New multi-functional oligopeptides
Patent Information
- Application Number
- EP2024710609
- Authority / Receiving Office
- EP · EP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-10-23
- Filing Date
- 2024-02-13
- Publication Date
- 2025-12-24
Smart Images
Figure CN2024077176_22082024_PF_FP
Abstract
Description
NEW MULTI-FUNCTIONAL OLIGOPEPTIDESField of the Invention
[0001] This invention relates to new peptides, the use of such peptides in human medicine, as pharmaceutically-active ingredients or otherwise, and to pharmaceutical compositions comprising them. In particular, the invention relates to the use of those peptides and compositions in the treatment of various conditions including inflammation.Background and Prior Art
[0002] Inflammation is typically characterized as a localised tissue response to e.g. invasion of microorganisms, certain antigens, damaged cells or physical and / or chemical factors. The inflammatory response is normally a protective mechanism which serves to destroy, dilute or sequester both the injurious agent and the injured tissue, as well as to initiate tissue healing.
[0003] Inflammation may result from physical trauma, infection, some chronic diseases (e.g. psoriasis and autoimmune diseases, such as rheumatoid arthritis) and / or chemical and / or physiological reactions to external stimuli (e.g. as part of an allergic response) . A complex series of events may be involved, in which inflammatory mediators increase blood flow and dilation of local blood vessels, resulting in redness and heat, the exudation of fluids, often resulting in localised swelling, leukocytic migration into the inflamed area, and pain.
[0004] Many conditions / disorders are characterized by, and / or are caused by, abnormal, tissue-damaging inflammation. Such conditions are typically characterized by activation of immune defence mechanisms, resulting in an effect that is more harmful than beneficial to the host, and are generally associated with varying degrees of tissue redness or hyperemia, swelling, hyperthermia, pain, itching, cell death, tissue destruction, cell proliferation and / or loss of function. Examples include inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, psoriasis, glomerulonephritis and transplant rejection.
[0005] Typically, a complex series of events results in inflammatory changes such as increased blood flow through dilation of local blood vessels, resulting in redness and heat, the extravasation of leukocytes and plasma, often resulting in localised swelling, activation of sensory nerves (resulting in pain in some tissues) and loss of function. These inflammatory changes are triggered by a cascade of cellular and biochemical events involving cells like neutrophils, monocytes, macrophages and lymphocytes together with inflammatory mediators such as vasoactive amines, cytokines, complement factors and reactive oxygen species.
[0006] Amongst other things, inflammation plays a key role in the wound healing process. Wounds and burns can therefore be classified as conditions with which inflammation is associated. Traditional thinking in the art is that anti-inflammatory drugs should not be applied directly to open wounds, as this would be detrimental to the progress of wound healing.
[0007] Fibrosis is defined by the excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM) such as collagen and fibronectin) in and around inflamed or damaged tissue. Although collagen deposition is typically a reversible part of wound healing, it can often evolve into a progressively irreversible fibrotic response if tissue injury is severe, or if the wound-healing response itself becomes dysregulated. Furthermore, fibrogenesis is known to be a major cause of morbidity and mortality in many chronic inflammatory diseases, as well as end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF) and heart failure. It is also a pathological feature of many chronic autoimmune diseases, such as scleroderma, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, myelofibrosis and systemic lupus erythematosus. Fibrosis may also influence the pathogenesis of many progressive myopathies, metastasis and graft rejection.
[0008] Mussel adhesive protein (MAP) , also known as Mytilus edulis foot protein (mefp) , is a protein that is secreted by marine shellfish species, such as Mytilus edulis, Mytilus coruscus and Perna viridis. Eleven identified separate adhesive protein subtypes have been derived from mussels, including the collagens pre-COL-P, pre-COL-D and pre-COL-NG; the mussel feet matrix proteins PTMP (proximal thread matrix protein) and DTMP (distal thread matrix protein) ; and mfp proteins mfp-2 (sometimes referred to as ‘mefp-2’ , hereinafter used interchangeably) , mfp-3 / mefp-3, mfp-4 / mefp-4, mfp-5 / mefp-5, mfp-6 / mefp-6 and, most preferably mfp-1 / mefp-1 (see, for example, Zhu et al., Advances in Marine Science, 2014, 32, 560-568 and Gao et al., Journal of Anhui Agr. Sci., 2011, 39, 19860-19862) .
[0009] A significant portion of mefp-1 consists of 70 to 90 tandem repeats of the decapeptide: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 1; see Waite, Int. J. Adhesion and Adhesives, 1987, 7, 9-14) . This decapeptide sequence may be isolated as a low molecular weight derivative of naturally-occurring MAPs, or may be synthesized, for example as described by Yamamoto in J. Chem. Soc., Perkin Trans., 1987, 1, 613-618. See also Dalsin et al., J. Am. Chem. Soc., 2003, 125, 4253-4258.
[0010] Analogues of the decapeptide, notably Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 78) have also been disclosed. See, for example, US 5, 616, 311 and WO 96 / 39128.
[0011] The use of lysine amino acid residues to prepare multi antigen peptides has been disclosed in, for example, Tam Proc. Natl. Acad., Sci. USA, 1988, 85, 5409-5413, Rao et al., J. Am. Chem. Soc., 1994, 116, 6975-6976, US 5,229,490 and WO 2010 / 038220.
[0012] The use of peptide-based scaffolds as drug delivery vehicles has been disclosed. See, for example, Brokx et al, J. Control. Release, 2002, 78, 115-123.
[0013] There is a clear need for new and / or improved medicines that may be used in the treatment of inflammation and conditions characterised thereby.
[0014] Disclosure of the Invention
[0015] According to a first aspect of the invention, there is provided a compound of formula I,
[0016] A-Q-B (I)
[0017] wherein:
[0018] A and B independently represent Z or A1-Q1-B1;
[0019] Q represents a structural fragment of formula (II) ,
[0020] wherein:
[0021] the squiggly lines represent points of attachment of Q to A and / or B; and
[0022] R is selected from the group consisting of:
[0023] wherein, when R represents one of the squiggly lines represents a point of attachment to the rest of the Q fragment, and the other squiggly line represents a point of attachment to Z or A1-Q1-B1;
[0024] wherein, when R represents one of the squiggly lines represents a point of attachment to the rest of the Q fragment, and the other squiggly line represents a point of attachment to Z;
[0025] n1 to n3 independently represent 1 to 10;
[0026] m1 to m3 independently represent 0 to 5;
[0027] p1 to p3 independently represent 0 or 1;
[0028] x represents 0 or 1;
[0029] A1 and B1 independently represent Z or A2-Q2-B2;
[0030] A2 and B2 independently represent Z or Z-Q3-Z;
[0031] Q1, Q2 and Q3 independently represent structural fragments of formula III,
[0032] wherein:
[0033] the squiggly lines adjacent to the NH groups represent points of attachment of Q1, Q2 and Q3 to A1 and / or B1, A2 and / or B2, and Z, respectively;
[0034] the squiggly line adjacent to the carbonyl group represents the point of attachment of Q1, Q2 and Q3 to Q, Q1 and Q2, respectively; and
[0035] n4 to n6 independently represent an integer selected from 1 to 10;
[0036] m4 to m6 independently represent an integer selected from 0 to 5;
[0037] p4 to p6 independently represent 0 or 1;
[0038] y represents 0 or 1;
[0039] on each occasion that it is employed, Z independently represents:
[0040] L- [ (W) m-Lys-X1-T- (U) m- (X2) m- (Y) m] n- (W) m-Lys-X1-T- (U) m- (X2) m- (Y) m (SEQ ID No: 1) ; or
[0041] L-Ala-Lys-Pro (SEQ ID No: 2) ; or
[0042] L-Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID No: 3) ; or
[0043] L- [Lys-X3] n-Lys-X3 (SEQ ID No: 196)
[0044] wherein:
[0045] Z attaches to the rest of the molecule through the N-terminus or C-terminus, as appropriate; and,
[0046] on each occasion that they are employed:
[0047] n represents 0 or an integer selected from 1 to 4;
[0048] W independently represents a 1 or 2 amino acid sequence, in which the amino acids are selected from one or more of the group Ser, Lys, Ala, DOPA and a 3, 4-dihydrocinnamic acid (HCA) residue, provided that, when present, the HCA residue is located at the N-terminus of the peptide sequence Z;
[0049] on each occasion that it is employed, m independently represents 0 or 1;
[0050] on each occasion that it is employed, X1 independently represents Pro or Hyp;
[0051] on each occasion that it is employed, T independently represents Ser or pSer;
[0052] on each occasion that it is employed, U independently represents Tyr, pTyr, DOPA, Hyp, diHyp, or Pro;
[0053] on each occasion that it is employed, X2 independently represents Thr, Ser, Pro, Hyp or diHyp;
[0054] on each occasion that it is employed, Y independently represents a 1 to 5 (e.g. a 1 to 4) amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Ala, Pro, Hyp, Thr, pThr, DOPA and Tyr;
[0055] L independently represents at least one optional lipid substituent, which lipid is selected from the group consisting of vitamin A, vitamin E, cholesterol and a fatty acid comprising one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, is linear or branched, saturated or unsaturated with between 1 and 10 carbon-carbon double bonds and / or substituted with between 1 and 10 -OH groups, or a derivative of any of these lipids; and
[0056] X3 represents a 2 to 4 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA and Tyr,
[0057] wherein, optionally, the amino acid residue at the N-terminus of the Z component is covalently bonded to a non-steroidal anti-inflammatory drug (NSAID) , or to montelukast, forming an amide linkage with the carboxylic acid group in said NSAID or montelukast,
[0058] as well as regioisomers, stereoisomers, and pharmaceutically-or cosmetically-acceptable salts of said compound,
[0059] which compounds, regioisomers, stereoisomers and salts are referred to together hereinafter as ‘the compounds of the invention’ .
[0060] The skilled person will be able to determine whether the peptide Z attaches to the rest of the molecule through the N-or C-terminus. For the avoidance of doubt, Z attaches to the rest of the molecule by forming an amide bond.
[0061] As such, when Z attaches to Formula (II) , Formula (III) or to R when R is Z attaches through the C-terminus.
[0062] Alternatively, when Z attaches to R when R is Z attaches through the N-terminus.
[0063] As used herein, “diHyp” refers to trans-2, 3-cis-3, 4-dihydroxyproline.
[0064] Compounds of the invention that may be mentioned in include those in which Z represents:
[0065] [ (W) m-Lys-X1-T- (U) m- (X2) m- (Y) m] n- (W) m-Lys-X1-T- (U) m- (X2) m- (Y) m (SEQ ID No: 1) ; or
[0066] Ala-Lys-Pro (SEQ ID No: 2) ; or
[0067] Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID No: 3) ,
[0068] in which the amino acid residue at the N-terminus of the Z component is optionally, covalently bonded to montelukast, forming an amide linkage with the carboxylic acid group in said montelukast,
[0069] On each occasion that they are employed, Q, Q1, Q2 and Q3 may each be attached to zero, one, two or three Z groups.
[0070] In this respect, preferred compounds of the invention include those in which: one of A or B represents Z and the other represents A1-Q1-B1; or, more preferably, A and B both represent Z, or both represent A1-Q1-B1.
[0071] Further preferred compounds of the invention also include those in which:
[0072] one of A1 and B1 represents Z and the other represents A2-Q2-B2; or, more preferably, A1 and B1 both represent Z, or both represent A2-Q2-B2.
[0073] Further preferred compounds of the invention also include those in which:
[0074] one of A2 and B2 represents Z and the other represents Z-Q3-Z; or, more preferably, A2 and B2 both represent Z, or both represent or Z-Q3-Z.
[0075] More preferred compounds of the invention include those in which:
[0076] A1 and B1 both represent Z; or
[0077] A2 and B2 both represent Z.
[0078] In some embodiments, each of p1 to p6 represent 0. In particular, such embodiments, each of m1 to m6 represent 0.
[0079] In some embodiments, x represents 0. In particular, such embodiments, each y independently represents 0.
[0080] In some embodiments, x represents 1. In particular, such embodiments, each y independently represents 0.
[0081] In some embodiments, each of p1 to p3 represent 1. In such embodiments, m1 to m3 independently represent 1 to 5.
[0082] In particular such embodiments, each of p4 to p6 represent 1 and each of m4 to m6 represent 1 to 5.
[0083] In some embodiments, R represents
[0084] In alternative embodiments, R represents
[0085] In some embodiments, n1 to n3 independently represent an integer from 1 to 5. In particular, such embodiments, n4 to n6 independently represent an integer from 1 to 5.
[0086] Peptide components of compounds of the invention that may be mentioned include those in which n is 0, 1 or 4, or, more preferably, n is 1 or, particularly, n is 0.
[0087] Compounds of the invention that may be mentioned include those in which the amino acid residue at the N-terminus of the Z component is covalently bonded to the NSAID or montelukast.
[0088] The term ‘non-steroidal anti-inflammatory drug’ (NSAID) will be understood by those skilled in the art to include one or more members of a class of drugs of that serves to reduce pain, inflammation and / or fever (as well as, in some cases, reduce blood clots) . The phrase ‘non-steroidal’ will be well understood to exclude other pain-relieving agents, and in particular corticosteroids from this definition.
[0089] NSAIDs typically work by inhibiting activity of cyclooxygenase (COX) enzymes, including COX-1 and COX-2, which are enzymes that are known to be involved in the synthesis of key inflammatory mediators, such as prostaglandins, as well as mediators that are involved in haemostasis, such as thromboxanes.
[0090] NSAIDs that may be mentioned include those that fall under the following structural classes, and especially includes those derived from carboxylic acids, including:
[0091] ● salicylic acid or ‘salicylates’ , including salicylic acid per se and its salts, salsalate, diflunisal and, especially, aspirin (acetylsalicylic acid) ; and 5-amino salicylic acid (mesalazine) ;
[0092] ● acetic acid, including indomethacin, acemetacin, the ‘fenacs’ (such as diclofenac, fenclofenac, aceclofenac and bromfenac) , ketorolac, etodolac, sulindac, fentiazac, as well as olmetin and nabumetone;
[0093] ● propionic acid, also known as ‘2-arylpropionic acid derivatives’ or ‘profens’ , including ibuprofen, naproxen, dexibuprofen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, pelubiprofen, zaltoprofen, fenbufen, carprofen and tiaprofenic acid;
[0094] ● enolic acid, also known as the ‘oxicams’ , including meloxicam, piroxicam, lornoxicam, isoxicam, tenoxicam and droxicam, as well as phenylbutazone (Bute) ; and
[0095] ● anthranilic acid, also known as ‘fenamates’ , including mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etofenamate, and chlofenamic acid.
[0096] Other NSAIDs that may be mentioned include pyrazolone derivatives, including oxyphenbutazone, propyphenazone, aminophenazone, antipyrine and analginum (metamizole) , as well as nefopam. Other analgesic compounds that may be employed instead of, and / or in addition to, NSAIDs include phenacetin and paracetamol (acetaminophen) .
[0097] NSAIDs that may also be mentioned but are less preferred include selective COX-2 inhibitors or ‘Coxibs’ , such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib; sulfonanilides, such as nimesulide; as well as clonixin, licofelone and H-harpagide.
[0098] Preferred NSAIDs include aspirin, salicylic acid, celecoxib and mesalazine.
[0099] It is preferred that the amino acid residue at the N-terminus of Z is covalently bonded to montelukast.
[0100] The optional NSAID substituent may be covalently bonded to the amino acid residue at the N-terminus of the Z component through amide bonds formed between respective carboxylic acid residues of the NSAID and the -NH2 residue at the N-terminus of Z.
[0101] The skilled person will understand that particular NSAIDs that may be covalently bonded to the amino acid sequence of Z through an amide bond include: salicylates (such as aspirin, salicylic acid and suitable salts, diflunisal, salsalate, 5-amino salicylic acid) , propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, pelubiprofen, zaltoprofen) , acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac) , anthranilic acid derivatives (such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid) , selective COX-2 inhibitors (Coxibs) (such as lumiracoxib) , and others (such as clonixin, licofelone) .
[0102] Compounds of the invention that may be mentioned include those in which: W represents a 1 or 2 amino acid sequence, in which the amino acids are selected from one or more of the group Ser, Lys, Ala and DOPA;
[0103] X1 represents Pro;
[0104] X2 represents Ser, Pro or Hyp;
[0105] Y represents a 1 to 5 (e.g. a 1 to 4) amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Ala, Pro, Hyp, Thr, DOPA and Tyr.
[0106] Preferred compounds of the invention include those in which:
[0107] X1 represents Hyp or, more preferably, Pro;
[0108] X2 represents Hyp;
[0109] W represents HCA-, HCA-Ala-, preferably Ala-or Lys-Ala-or, more preferably DOPA-or DOPA-Ala-; and / or
[0110] Y represents a 5, preferably a 3 or, more preferably, a 4 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Ala, Hyp, Thr, DOPA and Tyr.
[0111] More preferably, compounds of the invention also include those in which Y represents a 4 amino acid sequence selected from the group -Pro-Y1-Y2-Lys-or, more preferably, -Hyp-Y1-Y2-Lys-and -Thr-Y1-Y2-Lys-, wherein Y1 and Y2 are each independently selected from the group Pro or, more preferably, Ala, Hyp, Thr, DOPA and Tyr.
[0112] Further preferred compounds of the invention include those in which the amino acid sequence defined by Y is selected from the group:
[0113] -Pro-Thr-DOPA-Lys-;
[0114] -Pro-Thr-Tyr-Lys-;
[0115] -Thr-Tyr-Pro-Lys-; and
[0116] -Thr-DOPA-Pro-Lys-; and, more preferably,
[0117] -Thr-Tyr-Hyp-;
[0118] -Thr-DOPA-Hyp-;
[0119] -Tyr-Hyp-Lys-;
[0120] -Tyr-Pro-Lys-;
[0121] -Hyp-Thr-DOPA-;
[0122] -Hyp-pThr-DOPA-;
[0123] -Hyp-Thr-Tyr-;
[0124] -DOPA-Hyp-Lys-;
[0125] -Hyp-Thr-Tyr-Lys-;
[0126] -Hyp-Thr-Tyr-Hyp;
[0127] -Hyp-Thr-DOPA-Lys-;
[0128] -Hyp-Thr-DOPA-Hyp-;
[0129] -Hyp-Thr-Ala-Lys-;
[0130] -Hyp-pThr-DOPA-Hyp-;
[0131] -Thr-Tyr-Hyp-Lys-;
[0132] -Thr-Tyr-Lys-Hyp-;
[0133] -Thr-DOPA-Lys-Hyp-;
[0134] -Thr-DOPA-Hyp-Lys-; and
[0135] -Thr-Ala-Hyp-Lys-.
[0136] When Y represents a 2 amino acid sequence, preferred compounds of the invention include those in which the amino acid sequence defined by Y is selected from the group -DOPA-Lys-, -Tyr-Lys-, -Thr-Lys-and -Tyr-Pro-.
[0137] Other preferred compounds of the invention that may be mentioned include those in which the amino acid sequence defined by Y is selected from the group -DOPA-, -Tyr, -Hyp-, -Thr-, -Hyp-Thr-, -Thr-Tyr-, -Pro-Thr-, -Thr-DOPA, -Thr-Tyr-Lys-, -Tyr-Pro-Lys, -DOPA-Pro-Lys-, -Hyp-Thr-Tyr-, -Hyp-Thr-Tyr-Hyp-Lys-, -Hyp-Thr-DOPA-Hyp-Lys-, -Hyp-Thr-DOPA-Lys-DOPA-, -Hyp-Thr-Tyr-Lys-DOPA-, -Thr-DOPA-Hyp-Lys-DOPA-, -Thr-Tyr-Hyp-Lys-DOPA-and, more preferably, the group -Thr-Tyr-Hyp-Lys-DOPA-and -Hyp-Thr-DOPA-.
[0138] Compounds of the invention that may be mentioned include those in which:
[0139] U represents Tyr; and / or
[0140] W represents Ala.
[0141] In this respect, further compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0142] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 83) ;
[0143] Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5) ;
[0144] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6) ;
[0145] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7) ;
[0146] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8) ;
[0147] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 179) ;
[0148] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 180) ;
[0149] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 181) ;
[0150] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 182) ;
[0151] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 13) ;
[0152] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 14) ;
[0153] Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 18) ;
[0154] Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 19) ;
[0155] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 23) ;
[0156] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 24) ;
[0157] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 25) ;
[0158] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 26) ;
[0159] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 27) ;
[0160] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 28) ;
[0161] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 29) ;
[0162] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 30) ;
[0163] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 31) ;
[0164] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 32) ;
[0165] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 33) ;
[0166] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 34) ;
[0167] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 35) ;
[0168] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 36) ;
[0169] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 37) ;
[0170] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 38) ;
[0171] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 39) ;
[0172] Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 40) ;
[0173] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6) ;
[0174] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp (SEQ ID no. 61) ;
[0175] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA (SEQ ID no. 62) ;
[0176] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp (SEQ ID no. 63) ;
[0177] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp-Lys (SEQ ID no. 64) ;
[0178] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Lys (SEQ ID no. 65) ;
[0179] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr (SEQ ID no. 66) ;
[0180] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp (SEQ ID no. 67) ;
[0181] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp-Lys (SEQ ID no. 68) ;
[0182] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Lys (SEQ ID no. 69) ;
[0183] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 70) ;
[0184] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 71) ;
[0185] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 72) ;
[0186] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 73) ;
[0187] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID no. 74) ;
[0188] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 75) ;
[0189] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 76) ;
[0190] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 77) ;
[0191] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78) ;
[0192] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID no. 79) ;
[0193] Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (SEQ ID no. 80) ;
[0194] Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID no. 81) ;
[0195] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 82) ;
[0196] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0197] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID no. 84) ;
[0198] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 85) ;
[0199] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-DOPA-Lys (SEQ ID no. 86) ;
[0200] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8) ;
[0201] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) ;
[0202] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 87) ;
[0203] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 88) ;
[0204] Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no. 89) ;
[0205] Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no. 90) ;
[0206] Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (SEQ ID no. 91) ;
[0207] Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (SEQ ID no. 92) ;
[0208] Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 93) ;
[0209] Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID no. 171) ;
[0210] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 173) ;
[0211] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 174) ;
[0212] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 175) ;
[0213] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys- Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 176) ; and
[0214] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 177) .
[0215] Compounds of the invention that may be mentioned include those in which:
[0216] U represents Tyr; and / or
[0217] W represents Lys-Ala-.
[0218] In this respect, further compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0219] Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 96) ;
[0220] Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 97) ;
[0221] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 100) ;
[0222] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 101) ;
[0223] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 183) ;
[0224] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 184) ; and
[0225] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 185) .
