further contain a tonic modifier (such as sodium chloride).

[0135] Notwithstanding the foregoing, preferred modes of delivery of the compounds of the present invention include a suitable (e.g., pharmaceutically and topically acceptable) vehicle suitable for application to the skin and / or suitable mucosal surface, and / or topical delivery to the site of inflammation (e.g., mucous membranes including the oral cavity and / or nasal cavity, lungs, anorectal cavity and / or colon) in commercially available formulations, or more preferably to the skin, but oral, intravenous, cutaneous or subcutaneous, transnasal, intramuscular, intraperitoneal, or pulmonary delivery may also be included.

[0136] Administration by injection is particularly useful for administering the compounds of the present invention in the form of a suspension solution, for example, to the dermis (e.g., intradermal injection), joint cavity, or eye.

[0137] Intradermal injection (e.g., intradermal) administration is particularly useful for administering the compounds of the present invention into the dermis in the form of a solution or suspension (e.g., a skin filler). This is particularly useful as a means of administration for the melanin pigmentation therapy described above, or for the use of the compounds of the present invention in the treatment of wrinkles, for example.

[0138] Administration by injection is particularly useful, for example, to fill surgical sites in the nasal cavity, anal fistulas, and spaces between the gums and tooth roots or sinuses. It is especially useful for shaping support and / or lubrication.

[0139] The compounds of the present invention will generally be administered in the form of one or more pharmaceutical formulations, for example, mixed with an adjuvant, diluent, or carrier (e.g., pharmaceutically acceptable) which can be selected in full consideration of the intended route of administration (e.g., topical administration to the relevant mucous membrane (including the lungs) or preferably to the skin) and standard pharmaceutical or other (e.g., cosmetic) practices. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may not have harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate release or release regulation of the compounds of the present invention.

[0140] Suitable pharmaceutical formulations are either commercially available or described in the literature, e.g., Remington T. he Science and Practice of Pharmacy,22 nd edition, Pharmaceutical Press (2012), and M artindale-The Complete Drug Reference,38 thThe preparations can be made in accordance with the techniques described in Edition, Pharmaceutical Press (2014) and the documents referenced herein, and the relevant disclosures of all such documents are incorporated herein by reference. Otherwise, the preparation of suitable formulations containing the compounds of the present invention can be achieved by those skilled in the art using conventional techniques in ways not of the present invention.

[0141] The compounds of the present invention may be in the form of aqueous formulations such as emulsions, suspensions, and / or solutions (optionally buffered aqueous formulations such as physiological saline-containing formulations (e.g., solutions), phosphate-containing formulations (e.g., solutions), acetate-containing formulations (e.g., solutions), or borate-containing formulations (e.g., solutions), or lyophilized powders.

[0142] The compounds of the present invention can further and / or alternatively be prepared in combination with suitable excipients to prepare the following: ●Gel formulations (Suitable gel matrix materials include cellulose derivatives, carbomers and alginates, tragacanth gum, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, noncellulose polysaccharides, sugars such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and especially hyaluronic acid), ● Lotion (Suitable matrix materials for this include cellulose derivatives, glycerin, noncellulose polysaccharides, polyethylene glycol of different molecular weights, and propanediol), ● Paste or ointment (suitable paste matrix materials include glycerin, petrolatum, paraffin, polyethylene glycol of different molecular weights, etc.) ●Cream or foam (Suitable excipients (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycol of different molecular weights, sodium dodecyl sulfate, fatty alcohol sodium polyoxyethylene ethersulfonate, corn gluten powder, and acrylamide), ● Powdered aerosols (suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol, and polysorbate, e.g., dry powder inhalants), and / or ● Liquids for oral or inhalation, such as water (aerosol) sprays (suitable excipients include viscosity modifiers such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohol, water, preservatives, sweeteners, flavorings, etc.). ●When the compounds of the present invention are particularly combined with hyaluronic acid, certain injection solutions or suspensions that may be mentioned include skin fillers (e.g., injection fillers or soft tissue fillers).

[0143] Moisturizers such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic acid / capric 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. Furthermore, hexadecanol (cetyl alcohol), fatty acids (e.g., stearic acid), sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (e.g., glyceryl monostearate), polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, polyoxylglycerides, lauryldimethylamine The formulation may contain surfactants / emulsifiers such as oxides, bile salts (e.g., sodium deoxycholate), lipids (e.g., fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, glycolipids, polyketides), phospholipids, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), sugar esters, and polysorbates; preservatives such as phenoxyethanol and ethylhexylglycerin; and thickeners such as acryloyldimethyltaurate / VP copolymer. In particular, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, and octanoic acid / capric acid glyceride may be included, especially in cream formulations.

[0144] 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 mucous membranes. Thus, such formulations may be used to impregnate matrix materials such as gauze, nonwoven fabric, or silk paper. Alternatively, the therapeutic patch may be, for example, a band-aid, face mask, eye mask, hand mask, foot mask, etc.

[0145] While petroleum jelly may be used when applying such bandages to wounds, we have also found that bandages can be prepared without the need for petroleum jelly by combining a PEG (e.g., PEG400)-based ointment with the matrix material.

[0146] The compounds of the present invention may also be used in combination with solid supports (such as nasal dressings (e.g., for stopping nosebleeds), skin scaffolds (e.g., in wound healing), or artificial bone (e.g., in bone grafts / transplants)).

[0147] The compounds of the present invention may be administered for inhalation in the form of a suspension, dry powder, or solution. Suitable inhalation devices include pressurized metered-dose inhalers (pMDIs) that are manually or exhaled and can be used with or without a standard spacer device, dry powder inhalers (DPIs) which may be single-dose or multi-dose power-assisted, and soft mist inhalers (SMIs) or nebulizers in which the aerosol drug in a fine mist is delivered at a slower rate than, for example, a spray supplied using a pMDI.

[0148] In pMDI, the compounds of the present invention may be administered as a pressurized suspension of finely ground particles dispersed in a propellant (e.g., together with excipients such as HFA, mannitol, lactose, or sorbitol) or as an ethanol solution to deliver one or more metered doses of about 20 to about 100 μL in each action. Action can be performed by hand (e.g., by pressing) or by inhalation (respiratory action) and is accompanied by a spring-driven flow trigger system.

[0149] In a DPI, the compounds of the present invention may be administered alone or in combination with a larger particle-sized inert excipient (e.g., mannitol) in the form of micronized drug particles (approximately 1 to 5 μm in size) within a capsule that can be pre-filled in the device or manually filled. Inhalation from a DPI may break down the drug particles and disperse them into the airways.

[0150] In SMI, the compound of the present invention can be stored as a solution in a cartridge filled into the device. A spring can release the dose to a micropump so that when a button is pressed, the dose is released and a jet stream of the drug solution is released.

[0151] The compounds of the present invention can also be administered in the form of a fine mist of aerosolized solution using various nebulizers. Nebulizers may include exhalation-enhanced jet nebulizers (where an airflow moves through a jet with the help of a compressor to aerosolize the drug), exhalation-activated jet nebulizers (where, after the patient inhales, an airflow moves through a tube with the help of a compressor to aerosolize the drug), ultrasonic nebulizers (where a piezoelectric crystal vibrates and heats to induce aerosolization and atomization), and vibrating mesh nebulizers (where a piezoelectric crystal vibrates a mesh plate to induce aerosolization, producing very fine droplets without significantly changing the temperature of the solution during atomization).

[0152] A further aspect of the present invention provides a process for preparing a pharmaceutical composition / formulation as defined herein, comprising associating a compound of the present invention as defined above with one or more pharmaceutically acceptable excipients as defined above.

[0153] The compounds of the present invention can also be combined with one or more growth factors selected from platelet-type growth factors (including platelet-derived growth factor, PDGF), osteosarcoma-derived growth factor (ODGF), epidermal growth factor (EGF), transforming growth factors (TGFα and TGFβ), fibroblast growth factors (αFGF, βFGF), insulin-like growth factors (IGF-I, IGF-II), nerve growth factor (NGF), interleukin-type growth factors (IL-1, IL-1, IL-3), erythropoietin (EPO), and colony-stimulating factor (CSF).

[0154] A further aspect of the present invention provides 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 to mucous membranes (including oral and / or nasal mucosa, lungs, anorectal and / or colon), or more preferably to the skin, and thus include a topically acceptable adjuvant, diluent, or carrier.

[0155] Accordingly, pharmaceutical compositions comprising the compounds of the present invention, which are suitable for topical administration (e.g., to the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin), are presented, and the use of such formulations in the treatment of disorders including inflammation, inflammatory disorders, and / or conditions characterized by inflammation (e.g., as symptoms) by direct topical administration of the formulations (e.g., to mucous membranes including the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin).

[0156] To avoid misunderstanding with respect to this aspect of the present invention, topical formulations comprising the compounds of the present invention can be used in the treatment of any and all inflammatory disorders described herein, including the treatment of inflammation, and / or in the treatment of any and all conditions characterized by inflammation as referred to, defined, or described herein. Similarly, topical formulations comprising the compounds of the present invention that may be referred to include any and all of those referred to, defined, or described herein. Any and all of the relevant disclosures herein are incorporated herein by reference in combination with this aspect of the present invention.

[0157] Topical formulations (e.g., liquid or aqueous solution-based) containing the compounds of the present invention may be particularly useful in wound healing and may alleviate pain (including numbness), as well as pruritus / itching, 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 fluid exudation from a wound after a burn or wound, particularly during the acute inflammatory phase, e.g., the first 48 hours. This prevents the risk of infection and other physiological reactions. Such topical formulations 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 they are related to the wound.

[0158] The compound of the present invention may be administered continuously or intermittently. The mode of administration may also be determined by the timing and frequency of administration, but in the case of therapeutic treatment of inflammation, it may also be determined by the severity of the condition.

[0159] Depending on the disorder being treated, the patient, and the route of administration, the compounds of the present invention may be administered to patients requiring treatment at different therapeutically effective doses.

[0160] Similarly, the amount of the compound of the present invention depends on the severity of the condition being treated and the patient, but may be determined by those skilled in the art.

[0161] In any case, practitioners or other persons skilled in the art can routinely determine the most appropriate actual dosage for individual patients, depending on the severity of the condition and the route of administration. The dosages referred to herein are examples of average cases, and naturally, there may be individual cases for which higher or lower dosage ranges are appropriate, and these are also within the scope of the present invention.

[0162] The dosage can be administered once to four times a day (for example, three times).

[0163] The appropriate concentration of the compound of the present invention in the aqueous solution product can be about 0.01 (e.g., about 0.1) to about 15.0 mg / mL, calculated in all cases as a free (non-salt) peptide.

[0164] The appropriate topical dose of the compound of the present invention is approximately 5 μg / cm³, calculated in all cases as the free (non-salt) compound. 2 Treatment area, etc.: approximately 1 to approximately 10 μg / cm³ 2 The therapeutic area includes approximately 0.1 (e.g., approximately 0.5) to approximately 20 μg / cm³. 2 Treatment areas, etc., approximately 0.05 to approximately 50 μg / cm³ 2 This falls within the scope of treatment.

[0165] Appropriate doses of the compound of the present invention for intranasal administration (e.g., by inhalation) range from about 0.01 μg to about 2000 mg, for example, about 0.1 μg to about 500 mg, or 1 μg to about 100 mg. Specific doses for intranasal administration that may be mentioned include about 10 μg to about 1 mg, particularly a dose of about 0.1 mg (i.e., about 100 μg). Intranasal administration of about 0.1 mg of the compound of the present invention per day has been found to be particularly effective in the treatment of conditions associated with inflammation of the nasal cavity and mucosa, such as rhinitis (e.g., allergic rhinitis) and / or rhinosinusitis surgery.

[0166] Appropriate doses of the compound of the present invention for pulmonary administration (e.g., by inhalation) are in the range of about 0.01 μg to about 2000 mg, for example, about 0.1 μg to about 500 mg, or 1 μg to about 100 mg. Specific doses for pulmonary administration that may be mentioned include doses of about 10 μg to about 10 mg, particularly doses of about 0.6 mg (i.e., 60 μg) to 6 mg (for example, for use in the treatment of COPD or IPF).

[0167] The pH value of the formulation containing the compound of the present invention is preferably in the range of about 1.0 to about 9.0 (for example, about 3.0 to about 8.0).

[0168] In any case, the dose administered to mammals, particularly humans, must be sufficient in the context of the present invention to produce a therapeutic response in the mammal over a reasonable time frame (as described above). Those skilled in the art will recognize that the precise dose and composition, as well as the selection of the most appropriate delivery regimen, are also influenced, among other things, by the pharmacological properties of the formulation, the nature and severity of the condition being treated, the physical and mental state of the recipient, as well as the age, condition, weight, sex and response of the patient being treated, the stage / severity of the disease, and genetic differences among patients.

[0169] Therefore, the compounds of the present invention are useful in human or veterinary pharmaceuticals. In this regard, the compounds of the present invention, having a suitable degree of relevant pharmacological (or biological) activity in themselves, as described above, can be used as human and / or veterinary pharmaceuticals.

[0170] Certain compounds of the present invention, particularly compounds of formula I, and / or straight-chain compounds of the present invention, wherein the long-chain compound W representing HCA, HCA-Ala, or more preferably DOPA or DOPA-Ala representing DOPA, and / or U, in addition to having the biological activity described above, may also have adhesive properties.

[0171] These adhesive properties stem from the fact that the relevant W and / or U groups can crosslink with each other to form a three-dimensional network.

[0172] Such compounds of the present invention can adhere to a number of substrates, including inorganic substrates such as glass and metal, and organic substrates such as biological tissue.

[0173] 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 (for example, in corrosion prevention in ships, electronic equipment, pipelines, etc.), biochemical reagents, medical products, sterilization products, culture vessels for cell culture, and the like.

[0174] Such compounds of the present invention can form films on the wound surfaces of various skin and mucous membranes, such as burns, ulcers, frostbite, and pressure ulcers, to aid in healing. Such compounds of the present invention may also be used in surgical procedures, such as closing surgical incisions, bonding fractured bones, bonding mucous membranes, and coating human implants such as artificial bones, cartilage brackets, periosteum, artificial joints, dental implants, occlusion stents, spinal fixation devices, spinal spacers, and organ patches.

[0175] A further aspect of the present invention provides a compound of formula I and / or a straight-chain compound of the present invention, preferably where the straight-chain compound W represents HCA, HCA-Ala, or more preferably DOPA or DOPA-Ala, and U represents DOPA as an adhesive or film-forming material.

