WO2016190852A1 - Compositions thérapeutiques comprenant des composés chromanyle, des variants et des analogues associés, et leurs utilisations - Google Patents

Compositions thérapeutiques comprenant des composés chromanyle, des variants et des analogues associés, et leurs utilisations Download PDF

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WO2016190852A1
WO2016190852A1 PCT/US2015/032440 US2015032440W WO2016190852A1 WO 2016190852 A1 WO2016190852 A1 WO 2016190852A1 US 2015032440 W US2015032440 W US 2015032440W WO 2016190852 A1 WO2016190852 A1 WO 2016190852A1
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substituted
group
absent
hydrogen
alkenyl
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D. Travis Wilson
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Stealth Peptides International Inc
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Stealth Peptides International Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • compositions related to the treatment and/or amelioration of diseases and conditions comprising administration of chromanyl compounds and/or naturally or artificially occurring derivatives, analogues, stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide).
  • active agents e.g., an aromatic-cationic peptide
  • the present technology relates generally to aromatic-cationic peptide compositions where the aromatic-cationic peptide is conjugated to chromanyl compounds and/or naturally or artificially occurring derivatives, analogues, stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof and their use in the prevention and treatment of medical diseases and conditions.
  • Biological cells are generally highly selective as to the molecules that are allowed to pass through the cell membrane. As such, the delivery of compounds, such as small molecules and biological molecules into a cell is usually limited by the physical properties of the compound.
  • the small molecules and biological molecules may, for example, be pharmaceutically active compounds.
  • the present technology provides compositions and methods useful in the prevention, treatment and/or amelioration of diseases and conditions.
  • the present disclosure provides a composition comprising Formula
  • Z is absent, -NR 10 -, -S-, or -0-;
  • L is absent, -C(0)0-, -C(0)N(R a ) -, or L is a substituted or unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group;
  • Y is absent, -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen, amino, carboxyl, cyano, hydroxyl, halogen, nitro, or perhaloalkyl group, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, -C(0)-alkyl, -C(0)-aryl, -C(0)-aralkyl, ester, or amide group,
  • R 8 is a hydrogen, halogen, -Si(R a ) 3 , -C(0)R a , a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl group; wherein at least one of R 5 , 5, R7, and Rg is a group other than hydrogen, provided that R 8 is halogen only when Y is absent, and R 8 is -Si(R a ) 3 only when Y is absent or -0-;
  • R 9 is a hydrogen, halogen, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl group;
  • R 10 and R 11 are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, or aryl group, wherein
  • R 10 and R 11 are divalent groups joined together by -C(0)0- or
  • R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is connected to an atom of L in a cyclic structure
  • R 12 is absent, hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl,
  • cycloalkylalkyl alkenyl, alkynyl, aryl, or aralkyl group, wherein when R 12 is absent, the dashed line indicates that R 11 is connected to N by a double bond or when R 12 is absent, L is connected to N by a double bond;
  • R 13 is a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl group;
  • n 1, 2, 3, 4, or 5;
  • X " is an anion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the composition further comprises one or more additional active agents such as cyclosporine, a cardiac drug, an anti-inflammatory, an anti-hypertensive drug, an antibody, an ophthalmic drug, an antioxidant, a metal complexer, and an
  • Cc* collectively refers to derivatives, variants or analogues of the chromanyl compounds of the present technology, including, but not limited to, Formula (II), Formula (IIA), or Formula (IIB), stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof.
  • the present disclosure provides a method for treating or preventing mitochondrial permeability transition in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method of treating a disease or condition characterized by mitochondrial permeability transition, comprising administering a therapeutically effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the disease or condition comprises a neurological or neurodegenerative disease or condition, ischemia, reperfusion, hypoxia, atherosclerosis, ureteral obstruction, diabetes, complications of diabetes, arthritis, liver damage, insulin resistance, diabetic nephropathy, acute renal injury, chronic renal injury, acute or chronic renal injury due to exposure to nephrotoxic agents and/or radiocontrast dyes, hypertension, metabolic syndrome, an ophthalmic disease or condition such as dry eye, diabetic
  • retinopathy cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, oxygen-induced retinopathy, cardiomyopathy, ischemic heart disease, heart failure, hypertensive cardiomyopathy, vessel occlusion, vessel occlusion injury, myocardial infarction, coronary artery disease, or oxidative damage.