[0226] Compounds of the invention that may be mentioned include those in which:
[0227] U represents Tyr; and / or
[0228] W is absent.
[0229] In this respect, further compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0230] Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 102) ;
[0231] Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 103) ;
[0232] Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 104) ;
[0233] Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 105) ;
[0234] Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 106) ;
[0235] Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 107) ;
[0236] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 108) ;
[0237] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 109) ;
[0238] Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID no. 112) ;
[0239] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) ;
[0240] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 114) ;
[0241] Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID no. 118) ;
[0242] Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID no. 119) ;
[0243] Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 120) ;
[0244] Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID no. 122) ;
[0245] Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID no. 126) ;
[0246] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127) ;
[0247] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 128) ;
[0248] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 129) ;
[0249] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 130) ;
[0250] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 131) ;
[0251] Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 132) ;
[0252] Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 133) ;
[0253] Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 134) ;
[0254] Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 135) ; and
[0255] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136) .
[0256] Further compounds of the invention that may be mentioned include those in which: U represents Tyr; and / or
[0257] W represents HCA, HCA-Ala-or, more preferably, DOPA or DOPA-Ala-.
[0258] In this respect, compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0259] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 141) ;
[0260] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 142) ;
[0261] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 143) ;
[0262] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144) ;
[0263] DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 147) ;
[0264] DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 148) ;
[0265] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 153) ;
[0266] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 154) ;
[0267] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 155) ;
[0268] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 156) ;
[0269] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 157) ;
[0270] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 158) ;
[0271] HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 161) ; and
[0272] HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 162) .
[0273] Further compounds of the invention that may be mentioned include those in which:
[0274] U represents Tyr; and / or
[0275] W represents Ser.
[0276] In this respect, compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0277] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 163) ;
[0278] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 164) ;
[0279] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 165) ;
[0280] Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 166) ;
[0281] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 167) ;
[0282] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 168) ;
[0283] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 169) ; and
[0284] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 170) .
[0285] Other compounds of the invention that may be mentioned include those in which U represents DOPA.
[0286] In this respect, compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0287] Ala-Lys-Pro-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 186) ;
[0288] Ala-Lys-Hyp-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 187) ;
[0289] Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 10) ;
[0290] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11) ;
[0291] Lys-Pro-Ser-DOPA-Hyp-DOPA (SEQ ID no. 115) ;
[0292] Lys-Pro-Ser-DOPA-Hyp-DOPA-Lys (SEQ ID no. 116) ;
[0293] Lys-Pro-Ser-DOPA-Hyp-Tyr-Lys (SEQ ID no. 117) ;
[0294] Lys-Pro-Ser-DOPA-Hyp-Thr (SEQ ID no. 121) ;
[0295] Lys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID no. 123) ;
[0296] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID no. 20) ;
[0297] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11) ;
[0298] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 21) ;
[0299] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 22) ;
[0300] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 41) ;
[0301] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID no. 42) ;
[0302] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID no. 43) ;
[0303] Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys (SEQ ID no. 44) ;
[0304] Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys (SEQ ID no. 45) ;
[0305] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID no. 46) ;
[0306] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 47) ;
[0307] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID no. 48) ;
[0308] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 49) ;
[0309] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 50) ;
[0310] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 51) ;
[0311] Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 52) ;
[0312] Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no. 53) ;
[0313] Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no. 54) ;
[0314] Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys (SEQ ID no. 55) ;
[0315] Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys (SEQ ID no. 56) ;
[0316] Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys (SEQ ID no. 57) ;
[0317] Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 58) ;
[0318] Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no. 94) ;
[0319] Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no. 95) ;
[0320] Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no. 98) ;
[0321] Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no. 99) ;
[0322] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 172) ; and
[0323] Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 178) .
[0324] Further compounds of the invention that may be mentioned include those in which: U represents DOPA; and / or
[0325] W represents HCA, HCA-Ala-or, more preferably, DOPA or DOPA-Ala-.
[0326] Accordingly, particular compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0327] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 137) ;
[0328] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 138) ;
[0329] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 139) ;
[0330] DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 140) ;
[0331] DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 145) ;
[0332] DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 146) ;
[0333] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 149) ;
[0334] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 150) ;
[0335] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 151) ;
[0336] HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 152) ;
[0337] HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 159) ; and
[0338] HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 160) .
[0339] Further compounds of the invention that may be mentioned include those in which: U represents Hyp.
[0340] Accordingly, particular compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0341] Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 12) ; and
[0342] Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID no. 16) .
[0343] Further compounds of the invention that may be mentioned include those in which: U represents Pro.
[0344] Accordingly, particular compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0345] Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 15) ;
[0346] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID no. 17) ;
[0347] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (SEQ ID no. 59) ; and
[0348] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 60) .
[0349] Further compounds of the invention that may be mentioned include those in which: U represents pTyr.
[0350] Accordingly, particular compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0351] Lys-Hyp-Ser-pTyr-Hyp-DOPA (SEQ ID no. 110) ;
[0352] Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 111) ;
[0353] Lys-Pro-Ser-pTyr-Hyp-DOPA (SEQ ID no. 124) ; and
[0354] Lys-Pro-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 125) .
[0355] Further compounds of the invention that may be mentioned those wherein Z is selected from the group:
[0356] Ala-Lys-Pro-Ser (SEQ ID no. 4) ;
[0357] Ala-Lys-Pro (SEQ ID no. 2) ; and
[0358] Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID no. 3) .
[0359] In some embodiments, Z is selected from the group:
[0360] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 179) ;
[0361] Ala-Lys-Pro-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 180) ;
[0362] Ala-Lys-Pro-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 186) ;
[0363] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 181) ;
[0364] Ala-Lys-Hyp-Ser-Tyr-DiHyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 182) ;
[0365] Ala-Lys-Hyp-Ser-DOPA-DiHyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 187) ;
[0366] Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 10) ;
[0367] Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11) ;
[0368] Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 12) ;
[0369] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 13) ;
[0370] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 14) ;
[0371] Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 15) ;
[0372] Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID no. 16) ;
[0373] Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID no. 17) ;
[0374] Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 18) ;
[0375] Ala-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 19) ;
[0376] Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 102) ;
[0377] Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 103) ;
[0378] Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 104) ;
[0379] Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 105) ;
[0380] Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 106) ;
[0381] Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 107) ;
[0382] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 108) ;
[0383] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 109) ;
[0384] Lys-Hyp-Ser-pTyr-Hyp-DOPA (SEQ ID no. 110) ;
[0385] Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 111) ;
[0386] Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID no. 112) ;
[0387] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) ;
[0388] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 114) ;
[0389] Lys-Pro-Ser-DOPA-Hyp-DOPA (SEQ ID no. 115) ;
[0390] Lys-Pro-Ser-DOPA-Hyp-DOPA-Lys (SEQ ID no. 116) ;
[0391] Lys-Pro-Ser-DOPA-Hyp-Tyr-Lys (SEQ ID no. 117) ;
[0392] Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID no. 118) ;
[0393] Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID no. 119) ;
[0394] Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 120) ;
[0395] Lys-Pro-Ser-DOPA-Hyp-Thr (SEQ ID no. 121) ;
[0396] Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID no. 122) ; and
[0397] Lys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID no. 123) .
[0398] Compounds of the invention that may be mentioned include those in which:
[0399] A and B both represent Z;
[0400] one, or preferably both, Z groups represent:
[0401] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 13) ;
[0402] Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 14) ;
[0403] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 108) ;
[0404] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 109) ;
[0405] Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 102) ;
[0406] Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 103) ;
[0407] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 24) ;
[0408] Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 27) ;
[0409] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 32) ;
[0410] Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 36) ;
[0411] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 70) ;
[0412] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 75) ;
[0413] DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 147) ;
[0414] DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 148) ;
[0415] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 155) ;
[0416] HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 158) ;
[0417] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 100) ;
[0418] Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 101) ;
[0419] Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID no. 126) ;
[0420] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 129) ;
[0421] Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 131) ;
[0422] Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 133) ;
[0423] Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 135) ;
[0424] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 168) ; or
[0425] Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 170) ,
[0426] or, more preferably, one, or preferably both, Z groups represent:
[0427] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0428] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) ;
[0429] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78) ;
[0430] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0431] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127) ;
[0432] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136) ;
[0433] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) ;
[0434] Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 114) ;
[0435] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 87) ;
[0436] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 142) ; or
[0437] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144) .
[0438] Compounds of the invention that may be mentioned include those in which:
[0439] A and B both represent Z;
[0440] one, or preferably both, Z groups represent:
[0441] Ala-Lys-Pro (SEQ ID no. 2) ;
[0442] Ala-Lys-Pro-Ser (SEQ ID no. 4) ;
[0443] Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5) ;
[0444] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6) ;
[0445] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7) ;
[0446] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8) ; or
[0447] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) .
[0448] In each of the above peptide sequences Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0449] Further compounds of the invention that may be mentioned include those in which:
[0450] A and B both represent A1-Q1-B1;
[0451] A1 and B1 both represent Z;
[0452] one, or preferably both, Z groups represent:
[0453] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0454] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) ;
[0455] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78) ;
[0456] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0457] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144) ;
[0458] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127) ;
[0459] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136) ; or
[0460] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) .
[0461] Further compounds of the invention that may be mentioned include those in which:
[0462] A and B both represent A1-Q1-B1;
[0463] A1 and B1 both represent Z;
[0464] one, or preferably both, Z groups represent:
[0465] Ala-Lys-Pro (SEQ ID no. 2) ;
[0466] Ala-Lys-Pro-Ser (SEQ ID no. 4) ;
[0467] Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5) ;
[0468] Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6) ;
[0469] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7) ;
[0470] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8) ; or
[0471] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) .
[0472] In each of the above peptide sequences Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0473] Further compounds of the invention that may be mentioned include those in which:
[0474] A and B both represent A1-Q1-B1;
[0475] A1 and B1 both represent A2-Q2-B2;
[0476] A2 and B2 both represent Z;
[0477] one, or preferably both, Z groups represent:
[0478] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0479] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) ;
[0480] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78) ;
[0481] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0482] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144) ;
[0483] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127) ;
[0484] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136) ; or
[0485] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) .
[0486] Further compounds of the invention that may be mentioned include those in which:
[0487] A and B both represent A1-Q1-B1;
[0488] A1 and B1 both represent A2-Q2-B2;
[0489] A2 and B2 both represent Z-Q3-Z;
[0490] one, or preferably both, Z groups represent:
[0491] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0492] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) ;
[0493] Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78) ;
[0494] Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;
[0495] DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144) ;
[0496] Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127) ;
[0497] Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136) ; or
[0498] Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) .
[0499] In each of the above peptide sequences Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0500] Further compounds of the invention that may be mentioned include those in which:
[0501] A and B both represent Z;
[0502] one, or preferably both, Z groups represent a structural fragment of formula IV,
[0503] [Lys-X3] n-Lys-X3 (IV) (SEQ ID No: 197)
[0504] in which n and X3 are as hereinbefore defined, and wherein, for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0505] Further compounds of the invention that may be mentioned include those in which:
[0506] A and B both represent A1-Q1-B1;
[0507] A1 and B1 both represent Z;
[0508] one, or preferably both, Z groups represent a structural fragment of formula IV,
[0509] [Lys-X3] n-Lys-X3 (IV) (SEQ ID No: 197)
[0510] in which n and X3 are as hereinbefore defined, and wherein, for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0511] Further compounds of the invention that may be mentioned include those in which:
[0512] A and B both represent A1-Q1-B1;
[0513] A1 and B1 both represent A2-Q2-B2;
[0514] A2 and B2 both represent Z;
[0515] one, or preferably both, Z groups represent a structural fragment of formula IV,
[0516] [Lys-X3] n-Lys-X3 (IV) (SEQ ID No: 197)
[0517] in which n and X3 are as hereinbefore defined, and wherein, for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0518] Further compounds of the invention that may be mentioned include those in which:
[0519] A and B both represent A1-Q1-B1;
[0520] A1 and B1 both represent A2-Q2-B2;
[0521] A2 and B2 both represent Z-Q3-Z;
[0522] one, or preferably both, Z groups represent a structural fragment of formula IV,
[0523] [Lys-X3] n-Lys-X3 (IV) (SEQ ID No: 197)
[0524] in which n and X3 are as hereinbefore defined, and wherein, for each peptide sequence Z, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0525] When one or more Z groups represent a structural fragment of formula IV as defined above, it is preferred that, on each occasion that it is employed:
[0526] X3 represents a 3, a 4 or, more preferably, a 2 amino acid sequence;
[0527] that the amino acids in X3 are selected from the group Pro, Hyp, Lys, Tyr and DOPA. It is further preferred that, on each occasion that it is employed:
[0528] the amino acid in X3 that is adjacent to Lys is selected from Pro and Hyp;
[0529] that the N-terminal amino acid in X3 is selected from Tyr and DOPA and, especially, Lys; at least one of the other amino acids in the sequence defining X3 is Hyp.
[0530] Furthermore, in such cases, n may represent 1, such that Z is defined by the formula:
[0531] Lys-X3-Lys-X3 (SEQ ID No: 198)
[0532] or, more preferably, n represents 0, such that Z is defined by the formula:
[0533] Lys-X3 (SEQ ID No: 199)
[0534] wherein, on each occasion that it is employed, X3 is as hereinbefore defined.
[0535] When n is 0 and X3 represents a 2 amino acid sequence, preferred tripeptide sequences that Z may represent include:
[0536] Lys-Pro-Lys (SEQ ID No: 200) ;
[0537] Lys-Pro-Tyr (SEQ ID No: 201) ;
[0538] Lys-Pro-DOPA (SEQ ID No: 202) ; more preferably
[0539] Lys-Hyp-Tyr (SEQ ID No: 203) ;
[0540] Lys-Hyp-DOPA (SEQ ID No: 204) ; or, more particularly,
[0541] Lys-Hyp-Lys (SEQ ID No: 205) .
[0542] When n is 0 and X3 represents a 3 amino acid sequence, the C-terminal amino acid in X3 is Lys, such that preferred tetrapeptide sequences that Z may represent include:
[0543] Lys-Pro-Pro-Lys (SEQ ID No: 206) ;
[0544] Lys-Pro-Hyp-Lys (SEQ ID No: 207) ;
[0545] Lys-Hyp-Pro-Lys (SEQ ID No: 208) ; or more particularly,
[0546] Lys-Hyp-Hyp-Lys (SEQ ID No: 209) .
[0547] When n is 0 and X3 represents a 4 amino acid sequence, the C-terminal amino acid sequence in X3 comprises Pro-Lys or, more preferably, Hyp-Lys, such that preferred pentapeptide sequences that Z may represent include:
[0548] Lys-Pro-DOPA-Hyp-Lys (SEQ ID No: 210) ;
[0549] Lys-Pro-DOPA-Pro-Lys (SEQ ID No: 211) ;
[0550] Lys-Hyp-DOPA-Hyp-Lys (SEQ ID No: 212) ;
[0551] Lys-Hyp-DOPA-Pro-Lys (SEQ ID No: 213) ;
[0552] Lys-Pro-Tyr-Pro-Lys (SEQ ID No: 214) ;
[0553] Lys-Hyp-Tyr-Pro-Lys (SEQ ID No: 215) ; or, more particularly,
[0554] Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 216) ; or
[0555] Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 217) .
[0556] When n is 1, on each occasion that it is employed, X3 preferably represents a 2 amino acid sequence, such that the preferred hexapeptide sequences that Z may represent include:
[0557] Lys-Hyp-Tyr-Lys-Hyp-DOPA (SEQ ID No: 218) ;
[0558] Lys-Hyp-Tyr-Lys-Pro-Lys (SEQ ID No: 219) ;
[0559] Lys-Hyp-Tyr-Lys-Pro-Tyr (SEQ ID No: 220) ;
[0560] Lys-Hyp-Tyr-Lys-Pro-DOPA (SEQ ID No: 221) ;
[0561] Lys-Hyp-DOPA-Lys-Hyp-Tyr (SEQ ID No: 222) ;
[0562] Lys-Hyp-DOPA -Lys-Pro-Lys (SEQ ID No: 223) ;
[0563] Lys-Hyp-DOPA -Lys-Pro-Tyr (SEQ ID No: 224) ;
[0564] Lys-Hyp-DOPA -Lys-Pro-DOPA (SEQ ID No: 225) ;
[0565] Lys-Pro-Lys-Lys-Hyp-Tyr (SEQ ID No: 226) ;
[0566] Lys-Pro-Lys-Lys-Hyp-DOPA (SEQ ID No: 227) ;
[0567] Lys-Pro-Lys-Lys-Pro-Tyr (SEQ ID No: 228) ;
[0568] Lys-Pro-Lys-Lys-Pro-DOPA (SEQ ID No: 229) ;
[0569] Lys-Pro-Tyr-Lys-Hyp-Tyr (SEQ ID No: 230) ;
[0570] Lys-Pro-Tyr-Lys-Hyp-DOPA (SEQ ID No: 231) ;
[0571] Lys-Pro-Tyr-Lys-Pro-Lys (SEQ ID No: 232) ;
[0572] Lys-Pro-Tyr-Lys-Pro-DOPA (SEQ ID No: 233) ;
[0573] Lys-Pro-DOPA-Lys-Hyp-Tyr (SEQ ID No: 234) ;
[0574] Lys-Pro-DOPA-Lys-Hyp-DOPA (SEQ ID No: 235) ;
[0575] Lys-Pro-DOPA-Lys-Pro-Lys (SEQ ID No: 236) ;
[0576] Lys-Pro-DOPA-Lys-Pro-Tyr (SEQ ID No: 237) ; or, preferably,
[0577] Lys-Hyp-Tyr-Lys-Hyp-Tyr (SEQ ID No: 238) ;
[0578] Lys-Hyp-DOPA -Lys-Hyp-DOPA (SEQ ID No: 239) ;
[0579] Lys-Pro-Lys-Lys-Pro-Lys (SEQ ID No: 240) ;
[0580] Lys-Pro-Tyr-Lys-Pro-Tyr (SEQ ID No: 241) ;
[0581] Lys-Pro-DOPA-Lys-Pro-DOPA (SEQ ID No: 242) ; or, more preferably,
[0582] Lys-Hyp-Lys-Lys-Hyp-Tyr (SEQ ID No: 243) ;
[0583] Lys-Hyp-Lys-Lys-Hyp-DOPA (SEQ ID No: 244) ;
[0584] Lys-Hyp-Lys-Lys-Pro-Lys (SEQ ID No: 245) ;
[0585] Lys-Hyp-Lys-Lys-Pro-Tyr (SEQ ID No: 246) ;
[0586] Lys-Hyp-Lys-Lys-Pro-DOPA (SEQ ID No: 247) ; or, even more preferably,
[0587] Lys-Hyp-Tyr-Lys-Hyp-Lys (SEQ ID No: 248) ;
[0588] Lys-Hyp-DOPA -Lys-Hyp-Lys (SEQ ID No: 249) ;
[0589] Lys-Pro-Lys-Lys-Hyp-Lys (SEQ ID No: 250) ;
[0590] Lys-Pro-Tyr-Lys-Hyp-Lys (SEQ ID No: 251) ;
[0591] Lys-Pro-DOPA-Lys-Hyp-Lys (SEQ ID No: 252) ; or
[0592] Lys-Hyp-Lys-Lys-Hyp-Lys (SEQ ID No: 253) .
[0593] In each of peptide sequences represented by SEQ ID Nos: 197 to 253 inclusive, the amino acid residue at the N-terminus of the Z component may be covalently bonded to an NSAID as defined herein, or montelukast, forming an amide linkage with the carboxylic acid group in the NSAID or montelukast.
[0594] Preferred compounds of the invention include those in which the one or more optional lipids defined by L is / are selected from the group consisting of palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid and leukotriene B4 (LTB4) , or a derivative of any of these.
[0595] Further preferred compounds of the invention also include those in which the one or more optional lipids comprise a polyunsaturated fatty acid, or a derivative thereof. In such embodiments, the derivative may be a specialized pro-resolving mediator (SPM) .
[0596] Further preferred compounds of the invention also include those in which said one or more lipids comprise a derivative of a fatty acid, such as a glycerolipid, glycerophospholipid, sphingolipid or saccharolipid.
[0597] Further preferred compounds of the invention also include those in which said one or more lipids comprise palmitic acid, or a derivative thereof. In such embodiments, the derivative may be phosphatidylserine, or more preferably, the derivative is 1, 2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS) . In such embodiments, the derivative may be phosphatidylethanolamine, or more preferably, the derivative is 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) .
[0598] Further preferred compounds of the invention also include those in which said one or more lipids comprise stearic acid, or a derivative thereof. In such embodiments, the derivative may be 1, 2-distearoyl-sn-glycero-3-phospho-l-serine.
[0599] Further preferred compounds of the invention also include those in which said one or more lipids comprise oleic acid, or a derivative thereof. In such embodiments, the derivative may be 1, 2-dioleoyl-sn-glycero-3-phospho-L-serine.
[0600] Further preferred compounds of the invention also include those in which said one or more lipids comprise palmitoylethanolamide (PEA) .
[0601] Further preferred compounds of the invention also include those in which said one or more lipids are selected from the group consisting of vitamin E, vitamin A, and cholesterol, or a derivative of any of these. In such embodiments, the derivative of cholesterol may be cholesterol-acetic acid.
[0602] Further preferred compounds of the invention also include those in which the lipid is a fatty acid as hereinbefore defined, which fatty acid may comprise 1 to 5 -OH groups, such as 1 to 2 -OH groups. In other embodiments, the fatty acid may have 1 to 10 cyclic rings, such as 1 to 8 cyclic rings.
[0603] Compounds of the invention that may be mentioned include those in which L represents at least one lipid as hereinbefore defined.
[0604] Optional lipids defined by L may be covalently bonded to the amino acid sequence of the peptide in a compound of the invention through amide bonds formed between respective carboxylic acid residues of L and one or more free NH2 residues that are present in one or more amino acids of the peptide (including at the N-terminus of the peptide sequence) , and / or through ester bonds formed between respective -OH residues of L and one or more free carboxylic acid residues that may be present in one or more amino acids of the peptide (including at the C-terminus of the peptide sequence) .
[0605] It is preferred that, in compounds of the invention, taken together, the total number of optional lipids defined by L is no more than 8, more preferably no more than 4, such as 3, 2 or 1.
[0606] Preferred compounds of the invention include those in which L represents 2 lipids or, more preferably, 1 lipid as hereinbefore defined.
[0607] Preferred compounds of the invention include those in which each L group that is present represents the same lipid, such as palmitic acid, or a derivative thereof.