[0176] As mentioned above, naturally occurring MAPs are known for their adhesive properties, but it is important to remember that such adhesive properties may arise from the fact that they are high molecular weight linear peptides that can exist in multiple conformations, enabling intermolecular reactions / crosslinking of DOPA residues within the molecule, and thus adhesion. Conversely, it is surprising to the applicant that the compounds of the present invention, as defined above, are not linear polypeptides or proteins, but rather, for example, multiple branched low molecular weight residues, and yet possess similar properties (adhesive or biological) to naturally occurring MAPs.

[0177] Such crosslinking can be carried out by various chemicals (iodine vapor, glutaraldehyde, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC / NHS), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), or other water-soluble condensing agents) or by enzymatic means (e.g., tyrosinase, or as described below).

[0178] Regardless of the level of pharmacological activity that the compounds of the present invention may possess, they may, in any case, be combined with active pharmaceutical ingredients as part of a medical device and / or as part of a drug-medical device combination, either as a pharmaceutically acceptable excipient (e.g., adjuvant, diluent, or carrier) or as part thereof, in combination therapy (as described below) or by performing a function.

[0179] Accordingly, certain compounds of the present invention can be described as novel multifunctional excipients that can be used in a variety of applications in the pharmaceutical field. In this regard, such compounds of the present invention include those that can be used as adhesives and / or film-forming agents (as described above). Furthermore, such compounds of the present invention and / or different compounds of the present invention can be used as substitutes and / or even further as release-delay polymers, binders, suspending agents, gelling agents, coating agents, diluents, or carriers for active ingredients (drugs) of varying solubility.

[0180] The compounds of the present invention, which are particularly useful as pharmaceutical excipients, may be used in large-scale production, may exist without significant toxicity risks, may be described as such, and may be listed as "generally recognized as safe" (GRAS) by the U.S. Food and Drug Administration (FDA).

[0181] Such compounds of the present invention may also be used as excipients in veterinary medicine and in cosmetics.

[0182] A further aspect of the present invention provides a pharmaceutical formulation comprising an active pharmaceutical ingredient mixed with a pharmaceutically acceptable excipient system (such as a pharmaceutically acceptable adjuvant, diluent, or carrier system), the excipient system comprising one of the many compounds of the present invention.

[0183] Furthermore, the compounds of the present invention may be combined with pharmaceutical active ingredients and thus used as part of a drug-medical device combination, which comprises one or more pharmaceutical active ingredients and one or more compounds of the present invention, the one or more compounds of the present invention constituting a medical device component of the combination.

[0184] One of ordinary skill in the art will understand that when the compounds of the present invention are used as or as part of the medical device portion of a medical device or combination of a drug and a medical device, the compounds of the present invention, optionally, in combination with a pharmaceutically active ingredient, in a manner that affects the structure and / or one or more functions of the human or animal body, are used in medicaments for humans or animals, and achieve their main intended purpose (optionally, in a manner that does not rely on a compound of the present invention that is metabolized to achieve any of its main intended purposes) without exerting a chemical action inside or on the human or animal body.

[0185] In this regard, the compounds of the present invention can be combined with a number of known pharmaceutically active ingredients and can be so combined as follows, regardless of whether the compounds of the present invention are used. ● As a separate pharmaceutically active ingredient in combination therapy, ● As a medical device or as part of it, ● As a drug-medical device combination or as part of the medical device, or ● As a pharmaceutically acceptable excipient.

[0186] Such patients may also (and / or already) be undergoing therapy based on the administration of one or more of such other known pharmaceutically active ingredients, such that it is meant that they are receiving one or more prescription dosages of the active ingredients referred to herein before, in addition to, and / or after treatment with the compounds of the present invention.

[0187] Pharmaceutically active agents that can be co-administered with the compounds of the present invention include any agent or drug that can produce certain physiological effects in a biological subject, including particularly mammalian and particularly human subjects (patients), regardless of their therapeutic or prophylactic ability against a particular condition or disorder.

[0188] Furthermore, the compounds of the present invention, such as those that can be crosslinked as described above, can be used as pharmaceutical excipients and can be mixed with such pharmaceutically active ingredients before or after crosslinking and / or at least partial crosslinking, as described above, in order to form a stable pharmaceutical composition in which the compounds of the present invention act as excipients such as carriers. When used in this manner, it may be found that the compounds of the present invention can positively influence the physical, chemical and / or biological properties of such active ingredients, including their physical and / or chemical stability and / or their metabolism after administration.

[0189] Pharmaceutical agents that can be used with the compounds of the present invention may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antiparasitic agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing agents (growth factors).

[0190] The biologically active agents may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antiparasitic agents, antiviral agents (e.g., protease inhibitors), anesthetics, and wound healing agents (growth factors).

[0191] Non-limiting examples of anti-inflammatory drugs that can be used include: rheumatic diseases and / or arthritis (e.g., cataphram, betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodolac, meclofename, salsalate, methylprednisolone, piroxicam); osteoarthritis (e.g., sulindac, meloxicam, fenoprofen, etoricoxib, nabumetone); inflammation and its symptoms, e.g., fever, pain, itching, and / or swelling. (Mefenamic acid, indomethacin, aspirin, ketrolac, fluorometholone, loteprednol, hydrocortisone, fluorometholone, bromfenac, prednisolone acetate, indomethacin, and ibuprofen, etc.); allergies and their symptoms (pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, rhodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, emestine fumarate, Olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudoephedrine, fexofenadine, terfenadine, loratadine, Alexis, etc.; respiratory diseases including asthma and / or COPD (budesonide, ciclesonide, nedocromil, dexamethasone, ambroxol, pranlukast, etc.); skin diseases (mometasone, triamcinolone, desonide, sulfacetamide, ta This includes chlorimus, allantoin, triamcinolone, etc.; mastocytosis (cromolyn, etc.); gout (diclofenac, febuxostat, etc.); conjunctivitis (hydrobenzoyl hydrobenzene, pranoprofen, zinc sulfate, etc.); eye diseases (dextran 70, thyroxine / liothyronine, and eye extracts, etc.), known or commercially available pharmaceutically acceptable salts of any of the above, and those used to treat any combination of the above compounds and / or salts.

[0192] Anti-inflammatory agents that may be mentioned include endogenous (and / or exogenous) lipid-based proresolvings, anti-inflammatory molecules, or mediators such as lipoxins, resolvins, and protectins. Pro-inflammatory agents that may be mentioned include prostaglandins (e.g., latanoprost, prostaglandin E1, and prostaglandin E2) as well as leukotrienes (e.g., leukotriene B4).

[0193] Non-limiting examples of antibiotics that may be used include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomisocin, gentamicin, cetylpyridinium, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, clindamycin, metronidazole, azithromycin, mafenide, sulfamethoxazole, paracetamol, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, cephalexin, moxifloxacin, any known or commercially available pharmaceutically acceptable salts of any of the above, and any combination of any of the above compounds and / or salts.

[0194] Non-exclusive examples of antiviral drugs that may be used include tobramycin ribavirin, acyclovir, moloxidine, foscarnet, ganciclovir, idoxuridine, trifluridine, brivudine, vidarabine, entecavir, terbivudine, foscarnet, zidovudine, didanosine, zalcitabine, stabudine, lamivudine, abacavir, emtricitabine, nevirapine, delavirdin, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir, darunavir, telaprevir, boceprevir. Simeprevir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir pivoxil, homivirsen, podophyllox, imiquimod, synecatechins, interferon α2b (recombinant, human), any pharmaceutically acceptable known or commercially available salt of any of the above, as well as any combination of any of the above compounds and / or salts.

[0195] Non-limiting examples of anesthetics that may be used include articaine, dextropropoxifen, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxin, benzocaine, dibucaine, diclonin, tetracaine, bupivacaine, and any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0196] Non-limiting examples of usable wound regenerative agents include basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, human; yeast), rhEFG(I), acid fibroblast growth factor (recombinant, human), granulocyte-macrophage-stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, etaclizine, retinoids, calf blood deproteinized extract, carrageenan, amiotide, and any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0197] Such pharmaceutical active ingredients include those that, along with the compounds of the present invention, can be administered topically to, for example, the surface of the skin or mucous membranes.In this regard, preferred active ingredients from the above list include cyclosporine, chondroitin, loteprednol, fluorometholone, bromfenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, emestine fumarate, olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, Alexis, dexamethasone, ambroxol), and Sul. Phasetamide, tacrolimus, allantoin, triamcinolone, cromolyn, nedocromyl, diclofenac, eye extract, hydrobenzone, pranoprofen, zinc sulfate, dextran 70, thyroxine / liothyronine, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomisomycin, gentamicin, cetylpyridinium, neo Mycin, roxithromycin, silver sulfadiazine, clarithromycin, sulfamethoxazole, chloramphenicol, tobramycin ribavirin, acyclovir, moloxidine, foscarnet, ganciclovir, interferon α2b (recombinant, human), articaine, dextropropoxifen, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxin, benzocaine, dibucaine, diclonin, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human; recombinant, This also includes bovine (bovine), epidermal growth factor (recombinant, human; yeast), rhEFG(I), acid fibroblast growth factor (recombinant, human), granulocyte-macrophage-stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, etaclizine, retinoids, calf blood deproteinized extract, carrageenan, amiotide, and known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0198] Other pharmaceutically active ingredients that can be administered simultaneously with the compound of the present invention include those that can be administered to treat one of the gastrointestinal disorders described above.

[0199] Non-specific examples of gastrointestinal medications include oxalazine (orthalazine), sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, live bacillus (Clostridium butyricum, Rikeniformis, Cereus, etc.), probiotics (Bifidobacterium, etc.), tegaflu, nifuratel, amoxicillin, ampicillin, nistatin, allicin, and cereus. Fadroxyl, diclonin, carmoful, fluorouracil, mosapride, sodium carbosulfan, thrombin, pantoprazole, cimetidine, cisapride, ethylenediaminediacetamide, nimustine, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azasetron, lentinan, bismuth salts (e.g., aluminates, potassium citrate), and, for example, magnesium salts, magnesium trisilicate, bicarbonate, vitamin U, aluminum hydroxide Combination of belladonna extract, famotidine and calcium carbonate, magnesium hydroxide, hydrotalcite, proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, or esomeprazole), glycine, trypsin, allantoin, aluminum hydroxide, L-glutamin, sodium allenate, levanpet, rotandine, cuxipite, lafutidine, thymic protein, Elysium erinaceus, yl maleate This includes sogladine, nizatidine, L-glutamine and sodium azulene sulfonate (sodium guarenate), ranitidine, bismuth citrate, lactobacillin, bisacorzine, dimethylsiloxane, bioclostridium butyricum, loperamide hydrochloride, dibazole, secnidazole, zinc acetate, montmorillonite, tegaflu / gimeracil / oteracil, famotidine, oteracil, doxifluridine, capecitabine, or any known or commercially available pharmaceutically acceptable salt of any of the above.

[0200] Pharmaceutical active ingredients that may be mentioned for use in combination with the compounds of the present invention include active ingredients useful for treating inflammation and / or inflammatory disorders (other anti-inflammatory agents).

[0201] Anti-inflammatory agents that may be used in combination with the compounds of the present invention in the treatment of inflammation include therapeutic agents useful for treating inflammation and / or diseases characterized by inflammation as one of its symptoms, including those described above. Depending on the pathological condition being treated, such anti-inflammatory agents may include, for example, NSAIDs (e.g., aspirin), aminosalicylic acids (5-aminosalicylic acid (mesalazine)), leukotriene receptor antagonists (e.g., montelukast, pranlukast, and zafirlukast), corticosteroids, analgesics, and certain enzymes such as trypsin, as described below. The compounds of the present invention may also be combined with leukotrienes (e.g., cysteinyl leukotriene, leukotriene B4).

[0202] Other preferred agents that can be combined with the compounds of the present invention include LTB4 (for treating wounds and burns), NSAIDs (e.g., aspirin), montelukast (for treating inflammation in general), and trypsin (e.g., for treating inflammation of mucous membranes associated with viral infections).

[0203] The compounds of the present invention can also be combined with other therapeutic agents known to cause inflammation as a side effect when administered.

[0204] The conjugates of the present invention can also be combined with stem cells (e.g., totipotent, pluripotent (such as embryonic or induced pluripotent stem cells), multipotent (such as mesenchymal stem cells), oligopotent (such as hematopoietic stem cells), or unipotent (such as muscle stem cells).

[0205] Other known pharmacoactive ingredients can also be administered in combination with the compounds of the present invention in many ways.

[0206] For example, the compounds of the present invention can be administered together in the same (e.g., pharmaceutical) formulation or separately (simultaneously or sequentially) in various (e.g., pharmaceutical) formulations, in combination with a pharmaceutically active ingredient (or other pharmaceutically active ingredient) (or "therapeutic agent").

[0207] Thus, such combination products provide for the administration of a compound of the present invention in combination with a therapeutic agent (or other therapeutic agent), and can thus be presented as separate formulations (at least one of which contains a compound of the present invention and at least one of which contains a therapeutic agent (or other therapeutic agent)), or as a combined preparation (i.e., a formulation) (i.e., a single formulation containing a compound of the present invention and a therapeutic agent (or other therapeutic agent)).

[0208] Thus, (1) A (e.g., pharmaceutical) formulation (hereinafter referred to as a "combined preparation") containing a compound of the present invention, another pharmaceutically active ingredient, and optionally a pharmaceutically acceptable inert excipient (e.g., an adjuvant, diluent or carrier), and (2) A parts kit comprising (A) A compound of the present invention in the form of a (e.g., pharmaceutical) formulation optionally mixed with a pharmaceutically acceptable inert excipient (e.g., an adjuvant, diluent or carrier), and (B) Another pharmaceutically active ingredient in the form of a (e.g., pharmaceutical) formulation optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, where components (A) and (B) are each provided in a form suitable for combined administration with the other, are further provided.

[0209] In a further aspect of the present invention, there is provided a process for the preparation of a combined preparation (1) as defined above in the foregoing text, the process comprising associating a compound of the present invention, another pharmaceutically active ingredient, a therapeutic agent with at least one (e.g., pharmaceutically acceptable) excipient.

[0210] In a further aspect of the present invention, a process is provided for preparing a parts kit (2) as defined above herein, wherein the process includes relating components (A) and (B). As used herein, reference to relating means that the two components are suitable for administration in combination with each other.

[0211] Therefore, with respect to the process for preparing the parts kit as defined above, by "associating" the two components with respect to each other, we have determined that the two components of the parts kit are, (i) Provided separately (i.e., independently of each other), and then combined for use in combination therapy, (ii) It may be packaged and presented together as separate components of a “combination pack” for use in combination with each other in combination therapy.

[0212] therefore, (I) one of the components (A) and (B) as defined herein, (II) A parts kit is further provided, which includes instructions for using the component in combination with the other of the two components.

