Classifications

• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • 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
  • A61K9/0048—Eye, e.g. artificial tears

Definitions

• the present invention relates to peptides and pharmaceutical compositions for treating eye diseases.
• Dry eye syndrome or keratoconjunctivitis sicca may be defined, in a broad sense, as damage to the ocular surface due to tear secretion disorders (Joossen C et al ., Exp. Eye Res ., 146: 172-8, 2016). Dry eye syndrome is known to cause tear secretion disorders and damage and discomfort to the eyeball due to a combination of various factors. Although the onset of dry eye syndrome is closely related to age, the incidence thereof is increasing in younger age groups due to a long-term exposure to a dry environment as the use of contact lenses, computers, and smart devices (Stern ME et al., Int. Rev. Immunol., 32: 19-41, 2013).
• dry eye syndrome reduces the mucus secretion of the corneal and conjunctival epithelia and that of the mucus-secreting goblet cells, resulting in a sharp decrease in the lubrication of the eyeball.
• dry eye syndrome causes damage to the corneal surface, thereby increasing the penetration of a fluorescein dye into the cornea.
• These symptoms of dry eye syndrome can be evaluated as changes in the tear secretion through the Schirmer test, which uses cobalt chloride paper.
• the damage to the cornea that may accompany dry eye syndrome can be easily evaluated using a general fluorescent dye and a slit-lamp fluorophotometer.
• the present invention provides a salt of a compound represented by Formula (I):
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• the compound comprises at least one D-amino acid residue.
• the present invention provides a compound represented by Formula (I):
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• R 1 , R 2 , and R 3 are substituted or unsubstituted (C2- Cio)haloalkyl;
• R a or R c is heterocyclylalkyl, cycloalkyl, or
• the compound comprises at least one D-amino acid residue
• At least one occurrence of R a and at least one occurrence of R c at least one occurrence of R a and at least one occurrence of R c ; and at least one occurrence of R a and/or R c differs from the other occurrences;
• the invention provides a compound having the following structure:
• the invention provides a compound represented by Formula (V):
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 9 is hydrogen or alkyl
• the invention provides a compound represented by Formula (VI):
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 is hydrogen or alkyl
• R 9 is hydrogen or alkyl
• the invention provides a compound represented by Formula
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 is hydrogen or alkyl
• R 9 is hydrogen or alkyl
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• J is OH or -NR x R y ;
• R x and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R x and R y taken together with the intervening nitrogen atom form a ring.
• the present invention also provides compounds represented by Formula (X-am):
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• J is OH or -NR x R y ;
• R x and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxyla.lkyl, or R x and R y taken together with the intervening nitrogen atom form a ring.
• the invention also provides salts of the following compounds:
• compositions comprising a pharmaceutically acceptable carrier and a compound or salt of the invention.
• the invention also provides methods of treating eye disease, such as eye disease is selected from retinopathy, keratitis, dry-macular degeneration, wet-macular degeneration, dry eye syndrome, heratoconjunctivitis sicca and keratoconjunctival epithelium disorder, by administering a compound or salt of the invention, or a pharmaceutical composition comprising the same.
• eye disease such as eye disease is selected from retinopathy, keratitis, dry-macular degeneration, wet-macular degeneration, dry eye syndrome, heratoconjunctivitis sicca and keratoconjunctival epithelium disorder
• Fig. l is a diagram showing the sequence and characteristics of the peptides prepared according to an embodiment of the present invention.
• Fig. 2 is a diagram showing a process for synthesizing the peptides prepared according to an embodiment of the present invention.
• Fig. 3 is a diagram showing a purification procedure of the peptides prepared according to an embodiment of the present invention.
• Fig. 4 is a photograph showing a procedure of extraorbital lacrimal gland excision.
• Fig. 5 is a diagram showing a change in the body weight of a rat model whose eyes have been administered with YDE-001 to YDE-028.
• Fig. 6 is a diagram showing a change in the body weight of a rat model whose eyes have been administered with YDE-029 to YDE-043.
• Fig. 7 is a photograph showing a procedure of administering an agent to the eyes of a rat model.
• Fig. 8 is a photograph showing a procedure of measuring the amount of tear secretion of a rat model using cobalt chloride paper.
• Fig. 9 is a photograph showing the results of measuring the amount of tear secretion of a rat model whose eyes have been administered with YDE-001 to YDE-028 using cobalt chloride paper.
• Fig. 10 is a diagram showing the changes in the amount of tear secretion of a rat model whose eyes have been administered with YDE-001 to YDE-028.
• Fig. 11 is a photograph showing the results of measuring the amount of tear secretion of a rat model whose eyes have been administered with YDE-029 to YDE-043 using cobalt chloride paper.
• Fig. 12 is a diagram showing the changes in the amount of tear secretion of a rat model whose eyes have been administered with YDE-029 to YDE-043.
• Fig. 13 is a photograph showing a procedure of administering a fluorescent substance to the eyes of a rat model for confirming damage to the cornea thereof.
• Fig. 14 is a photograph showing the results of measuring damage to the cornea of a rat model whose eyes have been administered with YDE-001 to YDE-028 using a fluorescent substance.
• Fig. 15 is a diagram showing the permeability of a fluorescence dye to confirm the recovery of corneal damage of a rat model whose eyes have been administered with YDE- 001 to YDE-028.
• Fig. 16 is a photograph showing the results of measuring damage to the cornea of a rat model whose eyes have been administered with YDE-029 to YDE-043 using a fluorescent substance.
• Fig. 17 is a diagram showing the permeability of a fluorescence dye to confirm the recovery of corneal damage of a rat model whose eyes have been administered with YDE- 029 to YDE-043.
• FIG. 18 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 1.
• FIG. 19 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 2.
• FIG. 20 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 3.
• FIG. 21 is a diagram showing the cell growth rate after 48 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 4.
• FIG. 22 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 1.
• FIG. 23 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 2.
• FIG. 24 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 3.
• FIG. 25 is a diagram showing the cell growth rate after 72 hours from the treatment of hEGF on human corneal epithelial cells of plate No. 4.
• FIG. 26 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YY-101 on human corneal epithelial cells.
• FIG. 27 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YY-102 on human corneal epithelial cells.
• FIG. 28 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-011 on human corneal epithelial cells.
• FIG. 29 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-038 on human corneal epithelial cells.
• FIG. 30 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-042 on human corneal epithelial cells.
• FIG. 31 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-043 on human corneal epithelial cells.
• FIG. 32 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-044 on human corneal epithelial cells.
• FIG. 33 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-045 on human corneal epithelial cells.
• FIG. 34 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-049 on human corneal epithelial cells.
• FIG. 35 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-054 on human corneal epithelial cells.
• FIG. 36 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-057 on human corneal epithelial cells.
• FIG. 37 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-058 on human corneal epithelial cells.
• FIG. 38 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-059 on human corneal epithelial cells.
• FIG. 39 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-060 on human corneal epithelial cells.
• FIG. 40 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-072 on human corneal epithelial cells.
• FIG. 41 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-073 on human corneal epithelial cells.
• FIG. 42 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-074 on human corneal epithelial cells.