[0608] In respect of any one of the above specific peptide sequences defined by Z, at least one lipid defined by L (and particularly palmitic acid, or a derivative thereof) may be covalently bonded to the amino acid sequence of the peptide in a compound of the invention as described above, especially SEQ ID Nos: 127, 136, 205, 209, 217 and 253. In this respect, further compounds of the invention that may be mentioned include those wherein Z is selected from the group:
[0609] Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 254) ;
[0610] Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 255) ;
[0611] Palm-Lys-Hyp-Lys (SEQ ID No: 256) ;
[0612] Palm-Lys-Hyp-Hyp-Lys (SEQ ID No: 257) ;
[0613] Palm-Lys-Hyp-Tyr-Hyp-Lys (SEQ ID No: 258) ; or
[0614] Lys-Hyp-Lys (Palm) -Lys-Hyp-Lys (Palm) (SEQ ID No: 259) .
[0615] For the avoidance of doubt, compounds of the invention as hereinbefore defined, (acompound of formula I) , are referred to together hereinafter as ‘compounds of the invention’ .
[0616] As used herein, Pro represents proline, Ala represents alanine, Ser represents serine, Tyr represents tyrosine, Hyp represents hydroxyproline (including 3-hydroxyproline (3Hyp) and 4-hydroxyproline (4Hyp) ) , diHyp represents dihydroxyproline (including 3, 4-dihydroxyproline (3, 4diHyp) , 3, 5-dihydroxyproline (3, 5diHyp) and 4, 5-dihydroxyproline (4, 5diHyp) ) , Thr represents threonine, Lys represents lysine, Ala represents alanine, DOPA represents 3, 4-dihydroxyphenylalanine, Orn represents ornithine and Dap represents diaminopropionic acid. 3, 4-Dihydrocinnamic acid (HCA) residues are essentially DOPA residues but without the -NH2 group in the 2-or α-carbon position relative to the carboxylic acid that is attached to the N-terminal amino acid (whether Lys or Ala) .
[0617] Compounds of the invention, whether in the form of salts or otherwise, include regioisomers within amino acids of the peptides (for example diHyp, Hyp and Tyr moieties) , as well as mixtures of such regioisomers. For example, included within the definition of Tyr are, not only tyrosine (4-hydroxyphenylalanine) , but also 2-and 3-hydroxyphenylalanine. Included within the definition of Hyp are 4-hydroxyproline (4Hyp) , 3-hydroxyproline (3Hyp) and 5-hydroxyproline (5Hyp) . It is more preferred that Hyp residues are 4-hydroxyproline. Similarly, included within the definition of diHyp are 3, 4-dihydroxyproline (3, 4diHyp) , 3, 5-dihydroxyproline (3, 5diHyp) and 4, 5-dihydroxyproline (4, 5diHyp) . It is more preferred that diHyp residues are 3, 4-dihydroxyproline (3, 4diHyp) .
[0618] Also, in addition to the standard central carbon atom of the amino acids in the compounds of the invention (which are normally but not exclusively in the L-configuration) , certain amino acids in the sequence comprise further chiral carbon atoms. All such stereoisomers and mixtures (including racemic mixtures) thereof are included within the scope of the invention. In this respect, included within the definition of Hyp are trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, cis-3-hydroxy-L-proline, trans-5-hydroxy-L-proline and cis-5-hydroxy-L-proline, however we prefer that the Hyp that is employed in compounds of the invention is trans-4-hydroxy-L-proline. Similarly, corresponding definitions may be applied to diHyp, in which the two hydroxy groups can also be cis or trans relative to each other. In any event, individual enantiomers of compounds of formula I that may form part of a compound of the invention are included within the scope of the invention.
[0619] Compounds of the invention may be in the form of salts. Salts that may be mentioned include pharmaceutically-acceptable and / or cosmetically-acceptable salts, such as pharmaceutically-and / or cosmetically-acceptable acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration) . Salts may also be prepared by exchanging a counter-ion of the compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
[0620] Preferred salts include, for example, acetate, hydrochloride, bisulfate, maleate, mesylate, tosylate, alkaline earth metal salts, such as calcium and magnesium, or alkali metal salts, such as sodium and potassium salts. Most preferably, compounds of the invention may be in the form of acetate salts.
[0621] Compounds of the invention may be prepared by way of conventional techniques, for example by way of standard amino acid coupling techniques, using standard coupling reagents and solvents, for example as described hereinafter. Compounds of the invention may be synthesised from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B.M. Trost and I. Fleming, Pergamon Press, 1991. Further references that may be employed include “Heterocyclic Chemistry” by J.A. Joule, K. Mills and G. F. Smith, 3rd edition, published by Chapman &Hall, “Comprehensive Heterocyclic Chemistry II” by A.R. Katritzky, C.W. Rees and E.F.V. Scriven, Pergamon Press, 1996 and “Science of Synthesis” , Volumes 9-17 (Hetarenes and Related Ring Systems) , Georg Thieme Verlag, 2006.
[0622] Compounds of the invention may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention.
[0623] It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups may take place before or after a reaction.
[0624] Protecting groups may be applied and removed in accordance with techniques that are well-known to those skilled in the art and as described hereinafter. For example, protected compounds / intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in ‘Protective Groups in Organic Synthesis’ , 5th edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (2014) , the contents of which are incorporated herein by reference.
[0625] Compounds of the invention are useful as human and animal medicine. They are therefore indicated as pharmaceuticals (and / or in veterinary science) , although they may also be used as cosmetics and / or as part of a medical device.
[0626] Compounds of the invention may also possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. ‘protected’ ) derivatives of compounds of the invention may exist or may be prepared which may not possess such activity, but which may be administered and thereafter be metabolised or chemically transformed to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the active compounds to which they are metabolised / transformed) may therefore be described as ‘prodrugs’ of compounds of the invention.
[0627] As used herein, references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
[0628] When compounds of the invention possess pharmacological activity, they are particularly useful in the treatment of inflammation.
[0629] The term ‘treatment of inflammation’ includes the treatment of inflammation in any organ of the body (including soft tissue, joints, nerves, the vascular system, internal organs, especially mucosal surfaces, and particularly the skin) , irrespective of the cause, and also includes all such inflammatory disorders or conditions, and / or disorders or conditions characterized by inflammation (e.g. as a symptom) .
[0630] Inflammatory disorders and / or conditions may be (and are typically) characterized by activation of immune defence mechanisms, resulting in an effect that is more harmful than beneficial to the host. Such conditions are generally associated with varying degrees of tissue redness or hyperemia, swelling, edema, hyperthermia, pain (including aching) , exudation of body fluids, itching (pruritis) , cell death and tissue destruction, cell proliferation, and / or loss of function.
[0631] Inflammatory conditions that may be mentioned include arteritis, diabetes mellitus, metabolic syndrome, rosacea, asthma and allergy, 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, syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis and associated cardiovascular disorders. A disease state characterised by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD) . A further disease state characterised by inflammation that may be mentioned is inflammatory bowel diseases including Crohn’s disease and, especially, ulcerative colitis. Other disease states characterized by inflammation that may be mentioned are gynaecological diseases, such as cervicitis, vaginitis (e.g. radiation vaginitis) and colpitis. Diseases that affect the gastrointestinal tract, such as gastrohelcosis (e.g. gastritis, gastric ulcer, stress-induced gastritis, gastric cancer and other stomach mucosa diseases) as well as gastroesophageal reflux disease (GERD) , constipation, and gastritis, inflammation associated with cancers and infections (e.g. viral infections, such as the common cold or influenza) .
[0632] Inflammatory conditions that may be more especially mentioned include inflammations of the skin or mucosa (including the oral, nasal, ocular, vaginal, cervical and / or anorectal mucosae, more particularly the oral or nasal mucosae) , such as inflammation resulting from infections (such as viral and / or bacterial infections) , or allergic / atopic conditions (such as rhinitis (e.g. allergic rhinitis) , pharyngitis, periodontitis, gingivitis, xerophthalmia, conjunctivitis (e.g. allergic conjunctivitis) , dermatitis, urticaria (hives) and food allergy) ; and other inflammatory conditions, such as herpes, drug eruptions, polymorphous light eruptions, sunburn, early manifestations of skin cancers (erythema-like skin lesions) , pathological hair loss (including following skin grafting) , chemo rash, psoriasis, erythema multiforme, folliculitis, eczema and external otitis. A disease state that may be mentioned is polymorphous light eruptions.
[0633] More particularly, compounds may be used to treat certain conditions characterized by inflammation, and / or with which inflammation is associated. Such conditions may include wounds (including abrasions (scratches) , incisions (including operative incisions) , lacerations, punctures, avulsions, bruising and scarring) , and burns (including inflammation resulting from surgery following burns, such as skin grafting) and other conditions, such as hemorrhoids. Wounds may be acute or chronic, and / or may result from one or more inflammatory disorders as defined herein.
[0634] Wounds of the skin or mucosa may arise from internal or external physical injury to the membrane surface, or may be caused by (i.e. be a symptom of) an underlying physiological disorder.
[0635] Physical (e.g. ‘open’ ) wounds may be caused by sharp objects (cuts, incisions, punctures) or blunt objects / mechanical forces (lacerations, abrasions, avulsions) , physical blows (bruises) , heat or chemicals (burns and blisters) , UV light (sunburn) , cold (chilblains or frostbite) . Wounds may be superficial (damage only to the epidermis and / or dermis) or may be full thickness wounds (damage below the epidermis and / or dermis) . In serious cases, subcutaneous and / or submucosal tissues, such as muscles, bones, joints, and even internal organs, may be damaged.
[0636] Compounds of the invention may be used to relieve the pain (including aching) associated with inflammation and / or wounding. In particular, compounds of the invention may be used to relieve procedural pain and / or non-procedural pain. The skilled person will understand that the term ‘procedural pain’ (i.e. operation pain) refers to acute pain that is associated with medical investigations and treatments conducted for the purpose of healthcare. The term ‘non-procedural’ refers to general pain that is associated with inflammation and / or wounding (e.g. pain associated with dental ulcers, burns and / or scars) , and is not a consequence of a particular medical intervention.
[0637] Compounds of the invention may be used to treat not only the inflammation, pain (including aching) and / or pruritis (itching) associated with the wound itself and the healing process, but also to prevent the exudation of body fluids from wounds, the risk of infection, and the prevention of physiological reactions that result from inflammation and / or wound healing processes, such as scarring and melanin pigmentation.
[0638] Scarring is a consequence of inflammation and / or wound healing and is a general term for the formation of fibrotic tissue that is a consequence of such inflammation / healing.
[0639] Compounds of the invention may also be useful in the suppression of the production of melanin pigmentation, which may or may not result from inflammation and / or wound healing. Compounds of the invention may also be useful in the suppression of disorders associated with melanin pigmentation, such as chloasma, freckles, melanosis, malar rash and other chromatosis, skin cancers with melanoma, and chromatosis that is caused by exposure to the sun or skin diseases like acne.
[0640] Wounds may also arise as a consequence of (e.g. inflammatory) diseases or disorders. Such wounds may include blistering and / or ulcers of the skin and mucosa. These are common conditions that are often long-lasting and difficult to treat. Skin tissues can often be damaged, removed, liquefied, infected and / or necrotic. Ulcers can lead to secondary consequences to health particularly if they become infected, are hard to heal and are costly to treat. They can also cause significant psychological stress and economic loss to patients, affecting both general well-being and quality of life.
[0641] In the alternative, inflammatory skin conditions or diseases in which compounds of the invention find particular utility include psoriasis, acne, eczema and dermatitis, especially allergic / atopic dermatitis, as well as in the treatment of mucosal inflammation as characterized by rhinitis, especially allergic rhinitis, hemorrhoids, chronic obstructive pulmonary disease and ulcerative colitis, for example.
[0642] Psoriasis is a chronic, inflammatory skin disease with a tendency to recur (some patients never heal during their entire life) . Clinical manifestations of psoriasis mainly include erythema and scales. It can occur over the whole body, but is more commonly observed on the scalp and limbs.
[0643] Acne is a follicular (pilosebaceous unit) chronic, inflammatory skin disease, the occurrence of which is closely related to main factors like hypersteatosis, blocked pilosebaceous ducts (including closed and open comedones) , bacterial infection and inflammatory reactions, that tends to occur during youth, characterized by multiform skin lesions on the face. The term acne thus includes regular acne and acne rosacea (i.e. copper nose) .
[0644] Eczema is a skin inflammatory reaction with strong itching caused by a variety of internal and external factors. It has three phases, acute, sub-acute, and chronic. In the acute phase, there is a tendency for the production of exudates, while the chronic phase includes infiltration and hypertrophy. Skin lesions are often itchy and recur easily.
[0645] Dermatitis is a common skin disease characterized by coarseness, redness, itching, eczema, and dryness. Small lumps, refractory ulcers, and pigmented spots caused by dermatitis may, if not treated promptly, develop to basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Dermatitis may be caused by various internal and external infectious or non-infectious factors, including substances (contact dermatitis) or allergy (allergic / atopic dermatitis) . Also included is seborrheic dermatitis (seborrheic eczema) , cicatricial alopecia and related diseases, and all forms of steroid-dependent dermatitis (including light-sensitive seborrheic, perioral dermatitis, rosacea-like dermatitis, steroid-rosacea, steroid-induced rosacea, iatrosacea, steroid dermatitis resembling rosacea, topical corticosteroid-induced rosacea-like dermatitis and, more particularly, facial corticosteroid addictive dermatitis (FCAD) or facial corticosteroid-dependent dermatitis (FCDD) , as characterized by flushing, erythema, telangiectasia, atrophy, papules and / or pustules in the facial area after long-term treatment with (including uncontrolled use, abuse or misuse of) topical corticosteroids; see, for example, Xiao et al., J. Dermatol., 2015, 42, 697-702 and Lu et al., Clin. Exp. Dermatol., 2009, 35, 618-621) .
[0646] Rhinitis is irritation and inflammation of the mucous membrane inside the nose. Common symptoms of rhinitis include a stuffy nose, runny nose, sneezing and post-nasal drip. The most common kind of rhinitis is allergic rhinitis, caused by an allergen, such as pollen, dust, mould, or flakes of skin from certain animals. It has been surprisingly found that patients with allergic rhinitis who were treated with compounds of the invention experienced relief of eye itchiness, even when compounds of the invention were administered nasally (i.e. to the nasal mucosa) .
[0647] Hemorrhoids are swellings caused by inflammation of the hemorrhoidal blood vessels found inside or around the rectum and the anus. Symptoms include bleeding (i.e. wounding) after the passage of a stool, prolapse of the hemorrhoid, mucus discharge and itchiness, soreness, redness and swelling in the area of the anus. Hemorrhoids are believed to be a consequence of an increase of pressure in the abdomen, for example, as a result of constipation or diarrhea.
[0648] Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties, including emphysema (damage to the alveoli) and chronic bronchitis (long-term inflammation of the airways) . COPD occurs when the lungs become inflamed, damaged and narrowed. The damage to the lungs is usually irreversible and results in an impairment of the flow of air into and out of the lungs. Symptoms of COPD include breathlessness, productive cough, frequent chest infections and persistent wheezing. The most common cause of the disease is smoking, although other risk factors include high levels of air pollution and occupational exposure to dust, chemicals and fumes.
[0649] Compounds of the invention may have positive effects in mitigating erythema, redness and swelling, edema, blisters, and bullous pemphigoid caused by various conditions including those mentioned generally and specifically herein, and may inhibit exudation of subcutaneous tissue fluid, and suppressing itching and pain caused by such inflammatory conditions.
[0650] Other inflammatory conditions that may be mentioned include:
[0651] (a) Mucosal inflammation, such as oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis and enterocolitis (including bacillary dysentery, chronic amoebic dysentery, schistosomiasis, nonspecific ulcerative colitis and regional enteritis) , cervicitis and endocervicitis, endometritis, inflammation caused by inhalation injury and the like, as well as mucosal inflammation associated with cancers, and infections (e.g. viral infections, such as the common cold or influenza) , that affect mucosal surfaces, such as those in the oral cavity, the nasopharynx, the ear, the throat, the trachea, the gastrointestinal tract, the cervix, etc.
[0652] (b) Orthopedic inflammation associated with, for example bone fractures, pyogenic infection of bones and joints, inflammation caused by rheumatic bone diseases, as well as pyogenic osteomyelitis (acute, chronic, localized, sclerotic, post-traumatic) , pyogenic arthritis; bone tumors (osteoma, osteoid osteoma, chondroma) , bone cysts, osteoclastoma, primary bone sarcoma (osteosarcoma, chondrosarcoma, osteofibrosarcoma, Ewing's sarcoma, non-Hodgkin's lymphoma, myeloma, chordoma) , metastatic bone tumors, tumor-like lesions of bone (bone cyst, aneurysmal bone cyst, eosinophilic granuloma, fibrous dysplasia) ; and rheumatic arthritis.
[0653] (c) Nerve inflammation, such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, intercostal neuritis, etc.
[0654] (d) Subcutaneous and submucosal soft tissue inflammation, such as myositis, ligamentitis, tendonitis, panniculitis capsulitis, lymphadenitis, bubonadentitis, tonsillitis, synovitis, fasciitis, and soft tissue inflammation caused by injuries, contusion or laceration of muscles, ligaments, fascia, tendons, membrana synovialis, fat, articular capsules, and lymphoid tissue.
[0655] (e) Vascular inflammation, such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormalities in blood composition, and rheumatic vasculitis, as well as vascular inflammation associated with vascular cancers caused by allergic leukocytoclastic vasculitis, polyarteritis nodosa, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormalities in blood composition, and rheumatic vasculitis.
[0656] (f) Inflammation of the internal organs, such as the heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, and prostate, including but not limited to pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, splenitis, nephritis pancreatitis, cystitis, oophoritis, prostatitis and treatment of gastric ulcer.
[0657] (g) Inflammation of the eye and surrounding area, such as conjunctivitis, keratitis (e.g. acute epithelial keratitis, nummular keratitis, interstitial keratitis, disciform keratitis, neurotrophic keratitis, mucous plaque keratitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis acanthamoebic keratitis, onchocercal keratitis, superficial punctate keratitis, ulcerative keratitis, exposure keratitis photokeratitis and contact lens acute red eye) , optic neuritis, maculopathy of the retina, retinopathy, etc.
[0658] (h) Inflammation of the gums and the oral cavity, such as periodontitis, gingivitis, dental ulcers, etc.
[0659] (i) Inflammation associated with rheumatism, such as rheumatic vasculitis, rheumatoid arthritis, rheumatic bone diseases, ankylosing spondylitis, bursitis, Crohn's disease, gout, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, osteoporosis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, scleroderma, syndrome, spondyloarthropathies, systemic lupus erythematosus, tendinitis, etc.
[0660] Compounds of the invention may also be used in differentiation and regeneration of bone marrow cells and aplastic anemia (for example by systemic and topical administration) .
[0661] Compounds of the invention may also be used in the treatment of renal diseases, including end stage renal diseases and its complications, including uremic pruritus.
[0662] Compounds of the invention may also be used in the treatment of certain specific diseases of the digestive system, such as gastroesophageal reflux disease (GERD) , which may be characterized by an acidic taste in the mouth, regurgitation, heartburn, pain with swallowing and / or sore throat, increased salivation (water brash) , nausea, chest pain, and coughing. GERD may cause injury of the esophagus, including reflux esophagitis (i.e. inflammation of the esophageal epithelium which may cause ulceration at or around the junction of the stomach and esophagus) , esophageal strictures (i.e. the persistent narrowing of the esophagus caused by reflux-induced inflammation) , Barrett's esophagus (i.e. intestinal metaplasia (i.e. changes of epithelial cells from squamous to intestinal columnar epithelium of the distal esophagus) and / or esophageal adenocarcinoma (aform of cancer) ) .
[0663] Compounds of the invention may also be used in the treatment of certain specific diseases of the respiratory system, such as pulmonary cystic fibrosis, usual interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, pulmonary heart disease, pulmonary embolism, etc. A specific disease state that may be mentioned in idiopathic pulmonary fibrosis (IPF) .
[0664] IPF is a diffuse and fatal pulmonary interstitial disease with pathological features including alveolar epithelial damage, massive proliferation of lung fibroblasts, excessive deposition of extracellular matrix, ultimately leading to irreversible lung tissue damage. In the latter stages of the disease, subjects with IPF experience respiratory failure and death. It has been found that compounds of the invention may find utility in the treatment of IPF and / or alleviation of the symptoms associated with the disease.
[0665] Compounds of the invention are particularly useful in the treatment of the following lung and / or fibrotic conditions (whether otherwise mentioned herein or not) : lung fibrosis, renal fibrosis, liver fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, status asthmatics, bronchiectasis, upper respiratory tract infections (including the common cold and influenza) , allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, reckettsia, radiation pneumonia, pneumococcal (including staphylococcal, streptococcal and gram-negative bacillus) pneumonia, pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis and nocardiosis) , pulmonary mycosis, cryptococcosis, lung abscesses, anaphylactic pneumonia, extrinsic allergic alveolitis, pulmonary eosinophilia (including Loeffler’s syndrome and eosinophilosis) , obstructive pulmonary emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis / acidosis, acute lung injury, interstitial lung disease, empyema, lung fibroma and cor pulmonale.
[0666] Particular mucosal disorders and disease in which compounds of the invention find utility include anorectal diseases, such as diarrhea, hemorrhoids, abscesses, fistula, fissures, anal itching, anal sinusitis, warts and rectal prolapse; inflammatory bowel disease, including Crohn’s disease and, particularly, ulcerative colitis; gynaecological diseases, such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases, such as paradentitis, for example.
[0667] Compounds of the invention may further possess an antioxidation effect, by increasing SOD (superoxide dismutase) production and reducing lipid oxidation. Compounds of the invention may therefore be considered to have antioxidant properties.
[0668] Compounds of the invention may also possess antipyretic properties that allow for the treatment of a fever and / or alleviate the symptoms thereof; for example, by reducing a subject’s body temperature, which results in a reduction of fever. Compounds of the invention and formulations including them may therefore be considered to be antipyretics.
[0669] According to a further aspect of the invention there is provided a method of treatment of inflammation, of an inflammatory disorder, and / or of a disorder / condition characterised by inflammation (for example as a symptom) , which method comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
[0670] For the avoidance of doubt, in the context of the present invention, the terms ‘treatment’ , ‘therapy’ and ‘therapy method’ include the therapeutic, or palliative, treatment of patients in need of, as well as the prophylactic treatment and / or diagnosis of patients which are susceptible to, inflammation and / or inflammatory disorders.
[0671] Compounds of the invention may further possess antiviral properties that may allow for the treatment of a viral infection per se, that is treatment of a viral infection, or a viral disease, by interfering with the replication of the virus within a host, as opposed to the treatment of any symptoms of any viral infection or disease, such as pain and / or inflammation. Such antiviral properties may also allow for the prevention of the onset of such an infection or disease, the protection of cells in a host from (e.g. further) viral infection, prevention or arrest of the spread of viral infection or disease (within a single host, or from one host to a new host) , or for the prevention of reactivation of a virus after latency in a host.
