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WO2024260465A1 - Nouveaux oligopeptides multifonctionnels - Google Patents

Nouveaux oligopeptides multifonctionnels Download PDF

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Publication number
WO2024260465A1
WO2024260465A1 PCT/CN2024/100923 CN2024100923W WO2024260465A1 WO 2024260465 A1 WO2024260465 A1 WO 2024260465A1 CN 2024100923 W CN2024100923 W CN 2024100923W WO 2024260465 A1 WO2024260465 A1 WO 2024260465A1
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WO
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Prior art keywords
lys
hyp
tyr
compound
pro
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Pending
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English (en)
Inventor
Jesper Haeggstrom
Ming Gu
Maoqian SONG
Ruijuan Kang
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Enlitisa Shanghai Pharmaceutical Co Ltd
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Enlitisa Shanghai Pharmaceutical Co Ltd
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Publication of WO2024260465A1 publication Critical patent/WO2024260465A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • 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.
  • the invention relates to the use of those peptides and compositions in the treatment of various conditions including inflammation.
  • 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.
  • 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.
  • tissue-damaging inflammation 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ECM extracellular matrix
  • 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.
  • 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.
  • Fibrosis may also influence the pathogenesis of many progressive myopathies, metastasis and graft rejection.
  • Mussel adhesive protein also known as Mytilus edulis foot protein (mefp)
  • mefp Mytilus edulis foot protein
  • 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) .
  • 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: 61; 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.
  • Analogues of the decapeptide notably Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2) have also been disclosed. See, for example, US 5,616,311 and WO 96/39128, as well as international patent applications WO 2019/007355 A1, WO 2019/228307 A1, WO 2021/047648 A1, WO 2011/110061 A1 and WO 2021/110064 A1.
  • Japanese patent application JP 2003238589 A discloses certain di-and tripeptides as angiotensin converting enzyme inhibitors.
  • peptide-based scaffolds as drug delivery vehicles. See, for example, Brokx et al, J. Control. Release, 2002, 78, 115-123.
  • lipid-peptide conjugates such as palmitoyl tetrapeptide-7, palmitoyl tripeptide-1 and other palmitoyl oligopeptides
  • MS Ferreira. Cosmetics. 2000, 7, 91 See also Kamysz et al, which discloses palmitoyl tripeptides as antimicrobial agents.
  • Q a represents Z or A-Q-B
  • the squiggly lines represent points of attachment of Q to A and/or B;
  • R is selected from the group consisting of:
  • 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 a Z group;
  • n an integer 1 to 4.
  • a and B independently represent Z or A 1 -Q 1 -B 1 ;
  • a 1 and B 1 independently represent Z or A 2 -Q 2 -B 2 ;
  • a 2 and B 2 independently represent Z or Z-Q 3 -Z
  • Q 1 , Q 2 and Q 3 independently represent structural fragments of Formula III
  • the squiggly lines adjacent to the NH groups represent the points of attachment of Q 1 , Q 2 and Q 3 to A 1 and/or B 1 , A 2 and/or B 2 , and Z, respectively;
  • n is as defined above;
  • each L independently represents one or more lipids 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;
  • t represents an integer selected from 1 to 32;
  • D represents montelukast
  • b represents an integer selected from 0 to 16;
  • Z represents a structural fragment Formula IV, [ (W) r -Lys-X 1 -T-U-X 2 -Y] n - (W) r -Lys-X 1 -T-U-X 2 -Y (IV)
  • n an integer selected from 0 to 4.
  • r independently represents 0 or 1;
  • W independently represents a 1 or 2 amino acid sequence 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 Z;
  • X 1 independently represents Pro, Hyp or diHyp
  • T independently represents Ser or pSer
  • U independently represents Tyr, pTyr, DOPA, Hyp, or Pro;
  • X 2 independently represents Thr, Ser, Pro, Hyp or diHyp
  • Y independently represents a 1 to 5 (such as 1 to 4) amino acid sequence selected from one or more of the group Lys, Ala, Pro, Hyp, diHyp, Thr, pThr, DOPA, Tyr, which sequences is optionally terminated by dopamine (or, more properly, ‘adopamine fragment’ ) ;
  • each D is covalently bonded to Z through an amide bond between respective carboxylic acid residues thereof and one or more NH 2 residues of Z;
  • each of the L residues are covalently bonded to Z through an amide bond between respective carboxylic acid residues of L and one or more NH 2 residues of Z and/or through an ester bond between respective -OH residues of L and one or more carboxylic acid residues of Z,
  • the compounds of the invention as well as regioisomers, stereoisomers, and pharmaceutically-or cosmetically-acceptable salts of said compound, which compounds, regioisomers, stereoisomers and salts are referred to together hereinafter as ‘the compounds of the invention’ .
  • Z attaches to the rest of the molecule through the N-or C-terminus.
  • Z attaches to the rest of the molecule by forming an amide bond.
  • Preferred compounds of the invention include those in which 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.
  • lipid is a polyunsaturated fatty acid, or a derivative thereof.
  • the derivative may be a specialized pro-resolving mediator (SPM) .
  • lipid is a derivative of a fatty acid, such as a glycerolipid, glycerophospholipid, sphingolipid or saccharolipid.
  • the derivative may be phosphatidylserine, or more preferably, the derivative is 1, 2-dipalmitoyl-sn-glycero-3-phospho-l-serine, and most preferably, the derivative is 1, 2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS) .
  • the derivative may be phosphatidylethanolamine, or more preferably, the derivative is 1, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) .
  • lipid is stearic acid, or a derivative thereof.
  • the derivative may be 1, 2-distearoyl-sn-glycero-3-phospho-l-serine.
  • lipid is oleic acid, or a derivative thereof.
  • the derivative may be 1, 2-dioleoyl-sn-glycero-3-phospho-L-serine.
  • lipid is palmitoylethanolamide (PEA) .
  • lipid is selected from the group consisting of vitamin E, vitamin A, and cholesterol, or a derivative of any of these.
  • the derivative of cholesterol may be cholesterol-acetic acid.
  • lipid is a fatty acid comprising 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 thereof.
  • the fatty acid may have 6 to 24 carbons, such as 6 to 18 carbons.
  • the fatty acid may have 1 to 6 carbon-carbon double bonds, such as 1 to 5 carbon-carbon double bonds.
  • the fatty acid may have 1 to 5 -OH groups, such as 1 to 2 -OH groups.
  • the fatty acid may have 1 to 10 cyclic rings, such as 1 to 8 cyclic rings.
  • t represents an integer selected from 1 to 8; or, more preferably
  • t represents an integer selected from 1 to 4.
  • b represents an integer selected from 0 to 4; or, more preferably
  • dopamine and ‘dopamine fragment’ refer to a structural fragment of formula I,
  • Palm represents palmitic acid
  • Stea represents stearic acid
  • dopamine is as defined hereinbefore
  • Olei represents oleic acid
  • DHA represents docosahexaenoic acid
  • DPPS represents 1, 2-dipalmitoyl-sn-glycero-3-phospho-L-serine
  • LTB4 represents leukotriene B4
  • PEA represents palmitoylethanolamide.
  • Pro proline
  • Ala 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) , trans-2, 3-cis-3
  • 4-dihydroxyproline 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
  • Chol-Ac represents cholesterol-acetic acid:
  • HCA 4-Dihydrocinnamic acid residues are essentially DOPA residues but without the -NH 2 group in the 2-or ⁇ -carbon position relative to the carboxylic acid that is attached to the N-terminal amino acid (whether Lys or Ala) .
  • Q, Q 1 , Q 2 and Q 3 may each be covalently bonded to zero, one or two Z groups through an amide bond between respective carboxylic acid residues of Z and one or more NH 2 residues of Q, Q 1 , Q 2 and Q 3 .
  • preferred compounds of the invention include those in which:
  • one of A or B represents Z and the other represents A 1 -Q 1 -B 1 ; or, more preferably, A and B both represent Z, or both represent A 1 -Q 1 -B 1 ,
  • Q 1 preferably represents a Lys fragment and Z is as hereinbefore defined.
  • a 1 and B 1 represents Z and the other represents A 2 -Q 2 -B 2 ; or, more preferably, A 1 and B 1 both represent Z, or both represent A 2 -Q 2 -B 2 ,
  • Q 2 preferably represents a Lys fragment
  • Z is as hereinbefore defined.
  • a 2 and B 2 represents Z and the other represents Z-Q 3 -Z; or, more preferably, A 2 and B 2 both represent Z, or both represent or Z-Q 3 -Z,
  • Q 3 preferably represents a Lys fragment
  • Z is as hereinbefore defined.
  • More preferred compounds of the invention include those in which:
  • a 1 and B 1 both represent Z;
  • a 2 and B 2 both represent Z.