[0213] In relation to the above-mentioned parts kit, the compounds of the present invention may be provided in the form of a (e.g., pharmaceutical) formulation mixed with one or more additional pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers), although the present invention is provided primarily for the purpose of performing its function as a medical device or excipient, and may not be provided with such additional pharmaceutically acceptable excipients. In any case, it is preferable that the (other) pharmaceutically active ingredients of the parts kit be provided in the form of a pharmaceutical formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0214] The parts kits described herein may contain two or more appropriate amounts / doses of the compounds of the present invention (e.g., formulations containing them) and / or two or more appropriate amounts / doses of other pharmaceutically active ingredients (e.g., formulations containing them) to provide repeated doses. If two or more formulations containing any of the above or their amounts / doses exist, such formulations may be the same or different with respect to the dosage of any of the compounds, chemical compositions and / or physical forms.

[0215] With respect to the parts kits described herein, “administration in combination with ~” includes the administration of each component sequentially, separately, and / or simultaneously throughout the course of treatment of the relevant pathological condition.

[0216] Accordingly, with respect to the combination products of the present invention, the term "administered in combination with ~" means that, over the course of treatment of the relevant medical condition, the two components of the combination product (the compound of the present invention and other pharmaceutically active ingredients) are administered together or in sufficiently close proximity in time (optionally repeated) over the course of treatment of the relevant medical condition, enabling a greater beneficial effect to the patient than if either the compound of the present invention or the other agent were administered alone or without the other component (optionally repeated) over the course of treatment of the relevant medical condition. The determination of whether the combination provides a greater beneficial effect with respect to the treatment of a particular medical condition and over the course of treatment will depend on the medical condition being treated or prevented, but can be conventionally achieved by those skilled in the art.

[0217] Furthermore, in the context of the parts kit according to the present invention, the term “combined with ~” includes the fact that one or the other of the two components may be administered before, after, and / or simultaneously with (optionally repeated) the administration of the other component. When used in this context, the terms “co-administered” and “administered simultaneously with ~” include the fact that the individual amounts / doses of the relevant compounds of the present invention and other pharmaceutically active ingredients are administered within 48 hours (e.g., 24 hours) of each other.

[0218] With respect to the above-mentioned combined preparations and parts kits, the other active pharmaceutical ingredients are preferably anti-inflammatory agents or drugs known to cause inflammation as a side effect, as described above.

[0219] Whenever the term “approximately” is used herein in the context of quantities such as the concentration and / or dose of an active ingredient, molecular weight, or pH, it will be understood that such variables are approximations and can therefore vary by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%) from the numerical value specified herein. In this regard, the term “approximately 10%” means, for example, ±10% for the numerical value 10, i.e., 9% to 11%.

[0220] The compounds of the present invention have the advantage of having a wide variety of applications, including the following: ●As a biological agent for various pathological conditions characterized by inflammation, whether the condition itself is an organic inflammatory disease, related to inflammation (e.g., wound or burn), or characterized by inflammation, and / or for surgical and / or cosmetic applications as described above. ● Combining with active pharmaceutical ingredients by performing a more inactive function, either in combination therapy or as one of the following, or as part thereof. ○Pharmacologically acceptable excipients (e.g., adjuvants, diluents, or carriers), ○ Medical devices, and / or ○ The medical device portion of a drug-medical device combination.

[0221] The compounds, uses, and methods described herein may also have the advantage of being more convenient, effective, less toxic, having a broad range of activity, being potent, having fewer side effects, or having other useful pharmacological properties that surpass similar compounds or methods (treatments) known in the prior art, whether for use in treating inflammation, inflammatory disorders, or disorders characterized by inflammation as a symptom (including wounds), or in other methods, as mentioned above. The present invention is illustrated by the following embodiments. [Brief explanation of the drawing]

[0222] [Figure 1] This shows the recovery rate of unhealed wounds in an acute wound mouse model. [Figure 2] This shows the amount of VEGF measured. [Figure 3] This shows the measured TGFβ1 content in wound tissue from a diabetic wound mouse model. [Figure 4] This shows the effect of acute inflammation on swelling in a mouse ear swelling model. [Figure 5] This shows the Evans blue content in rectal and anal tissues, which indicates the vascular permeability of the test compound. [Figure 6] This shows the Evans blue content in rectal and anal tissues, which indicates the vascular permeability of the test compound. [Figure 7] This shows the effect on body weight in a TNBS-induced ulcerative proctitis model. [Figure 8] This shows the effect on the ulcerative surface in a TNBS-induced ulcerative proctitis model. [Figure 9] This shows the general impact on appearance in a TNBS-induced ulcerative proctitis model. [Figure 10] This is photographic evidence of the effect of the test compound on wound healing. [Figure 11] The present invention demonstrates the bioadhesion properties of the compound. [Figure 12]The plasma concentration-time curves for mesalazine and montelukast, respectively, when administered together with and without the compound of the present invention, are shown. [Figure 13] The plasma concentration-time curves for mesalazine and montelukast, respectively, when administered together with and without the compound of the present invention, are shown. [Examples]

[0223] Example 1 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2 (Sequence ID 40) Fmoc-Lys-Boc-Wang resin (9.15g, GLS180322-413 01 (GL Biochem, Shanghai, China) was packed into a glass reaction column.

[0224] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemi Cal Industry Co. Ltd. (Shandong, China) was added to the column, and the resin was immersed for approximately 30 minutes. Next, the DCM was removed by vacuum filtration.

[0225] Resin is N,N-dimethylformamide (DMF, 200 mL; Shandong Sh It was washed three times at itaifeng Fertilizer Industry Co.Ltd. (Shandong, China).

[0226] 20% piperidine solution in DMF (200 mL, Shandong Shitaif Fertilizer Industry Co. Ltd. (Shandong, China) was added as a deprotection solution and the reaction was allowed to proceed for 20 minutes. Next, the solution was removed by vacuum filtration, and the column was washed six times with DMF.

[0227] Fmoc-DOPA(Acetonide)-OH(4.14g;GLS190219 -21003, GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GLS170805-00705, GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N,N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co.Ltd., Jiangsu, China). After 30 minutes of reaction, a Kaiser test was performed using a small amount of resin, and the yellow and colorless gel of the solution indicated that the reaction was complete. The solvent was removed by vacuum filtration.

[0228] The above coupling step was repeated to couple the remaining amino acids in the same amounts (molars): Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH.

[0229] After coupling Fmoc-Ala-OH to the resin, the above coupling step was repeated, starting with Fmoc-Lys(Boc)-OH, followed by Fmoc-DOPA(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH.

[0230] In an alternative procedure, after bonding Fmoc-Ala-OH to the resin, a deprotection step was performed to remove the Fmoc protection of Dopa. The resin was washed three times with DMF (200 mL each time). 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. The resin was then decontaminated with the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scienti Each sample was washed three times at fic Co., Ltd. (Guangdong, China). The resin was dried under vacuum for approximately two hours.

[0231] 160.0 mL (i.e., 10 mL per gram of dry resin) of a solution consisting of 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added to immerse the peptide-containing compound bound to the resin. After approximately 2 hours of cutting, the solid support was removed by filtration, and the filtrate was collected under reduced pressure. 1600 mL (i.e., 10 mL per 1 ml of filtrate) of diethyl ether (Xilong Sc) was added to the filtrate. The compound was precipitated using ientific Co. Ltd. (Guangdong, China), and the precipitate was collected by filtration. The precipitate was vacuum-dried for approximately 2 hours to obtain 7.53 g of the crude title compound.

[0232] 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 used was Agilent ZOR. The system used was a BAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column, detection: 220 nm UV, solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient of solvent A concentration from 5% to 90% over 50 minutes; flow rate: 1.0 mL / min; sample volume: 10 μL).

[0233] The target peak eluted at 11.926 minutes, had the expected molecular weight (MS: m / z 2380.6), and had a purity of 60.345%.

[0234] Next, 7.5 g of the crude product was dissolved in 80 mL of pure water and purified using an LC3000 semi-preparative analyzer. The preparative column model was the Dubhe-C18 model (Hanbon Sci.&Tech.Co.,Ltd., Jiangsu, China) (50*250 mm column, 100 Å column, detection: 220 nm UV). A suitable gradient for elution was calculated from the LC-MS detection step (solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient of solvent A concentration from 5% to 20% over 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (the same column except that a linear gradient from solvent A concentration of 5% to 30% over 25 minutes was used).

[0235] Next, for the anion exchange step, the fractions were mixed to a purity of 98%. This was achieved using an LC3000 preparative apparatus (preparative column model: Dubhe-C18 model (above)). The fractions were diluted once with pure water and packed directly into the column. The column was then washed with pure water, 0.37% ammonium acetate for approximately 20 minutes, followed by pure water for another 20 minutes at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% HAc in MeCN, solvent B: 0.1% HAc in water, linear gradient of solvent A concentration from 5% to 20% over 30 minutes; flow rate 60.0 mL / min). The fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fractions to a purity of 98% were mixed and lyophilized to obtain 3.06 g of the purified title compound.

[0236] Example 2 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys) 3~5 (Sequences 41, 42, and 43) One or more of the steps described in Example 1 were repeated. Once the amino acids were bonded to the resin, this procedure was repeated three more times as described in Example 1 to provide (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)5 (SEQ ID NO: 43).

[0237] Five decapeptide repeat peaks were detected at 13.511 min by LCMS (analytical column model: GS-120-5-C18-BIO, 4.6*250 mm, detection: 220 nm UV, solvent A: 0.1% TFA in MeCN, solvent A: 0.1% TFA in water, gradient: 0-25 min, 5%-30% B, flow rate 1.0 mL / min, volume: 10 μL), and the compound was isolated. MS (5 decapeptide repeat products): m / z is 5924.6.

[0238] To provide (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)3 (SEQ ID NO: 41) and (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)4 (SEQ ID NO: 42), the procedure described in Example 1 is repeated once or twice as necessary. MS (three decapeptide repeat products): m / z is 3562.0. MS (four decapeptide repeat products): m / z is 4743.3.

[0239] Example 3 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2Lys (Sequence ID 45) Fmoc-Lys(fmoc)-Wang resin (9.9g, GLS191010-41 303 (GL Biochem, Shanghai, China) was packed into a glass reaction column.

[0240] This method was the same as the first method described in Example 1 above, except that Fmoc-Lys(Boc)-OH was first bonded to the resin, and then to Fmoc-Dopa(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH, and that the amounts of amino acids, TBTU, and DIPEA were twice as much (in moles) compared to Example 1.

[0241] Repeating essentially the same procedure yielded a further batch of the crude title compound (yield 7.89 g). Analysis showed that the target peak eluted at 11.376 min with the expected molecular weight (MS: m / z 2508.8). The purity was 68.985%.

[0242] Next, 7.8 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.57 g of the pure title compound was obtained.

[0243] Example 4 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Orn or -Dap (Sequences 46 and 47) The method is the same as that described in Example 3, except that the resin used is either Fmoc-Orn(fmoc)-Wang resin or Fmoc-Dap(fmoc)-Wang resin.

[0244] Example 5 [(Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Lys]2-Lys (SEQ ID NO: 48) The method was the same as that described in Example 3, starting with Fmoc-Lys(fmoc)-OH, followed by Fmoc-Lys(boc)-OH, Fmoc-Dopa(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH. The amounts of amino acids, TBTU, and DIPEA were twice as high (in moles) compared to Example 3.

[0245] Repeating essentially the same procedure yielded a further batch of the crude title compound (yield 15.29 g). Analysis showed that the target peak eluted at 11.563 mins with the expected molecular weight (MS: m / z 5127.62). The purity was 52.126%.

[0246] Next, 15.2 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.96 g of the pure title compound was obtained.

[0247] Example 6 [(Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Orn]2-Orn or -Dap]2-Dap (Sequence IDs 49 and 50) The method is the same as that described in Example 5, except that Fmoc-Orn(fmoc)-Wang resin or Fmoc-Dap acid(fmoc)-Wang resin is used instead. The first amino acid to bond to the resin is Fmoc-Orn(fmoc)-OH or Fmoc-Dap(fmoc)-OH, as needed, instead of Fmoc-Lys(fmoc)-OH.

[0248] Example 7 {[(Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 51) The method was the same as described in Example 5, except that the first amino acid bonded to the resin was Fmoc-Lys(fmoc)-OH, followed by Fmoc-Lys(fmoc)-OH, then Fmoc-Lys(boc)-OH, Fmoc-DOPA(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH, and the amounts of amino acids, TBTU, and DIPEA were twice as much (in moles) compared to Example 5.

[0249] Repeating essentially the same procedure yielded a further batch of the crude title compound (yield 28.14 g). Analysis showed that the target peak eluted at 11.753 min with the expected molecular weight (MS: m / z 10365.2). The purity was 30.423%.

[0250] Next, 28.1 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 5.72 g of the pure title compound was obtained.

[0251] The compound of Example 7 will be hereinafter referred to as "Compound B".

[0252] Example 8 {[(DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 52) The method was the same as that described in Example 7, except that the fourth amino acid bound to the resin was Fmoc-Tyr(tBu)-OH instead of Fmoc-DOPA(acetonide)-OH, and that after Fmoc-Ala-OH was last bound to the resin, another amino acid, Fmoc-DOPA(acetonide)-OH, was bound to the resin. MS:m / z 11671.1

[0253] The compound of Example 8 will be hereinafter referred to as "Compound A".

[0254] Example 9 {[(Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Orn or Dap]2-Orn or Dap}2-Orn or Dap (Sequence IDs 53 and 54) The method is the same as that described in Example 7, except that Fmoc-Orn(fmoc)-Wang resin or Fmoc-Dap acid(fmoc)-Wang resin is used instead. The first two amino acids bonded to the resin are Fmoc-Orn(fmoc)-OH or Fmoc-Dap(fmoc)-OH, as needed, instead of Fmoc-Lys(fmoc)-OH.

[0255] Example 10 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2 (SEQ ID NO: 40) Self-Crosslinking Product Mixture Four mg of the product from Example 1 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2 (SEQ ID NO: 40) and 0.33 mg of mushroom tyrosinase (Sigma: T3824-250KU, 2687 units / mg) were added to 2.2 mL of phosphate buffer (100 mM, pH 6.5) containing 25 mM ascorbic acid. The mixture was stirred for 2 hours. Next, 0.15 mL of 1 M HCl solution was added to the mixture to stop the reaction.

[0256] Samples were collected for MALDI-TOF mass spectrometry analysis. The results indicate that the molecular weight of the two repeating linear peptides (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2 can increase by 2 to 6 times compared to the original molecular weight.