[0672] According to a further aspect of the invention there is provided a method of treatment of a viral infection, which method comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
[0673] Viral infections that may be mentioned include those caused by viruses in the following families: adenoviridae (e.g. adenovirus) , papillomaviridae (e.g. human papillomavirus) , polyomaviridae (e.g. BK virus; JC virus) , herpesviridae (e.g. herpes simplex, type 1; herpes simplex, type 2; varicella-zoster virus; Epstein–Barr virus; human cytomegalovirus; human herpes virus, type 8) , poxviridae (e.g. smallpox) , hepadnaviridae (e.g. hepatitis B virus) , parvoviridae (e.g. parvovirus B19) , astroviridae (e.g. human astrovirus) , caliciviridae (e.g. norovirus; Norwalk virus) , picornaviridae (e.g. coxsackievirus, hepatitis A virus; poliovirus; rhinovirus) , coronoviridae (e.g. severe acute respiratory syndrome virus) , flaviviridae (e.g. hepatitis C virus; yellow fever virus; dengue virus; West Nile virus; tick-borne encephalitis virus) , retroviridae (e.g. human immunodeficiency virus; HIV) , togaviridae (e.g. rubella virus) , arenaviridae (e.g. Lassa virus) , bunyaviridae (e.g. hantavirus; Crimean-Congo hemorrhagic fever virus; Hantaan virus) , filoviridae (e.g. Ebola virus; Marburg virus; Ravn virus) , orthomyxoviridae (e.g. influenza viruses, including influenza A virus (e.g. H1N1 and H3N2 viruses) , influenza B virus or influenza C virus) , paramyxoviridae (e.g. measles virus; mumps virus; parainfluenza virus, respiratory syncytial virus) , rhabdoviridae (e.g. rabies virus) , hepeviridae (e.g. hepatitis E virus) , reoviridae (e.g. rotavirus; orbivirus; coltivirus; Banna virus) , as well as viruses not assigned to families, such as hepatitis D virus.
[0674] Viruses that may be more specifically mentioned include herpes simplex, type 1 and herpes simplex, type 2 viruses, human papillomavirus, influenza virus and parainfluenza virus.
[0675] Compounds of the invention may further possess antibacterial and / or bacteriostatic properties that may allow for the treatment of a bacterial infection per se, that is treatment of a bacterial infection, or a bacterial disease, by interfering with bacterial growth or proliferation in a host, as opposed to the treatment of any symptoms of any bacterial infection or disease, such as pain and / or inflammation. Compounds of the invention may therefore be considered to be bacteriocides and / or, preferably, bacteriostatic agents.
[0676] Such antibacterial properties may also allow for the prevention of the onset of such an infection or disease, the protection of cells in a host from (e.g. further) bacterial infection, prevention or arrest of the spread of bacterial infection or disease (within a single host, or from one host to a new host) , or for the prevention of reactivation of a bacterium after latency in a host.
[0677] According to a further aspect of the invention there is provided a method of treatment of a bacterial infection, which method comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
[0678] As disclosed herein, compounds of the invention may further possess anticancer properties that may allow for the treatment of a cancer per se, that is treatment of a cancer by interfering with the cancer as opposed to the treatment of any symptoms of the cancer, such as pain and / or inflammation. Such anticancer properties may also include the prevention of the onset of such a disease e.g. by treating inflammation and thereby preventing such onset.
[0679] According to another aspect of the invention, there is provided a method of treatment of cancer, which method comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
[0680] Particular cancers that may be mentioned include oral cancer, a nasopharynx cancer, a middle ear cancer, a conjunctival cancer, a throat cancer, a tracheal cancer, an esophageal cancer, a gastric cancer, an intestinal cancer, a cervical cancer, an endometrial cancer, skin cancer and the like caused by oral mucositis, rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophagitis, gastritis, enterocolitis, cervicitis, endometritis, erythema-like skin lesions and the like. A particular skin cancer that may be mentioned is basal cell carcinoma.
[0681] Fibrotic conditions of internal organs that may be mentioned include acute and / or severe internal fibrotic conditions characterised by the excessive accumulation of fibrous connective tissues (as described above) in and around inflamed or damaged tissues. Formulations of the invention may thus be useful in the treatment or prevention of fibrogenesis (as described above) and the morbidity and mortality that may be associated therewith. Thus, (e.g. acute and / or severe) fibrotic conditions of the internal organs that may be treated with formulations of the invention include fibrosis of the liver, the kidneys, the lungs, the cardiovascular system, including the heart and the vascular system, the pancreas, the spleen, the central nervous system (nerve fibrosis) , bone marrow fibrosis, the eyes, the vagina, the cervix, etc.
[0682] Inflammatory conditions of internal organs include any condition that is, or may develop into a condition that is, severe (i.e. one that requires intensive medical treatment) , and in which some sort of inflammatory component is apparent, as may be characterised by detectable inflammation, and further in which morbidity is manifested (or is expected) and / or is life-threatening.
[0683] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of internal organs (i.e. one or more conditions that require, or may develop into a condition that requires, immediate medical interventions) that are characterized by inflammation (e.g. as a symptom) , such as acute internal injuries, in one or more internal organs (including any of the organs mentioned hereinbefore) . By treating such acute inflammatory disorders, formulations of the invention may prevent or arrest the development of symptoms (acute or chronic) that are associated with such conditions, and also may arrest the progress of morbidity and / or mortality that is associated with such conditions.
[0684] Acute inflammatory conditions that may be mentioned thus include conditions such as peritonitis, pancreatitis, colitis, proctitis (including radiation proctitis) , gastritis, duodenitis, pharyngitis, GERD, parodontitis and stomatitis. Particular acute inflammatory conditions that may be mentioned include acute injury to one or more internal organs (including any of those mentioned hereinbefore) , such as acute lung injury, inhalation injury (such as burns) , acute respiratory distress syndrome (ARDS) , severe acute respiratory syndrome (SARS) , and multiple-organ inflammation, injury and / or failure.
[0685] Such conditions may be caused by internal or external trauma (e.g. injury or a burn) , or by an infection by e.g. viruses, bacteria or fungi.
[0686] For example, proctitis (which includes eosinophilic, gonorrheal and / or ulcerative proctitis) may be caused by inflammatory bowel disease, infections, radiation (e.g. for cancer) , drugs such as antibiotics, surgery or allergic conditions, such as food intolerances.
[0687] For example, multiple-organ inflammation, injury and / or failure may result from extensive and / or traumatic external injuries, including traumatic and / or extensive external burns. Traumatic external burns will be understood to include second-degree, and more particularly third-degree burns and fourth-degree, burns. Extensive external burns will be understood to include burns that affect at least about 10%, such as at least about 15%, including at least about 20%of a patient’s body area. External (and internal) burns may result from exposure to heat, chemicals and the like. Acute inflammatory and / or fibrotic conditions may also result from sepsis or septic shock, which can be caused by viral, bacterial or fungal infection. Furthermore, acute lung injury, ARDS and, particularly, SARS may be caused by viruses, such as coronaviruses, include the novel SARS coronavirus 2 (SARS-CoV-2) .
[0688] Thus, in addition, one or more of the aforementioned (e.g. acute) inflammatory conditions may (indeed in some cases will likely) result in some form of internal tissue damage and / or dysfunction of relevant internal tissues. Relevant tissues thus include (e.g. mucosal) tissues, such as the respiratory epithelium. Such tissue damage may also give rise to one or more of the fibrotic conditions mentioned hereinbefore. For example, the SARS disease caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19) is known in many cases to result in fibrosis, which arise from one or more of a number of factors, including inflammation.
[0689] In this respect, compounds of the invention and salts thereof find particular utility in the treatment of relevant inflammatory and / or fibrotic conditions on the basis that such conditions are often characterized by one or more comorbidities. By conditions that are ‘characterized by comorbidities’ , we include that the main condition in question results in (or from) further medical conditions, including (and indeed preferably) those mentioned hereinbefore, at the same time, which conditions may interact and / or overlap with each other in some way.
[0690] Thus, there are provided:
[0691] ● methods of treatment of at least one inflammatory and / or fibrotic disorder or condition of one or more internal organs of a patient, which method comprises direct systemic parenteral administration of a compound of the invention, or a pharmaceutically-acceptable salt thereof, to a patient in need of such treatment;
[0692] ● a method of treatment of two or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs of a patient, which method comprises direct systemic parenteral administration of a compound of the invention, or a pharmaceutically-acceptable salt thereof, to a patient in need of such treatment; and
[0693] ● a method of reduction in the incidence of morbidity and / or mortality that is or may be associated with one or more inflammatory and / or fibrotic disorders or conditions of one or more internal organs of a patient, which method comprises direct systemic parenteral administration of a compound of the invention, or a pharmaceutically-acceptable salt thereof, to a patient in need of such treatment.
[0694] In addition, compounds of the invention may be used in the treatment of a condition characterized by immunosuppression, immunodeficiency disorders, in the treatment of a patient with a compromised immune system, and / or for the restoration of the normal function of the immune system of a patient.
[0695] Conditions characterized by immunosuppression (or immunodeficiency disorders) include primary immunodeficiency disorders (PIDDs) , which are typically rare, congenital disorders that are usually inherited. PIDDs thus include humoral immunodeficiency disorders, such as common variable immunodeficiency, selective immunoglobulin deficiency (e.g. IgA deficiency) , transient hypogammaglobulinemia of infancy, X-linked agammaglobulinemia; cellular immunodeficiency disorders, such as chronic mucocutaneous candidiasis, DiGeorge syndrome, X-linked lymphoproliferative syndrome; combined humoral and cellular immunodeficiency disorders, such as ataxia-telangiectasia, hyperimmunoglobulinemia E syndrome, severe combined immunodeficiency, Wiskott-Aldrich syndrome; phagocytic immunodeficiencies, such as Chédiak-Higashi syndrome, chronic granulomatous disease, cyclic neutropenia, leukocyte adhesion defects; and complement deficiencies, such as complement component 1 (C1) inhibitor deficiency (or hereditary angioedema) , C3 deficiency, C4 deficiency, as well as C5, C6, C7, C8, and / or C9 deficiencies.
[0696] However, we prefer that the immunodeficiency disorders that is treated in accordance with the invention is a secondary immunodeficiency disorders (SIDD) , which are more common than PIDDs and tend to develop later in life SIDDs include immunodeficiency disorders that are caused by a secondary factor, such as old age, malnutrition (e.g. undernutrition) , a chronic disorder, one or more chemical agents (e.g. drugs) and / or (e.g. ionizing) radiation.
[0697] For the purposes of the present invention the term ‘SIDD’ may also include physical and / or mental stress, which stress may serve to compromise a patient’s immune system.
[0698] Physical stress may be brought on by trauma (injury, infection, surgery) , intense physical labour / over-exertion (e.g. over-training) , environmental pollution (pesticides, herbicides, toxins, heavy metals, inadequate light, radiation, noise, electromagnetic fields) , illness (viral, bacterial, or fungal agents) , fatigue, inadequate oxygen supply, hypoglycemia, hormonal and / or biochemical imbalances, dietary stress (nutritional deficiencies, food allergies and sensitivities, unhealthy eating habits) , dehydration, substance abuse, dental challenges, and musculoskeletal misalignments / imbalances.
[0699] Mental stress may include various forms of psychological and / or psychosocial stress, such as emotional stress (e.g. negative emotions, such as resentment, fear, frustration, sadness, anger, grief / bereavement) ; cognitive stress (information overload, worry, guilt, shame, jealousy, resistance, attachments, self-criticism, self-loathing, unworkable perfectionism, anxiety, panic attacks, a sense of generally being not being in control) ; perceptual stress (beliefs, roles, attitudes, values, meaning and / or purpose) ; death / loss of loved ones; relationship difficulties (with partners, siblings, children, extended family, employers, co-workers) ; lack of social support (e.g. friends and / or isolation) ; financial stress (e.g. due to loss of employment, investments, savings, bankruptcy, home foreclosure, etc. ) .
[0700] Disorders that can cause immunodeficiency in patients include cancers; disorders of the blood, such as aplastic anaemia, leukaemia, multiple myeloma; sickle cell disease; Down’s syndrome; infections such as viral infections, including varicella, cytomegalovirus, Epstein-Barr virus, HIV, measles and bacterial infections; diabetes mellitus; diseases of internal organs, such as chronic kidney disease, nephrotic syndrome, chronic hepatitis, liver failure; systemic lupus erythematosus; alcoholism, chronic burns; and operations, such as removal of the spleen.
[0701] Drugs that can cause immunodeficiency in patients include antiseizure drugs, such as lamotrigine, phenytoin, valproate; immunosuppressants, such as azathioprine, cyclosporine, everolimus, leflunomide, mycophenolate, mofetil, sirolimus, tacrolimus, tofacitinib; biologics, such as abatacept, adalimumab, anakinra, basiliximab, certolizumab, daclizumab, etanercept, golimumab, infliximab, ixekizumab, muromonab (OKT3) , natalizumab, rituximab, secukinumab , tocilizumab, ustekinumab, vedolizumab; and, particularly, corticosteroids, such as naturally-occurring corticosteroids, including cortisol (hydrocortisone) , aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally-occurring precursors and intermediates in corticosteroid biosynthesis, and other derivatives of naturally-occurring corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β, 17α, 21-trihydroxypregnenolone, 17α, 21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone and 18-hydroxyprogesterone, and synthetic corticosteroids, including those of the hydrocortisone-type (Group A) , such as cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol, prednicarbate and triamcinolone; acetonides and related substances (Group B) , such as amcinonide, budesonide, desonide, fluocinolone cetonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxycortide, flunisolide and fluocinolone acetonide, those of the (beta) methasone-type (Group C) , such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halometasone, mometasone and mometasone furoate, alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, difluocortolone, fluclorolone, flumetasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone and ulobetasol; those of the progesterone-type, such as flugestone, fluorometholone, medrysone and prebediolone acetate, and progesterone derivatives (progestins) , such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate and segesterone acetate; as well as other corticosteroids, such as cortivazol and 6-methyl-11β, 17β-dihydroxy-17α- (1-propynyl) androsta-1, 4, 6-trien-3-one. Particular corticosteroids that may be mentioned include cortisone, prednisone, prednisolone, methylprednisolone and dexamethasone.
[0702] Drugs that may cause immunodeficiency in patients that may particularly be mentioned however include chemotherapeutic treatments of cancers, such as alemtuzumab, busulfan, cyclophosphamide, melphalan.
[0703] Particular SIDDs that may be mentioned include those caused by radiation therapy that is employed to treat disorders such as cancer (i.e. radiation-induced immunosuppression) .
[0704] Ionizing radiation not only suppresses the immune system in the manner described hereinbefore, but also can alter the functions of the immune system in irradiated organs in other ways. For example, increased levels in inflammatory mediators, such as NF-κB and SMAD2 / 3, and cytokines, such as IL-1, IL-2, IL-6, IL-8, IL-33, tumor necrosis factor (TNF-α) , transforming growth factor beta (TGF-β) and interferon gamma (IFN-γ) are associated with the release of prostaglandins and free radicals, including reactive oxygen species (ROS) and nitric oxide (NO) . Exposure to high doses of radiation that may occur during accidental exposure (e.g. as a consequence of a nuclear or a radiologic disaster) may result in inflammatory responses and / or wounding, which may continue for years afterwards and / or disrupt the functions of irradiated organs.
[0705] Compounds of the invention may be employed not only to provide an immunorestorative effect, but also to simultaneously promote wound recovery and / or healing. This is particularly useful in view of the fact that wounds that are associated with such a condition are difficult, if not impossible, to treat properly in view of the immunosuppressive effect induced by the radiation and the absence of a normal endogenous inflammatory response.
[0706] By providing the aforesaid immunorestorative effect, this enables the body’s immune system and localised inflammatory response to become more effective and, in this respect, compounds of the invention may also be employed to provide an anti-inflammatory effect, at the same time as promoting further wound healing, but in a manner that does not compromise further the patient’s immune system (in the manner that a corticosteroid would if it were employed to treat the inflammation) .
[0707] According to a further aspect of the invention, there is provided the use of a compound of the invention or a pharmaceutically-acceptable salt thereof for the manufacture of a medicament for the treatment of inflammation and / or of a condition characterized by inflammation or wounding, in a patient that has, or is vulnerable to, a condition characterized by immunosuppression, which includes the treatment of radiation-induced conditions characterized by inflammation and / or wounds.
[0708] Diseases (including those characterised by inflammation and / or wounds) that are radiation-induced per se, and / or may result from radiation-induced immunosuppression, include those that may arise following accidental exposure to radiation (commonly known as ‘radiation poisoning’ ) , or following deliberate and / or targeted exposure to radiation, for example as a consequence of (e.g. ionizing) radiation therapy to treat a disease, such as cancer.
[0709] Radiation therapy is a type of e.g. cancer treatment that uses an external beam of intense energy to kill cancer cells. Radiation therapy most often uses X-rays, but protons or other types of energy also can be used. Radiation therapy may be used as a primary cancer treatment, in neoadjuvant therapy (shrinking a cancerous tumor before surgery) , adjuvant therapy (preventing proliferation of cancer cells after surgery) , to alleviate symptoms caused by advanced cancer, or two or more of the above in combination. Radiation therapy may also be used in combination with other treatments, such as chemotherapy.
[0710] Disorders characterised by inflammation and / or wounding of the mucosa and / or skin that may result from exposure to radiation are often associated with the part of the body that is targeted / irradiated. For example:
[0711] ● radiation-induced dermatitis and mucositis may occur in the skin or the mucosa, respectively, at locations that may be close to the part of the body that is irradiated. For example, radiation-induced oral mucositis may occur following irradiation of the head or neck;
[0712] ● radiation-induced encephalitis may also occur following irradiation of the head or neck; and
[0713] ● radiation pneumonitis and / or radiation esophagitis often result from radiation treatment of lung cancers, breast cancer, lymphomas, thymic tumours, or oesophageal cancer with radiation.
[0714] Radiation treatment that is aimed at the abdomen, pelvis or rectum (e.g. to treat cancer of the cervix, the prostate, the bladder or the rectum) may result in one or more of radiation enteropathy (or radiation enteritis, including radiation colitis) , radiation hepatitis, radiation myelitis, radiation vaginitis and, particularly, radiation proctitis.
[0715] In particular, radiation proctitis or radiation proctopathy is condition characterized by damage to the rectum after exposure to radiation during radiation therapy. Inflammation can be acute (acute radiation proctitis, as well as the related radiation colitis) , or chronic (e.g. radiation associated vascular ectasias (RAVE) and chronic radiation proctopathy) .
[0716] Initial symptoms of acute radiation proctitis include pelvic pain, diarrhoea and tenesmus but radiation damage to the rectum often causes incontinence and rectal bleeding, with severe cases leading to wounds, strictures and / or fistulae.
[0717] Thus, in the treatment of disorders induced by irradiation for e.g. cancer therapy, more particularly irradiation of the lower abdominal region, including disorders such as radiation proctitis as defined above, radiation colitis and radiation-induced dermatitis, compounds of the invention and salts thereof may be employed:
[0718] ● to provide an immunorestorative effect at the same time as treating wounds and / or promoting recovery and / or healing of wounds that are associated with such a disorder; and / or
[0719] ● to provide a more direct anti-inflammatory effect without compromising the patient’s immune system further, at the same time as being available to promote further wound healing.
[0720] According to two further aspects of the invention there are provided:
[0721] ● a method of treatment of a radiation-induced condition that is characterized by (i) immunosuppression, and (ii) inflammation and / or wounding; and
[0722] ● a method of treating inflammation and / or wounds that are associated with a radiation-induced immunodeficiency disorder whilst simultaneously restoring the normal function of the immune system of a patient,
[0723] which methods comprise administering a compound of the invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.
[0724] The methods of treatment and uses described above are particularly useful when the disorder that is induced by irradiation for e.g. cancer therapy, result from irradiation of the lower abdominal region as described above.
[0725] There is further provided a method of reduction in the incidence of morbidity and / or mortality that is or may be associated with of radiation- (e.g. ionizing radiation-) induced disorder characterised by inflammation and / or wounding in a patient, which method comprises administration of a compound of the invention, or a pharmaceutically-acceptable salt thereof to a patient in need of such treatment.
[0726] Conditions that compounds of the invention find particular utility in include skin inflammation, physiological reactions that result from skin inflammation and / or wound healing processes, such as scarring and melanin pigmentation; scalp &hair follicle inflammation and fibrosis, include seborrheic dermatitis, cicatricial alopecia and related conditions; gastritis, gastric ulcer and stress-induced gastritis; GERD; IBDs including Crohn’s disease, ulcerative colitis and or proctitis, radiation proctitis; arthritis; maculopathy of the retina; differentiation and regeneration of bone marrow cells and aplastic anemia; stress; as well as IPF, ALI / ARDS, uremic pruritis, COPD, asthma, bronchitis (including chronic bronchitis) , vasculitis, pancreatitis, multiple organ injury and / or viral infections.
[0727] In addition, compounds of the invention may be used in non-therapeutic, cosmetic treatments, such as anti-aging.
[0728] Therefore, a further aspect of the invention is the non-therapeutic use of the compounds of the invention in anti-aging, for example by promoting skin integrity in such a way that the skin has the appearance of younger skin.
[0729] A further aspect of the invention is a cosmetic composition comprising a compound of the invention. Such a composition may provide antiaging properties.
[0730] ‘Patients’ include reptilian, avian and, preferably, mammalian (particularly human) patients.
[0731] In accordance with the invention, compounds of the invention are preferably administered locally or systemically, for example orally, intravenously or intraarterially (including by intravascular and other perivascular devices / dosage forms (e.g. stents) ) , intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally) , rectally, intravaginally, intradermally, transdermally, nasally, pulmonarily (e.g. tracheally or bronchially) , for example by way of direct injection, or by way of any other parenteral route, preferably topically, or by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound (s) in pharmaceutically acceptable dosage form (s) .
[0732] Administration by inhalation (e.g. nasally) is particularly useful when the condition to be treated is rhinitis or inflammation resulting from viral infections of the airways (e.g. upper respiratory tract infections, such as the common cold and influenza) .
[0733] Pulmonary administration is particularly useful when the condition to be treated is COPD or IPF. Topical forms of administration may be enhanced by creating a spray comprising active ingredients, e.g. by using a powder aerosol or by way of an aqueous mist using an appropriate atomisation technique or apparatus, such as a nebulizer.
[0734] Anorectal administration is particularly useful when the condition to be treated is hemorrhoids or ulcerative colitis, using an appropriate delivery means, such as a solution of foam to be injected or a suppository.