  • m represents 1, 3 or, more preferably 4, such that one or more of Q, Q 1 , Q 2 and Q 3 represent Lys or, more properly, ‘a Lys fragment’ , in accordance with what are defined above as ‘the structural fragments of formulae II and III’ (as appropriate) .
  • Particularly preferred compounds of the invention include those in which:
  • n 0, 1 or 4, preferably n is 1 or, more preferably, n is 0.
  • R represents
  • t represents an integer selected from 1 to 4.
  • b is 0 or 1.
  • W represents a 1 or 2 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Ala, DOPA and HCA;
  • T Ser
  • U represents Tyr or DOPA
  • X 2 represents Ser, Pro, Hyp or diHyp
  • 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, diHyp, Thr, DOPA and Tyr.
  • T represents pSer
  • U represents pTyr, Hyp, or Pro
  • X 2 represents Thr
  • 1 to 5 (such as 1 to 4) of the amino acids in Y is pThr;
  • Y is optionally terminated by dopamine.
  • Preferred compounds of the invention include those in which:
  • X 1 represents Hyp or, more preferably, Pro
  • T Ser
  • U represents Tyr or DOPA
  • X 2 represents Hyp
  • W represents HCA-, HCA-Ala-, Lys-Ala-, DOPA-, DOPA-Ala-or, preferably, Ala; and/or
  • Y represents a 5, preferably a 3, more preferably a 2 or, most preferably, a 4 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Hyp, Thr, DOPA and Tyr, optionally terminated by a dopamine fragment.
  • Preferred compounds of the invention also include those in which Y represents a 4 amino acid sequence selected from the group -Pro-Y 1 -Y 2 -Lys-or, more preferably, -Hyp-Y 1 -Y 2 -Lys-and -Thr-Y 1 -Y 2 -Lys-, wherein Y 1 and Y 2 are each independently selected from the group Pro, Ala or, more preferably, Hyp, Thr, DOPA and Tyr, optionally terminated by a dopamine fragment.
  • preferred compounds of the invention include those in which the amino acid sequence defined by Y is selected from the group -Tyr-Pro-, preferably -Thr-Lys-and, more preferably, -DOPA-Lys-and -Tyr-Lys-, optionally terminated by a dopamine fragment.
  • amino acid sequence defined by Y is selected from the group:
  • Preferred compounds of the invention that may be mentioned include those wherein Z is selected from the group:
  • More preferred compounds of the invention that may be mentioned include those wherein Z is selected from the group:
  • Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 86) ;
  • Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87) ;
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 88) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 89) ;
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID No: 90) ;
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92) ;
  • Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 95) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 96) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID No: 98) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14) ;
  • Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 102) ;
  • Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 104) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID No: 105) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 106) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16) .
  • Preferred compounds of the invention that may be mentioned include those wherein Z is selected from the group:
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91) ;
  • Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 93) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100) ;
  • Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99) ;
  • Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92) .
  • More preferred compounds of the invention that may be mentioned include those wherein Z is selected from the group:
  • Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19) .
  • Compounds of the invention that may be mentioned include those wherein the amino acid residue at the N-terminus of a Z component is optionally, covalently bonded to montelukast, forming an amide linkage with the carboxylic acid group in montelukast.
  • r and n both represent 0;
  • X 1 represents Hyp or, more preferably, Pro
  • T represents pSer or, more preferably, Ser
  • U represents DOPA or, more preferably, Tyr
  • X 2 represents Hyp
  • Y represents a 1 to 5, preferably a 3, more preferably a 4 or, most preferably, a 2 amino acid sequence, in which the amino acids are selected from one or more of the group Lys, Hyp, Thr, DOPA and Tyr, optionally terminated by a dopamine fragment, as well as regioisomers, stereoisomers, and pharmaceutically-or cosmetically-acceptable salts of such peptide compounds.
  • Preferred peptide compounds Z include those of the following sequences:
  • Lys-Hyp-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 86) ;
  • Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87) ;
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 88) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 89) ;
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA (SEQ ID No: 90) ;
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 19) ;
  • Lys-Hyp-Ser-Tyr-Hyp-Tyr (SEQ ID No: 92) ;
  • Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA-Hyp-Lys (SEQ ID No: 95) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr-Hyp-Lys (SEQ ID No: 96) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr (SEQ ID No: 98) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14) ;
  • Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 102) ;
  • Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID No: 104) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID No: 105) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 106) ;
  • More preferred peptide may be selected from the group:
  • Lys-Hyp-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 91) ;
  • Lys-Pro-pSer-Tyr-Hyp-DOPA-Lys (SEQ ID No: 93) ;
  • Lys-Pro-Ser-Tyr-Hyp-DOPA (SEQ ID No: 100) ;
  • Lys-Pro-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 94) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr (SEQ ID No: 97) ;
  • Lys-Pro-Ser-Tyr-Hyp-Thr-Lys (SEQ ID No: 99) ;
  • Lys-Hyp-pSer-Tyr-Hyp-Tyr-Lys (SEQ ID No: 87) ;
  • Especially preferred peptide compounds may be selected from the group:
  • Lys-Pro-Ser-Tyr-Hyp-DOPA-Lys (SEQ ID No: 14) ;
  • Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16) ;
  • Compounds of the invention include regioisomers within amino acids of the peptides (for example diHyp, Hyp and Tyr moieties) , as well as mixtures of such regioisomers.
  • regioisomers within amino acids of the peptides (for example diHyp, Hyp and Tyr moieties) , as well as mixtures of such regioisomers.
  • Tyr 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.
  • diHyp 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) .
  • 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.
  • 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 4-hydroxy-L-proline.
  • 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.
  • 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.
  • compounds of the invention may be in the form of acetate salts.
  • 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.
  • 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, 3 rd 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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) .
  • 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.
  • Inflammatory conditions 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) .
  • COPD chronic obstructive pulmonary disease
  • 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
  • gastroesophageal reflux disease GFD
  • constipation constipation
  • gastritis inflammation associated with cancers and infections (e.g. viral infections, such as the common cold or influenza) .
  • 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
  • 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.
  • 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.
  • 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.
  • 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) .
  • subcutaneous and/or submucosal tissues such as muscles, bones, joints, and even internal organs, may be damaged.
  • Compounds of the invention may be used to relieve the pain (including aching) associated with inflammation and/or wounding.
  • compounds of the invention may be used to relieve procedural pain and/or non-procedural pain.
  • procedural pain i.e. operation pain
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • inflammatory skin conditions or diseases in which compounds of the invention find particular utility include viral skin diseases such as herpes zoster, bacterial skin diseases, fungal skin diseases, skin diseases induced by animal, sexually transmitted skin diseases, skin diseases related to allergy, autoimmune skin diseases, neutrophilic dermatosis, erythematous popular and squamous dermatosis, connective tissue diseases, bullous skin disease, pigmentary skin diseases, skin appendage disorders, genodermatoses, skin diseases related to nutritional and metabolic disorders, skin tumours, psoriasis, acne, eczema and dermatitis, especially allergic/atopic dermatitis and neurodermatitis, 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.
  • viral skin diseases such as herpes zoster, bacterial skin diseases, fungal skin diseases, skin diseases induced by animal,
  • 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.
  • 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) .
  • 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.
  • 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) .
  • 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; rosacea such as 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;
  • 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) .
  • 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.
  • COPD chronic obstructive pulmonary disease
  • emphysema damage to the alveoli
  • 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.
  • 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.
  • 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
  • mucosal surfaces such as those in the oral cavity, the nasopharynx, the ear, the throat, the trachea, the gastrointestinal tract, the cervix, etc.
  • bone tumors osteoma, osteoid osteoma, chondrom
  • Nerve inflammation such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, intercostal neuritis, etc.
  • 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.
  • 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.
  • 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 (including interstitial cystitis) , oophoritis, prostatitis and treatment of gastric ulcer.
  • pericarditis myocarditis, endocarditis, pneumonia, hepatitis, splenitis, nephritis pancreatitis, cystitis (including interstitial cystitis) , oophoritis, prostatitis and treatment of gastric ulcer.
  • 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.
  • keratitis e.g. acute epithelial keratitis, nummular keratitis, interstitial keratitis, disciform keratitis,
  • 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.
  • rheumatic vasculitis such as rheumatic vasculitis, rheumatoid arthritis, rheumatic bone diseases, ankylosing spondylitis, bursitis, Crohn's disease, gout, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, osteoporosis, polymyalgia rheumatic
  • 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) .
  • 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.
  • GSD gastroesophageal reflux disease
  • GERD gastroesophageal reflux disease
  • 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.
  • 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) .
  • Compounds of the invention may also be used in the treatment of certain specific diseases of the respiratory system, such as pulmonary cystic fibrosis, interstitial pneumonia, including usual interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, pulmonary heart disease, pulmonary embolism, etc.