[0257] Example 11 Further synthesis of bifurcated peptides The following peptides were synthesized following essentially the same process as described in Example 3 above, except that appropriate amino acids were used in appropriate peptide coupling sequences: (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys (SEQ ID NO: 55), (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys (SEQ ID NO: 56), (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys (Sequence ID 57) (DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys (SEQ ID NO: 58), (Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys (SEQ ID NO: 59), and (DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys (Sequence ID 60).

[0258] The crude yield, purity, retention time, MS values, and final yield from these peptide syntheses are shown in Table 1 below. [Table 1]

[0259] Example 12 Further synthesis of four-branched peptides The following peptides were synthesized following essentially the same process as described in Example 5 above, except that appropriate amino acids were used in appropriate peptide coupling sequences: [(Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys (SEQ ID NO: 61), [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 62), [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 63), [(DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 64), [(Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 65, hereafter referred to as "Compound C"), and [(DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (Sequence ID 66).

[0260] The crude yield, purity, retention time, MS values, and final yield from these peptide syntheses are shown in Table 2 below. [Table 2]

[0261] Example 13 Further synthesis of eight-branched peptides The following peptides were synthesized following essentially the same process as described in Example 7 above, except that appropriate amino acids were used in appropriate peptide coupling sequences: {[(Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 67), {[(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 68), {[(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 69), {[(DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 70), {[(Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 71), and {[(DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys}2-Lys (Sequence ID 72).

[0262] The crude yield, purity, retention time, MS values, and final yield from these peptide syntheses are shown in Table 3 below. [Table 3]

[0263] Example 14 (HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys (SEQ ID NO: 73) The title compound was prepared using essentially the same process as described in Example 3 above, except that a final coupling with 3,4-dihydroxyhydrocinnamic acid (3.28 g, Macklin, Shanghai, China) was performed to obtain 7.78 g of the crude title compound.

[0264] Analysis revealed that the target peak eluted at 10.684 mins with the expected molecular weight (MS: m / z 2805.0). The purity was 62.283%.

[0265] Next, 7.7 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.46 g of the pure title compound was obtained.

[0266] Example 15 [(HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 74) The title compound was prepared using essentially the same process as described in Example 5 above, except that a final coupling with 3,4-dihydroxyhydrocinnamic acid (6.56 g) was performed to obtain 15.77 g of the crude title compound.

[0267] Analysis revealed that the target peak eluted at 10.727 mins with the expected molecular weight (MS: m / z 5720.1). The purity was 48.274%.

[0268] Next, 15.7 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.59 g of the pure title compound was obtained.

[0269] Example 16 {[(HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 75) The title compound was prepared using essentially the same process as described in Example 7 above, except that a final coupling with 3,4-dihydroxyhydrocinnamic acid (13.12 g) was performed to obtain 28.69 g of the crude title compound.

[0270] Analysis revealed that the target peak eluted at 10.833 mins with the expected molecular weight (MS: m / z 11551.1). The purity was 28.821%.

[0271] Next, 28.6 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 5.62 g of the pure title compound was obtained.

[0272] Example 17 [(Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys)2-Lys]2-Lys (Sequence ID 76) The title compound was prepared using essentially the same process as described in Example 5 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 14.97 g of the crude title compound.

[0273] Analysis revealed that the target peak eluted at 11.578 mins with the expected molecular weight (MS: m / z 5191.2). The purity was 52.553%.

[0274] Next, 14.9 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.87 g of the pure title compound was obtained.

[0275] Example 18 [(HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys (SEQ ID NO: 77) The title compound was prepared using essentially the same process as described in Example 15 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 15.66 g of the crude title compound.

[0276] Analysis revealed that the target peak eluted at 10.697 min with the expected molecular weight (MS: m / z 5720.0). The purity was 49.033%.

[0277] Next, 15.6 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.62 g of the pure title compound was obtained.

[0278] Example 19 (HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys)2-Lys (Sequence ID 78) The title compound was prepared using essentially the same process as described in Example 14 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 7.83 g of the crude title compound.

[0279] Analysis revealed that the target peak eluted at 10.594 mins with the expected molecular weight (MS: m / z 2869.1). The purity was 61.036%.

[0280] Next, 7.8 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.51 g of the pure title compound was obtained.

[0281] Example 20 [(DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys)2-Lys]2-Lys (Sequence ID 79) The title compound was prepared using essentially the same process as described in Example 5 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 14.67 g of the crude title compound.

[0282] Analysis revealed that the target peak eluted at 11.554 mins with the expected molecular weight (MS: m / z 5191.3). The purity was 50.576%.

[0283] Next, 14.6 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.64 g of the pure title compound was obtained.

[0284] Example 21 (DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys)2-Lys (Sequence ID 80) The title compound was prepared using essentially the same process as described in Example 3 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 7.75 g of the crude title compound.

[0285] Analysis revealed that the target peak eluted at 11.059 mins with the expected molecular weight (MS: m / z 2540.6). The purity was 65.384%.

[0286] Next, 7.7 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.36 g of the pure title compound was obtained.

[0287] Example 22 (HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys)2-Lys (SEQ ID NO: 81) The title compound was prepared using essentially the same process as described in Example 14 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 7.45 g of the crude title compound.

[0288] Analysis revealed that the target peak eluted at 10.489 min with the expected molecular weight (MS: m / z 2446.1). The purity was 65.457%.

[0289] Next, 7.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.27 g of the pure title compound was obtained.

[0290] Example 23 [(HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys)2-Lys]2-Lys (Sequence ID 82) The title compound was prepared using essentially the same process as described in Example 15 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 14.79 g of the crude title compound.

[0291] Analysis revealed that the target peak eluted at 11.235 mins with the expected molecular weight (MS: m / z 5067.5). The purity was 53.853%.

[0292] Next, 14.7 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.37 g of the pure title compound was obtained.

[0293] Example 24 [(Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr)2-Lys]2-Lys (SEQ ID NO: 83) The title compound was prepared using essentially the same process as described in Example 5 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 14.26 g of the crude title compound.

[0294] Analysis revealed that the target peak eluted at 11.478 mins with the expected molecular weight (MS: m / z 5063.3). The purity was 49.642%.

[0295] Next, 14.2 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.33 g of the pure title compound was obtained.

[0296] Example 25 (Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA)2-Lys (Sequence ID 84) The title compound was prepared using essentially the same process as described in Example 3 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 7.37 g of the crude title compound.

[0297] Analysis revealed that the target peak eluted at 10.672 mins with the expected molecular weight (MS: m / z 2540.2). The purity was 61.252%.

[0298] Next, 7.3 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 2.28 g of the pure title compound was obtained.

[0299] Example 26 [(Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA)2-Lys]2-Lys (Sequence ID 85) The title compound was prepared using essentially the same process as described in Example 5 above, except that appropriate amino acids were used in an appropriate peptide coupling sequence to obtain 14.06 g of the crude title compound.

[0300] Analysis revealed that the target peak eluted at 11.223 mins with the expected molecular weight (MS: m / z 5255.3). The purity was 50.577%.

[0301] Next, 14.0 g of the crude product was purified as described in Example 1 above, and after freeze-drying, 4.25 g of the pure title compound was obtained.

[0302] Example 27 Air bag model Healthy adult male C57BL / 6 mice weighed at 20-30g were used in Changzho The mice were supplied by Cvens Experimental Animal Co. Ltd. Before the experiment, the mice were housed under standardized conditions (constant temperature or 22±2°C with alternating 12 hours of light and dark) and fed standard mouse diet including water for about one week. The mice were randomly divided into nine groups of seven, as shown in Table 4.

[0303] General anesthesia was induced using intraperitoneal delivery of 3% chloral hydrate (Sinopharm Chemical Reagent Co., Ltd., Shanghai, China; 1 mL / 10 g body weight). One day prior to sterile air injection, the entire back was shaved and depilated.

[0304] Air sacs were created by subcutaneously injecting sterile air (5 mL) into the scapular region of mice. Three days later, another injection of air (3 mL) was given to maintain the sac. Three days after the second injection, the animals were given sterile carrageenan solution (CP Kel) to induce acute inflammation. The mice were injected with carrageenan (produced by adding 0.1 g of carrageenan powder to a beaker containing 10 mL of 0.9% physiological saline and stirring). Mice were pretreated with the test sample or vehicle 1 hour and 23 hours before and after carrageenan injection into the subcutaneous air sac. The animals were sacrificed 24 hours after carrageenan injection.

[0305] A skin biopsy was taken from the air sac. A portion of the biopsy was treated with formalin (50 mL of 40% formaldehyde solution (Nanchang Rain Dew Experimental)). The samples were fixed in a solution (prepared by adding ultrapure water to a total volume of 500 mL) produced by Equipment Co., Ltd. (Nanchang, Hubei Provence, China), and analyzed by histological embedding in paraffin wax, sectioning, and staining.

[0306] Histological specimens were analyzed to estimate inflammation and edema scores. Inflammation scores were estimated by observing slices stained with hematoxylin and eosin (HE) under a light microscope. Scores (1–3 points) were assigned according to the perceived level of inflammation (e.g., 1 point for scattered small amounts of inflammatory cells in the area (mild); 2 points for many inflammatory cells (moderate); 3 points for diffuse infiltration (severe)). After the overall observation, a similar scoring system was used for edema levels (3 points for most severe, 1 point for mild). The scores for each group are shown in Table 5.

[0307] After conducting several preliminary experiments to validate this model, experiments were carried out in which mice were treated by administering test samples or vehicles according to Table 4 below. Compounds A and B were dissolved in physiological saline at the concentrations shown in Table 4 below (L = low dose, M = medium dose, H = high dose).

[0308] Compounds A and B were synthesized as described in Examples 8 and 7 above, respectively. The peptide powders were stored at -20°C before use. Dexamethasone (Dex) was obtained from Shanghai Aladdin Bio-Chem Technology Co., Ltd., Shanghai, China. [Table 4]

[0309] The histological specimens were analyzed and scored as described above, as shown in Table 5 below. [Table 5]

[0310] Histological analysis results indicate that compounds A and B possess several anti-inflammatory effects compared to the model group.

[0311] Example 28 Acute wound model Male C57BL / 6 mice aged 6-8 weeks were used in Changzhou Cvens Exp. erimental Animal Co.Ltd(Changzhou, Jiangs The mice were supplied from U Province, China. Before each experiment, the mice were kept under standardized conditions of alternating light and dark cycles at a constant temperature of 22±2°C for 12 hours, and fed standard mouse feed with water for about a week.

[0312] General anesthesia was induced using intraperitoneal administration of 3% chloral hydrate (1 mL / 10 g body weight). The hair on the back was shaved with an infant hair trimmer and depilated with cream. The skin area was wiped clean and sterilized twice with 75% alcohol.

[0313] 12mm EMS skin biopsy punch (Electron Microscopy Sciences, POBox 550, 1560 Industry Road, Hat Using field (PA 19440), two rounded wounds were made along the midline of the back. The two wounds were tangential to each other, and the skin between the circles was cut along the upper and lower tangents. The wounds were trimmed with scissors. The entire thickness of skin was removed, reaching the fascia. The wounds were oval-shaped and left open without sutures.

[0314] As shown in Table 6 below, the following different drugs were administered topically once daily at a dose of 50 μL per wound from day 0 to day 7. The control group did not receive any wounds. The model groups were given the same amount of saline solution. Each group contained 10 mice, excluding the control group which had 5 mice.

[0315] Recombinant human epidermal growth factor (rhEGF, Shanghai Haohai Biolo The product was purchased from gical Technology Co. Ltd. (Shanghai, China) and prepared according to the manufacturer's instructions. Lyophilized rhEGF powder (100,000 IU / vial) was dissolved in 20 mL of physiological saline to prepare a solution with a concentration of 5,000 IU / mL. The dose of rhEGF for this experiment was 1,285 IU / wound. Compounds A and B were dissolved in physiological saline at the concentrations shown in Table 6 (L = low dose, M = medium dose, H = high dose). [Table 6]

[0316] Each wound was photographed every other day starting from day 0. The photographs were scanned into a computer, and the wound area was calculated using ImageJ image analysis software (National Institutes of Health).

[0317] The unhealed wound area was expressed as a percentage of the original wound area. A t / A0×100%, In the formula, A0 and A t These terms refer to the initial wound area on day 0 and the wound area on the measurement day (time t), respectively.

[0318] The rate of unhealed wounds is shown in Figure 1. All wounds in the test group healed faster than those in the model group. Compounds A and B appeared to significantly improve wound healing, particularly at medium concentrations of compound A and high concentrations of compound B.

[0319] Example 29 Diabetic wound model 8-12 week old male db / db mice (C57BL / KsJ-db / db, body weight 35-45g / mouse) were introduced at Changzhou Cvens Experimental. The mice were supplied by Animal Co. Ltd. Before conducting the experiment, the mice were housed under standardized conditions of alternating light and dark cycles for 12 hours at a constant temperature of 22±2°C and fed a standard mouse diet including water for approximately one week.

[0320] 3% of chloral hydrate in the peritoneal cavity (Sinopharm Chemical Reage General anesthesia was induced using nt Co., Ltd. (1 mL / 10 g body weight). The hair on the back was shaved with an infant hair trimmer and depilated with cream. The skin area was wiped clean and sterilized twice with 75% alcohol.

[0321] A rounded wound was made on the back using an 18mm diameter EMS skin biopsy punch. The entire thickness of the skin was removed, and the wound depth reached the fascia. The wound was left open without suturing.

[0322] As shown in Table 7 below, different drugs were administered topically once daily at a dose of 50 μL per wound from day 0 to day 18. The control group did not receive any wounds.

[0323] The model group was given the same amount of saline solution. Each group contained 12 mice, with the exception of the control group which had 8 mice. Skin samples taken during wound creation were used as samples from the control group on day 7.

[0324] Recombinant human epidermal growth factor (rhEGF) was purchased and prepared according to the manufacturer's instructions. Freeze-dried rhEGF powder (100,000 IU / vial) was dissolved in 20 mL of physiological saline to prepare a solution with a concentration of 5,000 IU / mL. The working dose of rhEGF in this experiment was 1,285 IU / wound.

[0325] Compounds A and B were dissolved in physiological saline at the concentrations shown in Table 7 below (L = low dose, M = medium dose, H = high dose). 50 μL of each solution was applied to the wound surface daily. [Table 7]

[0326] Vascular endothelial growth factor (VEGF) and transforming growth factor-beta-1 (TGF-β1) play important roles in the wound healing process. VEGF and TGF-β1 are often co-expressed in tissues where angiogenesis occurs. The levels of these two factors in wound tissue were also detected and are shown in Figures 2 and 3.

[0327] These results showed that the VEGF and TGF-β1 content in all test groups was higher than in the model group at different time points, indicating that compounds A and B stimulated the production of VEGF and TGF-β1.