• FIG. 43 is a diagram showing the cell growth rate after (a) 48 hours or (b) 72 hours from the treatment of YDE-075 on human corneal epithelial cells.
• FIG. 44 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-078 on human corneal epithelial cells.
• FIG. 45 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-080 on human corneal epithelial cells.
• FIG. 46 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-081 on human corneal epithelial cells.
• FIG. 47 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-083 on human corneal epithelial cells.
• FIG. 48 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-084 on human corneal epithelial cells.
• FIG. 49 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-086 on human corneal epithelial cells.
• FIG. 50 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-001 on human corneal epithelial cells.
• FIG. 51 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-010 on human corneal epithelial cells.
• FIG. 52 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-029 on human corneal epithelial cells.
• FIG. 53 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-092 on human corneal epithelial cells.
• FIG. 54 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-053 on human corneal epithelial cells.
• FIG. 55 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-064 on human corneal epithelial cells.
• FIG. 56 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-066 on human corneal epithelial cells.
• FIG. 57 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-012 on human corneal epithelial cells.
• FIG. 58 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-019 on human corneal epithelial cells.
• FIG. 59 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-055 on human corneal epithelial cells.
• FIG. 60 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-085 on human corneal epithelial cells.
• FIG. 61 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-047 on human corneal epithelial cells.
• FIG. 62 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-048 on human corneal epithelial cells.
• FIG. 63 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-050 on human corneal epithelial cells.
• FIG. 64 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-051 on human corneal epithelial cells.
• FIG. 65 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-052 on human corneal epithelial cells.
• FIG. 66 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-056 on human corneal epithelial cells.
• FIG. 67 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-061 on human corneal epithelial cells.
• FIG. 68 is a diagram showing the cell growth rate after 48 hours and 72 hours from the treatment of YDE-062 on human corneal epithelial cells.
• the present invention is based on the surprising discovery of therapeutic agents for treating eye diseases such as dry eye syndrome.
• the effectiveness of the agents has been demonstrated by synthesizing these peptides, administering them to the eyes of rats with dry eye syndrome, and confirming the eye protection effect through the Schirmer test and the fluorescent dye deposition test.
• novel peptide of the present invention When the novel peptide of the present invention is administered to the eye, it increases the amount of tear secretion and promotes recovery of the damaged cornea. Hence, they can be advantageously used as therapeutic agents for treating eye diseases. Definitions
• Alkyl is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof.
• an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl).
• Examples of a suitable alkyl group include methyl (Me, -CEE), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl,
• Alkoxy refers to a group having the formula -O-alkyl, wherein the alkyl group as defined above is attached to the parent compound via an oxygen atom.
• the alkyl moiety of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C10 alkoxy), or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy).
• Examples of a suitable alkoxy group include methoxy (- O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH 3 ) 3 or -O-tBu), but it is not limited thereto.
• Haloalkyl is an alkyl group in which at least one of the hydrogen atoms of the alkyl group as defined above is replaced by a halogen atom.
• the alkyl moiety of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., Ci- C12 haloalkyl), 1 to 10 carbon atoms (i.e., C1-C10 haloalkyl), or 1 to 6 carbon atoms (i.e., Ci-Ce haloalkyl).
• a suitable haloalkyl group include
• Alkenyl is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof, and having at least one unsaturated region, i.e., a carbon-carbon sp 2 double bond.
• an alkenyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl).
• Alkynyl is a hydrocarbon having primary, secondary, tertiary, and/or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof, and having at least one carbon-carbon sp triple bond.
• an alkynyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 12 carbon atoms (i.e., C2- C12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C10 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl).
• Examples of a suitable alkenyl group include acetylenic (-CoCH) and propargyl (- CH2CoCH), but it is not limited thereto.
• Alkylene refers to a saturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moeities) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane.
• an alkylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
• Examples of a typical alkylene group include 1,2-ethylene (-CH2-CH2-), but it is not limited thereto.
• Alkenylene refers to an unsaturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moeities) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkene.
• an alkenylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
• Alkynylene refers to an unsaturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moeities) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkyne.
• an alkynylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
• Examples of a typical alkynylene radical include acetylenylene (-CoC-), propargylene (-CH2CoC-), and 4- pentynylene (-CEhCEhCEhC ⁇ C-), but it is not limited thereto.
• Aryl refers to an aromatic hydrocarbon group.
• an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
• Examples of a typical aryl group include a radical derived from benzene (e.g., phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, and the like, but it is not limited thereto.
• Arylalkyl refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or other sp 3 carbon atom, is replaced by an aryl group.
• Examples of a typical arylalkyl group include benzyl, 2-phenylethan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl, and the like (each of which may be substituted or unsubstituted), but it is not limited thereto.
• An arylalkyl group may have 7 to 20 carbon atoms.
• the alkyl moiety thereof may have 1 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms.
• Arylalkenyl refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp 3 carbon atom, although an sp 2 carbon atom may also be used, is replaced by an aryl group.
• the aryl moiety of the arylalkenyl may be, for example, any aryl group described herein, and the alkenyl moiety of the arylalkenyl may comprise, for example, any of the alkenyl groups described herein.
• An arylalkenyl group may have 8 to 20 carbon atoms.
• the alkenyl moiety thereof may have 2 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms.
• Arylalkynyl refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp 3 carbon atom, although an sp carbon atom may also be used, is replaced by an aryl group.
• the aryl moiety of the arylalkynyl may be, for example, any aryl group described herein, and the alkynyl moiety of the arylalkynyl may comprise, for example, any of the alkynyl groups described herein.
• An arylalkynyl group may have 8 to 20 carbon atoms.
• the alkynyl moiety thereof may have 2 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms.
• Cycloalkyl refers to a saturated monocycle or polycycle that comprises only carbon atoms in the ring.
• a cycloalkyl group may have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
• a monocyclic cycloalkyl has 3 to 7 ring atoms, more typically 5 or 6 ring atoms.
• a bicyclic cycloalkyl may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic ring system, or a bridged ring system.
• exemplary cycloalkyl groups the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system.
• a monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or unsubstituted).
• substituted cycloalkyl means that at least one hydrogen atom of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl, or carbocyclyl (e.g., cycloalkyl) is each independently replaced by a non-hydrogen substituent.
• Heteroalkyl refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as O, N, or S.
• the resulting heteroalkyl group may be an alkoxy group (e.g., -OCH3), an amine group (e.g., -NHCH3, - N(03 ⁇ 4)2, or the like), or a thioalkyl group (e.g., -SCH3), respectively.
• a heteroatom e.g., O, N, or S
• the resulting heteroalkyl group may be an alkoxy group (e.g., -OCH3), an amine group (e.g., -NHCH3, - N(03 ⁇ 4)2, or the like), or a thioalkyl group (e.g., -SCH3), respectively.
• the resulting heteroalkyl group may be an alkyl ether (e.g., - CH2CH2-O-CH3 or the like), an alkylamine (e.g., -CH2NHCH3, -03 ⁇ 4N(03 ⁇ 4)2, or the like), or a thioalkyl ether (e.g., -CH2-S-CH3), respectively.