  • pulmonary cystic fibrosis including usual interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, pulmonary heart disease, pulmonary embolism, etc.
  • IPF idiopathic pulmonary fibrosis
  • 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.
  • lung fibrosis 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
  • 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.
  • 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
  • dental diseases such as paradentitis, for example.
  • 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.
  • 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.
  • Compounds of the invention are especially useful in the treatment of:
  • ⁇ skin diseases including acne, rosacea, dermatitis, seborrheic dermatitis, neurodermatitis, eczema, melanin pigmentation, scar (fibrosis) , hair loss, seborrheic alopecia, alopecia cicatrisata and paronychia;
  • oral diseases including periodontitis, gingivitis, oral mucositis (including radiation-induced mucositis) , hemodia and gingival recession;
  • ⁇ gynecological diseases including vaginitis, vulvitis, leukoplakia of external genitalia, cervicitis, lateral incision of external genitalia and radiation vaginitis; and/or
  • IBDs ⁇ inflammatory Bowel Diseases
  • a method of treatment of inflammation, of an inflammatory disorder, and/or of a disorder/condition characterised by inflammation comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
  • treatment 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.
  • 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.
  • 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.
  • a method of treatment of a viral infection comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
  • Viral infections 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.
  • 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.
  • HIV human immunodeficiency virus
  • 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.
  • rhabdoviridae e.g. rabies virus
  • hepeviridae e.g. hepatitis E virus
  • reoviridae e.g. rotavirus; orbivirus; coltivirus; Banna virus
  • viruses not assigned to families such as hepatitis D virus.
  • 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.
  • 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.
  • 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.
  • a method of treatment of a bacterial infection comprises the administration of a compound of the invention or a salt thereof to a patient in need of such treatment.
  • 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.
  • anticancer properties may also include the prevention of the onset of such a disease e.g. by treating inflammation and thereby preventing such onset.
  • 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.
  • 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 (including severe 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.
  • Fibrotic conditions of internal organs 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.
  • 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.
  • 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.
  • Inflammatory conditions 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) .
  • a symptom e.g. as a symptom
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • acute lung injury, ARDS and, particularly, SARS may be caused by viruses, such as coronaviruses, include the novel SARS coronavirus 2 (SARS-CoV-2) .
  • 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.
  • tissue damage may also give rise to one or more of the fibrotic conditions mentioned hereinbefore.
  • SARS disease caused by the novel coronavirus SARS-CoV-2 coronavirus disease 2019 or COVID-19
  • 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.
  • 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.
  • conditions that are ‘characterized by comorbidities’ we include that the main condition in question results in (or from) one more 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.
  • ⁇ 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;
  • 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;
  • ⁇ 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.
  • 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.
  • PIDDs primary immunodeficiency disorders
  • PIDDs primary immunodeficiency disorders
  • 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.
  • C1 complement component 1
  • 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.
  • a secondary factor such as old age, malnutrition (e.g. undernutrition)
  • a chronic disorder such as a chronic disorder, one or more chemical agents (e.g. drugs) and/or (e.g. ionizing) radiation.
  • SIDD may also include physical and/or mental stress, which stress may serve to compromise a patient’s immune system.
  • 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.
  • trauma injury, infection, surgery
  • intense physical labour/over-exertion e.g. over-training
  • environmental pollution precludedicides, 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
  • 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, ashamedy, 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. ) .
  • emotional stress e.g. negative emotions, such as resentment, fear, frustration, sadness, anger, grief/bereavement
  • cognitive stress information overload, worry, guilt, shame, ashamed
  • 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.
  • 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, ne
  • 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 (hydrocor
  • Drugs that may cause immunodeficiency in patients that may particularly be mentioned however include chemotherapeutic treatments of cancers, such as alemtuzumab, busulfan, cyclophosphamide, melphalan.
  • 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) .
  • 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.
  • inflammatory mediators such as NF- ⁇ B and SMAD2/3, and cytokines, such as IL-1, IL-2, IL-6, IL-8, IL-33, tumor necrosis factor (TNF- ⁇ ) , transforming growth factor beta (TGF- ⁇ ) and interferon gamma (IFN- ⁇ ) are associated with the release of prostaglandins and free radicals, including reactive oxygen species (ROS) and nitric oxide (NO) .
  • ROS reactive oxygen species
  • NO nitric oxide
  • 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.
  • 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.
  • Radio-induced per se and/or may result from radiation-induced immunosuppression
  • diseases 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.
  • radiation poisoning commonly known as ‘radiation poisoning’
  • 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.
  • 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.
  • 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.
  • 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.
  • ⁇ 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.
  • radiation-induced oral mucositis may occur following irradiation of the head or neck;
  • ⁇ radiation-induced encephalitis may also occur following irradiation of the head or neck;
  • ⁇ radiation pneumonitis and/or radiation esophagitis often result from radiation treatment of lung cancers, breast cancer, lymphomas, thymic tumours, or oesophageal cancer with radiation.
  • Radiation treatment that is aimed at the abdomen, pelvis or rectum may result in one or more of radiation enteropathy (or radiation enteritis, including radiation colitis and radiation enterocolitis) , radiation hepatitis, radiation myelitis, radiation vaginitis and, particularly, radiation proctitis.
  • radiation enteropathy or radiation enteritis, including radiation colitis and radiation enterocolitis
  • radiation hepatitis or radiation myelitis
  • radiation vaginitis e.g., radiation proctitis.
  • 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) .
  • RAVE radiation associated vascular ectasias
  • 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:
  • ⁇ a method of treatment of a radiation-induced condition that is characterized by (i) immunosuppression, and (ii) inflammation and/or wounding;
  • 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.
  • 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.
  • radiation- e.g. ionizing radiation-induced disorder
  • 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, conditions characterised by pathological hair loss, including cicatricial alopecia and related conditions, such as seborrheic alopecia and fibrous alopecia; 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 (retinal macular degeneration) ; 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.
  • compounds of the invention may be used in non-therapeutic, cosmetic treatments, such as anti-aging.
  • 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.
  • a further aspect of the invention is a cosmetic composition comprising a compound of the invention.
  • Such a composition may provide antiaging properties.
  • Patients include reptilian, avian and, preferably, mammalian (particularly human) patients.
  • 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) .
  • Administration by inhalation 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) .
  • 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.
  • 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.
  • 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.
  • distinct parts of the upper or lower intestine may be targeted.
  • colonic administration can also be achieved by way of colon-targeted drug delivery means that are initially administered perorally or parenterally.
  • 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.
  • Compounds of the invention are preferably administered by intradermal injection, by inhalation, or by topical administration (such as to the skin or mucosal surfaces, such as the oral mucosa, the ocular mucosa, the nasal mucosa, the vaginal mucosa, the rectal mucosa, the colonic mucosa, the oesophageal mucosa, to the throat, or to the dental periphery, the gingiva and/or the teeth) .
  • topical administration such as to the skin or mucosal surfaces, such as the oral mucosa, the ocular mucosa, the nasal mucosa, the vaginal mucosa, the rectal mucosa, the colonic mucosa, the oesophageal mucosa, to the throat, or to the dental periphery, the gingiva and/or the teeth.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically-acceptable adjuvant diluent or carrier
  • 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.
  • 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) ) .
  • a solution e.g. an (optionally) buffered aqueous formulation (e.g. solution)
  • a physiological saline-containing formulation e.g. solution
  • a phosphate-containing formulation e.g. solution
  • a borate-containing formulation e.g. solution
  • 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.
  • solvents e.g. water
  • co-solvents e.g. cyclodextrins
  • solubilizing agents e.g. cyclodextrins
  • 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) .
  • 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
  • tonicity-modifying agents such as sodium chloride
  • 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.
  • an appropriate vehicle for example pharmaceutically-and topically-acceptable
  • 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.
  • a solution of suspension into e.g. the dermis (e.g. intradermal injection) , joint cavity or the eyes.
  • Administration by intradermal injection 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.
  • a solution or suspension e.g. a dermal filler
  • 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.
  • 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.
  • 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.
  • a 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.
  • 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, 22 nd edition, Pharmaceutical Press (2012) and Martindale –The Complete Drug Reference, 38 th 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.
  • 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.