[0328] Example 30 Mouse ear swelling model Thirty healthy male BALB / c mice, 6-8 weeks old and with an average weight of 18-25g, supplied by Changzhou Cvens Experimental Animal Co. Ltd., were reared and cared for for approximately one week prior to the experiment. The housing temperature was approximately 25-27°C, the humidity 74%, and the mice were given free access to food and water under alternating 12-hour light-dark cycles. The mice were randomly divided into six groups of five, as shown in Table 8. Compounds A and B were dissolved at the concentrations shown in Table 8 below (L = low dose, M = medium dose, H = high dose). [Table 8]

[0329] Hydrogels containing methylcellulose (2.5%), propanediol (11%), glycerol (11%), and the peptides listed in Table 8 were prepared, and the pH was adjusted to 5.5 by adding acetic acid (pH adjuster; 0-0.5 g). All excipients were Sinop Obtained from harm Chemical Reagent Co. Ltd. The gel was prepared with water for injection.

[0330] Dexamethasone Acetate Cream (Dex Cream; 5mg / 10g (meaning 5mg of Dex is contained in 10g of cream)), Fuyuan Pharmaceu Till Co., Ltd. (Anhui, China) was used as a positive control.

[0331] The left ear of each mouse was used as a self-control. The right ear of each mouse was treated with the compound described above at the stated concentrations (Table 8).

[0332] Approximately 0.1 g of various gels and Dex creams were applied to both the inner and outer surfaces of the right ear of mice in each group. A blank gel base was applied to the ears of the model group. After 1 hour, 20 μL of xylene (Shanghai Aladdin Bio-ChemTec) was added. The same ear of each mouse was treated with hnology Co., Ltd.

[0333] Mice were sacrificed by neck dislocation 40 minutes after xylene application. Both ears were amputated. Using an 8 mm diameter EMS skin biopsy punch, a portion of the ear was taken from the same site on both ears. Its weight was recorded, and the swelling rate was calculated as a percentage according to the following formula. (Weight of right ear - Weight of left ear) / Weight of left ear × 100%

[0334] The results are shown in Table 9 and Figure 4. [Table 9]

[0335] These results demonstrated that compounds A and B could significantly eliminate inflammation-induced edema.

[0336] Example 31 Preparation of films coated with compound A and compound B A 0.2 μm microfiltration membrane (Jinteng Corp, China) was cut into 2.5 cm diameter discs and placed in three different containers (10-15 discs each). Approximately 10 mL of 5 mg / ml stock solutions of compound A and compound B were added to each container, ensuring that all membranes were completely immersed. PBS buffer (pH 8.0) was added dropwise to the containers while shaking. The pH of the reaction mixture was checked periodically until it reached 7. The containers were carefully covered and shaken continuously for 8 hours. Next, the reaction mixture was poured out, and the membranes were washed with 5 mL of PBS buffer each time until the washing eluent was colorless. Finally, the membranes were dried in the shade. The resulting membranes coated with compound A and compound B were used for antioxidant testing.

[0337] The antioxidant capacity (AC) was measured using the modified DPPH (2,2-diphenyl-1-picrylhydrazyl) method (as described below). Each membrane was cut into equal weights and placed separately in 2 mL centrifuge tubes. A 0.1 mM solution of DPPH in methanol was prepared, and 600 μL of the DPPH solution was added to ensure that all components were completely immersed. The tubes were then kept at room temperature in the dark for 3 hours, followed by centrifugation for 5 minutes. 300 μL of the supernatant was added to a 96-well plate and measured at 517 nm using a microplate reader. The AC value for each membrane was calculated according to the formula shown below, where A0 is the absorbance of the DPPH solution only, and A m This represents the absorbance of each film sample. AC(%)=(A0-A m ) / A0×100%

[0338] The antioxidant properties of films coated with compounds A and B were tested on day 0 (D0), day 3 (D3), day 7 (D7), and day 10 (D10) to confirm their stability. The results are shown in Table 10. [Table 10]

[0339] These results demonstrate that both compound A and compound B can coat the film. The coated film possesses antioxidant properties that may last for at least 10 days.

[0340] Example 32 A rat model of croton oil-induced anal swelling. Croton oil mixture: 1 part distilled water, pyridine (Nanjing Chemical R eagent Co.,Ltd.) 4th Division, Ether (China Pharmaceutical) ical Group Chemical Reagents Co., Ltd.) 5 parts, and 6% croton oil (Shanghai Yuanye Biotechnolo It was prepared by mixing 10 parts of gy Co., Ltd. ether solution.

[0341] Six-to-eight-week-old Sprague Dawley (SD) rats with an average weight of 180-220g were supplied by Changzhou Cvens Experimental Animal Co. Ltd. (Changzhou, Jiangsu Province, China), and consisted of half males and half females. Before each experiment, the rats were housed under standardized conditions (a constant temperature of 22±2°C with alternating 12-hour light-dark cycles) and fed standard mouse diet with water for approximately one week.

[0342] Fifty-six mice were randomly divided into seven groups of eight mice each (as shown in Table 11 below). Compound A, Compound B, and MaYinglong hemorrhoid ointment were dissolved at the concentrations shown in Table 11 below (L = low dose, M = medium dose, H = high dose). [Table 11]

[0343] Rats were anesthetized by inhalation of isoflurane (China Pharmaceutical Group Chemical Reagents Co., Ltd). The skin around the anus was disinfected using a cotton ball soaked in 75% alcohol. Next, 0.16 mL of croton oil mixture was slowly dropped onto a cotton swab inserted 0.5 cm into the rat's anus. The rat was lifted and its head was kept upward (maintaining this position for 10 seconds), then the cotton swab was withdrawn and the croton oil mixture was evenly spread on the surrounding skin. The control group was given the same volume of olive oil.

[0344] One hour after modeling, rats from each group were treated according to Table 11. The positive control drug was MaYinglong hemorrhoid ointment (MaYinglong Pharmaceutical Group Co., Ltd.). Gels of compound A and compound B were prepared as described in Example 14. The drugs were administered twice daily, once in the morning and once in the evening, for three consecutive days.

[0345] 200 μL of the corresponding drug was drawn 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 portion of each test substance was applied to the skin around the anus. The skin around the anus was held firmly for 1 minute to prevent the drug from being expelled.

[0346] On the morning of the fourth day, 1% Evans blue (EB) was injected into the tail vein 30 minutes after drug administration (200 μL / 100 g). 30 minutes later, the rats were sacrificed by cervical dislocation.

[0347] Rats were placed supine on dissection plates, and their abdomens were opened. Rectal and anal tissue (15 mm in length) was isolated and weighed, and EB dye present in the tissue was extracted using 1 mL of formamide.

[0348] All samples were transferred to a 55°C water bath or heating block. EB was extracted from the tissue by 24-hour incubation. The formamide / EB mixture was centrifuged to pelletize any remaining tissue fragments. 500 μL of formamide was used as a blank, and absorbance was measured at 610 nm.

[0349] The EB content in rectal and anal tissue was calculated using the amount of EB exuded per 1 mg of tissue (in ng units), and vascular permeability was assessed. These results are shown in Figure 5, which demonstrate that gels of compound A and compound B can reduce inflammatory swelling caused by croton oil application, as indicated by the changes in EB content under various treatments. A decrease in EB concentration was an indicator of vascular permeability.

[0350] Example 33 Radiation proctitis A gel containing 0.5 g of compound C (see Example 12 above) was prepared, which also contained the following components: methylcellulose (2.2 g; Shandong Guangda Technology Development Co., Ltd., Shan Dong, China), glycerin (11 g), and propanediol (11 g; both Sinop It consists of harm Chemical Reagent Co. Ltd. and pure water (75.3g).

[0351] For a 1.5 mg / g gel, the amounts of compound C and water were adjusted accordingly.

[0352] 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.

[0353] Male Wistar rats weighing between 180 and 220 g were obtained from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. All animals were kept in standard cages with alternating 12-hour light / dark cycles, fed standard Rodent solid feed and tap water.

[0354] Rats were anesthetized by intraperitoneal injection of 10% chloral hydrate (3.3 mL / kg). The rats were restrained by their tails and limbs to a cardboard sheet in a supine position and secured with tape. Irradiation was performed using an Elekta Synergy medical linear accelerator (Elekta limited, UK). All animals except the sham group received a single continuous pelvic irradiation. The distance from the animals to the source was 100 cm. The radiation area was 2 cm × 5 cm 5 cm above the anal opening. The radiation dose was 17.5 Gy at a dose rate of 600 cGy / min.

[0355] After irradiation, the animals were returned to their cages for natural recovery. Animals in the sham surgery group ("sham") were anesthetized intraperitoneally without irradiation. The rats' daily feed intake and body weight were measured, and general observations were performed daily.

[0356] Day 1 (D1) was defined as the day of drug administration 24 hours after modeling. Blank gel was given to rats in the sham surgery group and the model group ("model"). Rats in the treatment group were given a rectal dressing containing either a high dose (1.5 mg / g; 'C-H') or a low dose (0.5 mg / g; 'C-L') of gel (300 μL / rat), once daily for 7 consecutive days (D1 to D7). To reduce intestinal motility and prolong the duration of gel in the rectum, all animals received daily intraperitoneal injections of 6 mL / kg of 5% chloral hydrate before administration. The drug was introduced approximately 6 cm into the rectum via an intragastric needle. Sampling was performed on day 8 (D8). Rats were fasted for at least 12 hours prior to administration.

[0357] After anesthetizing rats with intraperitoneal injection of chloral hydrate, they were frightened by posterior carotid artery phlebotomy. Approximately 7 cm of the colorectal canal was separated by about 0.3 cm from the end of the perianal fur. The specimens were trimmed, and 1 cm each of the proximal and distal colorectal samples were cut from the same human.

[0358] Next, the intestinal tract was incised longitudinally, photographed, and weighed. The specimens were fixed in a 10% formaldehyde solution for 48 hours, stained with HE, and then examined by a pathologist (who was unaware of the study) using a light microscope.

[0359] Each specimen was evaluated as follows: 0 = normal or minor changes that cannot be (definitely) attributed to radiation; 1 = slight radiation damage (mild inflammation and / or slight crypt changes); 2 = minor damage (more significant inflammation and / or crypt damage); 3 = moderate damage (significant epithelial loss, degree of inflammation must vary); and 4 = severe damage (ulceration, necrosis).

[0360] The weight gain rate on D8 (definition: weight on D8 - initial weight) / initial weight × 100%) is shown in Table 12 below. A higher rate indicates a better physiological condition. Compound C was dissolved at the concentrations shown in Table 12 below (L = low dose, H = high dose). [Table 12]

[0361] These results indicate that the gel containing compound C prevents weight loss caused by radiation proctitis in a dose-dependent manner.

[0362] Example 34 Radiation vaginitis A 45-year-old woman diagnosed with cervical cancer was treated with radiation therapy. The radiation was delivered using high-energy 6-12 MVX rays. The radiation dose was 1.8-2.0 Gy, five times per week. The radiation therapy was scheduled to be completed within four weeks.

[0363] Two weeks after her first radiation treatment, she began experiencing pain and eventually developed vaginal bleeding and ulcers. This was diagnosed as radiation vaginitis.

[0364] The patient began using a 1.5 mg / g x 3 g gel prepared as described in Example 33 above, which was filled into a special vaginal applicator. This was used twice a day during her radiation therapy. After three days, her bleeding stopped and her pain was reduced. After the completion of radiation therapy, she continued to use the gel for another two weeks. Her doctor examined her vagina and found that the ulcer had disappeared and there was no evidence of any other damage.

[0365] Example 35: A model of croton oil-induced anal swelling in rat II. The procedure essentially the same as that described in Example 32 above was carried out using the compound C gel described in Example 33 above on 50 rats randomly divided into five groups (using compound C at low and high doses of 0.5 mg / g instead of the corresponding compound A and compound B gels).

[0366] The EB content in rectal and anal tissue (8 mm in length) was calculated to evaluate vascular permeability, as in Example 32, and the results are shown in Figure 6. These results indicate that compound C gel reduces inflammatory swelling caused by croton oil application in a dose-dependent manner.

[0367] Example 36 Ulcerative colitis model A total of 50 SD rats were randomly divided into the following five groups, each containing 10 rats: (sham surgery (sham); model (blank gel; model); positive control (sulfasalazine, SSZ, 360 mg / kg; SSZ); compound C (1.5 mg / g dose (high)); and compound C (0.5 mg / g dose (low) (both prepared as described in Example 33 above))).

[0368] After 24 hours of fasting, the animals were anesthetized with isoflurane. Separately from the sham surgery group, the other four groups were perfused rectally with 0.5 mL of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 1 mL; Dalian Meilun Biotechnology Co., Ltd., China) via a latex hose under anesthesia in ethanol (6.05 mL; Shanghai Aladdin Biochemical Technology Co., Ltd., China) and 18.071 mL of sterile water (i.e., 18 mg TNBS / rat).

[0369] The length of the hose inserted into the rectum was approximately 8 cm. After removing the hose, the rats were kept under isoflurane anesthesia for another 15 minutes (modeling day was day 0), and then returned to their cages. The sham surgery group was given the same volume of saline solution.

[0370] On the day following modeling (day 1), after anesthesia (intraperitoneal injection of pentobarbital (35 mg / kg, 1.5%, 0.233 mL / 100 g)), the gel (model and compound group C) was administered rectally at a dose of 0.5 mL / rat. The anus was clamped for 1 hour after administration and then released. In the positive control group, sulfasalazine was administered orally to SSZs once daily for 7 consecutive days (days 1 to 7). The sham surgery group received no treatment.

[0371] The rats' overall condition, disease activity index (DIA), and body weight were observed daily. On the day following the final dose (day 8), the animals were dissected, the entire colonic tissue was removed, and the colonic contents were washed. After measuring body weight, the colon was opened longitudinally to reveal the ulcerative surface, which was measured, its general appearance evaluated, and photographed.

[0372] These results are shown in Figure 7 (body weight), Figure 8 (ulcerated surface), and Figure 9 (general appearance), respectively, demonstrating that compound C dose-dependently reduces the severity of TNBS-induced ulcerative proctitis and therefore may promote ulcer healing.

[0373] Example 37 Experimental gastric ulcer model In this experiment, which had 10 rats in each group, SPF-grade SD rats were used. According to the evaluation method for health foods for gastric ulcers issued by the China Food and Drug Administration, the protective effect of compound B against acute gastric ulcers induced by anhydrous alcohol was observed after 30 days of continuous forced feeding.