• alkyl ether e.g., - CH2CH2-O-CH3 or the like
• an alkylamine e.g., -CH2NHCH3, -03 ⁇ 4N(03 ⁇ 4)2, or the like
• a thioalkyl ether e.g., -CH2-S-CH3
• the resulting heteroalkyl group may be a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., - CH2NH2), or an alkylthiol group (e.g., -CH2CH2-SH), respectively.
• a heteroalkyl group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
• a heteroalkyl group has from 2 to 20, 2 to 10, or 2 to 6 total atoms in the chain (i.e., carbon atoms plus heteroatoms combined).
• a C1-C6 heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.
• heterocycle or“heterocyclyl” used herein includes those described in the documents such as Paquette, Leo A., Principles of Modem Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, from 1950 to the present), specifically Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566, but it is not limited thereto.
• heterocycle includes carbocycle as defined herein in which at least one (e.g., 1, 2, 3, or 4) carbon atom is replaced by a heteroatom (e.g., O, N, or S).
• a heteroatom e.g., O, N, or S.
• heterocycle or“heterocyclyl” includes saturated, partially unsaturated, and aromatic rings (i.e., a heteroaromatic ring).
• Substituted heterocycle for example, includes a heterocyclic ring substituted with any of the substituents disclosed herein, inclusive of a carbonyl group.
• heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl(piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl,
• pyrrolidinyl 2-pyrrolidonyl
• pyrrolinyl tetrahydrofuranyl
• tetrahydroquinolinyl tetrahydroisoquinolinyl
• decahydroquinolinyl octahydroisoquinolinyl
• azocynyl triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thianthrenyl
• pyranyl isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H-quinolizinyl
• phenanthrolinyl phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, and benzoxazolinyl (each of which may be substituted or unsubstituted), but it is not limited thereto.
• a carbon-bonded heterocycle may be bonded at the 2, 3, 4, 5, or 6- position of pyrazine, at the 3, 4, 5, or 6-position of pyridazine, at the 2, 4, 5, or 6-position of pyrimidine, at the 2, 3, 5, or 6-position of pyrazine, at the 2, 3, 4, or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, at the 2, 4, or 5-position of oxazole, imidazole, or thiazole, at the 3, 4, or 5-position of isoxazole, pyrazole, or isothiazole, at the 2 or 3-position of aziridine, at the 2, 3, or 4-position of azetidine, at the 2, 3, 4, 5, 6, 7, or 8-position of quinoline, or at the 1, 3, 4, 5, 6, 7, or 8-position of
• examples of a carbon-bonded heterocycle include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3 -pyridazinyl, 4- pyridazinyl, 5 -pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6- pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl (each of which may be substituted or unsubstituted).
• a nitrogen-bonded heterocycle may be bonded at the 1 -position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or lH-indazole, at the 2-position of isoindole or isoindoline, at the 4-position of morpholine, and at the 9-position of carbazole or b-carboline (each of which may be substituted or unsubstituted), but it is not limited thereto.
• examples of a nitrogen-bonded heterocycle include 1-aziridinyl, 1-azetidyl, 1-pyrrolyl, 1- imidazolyl, 1-pyrazolyl, and 1-piperidinyl (each of which may be substituted or
• Heterocyclylalkyl refers to an acyclic alkyl radical in which one hydrogen atom bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced by a heterocyclyl radical (i.e., a heterocyclyl-alkylene moiety).
• a typical heterocyclylalkyl group include heterocyclyl-CEh-, 2-(heterocyclyl)ethan-l-yl, and the like, but it is not limited thereto.
• The“heterocyclyl” moiety thereof used herein includes those described in the document such as“Principles of Modern Heterocyclic Chemistry” and any heterocyclyl group described above.
• the heterocyclyl group may be attached to the alkyl moiety of the heterocyclylalkyl through a carbon-to-carbon bond or a carbon-to-heteroatom bond.
• a heterocyclylalkyl group may have 2 to 20 carbon atoms.
• the alkyl moiety of the heterocyclylalkyl group may have 1 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms.
• the heterocyclylalkyl include a 5-membered heterocycle containing sulfur, oxygen, and/or nitrogen such as
• thiadiazolylmethyl and the like; and a 6-membered heterocycle containing sulfur, oxygen, and/or nitrogen such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazylmethyl, pyrimidylmethyl, pyrazinylmethyl, and the like (each of which may be substituted or unsubstituted), but it is not limited thereto.
• Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom although an sp 2 carbon atom may also be used, is replaced by a heterocyclyl radical (i.e., a heterocyclyl-alkenylene moiety).
• the heterocyclyl moiety of the heterocyclylalkenyl group includes those described in the document such as“Principles of Modern Heterocyclic Chemistry” and any heterocyclyl group described herein.
• the alkenyl moiety of the heterocyclylalkenyl group includes any alkenyl group described herein.
• the heterocyclyl group may be attached to the alkenyl moiety of the heterocyclylalkenyl via a carbon-to-carbon bond or a carbon-to-heteroatom bond.
• a heterocyclylalkenyl group may have 3 to 20 carbon atoms.
• the alkenyl moiety of the heterocyclylalkenyl group may have 2 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms.
• Heterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom although an sp carbon atom may also be used, is replaced by a heterocyclyl radical (i.e., a
• heterocyclyl-alkynylene moiety The heterocyclyl moiety of the heterocyclylalkynyl group includes those described in the document such as“Principles of Modern Heterocyclic Chemistry” and any heterocyclyl group described herein.
• the alkynyl moiety of the heterocyclylalkynyl group includes any alkynyl group described herein. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkynyl moiety of the heterocyclylalkynyl via a carbon-to-carbon bond or a carbon-to-heteroatom bond.
• a heterocyclylalkynyl group may have 3 to 20 carbon atoms.
• the alkynyl moiety of the heterocyclylalkynyl group may have 2 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms.
• Heteroaryl refers to an aromatic heterocyclyl containing at least one heteroatom in the ring.
• Non-limiting examples of a suitable heteroatom that may be contained in the aromatic ring include oxygen, sulfur, and nitrogen.
• Non-limiting examples of a heteroaryl ring include all of those enumerated in the definition of“heterocyclyl” herein, inclusive of pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, and the like (each of which may be substituted or unsubstituted).
• Carbocycle or“carbocyclyl” refers to a saturated, partially unsaturated, or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
• a monocyclic carbocycle has 3 to 7 ring atoms, more typically 5 or 6 ring atoms.
• a bicyclic cycloalkyl may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic ring system, or a bridged ring system.
• exemplary cycloalkyl groups the atoms are arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system.
• a monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or
• Arylheteroalkyl refers to a heteroalkyl as defined herein, wherein a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) is replaced by an aryl group as defined herein. If the resulting group is chemically stable, the aryl group may be attached to a carbon atom of the heteroalkyl group or the heteroatom of the heteroalkyl group.
• an arylheteroalkyl group may have a formula of -alkylene-O-aryl, - alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, or the like.
• any alkylene moiety in the above formulae may be further substituted with any of the substituents defined or exemplified herein.
• Heteroarylalkyl refers to an alkyl group as defined herein, wherein a hydrogen atom is replaced by a heteroaryl group as defined herein.