  • the neurological or neurodegenerative disease or condition comprises Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, Huntington's disease or Multiple Sclerosis.
  • ALS Amyotrophic Lateral Sclerosis
  • Parkinson's disease Huntington's disease or Multiple Sclerosis.
  • the subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue.
  • the present disclosure provides a method for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing a disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • the subject is diagnosed as having, suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy, or obesity.
  • ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy, or obesity.
  • the present disclosure provides a method for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
  • the present disclosure provides a method for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
  • the present disclosure provides a method of reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, or ALS.
  • the present disclosure provides a method for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing mechanical ventilation-induced diaphragm dysfunction in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg- 2'6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for preventing
  • norepinephrine uptake in a subject in need of analgesia comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic- cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating atherosclerotic renal vascular disease (ARVD) in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising chromanyl compounds and/or Cc*, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 . .
  • the composition comprises chromanyl compounds, derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Cc*).
  • the composition further comprises one or more of at least one pharmaceutically acceptable pH-lowering agent; and at least one absorption enhancer effective to promote bioavailability of the active agent, and one or more lamination layers.
  • the pH-lowering agent is selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc* as well as methods for their use.
  • Such molecules are referred to hereinafter as "peptide conjugates.”
  • At least one chromanyl compound and/or Cc* and at least one aromatic-cationic peptide associate to form a peptide conjugate.
  • the chromanyl compound and/or Cc* and aromatic- cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds.
  • Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking.
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-chromanyl compound
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-chromanyl compound
  • the type of association between the chromanyl compound and/or Cc* and aromatic- cationic peptides typically depends on, for example, functional groups available on the chromanyl compound and/or Cc* and functional groups available on the aromatic-cationic peptide.
  • the peptide conjugate linker may be nonlabile or labile.
  • the peptide conjugate linker may be enzymatically cleavable.
  • the present technology provides a peptide conjugate comprising chromanyl compound and/or Cc* conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: Phe-D-Arg-Phe-Lys-NH 2 , D-Arg-2'6'-Dmt-Lys-Phe-NH 2 , 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , or any peptide described in Section II; and wherein the chromanyl compound and/or Cc* is a compound described in Section I.
  • the chromanyl compound and/or Cc* is conjugated to the aromatic-cationic peptide by a linker.
  • the chromanyl compound and/or Cc* and aromatic-cationic peptide are chemically bonded.
  • the chromanyl compound and/or Cc* and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the chromanyl compound and/or Cc* are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the chromanyl compound and/or Cc*.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for delivering an aromatic-cationic peptide and/or chromanyl compound and/or Cc* to a cell, the method comprising contacting the cell with a peptide conjugate, wherein the peptide conjugate comprises the chromanyl compound and/or Cc* conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: Phe-D-Arg- Phe-Lys-NH 2 , D-Arg-2'6'-Dmt-Lys-Phe-NH 2 , or any peptide described in Section II; and wherein the chromanyl compound and/or Cc* is a compound described in Section I.
  • the chromanyl compound and/or Cc* is conjugated to the aromatic-cationic peptide by a linker.
  • the chromanyl compound and/or Cc* and aromatic-cationic peptide are chemically bonded.
  • the chromanyl compound and/or Cc* and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the chromanyl compound and/or Cc* are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the chromanyl compound and/or Cc*.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for treating, ameliorating or preventing a medical disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc* to the subject thereby treating, amelioration or preventing the medical disease or condition.