[0374] Various groups and dosages are shown in Table 13 below. [Table 13]

[0375] Omeprazole enteric-coated capsules (20 mg / capsule; Heilongjiang Norgas Pharmaceutical Co., Ltd., China) were opened, and the powder was dissolved in water to prepare a 2 mg / mL solution. Compound B (see Example 7 above) powder was dissolved in water to prepare two solutions with concentrations of 0.25 mg / mL and 0.75 mg / mL. The dosage was 2 mg / kg.

[0376] All drugs were administered orally once daily for 30 consecutive days, as shown in Table 13. The rats had free access to water. On day 30, the rats were fasted for 24 hours following the last drug administration. On day 31, 1.0 mL of anhydrous ethanol per rat was administered orally to each rat in all experimental groups except the control group.

[0377] One hour later, all rats were sacrificed and dissected to expose the intact stomachs, after which the pylorus was ligated. A 10% formaldehyde solution was administered to the stomachs by perfusion and fixed for 20 minutes. After fixation, the stomachs were separated and cut open along the larger curvature. The stomach contents were washed away from the lining with saline to reveal the gastric mucosa.

[0378] The length and width of gastric mucosal bleeding were measured using calipers under a stereomicroscope or with the naked eye. A score was assigned to assess the damage based on the evaluation criteria shown in Table 14 below. [Table 14]

[0379] The results are shown in Table 15 below. [Table 15]

[0380] These results indicate that compound B can reduce alcohol-induced gastric bleeding and thus protect the gastric mucosa.

[0381] Example 38 Intranasal radiation damage A 50-year-old male patient was diagnosed with sinus cancer and underwent radiation therapy. After two weeks of treatment, he developed inflammation in his nose and sinuses, feeling nasal congestion and shortness of breath. The mucus in his nasal cavity and sinuses became thicker and drier.

[0382] This patient used a nasal spray containing compound B (see Example 7 above) dissolved in water at a concentration of 0.5 mg / mL once every two hours during the day, and then refilled a nasal spray bottle. After three days, his nose was clear and he no longer experienced shortness of breath. He continued to use the nasal spray as his radiation therapy progressed, and his nasal discomfort did not worsen.

[0383] Example 39 Radiation stomatitis A 79-year-old male patient was diagnosed with oral cancer and underwent radiation therapy.

[0384] Three weeks later, oral mucositis developed, with ulcers forming on the mucous membranes of the mouth, throat, and esophagus. It was extremely painful, and the patient was unable to eat.

[0385] Next, the patient used compound B solution (0.5 mg / mL; prepared as described in Example 38 above) as a mouthwash as frequently as possible. Immediately after application, the pain was greatly relieved, and this relief sometimes lasted for 1-2 hours. As his treatment continued, the patient's stomatitis did not worsen.

[0386] Example 40 Postoperative pain and bleeding A 54-year-old man underwent surgery on his right leg to remove black tissue hyperplasia, as shown in Figure 10 (left pane). Immediately after the surgery, he applied a 0.5 mg / mL Compound B spray (described in Example 38, but packaged in a standard spray bottle) directly to the wound.

[0387] The pain on the right side of Figure 10 was photographed one hour after the surgery. The bleeding had stopped, and there was only slight pain. A week later, the wound had completely healed. The doctor stated that it usually takes at least 10 days for a patient to fully recover from such a procedure with standard care.

[0388] Example 41 Relief of itching A 36-year-old woman had suffered from hemorrhoids for many years. While she usually experienced no pain or bleeding, she was greatly troubled by itching. The patient also had constipation.

[0389] The patient began using compound C gel (0.5 mg / g x 3 g; see Example 33 above) packed in a rectal applicator, and she used it once a day before bedtime.

[0390] The next day, her itching lessened, and after a week it disappeared completely. At the same time, the patient's constipation became less frequent.

[0391] Example 42 ulcerative colitis A 39-year-old woman was diagnosed with an acute attack of ulcerative colitis. She had to go to the toilet more than 11 times a day and experienced severe bleeding from her colon.

[0392] She was treated with oral 5-aminosalicylic acid (also known as mesalazine or mesalamine) for three days, but her symptoms did not improve.

[0393] Subsequently, she was given the same compound C gel as described in Example 41 above, in the same dose, three times over the first two days.

[0394] The frequency of her need to go to the toilet decreased to 3-4 times a day. She continued using the gel once a day for another 7 days, after which her symptoms disappeared.

[0395] Example 43 Bioadhesives The experiment was conducted on rats. Two incisions, approximately 1 cm in size, were made on the left side of each SD rat (under isoflurane inhalation anesthesia). The left incision was left untreated, while the right incision was covered with a pinch of compound C powder. Each incision was closed with forceps for 10 seconds. The rats were then returned to their cages. After about 20 minutes, the rats woke up and moved around. The untreated wound had torn, while the treated wound remained closed. After 24 hours, both incisions had almost completely healed, with the treated wound being smoother than the untreated one. The photograph on the left (Figure 11) was taken immediately after the surgery, and the photograph on the right was taken 24 hours later.

[0396] Example 44 Preparation of the pre-crosslinked compound of the present invention using glutaraldehyde I React 100 mg of one of the peptides from SEQ ID NOs. 45, 48, 51, 57, 58, 63, 64, 69, or 70 with 2 to 100 mL of 0.01 to 0.5 M buffer containing 0.01% to 5.0% glutaraldehyde at different pH values ​​(approximately 3.0 to 8.0) (e.g., 0.01 M sodium acetate (pH 3.0), 0.1 M sodium acetate (pH 5.0), 0.2 M sodium phosphate (pH 6.0), 0.5 M sodium phosphate (pH 8.0)) at room temperature for 1 to 300 minutes. At the end of the reaction, add a certain amount of NaHSO3 (equivalent to 80% of the glutaraldehyde) to stop the reaction. Then, dialyze the preparation thoroughly against water to produce the corresponding title compound.

[0397] Example 45 Preparation of the pre-crosslinking compound of the present invention using glutaraldehyde II Following essentially the same method as described in Example 44 above, 100 mg of [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 63) is reacted with 10 mL of 0.1 M sodium acetate buffer (pH 5.0) containing 0.05% glutaraldehyde at room temperature for 10 minutes. The crosslinking range is detected by size exclusion chromatography (SE-HPLC).

[0398] Example 46 Preparation of the pre-crosslinking compound of the present invention using the amide formation method I Mix 100 mg of any one peptide from SEQ ID NOs. 45, 48, 51, 57, 58, 63, 64, 69, or 70 with 2 to 100 mL of pure water or 0.01 to 0.5 M buffer of different pH values ​​(approximately 3.0 to 8.0) (e.g., 0.01 M sodium acetate (pH 4.0), 0.05 M MES buffer (pH 5.0), 0.1 M MES buffer (pH 6.0), 0.5 M sodium phosphate (pH 7.0)) containing 1 to 500 mg of each condensing agent (e.g., N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC / NHS) or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM) or other water-soluble condensing agents) at room temperature for 0.5 to 72 hours. At the end of the reaction, the preparation is thoroughly dialyzed against water to remove DMTMM and yield the corresponding title compound.

[0399] Example 47 Preparation of the pre-crosslinking compound of the present invention using the amide formation method II Using essentially the same method as described in Example 46 above, 100 mg of [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 63) is reacted with 10 mL of 0.05 M MES buffer (pH 5.5) containing 100 mg of DMTMM at room temperature for 6 hours. The crosslinking range is detected by size exclusion chromatography (SE-HPLC).

[0400] Example 48 Preparation of the pre-crosslinking compound of the present invention using the DOPA oxidation method I React 100 mg of any one peptide, such as SEQ ID NOs. 45, 48, 51, 57, 58, 63, 64, 69, or 70, with 2 to 100 mL of pure water or 0.01 to 0.5 M buffer (approximately 3.0 to 8.0) with varying pH values ​​(e.g., 0.01 M sodium acetate (pH 5.0), 0.05 M MES buffer (pH 5.0), 0.5 M sodium phosphate (pH 7.0), 0.1 M Tris buffer (pH 8.0)) at room temperature for 0.5 to 72 hours. At the end of the reaction, add a 0.5% to 5% (v / v) 1 M HCl solution to the mixture to stop the reaction and produce the title compound before crosslinking.

[0401] Example 49 Preparation of the pre-crosslinking compound of the present invention using the DOPA oxidation method II Using essentially the same method as described in Example 48 above, 100 mg of [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 63) is reacted with 10 mg of mushroom tyrosinase (Sigma: T3824-250KU, 2687 units / mg) in 10 mL of phosphate buffer (100 mM, pH 6.5). The mixture is stirred for 2 hours. Then, 1.5 mL of 1 M HCl solution is added to the mixture to stop the reaction. The sample is taken for MALDI-TOF mass spectrometry analysis. These results indicate that the molecular weight of the product increases to 2–6 times the original molecular weight.

[0402] Example 50 Effect of the compound of the present invention on the activity of human influenza A virus H1N1 Serum-free 1640 medium (RPMI1640 medium; GIBCO / BRL; Thermo Fisher Scientific China, Nanjing, China) was prepared according to the manufacturer's instructions. Before use, newborn bovine serum (Zhejiang Tianhang Biotechnology Co. Ltd., Luoshe, China) was added to prepare a complete medium containing 10% serum, or the same serum was added at 2% to prepare a maintenance medium.

[0403] A 20 mg / mL stock solution was prepared by dissolving 40 mg of compound C in 2 mL of sodium chloride aqueous solution (AquaPro Injection, Jiangsu Hengrui Medicine Co., Ltd., Jiangsu Province, China).

[0404] 0.05 mL of stock solution was added to 1.95 mL of complete medium to formulate a 500 μg / mL drug solution (in antiviral tests No. 3 and 4 below, maintenance solution was used instead of complete medium). Diluted standard solutions at concentrations of 250, 125, 62.5, 31.25, 15.625, 7.8125, 3.9063, 1.9531, and 0.9766 μg / mL were prepared by 2-fold dilution.

[0405] Cytotoxicity of compound C Vero cells were seeded in a 96-well culture plate and grown in a monolayer. 0.2 mL of compound C was added per well at various concentrations (as described above). This was repeated in three wells at each concentration. The solvent and normal cell cultures were used as negative controls. The cells were cultured at 35°C (5% CO2) for 24 hours. 10 μl of Cell Counting Kit-8 (CCK-8, Sigma) was added to each well, mixed well, and cultured at 37°C for 2 hours. OD 450The absorbance values ​​(optical density) were detected by enzyme-linked immunosorbent assay. The cytotoxicity rate was calculated by setting the cell viability of untreated cells to 100%. Cytotoxicity rate (%) = (average absorbance of untreated cells - average absorbance of drug treatment wells) / average absorbance of untreated cells × 100%. The median lethal concentration (LC50) of the test drug was calculated. The results showed that compound C was not cytotoxic at the tested concentrations.

[0406] Effect of compound C on the cytotoxic activity of the virus after direct action on H1N1 Vero cells were seeded in 24-well plates and allowed to stand until a degree of fusion of 70%–80% was reached. The virus was mixed with various concentrations of the test drug. The final concentrations of compound C reached 2 μg / mL, 4 μg / mL, 8 μg / mL, 16 μg / mL, 32 μg / mL, 64 μg / mL, and 128 μg / mL. 0.1% SDS (manufactured by AMRESCO LLC, Solon, OH, USA, and packaged by Biosharp Company, Hefei, China; purity: 99%) was used as a positive control and mixed with the virus for 1 hour. After removing the cell culture medium and washing the cells three times with PBS, the virus / drug mixture was added and incubated for 1 hour. Untreated virus was used as a negative control. After 1 hour incubation, the cultures were washed three times with PBS and cultured continuously for 16–24 hours. RNA was extracted and fluorescence quantification was performed using a one-step QRT PCR kit to detect antiviral effects.

[0407] The viral inhibition rate was calculated. Cells in the non-drug challenge group were set up to be the same as 0%. Virus inhibition rate (%) = (1 drug treatment group viral RNA%) × 100%. The IC50 for a 50% effective concentration was calculated.

[0408] These results indicate that the IC50 for compound C in this study was >32 μg / mL.

[0409] Example 51 The effect of pre-administration of [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 63) on the pharmacokinetics of mesalazine. A solution of [(Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 63; hereinafter referred to as "sMAP"#) was prepared by weighing 22.5 mg and adding physiological saline up to 15 mL to a concentration of 1.5 mg / mL. Rats were treated by administering the test sample. Mesalazine suppositories were dissolved in a 40°C water bath to suspend the mesalazine suppositories.

[0410] Twelve SD rats (6 males, 6 females) were sent to the Beijing Vital River The rats were supplied by Laboratory Animal Technology Co., Ltd. and reared in a barrier facility for 7 days. The rearing temperature was 20-26°C, with alternating periods of 40-70% light and 12 hours of darkness, and the rats had free access to food and water. The rats were randomized into two groups, each containing 6 rats (3 males and 3 females), as described in Table 16 below. [Table 16]

[0411] Rats were anesthetized with 2% isoflurane inhalation. The rats were placed in a supine position, rectal-tip feces were pushed out, and the skin area around the anus was disinfected using a 75% alcohol cotton ball.

[0412] Group 1 was administered mesalazine suppository suspension directly, while Group 2 was treated with sMAP solution enema for 15 minutes before being administered mesalazine suppository suspension (details of enema dosage and administration method are shown in Table 17 below). [Table 17]

[0413] The airbag cavity was retracted using a 2 mL syringe, and after filling with water, it was confirmed that there was no air inside the airbag. A catheter (2-WAY 8Ch / Fr3-5 mm) was inserted into the rat's anus to a depth of approximately 3 cm (the catheter tip was cut 2 cm from the end of the balloon, below the position of the urethral catheter tip, making it as short as possible while maintaining the integrity of the air cavity. The guidewire was removed, and the urethral catheter was sealed with neutral glass adhesive, ensuring a smooth sealed end to reduce damage to the rectal mucosa). Using a 1 mL syringe, the mesalazine suppository suspension was drawn up into a disposable force-feeding needle (soft needle) and inserted into the anus (approximately 3.5 cm), and the contents of the 200 μL syringe were slowly pushed into each rat.

[0414] The skin around the anus was held to secure the catheter and forced oral administration needle, and 1 mL of water was injected into the airbag cavity with a 2 mL syringe to expand it. After that, the needle was quickly released and observed for any gel leakage.

[0415] After injection, the catheter was secured by wrapping adhesive tape around the tail ridge (the catheter was incised approximately 3-5 cm from the anus, ligated, cut, and secured by wrapping adhesive tape around the tail ridge. The pressure-sensitive adhesive tape was secured based on the criteria for a urethral catheter that is not loose, and this must not be too tight for the animal to bite and cause discomfort. The catheter needed to be secured twice with tape; the catheter was tied the first time, and the remaining catheter was secured to the end of the tail the second time. The 3 cm mark on the catheter should be at the anus, and the catheter should not be removed while the knot was tied). After administration, the rats were returned to their cages.