• heteroarylalkyl include -CFh-pyridinyl, -CFh-pyrrolyl, -CFh-oxazolyl, -CFh-indolyl, -CFh- isoindolyl, -CFh-furanyl, -CFh-thienyl, -CFh-benzofuranyl, -CFh-benzothiophenyl, -CFh- carbazolyl, -CFh-imidazolyl, -CFh-thiazolyl, -CFh-isoxazolyl, -CFh-pyrazolyl, -CFh- isothiazolyl, -CFh-quinolyl, -CFh-isoquinolyl, -CFh-pyridazyl, -CFh-pyrimidyl, -CFh- pyrazyl, -CH(CH3)-pyrrolyl, -CH(CH3)-pyrrolyl, -CH(CH
• silyloxy refers to the group -O-S1R3, wherein each R independently is alkyl, aryl (which is substituted or unsubstituted), or heteroaryl (which is substituted or unsubstituted).
• Non-limiting examples of silyloxy include -0-Si(CH3)3, -0-Si(CH3)2tBu, -0-Si(tBu)2CH3, - 0-Si(tBu) 3 , -0-Si(CH3) 2 Ph, -0-Si(Ph) 2 CH 3 , and -0-Si(Ph) 3 .
• optionally substituted refers to a particular moiety (e.g., an optionally substituted aryl group) of the compound of Formula I that optionally has one, two, or more substituents.
• the R moiety of the ester may be any carbon-containing group that forms a stable ester moiety, which includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof.
• the ester may also include an ester such as those described above of a“tautomeric end” as described below.
• the invention provides a salt of a compound represented by Formula (I):
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• the compound comprises at least one D-amino acid residue.
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR b , hydroxyalkyl, -CH20R b , and halo;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• R 6 is hydrogen or substituted or unsubstituted alkyl; and R 7 , R 8 , and R 9 are each independently hydrogen or alkyl.
• R a independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl;
• R c independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• R a independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R c , independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• R a independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl
• R c independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.
• the compound has the structure of formula (I-10L):
• the compound may have the structure of formula (I-10D):
• R 1 is substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.
• R 1 may be selected from substituted or unsubstituted alkyl
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R 1 groups include
• the compound has the structure of formula (I-1L):
• the compound may have the structure of formula (I-1D) (R 4 )p R R CH
• R 2 is H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylal ZIkyl.
• R 2 is selected from hydrogen, substituted or unsubstituted
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R 2 groups include ,
• R 2 is hydrogen
• the compound has the structure of formula (I-2L):
• the compound may have the structure of formula (I-2D):
• R is substituted or unsubstituted alkyl or arylalkyl. In some embodiments, R 3 is selected from substituted or unsubstituted alkyl,
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R 3 groups include
• the compound has the structure of formula (I-3L):
• the compound may have the structure of formula (I-3D):
• p is 1 or 2; and R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, -OR b , -CH20R b , halo, hydroxyl, and hydroxy alkyl.
• p is 1 or 2; and R 4 , independently for each occurrence, is selected from -CEE, halo, hydroxyl, and hydroxyalkyl.
• R 4 is hydroxyl. In alternative preferred embodiments, R 4 is -CEE.
• p may be 1.
• the compound has the structure of formula (I-4Lg):
• the compound has the structure of formula (I-4La):
• the compound has the structure of formula (I-4Lb):
• the compound has the structure of formula (I-4Lc):
• R 4 is not hydroxyl.
• the compound has the structure of formula (I-4Dg):
• the compound has the structure of formula (I-4Da):
• the compound has the structure of formula (I-4Db):
• the compound has the structure of formula (I-4Dc):
• R 4 is not hydroxyl.
• R 4 is oxo
• the compound has the structure of formula (I-4Ld):
• the compound has the structure of formula (I-4Le):
• the compound has the structure of formula (I-4Dd):
• the compound has the structure of formula (I-4De):
• R 6 may
• the compound has the structure of formula (I-6L):
• the compound may have the structure of formula (I-6D):
• R 7 is (Ci-Cio)alkyl, preferably
• the compound has the structure of formula (I-7L):
• the compound may have the structure of formula (I-7D):
• the compound has the structure of formula (1-11L):
• the compound may have the structure of formula (1-1 ID):
• R 8 is -CH3 or -H, preferably -H.
• R 9 is -CH3 or -H, preferably -H.
• the compound comprises at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight D-amino acid residues.
• the invention provides a salt of a compound of formula (I), wherein the compound is selected from the following:
• the present invention also provides a compound represented by Formula (I):
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• R 1 , R 2 , and R 3 are substituted or unsubstituted (C2- Cio)haloalkyl;
• R a or R c is heterocyclylalkyl, cycloalkyl, or
• the compound comprises at least one D-amino acid residue
• At least one occurrence of R a and at least one occurrence of R c at least one occurrence of R a and at least one occurrence of R c ; and at least one occurrence of R a and/or R c differs from the other occurrences;
• At least one of R 1 , R 2 , and R 3 is substituted or unsubstituted (C2-Cio)haloalkyl.
• R a or R c is heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• the compound comprises at least one D-amino acid residue. In certain embodiments, the compound has:
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR b , hydroxyalkyl, -CH20R b , and halo;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl.
• R a independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl;
• R c independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• R a independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl;
• R c independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• R a independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl
• R c independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.
• the compound has the structure of formula (I-10L):
• the compound may have the structure of formula (I-10D):
• R 1 is substituted or unsubstituted (C2-Cio)haloalkyl. In certain embodiments, R 1 is substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.
• R 1 may be selected from substituted or unsubstituted alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• Exemplary R 1 groups include In some preferred embodiments, alternative preferred
• the compound has the structure of formula (I-1L):
• the compound may have the structure of formula (I-1D)
• R 2 is substituted or unsubstituted (C2-Cio)haloalkyl.
• R 2 is H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.
• R 2 is selected from hydrogen, substituted or unsubstituted
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R groups include
• R 2 is hydrogen.
• the compound has the structure of formula (I-2L):
• the compound may have the structure of formula (I-2D):
• R 3 is substituted or unsubstituted (C2-Cio)haloalkyl. In certain embodiments, R 3 is substituted or unsubstituted alkyl or arylalkyl. In some embodiments, R 3 is selected from substituted or unsubstituted alkyl,
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R groups include
• the compound has the structure of formula (I-3L):
• the compound may have the structure of formula (I-3D):
• p is 1 or 2; and R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, -OR b , -CH20R b , halo, hydroxyl, and hydroxy alkyl.
• p is 1 or 2; and R 4 , independently for each occurrence, is selected from -CH3, halo, hydroxyl, and hydroxyalkyl.
• R 4 is hydroxyl. In alternative preferred embodiments, R 4 is -CH3.
• p may be 1.
• the compound has the structure of formula (I-4Lg):
• the compound has the structure of formula (I-4La):
• the compound has the structure of formula (I-4Lb):
• the compound has the structure of formula (I-4Lc):
• R 4 is not hydroxyl.
• the compound has the structure of formula (I-4Dg):
• the compound has the structure of formula (I-4Da):
• the compound has the structure of formula (I-4Db):
• the compound has the structure of formula (I-4Dc):
• R 4 is not hydroxyl.