[0735] Administration to the lower gastrointestinal tract may also be achieved by parenteral, and particularly by peroral, delivery, by means of standard delayed-or extended- release coating techniques known to those skilled in the art. In particular, distinct parts of the upper or lower intestine may be targeted. For example, colonic administration can also be achieved by way of colon-targeted drug delivery means that are initially administered perorally or parenterally.
[0736] Compounds of the invention may in the alternative be administered by direct systemic parenteral administration. Such administration may be useful in methods of treatment of one or more of the aforementioned disorders or conditions of one or more internal organs of a patient.
[0737] Internal organs that may be mentioned include the stomach, the intestines, the pancreas, the liver, the spleen, the bladder, the vascular system, the ovaries, the prostate, preferably the heart and the kidneys and more preferably the lungs.
[0738] Standard delayed-or extended-release techniques known to those skilled in the art may be used for means of administration other than peroral, such a subcutaneous or intramuscular depot-forming technologies or via alternative means of parenteral administration.
[0739] Pharmaceutically-acceptable formulations for use in the above-mentioned routes of administration may thus comprise compounds of the invention in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of direct parenteral administration and standard pharmaceutical practice. Such pharmaceutically-acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically-acceptable carriers may also impart an immediate, or a modified, release of the compound of the invention.
[0740] Formulations for injection may thus be in the form of an aqueous formulation such as an a suspension and / or, more preferably a solution (e.g. an (optionally) buffered aqueous formulation (e.g. solution) , such as a physiological saline-containing formulation (e.g. solution) , a phosphate-containing formulation (e.g. solution) , an acetate-containing formulation (e.g. solution) or a borate-containing formulation (e.g. solution) , or a freeze-dried powder that may be reconstituted with a vehicle, such as an aqueous vehicle prior to use (e.g. injection) ) .
[0741] Formulations for injection may include other suitable excipients known to those skilled in the art, such as solvents (e.g. water) , co-solvents, solubilizing agents (e.g. cyclodextrins) , wetting agents, suspending agents, emulsifying agents, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, bulking agents and / or protectants.
[0742] Formulations for injection are preferably buffered by standard techniques to physiologically-acceptable pH values (e.g. pHs of between about 4.5 and about 9.5, e.g. about 6 and about 9, such as between about 6.5 and about 8.5) using buffers and / or pH modifiers as described herein, and / or may further comprise tonicity-modifying agents (such as sodium chloride) .
[0743] The above notwithstanding, preferred modes of delivery of compounds of the invention include topically to the site of inflammation (e.g. the mucosa, including the oral and / or nasal mucosa, the lung, the anorectal area and / or the colon or, more preferably, the skin) in an appropriate (for example pharmaceutically-and topically-acceptable) vehicle suitable for application to the skin and / or the appropriate mucosal surface, and / or a commercially-available formulation, but may also include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, or pulmonary delivery.
[0744] Administration by injection is particularly useful for administering the compounds of the invention, in the form of a solution of suspension into e.g. the dermis (e.g. intradermal injection) , joint cavity or the eyes.
[0745] Administration by intradermal injection (e.g. intradermally) is particularly useful for administering the compound of the invention, in the form of a solution or suspension (e.g. a dermal filler) , into the dermis. This is particularly useful as a means of administration for melanin pigmentation therapy as described hereinbefore or for the use of the compounds of the invention in the treatment of, e.g. wrinkles.
[0746] Administration by injection is particularly useful to fill, e.g. the surgical site of the nasal cavity, the anal fistula, the space between the gingival and the root or the sinus. This is particularly useful for shaping support and / or lubrication.
[0747] Compounds of the invention will generally be administered in the form of one or more for example pharmaceutical formulations in admixture with a (e.g. pharmaceutically acceptable) adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration (e.g. topical to the relevant mucosa (including the lung) or, preferably, the skin) and standard pharmaceutical or other (e.g. cosmetic) practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart an immediate, or a modified, release of the compound of the invention.
[0748] Suitable pharmaceutical formulations may be commercially available or otherwise prepared according to techniques that are described in the literature, for example, Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press (2012) and Martindale –The Complete Drug Reference, 38th Edition, Pharmaceutical Press (2014) and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations including compounds of the invention may be achieved non-inventively by the skilled person using routine techniques.
[0749] Compounds of the invention may be in the form of an aqueous formulation such as an emulsion, a suspension and / or a solution (e.g. an (optionally) buffered aqueous formulation (e.g. solution) , such as a physiological saline-containing formulation (e.g. solution) , a phosphate-containing formulation (e.g. solution) , an acetate-containing formulation (e.g. solution) or a borate-containing formulation (e.g. solution) ) , or a freeze-dried powder.
[0750] Compounds of the invention may further and / or in the alternative be combined with appropriate excipients to prepare:
[0751] ● gel formulations (for which suitable gel matrix materials include cellulose derivatives, carbomer and alginates, gummi tragacanthae, gelatin, pectin, carrageenan, gellan gum, starch, Xanthan gum, cationic guar gum, agar, noncellulosic polysaccharides, saccharides such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymer and, particularly, hyaluronic acid) ;
[0752] ● lotions (for which suitable matrix materials include cellulose derivatives, glycerin, noncellulosic polysaccharides, polyethylene glycols of different molecular weights and propanediol) ;
[0753] ● pastes or ointments (for which suitable paste matrix materials include glycerin, vaseline, paraffin, polyethylene glycols of different molecular weights, etc. ) ;
[0754] ● creams or foams (for which suitable excipients (e.g. foaming agents) include hydroxypropyl methyl cellulose, gelatin, polyethylene glycols of different molecular weights, sodium dodecyl sulfate, sodium fatty alcohol polyoxyethylene ether sulfonate, corn gluten powder and acrylamide) ;
[0755] ● powder aerosols (for which suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol and polysorbates, e.g. a dry powder inhalant) ; and / or
[0756] ● liquid, for example, water (aerosol) sprays for oral use or for inhalation (for which suitable excipients include viscosity modifiers, such as hyaluronic acid, sugars, such as glucose and lactose, emulsifiers, buffering agents, alcohols, water, preservatives, sweeteners, flavours, etc. ) ;
[0757] ● injectable solutions or suspensions (which may be aqueous or otherwise and for which suitable excipients include solvents and co-solvents, solubilizing agents, wetting agents, suspending agents, emulsifying agents, thickening agents, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers and / or pH modifiers, bulking agents, protectants and tonicity-modifying agents) , particular injectable solutions or suspensions that may be mentioned include dermal fillers (i.e. injectable fillers or soft-tissue fillers) , particularly when the compound of the invention is combined with hyaluronic acid.
[0758] Moisturizing agents, such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and salts (e.g. sodium and potassium salts) thereof, octanoic / caprylic triglyceride, and the like; and / or antioxidants, such as vitamins and glutathione; and / or pH modifiers, such as acids, bases and pH buffers, may also be included in such formulations, as appropriate. Furthermore, surfactants / emulsifiers, such as hexadecanol (cetyl alcohol) , fatty acids (e.g. stearic acid) , sodium dodecyl sulfate (sodium lauryl sulfate) , sorbitan esters (e.g. sorbitan stearate, sorbitan oleate, etc. ) , monoacyl glycerides (such as glyceryl monostearate) , polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (e.g. polyoxyethylene sorbitan monooleate) , polyoxyethylene castor oil derivatives, ethoxylated fatty acid esters, polyoxylglycerides, lauryl dimethyl amine oxide, bile salts (e.g. sodium deoxycholate, sodium cholate) , lipids (e.g. fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids, polyketides) , phospholipids, N, N-dimethyldodecylamine-N-oxide, hexadecyltrimethyl-ammonium bromide, poloxamers, lecithin, sterols (e.g. cholesterol) , sugar esters, polysorbates, and the like; preservatives, such as phenoxyethanol, ethylhexyl glycerin, and the like; and thickeners, such as acryloyldimethyltaurate / VP copolymer, may be included. In particular, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, octanoic / capric glyceride etc. may be included, particularly in cream formulations.
[0759] Compounds of the invention, and (e.g. pharmaceutical) formulations (e.g. aqueous solutions, gels, creams, ointments, lotions, foams, pastes and / or dry powders as described above) including them, may further be combined with an appropriate matrix material to prepare a dressing or a therapeutic patch for application on a biological surface, such as the skin or a mucosal surface. Such formulations may thus be employed to impregnate a matrix material, such as gauze, non-woven cloth or silk paper. The therapeutic patch may alternatively be, for example, a band-aid, a facial mask, an eye mask, a hand mask, a foot mask, etc.
[0760] Vaseline may be employed for use in applying such dressings to wounds, but we have also found that ointments based on PEGs (e.g. PEG 400) may be combined with matrix materials to prepare dressings without the need to use Vaseline.
[0761] Compounds of the invention may also be used in combination with solid supports (such as nasal dressings (for example, to stop nasal bleeding) , dermal scaffolds (for example, in wound healing) or artificial bones (for example, in the case of bone grafting / implantation) .
[0762] Compounds of the invention may be administered for inhalation by way of suspension, a dry powder or a solution. Suitable inhalation devices include pressurized metered-dose inhalers (pMDIs) , which may be hand-or breath-actuated and employed with or without a standard spacer device, dry powder inhalers (DPIs) , which may be single-dose, multi-dose, and power-assisted, and soft mist inhalers (SMIs) or nebulizers, in which aerosol drug in a fine mist is delivered with slower velocity than a spray delivered using, for example, a pMDI.
[0763] In pMDIs, compounds of the invention may be administered as a pressurized suspension of micronized particles distributed in a propellant (e.g. HFA, along with excipients, such as mannitol, lactose, sorbitol, etc. ) , or as an ethanolic solutions, to deliver one or more metered dose of between about 20 and about 100 μL with each actuation. Actuation may be effected by hand (e.g. pressing) or by inhalation (breath-actuation) , involving a flow-triggered system driven by a spring.
[0764] In DPIs, compounds of the invention may be administered in the form of micronized drug particles (of a size between about 1 and about 5 μm) , either alone or blended with inactive excipient of larger particle size (e.g. mannitol) , inside a capsule, which may be pre-loaded or manually loaded into the device. Inhalation from a DPI may de-aggregate the medication particles and disperse them within the airways. In SMIs, compounds of the invention may be stored as a solution inside a cartridge, which is loaded into the device. A spring may release the dose into a micropump, such that the dose is released when a button is pressed, releasing jet streams of drug solution.
[0765] Various nebulizers may also be used to administer compounds of the invention in the form of a fine mist of aerosolized solution. Nebulizers may include breath-enhanced jet nebulizer (in which, with the assistance of a compressor, an air stream moves through jet causing drug solution to be aerosolized) ; breath-actuated jet nebulizers (in which, after a patient inhales, with the assistance of a compressor, an air stream moves through a tube causing the drug solution to be aerosolized) ; ultrasonic nebulizers (in which piezoelectric crystals vibrate causing aerosolization by heating causing nebulization) ; vibrating mesh nebulizers (in which piezoelectric crystals vibrate a mesh plate causing aerosolization to give very fine droplets without a significant change in temperature of the solution during nebulization) .
[0766] According to a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition / formulation, as defined herein, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient, as hereinbefore defined.
[0767] Compounds of the invention may also be combined in treatment with one or more growth factors selected from platelet-type growth factors (including platelet-derived growth factors, PDGFs) ; osteosarcoma-derived growth factors (ODGF) , epidermal growth factors (EGFs) , transforming growth factors (TGFα and TGFβ) , fibroblast growth factors (αFGF, βFGF) , insulin-like growth factors (IGF-I, IGF-II) , nerve growth factors (NGF) , interleukin-type growth factors (IL-1, IL-1, IL-3) , erythropoietin (EPO) , and colony stimulating factor (CSF) .
[0768] According to a further aspect of the invention there is provided a (e.g. pharmaceutical) composition comprising a compound of the invention and one or more pharmaceutically-acceptable excipient, such as an adjuvant, diluent or carrier. Preferred formulations are suitable for application locally to e.g. the mucosa (including the oral and / or nasal mucosa, the lung, the anorectal area and / or the colon) or, more preferably, the skin and therefore comprise a topically-acceptable adjuvant, diluent or carrier.
[0769] There is, thus, further provided pharmaceutical compositions comprising compounds of the invention that are suitable for, adapted for, and / or packaged and presented for topical administration (e.g. to the mucosa, including the oral and / or nasal mucosa, the lung, the anorectal area and / or the colon, or, preferably, to the skin) , as well as the use of such a formulation in the treatment of a disorder including inflammation, an inflammatory disorder and / or a condition characterized by inflammation (e.g. as a symptom) by way of direct topical administration of that formulation (e.g. to the mucosa, including the oral and / or nasal mucosa, the lung, the anorectal area and / or the colon, or, preferably, to the skin) .
[0770] In relation to this aspect of the invention, for the avoidance of doubt, topical formulations comprising compounds of the invention may be used in any and all conditions described herein, including treatments of inflammation, in the treatment of any and all inflammatory disorder (s) , and / or in the treatment of any and all condition (s) characterized by inflammation, as hereinbefore mentioned, defined or described. Similarly, topical formulations comprising compounds of the invention that may be mentioned include any and all of those mentioned, defined or described herein. Any and all of the relevant disclosures herein are hereby incorporated by reference in conjunction with this aspect of the invention.
[0771] Topical (e.g. liquid-or (e.g. aqueous) solution-based) formulations comprising compounds of the invention may be particularly useful in wound recovery, and may alleviate pain (including aching) and, particularly, pruritis / itching that is associated with the wound itself and the wound healing process. Such topical formulations comprising compounds of the invention may be particularly useful in the prevention and / or suppression of the exudation of body fluids from wounds, particularly during the acute inflammation stage, for example during the first 48 hours, after a burn or wound has been inflicted. This prevents the risk of infection, and other physiological reactions. Such topical formulations comprising compounds of the invention may also be particularly useful in the prevention and / or suppression of scarring and melanin pigmentation (vide supra) , whether associated with wounds or otherwise.
[0772] Administration of compounds of the invention may be continuous or intermittent. The mode of administration may also be determined by the timing and frequency of administration, but is also dependent, in the case of the therapeutic treatment of inflammation, on the severity of the condition.
[0773] Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof.
[0774] Similarly, the amount of compound of the invention in a formulation will depend on the severity of the condition, and on the patient, to be treated, but may be determined by the skilled person.
[0775] In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient, depending on the severity of the condition and route of administration. The dosages mentioned herein are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
[0776] Doses may be administered between once and four (e.g. three) times daily.
[0777] Appropriate concentrations of compounds of the invention in an aqueous solution product may be about 0.01 (e.g. about 0.1) to about 15.0 mg / mL, in all cases calculated as the free (non-salt) compound.
[0778] Appropriate topical doses of compounds of the invention are in the range of about 0.05 to about 50 μg / cm2 of treated area, such as about 0.1 (e.g. about 0.5) to about 20 μg / cm2 of treated area, including about 1 to about 10 μg / cm2 of treated area, such as about 5 μg / cm2 of treated area, in all cases calculated as the free (non-salt) compound.
[0779] Appropriate doses of compounds of the invention for nasal administration (e.g. by inhalation) are in the range of about 0.01 μg to about 2000 mg, for example between about 0.1 μg to about 500 mg, or between 1 μg to about 100 mg. Particular doses for nasal administration that may be mentioned include between about 10 μg to about 1 mg, particularly a dose of about 0.1 mg (i.e. about 100 μg) . Nasal administration of about 0.1 mg per day of compounds of the invention has been found to be particularly effective in the treatment of conditions associated with inflammation of the nasal passages and mucosae, such as rhinitis (e.g. allergic rhinitis) and / or conditions associated with nasosinusitis surgery.
[0780] Appropriate doses of compounds of the invention for pulmonary administration (e.g. by inhalation) are in the range of about 0.01 μg to about 2000 mg, for example between about 0.1 μg to about 500 mg, or between 1 μg to about 100 mg. Particular doses for pulmonary administration that may be mentioned include between about 10 μg to about 10 mg, particularly a dose of about 0.6 mg (i.e. 60 μg) to 6 mg (e.g. for use in treating COPD or IPF) .
[0781] We prefer that pH values of formulations comprising compounds of the invention are in the range of about 1.0 to about 9.0 (for example about 3.0 to about 8.0) .
[0782] In any event, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe (as described hereinbefore) . One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the age, condition, body weight, sex and response of the patient to be treated, and the stage / severity of the disease, as well as genetic differences between patients.
[0783] Compounds of the invention are useful in human and animal medicine. In this respect, and as described above, compounds of the invention that possess an appropriate degree of relevant pharmacological (or biological) activity per se may be used as human, and / or animal, medicines.
[0784] Certain compounds of invention, particularly compounds of formula I, may in addition and / or instead of possessing the aforementioned biological activity, possess adhesive properties.
[0785] These adhesive properties stem from the fact that the relevant W and / or U groups are capable of cross-linking with each other in order to form three-dimension networks.
[0786] Such compounds of the invention may adhere to a number of substrates including inorganic substrates, such as glass, metal and the like, as well as organic substrates, such as biological tissue.
[0787] In respect, such compounds of the invention may also be used as wound surface repair products, wound surface protecting products, medical biological adhesive products, medical coating products, industrial coating products (e.g. in corrosion prevention in ships, electronic apparatuses, pipelines and the like) , biochemical reagents, medical products, sterilization products, culture vessels for cell culture and the like.
[0788] Such compounds of the invention may form a film over various skin and mucous wound surfaces such as burns, scalds, ulcers, chilblains, and bedsores to aid in recovery. Such compounds of the invention may also be used in surgery, e.g. in the closure of surgical incisions, adhesion of fractured bones, adhesion of mucous membranes, coatings of human body implants such as artificial bones, cartilage brackets, periostea, artificial joints, dental implants, plugging stents, spinal fusion devices, spinal spacers and organ patches.
[0789] According to a further aspect of the invention, there is provided a compound of formula I as an adhesive or a film-forming material.
[0790] As discussed hereinbefore, naturally occurring MAP is known for its adhesive properties, but it should be remembered that such adhesives properties may arise from the fact that that is a high molecular weight, linear peptide that can exist in multiple conformations, enabling inter-and intramolecular reactions / cross-linking of DOPA residues in molecules, and thereby adhesion. Conversely, compounds of the invention as defined above are not linear polypeptides or proteins but are instead, for example multiply-branched lower molecular weight residues and it is a surprise to the applicant that similar properties (whether adhesive or biological) to naturally-occurring MAP are observed.
[0791] Such crosslinking may be carried out by a variety of chemicals (e.g. iodine vapour, glutaraldehyde, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC / NHS) , 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM) , or other water soluble condensation agents) or enzymatic means (e.g. tyrosinase, or as described hereinafter) .
[0792] Irrespective of the level of pharmacological activity that compounds of the invention may possess, they may in any event be (and / or may be further) combined with active pharmaceutical ingredients, either in combination therapy (as described hereinafter) , or by performing a function either as, or as part of, a pharmaceutically-acceptable excipient (e.g. an adjuvant, diluent or carrier) , as part of a medical device, and / or as part of a drug-medical device combination.
[0793] Certain compounds of the invention may thus be described as novel multifunctional excipients, which may be used for a variety of applications in the pharmaceutical field. In this respect, such compounds of the invention include those that may be used as adhesives and / or as film-forming agents (as described hereinbefore) , Furthermore, such compounds of the invention and / or different compounds of the invention may in the alternative, and / or in addition, be used as release retarding polymers, as binders, as suspending agents, as gelling agents, as coating agents, as diluents or as carriers for active ingredients (drugs) of varying solubilities.
[0794] Compounds of the invention that are particularly useful as pharmaceutical excipients may be adopted for large-scale production and may present no significant toxicity risk and may so be described and listed as ‘Generally Recognized as Safe’ (GRAS) by the US Food &Drug Administration (FDA) .
[0795] Such compounds of the invention may also be employed as excipients in veterinary science, as well as in cosmetics.
[0796] According to a further aspect of the invention, there is provided a pharmaceutical formulation comprising an active pharmaceutical ingredient in admixture with a pharmaceutically-acceptable excipient system (such as a pharmaceutically-acceptable adjuvant, diluent or carrier system) , which excipient system comprises one of more compounds of the invention.
[0797] Furthermore, compounds of the invention may be combined with active pharmaceutical ingredients, and may thus be employed as part of a drug-medical device combination, which combination comprises one or more active pharmaceutical ingredients and one or more compounds of the invention, in which said one or more compounds of the invention constitute the medical device component of that combination.
[0798] When used as, or as part of, a medical device or the medical device part of a drug-medical device combination, the skilled person will understand that the relevant compound of the invention will be employed in human or animal medicine, optionally in conjunction with an active pharmaceutical ingredient, in such a way as to affect the structure, and / or one or more functions, of a human or an animal body, and will achieve its primary intended purposes without exerting a chemical action within or on said human or animal body (optionally in a manner that is not dependent upon the compound of the invention being metabolized for the achievement of any of its primary intended purposes) .
[0799] In this respect, compounds of the invention may be combined with a multitude of known pharmaceutically-active ingredients and may be so combined irrespective of whether the compound of the invention is employed:
[0800] ● as a separate pharmaceutically-active ingredient per se in combination therapy;
[0801] ● as, or as part of, a medical device;
[0802] ● as, or as the medical device part of, a drug-medical device combination; or
[0803] ● as a pharmaceutically-acceptable excipient.
[0804] Such patients may also (and / or may already) be receiving therapy based upon administration of one or more of such other, known pharmaceutically-active ingredients, by which we mean receiving a prescribed dose of one or more of the active ingredients mentioned herein, prior to, in addition to, and / or following, treatment with a compound of the invention.
[0805] Pharmaceutically-active agents that may be co-administered with a compound of the invention include any agent, or drug, that is capable of producing some sort of physiological effect (whether in a therapeutic or prophylactic capacity against a particular disease state or condition) in a living subject, including, in particular, mammalian and especially human subjects (patients) .
[0806] In addition, compounds of the invention such as those that may be crosslinked as hereinbefore described may be employed as pharmaceutical excipients and may be mixed with such pharmaceutically-active ingredients either before or after crosslinking and / or at least partial crosslinking, as hereinbefore described, in order to form a stable pharmaceutical composition in which a compound of the invention acts an excipient, such as a carrier. When employed in this way, it may be found that compounds of the invention may affect, in a positive way, physical, chemical and / or biological properties of such active ingredients, including their physical and / or chemical stability and / or their metabolism following administration.
[0807] Pharmaceutically-active agents that may be used along with compounds of the invention may, for example, be selected from anti-inflammatory agents, pro-inflammatory agents, antibiotics, anti-bacterial and / or antiprotozoal agents, antiviral agents (e.g. protease inhibitors) , anaesthetics and wound recovery drugs (e.g. growth factors) .