[0416] To extend the retention time of the drug in the animals' bodies, an anal plug was kept in the rectum for 4 hours. The anal plug was dropped in within 4 hours of drug administration, and the approximate time of descent was recorded.

[0417] Blood samples were processed by coating all centrifuge tubes with EDTA-K2 and storing them in a light-protected refrigerator (2-8°C) or ice-filled cooler before use. The collected blood was transferred to the centrifuge tubes, manually mixed by inverting the tubes at least five times, and then stored in a light-protected icebox. Subsequently, within two hours of blood collection, the samples were centrifuged at 1800g for 10 minutes at 2-8°C. After centrifugation, the collected plasma samples were transferred to newly labeled centrifuge tubes, dispensed into two sets, and stored below -70°C, away from light.

[0418] Plasma concentrations of mesalazine were analyzed using LC-MS / MS. AUC, Cmax, Tmax, and any other parameters as needed were calculated using WinNonlin software. Statistical analysis of the data, such as mean, standard deviation (SD), and coefficient of variation (CV), was performed using Microsoft Office Excel. Differences in pharmacokinetic parameters between the two groups were compared.

[0419] Detailed pharmacokinetic parameters are shown in Table 18 below. The plasma concentration versus time curve is shown in Figure 12. [Table 18]

[0420] The result was C of mesalazine in group 2. max and AUC last This indicates that the levels are lower than those in group 1. The results show that when mesalazine and sMAP (SEQ ID NO: 66) are co-administered to rats, sMAP reduces the absorption and systemic exposure of mesalazine, improves safety, and extends the residence time of local administration, thereby improving local efficacy.

[0421] Example 52 Effect of pre-administration of the compound of the present invention on the pharmacokinetics of montelukast The experiment was carried out in the same manner as in Example 51, except that a montelukast sodium suspension was used instead of a mesalazine suppository suspension.

[0422] Montelukast sodium suspension was prepared by weighing an appropriate amount of montelukast sodium and adding it to water to a concentration of 1 mg / mL. A combined formulation was prepared by weighing an appropriate amount of montelukast sodium and synthetic MAP, and this was added to water to obtain a suspension containing 1 mg / mL of montelukast sodium and 1.5 mg / mL of sMAP, which was used immediately after preparation.

[0423] Twelve SD rats (6 males, 6 females) were brought to the Beijing Vital River The rats were supplied by Laboratory Animal Technology Co., Ltd. and reared in a barrier facility for 7 days. The rearing temperature was 20-26°C, with alternating periods of 40-70% light and 12 hours of darkness, and the rats had free access to food and water. The rats were randomized into two groups, each containing 6 rats (3 males and 3 females), as described in Table 19 below. [Table 19]

[0424] The administration of the dose, as well as the collection of blood samples and pharmacokinetic analysis, were carried out in the same manner as in Example 51. Detailed pharmacokinetic parameters are shown in Table 20 below, and the plasma concentration-time curve is shown in Figure 13. [Table 20]

[0425] The result was C from Montelukast in Group 2. max and AUC last This indicates that it is lower than that of Group 1. The results show that when montelukast is administered to rats in combination with sMAP (SEQ ID NO: 66), sMAP reduces the absorption and systemic exposure of montelukast, improves safety, and extends the residence time of local administration, thereby improving local efficacy.

[0426] Example 53 Pre-administration of the compound of the present invention that affects the stability and / or pharmacokinetics of different drugs. A solution of sMAP was prepared by weighing 22.5 mg and adding it to 15 mL of normal physiological saline to a concentration of 1.5 mg / mL. Rats were treated by administering the test samples. Test sample 1 was a 5-aminosalicylic acid (mesalazine) suppository, which was dissolved in a 40°C water bath. Test sample 2 was montelukast sodium gel prepared as described in Example 52.

[0427] 18 SD rats (9 males, 9 females) were sent to the Beijing Vital River The rats were supplied by Laboratory Animal Technology Co., Ltd. and reared in a barrier facility for 7 days. The rearing temperature was 20-26°C, the humidity was 40-70%, and there were alternating 12-hour periods of light and darkness. Food and water were freely available. As shown in Table 21, the rats were randomly divided into three groups of 6 rats each (3 males and 3 females per group). [Table 21]

[0428] Rats were anesthetized by 2% isoflurane inhalation. The rats were placed in a supine position, rectal end feces were pushed out, and the perianal skin area was disinfected with a 75% alcohol cotton ball. After treating the animals with MAP solution enema for 15 minutes, the first group was given a 5-aminocyclic acid (mesalazine) suppository suspension directly, and the second and third groups were given montelukast sodium gel and 5-aminocyclic acid (mesalazine) suppository suspension (details of enema dosage and method are shown in Table 17 below). [Table 22]

[0429] The airbag cavity was retracted using a 2 ml syringe, and after filling with water, it was confirmed that there was no air inside the airbag. A catheter (2-WAY 8Ch / Fr3-5 mm) was inserted into the rat anus to a depth of approximately 3 cm (2 cm from the end of the balloon), the tip of the catheter was cut below the position of the urethral catheter tip, making it as short as possible while maintaining the integrity of the air cavity, the guidewire was removed, and the urethral catheter was sealed with neutral glass adhesive to ensure a smooth sealed end to reduce damage to the rectal mucosa). Using a 1 ml syringe, montelukast sodium gel (UP-611 gel (5 mg / g)) and 5-aminocyclic acid (mesalazine) suppository suspension (respectively) were drawn into disposable garbage needles (soft needles) and inserted into the anus (approximately 3.5 cm), and the contents of the 200 μL syringe were slowly pushed into each rat.

[0430] The skin around the anus was held to secure the catheter and forced oral administration needle, and 1 mL of water was injected into the airbag cavity with a 2 mL syringe to expand it. After that, the needle was quickly released and observed for any gel leakage.

[0431] After injection, the catheter was secured by wrapping adhesive tape around the tail ridge (the catheter was incised approximately 3-5 cm from the anus, ligated, cut, and secured by wrapping adhesive tape around the tail ridge. The pressure-sensitive adhesive tape was secured based on the criteria for a urethral catheter that is not loose, and this must not be too tight for the animal to bite and cause discomfort. The catheter needed to be secured twice with tape; the catheter was tied the first time, and the remaining catheter was secured to the end of the tail the second time. The 3 cm mark on the catheter should be at the anus, and the catheter should not be removed while the knot was tied). After administration, the rats were returned to their cages.

[0432] To extend the retention time of the drug in the animals' bodies, an anal plug was kept in the rectum for 4 hours. The anal plug was dropped in within 4 hours of drug administration, and the approximate time of descent was recorded.

[0433] Blood samples were processed by coating all centrifuge tubes with EDTA-K2 and storing them in a light-protected refrigerator (2-8°C) or ice-filled cooler before use. The collected blood was transferred to the centrifuge tubes, manually mixed by inverting the tubes at least five times, and then stored in a light-protected icebox. Subsequently, the samples were centrifuged at 1800 rpm for 10 minutes at 2-8°C within two hours of blood collection. After centrifugation, the collected plasma samples were transferred to newly labeled centrifuge tubes, dispensed into two sets, and stored below -70°C, away from light.

[0434] Pharmacokinetic Analysis: Plasma concentrations of 5-aminocyclic acid (mesalazine) and montelukast were analyzed using LC-MS / MS and associated standard operating procedures (SOPs). AUC, Cmax, Tmax, and any other parameters as needed were calculated using WinNonlin software. Microsoft Of fice Excel will be used for data statistical analysis, including mean, standard deviation (SD), and coefficient of variation (CV). Differences in pharmacokinetic parameters between the control group and the MAP enema group will be compared. Detailed analysis documentation will be retained in the study file.

[0435] Example 54 Compounds of the present invention for use as coatings Prepare 0.01-0.5M buffer solutions with various pH levels (6.0-9.0), including 0.01M sodium phosphate (pH 6.0), 0.1M sodium bicarbonate (pH 8.5), 0.2M sodium carbonate (pH 9.0), and 0.5M sodium phosphate (pH 7.0).

[0436] The buffer is added to the container whose surface (e.g., cell culture surface) will be coated. The volume to immerse the surface to be coated and the total area covered by the buffer are calculated. 90% of the total volume required (to coat the surface) is covered with the buffer, and the remaining 10% of the total volume is covered with a solution (at various concentrations, e.g., 1 μg / mL to 100 mg / mL) of one or more compounds of the present invention (SEQ ID NOs. 48, 51, 54, 60, 61, 66, 67, 72, 73, etc.) or a pre-crosslinked version (see above).

[0437] Thoroughly mix the buffer solution and the compound of the present invention in the container (i.e., the coating solution), and leave it to coat the surface at 4-80°C for about 10 minutes to 48 hours. Then, pour out or transfer the coating solution and wash the surface with water (using the same total amount as the coating solution).

[0438] Coating density (mg / cm³) 2 ) is the total amount (mg) of added or pre-crosslinked sMAPs covered by the solution (cm²). 2 It can be roughly calculated by dividing by ).

[0439] Example 55 {[(DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 70) coated cell culture plate Using essentially the same method as described in Example 54 above, a 0.1 M sodium bicarbonate (pH 8.5) solution was newly prepared by dissolving 8.4 g of sodium bicarbonate in pure water to a total volume of 1 L, with the pH of the solution being approximately 8.5.

[0440] Prepare two Corning Coaster 24-well cell culture plates. 400 μL of solution per well is sufficient to coat the bottom of each cell culture plate. The total surface area covered by the solution is approximately 3 cm². 2Add 360 μL of 0.1 M sodium bicarbonate (pH 8.5) solution (prepared as described above) to each well to be coated.

[0441] Prepare 10 mL of {[(DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys}2-Lys (SEQ ID NO: 70) solution at concentrations of 2.25 mg / mL and 1.125 mg / mL by dissolving 22.5 mg and 11.25 mg of peptide, respectively, in pure water to a final volume of 10 mL. Add 40 μL of the 2.25 mg / mL peptide solution to one Corning Coaster 24-well cell culture plate pre-filled with 0.1 M sodium bicarbonate (pH 8.5) solution and mix thoroughly. Add 40 μL of the 1.125 mg / mL peptide solution to another Corning Coaster 24-well cell culture plate pre-filled with 0.1 M sodium bicarbonate (pH 8.5) solution and mix thoroughly. Then, leave both plates at room temperature to coat with the solutions for 18 hours. Pour out the coating solution and rinse the coated wells once with the same amount of distilled water as the coating solution.

[0442] Coating density of coated cell culture plates (mg / cm³) 2 ) is calculated by dividing the total amount of added peptide (mg) by the total area (cm²) covered by the solution. 2 It can be roughly calculated by dividing by ). As a result, the coating density is 30 μg / cm³ each. 2 and 15 μg / cm³ 2 It will become.

[0443] Example 56 The compound of the present invention as a carrier for heparin sodium for blood transfusion management A 1 mg / mL solution of [(DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys)2-Lys]2-Lys (SEQ ID NO: 64) is obtained by dissolving it in purified water using the method described in Example 55 of the previous examples.

[0444] The peptide solution is injected into the catheter at a flow rate of 0.5 mL / min, and the solution is left in the catheter for 30 minutes to dry at room temperature.

[0445] Heparin sodium powder (185 USP units / mg, Aladdin) is prepared as a 200 μg / ml solution in normal physiological saline. The heparin sodium solution is pumped into a catheter containing a peptide layer at a flow rate of 0.1 mL / min. The heparin sodium is adsorbed to the inner wall of the catheter by electrostatic interaction.

[0446] Catheters prepared using the method described above can be used in blood transfusion systems such as ECMO.

[0447] Example 57 Preparation of omeprazole enteric-coated tablets Each tablet contains 7.5 mg of sMAP and 20 mg of omeprazole. The formulation is based on 10,000 tablets. Table 21 shows the various steps and amounts of each component in the formulation. [Table 23-1] [Table 23-2]

[0448] Omeprazole granules Disodium hydrogen phosphate and Tween 80 are dissolved in purified water by stirring. Omeprazole is added and the mixture is mixed uniformly. Microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose are added to the mixture, then the prepared omeprazole solution is added, the mixture is stirred uniformly, granulated, dried, and left to stand.

[0449] Omeprazole particle-coated spacer Hydroxypropyl methylcellulose is slowly added to purified water and stirred until clear and transparent. The omeprazole granules are placed in a coating machine for coating. After coating, the material is dried at 40-50°C.

[0450] sMAP granules Dissolve sMAP in purified water and stir to dissolve it. After mixing the proportions of microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose, add the prepared sMAP solution, granulate, dry, and pelletize.

[0451] tablet After mixing omeprazole-coated granules with sMAP granules, magnesium stearate is added, the suspension is mixed, and then compressed.

[0452] Separation coating Slowly add hydroxypropyl methylcellulose to purified water and stir the mixture until clear and transparent. Coat the omeprazole tablets in a coating machine and then dry them.

[0453] Enteric coating Dissolve polyethylene glycol in purified water. Add Eudragit l30d-55 ss, stir the mixture uniformly, and sift it. Place the cores in a coating pot, coat them, dry them, and sample them for testing.

[0454] Example 58 Preparation of famotidine enteric-coated tablets Each tablet contains 7.5 mg of sMAP and 20 mg of famotidine. The formulation is based on 10,000 tablets. Table 22 shows the various steps and amounts of each component in the formulation. [Table 24]

[0455] Famotidine granules Add Tween 80 to purified water and stir to dissolve. Add famotozine uniformly to the mixture. After adding microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose to the mixture, add the prepared omeprazole solution, stir the mixture uniformly, granulate, dry, and let stand.

[0456] sMAP granules Dissolve sMAP in purified water and stir until dissolved. After mixing microcrystalline cellulose, mannitol, lactose, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose, add the prepared sMAP solution, granulate, dry, and pelletize.

[0457] tablet Mix the famotidine granules with the sMAP granules. Add magnesium stearate, mix the mixture, and then compress it.

[0458] Separation coating Slowly add hydroxypropyl methylcellulose to purified water and stir until clear and transparent. Place the famotidine tablets in a coating machine, coat them, and dry them.

[0459] Enteric coating Dissolve polyethylene glycol in purified water, add Eudragit l30d-55, stir the mixture uniformly, and sift it. Place the cores in a coating pot, coat them, dry them, and sample them for testing.