• R 4 is oxo
• the compound has the structure of formula (I-4Ld):
• the compound has the structure of formula (I-4Le):
• the compound has the structure of formula (I-4Dd):
• the compound has the structure of formula (I-4De):
• R 6 may
• the compound has the structure of formula (I-6L):
• the compound may have the structure of formula (I-6D):
• R 7 is (Ci-Cio)alkyl, preferably
• the compound has the structure of formula (I-7L):
• the compound may have the structure of formula (I-7D):
• the compound has the structure of formula (1-11L):
• the compound may have the structure of formula (1-1 ID):
• R 8 is -CH3 or -H, preferably -H.
• R 9 is -CH3 or -H, preferably -H.
• the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys;
• Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Val, lie, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me); and
• At least one amino acid residue in the peptide is a D-amino acid residue.
• At least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.
• the peptide may be a variant of a collagen type II al -derived peptide.
• the collagen type II al may be isolated from the extracellular matrix derived from animal chondrocytes.
• peptide used in the present invention refers to a compound in which two or more amino acids are linked by a peptide bond. Further, it is classified into dipeptide, tripeptide, tetrapeptide, and the like according to the number of constituent amino acids.
• An oligopeptide has about 10 or fewer peptide bonds, and a polypeptide has a plurality of peptide bonds.
• a peptide in the present invention includes a mutated peptide in which its amino acid residue is substituted.
• HyP refers to an amino acid called hydroxyproline, in which a hydroxyl group (-OH) is bonded to the carbon atom at the 4- position of proline.
• HyP has a structure of C5H9NO3 and may be depicted as follows:
• HyP may include all isomers.
• HyP may be an isomer represented by the stereochemistry of“2S,4R” unless otherwise specified.
• homo-Ser used in the present invention is called homoserine and refers to an a-amino acid having a hydroxyl group in the side chain.
• Homo-Ser is an intermediate present in the biosynthesis of threonine and methionine in microorganisms and plants.
• Homo-Ser may be depicted as follows:
• Asp(Me) indicates an amino acid in which the hydrogen atom of the hydroxyl group (OH) bonded to the carbon atom at the 4-position of aspartic acid is substituted by a methyl group (CH3). Asp(Me) may be depicted as
• Asn(Me) indicates an amino acid in which the hydrogen atom of the amine group (NH2) bonded to the carbon atom at the 4-position of asparagine is substituted by a methyl group (CH3).
• Asn(Me) may be depicted as follows:
• (N-Me)Gly indicates an amino acid in which the hydrogen atom of the amine group (NLh) bonded to the carbon atom at the 2-position of glycine is replaced by a methyl group (CLL).
• (N-Me)Gly may be depicted as follows:
• the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys;
• Xaa is selected from Val, lie, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;
• At least one amino acid residue in the peptide is a D-amino acid residue.
• At least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.
• the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa;
• Xaa is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-OH);
• At least one amino acid residue in the peptide is a D-amino acid residue.
• At least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.
• the compound is a peptide having an amino acid sequence represented by Xaa-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;
• Xaa is selected from:
• At least one amino acid residue in the peptide is a D-amino acid residue.
• at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.
• the invention provides a compound having the following
• the invention provides a compound represented by Formula (V):
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 9 is hydrogen or alkyl
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl
• R 4 for each occurrence is hydroxyl
• R 1 is substituted or unsubstituted alkyl, such In certain embodiments, the compound has the structure of formula (V-1L)
• the compound may have the structure of formula (V-1D)
• R 2 is H.
• p is 1 and R 4 is hydroxyl.
• the compound has the structure of formula (V-4La):
• the compound has the structure of formula(V-4Lb):
• the compound has the structure of formula (V-4Da):
• the compound has the structure of formula (V-4Db):
• the compound has the structure of formula (V-6L):
• the compound may have the structure of formula (V-6D):
• the compound is selected from the following: pharmaceutically acceptable salt thereof.
• the invention provides a compound represented by Formula
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 is hydrogen or alkyl
• R 9 is hydrogen or alkyl
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl
• R 4 for each occurrence is hydroxyl
• the compound has the structure of formula (VI-1L)
• the compound may have the structure of formula (VI- ID)
• p is 1 and R 4 is hydroxyl.
• the compound has the structure of formula (VI-4La):
• the compound has the structure of formula(VI-4Lb):
• the compound has the structure of formula (VI-4Da):
• the compound has the structure of formula (VI-4Db):
• the compound has the structure of formula (VI-6L):
• the compound may have the structure of formula (VI-6D):
• R y is -H.
• R 7 is (Ci-Cio)alkyl, such
• the compound has the structure of formula (VI-7L):
• the compound may have the structure of formula (VI-7D):
• the invention provides a compound represented by Formula
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 is hydrogen or alkyl
• R 9 is hydrogen or alkyl
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl
• R 4 for each occurrence is hydroxyl
• R 1 is substituted or unsubstituted alkyl, such In certain embodiments, the compound has the structure of formula (VII- 1L)
• the compound may have the structure of formula (VII-1D)
• R 2 is H.
• p is 1 and R 4 is hydroxyl.
• the compound has the structure of formula (VII-4La):
• the compound has the structure of formula(VII-4Lb):
• the compound has the structure of formula (VII-4Da):
• the compound has the structure of formula (VII-4Db):
• the compound has the structure of formula (VII-6L):
• the compound may have the structure of formula (VII-6D):
• R 7 is (Ci-Cio)alkyl, such
• the compound has the structure of formula (VII- 7L):
• the compound may have the structure of formula (VII- 7D):
• the compound has the structure of formula (VII- 10L):
• the compound may have the structure of formula VII- 10D):
• the present invention also provides a compound represented by Formula (IX):
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• J is OH or -NR x R y ;
• R x and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R x and R y taken together with the intervening nitrogen atom form a ring.
• Exemplary compounds of Formula (IX) include YDE-100 through YDE-107.
• R 1 and R 2 are each independently H or substituted or unsubstituted alkyl
• R 4 for each occurrence is hydroxyl
• R 1 is substituted or
• the compound has the structure of formula (IX-IL):
• the compound has the structure of formula (IX- ID):
• the compound has the structure of formula (IX-4La):
• the compound has the structure of formula (IX-4Lb):
• the compound has the structure of formula (IX-4Da):
• the compound has the structure of formula (IX-4Db):
• R 6 may
• the compound has the structure of formula (IX-6L):
• the compound has the structure of formula (IX-6D):
• R 7 is (Ci-Cio)alkyl.
• R 7 may be or
• the compound has the structure of formula (IX-7L):
• the compound has the structure of formula (IX-7D):
• the compound has the structure of formula (IX-10L):
• the compound has the structure of formula (IX-10D):
• the compound has the structure of formula (IX-11L):
• the compound has the structure of formula (IX-1 ID):
• J is OH.
• J is-NR x R y .
• R x and R y are each independently alkyl.
• R x and R y may be taken together with the intervening nitrogen atom form a ring.
• the present invention also provides a compound compound represented by Formula (X-am):
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -OR b , -CH20R b , halo, hydroxyl, and hydroxyalkyl;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• p 0, 1, or 2;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl
• J is OH or -NR x R y ;
• R x and R y are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R x and R y taken together with the intervening nitrogen atom form a ring.