  • a aqueous formulation such as an emulsion, a suspension and/or a solution
  • a solution e.g. an (optionally) buffered aqueous formulation (e.g. solution)
  • a physiological saline-containing formulation e.g. solution
  • a phosphate-containing formulation e.g. solution
  • an acetate-containing formulation e.g. solution
  • borate-containing formulation
  • ⁇ 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) ;
  • ⁇ lotions for which suitable matrix materials include cellulose derivatives, glycerin, noncellulosic polysaccharides, polyethylene glycols of different molecular weights and propanediol
  • suitable matrix materials include cellulose derivatives, glycerin, noncellulosic polysaccharides, polyethylene glycols of different molecular weights and propanediol
  • pastes or ointments for which suitable paste matrix materials include glycerin, vaseline, paraffin, polyethylene glycols of different molecular weights, etc. ) ;
  • ⁇ 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) ;
  • suitable excipients e.g. foaming agents
  • suitable excipients 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
  • ⁇ powder aerosols for which suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol and polysorbates, e.g. a dry powder inhalant) ; and/or
  • liquid for example, mouthwash, water (aerosol) sprays for oral use, inhalation, or facial use (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. ) ;
  • viscosity modifiers such as hyaluronic acid
  • sugars such as glucose and lactose
  • emulsifiers emulsifiers
  • buffering agents alcohols, water, preservatives, sweeteners, flavours, etc.
  • 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
  • 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
  • suitable injectable solutions or suspensions include dermal fillers (i.e. injectable fillers or soft-tissue fillers) , particularly when the compound of the invention is combined with hyaluronic acid.
  • ⁇ oral tablets for which suitable excipients include binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate) .
  • suitable excipients include binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium la
  • 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.
  • 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.
  • 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.
  • stearic acid glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, octanoic/capric glyceride etc. may be included, particularly in cream formulations.
  • Compounds of the invention 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.
  • 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.
  • 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.
  • PEGs e.g. PEG 400
  • 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) .
  • 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) .
  • 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.
  • pMDIs pressurized metered-dose inhalers
  • DPIs dry powder inhalers
  • SMIs soft mist inhalers
  • nebulizers in which aerosol drug in a fine mist is delivered with slower velocity than a spray delivered using, for example, a pMDI.
  • 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 ⁇ L with each actuation.
  • a propellant e.g. HFA, along with excipients, such as mannitol, lactose, sorbitol, etc.
  • Actuation may be effected by hand (e.g. pressing) or by inhalation (breath-actuation) , involving a flow-triggered system driven by a spring.
  • compounds of the invention may be administered in the form of micronized drug particles (of a size between about 1 and about 5 ⁇ m) , 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.
  • micronized drug particles of a size between about 1 and about 5 ⁇ m
  • inactive excipient of larger particle size e.g. mannitol
  • Inhalation from a DPI may de-aggregate the medication particles and disperse them within the airways.
  • 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.
  • 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) .
  • a process for the preparation of a pharmaceutical composition/formulation which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient, as hereinbefore defined.
  • 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 (TGF ⁇ and TGF ⁇ ) , fibroblast growth factors ( ⁇ FGF, ⁇ FGF) , 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) .
  • platelet-type growth factors including platelet-derived growth factors, PDGFs
  • ODGF epidermal growth factors
  • TGF ⁇ and TGF ⁇ transforming growth factors
  • ⁇ FGF, ⁇ FGF fibroblast growth factors
  • IGF-I, IGF-II insulin-like growth factors
  • a composition comprising a compound of the invention and one or more pharmaceutically-acceptable excipient, such as an adjuvant, diluent or carrier.
  • a 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.
  • 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) .
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof.
  • 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.
  • 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.
  • Doses may be administered between once and four (e.g. three) times daily.
  • 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.
  • Appropriate topical doses of compounds of the invention are in the range of about 0.05 to about 50 ⁇ g/cm 2 of treated area, such as about 0.1 (e.g. about 0.5) to about 20 ⁇ g/cm 2 of treated area, including about 1 to about 10 ⁇ g/cm 2 of treated area, such as about 5 ⁇ g/cm 2 of treated area, in all cases calculated as the free (non-salt) compound.
  • Appropriate doses of compounds of the invention for nasal administration are in the range of about 0.01 ⁇ g to about 2000 mg, for example between about 0.1 ⁇ g to about 500 mg, or between 1 ⁇ g to about 100 mg.
  • Particular doses for nasal administration include between about 10 ⁇ g to about 1 mg, particularly a dose of about 0.1 mg (i.e. about 100 ⁇ g) .
  • 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.
  • Appropriate doses of compounds of the invention for pulmonary administration are in the range of about 0.01 ⁇ g to about 2000 mg, for example between about 0.1 ⁇ g to about 500 mg, or between 1 ⁇ g to about 100 mg.
  • Particular doses for pulmonary administration include between about 10 ⁇ g to about 10 mg, particularly a dose of about 0.6 mg (i.e. 60 ⁇ g) to 6 mg (e.g. for use in treating COPD or IPF) .
  • 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) .
  • 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) .
  • a mammal particularly a human
  • 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.
  • Certain compounds of invention may in addition and/or instead of possessing the aforementioned biological activity, possess adhesive properties.
  • 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.
  • 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.
  • 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.
  • a compound of formula I as an adhesive or a film-forming material.
  • MAP 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.
  • 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.
  • 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) .
  • 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
  • compounds of the invention 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.
  • a pharmaceutically-acceptable excipient e.g. an adjuvant, diluent or carrier
  • 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.
  • such compounds of the invention include those that may be used as adhesives and/or as film-forming agents (as described hereinbefore)
  • 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.
  • GRAS Generally Recognized as Safe
  • Such compounds of the invention may also be employed as excipients in veterinary science, as well as in cosmetics.
  • 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.
  • a pharmaceutically-acceptable excipient system such as a pharmaceutically-acceptable adjuvant, diluent or carrier system
  • 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.
  • 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) .
  • 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:
  • 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.
  • 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) .
  • 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.
  • a compound of the invention acts an excipient, such as a carrier.
  • 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.
  • 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) .
  • 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) .
  • 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.
  • 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, etoricoxi
  • 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,
  • Antiinflammatory drugs include endogenous (and/or exogenous) lipid-based pro-resolving, antiinflammatory molecules or mediators, such as lipoxins, resolvins, and protectins.
  • Pro-inflammatory agents include prostaglandins (e.g. latanoprost, prostaglandin E1, and prostaglandin E2) , and leukotrienes (e.g. Leukotriene B4) .
  • 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
  • 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,
  • 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.
  • 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.
  • basic fibroblast growth factor recombinant, human; recombinant, bovine
  • epidermal growth factor recombinant, human
  • 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.
  • 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,
  • compositions of the invention include those that may be administered to treat one or of the gastrointestinal disorders mentioned hereinbefore.
  • 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, ethylenedi
  • 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, di
  • 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) .
  • 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.
  • 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) .
  • LTB4 to treat wounds and burns
  • NSAIDS e.g. aspirin
  • montelukast to treat inflammation generally
  • trypsin to treat inflammation of the mucosa associated with e.g. viral infections
  • 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.
  • 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) ) .
  • 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) ) .
  • stem cells e.g. totipotent (omnipotent) , pluripotent (such as embryonic or induced pluripotent stem cells) , multipotent (such as mesenchymal stem cells) , oligopot
  • 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.
  • 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) .
  • a pharmaceutically-acceptable inactive excipient e.g. adjuvant, diluent or carrier
  • a pharmaceutically-acceptable inactive excipient e.g. adjuvant, diluent or carrier
  • components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
  • a process for the preparation of a combined preparation (1) as hereinbefore defined comprises bringing into association a compound of the invention, the other pharmaceutically-active ingredient, and at least one (e.g. pharmaceutically-acceptable) excipient.
  • a process for the preparation of a kit-of-parts (2) as hereinbefore defined which process comprises bringing into association components (A) and (B) .
  • 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.
  • 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:
  • kit of parts comprising:
  • 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)
  • additional pharmaceutically-acceptable excipients e.g. adjuvants, diluents or carriers
  • the compound of the invention when 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.
  • 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.
  • 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) .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutically-acceptable excipient e.g. an adjuvant, diluent or carrier
  • 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.
  • Figure 1 shows the results of ear swelling in a mouse model treated with xylene and test Compounds A, B and C.
  • Figure 2 shows the results of ear swelling in a mouse model treated with xylene and test Compounds D, E, F, G and H.
  • Figure 3 shows the results of ear swelling in a mouse model treated with xylene, test Compounds E, I, J and palmitic acid + DMSO.
  • Figure 4 shows the results of ear swelling in a mouse model treated with xylene and test Compound E.
  • Figure 5 shows the results for radiation oral mucositis scores in a hamster model treated with test Compound E.
  • Figure 6 shows the results of mechanical pain threshold in an SD rat model treated with test Compound E and lidocaine.
  • Figure 7 shows the results for 5-FU induced oral mucositis scores in an SD rat model treated with test Compound E.
  • Figure 8 shows the results of a human subject with rosacea treated with test Compound E.
  • Figure 9 shows the results of the severity of esophagitis in GERD rat model treated with test Compounds K, L and M.
  • Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 3)
  • Fmoc-Lys (Boc) -Wang resin (9.32 g, 3mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.