[0808] Biologically-active agents may, for example, be selected from anti-inflammatory agents, pro-inflammatory agents, antibiotics, anti-bacterial and / or antiprotozoal agents, antiviral agents (e.g. protease inhibitors) , anaesthetics and wound recovery drugs (e.g. growth factors) .
[0809] Non-limiting examples of anti-inflammatory drugs which may be used also include those used in the treatment of rheumatic diseases and / or arthritis (such as cataflam, betamethasone, naproxen, cyclosporin, chondroitin, celecoxib, etodolac, meclofenamate, salsalate, methylprednisolone, and piroxicam) ; osteoarthritis (such as sulindac, meloxicam, fenoprofen, etoricoxib, and nabumetone) ; inflammation and its symptoms, e.g. fever, pain, itchiness and / or swelling (such as mefenamic acid, indomethacin, aspirin, ketorolac, fluorometholone, loteprednol, hydrocortisone, fluorometholone, bromfenac, prednisolone acetate, indomethacin, and ibuprofen) ; allergies and their symptoms (such as pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, lodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, emestine fumarate, olopatadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudophedrine, fexofenadine, terfenadine, loratadine, and alexis) ; respiratory diseases, including asthma and / or COPD (such as budesonide, ciclesonide, nedocromil, dexamethasone, ambroxol, and pranlukast) ; skin diseases (such as mometasone, triamcinolone, desonide, sulfacetamide, tacrolimus, allantoin, and triamcinolone) ; mastocytosis (such as cromolyn) ; gout (such as diclofenac, and febuxostat) ; conjunctivitis (such as hydrobenzole, pranoprofen, and zinc sulfate) ; eye diseases (such as dextran 70, thyroxine / liothyronine, and ocular extractives) , known or commercially-available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the forgoing compounds and / or salts.
[0810] Anti-inflammatory drugs that may be mentioned include endogenous (and / or exogenous) lipid-based pro-resolving, anti-inflammatory molecules or mediators, such as lipoxins, resolvins, and protectins. Pro-inflammatory agents that may be mentioned include prostaglandins (e.g. latanoprost, prostaglandin E1, and prostaglandin E2) , and leukotrienes (e.g. Leukotriene B4) .
[0811] Non-limiting examples of anti-bacterial drugs which may be used also include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomicin, gentamicin, cetylpyridinium, neomycin, roxithromycin, sulfadiazine silver, clarithromycin, clindamycin, metronidazole, azithromycin, mafenide, sulfamethoxazole, paracetamol, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, cefalexin, moxifloxacin, known or commercially-available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.
[0812] Non-limiting examples of antiviral drugs which may be used also include tobramycin ribavirin, acyclovir, moroxydine, foscarnet, ganciclovir, idoxuridine, trifluridine, brivudine, vidarabine, entecavir, telbivudine, foscarnet, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir, darunavir, telaprevir, boceprevir, simeprevir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir dipivoxil, fomivirsen, podofilox, imiquimod, sinecatechins, interferon-α 2b (recombinant, human) , known or commercially-available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.
[0813] Non-limiting examples of anaesthetics which may be used also include articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine and known or commercially-available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.
[0814] Non-limiting examples of wound recovery drugs which may be used also include basic fibroblast growth factor (recombinant, human; recombinant, bovine) , epidermal growth factor (recombinant, human; yeast) , rhEFG (I) , acidic fibroblast growth factor (recombinant, human) , granulocyte macrophage stimulating factor (recombinant, human) , sulfadiazine silver, sulfadiazine zinc, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, retinoids, calf blood deproteinized extract, carraghenates, amiotide and known or commercially-available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.
[0815] Such pharmaceutically-active ingredients include those that may be administered topically, e.g. to the skin or to a mucosal surface along with a compound of the invention. In this respect, preferred active ingredients from the above list include cyclosporin, 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) , sulfacetamide, tacrolimus, allantoin, triamcinolone, cromolyn, nedocromil, diclofenac, hydrobenzole, pranoprofen, zinc sulfate, dextran 70, thyroxine / liothyronine, ocular extractives, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomicin, gentamicin, cetylpyridinium, neomycin, roxithromycin, sulfadiazine silver, clarithromycin, sulfamethoxazole, chloramphenicol, tobramycin ribavirin, acyclovir, moroxydine, foscarnet, ganciclovir, interferon-α 2b (recombinant, human) , articaine, dextropropoxyphene, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxine, benzocaine, dibucaine, diclonine, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human; recombinant, bovine) , epidermal growth factor (recombinant, human; yeast) , rhEFG (I) , acidic fibroblast growth factor (recombinant, human) , granulocyte macrophage stimulating factor (recombinant, human) , sulfadiazine silver, sulfadiazine zinc, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, ethacridine, retinoids, calf blood deproteinized extract, carraghenates, amiotide, and known or commercially-available pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing compounds and / or salts.
[0816] Other pharmaceutically-active ingredients that may be co-administered with a compound of the invention include those that may be administered to treat one or of the gastrointestinal disorders mentioned hereinbefore.
[0817] Non-limiting examples of gastrointestinal drugs include oxalazine (olsalazine) , sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, live bacillus (such as clostridium butyricum, licheniformis, cereus) , probiotics (such as bifidobacterium) tegafur, nifuratel, amoxicillin, ampicillin, nystatin, allicin, cefadroxil, dyclonine, carmofur, fluorouracil, mosapride, sodium carbosulfan, thrombin, pantoprazole, cimetidine, cisapride, ethylenediamine diacetamine, nimustine, famotidine, barium sulfate, aminocaproic acid, roxatidine acetate, vincristine, azasetron, lentinan, bismuth salts (e.g. aluminate, potassium citrate) in combination with e.g. magnesium salts, magnesium trisilicate, bicarbonate, vitamin U, aluminium hydroxide, belladonna extract, famotidine and calcium carbonate, magnesium hydroxide, hydrotalcite, proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole or esomeprazole) , glycine, trypsin, allantoin aluminium hydroxide, sodium L-glutamine gualenate, rebampette, rotundine, quxipite, lafutidine, thymus protein, hericium erinaceus, irsogladine maleate, nizatidine, L-glutamine and sodium azulene sulfonate (sodium gualenate) , ranitidine, bismuth citrate, lactobacillin, bisacordine, dimethylsiloxane, live clostridium butyricum, loperamide hydrochloride, dibazol, secnidazole, zinc acephate, montmorillonite, tegafur / gimeracil / oteracil, famotidine, oteracil, doxifluridine, capecitabine and known or commercially-available pharmaceutically acceptable salts of any of the foregoing.
[0818] Pharmaceutically-active ingredients that may be mentioned for use in combination with compounds of the invention include active ingredients that are useful in the treatment of inflammation and / or inflammatory disorders (other anti-inflammatory agents) .
[0819] Anti-inflammatory agents that may be used in combination with compounds of the invention in the treatment of inflammation include therapeutic agents that are useful in the treatment of inflammation and / or of diseases characterized by inflammation as one of its symptoms, including those described hereinbefore. Depending on the condition to be treated, such anti-inflammatory agents may include NSAIDs (e.g. aspirin) , aminosalysates (e.g. 5-aminosalicyclic acid (mesalazine) ) , leukotriene receptor antagonists (e.g. montelukast, pranlukast, and zafirlukast) , corticosteroids, analgesics and certain enzymes, such as trypsin, for example as described hereinafter. Compounds of the invention may also be combined with leukotrienes (e.g. cysteinyl leukotrienes, and leukotriene B4) .
[0820] Other preferred agents that may be combined with compounds of the invention include LTB4 (to treat wounds and burns) , NSAIDS (e.g. aspirin) or montelukast (to treat inflammation generally) and trypsin (to treat inflammation of the mucosa associated with e.g. viral infections) .
[0821] Compounds of the invention may also be combined with other therapeutic agents which, when administered, are known to give rise to inflammation as a side-effect.
[0822] Conjugates of the invention may also be combined with stem cells (e.g. totipotent (omnipotent) , pluripotent (such as embryonic or induced pluripotent stem cells) , multipotent (such as mesenchymal stem cells) , oligopotent (such as hematopoietic stem cells) , or unipotent (such as muscle stem cells) .
[0823] Other known pharmaceutically-active ingredients may also be administered in combination with compounds of the invention in numerous ways.
[0824] For example, compounds of the invention may be ‘combined’ with the (or with the other) pharmaceutically-active ingredients (or ‘therapeutic agents’ ) for administration together in the same (e.g. pharmaceutical) formulation, or administration separately (simultaneously or sequentially) in different (e.g. pharmaceutical) formulations.
[0825] Thus, such combination products provide for the administration of compounds of the invention in conjunction with the (or with the other) therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the (or the other) therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the (or the other) therapeutic agent) .
[0826] Thus, there is further provided:
[0827] (1) a (e.g. pharmaceutical) formulation including a compound of the invention; another pharmaceutically-active ingredient; and, optionally, a pharmaceutically-acceptable inactive excipient (e.g. adjuvant, diluent or carrier) , which formulation is hereinafter referred to as a ‘combined preparation’ ; and
[0828] (2) a kit of parts comprising components:
[0829] (A) a compound of the invention, optionally in the form of a (e.g. pharmaceutical) formulation in admixture with a pharmaceutically-acceptable inactive excipient (e.g. adjuvant, diluent or carrier) ; and
[0830] (B) another pharmaceutically-active ingredient, optionally in the form of a (e.g. pharmaceutical) formulation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,
[0831] which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
[0832] In a further aspect of the invention, there is provided a process for the preparation of a combined preparation (1) as hereinbefore defined, which process comprises bringing into association a compound of the invention, the other pharmaceutically-active ingredient, and at least one (e.g. pharmaceutically-acceptable) excipient.
[0833] In a further aspect of the invention, there is provided a process for the preparation of a kit-of-parts (2) as hereinbefore defined, which process comprises bringing into association components (A) and (B) . As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.
[0834] Thus, in relation to the process for the preparation of a kit-of-parts as hereinbefore defined, by bringing the two components ‘into association with’ each other, we include that the two components of the kit-of-parts may be:
[0835] (i) provided separately (i.e. independently of one another) , which are subsequently brought together for use in conjunction with each other in combination therapy; or
[0836] (ii) packaged and presented together as separate components of a ‘combination pack’ for use in conjunction with each other in combination therapy.
[0837] Thus, there is further provided a kit of parts comprising:
[0838] (I) one of components (A) and (B) as defined herein; together with
[0839] (II) instructions to use that component in conjunction with the other of the two components.
[0840] In relation to kits of parts described above, although the compound of the invention may be provided in the form of an (e.g. pharmaceutical) formulation, in admixture with one or more additional pharmaceutically-acceptable excipients (e.g. adjuvants, diluents or carriers) , when the compound of the invention is provided with a view to it primarily performing its function as a medical device or as an excipient, it may not be provided along with such additional pharmaceutically-acceptable excipients. In any event, it is preferred that the (other) pharmaceutically-active ingredient of the kit of parts is provided in the form of a pharmaceutical formulation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
[0841] The kits of parts described herein may comprise more than one (e.g. formulation including an) appropriate quantity / dose of a compound of the invention, and / or more than one (e.g. formulation including an) appropriate quantity / dose of the other pharmaceutically-active ingredient, in order to provide for repeat dosing. If more than one formulation comprising or quantity / dose of either of the foregoing is present, such may be the same, or may be different in terms of the dose of either compound, chemical composition (s) and / or physical form (s) .
[0842] With respect to the kits of parts as described herein, by ‘administration in conjunction with’ , we include that respective components are administered, sequentially, separately and / or simultaneously, over the course of treatment of the relevant condition.
[0843] Thus, in respect of the combination product according to the invention, the term ‘administration in conjunction with’ includes that the two components of the combination product (compound of the invention and other pharmaceutically-active ingredient) are administered (optionally repeatedly) , either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either the compound of the invention, or (e.g. a formulation comprising) the other agent, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
[0844] Further, in the context of a kit of parts according to the invention, the term ‘in conjunction with’ includes that one or other of the two components may be administered (optionally repeatedly) prior to, after, and / or at the same time as, administration of the other component. When used in this context, the terms ‘administered simultaneously’ and ‘administered at the same time as’ include that individual quantities / doses of the relevant compound of the invention and other active pharmaceutical ingredient are administered within 48 hours (e.g. 24 hours) of each other.
[0845] In relation to combined preparations and kits of parts described above, it is preferred that the other pharmaceutically-active ingredient is an anti-inflammatory agent, or agent known to give rise to inflammation as a side-effect, as hereinbefore described.
[0846] Wherever the word ‘about’ is employed herein, for example in the context of amounts, such as concentrations and / or doses of active ingredients and / or compounds of the invention, molecular weights or pHs, it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5%and preferably ± 2%(e.g. ± 1%) from the numbers specified herein. In this respect, the term ‘about 10%’ means e.g. ±10%about the number 10, i.e. between 9%and 11%.
[0847] Compounds of the invention have the advantage that they have a wide variety of uses, including:
[0848] ● as biologically-active agents in variety of conditions characterised by inflammation, whether that condition is an organic inflammatory disease per se or is associated with, or is characterised by, inflammation (e.g. a wound or a burn) , and / or in surgical and / or cosmetic applications as described hereinbefore; and / or
[0849] ● in combination with active pharmaceutical ingredients, either in combination therapy, or by performing a more inert function either as, or as part of:
[0850] ○ a pharmaceutically-acceptable excipient (e.g. an adjuvant, diluent or carrier) ,
[0851] ○ a medical device, and / or
[0852] ○ the medical device part of a drug-medical device combination.
[0853] The compounds, uses and methods described herein may also have the advantage that, in the treatment of the conditions mentioned hereinbefore, they may be more convenient for the physician and / or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it / they may have other useful pharmacological properties over, similar compounds or methods (treatments) known in the prior art, whether for use in the treatment of any of the aforementioned conditions, including inflammation, inflammatory disorders, or disorders characterised by inflammation as a symptom (including wounds) , or otherwise.
[0854] Brief description of Figures
[0855] Figures 1 and 2 show the degree of swelling obtained in the mouse model experiments of Examples 21 and 22, respectively.Examples
[0856] As used herein, “N- (acid-PEG3) -N-bis (PEG3-amine) ” refers to the following structure, having the CAS No. 2183440-35-7:
[0857] the following fragment (as appropriate) :
[0858] The names “N-bis (amine-PEG3) -N- (acid-PEG3) ” , “N-bis (PEG3-amine) -N- (PEG3-acid) ” , “N-bis (PEG3-amine) -N-PEG3-acid” and “N-bis (amine-PEG3) -N- (PEG3-acid) ” are used interchangeably with “N- (acid-PEG3) -N-bis (PEG3-amine) ” .
[0859] In the examples below, when a peptide is bound to the two amines in N- (acid-PEG3) -N-bis (PEG3-amine) , this is indicated in the names of the compounds as follows: N- (acid-PEG3) -N-bis (peptide-NH-PEG3) , wherein the amino acid fragment adjacent to “NH” is the amino acid bound to the amine.
[0860] Examples wherein a peptide is bound at only one of the amines are named in an analogous manner.
[0861] As used herein, “tri (Amino-PEG3-amide) -amine” refers to the following structure having the CAS no. 2523025-40-1:
[0862] Example 1
[0863] N-Bis (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3) -N- (PEG3 acid) (SEQ ID No: 188)
[0864] N-Bis (Fmoc-NH-PEG3) -N- (PEG3-acid) -Wang resin (13.5 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.
[0865] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and allowed to soak the resin for about half an hour. The DCM was then removed by vacuum filtration.
[0866] The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
[0867] A 20%piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) solution in DMF (DBLK, 200 mL) was added as deprotection solution and reacted for 20 minutes. The solution was then removed by vacuum filtration and the column was washed with DMF for six times.
[0868] Fmoc-Lys (Boc) -OH (8.44 g; GL Biochem, Shanghai, China) and 2- (1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethylaminium tetrafluoroborate (TBTU, 5.78 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N, N-diisopropylethylamine (DIPEA, 4.66 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China) . A Kaiser Test was carried out with few of the resin after 30 minutes reaction, a yellow color of the solution and colorless gel indicating the reaction was complete. The solvent was removed by vacuum filtration.
[0869] The above coupling steps were repeated to couple the remaining amino acids in the same amounts (by mols) : Fmoc-4-Hyp (tBu) -OH, Fmoc-DOPA (Acetonide) -OH, Fmoc-Thr (tBu) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Lys (Boc) -OH and Fmoc-Ala-OH.
[0870] In a separate procedure, after Fmoc-Ala-OH was coupled on the resin, a deprotection step was carried out to remove the Fmoc protection on Alanine. The resin was washed 3 times with DMF (200 mL each time) . A 20%piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. Then, the resin was washed three times each with the following solvents, DMF (200 mL each time) , DCM (200 mL each time) and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China) . The resin was dried under vacuum for about 2 hours.
[0871] 190.0 mL (i.e. 10 mL per gram of the dried resin) of lysate, which comprised of 95%trifluoroacetic acid (TFA, Macklin, Shanghai, China) , 2.5%water and 2.5%triisopropylsilane (Tis, Macklin, Shanghai, China) , were added to immerse the resin-bounded peptide-containing compound. After cleavage for about 2 hours, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1700 mL (i.e. 10 mL per ml of the filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China) and the sediment was collected by filtration. The sediment was dried by vacuum for about 2 hours, yielding 8.58 g of crude title compound.
[0872] The crude product was firstly analysed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan) . The analysis column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～90%solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL) .
[0873] The target peak was eluted at 10.378 minutes and had the expected molecular weight, with a purity of 71.382%.
[0874] MS: m / z 2934.6
[0875] 8.5 g of crude product was then dissolved in 90 mL of pure water and purified using NP7010C semi-preparation equipment (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) . The preparation column model was a Dubhe-C18 model (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) (50*250 mm, column; detection: UV at 220 nm) . The appropriate gradient for elution was calculated from LCMS detection step (Solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min; ) . Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) (column as above, except with a linear gradient from 5%-30%solvent A concentration in 25 minutes) .
[0876] Fractions with a purity of higher than 90%were then mixed together for an anion exchange step. This was achieved using a NP7010C semi-preparation equipment, preparation column model: Dubhe-C18 model (as above) . The fractions were diluted one time with pure water and loaded to the column directly, after that the column was washed with 3.2%of ammonium acetate in pure water for about 20 minutes followed by pure water for another 10 minutes at the flow rate of 60 mL / min, then eluted with the following gradient (Solvent A: 0.1%hAc in MeCN, solvent B: 0.1%hAc in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min) . Fractions were collected and analyzed using Shimadzu LC-20 HPLC system (column and conditions as above) . Fractions with a purity of higher than 95%were mixed and freeze-dried to give 3.78 g of the purified title compound.
[0877] Example 2
[0878] N-Bis { [N-Bis (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3) -N- (PEG3 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 189)
[0879] The method was the same as described in Example 1, starting with N-Bis (Fmoc-NH-PEG3) -N- (PEG3 acid) followed by Fmoc-Lys (boc) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Dopa (Acetonide) -OH, Fmoc-Thr (tBu) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Lys (Boc) -OH and Fmoc-Ala-OH, and the amounts of the amino acids, TBTU and DIPEA were doubled (by mol) except N-Bis(Fmoc-amido-PEG3) -N-PEG3 acid coupling step was not doubled compared with Example 1.
[0880] MS: m / z 6404.3
[0881] Repeating essentially the same procedure gave a further batch of crude title compound (yield 17.25 g) . Analysis showed a target peak that was eluted at 11.732 minutes with the expected molecular weight (MS: m / z 6404.3) . The purity was 50.281%.
[0882] 17 g of the crude product was then purified as described in Example 1 above to give 5.73 g of pure title compound after freeze-drying.
[0883] Example 3
[0884] N-Bis (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3) -N- (PEG3 amide) (SEQ ID No: 190)
[0885] The method was the same as described in Example 1 except that N-Bis (Fmoc-NH-PEG3) -N- (PEG3 acid) -AM resin (12.9 g, GL Biochem, Shanghai, China) was used as the starting material compared with Example 1.
[0886] MS: m / z 2949.6
[0887] Repeating essentially the same procedure gave a further batch of crude title compound (yield 7.36 g) . Analysis showed a target peak that was eluted at 10.246 minutes with the expected molecular weight (MS: m / z 2949.6) . The purity was 71.377%.
[0888] 7 g of the crude product was then purified as described in Example 1 above to give 3.67 g of pure title compound after freeze-drying.
[0889] Example 4
[0890] N-Bis { [N-Bis (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG5) -N- (PEG5 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 191)
[0891] The method was the same as described in Example 1, starting with N-Bis (Fmoc-NH-PEG5) -N- (PEG5 acid) followed by Fmoc-Lys (boc) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Dopa (Acetonide) -OH, Fmoc-Thr (tBu) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Lys (Boc) -OH and Fmoc-Ala-OH, and the amounts of the amino acids, TBTU and DIPEA were doubled (by mol) except N-Bis (Fmoc-amido-PEG5) -N-PEG5 acid coupling step was not doubled compared with
[0892] Example 1.
[0893] MS: m / z 6668.3
[0894] Repeating essentially the same procedure gave a further batch of crude title compound (yield 18.17 g) . Analysis showed a target peak that was eluted at 12.072 minutes with the expected molecular weight (MS: m / z 6668.3) . The purity was 51.392%.
[0895] 18 g of the crude product was then purified as described in Example 1 above to give 5.96 g of pure title compound after freeze-drying.
[0896] Example 5
[0897] N-Bis (Montelukast-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3) -N- (PEG3 acid) (SEQ ID No: 192)
[0898] The method was the same as described in Example 1 except that after Fmoc-Ala-OH was connected and deprotected, a further coupling step with montelukast sodium was carried out compared with Example 1.
[0899] MS: m / z 4071.0
[0900] Repeating essentially the same procedure gave a further batch of crude title compound (yield 10.19 g) . Analysis showed a target peak that was eluted at 32.847 minutes with the expected molecular weight (MS: m / z 4071.0) . The purity was 47.93%.
[0901] 10 g of the crude product was then purified as described in Example 1 above to give 2.95 g of pure title compound after freeze-drying.
[0902] Example 6
[0903] N-Bis (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3 acid) -Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 193)
[0904] Fmoc-Lys (Boc) -Wang resin (9.15 g; GL Biochem, Shanghai, China) was loaded into a glass reaction column.
[0905] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and allowed to soak the resin for about half an hour. The DCM was then removed by vacuum filtration.
[0906] The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
[0907] A 20%piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) solution in DMF (DBLK, 200 mL) and was added as deprotection solution and reacted for 20 minutes. The solution was then removed by vacuum filtration and the column was washed with DMF for six times.