• Exemplary compounds of Formula (X-am) include YDE-93 and YDE-96.
• R 1 , R 2 , and R 3 are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl;
• R 4 independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -OR b , hydroxyalkyl, -CH20R b , and halo;
• R b is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;
• R 6 is hydrogen or substituted or unsubstituted alkyl
• R 7 , R 8 , and R 9 are each independently hydrogen or alkyl.
• R a independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R c , independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• R a independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and R c , independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.
• R a independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl;
• R c independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.
• the compound has the structure of formula (X-am-10L):
• the compound has the structure of formula (X-am-10D):
• R 1 is substituted or unsubstituted (C 2 -Cio)haloalkyl.
• R 1 may be substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. In still further embodiments, R 1 is selected from substituted or unsubstituted alkyl,
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R 1 is selected from
• the compound has the structure of formula (X-am-lL):
• the compound has the structure of formula (X-am-lD):
• R 2 is substituted or unsubstituted (C2-Cio)haloalkyl.
• R 2 may be H or substituted or unsubstituted alkyl, arylalkyl, or
• R 2 is selected from hydrogen, substituted or unsubstituted
• R a is hydrogen or alkyl
• n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• R 2 may be selected from ?
• R 2 is hydrogen
• the compound has the structure of formula (X-am-2L):
• the compound has the structure of formula (X-am-2D):
• R 3 is substituted or unsubstituted (C2-Cio)haloalkyl.
• R 3 may be substituted or unsubstituted alkyl or arylalkyl.
• R is selected from substituted or unsubstituted alkyl, hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.
• the compound has the structure of formula (X-am-3L):
• the compound has the structure of formula (X-am-3D):
• p is 1 or 2; and R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, -OR b , -CH20R b , halo, hydroxyl, and hydroxy alkyl.
• p is 1 or 2; and R 4 , independently for each occurrence, is selected from -CH3, halo, hydroxyl, and hydroxyalkyl.
• R 4 is hydroxyl or R 4 is - CH3.
• p is 1.
• the compound has the structure of formula (X-am-4Lg):
• the compound has the structure of formula (X-am-4La):
• the compound has the structure of formula (X-am-4Lb):
• the compound has the structure of formula (X-am-4Lc):
• R 4 is not hydroxyl.
• the compound has the structure of formula (X-am-4Dg):
• the compound has the structure of formula (X-am-4Da):
• the compound has the structure of formula (X-am-4Db):
• the compound has the structure of formula (X-am-4Dc):
• R 4 is not hydroxyl.
• R 4 is oxo
• the compound has the structure of formula (X-am-4Ld):
• the compound has the structure of formula (X-am-4Le):
• the compound has the structure of formula (X-am-4Dd):
• the compound has the structure of formula (X-am-4De):
• R 6 may be -CH3 or R 6 may In certain embodiments, the compound has the structure of formula (X-am-6L):
• the compound has the structure of formula (X-am-6D):
• R 7 is (Ci-Cio)alkyl.
• R 7 may be ⁇ 3 or
• the compound has the structure of formula (X-am-7L):
• the compound has the structure of formula (X-am-7D):
• the compound has the structure of formula (X-am-11L):
• the compound has the structure of formula (X-am-1 ID):
• R 8 is -CFb or -H, preferably -H.
• R 9 is -CFb or -H, preferably -H.
• R x and R y are each independently optionally substituted alkyl. In alternative embodiments, R x and R y are each independently optionally substituted alkoxylalkyl. In further alternative embodiments, R x and R y taken together with the intervening nitrogen atom form a ring.
• the invention also provides a salt of a compound represented by Formula 8:
• the compound may be a prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, a carboxylic acid present in the parent compound is presented as an ester, or an amino group is presented as an amide.
• the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).
• compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee,
• the compounds of the invention have more than one stereocenter. Accordingly, the compounds of the invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de. In certain embodiments, the compounds of the invention have substantially one isomeric configuration at one or more stereogenic centers, and have multiple isomeric configutations at the remaining stereogenic centers.
• the enantiomeric excess of a given stereocenter in the compound is at least 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, 92% ee, 94% ee, 95% ee, 96% ee, 98% ee or greater ee.
• hashed or bolded wedge bonds indicate absolute stereochemical configuration.
• a therapeutic preparation of the compound of the invention may be enriched to provide predominantly one enantiomer of a compound.
• enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
• the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
• composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
• a therapeutic preparation may be enriched to provide predominantly one diastereomer of the compound of the invention.
• a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is formulated for topical administration to the eye, e.g., as eye drops.
• At least 50%, 60%, 70%, 80%, or 90% of the compound is present as a salt.
• at least 95% of the compound is present as a salt.
• at least 99% of the compound is present as a salt.
• the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any salt or compound of the invention, and one or more pharmaceutically acceptable excipients.
• the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein.
• the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.
• One embodiment of the present invention provides a pharmaceutical kit comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof, and optionally directions on how to administer the compound.
• compositions and methods of the present invention may be utilized to treat an individual in need thereof.
• the individual is a mammal such as a human, or a non-human mammal.
• the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
• the aqueous solution is pyrogen-free, or substantially pyrogen-free.
• the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
• the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
• the composition can also be present in a transdermal delivery system, e.g., a skin patch.
• the composition can also be present in a solution suitable for topical administration, such as an eye drop.
• a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
• physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
• the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
• the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
• the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
• Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be
• pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
• oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil
• glycols such as propylene glycol
• polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
• esters such as ethyl oleate and ethyl laurate
• (13) agar (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
• alginic acid (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
• a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules
• the compound may also be formulated for inhalation.
• a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
• Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
• an active compound such as a compound of the invention
• the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• Compositions or compounds may also be administered as a bolus, electuary or paste.
• the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
• pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
• the pharmaceutical compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
• compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the
• compositions that can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ (e.g., wheat germ), olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
• compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
• Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
• Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
• the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
• dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
• Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
• Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744,
• liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids.
• a preferred route of administration is local administration e.g ., topical administration, such as eye drops, or administration via an implant).
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,
• compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
• microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
• various antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
• isotonic agents such as sugars, sodium chloride, and the like into the compositions.
• prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
• the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
• delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
• the rate of drug release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
• active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• Methods of introduction may also be provided by rechargeable or biodegradable devices.
• Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious
• biopharmaceuticals A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
• the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple
• a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
• the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
• the active compound may be administered two or three times daily.
• the active compound will be administered once daily.
• the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
• compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
• the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g ., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds).
• the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially.
• the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
• an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
• conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., a compound of formula I, V, VI, or VII) or the one or more additional therapeutic agent(s).
• the compound of the invention e.g., a compound of formula I, V, VI, or VII
• additional therapeutic agent(s) e.g., a compound of formula I, V, VI, or VII
• the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).
• compositions and methods of the present invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention.
• pharmaceutically acceptable salt includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, oxalic, mandelic and other acids.
• compositions can include forms wherein the ratio of molecules comprising the salt is not 1 : 1.
• the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I, V, VI, or VII.
• the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I, V, VI, or VII per molecule of tartaric acid.
• contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine,
• contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
• the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
• the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (
• the present invention also provides methods of treating eye disease, comprising administering to a subject in need thereof salt of the invention, a compound of the invention, or a pharmaceutical composition comprising a salt or compound of the invention.
• the eye disease may be selected from retinopathy, keratitis, dry- macular degeneration, wet-macular degeneration, dry eye syndrome, keratoconjunctival epithelium disorder, proliferative vitreoretinopathy, pigmentary retinopathy, diabetic retinopathy, retinopathy of prematurity, retinopathy of immaturity, proliferative
• the eye disease may be selected from retinopathy, keratitis, macular degeneration, dry eye syndrome and keratoconjunctival epithelium disorder.
• the eye disease is selected from retinopathy, keratitis, dry-macular degeneration, wet-macular degeneration, dry eye syndrome, heratoconjunctivitis sicca and keratoconjunctival epithelium disorder.
• the pharmaceutical composition for treating an eye disease which comprises a salt or compound of the invention as an active pharmaceutical ingredient, may further comprise at least one additive selected from the group consisting of a carrier, an excipient, a disintegrant, a sweetener, a coating agent, a swelling agent, a lubricant, a slip agent, a flavor, an antioxidant, a buffer, a bacteriostat, a diluent, a dispersant, a surfactant, and a binder.
• a formulation for parenteral administration may be a sterilized aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized preparation, a suppository, or the like.
• the dose of the salt or compound of the invention that is administered to the subject may be adjusted depending on such various factors as the kind of the disease, the severity of the disease, the kinds and amounts of the active pharmaceutical ingredient and other ingredients contained in the pharmaceutical composition, the type of the formulation, the age, body weight, general health condition, sex, and diet of the patient, the time and the route of administration, the duration of treatment, and the drugs concurrently used.
• the effective amount of the salt or compound contained in the pharmaceutical composition may be 0.0001 pg/day to 100 pg/day.
• the administration may be carried out once a day, or divided into several doses.
• the concentration of the salt or compound contained in the pharmaceutical composition may be 1000 pM to 0.001 pM.
• the concentration of the salt or compound contained in the pharmaceutical composition may be 100 pM to 0.005 pM or 50 pM to 0.02 pM.
• the concentration of the salt or compound contained in the pharmaceutical composition may be 30 pM to 1 pM. Further, the concentration of the compound or the peptide contained in the pharmaceutical composition may be 0.01 pM to 1 pM.
• the subject may be a mammal, particularly a human.
• the administration route may be appropriately selected by a person skilled in the art in consideration of the administration method, the volume and viscosity of the body fluid, and the like.
• the administration may be carried out through any one route selected from the group consisting of an application, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, percutaneous, intranasal, inhalation, topical, rectal, oral, intraocular, and intradermal.
• the administration comprises topical administration to the eye of the subject.
• it may preferably be applied to the eye for use as an eye drop.
• a protein analysis of the extracellular matrix derived from animal chondrocytes was performed in Baek’s group of Center of Biomedical Mass Spectrometry (Diatech Korea Co., Ltd., Seoul, Korea).
• Proline-GQDGLAGPK (P-GQDGLAGPK), which is a part of the amino acid sequence of the collagen type II al protein, was obtained through the above protein analysis.
• An exemplary protein synthesis for YDE-011 follows.
• the other compounds of the invention e.g., YDE-001 - YDE-086) are made through an analogous procedure by, e.g., substituting in a different amino acid building block reagent in a desired step.
• Fmoc-Pro-Lys(Boc)-Wang resin (1) a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Gly-OH (3.0g, 10 mmole) in DMF (25 mL) and a solution of HBTU(3.8g, 10 mmole) and N-Methylmorpholine(2.0g, 20 mmole) in DMF (25mL) were added respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.
• Fmoc-Gly-Pro-Lys(Boc)-Wang resin (2) a solution of piperidine (10 mL) in DMF (40mL) was added and stirred for 5 minutes then the resin was drained. The resin was washed 6 times with DMF (50 mL). To the resin, a solution of Fmoc-Ala-OH (3. lg, 10 mmole.) in DMF (25 mL) and a solution of HBTU (3.8g, 10 mmole) and N- Methylmorpholine (2.0g, 20 mmole) in DMF (25mL) were added respectively. The reaction mixture was stirred for 1 h and the resin was drained. The resin was used to next step without further purification.
• the Purified compound was exchanged from TFA salt to AcOH salt by Ion Exchange resin.
• the Ion exchanged peptide was dried by lyophilizer.
• YDE-001 to YDE-092 peptides were synthesized by ANYGEN (Gwangju, Korea) in a manner analogous to the exemplary procedure shown above, by substituting one or more different amino acid residues into the peptide Proline-GQDGLAGPK (Fig. 1 and Table 1).
• the YDE derivatives prepared in Example 1 were analyzed by HPLC. As a result, it was confirmed that the purities of YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-009, YDE-010, YDE-011 , YDE-012, YDE-013 ,
• YDE derivatives prepared in Example 1 were analyzed by Ion-Mass. As a result, it was confirmed that the molecular weights of YDE-001, YDE-002, YDE-003, YDE-004, YDE-005, YDE-006, YDE-007, YDE-008, YDE-009, YDE-010, YDE-011, YDE-012, YDE-013, YDE-014, YDE-015, YDE-016, YDE-017, YDE-018, YDE-019, YDE-020, YDE-021, YDE-022, YDE-023, YDE-024, YDE-025, YDE-026, YDE-027, YDE-028, YDE-029, YDE-030, YDE-031, YDE-032, YDE-033, YDE-034, YDE-035, YDE-036, Y
• YDE peptides (YDE-093, YDE-096, and YDE-101 through YDE- 107), derivatives of the amino acid sequence of the YDE-011, were obtained through the C-terminal modification of a YDE peptide such as YDE-011.
• Fmoc solid-phase peptide synthesis SPPS was conducted, based on a standard procedure described in WO 2018/225961 and further a C-terminal amidation reaction was carried out.
• the peptides of the invention are made through an analogous procedure by, e.g., substituting in a different amino acid building block reagent in a desired step.
• YDE-093, YDE-096, and YDE-101 through YDE-107 are depicted in Table 1A below.
• the YDE peptides prepared in Example 2 were analyzed by HPLC. As a result, it was confirmed that the purities of YDE-093, YDE-096, YDE-101, YDE- 102, YDE- 103, YDE-105, YDE- 106 and YDE-107 synthesized were 99.1%, 95.4%, 96.7%, 97.2%, 97.9%,
• the YDE derivatives prepared in Example 2 were analyzed by Ion-Mass. As a result, it was confirmed that the molecular weights of YDE-093, YDE-096, YDE-101, YDE- 102, YDE- 103, YDE-105, YDE-106 and YDE-107 synthesized were 1139.0, 1173.6, 851.9, 880.1, 864.5, 866.1, 878.4 and 894.3, respectively.
• Example 3 Evaluation of the eye protection effect on dry eye syndrome by the YDE derivatives
• YDE-028 prepared in Example 1, a total of 320 Sprague-Dawley-type male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Thereafter, dry eye syndrome was induced in 264 test rats through extraorbital lacrimal gland excision (hereinafter, ELGE). 8 test rats without the eye abnormality were subjected to a sham operation as a control group.