  • the resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
  • DMF N, N-dimethylformamide
  • the resin was washed three times, each time with the following solvents, DMF (200 mL) , DCM (200 mL) and methanol (200 mL; Xilong Scientific Co., Ltd., Guangdong, China) .
  • the resin was dried under vacuum for about 2 hours.
  • 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 ⁇ m 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 ⁇ L) .
  • the target peak was eluted at 35.232 minutes and had the expected molecular weight, (MS: m/z 1421.7) , with a purity of 64.564%.
  • 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 50%-80%solvent A concentration in 30 minutes; flow rate 60.0 mL/min) .
  • Solvent A 0.1%HAc in MeCN
  • solvent B 0.1%HAc in water
  • the title compound was prepared using essentially the same process as that described in Example 1 above, except that stearic acid was used instead of palmitic acid in the same amounts (by mols) in the last coupling step.
  • Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID No: 10)
  • the title compound was prepared using essentially the same process as that described in Example 1 above except that the coupling steps were carried out by the following sequence 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, Fmoc-Ala-OH and palmitic acid.
  • Fmoc-4-Hyp (tBu) -OH Fmoc-DOPA (Acetonide) -OH, Fmoc-Thr(tBu) -OH, Fmoc-4-Hyp (tBu) -OH, Fmoc-Tyr
  • Palm-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-Dopamine SEQ ID No: 109
  • the title compound was synthesized from Lys as the first amino acid with Fmoc-Lys (Boc) -Wang resin, using almost the same process as described in Example 1 above.
  • the resin was washed three times, each time with the following solvents, DMF (200 mL) , DCM (200 mL) and methanol (200 mL) . Then the resin was dried by vacuum for about 2 hours.
  • the title compound was prepared using essentially the same process as that described in Example 1 above, except that oleic acid was used instead of palmitic acid in the same amounts (by mols) in the last coupling step.
  • the title compound was prepared using essentially the same process as that described in Example 1 above, except that docosahexaenoic acid was used instead of palmitic acid in the same amounts (by mols) in the last coupling step.
  • Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys SEQ ID No: 17
  • the title compound was synthesized using essentially the same procedure as that described in Example 1 above, except that the appropriate amino acids were used as in the relevant peptide coupling sequences.
  • the title compound was synthesized using essentially the same procedure as that described in Example 6 above, except that the appropriate amino acids and fatty acids were used in the relevant peptide coupling sequences.
  • the title compound was prepared using essentially the same process as that described in Example 1 above, except that Fmoc-DPPS-OH was used instead of palmitic acid in the same amounts (by mols) in the last coupling step. After Fmoc-DPPS-OH was coupled on the resin, a deprotection step was carried out to remove the Fmoc protection on DPPS.
  • the title compound was prepared using essentially the same process as that described in Example 1 above, except that LTB4 was used instead of palmitic acid in the same amounts (by mols) in the last coupling step.
  • Fmoc-Lys (Boc) -Wang resin (9.15 g, GL Biochem, Shanghai, China) was loaded into a glass reaction column.
  • the resin was washed 6 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co Ltd, Shandong, China) .
  • DMF N, N-dimethylformamide
  • Palmitic acid (2.31 g, 9 mmol; Macklin Biochemical Co. Ltd., 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) .
  • DIPEA N-diisopropylethylamine
  • a Kaiser Test was carried out with few of the resin after 30 minutes reaction, a yellow color of the solution and colorless gel indicated that the reaction was complete. The solvent was removed by vacuum filtration.
  • the title compound was prepared using essentially the same process as that described in Example 10 above, except that oleic acid was used instead of montelukast sodium in the same amounts (by mols) in the last coupling step.
  • Palm-Lys-Hyp-Ser-Tyr-Hyp-Tyr-Lys SEQ ID No: 20
  • the title compound was synthesized using essentially the same procedure as that described in Example 8 above, except that the appropriate amino acids were used as in the relevant peptide coupling sequences.
  • the title compound was synthesized using essentially the same procedure as that described in Example 10 above, except that the appropriate amino acids were used as in the relevant peptide coupling sequences.
  • the title compound was synthesized using essentially the same procedure as that described in Example 12 above, except that Fmoc-Lys (Boc) -AM resin (6.98 g, USUN pharma, Jiangsu, China) was used as the starting material compared with Example 12. After the side chain of Fmoc-Lys (Boc) -AM resin was deprotected, cholesterol-acetic acid (self-synthesized) was connected to the side chain of Fmoc-Lys-AM resin. The appropriate amino acids were used as in the relevant peptide coupling sequences compared with Example 12, to obtain the title compound.
  • the title compound was synthesized from Lysine as the first amino acid with Fmoc-Lys(Boc) -CTC resin (7.23 g, USUN pharma, Jiangsu, China) as the solid support.
  • the peptide sequence Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 16) was synthesized using essentially the same procedure as that described in Example 1 above, except that the appropriate amino acids (Boc-Lys (Boc) -OH was used in the last coupling step) were used as in the relevant peptide coupling sequences compared with Example 1.
  • Fmoc-Lys (Fmoc) -Wang resin (10.23 g, 3mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column. 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. DCM was removed by vacuum filtration. The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
  • DCM N, N-dimethylformamide
  • the title compound was prepared using essentially the same process as that described in Example 8 above, except that the amount of the amino acids, palmitic acid and the condensation agents (TBTU and DIPEA) was doubled (by mols) .
  • the title compound was synthesized using essentially the same procedure as that described in Example 18 above, except that the appropriate amino acids were used as in the relevant peptide coupling sequences.
  • Fmoc-Lys (Dde) -Wang resin (9.97 g, 3mmol; GL Biochem, Shanghai, China) was loaded into a glass reaction column.
  • Resin wash The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
  • DMF N, N-dimethylformamide
  • Resin wash The resin was washed 3 times with N, N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China) .
  • DMF N, N-dimethylformamide
  • Palmitic acid was coupled to the side chain of the de-protected Lysine residue, further coupling steps were repeated to couple the following 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 then Boc-Lys (Boc) -OH, using essentially the same method as above.
  • Example 2 Repeating essentially the same procedure as Example 1 gave a further batch of crude title compound (yield 6.3 g) . Analysis showed a target peak that was eluted at 31.282 minutes with the expected molecular weight (MS: m/z 2254.9) . The purity was 50.872%. 6.3 g of the crude product was then purified as described in Example 1 above to give 2.01 g of pure title compound after freeze-drying.
  • the Compound E cream contained a mixture of the following substances in Table 1 below. Ingredients of phase A were mixed, heated to 85°C, and stirred for 30 minutes at 85 °C. Phase B was added, the mixture homogenized for 5 minutes, then stirred to cool down. When the temperature dropped to 45 °C, the raw materials of phase C were added and the mixture homogenized for 1 minute. Phase D was added and the mixture homogenized for 3-5 minutes until the system was uniform to obtain the Compound E Cream -1.
  • Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys (SEQ ID No: 17)
  • the Compound E oral spray contained a mixture of the following substances in Table 2 below.
  • the ingredients of phase A were mixed, heated to 85 °C, and stirred for 30 minutes at 85 °C. When the temperature dropped to 45 °C, the pre-mixed raw materials of phase B were added. The mixture was stirred for 3-5 minutes until phase B was dissolved and the system was uniform to obtain the Compound E Oral Spray.
  • the Compound E Facial Spray -1 contained a mixture of the following substances in Table 3 below.
  • the ingredients of phase A were mixed and heated to 85 °C and stirred for 30 minutes at 85 °C. When the temperature dropped to 45 °C phase B was added. The mixture was stirred for 3-5 minutes until phase B was dissolved and the system was uniform to obtain the Compound E Facial Spray -1.
  • the Compound E Facial Spray -2 contained a mixture of the following substances in Table 4 below.
  • the ingredients of phase A were mixed and heated to 85 °C. The mixture was stirred for 30 minutes at 85 °C. When the temperature dropped to 45 °C, phase B was added and stirred for 3-5 minutes until phase B was dissolved and the system was uniform to obtain the Compound E Facial Spray -2.
  • the Compound E mouthwash contained a mixture of the following substances in Table 5 below.
  • the ingredients of phase A were mixed and heated to 85 °C and stirred for 30 minutes at 85 °C. When the temperature dropped to 45 °C, phase B was added and stirred for 3-5 minutes until phase B was dissolved the system was uniform to obtain the Compound E Mouthwash -1.
  • the Compound E Cream –2 and its placebo sample contained a mixture of the following substances in Tables 6 and 7 below, respectively.
  • the ingredients of phase A were mixed, heated to 80 °C, and stirred for 30 minutes at 80 °C.
  • the ingredients of phase B were mixed, heated to 80 °C and stirred for 30 minutes at 80 °C.
  • the solution of phase B was transferred to the solution of phase A and homogenized for 5 minutes. The sample was allowed to cool until the system was uniform to obtain the Compound E Cream –1 or its placebo sample.
  • Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys SEQ ID No: 17
  • the Compound E Hair Care Essence and its placebo sample contained the following substances in Table 8 and 9 below, respectively.
  • the ingredients of phase A were mixed, heated to 80 °C and stirred for 30 minutes at 80 °C. The sample was allowed to cool until the system was uniform to obtain the Compound E Hair Care Essence or its placebo sample.
  • the Compound E Mouthwash -2 and its placebo sample contained a mixture of the following substances in Tables 10 and 11 below, respectively.
  • the ingredients of phase A were mixed, heated to 80 °C and stirred for 30 minutes at 80 °C. The sample was allowed to cool until the system was uniform to obtain the Compound E Mouthwash –2 or its placebo sample.
  • the Compound E Foam Formula -1 contained a mixture of the following substances in Table 12 below. The ingredients of phase A were mixed and stirred for 30 minutes until the system was uniform to obtain the Compound E Foam Formula -1.
  • the Compound E Foam Formula -2 contained a mixture of the following substances in Table 13 below.
  • the ingredients of phase A were mixed and stirred for 30 minutes until the system was uniform.
  • Sodium hydroxide was added to adjust the pH of the solution to 6.5-7.0 while stirring to obtain the Compound E Foam Formula –2.
  • the Compound E Foam Formula –3 contained a mixture of the following substances in Table 14 below. The procedures for preparing the Compound E Foam Formula –3 were the same as that described for Formula –2.
  • the preparation of the Compound E Gel contained a mixture of the following substances in Table 15 below.
  • the ingredients of phase A were mixed, heated to 80 °C and stirred for 30 minutes at 80 °C. The sample was allowed to cool until the system was uniform to obtain the Compound E Gel.
  • Compound B Stea-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 4)
  • mice 25 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 the experiment.
  • the housing conditions were at 25-27 °C, 74%humidity, 12h dark-light cycle, and the mice had free access to food and water.
  • mice were randomly divided into 5 groups (5 mice in each group) as described in Table 16 below.
  • the left ear of each mouse was used as the autologous control and the right ear of each mouse was treated with a different treatment: 20 ⁇ l 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 ⁇ l of drugs was applied to the right ear in each group. The mice were placed back in the cages.
  • Dexamethasone Acetate Cream (0.75 mg/g, China resources group) was purchased on the local drug store.
  • Compounds A-C were synthesized by the Chinese Peptide Company as described above. 15 mg of each compound (powder) was dissolved in 10 ml of normal saline to make a solution of 1.5 mg/ml. The resultant solution was applied to the mice accordingly.
  • 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 rate of swelling, shown in Table 17 below and in Figure 1.
  • a skin pouch Electric Microscopy Sciences, P. O. Box 550, 1560 Industry Road, Hatfield, PA 19440
  • the weights were recorded and used to calculate the rate of swelling, shown in Table 17 below and in Figure 1.
  • mice were divided into 7 groups as described in Table 18 below, and the results are shown in Table 19 below and in Figure 2.
  • mice were divided into 7 groups as described in Table 20 below and the results are shown in Table 21 below and in Figure 3.
  • mice were divided into 8 groups as described in Table 22 below and the results are shown in Table 23 below and in Figure 4.
  • Compound E was effective as an anti-inflammatory in the mouse ear swelling model and provides guidance for future clinical anti-inflammatory use. Compound E also has good dose dependence in anti-inflammation.
  • a 28-year-old male was presented with a skin lesion with a constant itch and scaling on his left elbow. It was diagnosed as neurodermatitis a year 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 E solution spray. After 1 spray on the lesion, the itching symptom was completely relieved after about 30 mins. The patient reported that the itching symptom had stopped during the day following administration.
  • Compound E was shown to improve mucositis according to the Sonis’ scoring criteria and SOM duration in radiation induced mucositis in hamsters. Compound E showed good dose dependence in this model. It was therefore shown that Compound E may alleviate patient symptoms associated with mucositis in clinical practice.
  • Compound E was shown to relieve acetic acid induced pain in SD rats and showed a pain relief effect equivalent to lidocaine. Compound E showed good dose dependence in this model. It has therefore been shown that Compound E may alleviate symptoms associated with ulcers of the oral mucosa in patients.
  • mice were intraperitoneally injected with 5-FU (MCE, China) , with a dosage of 50 mg/kg and a dosage volume of 2 ml/kg.
  • 5-FU Methylcholine
  • rats were intraperitoneally injected with further 5-FU followed by inhalation of 2.5%isoflurane (Sigma-Aldrich) to anesthetize the animals.
  • the animals were placed in the right supine position and the upper and lower jaws of the rats were opened using a self-made mouthpiece to expose the right cheek mucosa.
  • 6 mm filter paper was placed on the right cheek mucosa, and 80%acetic acid (5 ⁇ L, Sigma-Aldrich) was dripped onto the filter paper. After maintaining contact for 20 seconds, the filter paper was removed and the residual liquid on the cheek mucosa was wiped with a cotton swab.
  • the sham surgery group used the same method but with 5 ⁇ L saline dripped onto the filter paper.
  • the ulcer scores in all animals except those in the sham group were assessed and re-grouped accordingly.
  • the animals were treated according to the study plan described in Table 27, and assessed using the following criteria every day: 0-Normal mucosal appearance, without erythema or congestion; 1-The oral mucosa has erythema or congestion, but the mucosa is intact; 2-Large area erythema of oral mucosa with punctate diffuse ulcers; 3-Oral mucosal flake ulcer covering an area less than 1/4 of the cheek mucosal area (+) ; 4-Oral mucosal ulcer covering an area less than 1/2 of the buccal mucosa (++) ; 5-Buccal mucosal ulcers larger than half of the area (+++) .
  • the cell laying rate reached 40%-60%in a 96 well plate
  • 200 ⁇ L culture medium containing 10%PBS (Sigma) was added to each well in the control group
  • 200 ⁇ L culture medium containing 10%DMSO was added to each well in the positive control group
  • 200 ⁇ L culture medium containing corresponding concentration samples was added to each well of the sample group
  • 200 ⁇ L cell culture medium was added to the zero group without cell inoculation.
  • the 96 well plate was placed in a culture incubator (37 °C, 5%CO 2 ) for cultivation. After 24 hours of cell incubation, the supernatant was discarded and MTT working solution (0.5 mg/mL) was added.
  • the 96 well plate was incubated at 37 °C in the dark for 2 hours. After incubation, the supernatant was discarded and 100 ⁇ L of DMSO was added to each well. The OD value was read at 490 nm.
  • PBMC peripheral blood mononuclear cells
  • T cell concentration was adjusted to 0.1M per well (50 ⁇ L) using the 1640 full culture medium.
  • 50ul of LPS (Sigma-Aldrich) was added to the cells four times.
  • 100 ⁇ L of blank culture medium/Compound E or dexamethasone of different concentrations/culture medium containing 0.4%DMSO+highest concentration was added to the corresponding holes separately.
  • the LPS group was incubated for 24 hours. The cell supernatant was collected to detect the secretion of relevant inflammatory factors. Flow cytometry was used to detect cell proliferation and viability.
  • the culture medium was added to the blank control group; a culture medium containing LPS (Sigma-Aldrich) was added to the model control group; a culture medium containing LPS and dexamethasone was added to the positive control group; and a culture medium containing LPS and a certain concentration of Compound E was added to the sample group.
  • the groups were exposed for 24 hours. After incubation, the cell supernatant was collected and stored in a -80 °C ultra-low temperature freezer. The content of IL-1 ⁇ , IL-6, IL-8, and TNF- ⁇ was measured according to the instructions of the ELISA kit (R&D Systems) .
  • the culture medium was added to the blank control group; a culture medium containing LPS (Sigma-Aldrich) was added to the model control group added; a culture medium containing LPS and dexamethasone was added to the positive control group; and a culture medium containing LPS and a certain concentration of Compound E was added to the sample group.
  • the groups were exposed for 24 hours. After incubation, the cell supernatant was collected and stored in a -80 °C ultra-low temperature freezer.
  • the levels of IL-6, TNF- ⁇ , and NO were measured according to the instructions of the ELISA kit (R&D Systems) .
  • mice (Beijing Chairs River Experimental Animal Technology Co., Ltd) were divided into two cages, male and female, with 5 animals in each cage. Before the experiment, animals were fasted overnight and there were no restrictions on drinking water. Using a maximum limit experiment, animals were weighed and administered the toxin by gavage, at a capacity of 2 mL/100g and a dose of 5000 mg/kg body weight. The animals were poisoned once in 24 hours. After being poisoned, the animals were fasted for 3h-4h. After being poisoned, the abnormal situation of the animals was observed every day, and autopsies were performed on the dead animals during the observation period and the animals were euthanized at the end of the observation period. The tissues and organs were observed for abnormalities with the naked eye and histopathological examination was conducted when necessary. The results are shown in Table 28 below.