  • the medical disease or condition is characterized by mitochondrial permeability transition.
  • the medical disease or condition comprises a neurological or neurodegenerative disease or condition, ischemia, reperfusion, hypoxia, atherosclerosis, ureteral obstruction, diabetes, complications of diabetes, arthritis, liver damage, insulin resistance, diabetic nephropathy, acute renal injury, chronic renal injury, acute or chronic renal injury due to exposure to nephrotoxic agents and/or radiocontrast dyes, hypertension, Metabolic Syndrome, an ophthalmic disease or condition such as dry eye, diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, oxygen-induced retinopathy, cardiomyopathy, ischemic heart disease, heart failure, hypertensive cardiomyopathy, vessel occlusion, vessel occlusion injury, myocardial infarction, coronary artery disease, oxidative damage.
  • the neurological or neurodegenerative disease or condition comprises
  • Alzheimer's disease Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease,
  • the subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue.
  • the present technology provides methods for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for treating, ameliorating or preventing a medical disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the subject is diagnosed as having, is suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
  • ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
  • the present technology provides methods for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
  • the present technology provides methods for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
  • the present technology provides methods for reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the neurodegenerative diseases comprise Alzheimer's disease, Parkinson's disease, or ALS.
  • the present technology provides methods for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for treating or preventing mechanical ventilation-induced diaphragm dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for preventing norepinephrine uptake in a subject in need of analgesia, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for treating,
  • ameliorating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the present technology provides methods for treating
  • Atherosclerotic renal vascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • the aromatic-cationic peptide is defined by Formula A.
  • R 1 and R 2 are each independently selected from
  • R and R 4 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from (i) hydrogen;
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • the peptide is defined by Formula B:
  • R 1 and R 2 are each independently selected from
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
  • the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
  • the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
  • Aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), and Trp (W). In some embodiments, the Aromatic residue may be substituted with
  • the Cationic residue is a residue selected from the group consisting of: Arg (R), Lys (K), and His (H).
  • the Cationic residue may be substituted with norleucine (Nle) or 2-amino-heptanoic acid (Ahe).
  • Figure 1 shows an illustrative example of an aromatic-cationic peptide of the present disclosure linked by a labile bond to a chromanyl compound and/or Cc*.
  • Figure 2 shows illustrative examples of aromatic-cationic peptides of the present disclosure linked by covalent attachment to self-immolating moieties.
  • Figure 3 shows an illustrative example of aromatic-cationic peptides of the present disclosure incorporating spacer units to link the additional moieties to the peptide.
  • Figure 4 shows illustrative peptide chemistry to form amide bonds, where the R 2 free amine is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 and Ri is selected from a linker bearing the formula:— (linker)— COOH; or where linker consists of one or more carbon atoms. In some embodiments, the linker consists of two or more carbon atoms.
  • Figures 5A and 5B show exemplary linking chemistry of the present disclosure.
  • R is a chromanyl compound and/or Cc* containing a pendant COOH group and R' is a linker bearing the formula:— (linker)— OH where linker consists of at least one or more carbon atoms.
  • R is a linker bearing the formula:— (linker)— COOH where linker consists of at least one or more carbon atoms; and R' is a chromanyl compound and/or Cc* containing a pendant OH group.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to a chromanyl compound and/or Cc*.
  • Such molecules are referred to hereinafter as peptide conjugates.
  • At least one chromanyl compound and/or Cc*as described in Section I and at least one aromatic-cationic peptide as described in Section II associate to form a peptide conjugate.
  • the chromanyl compound and/or Cc*and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking. [0070] In some embodiments, the peptide conjugates have the general structure shown below: aromatic-cationic peptide-chromanyl compound
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-chromanyl compound
  • the type of association between the chromanyl compound and/or Cc* and aromatic- cationic peptides typically depends on, for example, functional groups available on the chromanyl compound and/or Cc* and functional groups available on the aromatic-cationic peptide.