• ELGE extraorbital lacrimal gland excision
• the rat was systemically anesthetized by inhaling a mixed gas of 2% to 3% of isoflurane (Hana Pharm. Co., Hwasung, Korea), 70% of N2O, and 28.6% of O2 using a rodent anesthesia machine (Surgivet, Waukesha, Wis., USA) and a ventilator (Model 687, Harvard Apparatus, Cambridge, UK). Thereafter, the extraorbital lacrimal gland located in the subdermal area above the masseter muscle and under the optic nerve was excised through a transverse incision in a size of 10 mm on the anterior part of the left ear tragus. The skin was sutured by a general method.
• the ELGE operation time did not exceed 5 minutes for each rat. After 6 days from the ELGE operation, it was checked through the Schirmer test by measuring the amount of tear secretion whether dry eye syndrome had been induced. Meanwhile, each rat of the control group with the sham operation was checked for the presence and location of the extraorbital lacrimal gland through a skin incision, and the skin was then sutured without the excision thereof (Fig. 4).
• the average weight of the ELGE test group measured before the ELGE operation was 241.59 ⁇ 13.56 g, and the average weight measured after 6 days from the ELGE operation was 297.38 ⁇ 34.02 g.
• the average weight of the control group measured before the sham operation was 240.13 ⁇ 25.63 g, and the average weight measured after 6 days from the sham operation was 297.38 ⁇ 34.02 g (Fig. 5).
• the average amount of tear secretion of the control group was 8.34 ⁇ 0.73 mm 3
• the average amount of tear secretion of the ELGE test group was 3.55 ⁇ 0.70 mm 3 . 8 rats per group and a total of 32 groups were selected based on the average amount of tear secretion.
• a total of 200 Sprague-Dawley-type male rats (OrientBio, Seungnam, Korea) were adapted for 7 days. Dry eye syndrome was induced in 165 test rats through the ELGE. 8 test rats without the eye abnormality were subjected to the sham operation as a control group.
• the ELGE was carried out as described above.
• the average weight of the ELGE test group measured before the ELGE operation was 264.09 ⁇ 11.53 g, and the average weight measured after 6 days from the ELGE operation was 316.13 ⁇ 15.77 g.
• the average weight of the control group measured before the sham operation was 263.50 ⁇ 9.24 g, and the average weight measured after 6 days from the sham operation was 315.25 ⁇ 10.85 g (Fig. 6).
• the average amount of tear secretion of the control group was 10.90 ⁇ 1.69 mm 3
• the average amount of tear secretion of the ELGE test group was 4.83 ⁇ 0.99 mm 3 . 8 rats per group and a total of 20 groups were selected based on the average amount of tear secretion.
• YY-102 and the 28 YDE-series were each dissolved in physiological saline at a concentration of 3 mg/ml and administered at a dose of 5 m ⁇ /eye at 9:30 am and 3:30 pm daily for 14 days after 7 days from the ELGE operation for a total of 28 times.
• the DS solution was dissolved in physiological saline at a concentration of 30 mg/ml and administered at a dose of 5 m ⁇ /eye twice a day for 14 days after 7 days from the ELGE operation for a total of 28 times.
• the same stimulation as the administration was applied.
• the same volume of physiological saline was applied in the same manner in place of the test substances.
• YDE-029 to YDE-043 were each dissolved in physiological saline at a concentration of 3 mg/ml and administered at a dose of 5 m ⁇ /eye at 9:30 am and 3:30 pm daily for 14 days after 7 days from the ELGE operation for a total of 28 times.
• the DS solution was dissolved in physiological saline at a concentration of 30 mg/ml and administered at a dose of 5 m ⁇ /eye twice a day for 14 days after 7 days from the ELGE operation for a total of 28 times.
• the same stimulation as the administration was applied.
• the same volume of physiological saline was applied in the same manner in place of the test substances (Fig. 7).
• the changes in the amount of tear secretion were measured at day 7 and day 14 after the administration of YDE-001 to YDE-043.
• the amount of tear secretion was measured by the decrease in the travel distance of tears absorbed by cobalt chloride paper in a size of 1 x 15 mm (Toyo Roshi Kaisha, Japan).
• the cobalt chloride paper was placed in the lateral canthus of a rat for 60 seconds to absorb tears (Fig. 9).
• the length of the area absorbed from the corner of the cobalt chloride paper was measured with an electronic digital caliper (Mytutoyo, Tokyo, Japan) (Fig. 8).
• Fig. 9 shows the results of the test, wherein A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 administered group, and E to AF are for the YDE-001 to YDE-028 administered groups in order.
• the amount of tear secretion was decreased after 6 days from the ELGE operation at days 7 and 14 after the application of physiological saline in the ELGE control group as compared with the sham control group.
• the amount of tear secretion was increased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-9, YDE-10, YDE-17, YDE-19, YDE-20, YDE-21, YDE-22, YDE-25, YDE-27, and YDE-28, which did not show any significant changes in the amount of tear secretion after the administration thereof for 14 days.
• the amount of tear secretion was increased by more than 20% in the groups treated with a 3% solution of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102 as compared with the DS reference group.
• Fig. 11 shows the results of the test, wherein A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 administered group, and E to S are for the YDE-029 to YDE-043 administered groups in order.
• A is for the sham control group
• B is for the ELGE control group
• C is for the DS reference group
• D is for the YY-102 administered group
• E to S are for the YDE-029 to YDE-043 administered groups in order.
• the amount of tear secretion was increased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-029, YDE-030, YDE-032, YDE-033, YDE-034, YDE-036, and YDE- 41, which did not show any significant changes in the amount of tear secretion after the administration thereof for 14 days.
• the amount of tear secretion was increased by more than 20% in the groups treated with a 3% solution of YDE-040, YDE-043, and YDE-042 in order as compared with the DS reference group.
• Zolethyl 50TM (Virbac Lab., Carros, France), an animal anesthetic, was intraperitoneally injected at a dose of 25 mg/kg.
• Fig. 14 shows the results of the test, wherein A is for the sham control group, B is for the ELGE control group, C is for the DS reference group, D is for the YY-102 administered group, and E to AF are for the YDE-001 to YDE-028 administered groups in order.
• the permeability of the fluorescent dye was increased in the ELGE control group as compared with the sham control group.
• the permeability of the fluorescent dye was not decreased in the groups treated with a 3% solution of YDE- 10, YDE-20, YDE-22, YDE-25, YDE-27, and YDE-28 as compared with the ELGE control group at day 14 after the administration.
• the corneal permeability of the fluorescent dye was decreased as compared with the ELGE control group, except for the groups treated with a 3% solution of YDE-10, YDE-20, YDE- 22, YDE-25, YDE-27, and YDE-28.
• the permeability of the fluorescent dye was decreased by more than 20% in the groups treated with a 3% solution of YDE-15, YDE-11, YDE-08, YDE-26, YDE-16, YDE-01, YDE-23, and YY-102, as compared with the DS reference group.
• YDE-029 to YDE-043 were each administered to the eyes 14 times, and the changes in the corneal permeability were then checked. The measurement of the corneal permeability was carried out in the same manner as described above (Fig. 16).

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