  • the animals (Beijing Chairs River Experimental Animal Technology Co., Ltd) were divided into two cages, male and female, with 5 animals in each cage.
  • the test area was approximately 30-40cm 2 .
  • the animals were acclimated to the experimental animal room environment for 3 days to ensure that the enrolled animals were healthy and had no skin damage.
  • the fur on the back of the animal's trunk in the area to be contaminated was cut off. When removing the fur, it was ensured that the skin was not damaged.
  • the experiment adopted a maximum limit test, with a toxic dose of 2180 mg/kg; After weighing the animal, the test substance was moistened with water and applied evenly to the contaminated area of the animal's back skin.
  • the skin was covered with a thin film and fixed with non-irritating adhesive tape. The skin was closed and covered from contact for 24 hours. After poisoning, the residual test substance was removed with warm water. After being poisoned, the abnormal situation of the animals was observed every day, and autopsies on the dead animals were performed during the observation period and the animals euthanized after the observation period. The tissue was observed with the naked eye for abnormalities, and if necessary, histopathological examination was performed. The observation time was 14 days. The weight of active objects was recorded during the observation period at 0 days, 1 day, 7 days, and 14 days (D0-14) . The results are shown in Table 29 below.
  • Compound E was applied to adult subjects for 28 consecutive days under normal conditions according to the instructions to evaluate whether the product showed efficacy in acne reduction, oil control, moisturizing, repair, and soothing, and whether it was gentle (non-irritating) and suitable for sensitive skin.
  • a fingertip unit of Compound E was used twice a day for a total of 28 days.
  • the dosage of cream is based on the fingertip unit (FTU) , and 1 fingertip unit refers to the amount of cream from the index finger to the first interphalangeal joint squeezed from 5 mm open tube (approximately 0.5g) .
  • An image capture was taken with VISIA 7 to analyze the skin color, redness area and porphyrin with IPP.
  • An image capture was taken to analyze acne volume with Antera 3D (Miravex Limited, Ireland) .
  • Skin hydration was measured with CM825 (Courage+Khazaka electronic GmbH, Germany) .
  • Skin transepidermal waterloss was measured with Tewameter HEX 5 (Courage+Khazaka electronic GmbH, Germany) .
  • Skin sebum was measured with Sebumeter SM 815 (Courage+Khazaka electronic GmbH, Germany) .
  • a dermatologist assessment and self-assessment was taken.
  • the aim of the clinical study was to test the efficacy of Compound E as a novel raw material for use in a Gum-protecting peptide mouthwash and for the control of gingivitis. Seventy subjects with gingivitis aged 18 to 60 years were included in this study, with an estimated number of ⁇ 60 subjects completing the whole study, i.e. ⁇ 30 per group.
  • the Inclusion criteria was: 1) Good general condition and no systemic diseases; 2) Aged 18 to 60 years, male or female; 3) Having more than 20 intact teeth, no large restorations at the gingival margin, untreated cavities and severe gingival recession and severe periodontal diseases; 4) Modified Quigley-Hein plaque index ⁇ 1.5; 5) Loe-Silness gingival index ⁇ 2.0, bleeding index ⁇ 2.0.
  • the test product was the mouthwash composed of the following ingredients: 0.05%ammonium chloride, 0.02%galactose trichloride, 0.01%water-soluble menthol, 0.03%Compound E and water for injection.
  • the placebo was the same formulation without Compound E.
  • the pH of the mouthwash was 6.0.
  • Compound E is effective in alleviating gingivitis and has significant benefits for patients using it.
  • test product was prepared as described in Example 27 above. 66 healthy subjects aged 25 to 60 years were included in the study, with an estimated number of ⁇ 60 subjects completing the whole study, i.e. ⁇ 30 per group.
  • the Inclusion criteria was: 1) Hair length ⁇ 3cm, 2) No severe hair loss, with hair roots covering at least 70%of the scalp, 3) Dandruff level ⁇ 3 points, 4) Self perceived itching and redness on the scalp.
  • test subjects were randomly divided into the test group and placebo group. After 2 weeks wash off period, when the subjects washed their hair every two days using the provided shampoo, they started to use the test product, Compound E Hair Care Essence or the placebo.
  • the test product was applied evenly to the scalp using a scalp applicator in a dry hair state, once a day, 3 ml each time. If the product was used after washing hair, it was necessary to dry the hair before use.
  • the efficacies were evaluated after 28 days. Evaluation included the measurement of scalp skin oil content (Sebumeter SM815, Courage+Khazaka electronic GmbH, Germany) , stratum corneum moisture content (Corneometer CM825, Courage+Khazaka electronic GmbH, Germany) , and transdermal water diversion loss rate (Tewameter, Courage+Khazaka electronic GmbH, Germany) by laboratory technicians. General scalp condition, itching, dandruff, dryness and redness were evaluated by a dermatologist.
  • Compound E is effective in relieving symptoms related to seborrheic dermatitis and has significant benefits for patients using it.
  • the housing temperature was 25-27°C with 74%humidity, with alternating 12-hour periods of light and darkness, and free access to food and water.
  • the rats were randomly divided into 5 groups, with 4 rats in each group.
  • the groups were as follows: sham group, model group, compound K, L and M groups.
  • the rats were anesthetized with 2%isoflurane inhalation and placed into a supine position.
  • the surgical area was shaved with a hair clipper and the skin was disinfected with iodophor.
  • a 2 cm incision was made along the midline of the abdomen, 0.5 cm below the xiphoid to open the abdominal cavity and expose the surgical field.
  • the connective tissues were separated and cut between the liver and the stomach.
  • the vessel bundle was ligated and cut between the spleen and the fundus to completely free up the fundus.
  • the fundus was turned slightly to the left, exposing the left side of the gastroesophageal junction in the field.
  • a 5 mm longitudinal incision was made on the muscle along the distal esophagus using a pair of sharp scissors to expose the gastroesophageal junction.
  • the dorsal side of the esophagus was gently separated from the blood vessels behind the esophagus. A small cotton tip was passed between the esophagus and blood vessels. Two 5 mm longitudinal incisions were made on each of the gastroesophageal junction and the proximal end of duodenum adjacent to the pylorus with sharp operating scissors. For the incision on the duodenum, blood vessels were avoided and placed on the anti-mesenteric border. The incisions were anastomosed with accurate mucosal to mucosal opposition using interrupted 8-0 Prolene sutures. 3-4 sutures were placed on the dorsal side and 2-3 sutures on the front side.
  • the abdominal cavity was washed with normal saline and the abdominal wall and the skin was closed.
  • the surgery was performed for each rat except for those in sham surgery group. After anesthesia and laparotomy, the lower esophagus, duodenum, and gastric fundus were separated in the sham surgery group, without incision.
  • Postoperative fasting and water deprivation was done for 30 hours, the rats were given glucose injection via tail vein infusion, 8 ml/animal, once a day, for 2 consecutive days.
  • the rats were given intramuscular injection of 50000 IU of penicillin once a day to prevent infection, continuously administered for 3 days. 1 week after the operation, different interventions were given to the rats by gavage, according to Table 33 below.
  • the interventions were given once daily for 2 weeks.
  • the body weights were measured every three days.
  • the animals were scarified, and the chest cavities were opened.
  • the esophagus was peeled off and longitudinally cut open, to expose the anastomotic site.
  • the severity of esophagitis was evaluated according to the scoring criteria in Table 34 below.
  • Compound E 1mg Compound E dissolved in 1 ml normal saline to make a 1 mg/ml solution.
  • Compound E + PL429 PL429 (Guangzhou Jizhou Trading Co., Ltd) is a transdermal enhancer. 0.5%PL429 was added into the above solution.
  • the instrument used was a high pressure transdermal nutrition supplement instrument (Guangzhou Tuonasi Beauty Instrument Co., Ltd, China) .
  • the hair on the administration site (left back skin of the spine) was shaved with an area of 4.0 cm 2 .
  • the area of the administration was 3 cm 2 which was marked.
  • the administration was on the intact skin (without any damage) .
  • Sample processing Approximately 200 ⁇ L of the whole blood was collected from the carotid arteries of each group of animals at each time point and injected into an EP tube containing EDTA-K anticoagulant. Immediately, it was manually shaken and placed in wet ice. The samples were centrifuged at 1800g, 4 °C for 10 minutes. Within 2 hours, the plasma was separated and stored at -80 °C. At the same time, the skin tissue from the administration site was collected. Before collecting the tissue samples, site was cleaned with normal saline and the water was dried. After collection, the samples were stored at -80 °C for further analysis.