[0908] Fmoc-DOPA (Acetonide) -OH (4.14 g; GL Biochem, Shanghai, China) and 2- (1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N, N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China) . A Kaiser Test was carried out with few of the resin after 30 minutes reaction, a yellow color of the solution and colorless gel indicating the reaction was complete. The solvent was removed by vacuum filtration.
[0909] The above coupling steps were repeated to couple the remaining amino acids in the same amounts (by mols) : Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Lys (Boc) -OH and N-Bis (Fmoc-NH-PEG3) -N- (PEG3 acid) .
[0910] After N-Bis (Fmoc-NH-PEG3) -N- (PEG3 acid) was coupled on the resin, a deprotection step was carried out to remove the Fmoc protection on N-Bis (amino-PEG3) -N- (PEG3 acid) . The resin was washed 3 times with DMF (200 mL each time) . A 20%piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. Then, the resin was washed with DMF for six times.
[0911] Then another coupling steps were carried out starting with Fmoc-Lys (Boc) -OH followed by Fmoc-DOPA (Acetonide) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser(tBu) -OH, Fmoc-Pro-OH and Fmoc-Lys (Boc) -OH, and in this coupling steps the amounts of the amino acids, TBTU and DIPEA were doubled (by mol) compared with former coupling steps.
[0912] In a separate procedure, after Fmoc-Lys (Boc) -OH was coupled on the resin, a deprotection step was carried out to remove the Fmoc protection on Lysine. The resin was washed 3 times with DMF (200 mL each time) . A 20%piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. Then, the resin was washed three times each with the following solvents, DMF (200 mL each time) , DCM (200 mL each time) and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China) . The resin was dried under vacuum for about 2 hours.
[0913] 180.0 mL (i.e. 10 mL per gram of the dried resin) of lysate, which comprised of 95%trifluoroacetic acid (TFA, Macklin, Shanghai, China) , 2.5%water and 2.5%triisopropylsilane (Tis, Macklin, Shanghai, China) , were added to immerse the resin-bounded peptide-containing compound. After cleavage for about 2 hours, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1600 mL (i.e. 10 mL per ml of the filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China) and the sediment was collected by filtration. The sediment was dried by vacuum for about 2 hours, yielding 7.23 g of crude title compound.
[0914] The crude product was firstly analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan) . The analysis column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～90%solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL) .
[0915] The target peak was eluted at 15.232 minutes and had the expected molecular weight, with a purity of 64.322%.
[0916] MS: m / z 3259.8
[0917] 7.2 g of crude product was then dissolved in 70 mL of pure water and purified using NP7010C semi-preparation equipment (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) . The preparation column model was a Dubhe-C18 model (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) (50*250 mm, column; detection: UV at 220 nm) . The appropriate gradient for elution was calculated from LCMS detection step (Solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min; ) . Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) (column as above, except with a linear gradient from 5%-30%solvent A concentration in 25 minutes) .
[0918] Fractions with a purity of higher than 90%were then mixed together for an anion exchange step. This was achieved using a NP7010C semi-preparation equipment, preparation column model: Dubhe-C18 model (as above) . The fractions were diluted one time with pure water and loaded to the column directly, after that the column was washed with 3.2%of ammonium acetate in pure water for about 20 minutes followed by pure water for another 10 minutes at the flow rate of 60 mL / min, then eluted with the following gradient (Solvent A: 0.1%hAc in MeCN, solvent B: 0.1%hAc in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min) . Fractions were collected and analyzed using Shimadzu LC-20 HPLC system (column and conditions as above) . Fractions with a purity of higher than 95%were mixed and freeze-dried to give 2.55 g of the purified title compound.
[0919] Example 7
[0920] N- (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) - (PEG3 acid) -Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 194)
[0921] Fmoc-Lys (Boc) -Wang resin (9.15 g; GL Biochem, Shanghai, China) was loaded into a glass reaction column.
[0922] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and allowed to soak the resin for about half an hour. The DCM was then removed by vacuum filtration.
[0923] The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
[0924] A 20%piperidine (Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) solution in DMF (DBLK, 200 mL) and was added as deprotection solution and reacted for 20 minutes. The solution was then removed by vacuum filtration and the column was washed with DMF for six times.
[0925] Fmoc-DOPA (Acetonide) -OH (4.14 g; GL Biochem, Shanghai, China) and 2- (1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N, N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd., Jiangsu, China) . A Kaiser Test was carried out with few of the resin after 30 minutes reaction, a yellow color of the solution and colorless gel indicating the reaction was complete. The solvent was removed by vacuum filtration.
[0926] The above coupling steps were repeated to couple the remaining amino acids in the same amounts (by mols) : Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Lys (Boc) -OH and N- (Fmoc-NH-PEG3) -N- (Dde-NH-PEG3) -(PEG3 acid) .
[0927] After N- (Fmoc-NH-PEG3) -N- (Dde-NH-PEG3) - (PEG3 acid) was coupled on the resin, a deprotection step was carried out to remove the Fmoc protection on N-Bis (amino-PEG3) -N- (PEG3 acid) . The resin was washed 3 times with DMF (200 mL each time) . A 20%piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. Then, the resin was washed with DMF for six times.
[0928] Then another coupling steps were carried out starting with Fmoc-Lys (Boc) -OH followed by Fmoc-Tyr (tBu) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH and Fmoc-Lys (Boc) -OH, the amounts of the amino acids, TBTU and DIPEA were the same (by mol) compared with former coupling steps.
[0929] After Fmoc-Lys (Boc) -OH was coupled on the resin, a deprotection step was carried out to remove the Dde protection on N-Bis (amino-PEG3) -N- (PEG3 acid) . The resin was washed 3 times with DMF (200 mL each time) . A 5%hydrazine hydrate solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. Then, the resin was washed with DMF for six times.
[0930] Then the other coupling steps were carried out starting with Fmoc-Lys (Boc) -OH followed by Fmoc-DOPA (Acetonide) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-4-Hyp (tBu) -OH and Fmoc-Lys (Boc) -OH, the amounts of the amino acids, TBTU and DIPEA were the same (by mol) compared with former coupling steps.
[0931] In a separate procedure, after Fmoc-Lys (Boc) -OH was coupled on the resin, a deprotection step was carried out to remove the Fmoc protection on Lysine. The resin was washed 3 times with DMF (200 mL each time) . A 20%piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. Then, the resin was washed three times each with the following solvents, DMF (200 mL each time) , DCM (200 mL each time) and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China) . The resin was dried under vacuum for about 2 hours.
[0932] 180.0 mL (i.e. 10 mL per gram of the dried resin) of lysate, which comprised of 95%trifluoroacetic acid (TFA, Macklin, Shanghai, China) , 2.5%water and 2.5%triisopropylsilane (Tis, Macklin, Shanghai, China) , were added to immerse the resin-bounded peptide-containing compound. After cleavage for about 2 hours, the solid support was removed by filtration and the filtrate was collected under reduced pressure. The filtrate was precipitated with 1600 mL (i.e. 10 mL per ml of the filtrate) of diethyl ether (Xilong Scientific Co., Ltd., Guangdong, China) and the sediment was collected by filtration. The sediment was dried by vacuum for about 2 hours, yielding 7.15 g of crude title compound.
[0933] The crude product was firstly analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan) . The analysis column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～90%solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL) .
[0934] The target peak was eluted at 15.322 minutes and had the expected molecular weight, with a purity of 61.453%.
[0935] MS: m / z 3259.8
[0936] 7.1 g of crude product was then dissolved in 70 mL of pure water and purified using NP7010C semi-preparation equipment (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) . The preparation column model was a Dubhe-C18 model (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) (50*250 mm, column; detection: UV at 220 nm) . The appropriate gradient for elution was calculated from LCMS detection step (Solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min; ) . Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) (column as above, except with a linear gradient from 5%-30%solvent A concentration in 25 minutes) .
[0937] Fractions with a purity of higher than 90%were then mixed together for an anion exchange step. This was achieved using a NP7010C semi-preparation equipment, preparation column model: Dubhe-C18 model (as above) . The fractions were diluted one time with pure water and loaded to the column directly, after that the column was washed with 3.2%of ammonium acetate in pure water for about 20 minutes followed by pure water for another 10 minutes at the flow rate of 60 mL / min, then eluted with the following gradient (Solvent A: 0.1%hAc in MeCN, solvent B: 0.1%hAc in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min) . Fractions were collected and analyzed using Shimadzu LC-20 HPLC system (column and conditions as above) . Fractions with a purity of higher than 95%were mixed and freeze-dried to give 2.49 g of the purified title compound.
[0938] Example 8
[0939] Tri (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3-amide) -amine (SEQ ID No: 195)
[0940] The title compound was synthesized from Lysine as the first amino acid with Fmoc-Lys (Boc) -CTC resin as the solid support.
[0941] Fmoc-Lys (Boc) -CTC resin (7.35 g, USUN pharma, Jiangsu, China) was loaded into a glass reaction column.
[0942] Methylene chloride (DCM, 200 mL; Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column and allowed to soak the resin for about half an hour. The DCM was then removed by vacuum filtration.
[0943] The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co Ltd, Shandong, China) .
[0944] A 20%piperidine solution in DMF (200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd, Shandong, China) was added as deprotection solution and reacted for 20 minutes.
[0945] The solution was then removed by vacuum filtration and the resin in column was washed with DMF six times.
[0946] Fmoc-DOPA (Acetonide) -OH (4.14 g; GL Biochem, Shanghai, China) and 2- (1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g; 00705, GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by N, N-diisopropylethylamine (DIPEA, 2.33 g; Suzhou Highfine Biotech Co. Ltd, Jiangsu, China) . A Kaiser Test was carried out with few of the resin after 30 minutes reaction, a yellow color of the solution and colorless gel indicating the reaction was complete. The solvent was removed by vacuum filtration.
[0947] The above coupling steps were repeated to couple the remaining amino acids in the same amounts (by mols) : Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH and Boc-Lys (Boc) -OH.
[0948] After Boc-Lys (Boc) -OH was coupled on the resin, the resin was washed three times each with the following solvents, DMF (200 mL each time) , DCM (200 mL each time) and methanol (200 mL each time) . Then the resin is dried by vacuum for about 2 hours.
[0949] 120.0 mL (i.e. 10 mL per gram of the dried resin) of lysate, which comprised of 2%trifluoroacetic acid (TFA) in DCM, was added to immerse the resin-bounded peptide-containing compound. After cleavage for about 2 hours, the solid support was removed by filtration and the filtrate is collected under reduced pressure. Then the filtrate was concentrated by rotary distillation under reduced pressure. After all solvents were removed, Tri (Amino-PEG3-amide) -amine (0.38g, CAS: 2523025-40-1; GL Biochem, Shanghai, China) was added, followed by pyridine (100 mL) was added to the flask to dissolve the solids, then phosphorus oxychloride (0.3ml, Adamas-beta Co. Ltd., Shanghai, China) was added to the reaction solution. After 3 hours of the reaction, the reaction was completed. Precipitation of the final solution was carried out by adding 1200 mL (i.e. 10 mL per ml of the final solution) of saturated citric acid (Aladdin, Shanghai, China) water solution and sediment is collected by filtration. The sediments were then added 120 mL (i.e. 10 mL per gram of the solid) of lysate, which comprised of 95%trifluoroacetic acid (TFA) , 2.5%water and 2.5%triisopropylsilane (Tis) , was added to dissolve the peptide-containing solid. The side chains were deprotected during cleavage. After cleavage for about 2 hours, the solution was precipitated with 1200 mL (i.e. 10 mL per ml of the filtrate) of diethyl ether and sediment is collected by filtration. The sediment is dried by vacuum for about 2 hours. Finally, 7.11g of crude title compound was obtained.
[0950] The crude product was firstly analysed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system (Shimadzu, Japan) . The analysis column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column; detection: UV at 220 nm; solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～90%solvent A concentration in 50 minutes; flow rate 1.0 mL / min; sample volume: 10 μL) .
[0951] The target peak was eluted at 17.123 minutes and had the expected molecular weight, with a purity of 55.284%.
[0952] MS: m / z 3444.1
[0953] 7.1 g of crude product was then dissolved in 70 mL of pure water and purified using NP7010C semi-preparation equipment (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) . The preparation column model was a Dubhe-C18 model (Hanbon Sci. &Tech. Co., Ltd., Jiangsu, China) (50*250 mm, column; detection: UV at 220 nm) . The appropriate gradient for elution was calculated from LCMS detection step (Solvent A: 0.1%TFA in MeCN, solvent B: 0.1%TFA in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min; ) . Fractions were collected and analyzed using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) (column as above, except with a linear gradient from 5%-30%solvent A concentration in 25 minutes) .
[0954] Fractions with a purity of higher than 90%were then mixed together for an anion exchange step. This was achieved using a NP7010C semi-preparation equipment, preparation column model: Dubhe-C18 model (as above) . The fractions were diluted one time with pure water and loaded to the column directly, after that the column was washed with 3.2%of ammonium acetate in pure water for about 20 minutes followed by pure water for another 10 minutes at the flow rate of 60 mL / min, then eluted with the following gradient (Solvent A: 0.1%hAc in MeCN, solvent B: 0.1%hAc in water, with a linear gradient from 5%～20%solvent A concentration in 30 minutes; flow rate 60.0 mL / min) . Fractions were collected and analyzed using Shimadzu LC-20 HPLC system (column and conditions as above) . Fractions with a purity of higher than 95%were mixed and freeze-dried to give 2.04 g of the purified title compound.
[0955] Example 9
[0956] N-Bis { [N-Bis (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (PEG3-acid) ] -NH-PEG3} -N- (PEG3-acid) (SEQ ID No: 260)
[0957] The title compound was prepared using essentially the same process as that described in Example 2 above, except that the appropriate amino acids were used as in the relevant peptide coupling sequences.
[0958] MS: m / z 5199.1
[0959] Repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 14.12 g) . Analysis showed a target peak that was eluted at 10.792 minutes with the expected molecular weight (MS: m / z 5199.1) . The purity was 53.223%.
[0960] 14.1 g of the crude product was then purified as described in Example 1 above to give 3.92 g of pure title compound after freeze-drying.
[0961] Example 10
[0962] N-Bis { [N-Bis (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3-acid) ] -NH-PEG3} -N- (PEG3-acid) (SEQ ID No: 261)
[0963] The title compound was prepared using essentially the same process as that described in Example 9 above, except that Fmoc-DOPA (Acetonide) -OH was used instead of Fmoc-Tyr(tBu) -OH in the same amounts (by mols) in corresponding coupling step.
[0964] MS: m / z 5263.1
[0965] Repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 14.25 g) . Analysis showed a target peak that was eluted at 10.543 minutes with the expected molecular weight (MS: m / z 5263.1) . The purity was 55.833%.
[0966] 14.2 g of the crude product was then purified as described in Example 1 above to give 4.01 g of pure title compound after freeze-drying.
[0967] Example 11
[0968] N-Bis { [N-Bis (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (PEG3-acid) ] -NH-PEG3} -N- (PEG3-acid) (SEQ ID No: 262)
[0969] The title compound was prepared using essentially the same process as that described in Example 9 above, except that after the last amino acid Fmoc-Lys (Boc) -OH was coupled on the resin, a further coupling step was carried out to couple palmitic acid to the resin. Palmitic acid was used in the same amounts (by mols) as the other amino acids.
[0970] After palmitic acid was coupled, the resin was directly washed three times each with the following solvents, DMF (200 mL each time) , DCM (200 mL each time) and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China) . The resin was then dried under vacuum for about 2 hours.
[0971] MS: m / z 6152.7
[0972] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 15.83 g) . Analysis showed a target peak that was eluted at 39.857 minutes with the expected molecular weight (MS: m / z 6152.7) . The purity was 50.202%.
[0973] 15.8 g of the crude product was then purified as described in Example 1 above to give 4.78 g of pure title compound after freeze-drying.
[0974] Example 12
[0975] N-Bis { [N-Bis (Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3-acid) ] -NH-PEG3} -N- (PEG3-acid) (SEQ ID No: 263)
[0976] The title compound was prepared using essentially the same process as that described in Example 11 above, except that Fmoc-DOPA (Acetonide) -OH was used instead of Fmoc-Tyr (tBu) -OH in the same amounts (by mols) in corresponding coupling step.
[0977] MS:m / z 6216.7
[0978] Repeating essentially the same procedure gave a further batch of crude title compound (yield 15.71 g) . Analysis showed a target peak that was eluted at 38.788 minutes with the expected molecular weight (MS: m / z 6216.7) . The purity was 50.482%. 15.7 g of the crude product was then purified as described in Example 1 above to give 4.52 g of pure title compound after freeze-drying.
[0979] Example 13
[0980] N-Bis (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (PEG3-acid) (SEQ ID No: 264)
[0981] The title compound was prepared using essentially the same process as that described in Example 1 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences. After the last amino acid Fmoc-Lys (Boc) -OH was coupled on the resin, a further coupling step was carried out to couple palmitic acid to the resin. Palmitic acid was used in the same amounts (by mols) as the other amino acids.
[0982] After palmitic acid was coupled, the resin was directly washed three times each with the following solvents, DMF (200 mL each time) , DCM (200 mL each time) and methanol (200 mL each time; Xilong Scientific Co., Ltd., Guangdong, China) . The resin was then dried under vacuum for about 2 hours.
[0983] MS: m / z 2808.6
[0984] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 7.81 g) . Analysis showed a target peak that was eluted at 35.839 minutes with the expected molecular weight (MS: m / z 2808.6) . The purity was 65.748%.
[0985] 7.8 g of the crude product was then purified as described in Example 1 above to give 3.55 g of pure title compound after freeze-drying.
[0986] Example 14
[0987] N-Bis (Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3-acid) (SEQ ID No: 265)
[0988] The title compound was prepared using essentially the same process as that described in Example 13 above, except that Fmoc-DOPA (Acetonide) -OH was used instead of Fmoc-Tyr (tBu) -OH in the same amounts (by mols) in corresponding coupling step.
[0989] MS: m / z 2840.6
[0990] Repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 7.74 g) . Analysis showed a target peak that was eluted at 36.221 minutes with the expected molecular weight (MS: m / z 2840.6) . The purity was 53.211%.
[0991] 7.7 g of the crude product was then purified as described in Example 1 above to give 3.29 g of pure title compound after freeze-drying.
[0992] Example 15
[0993] N-Bis (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (PEG3-acid) (SEQ ID No: 266)
[0994] The title compound was prepared using essentially the same process as that described in Example 1 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.
[0995] MS: m / z 2331.7
[0996] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 7.05 g) . Analysis showed a target peak that was eluted at 9.882 minutes with the expected molecular weight (MS: m / z 2331.7) . The purity was 68.473%.
[0997] 7.0 g of the crude product was then purified as described in Example 1 above to give 3.57 g of pure title compound after freeze-drying.
[0998] Example 16
[0999] N-Bis (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3-acid) (SEQ ID No: 267)
[1000] The title compound was prepared using essentially the same process as that described in Example 15 above, except that Fmoc-DOPA (Acetonide) -OH was used instead of Fmoc-Tyr (tBu) -OH in the same amounts (by mols) in corresponding coupling step.
[1001] MS: m / z 2363.7
[1002] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 6.91 g) . Analysis showed a target peak that was eluted at 9.988 minutes with the expected molecular weight (MS: m / z 2363.7) . The purity was 65.832%.
[1003] 6.9 g of the crude product was then purified as described in Example 1 above to give 3.56 g of pure title compound after freeze-drying.
[1004] Example 17
[1005] N-Bis (Palm-Lys-Hyp-Lys-NH-PEG3) -N- (PEG3-acid) (SEQ ID No: 268)
[1006] The title compound was prepared using essentially the same process as that described in Example 13 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.
[1007] MS: m / z 1787.5
[1008] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 5.28 g) . Analysis showed a target peak that was eluted at 29.812 minutes with the expected molecular weight (MS: m / z 1787.5) . The purity was 70.928%.
[1009] 5.2 g of the crude product was then purified as described in Example 1 above to give 2.98 g of pure title compound after freeze-drying.
[1010] Example 18
[1011] N-Bis (Lys-Hyp-Lys-NH-PEG3) -N- (PEG3-acid) (SEQ ID No: 269)
[1012] The title compound was prepared using essentially the same process as that described in Example 1 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.
[1013] MS: m / z 1310.6
[1014] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 4.65 g) . Analysis showed a target peak that was eluted at 9.883 minutes with the expected molecular weight (MS: m / z 1310.6) . The purity was 75.291%.
[1015] 4.6 g of the crude product was then purified as described in Example 1 above to give 2.57 g of pure title compound after freeze-drying.
[1016] Example 19
[1017] N-Bis { [N-Bis (Palm-Lys-Hyp-Lys-NH-PEG3) -N- (PEG3-acid) ] -NH-PEG3} -N- (PEG3-acid) (SEQ ID No: 270)
[1018] The title compound was prepared using essentially the same process as that described in Example 11 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.
[1019] MS: m / z 4110.6
[1020] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 12.52 g) . Analysis showed a target peak that was eluted at 41.282 minutes with the expected molecular weight (MS: m / z 4110.6) . The purity was 41.938%.
[1021] 12.5 g of the crude product was then purified as described in Example 1 above to give 4.34 g of pure title compound after freeze-drying.
[1022] Example 20
[1023] N-Bis { [N-Bis (Lys-Hyp-Lys-NH-PEG3) -N- (PEG3-acid) ] -NH-PEG3} -N- (PEG3-acid) (SEQ ID No: 271)
[1024] The title compound was prepared using essentially the same process as that described in Example 2 above, except that appropriate amino acids were used as appropriate in the relevant peptide coupling sequences.
[1025] MS: m / z 3157.0
[1026] After the resin was dried, repeating essentially the same procedure as described in Example 1 gave a further batch of crude title compound (yield 9.38 g) . Analysis showed a target peak that was eluted at 13.123 minutes with the expected molecular weight (MS: m / z 3157.0) . The purity was 43.126%.
[1027] 9.3 g of the crude product was then purified as described in Example 1 above to give 3.27 g of pure title compound after freeze-drying.
[1028] Example 21
[1029] Ear Swelling Mouse Model
[1030] Test compounds:
[1031] Compound A: N-Bis { [N-Bis (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-NH-PEG3) -N-(PEG3 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 189) which is equal to: (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys) 4- (N-Bis (PEG3-amine) -N- (PEG3-acid) ) 2-N-Bis (PEG3-amine) -N- (PEG3-acid)
[1032] Compound G: ( (Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys) 4-Lys) 2-Lys
[1033] 20, 6 to 8 week old, healthy male BALB / c mice with average body weights of 18-25 g (Hangzhou Ziyuan Experimental Animal Technology Co., Ltd. Hangzhou, China) were housed and cared for about 1 week prior to experiment. The housing conditions were at 25-27℃, 74%humidity, 12h dark-light cycle, and the mice had free access to food and water. These mice were randomly divided into 4 groups (5 mice in each group) as described in Table 1.