[0460] Example 59 Preparation of omeprazole enteric-coated capsules Each capsule contains 7.5 mg of sMAP and 20 mg of omeprazole. The formulation is calculated based on 10,000 tablets. Table 25 shows the various steps and amounts of each component in the formulation. [Table 25]

[0461] Omeprazole granules Add disodium hydrogen phosphate and Tween 80 to purified water and stir to dissolve. Add omeprazole and stir the mixture to disperse uniformly. Add microcrystalline cellulose, dextrin, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose to the mixture, and then add to the solution for granulation, drying, and pelletization. Let it stand.

[0462] Omeprazole package spacer Slowly add hydroxypropyl methylcellulose to purified water and stir until clear and transparent. Place omeprazole granules into a coating machine for coating. After coating, dry the material at 40-50°C.

[0463] sMAP granules SMAP was dissolved in purified water and stirred until dissolved. Microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose were mixed and added to the solution, after which granulation, drying, and pelletizing were performed.

[0464] Filled capsule Mix the omeprazole-coated particles and sMAP granules. Add magnesium stearate, then fill the enteric-coated capsules with the mixture.

[0465] Example 60: Preparation of famotidine enteric-coated capsules Each capsule contains 7.5 mg of sMAP and 20 mg of famotidine. The formulation is based on 10,000 pills. Table 26 below shows the various steps and amounts for adding each component to the formulation. [Table 26]

[0466] Famotidine granules Add Tween 80 to purified water and stir to dissolve. Add Modine evenly to the mixture. Mix microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose, then add to the solution, followed by granulation, drying, and pelletization. Allow to stand.

[0467] Separation layer coated with famotidine granules Slowly add hydroxypropyl methylcellulose to purified water and stir until the mixture is clear and transparent. Place famotidine granules into a coating machine for coating. After coating, dry the material at 40-50°C.

[0468] sMAP granules SMAP was dissolved in purified water, and the mixture was stirred to dissolve it. Microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose were mixed and then added to the solution, after which granulation, drying, and pelletization were performed.

[0469] Filled capsule Mix famotidine granules and sMAP granules. Add magnesium stearate, and then use the mixture to fill enteric coated capsules.

[0470] Example 61 Preparation of omeprazole / sMAP capsules for use in proctitis Table 27 below shows the various steps and amounts for adding each component to the formulation. [Table 27]

[0471] Omeprazole granules Disodium hydrogen phosphate and Tween 80 were added to purified water. The mixture was stirred to dissolve. Omeprazole was stirred into the mixture to disperse it uniformly. Microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose were mixed and then added to the solution, after which granulation, drying, and pelletization were performed. It was then left to stand.

[0472] Omeprazole particle-coated spacer Hydroxypropyl methylcellulose was slowly added to purified water, and the mixture was stirred until it became clear and transparent. Omeprazole granules were placed in a coating machine for coating. After coating, the material was dried at 40-50°C.

[0473] sMAP granules SMAP was dissolved in purified water and stirred until dissolved. Microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose were mixed and then added to the solution, after which granulation, drying, and pelletization were performed.

[0474] Filled capsule After mixing omeprazole-coated granules and sMAP granules, magnesium stearate was added to the mixture, and then hydroxypropyl methylcellulose hollow capsules were filled with the mixture.

Claims

1. Compound of formula I A-Q-B I And in the formula, A and B are independent of Z or A １ - Q １ -B １ This represents, Q is Equation II 【Chemistry 1】 This represents a structural fragment of the formula, in which, The wavy line represents the connection point from Q to A and / or B. m represents an integer from 1 to 4. A １ and B １ Independently, Z or A ２ - Q ２ -B ２ This represents, A ２ and B ２ each independently represents Z or Z-Q ３ -Z, Q １ Q ２ and Q ３ Independently, Equation III 【Chemistry 2】 This represents a structural fragment of the formula, in which, The dashed line adjacent to the NH element is Q １ Q ２ and Q ３ From A １ and / or B １ A ２ and / or B ２ These represent the connection points to Z, respectively. The dash adjacent to the O atom is Q １ Q ２ , and Q ３ Q, Q １ and Q ２ These represent the connection points to each, m is as defined above, Each time it is used, Z is the amino acid sequence [W-Lys-X １ -Ser-U-X ２ -Y] ｎ -W-Lys-X １ -Ser-U-X ２ -Y--- (Sequence No. 3) Represents the peptide component, in the formula, The dashed line represents the Z bond point to the rest of this molecule. n represents an integer from 0 to 4. Each time it is used, W represents a sequence of one or two amino acids, wherein the amino acids are selected from one or more of the group consisting of Lys, Ala, DOPA, and 3,4-dihydrocinnamic acid (HCA) residues, provided that, if present, the HCA residue is located at the N-terminus of peptide sequence Z. X １ This represents Pro, Hyp, or jiHyp, U stands for Tyr or DOPA, X ２ This represents Ser, Pro, Hyp, or jiHyp. Y represents a sequence of 1 to 5 amino acids, and the amino acids are selected from one or more of the group Lys, Ala, Pro, Hyp, diHyp, Thr, DOPA, and Tyr, in a compound. Also, stereoisomers of the compound, and pharmaceutically or cosmetically acceptable salts.

2. The compound according to claim 1, wherein m represents 4.

3. Both A and B represent Z, or both are A １ -Q １ -B １ A compound according to claim 1 or 2, which represents the compound described in claim 1 or 2.

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

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

6. A compound according to any one of claims 1 to 5, wherein n represents 0.

7. X １ A compound according to any one of claims 1 to 6, wherein Pro is represented.

8. X ２ A compound according to any one of claims 1 to 7, wherein the compound represents Hyp.

9. The compound according to any one of claims 1 to 8, wherein W is selected from the group consisting of HCA, HCA-Ala-, Ala, DOPA, Lys-Ala, and DOPA-Ala.

10. The compound according to any one of claims 1 to 9, wherein Y represents a sequence of four amino acids, and the amino acids are selected from one or more of the group consisting of Lys, Ala, Hyp, Thr, DOPA, and Tyr.

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

12. The compound according to claim 10 or 11, wherein the amino acid sequence defined by Y is selected from the group consisting of -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys-, and -Thr-Ala-Hyp-Lys-.

13. The compound according to any one of claims 1 to 10, wherein the amino acid sequence defined by Y is selected from the group -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

14. The compound according to any one of claims 1 to 13, wherein U represents Tyr.

15. The compound according to any one of claims 1 to 14, wherein W represents Ala or Lys-Ala-.

16. Z is Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys --- (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA---(SEQ ID NO: 6), Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys- (SEQ ID NO: 7), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-H yp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 8), Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr --- (SEQ ID NO: 9), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 10), and A compound according to any one of claims 1 to 15, selected from the group Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(SEQ ID NO: 11).

17. W is HCA, A compound according to any one of claims 1 to 14, representing HCA-Ala-, DOPA, or DOPA-Ala-.

18. Z is HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 13), HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 14), HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 15), DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 16), DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 17), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(Sequence ID 18), and A compound according to claim 17, selected from the group DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 19).

19. The compound according to any one of claims 1 to 13, 15, or 17, wherein U represents DOPA.

20. Z is Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 20), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 21), Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 22), Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 23), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 24), and A compound according to claim 19, selected from the group Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 25).

21. Z is HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 26), HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 27), HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 28), HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 29), DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 30), DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 31), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 33), and A compound according to any one of claims 1 to 13, 17, or 19, selected from the group DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(SEQ ID NO: 34).

22. Both A and B represent Z, and one or both Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 15), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-- (SEQ ID NO: 18), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 20), Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 22), HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 26), DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 31), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 2), or This represents Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys--- (Sequence ID 1), A compound according to any one of claims 1 to 21, wherein Q represents a Lys fragment.

23. Both A and B are A １ - Q １ -B １ This represents A １ and B １ Both represent Z, and one or both Z groups Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 11), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 13), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 18), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 20), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 21), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 10), HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 28), DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 30), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 2), or This represents Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys--- (Sequence ID 1), Q １ The compound according to any one of claims 1 to 21, wherein the compound represents a Lys fragment.

24. Both A and B are A １ - Q １ -B １ This represents A １ and B １ Both are A ２ - Q ２ -B ２ This represents A ２ and B ２ Both represent Z, and one or both Z groups Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 18), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 21), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys--(SEQ ID NO: 19) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 2), or This represents Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys--- (Sequence ID 1), Q １ and Q ２ The compound according to any one of claims 1 to 21, wherein both of the components represent a Lys fragment.

25. Both Z groups, Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys --- (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 4), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 5), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 12), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 18), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 20), or DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 32) A compound according to any one of claims 22 to 24, which represents the compound described in that claim.

26. amino acid sequence [Ala-Lys-X １ -Ser-U-X ２ -Y] ｐ -Ala-Lys-X １ -Ser-U-X １ -Y-G (SEQ ID NO: 35) A peptide compound of which, in the formula, p represents an integer from 1 to 4, G is either absent or represents DOPA or dopamine. X １ , U, X ２ and Y are peptide compounds as described in any one of claims 1 to 14 or 19. Also, stereoisomers of the compound, and pharmaceutically or cosmetically acceptable salts.

27. The compound according to claim 26, wherein n is 1 or 4.

28. amino acid sequence Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID NO: 36), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 37), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 38), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 39), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 40), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 41), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-L ys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 42), or Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 43) The compound according to claim 26 or 27, wherein the compound is as described above.

29. A compound according to any one of claims 1 to 28, for use in human or veterinary pharmaceuticals.

30. A compound according to any one of claims 1 to 28, for use as a pharmaceutical product.

31. A pharmaceutical preparation comprising the compound described in any one of claims 1 to 28.

32. The pharmaceutical formulation according to claim 31, further comprising a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

33. The pharmaceutical formulation according to claim 31 or 32, wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier is suitable for topical administration, is adapted and / or presented in packaging, and is a topical adjuvant, diluent or carrier.

34. A pharmaceutical preparation according to any one of claims 31 to 33, in the form of a gel, spray, cream, ointment, or dry powder.

35. A pharmaceutical preparation according to any one of claims 31 to 34, further comprising a pharmaceutical active ingredient or a further pharmaceutical active ingredient.

36. It is a parts kit, and its components are: (A) A compound according to any one of claims 1 to 28, or a pharmaceutical preparation according to any one of claims 31 to 34, (B) A pharmaceutical preparation comprising a pharmaceutically active ingredient or a further pharmaceutically active ingredient mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, A parts kit in which components (A) and (B) are provided in a form suitable for administration in combination with the other.

37. The pharmaceutical formulation according to claim 35, or the parts kit according to claim 36, wherein the pharmaceutically active ingredient is an anti-inflammatory agent, an anti-inflammatory agent, an antibiotic, an antibacterial agent and / or an antiparasitic agent, an antiviral agent, an anesthetic agent and / or a wound healing agent.

38. The pharmaceutical formulation or parts kit according to claim 37, wherein the pharmaceutically active ingredient is an anti-inflammatory agent.

39. A compound according to any one of claims 1 to 28, a formulation according to any one of claims 31 to 35, 37 or 38, or a parts kit according to any one of claims 36 to 38, for use in the treatment of inflammation, inflammatory disorders and / or disorders characterized by inflammation.

40. Use of a compound according to any one of claims 1 to 28, a formulation according to any one of claims 31 to 35, 37 or 38, or a parts kit according to any one of claims 36 to 38 for manufacturing a drug for the treatment of inflammation, inflammatory disorders and / or disorders characterized by inflammation.

41. The compound, formulation, or parts kit according to claim 39, wherein the injury characterized by inflammation is a wound or burn, or causes such a wound or burn.

42. The compound, formulation, or parts kit according to claim 41, wherein the disorder causing the wound is hemorrhoids or ulcerative colitis.

43. The compound, formulation, or parts kit according to any one of claims 29 to 42, wherein the compound or a salt thereof is administered locally in the form of a topical formulation.

44. The compound, formulation, or parts kit according to claim 43, wherein the associated pathological condition is treated by direct topical administration to the skin.

45. The compound, formulation, or parts kit according to claim 43, wherein the associated pathological condition is treated by direct local administration to the mucosal surface.

46. The compound, formulation, or parts kit according to any one of claims 29 to 45, wherein the compound is administered by oral, intravenous, skin or subcutaneous, nasal, intramuscular, intraperitoneal, lung, or anorectal delivery.

47. A compound, formulation, or parts kit according to any one of claims 35 to 46, wherein the compound according to any one of claims 1 to 28 functions as an excipient, as a medical device, or as a component of a medical device in a drug-medical device combination.

48. The compound, formulation, or parts kit according to any one of claims 35 to 47, wherein the compound is as described in any one of claims 1 to 13 or 17 to 26, or the compound is as described in claim 27 or 28, W is as described in claim 17, and / or U is as described in claim 19, and is crosslinked before or after administration to a subject.

49. The compound according to claim 48, for use as an adhesive or a film-forming material.

50. The compound according to claim 49, wherein the use is as a wound surface repair product, a wound surface protection product, a medical biological adhesive product, a medical coating product, an industrial coating product, a biochemical reagent, a medical product, a sterilization product, or as a culture vessel for cell culture.

51. The compound according to claim 49 or 50, wherein a film is formed on the surface of a skin or mucous membrane wound to aid in healing.

52. The compound according to any one of claims 49 to 51, wherein the use is in the closure of a surgical incision, bonding of fractured bones, bonding of mucous membranes, or coating of a human implant.

53. A pharmaceutical formulation comprising the compound described in claim 49 and a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

54. The pharmaceutical formulation according to claim 53, wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier is suitable for topical administration, is adapted, and / or presented in packaging, and is a topical adjuvant, diluent, or carrier.

55. A pharmaceutical formulation according to claim 53 or 54, in the form of a gel, spray, cream, ointment, or dry powder.

56. The use according to claim 40, wherein the injury characterized by inflammation is a wound or burn, or causes such a wound or burn.

57. The use according to claim 56, wherein the disorder causing the wound is hemorrhoids or ulcerative colitis.

58. The use according to any one of claims 40, 56, or 57, wherein the compound or a salt thereof is administered topically in the form of a topical formulation.

59. The use according to claim 58, wherein the related pathological condition is treated by direct topical administration to the skin.

60. The use according to claim 58, wherein the related pathological condition is treated by direct local administration to the mucosal surface.

61. The use according to any one of claims 40 or 56-60, wherein the compound is administered by oral, intravenous, skin or subcutaneous, nasal, intramuscular, intraperitoneal, lung, or anorectal delivery.

62. The use according to any one of claims 1 to 28, wherein the compound functions as an excipient, as a medical device, or as a medical device component of a drug-medical device combination, according to claim 40 or any one of claims 56 to 61.

63. The compound is as described in any one of claims 1 to 13 or 17 to 26, or the compound is as described in claim 27 or 28, W is as described in claim 17, and / or U is as described in claim 19, and is crosslinked before or after administration to a subject, as described in claim 40 or any one of claims 56 to 62.

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