  • Compound E 1 mg of Compound E dissolved in 1 ml of normal saline to make a 1 mg/ml solution.
  • Dermashine pro Humans Meditech, Republic of Korea
  • Dermashine pro an automatic mesotherapy injector using vacuum pressure. It has been used for replenishing moisture and nutrition to the skin.
  • a 56-year-old woman was presented with pigment deposition on her checks after a beach trip. During her staying on the beach, the subject was exposed to the sun, causing reddening of the skin. After a few days, pigmentation was present. The subject went to a beauty salon for treatment. The subject was treated with Compound E by Dermashine injection to the whole face. The solution was filtrated by a 0.22 ⁇ m High Flow filter (Sartorius, Germany) . A total of 3 ml of solution was injected. The treatment was repeated after 2 weeks. A week after the second injection, the pigmentation disappeared, and the dullness and roughness of the skin had improved significantly.
  • Compound K (Palm-Lys-Pro-Ser-Tyr-Hyp-Tyr-Lys) 2 -Lys (SEQ ID No: 113) was dissolved in normal saline to make a 1 mg/ml solution.
  • a 32-year-old woman was presented with pigmentation on both of her checks after giving birth to a baby girl. 6 months after the birth, she sought treatment for her face. The subject went to a beauty salon and was recommended to use a non-invasive treatment with the above-mentioned solution.
  • a High-pressure transdermal nutrition supplement instrument (Guangzhou Tuonasi Beauty Instrument Co., Ltd, China) was used to enhance the absorption of the solution. The treatment was conducted every week. After two months, the skin became tight and flawless.
  • a total of 67 male SD rats were randomly assigned into a normal control group (10 rats) and a model group (57 rats) for the first grouping according to animal weight.
  • the animals in the normal control group were intraperitoneal injected and intra-trachea nebulized with sodium chloride injection.
  • the animals in the model group were intraperitoneal injected and intra-trachea nebulized with lipopolysaccharide (LPS) to induce the model of acute lung injury (intraperitoneal injection of 2 mg/kg on Day 0, intra-trachea nebulization of 4 mg/kg on Day 1, with an interval of about 16 hours) .
  • LPS lipopolysaccharide
  • the animals in the model group were randomly assigned again into: vehicle control group according to weight; test article Compound N group (0.5 mg/kg) ; test article Compound O group (0.5 mg/kg) ; test article Compound M group (0.5 mg/kg) ; and positive control group (2.5 mg/kg) .
  • vehicle control group according to weight
  • test article Compound N group 0.5 mg/kg
  • test article Compound O group 0.5 mg/kg
  • test article Compound M group 0.5 mg/kg
  • positive control group 2.5 mg/kg
  • Both the normal control group and the vehicle control group were given intravenous injection of 0.9%sodium chloride injection; the test article Compound N, Compound O and Compound M groups were given intravenous injection of the corresponding dose once daily for 1 day; and animals in the positive control group were intraperitoneally injected with dexamethasone sodium phosphate injection once daily for 1 day. On Day 2, the animals were anesthetized and euthanized, and the lung lavage fluid test and lung weight index test were performed.
  • the bronchoalveolar lavage fluid (BALF) : Compared with the corresponding indicators of animals in the vehicle control group, showed that the mean values of WBC, Neut, Lymph and Mono of animals in test article Compound N, Compound O and Compound M groups and positive control group were significantly reduced.
  • the maximum decreases in WBC were about 62%, 74%, 84%and 87%, respectively, with statistical differences.
  • the maximum decreases of Neut were about 73%, 79%, 92%and 93%, respectively, with statistical differences.
  • the maximum decreases of Lymph were about 65%, 76%, 82%and 84%, respectively, with statistical differences.
  • the maximum decrease of Mono were about 71%, 85%, 88%and 91%, respectively, with statistical differences.
  • Total protein Compared with the total protein in BALF of animals in the vehicle control group, the mean values of total protein of the animals in the test article Compound N, Compound O and Compound M groups, and positive control group showed a significant decrease. The maximum decreases of total protein were about 68%, 72%, 77%and 56%, respectively, with statistical differences.
  • Lung weight index Compared with the lung weight index of animals in the vehicle control group, the mean values of lung weight index of the animals in the test article Compound N, Compound O and Compound M groups, and positive control group showed a significant decrease. The maximum decreases of lung weight index were about 20%, 23%, 25%, and 29%, respectively, with statistical differences.
  • Inflammatory factors Compared with the serum and BALF, inflammatory factors (Ang-2, LTD4) of animals in the vehicle control group, the test article Compound N, Compound O and Compound M groups, and positive control group significantly decreased.
  • the maximum decrease of Ang-2 in the serum was about 25%, 31%, 40%and 46%, respectively.
  • the maximum decrease of Ang-2 indicators in the BALF was about 25%, 27%, 37%and 55%, respectively, with statistical differences in the positive control group.
  • the maximum decrease of LTD4 indicators in the serum was about 35%, 32%, 37%and 32%, respectively.
  • the maximum decrease of LTD4 in BALF was about 5%, 15%, 10%and 25%, respectively.
  • test articles that were administered Compound N, O and M intravenously once a day at doses of 0.5 mg/kg reduced the total white blood cell count, neutrophil count, total protein, lung weight index, Ang-2 and LTD4 in serum and BALF indicators in acute lung injury model rats, indicating that the compounds are effective in treating acute lung injury.
  • the preparation of the Compound P Foam contained a mixture of the following substances in Table 37 below.
  • phase A The ingredients of phase A were mixed and stirred for 30 minutes, until the system was uniform. Sodium hydroxide was added to adjust the pH of the solution to 6.5.0 while stirring to obtain the Compound P Foam.
  • This foam is intended to be used as an anti-inflammatory for the repairing of vaginal mucosa damages caused by disorders and operation.
  • the preparation of the Compound P Gel contained a mixture of the following substances in Table 38 below.
  • phase A The ingredients of phase A were mixed, heated to 80 °C and stirred for 30 minutes at 80°C. The sample was allowed to cool down until the system was uniform to obtain the Compound P Gel.
  • This gel is intended to be used as anti-inflammatory in the repairing of colorectal mucosa damages caused by disorders and operation.
  • the preparation of the Compound P Tablet contained a mixture of the following substances in Table 39 below.
  • phase A The ingredients of phase A were sieved through a 100-mesh sieve.
  • the pharmaceutic adjuvants were added to the Compound P in sequence and mixed evenly.
  • 50%ethyl alcohol was used as a wetting agent while adding the pharmaceutic adjuvants, and the mixture was stirred continuously to make it evenly wetted.
  • the humidity of the material was adjusted to make a soft material that could be kneaded into a ball by hand and dispersed when lightly pressed.
  • the prepared soft material was sieved through a 20-mesh standard sieve to obtain wet granules.
  • the prepared wet granules were evenly spread on a tray with a granule layer thickness of 2 cm to 3 cm.
  • the granules were dried at 55°C for 1 h, turning the granules over every 15 min to speed up the drying process and ensure uniform drying until the moisture content was below 3%.
  • the dried granules were sieved again, sized, mixed with a certain amount of lubricant magnesium stearate, and put into a tablet press for tableting to obtain the Compound P Tablet.
  • This tablet is intended for use as an anti-inflammatory and the repairing of gastrointestinal tract mucosa damages caused by disorders and operation.

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Abstract

L'invention concerne un composé de formule I, dans laquelle : Qa représente Z ou A-Q-B, et Q est un fragment structural de la formule II, les lignes sinueuses, R et m étant définies dans la description, et A et B étant définis dans la description, mais pouvant représenter un composant peptidique de la formule (IV),[(W)r-Lys-X1-T-U-X2-Y] n-(W)r-Lys-X1-T-U-X2-Y (IV) (SEQ ID No : 1), n, r, T, W, X1, U, X2 et Y étant définis dans la description, chaque L représentant indépendamment un lipide tel que défini dans la description, et D représentant une ou plusieurs fractions optionnelles de montélukast, lesquels composés étant utiles en médecine, notamment en tant qu'excipients pharmaceutiques, adhésifs et matériaux filmogènes, et/ou étant utiles dans le traitement de pathologies caractérisées par une inflammation, notamment les plaies, les brûlures et les troubles de la muqueuse, telles que les maladies anorectales, les maladies inflammatoires de l'intestin, les maladies gynécologiques et les affections dentaires.
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WO2025195444A1 (fr) 2024-03-20 2025-09-25 Enlitisa (Shanghai) Pharmaceutical Co., Ltd. Nouvelle utilisation de peptides dérivés du peptide intestinal vasoactif

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WO2025195444A1 (fr) 2024-03-20 2025-09-25 Enlitisa (Shanghai) Pharmaceutical Co., Ltd. Nouvelle utilisation de peptides dérivés du peptide intestinal vasoactif

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