[1034] Table 1
[1035] The left ear of each mouse was used as autologous control. And the right ear of each mouse was treated with a different treatment: 20 μl of xylene (Shanghai Aladdin Bio-Chem Technology Co., LTD, Shanghai, China) was applied to the right ear of each mouse, both the inside and outside. The ear started to swell after about 4 mins. Then 40 μl of drugs was applied to the right ear in each group. The mice were placed back in the cages.
[1036] Dexamethasone Acetate Cream (0.75 mg / g, China resources group) was purchased on the local drug store. Compounds A and G were synthesized by the Chinese Peptide Company as described above. 15 mg each compound (powder) was dissolved in 10 ml of normal saline to make a solution of 1.5 mg / ml. The resultant solutions were applied to the mice accordingly.
[1037] The mice were sacrificed by cervical dislocation after 40 mins. The left and right ears were cut off. A skin pouch (Electron Microscopy Sciences, P. O. Box 550, 1560 Industry Road, Hatfield, PA 19440) with a diameter of 8 mm was used to take a piece of ear from the same site on both ears. The weights were recorded and used to calculate the degree of swelling, shown in Table 2 and Figure 1.
[1038] Degree of swelling (%) = (right ear weight -left ear weight) / left ear weight ×100%
[1039] Table 2
[1040] The results showed that all two compounds could significantly reduce the xylene induced ear swelling in the mouse model, especially Compound A, which has better effect than dexamethasone.
[1041] Example 22
[1042] Ear Swelling Mouse Model
[1043] Test compounds:
[1044] Compound B: N-Bis { [N-Bis (Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 263) which is equal to:
[1045] (Palm-Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys) 4- (N-Bis (PEG3-amine) -N- (PEG3-acid) ) 2-N-Bis(PEG3-amine) -N- (PEG3-acid)
[1046] Compound C: N-Bis { [N-Bis (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (PEG3 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 262) which is equal to:
[1047] (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys) 4- (N-Bis (PEG3-amine) -N- (PEG3-acid) ) 2-N-Bis(PEG3-amine) -N- (PEG3-acid)
[1048] Compound D: N-Bis { [N-Bis (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys-NH-PEG3) -N- (PEG3 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 261) which is equal to:
[1049] (Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys) 4- (N-Bis (PEG3-amine) -N- (PEG3-acid) ) 2-N-Bis (PEG3-amine) -N- (PEG3-acid)
[1050] Compound E: N-Bis { [N-Bis (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys-NH-PEG3) -N- (PEG3 acid) ] -NH-PEG3} -N- (PEG3 acid) (SEQ ID No: 260) which is equal to:
[1051] (Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys) 4- (N-Bis (PEG3-amine) -N- (PEG3-acid) ) 2-N-Bis (PEG3-amine) -N- (PEG3-acid)
[1052] The experimental procedure and recording of results were the same as that described in Example 1 above. Ear swelling was induced by xylene in mice. 40 mice were divided into 8 groups as described in Table 3.
[1053] Table 3
[1054] The results are shown in Table 4 and Figure 2.
[1055] Table 4
[1056] The results showed that compound B, C and D were effective in reducing the degree of swelling in the mouse model treated with xylene, which have relative effect with dexamethasone. Compound E was also effective, but not as effective as other compounds.
[1057] Example 23
[1058] Pain Relief in Radiation-induced Oral Mucositis
[1059] One patient was undergoing radiotherapy on the head. The patient experienced severe oral mucositis, diagnosed as greed 4 (most severe level) and oral mucosal ulcers. The patient also experienced high levels of pain and difficulties in eating. The patient was suggested to use 1.5 mg / ml x 5 ml Compound A solution three times a day as mouth rinse. After 7 days, the patient reported very positive feedbacks. The VAS score for pain was reduced from 8 to 1.
[1060] Example 24
[1061] Itch Relief in Neurodermatitis
[1062] A 33-year-old female was presented with a skin lesion with a constant itch and scaling on her back. It was diagnosed as neurodermatitis two years ago. The patient had previously used glucocorticoids to treat the lesion, but its effects were temporary. The itch became worse when he was stressed. The patient tried 3 mg / ml of Compound A solution spray. After 1 spray on the lesion, the itching symptom was completely relieved after about 60 minutes. The patient reported that the itching symptom had stopped during the day following administration.
Claims
1.A compound of formula I, A-Q-B (I)wherein:A and B independently represent Z or A1-Q1-B1;Q represents a structural fragment of formula (II) ,wherein:the squiggly lines represent points of attachment of Q to A and / or B; andR is selected from the group consisting of:wherein, when R representsone of the squiggly lines represents a point of attachment to the rest of the Q fragment, and the other squiggly line represents a point of attachment to Z or A1-Q1-B1;wherein, when R representsone of the squiggly lines represents a point of attachment to the rest of the Q fragment, and the other squiggly line represents a point of attachement to Z;n 1 to n3 independently represent 1 to 10;m1 to m3 independently represent 0 to 5;p1 to p3 independently represent 0 or 1;x represents 0 or 1;A1 and B1 independently represent Z or A2-Q2-B2;A2 and B2 independently represent Z or Z-Q3-Z;Q1, Q2 and Q3 independently represent structural fragments of formula III,wherein:the squiggly lines adjacent to the NH groups represent points of attachment of Q1, Q2 and Q3 to A1 and / or B1, A2 and / or B2, and Z, respectively;the squiggly line adjacent to the carbonyl group represents the point of attachment of Q1, Q2 and Q3 to Q, Q1 and Q2, respectively; andn4 to n6 independently represent 1 to 10;m4 to m6 independently represent 0 to 5;p4 to p6 independently represent 0 or 1;y represents 0 or 1;on each occasion that it is employed, Z independently represents:L- [ (W) m-Lys-X1-T- (U) m- (X2) m- (Y) m] n- (W) m-Lys-X1-T- (U) m- (X2) m- (Y) m(SEQ ID No: 1) ; orL-Ala-Lys-Pro (SEQ ID No: 2) ; orL-Ala-Pro-Ser-Hyp-Hyp-Thr (SEQ ID No: 3) ; orL- [Lys-X3] n-Lys-X3 (SEQ ID No: 196)wherein:Z attaches to the rest of the molecule through the N-or C-terminus, as appropriate; and,on each occasion that they are employed:n represents 0 or an integer 1 to 4;W independently represents a 1 or 2 amino acid sequence, in which the amino acids are selected from one or more of the group Ser, Lys, Ala, DOPA and a 3, 4-dihydrocinnamic acid (HCA) residue, provided that, when present, the HCA residue is located at the N-terminus of the peptide sequence Z;on each occasion that it is employed, m independently represents 0 or 1;on each occasion that it is employed, X1 independently represents Pro or Hyp;on each occasion that it is employed, T independently represents Ser or pSer;on each occasion that it is employed, U independently represents Tyr, pTyr, DOPA, Hyp, or Pro;on each occasion that it is employed, X2 independently represents Thr, Ser, Pro, Hyp or diHyp;on each occasion that it is employed, Y independently represents a 1 to 5 (e.g. a 1 to 4) amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Ala, Pro, Hyp, Thr, pThr, DOPA and Tyr;L independently represents at least one optional lipid substituent, which lipid is selected from the group consisting of vitamin A, vitamin E, cholesterol and a fatty acid comprising one or more carboxylic acid groups, 1 to 50 carbons, and / or one or more cyclic rings, is linear or branched, saturated or unsaturated with between 1 and 10 carbon-carbon double bonds and / or substituted by between 1 to 10 -OH groups, or a derivative of any of these lipids; andX3 represents a 2 to 4 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Pro, Hyp, diHyp, Thr, pThr, DOPA and Tyr,wherein, optionally, the amino acid residue at the N-terminus of the Z component is covalently bonded to a non-steroidal anti-inflammatory drug, or to montelukast, forming an amide linkage with the carboxylic acid group in said non-steroidal anti-inflammatory drug or montelukast,as well as regioisomers, stereoisomers, and pharmaceutically-or cosmetically-acceptable salts of said compound.2.A compound as claimed in Claim 1, wherein A and B both represent Z, or both represent A1-Q1-B1.3.A compound as claimed in any one of the preceding claims, wherein A1 and B1 both represent Z, or both represent A2-Q2-B2.4.A compound as claimed in any one of the preceding claims, wherein A2 and B2 both represent Z, or both represent Z-Q3-Z.5.A compound as claimed in any one of the preceding claims, wherein:p1 to p6 represent 0; andm1 to m6 represent 0.6.A compound as claimed in any one of the preceding claims, wherein x and y represent 0.7.A compound as claimed in any one of Claims 1 to 4 and 6, wherein p1 to p6 represent 1.8.A compound as claimed in any one of Claims 1 to 4, 6 and 7, wherein m1 to m6 independently represent 1 to 6.9.A compound as claimed in any one of the preceding claims, wherein R represents 10.A compound as claimed in any one of Claims 1 to 4 and 6 to 8, wherein R represents 11.A compound as claimed in any one of the preceding claims, wherein n 1 to n6 independently represent 1 to 5.12.A compound as claimed in any one of the preceding claims, wherein the amino acid residue at the N-terminus of the Z component is covalently bonded to Montelukast.13.A compound as claimed in any one of the preceding claims, wherein n is 0.14.A compound as claimed in any one of the preceding claims, wherein T is Ser.15.A compound as claimed in any one of the preceding claims, wherein X1 represents Pro.16.A compound as claimed in any one of the preceding claims, wherein X2 represents Hyp.17.A compound as claimed in any one of the preceding claims, wherein W is selected from the group Ser, HCA, HCA-Ala-, Ala, DOPA, Lys-Ala and DOPA-Ala.18.A compound as claimed in any one of the preceding claims, wherein U represents Tyr or DOPA.19.A compound as claimed in any one of the preceding claims, wherein W represents Ala or Lys-Ala-.20.A compound as claimed in any one of the preceding claims, wherein Z is selected from the group:Ala-Lys-Pro (SEQ ID no. 2) ;Ala-Lys-Pro-Ser (SEQ ID no. 4) ;Ala-Lys-Pro-Ser-Tyr (SEQ ID no. 5) ;Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 7) ; andAla-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8) ,and optionally the amino acid residue at the N-terminus of the Z component is covalently bonded to montelukast, forming an amide linkage with the carboxylic acid group in montelukast.21.A compound as claimed in Claim 19, wherein Z is selected from the group:Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 10) ;Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11) ;Ala-Lys-Hyp-Ser-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 12) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 13) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 14) ;Ala-Lys-Hyp-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 15) ;Ala-Lys-Pro-Ser-Hyp-Thr-Tyr-Pro-Lys (SEQ ID no. 16) ;Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Hyp-Lys (SEQ ID no. 17) ;Ala-Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 18) ; andAla-Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 19) .22.A compound as claimed in Claim 19, wherein Z is selected from the group:Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID no. 20) ;Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 11) ;Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 21) ;Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 22) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 23) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 24) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 25) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 26) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 27) ;Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 28) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 29) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 30) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 31) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 32) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 33) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 34) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 35) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 36) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 37) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 38) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 39) ;Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 40) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 41) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID no. 42) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID no. 43) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys (SEQ ID no. 44) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys (SEQ ID no. 45) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID no. 46) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 47) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID no. 48) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 49) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 50) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 51) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 52) ;Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no. 53) ;Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no. 54) ;Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys (SEQ ID no. 55) ;Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys (SEQ ID no. 56) ;Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys (SEQ ID no. 57) ;Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 58) ;Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (SEQ ID no. 59) ;Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 60) ;Ala-Lys-Pro-Ser-Tyr-Hyp (SEQ ID no. 6) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp (SEQ ID no. 61) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA (SEQ ID no. 62) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp (SEQ ID no. 63) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Hyp-Lys (SEQ ID no. 64) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-DOPA-Lys (SEQ ID no. 65) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr (SEQ ID no. 66) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp (SEQ ID no. 67) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Hyp-Lys (SEQ ID no. 68) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-pThr-Tyr-Lys (SEQ ID no. 69) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 70) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 71) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 72) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 73) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID no. 74) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 75) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 76) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 77) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 78) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID no. 79) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (SEQ ID no. 80) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID no. 81) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 82) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 83) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID no. 84) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Lys-Hyp (SEQ ID no. 85) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-DOPA-Lys (SEQ ID no. 86) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 8) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 9) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID no. 87) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Lys-Hyp (SEQ ID no. 88) ;Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (SEQ ID no. 89) ;Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID no. 90) ;Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (SEQ ID no. 91) ;Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (SEQ ID no. 92) ; andAla-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID no. 93) .23.A compound as claimed in Claim 19, wherein Z is selected from the group:Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no. 94) ;Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no. 95) ;Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 96) ;Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 97) ;Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID no. 98) ;Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr (SEQ ID no. 99) ;Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 100) ; andLys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 101) .24.A compound as claimed in any one of Claims 1 to 18, wherein m in reference to (W) m is 0; and n is 0.25.A compound as claimed in Claim 24, wherein Z is selected from the group:Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 102) ;Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 103) ;Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 104) ;Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 105) ;Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID no. 106) ;Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID no. 107) ;Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID no. 108) ;Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID no. 109) ;Lys-Hyp-Ser-pTyr-Hyp-DOPA (SEQ ID no. 110) ;Lys-Hyp-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 111) ;Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID no. 112) ;Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 113) ;Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 114) ;Lys-Pro-Ser-DOPA-Hyp-DOPA (SEQ ID no. 115) ;Lys-Pro-Ser-DOPA-Hyp-DOPA-Lys (SEQ ID no. 116) ;Lys-Pro-Ser-DOPA-Hyp-Tyr-Lys (SEQ ID no. 117) ;Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID no. 118) ;Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID no. 119) ;Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID no. 120) ;Lys-Pro-Ser-DOPA-Hyp-Thr (SEQ ID no. 121) ;Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID no. 122) ; andLys-Pro-Ser-DOPA-Hyp-Thr-Lys (SEQ ID no. 123) .26.A compound as claimed in Claim 24, wherein Z is selected from the group:Lys-Pro-Ser-pTyr-Hyp-DOPA (SEQ ID no. 124) ;Lys-Pro-Ser-pTyr-Hyp-DOPA-Lys (SEQ ID no. 125) ;Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID no. 126) ;Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID no. 127) ;Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (SEQ ID no. 128) ;Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 129) ;Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (SEQ ID no. 130) ;Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 131) ;Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 132) ;Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 133) ;Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 134) ;Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 135) ; andLys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID no. 136) .27.A compound as claimed in any one of Claims 1 to 18, wherein W represents HCA, HCA-Ala-, DOPA or DOPA-Ala-.28.A compound as claimed in Claim 27, wherein Z is selected from the group:DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 137) ;DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 138) ;DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 139) ;DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 140) ;DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 141) ;DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 142) ;DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 143) ;DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 144) ;DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 145) ;DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 146) ;DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 147) ;DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 148) ;HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 149) ;HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 150) ;HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 151) ;HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 152) ;HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 153) ;HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 154) ;HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 155) ;HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 156) ;HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 157) ;HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 158) ;HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 159) ;HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 160) ;HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID no. 161) ; andHCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID no. 162) .29.A compound as claimed in any one of Claims 1 to 18, wherein W represents Ser.30.A compound as claimed in Claim 29, wherein Z is selected from the group:Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID no. 163) ;Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 164) ;Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID no. 165) ;Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 166) ;Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID no. 167) ;Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID no. 168) ;Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID no. 169) ; andSer-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID no. 170) .31.A compound as claimed in any one of Claims 1 to 19, wherein n is 1 or 4.32.A compound as claimed in Claim 31, wherein Z is selected from the group:Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID no. 171) ;Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 172) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 173) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 174) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 175) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID no. 176) ;Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 177) ; andAla-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID no. 178) .33.A compound as claimed in any one of the preceding claims, wherein Y represents a 4 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Ala, Hyp, Thr, DOPA and Tyr.34.A compound as claimed in Claim 10, wherein Y represents an amino acid sequence selected from the group -Hyp-Y1-Y2-Lys-and -Thr-Y1-Y2-Lys-, wherein Y1 and Y2 are each independently selected from the group Ala, Hyp, Thr, DOPA and Tyr.35.A compound as claimed in Claim 33 or Claim 34, wherein the amino acid sequence defined by Y is selected from the group -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys-and -Thr-Ala-Hyp-Lys-.36.A compound as claimed in any one of Claims 1 to 32, wherein the amino acid sequence defined by Y is selected from the group -Thr-Tyr-Hyp-Lys-DOPA-and -Hyp-Thr-DOPA-.37.A compound as claimed in any one of the preceding claims, wherein U represents Tyr or pTyr.38.A compound as claimed in any one of the preceding claims 1 to 19, wherein L represents at least one lipid as defined in Claim 1.39.A compound as claimed in Claim 38, wherein L represents a lipid selected from a derivative of a fatty acid as defined in Claim 1.40.A compound as claimed in Claim 38, wherein the lipid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, octadecanedioic acid, docosahexaenoic acid and leukotriene B4 (LTB4) , or a derivative of any of these.41.A compound as claimed in any one of Claims 38 to 40, wherein the lipid is palmitic acid, or a derivative thereof.42.A compound as defined in any of the preceding claims, for use in human or animal medicine.43.A compound as defined in any one of Claims 1 to 41, for use as a pharmaceutical.44.A pharmaceutical formulation comprising a compound as defined in any one of Claims 1 to 41.45.A pharmaceutical formulation as claimed in Claim 44, which further comprises a pharmaceutically-or cosmetically-acceptable, adjuvant, diluent or carrier.46.A pharmaceutical formulation as claimed in Claim 44 or Claim 45 that is suitable for, adapted for, and / or packaged and presented for, topical administration, wherein the pharmaceutically-or cosmetically-acceptable adjuvant, diluent or carrier is a topical adjuvant, diluent or carrier.47.A pharmaceutical formulation as claimed in any one of Claims 44 to 46, which is in the form of a gel, a spray, a cream, an ointment or a dry powder.48.A pharmaceutical formulation as claimed in any one of Claims 44 to 47, which further includes a, or a further, pharmaceutically-active ingredient.49.A kit of parts comprising components:(A) a compound as defined in any one of Claims 1 to 41 or a pharmaceutical formulation as defined in any one of Claims 44 to 48; and(B) a pharmaceutical formulation including a, or a further, pharmaceutically-active ingredient in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.50.A pharmaceutical formulation as claimed in Claim 48, or a kit of parts as claimed in Claim 49 wherein the pharmaceutically-active ingredient is an anti-inflammatory agent, a pro-inflammatory agent, an antibiotic, an anti-bacterial and / or antiprotozoal agent, an antiviral agent, an anaesthetic and / or a wound recovery drug.51.A pharmaceutical formulation or a kit of parts as claimed in Claim 50, wherein the pharmaceutically-active ingredient is an anti-inflammatory agent.52.A compound as defined in any one of Claims 1 to 41, a formulation as claimed in any one of Claims 44 to 48, 50 or 51, or a kit of parts as claimed in any one of Claim 49 to 51, for use in the treatment of inflammation, an inflammatory disorder, and / or of a disorder characterised by inflammation.53.The use of a compound as defined in any one of Claims 1 to 41, a formulation as claimed in any one of Claims 44 to 48, 50 or 51, or a kit of parts as claimed in any one of Claim 49 to 51, for the manufacture a medicament for the treatment of inflammation, an inflammatory disorder, and / or of a disorder characterised by inflammation.54.A method of treatment of inflammation, an inflammatory disorder, and / or of a disorder characterised by inflammation, which method comprises the administration of a compound as defined in any one of Claims 1 to 41, a formulation as claimed in any one of Claims 44 to 48, 50 or 51, or a kit of parts as claimed in any one of Claim 49 to 51, to a patient in need of such treatment.55.A compound, formulation or kit of parts for use as claimed in Claim 52, a use as claimed in Claim 53, or a method as claimed in Claim 54, wherein the disorder characterised by inflammation is, or results in, a wound or a burn.56.A compound, formulation or kit of parts for use, use or method as claimed in Claim 55, wherein the disorder resulting in a wound is haemorrhoids or ulcerative colitis.57.A compound, formulation or kit of parts for use, use or method as claimed in any one of Claims 42 to 56 (as appropriate) , wherein the compound (s) or salt thereof is administered topically in the form of a topical formulation.58.A compound, formulation or kit of parts for use, use or method as claimed in Claim 57 wherein the relevant condition is treated by way of direct topical administration to the skin.59.A compound, formulation or kit of parts for use, use or method as claimed in Claim 57, wherein the relevant condition is treated by way of direct topical administration to a mucosal surface.60.A compound, a formulation, or a kit of parts, for use, a use or a method as claimed in any one of Claims 41 to 59 (as appropriate) , wherein the compound (s) is / are administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, pulmonary or anorectal delivery.61.A compound, a formulation, or a kit of parts, for use, a use or a method as claimed in any one of Claims 48 to 60 (as appropriate) , wherein the compound as defined in any of Claim 1 to 41 functions as an excipient, as a medical device, or as a medical device component of a drug-medical device combination.62.A compound, a formulation, or a kit of parts, for use, a use or a method as claimed in any one of Claims 45 to 61 (as appropriate) , wherein the compound is as defined in any of Claims 1 to 41, wherein W is as defined in Claim 27 and / or U is as defined in Claim 18, and is crosslinked, before or after administration to a subject.63.A compound as defined in Claim 62 for use as an adhesive or as a film-forming material.64.A compound for use as claimed in Claim 63, wherein the use is as a wound surface repair product, a wound surface protecting product, a medical biological adhesive product, a medical coating product, an industrial coating product, a biochemical reagent, a medical product, a sterilization product or as a culture vessel for cell culture.65.A compound for use as claimed in Claim 63 or Claim 64, wherein a film is formed over a skin or a mucosal wound surfaces to aid in recovery.66.A compound for use as claimed in any one of Claims 63 to 65, wherein the use is in closure of a surgical incision, adhesion of a fractured bone, adhesion of a mucous membrane or coating of a human body implant.67.A pharmaceutical formulation comprising a compound as defined in Claim 63 and a pharmaceutically-or cosmetically-acceptable, adjuvant, diluent or carrier.68.A pharmaceutical formulation as claimed in Claim 67 that is suitable for, adapted for, and / or packaged and presented for, topical administration, wherein the pharmaceutically-or cosmetically-acceptable adjuvant, diluent or carrier is a topical adjuvant, diluent or carrier.69.A pharmaceutical formulation as claimed in Claim 67 or Claim 68, which is in the form of a gel, a spray, a cream, an ointment or a dry powder.