  • the peptide conjugate linker may be nonlabile or labile.
  • the peptide conjugate linker may be enzymatically cleavable.
  • the peptide conjugates described herein can occur and can be used as the neutral (non-salt) peptide conjugate, the description is intended to embrace all salts of the peptide conjugates described herein, as well as methods of using such salts of the peptide conjugates.
  • the salts of the peptide conjugates comprise
  • Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound).
  • the desired salt of a basic peptide conjugate may be prepared by methods known to those of skill in the art by treating the compound with an acid.
  • inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
  • Salts of basic peptide conjugates with amino acids such as aspartate salts and glutamate salts, can also be prepared.
  • the desired salt of an acidic peptide conjugate can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • inorganic salts of acid conjugates include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
  • organic salts of acid peptide conjugates include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, ⁇ , ⁇ '-dibenzylethylenediamine, and
  • salts of acidic peptide conjugates with amino acids can also be prepared.
  • the present technology also includes all stereoisomers and geometric isomers of the peptide conjugates, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
  • the present technology also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures.
  • the "administration" of an agent, drug, or peptide to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or
  • Administration includes self-administration and the administration by another.
  • amino acid includes naturally-occurring amino acids and synthetic amino acids, as well as amino acid analogues and amino acid mimetics that function in a manner similar to the naturally-occurring amino acids.
  • Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
  • Amino acid analogues refer to compounds that have the same basic chemical structure as a naturally-occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogues have modified R groups ⁇ e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally-occurring amino acid.
  • Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally- occurring amino acid. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • Cc* collectively refers to derivatives, variants or analogues of the chromanyl compounds of the present technology, including, but not limited to, Formula (II), Formula (IIA), or Formula (IIB), stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof.
  • the term "effective amount" refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or disorder or one or more signs or symptoms associated with a disease or disorder.
  • the amount of a composition administered to the subject will depend on the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • the compositions can also be administered in combination with one or more additional therapeutic compounds.
  • the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.
  • an "isolated” or “purified” polypeptide or peptide is substantially free of cellular material or other contaminating polypeptides from the cell or tissue source from which the agent is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.
  • an isolated aromatic-cationic peptide would be free of materials that would interfere with diagnostic or therapeutic uses of the agent.
  • interfering materials may include enzymes, hormones and other proteinaceous and nonproteinaceous solutes.
  • non-naturally-occurring refers to a composition which is not found in this form in nature.
  • a non-naturally-occurring composition can be derived from a naturally-occurring composition, e.g., as non-limiting examples, via purification, isolation, concentration, chemical modification ⁇ e.g., addition or removal of a chemical group), and/or, in the case of mixtures, addition or removal of ingredients or compounds.
  • a non-naturally-occurring composition can comprise or be derived from a non-naturally- occurring combination of naturally-occurring compositions.
  • a non-naturally-occurring composition can comprise a mixture of purified, isolated, modified and/or concentrated naturally-occurring compositions, and/or can comprise a mixture of naturally-occurring compositions in forms, concentrations, ratios and/or levels of purity not found in nature.
  • net charge refers to the balance of the number of positive charges and the number of negative charges carried by the amino acids present in the aromatic-cationic peptides of the present technology.
  • net charges are measured at physiological pH.
  • the naturally occurring amino acids that are positively charged at physiological pH include L-lysine, L-arginine, and L-histidine.
  • the naturally occurring amino acids that are negatively charged at physiological pH include L- aspartic acid and L-glutamic acid.
  • polypeptide As used herein, the terms "polypeptide,” “peptide,” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
  • Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art.
  • prevention or “preventing” of a disorder or condition refers to one or more compounds that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 3rd Ed. (John Wiley & Sons, Inc., New York).
  • Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBz or Z), t- butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS), 9- fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, ⁇ -, ⁇ -dimethyldimethoxybenzyloxycarbonyl (DDZ), 5- bromo-7-nitroindolinyl, and the like. Hydroxyl protecting groups include, but are not limited to, Fmoc, TBS, photolabile protecting groups (such as nitroveratryl oxymethyl ether
  • the term "separate" therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes.
  • sequential therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.
  • the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
  • the terms "subject,” “individual,” or “patient” can be an individual organism, a vertebrate, a mammal, or a human.
  • a "synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of agents. For example, lower doses of one or more agents may be used in treating a disease or disorder, resulting in increased therapeutic efficacy and decreased side-effects.
  • a "therapeutically effective amount" of a compound refers to compound levels in which the physiological effects of a disease or disorder are, at a minimum, ameliorated.
  • a therapeutically effective amount can be given in one or more administrations.
  • the amount of a compound which constitutes a therapeutically effective amount will vary depending on the compound, the disorder and its severity, and the general health, age, sex, body weight and tolerance to drugs of the subject to be treated, but can be determined routinely by one of ordinary skill in the art.
  • Treating covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • the various modes of treatment or prevention of medical diseases and conditions as described are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
  • the treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition.
  • substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group may be substituted with one or more substituents, unless otherwise specified.
  • a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (i.e., F, CI, Br, and I); hydroxyl; alkoxy, (halo)alkoxy, alkenoxy, aryloxy, aralkyloxy, heteroaryloxy and heteroaralkoxy groups; heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; alkanoyl and alkanoyloxy groups; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides (i.e., -N 3 ); amides; ureas; amidines; guanidines; enamines;
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with a substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
  • Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, or 1 , 2, 3, 4, 5, or 6 carbon atoms, or any range therein (e.g., 1-4).
  • straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Alkyl groups may be substituted or unsubstituted.
  • substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, (halo)alkoxy, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.
  • substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, (halo)alkoxy, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.
  • alkoxy refers to a substituted or unsubstituted alkyl group bonded to an oxygen atom. Examples include but are not limited to methoxy and ethoxy. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above, such as methoxymethyl and fluoromethoxy.
  • Ci-C 6 alkyl refer, unless otherwise provided, to any straight or branched Ci-C 6 alkyl group, hence also comprising n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, n-hexyl, and the like.
  • Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 3 to 10 carbon atoms in the ring(s), or, in some embodiments, 3 to 8, 3 to 6, or 3 to 4, 5, or 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalin and the like.
  • Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with, non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl and substituted alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, substituted with substituents such as those listed above.
  • Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • Alkenyl groups have from 2 to 12 carbon atoms, e.g., from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, e.g., 2, 3, 4, 5, or 6 carbon atoms or any range therein (e.g., 2-4, 2-5, etc.).
  • the alkenyl group has one, two, or three carbon-carbon double bonds.
  • Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be
  • Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms.
  • Alkynyl groups have from 2 to 12 carbon atoms, e.g., from 2 to 10 carbons or, in some embodiments, from 2 to 8, e.g., 2, 3, 4, 5, or 6 carbon atoms or any range therein (e.g., 2-4, 2-5, etc.).
  • the alkynyl group has one, two, or three carbon-carbon triple bonds.
  • Alkynyl groups may be substituted or unsubstituted.
  • Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
  • Heteroalkyl group include straight and branched chain alkyl groups as defined above and further include 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from oxygen, sulfur, and nitrogen.
  • heteroalkyl groups include 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, or 1, 2, 3, 4, 5, or 6 carbon atoms, or any range therein (e.g., 1-4).
  • heteroalkyl groups include, but are not limited to, -(CH 2 CH 2 0)i_ 5 CH 3 , -(CH 2 )i_ 6 0(CH 2 )i_ 6 CH 3 , -(CH 2 )i_ 6 NR a (CH 2 )i_ 6 CH 3 , -(CH 2 )i_ 6 S(CH 2 )!_ 6 CH 3 , -(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 CH 3 , -(CH 2 )i- 6 NR a (CH 2 )i_ 6 NR a (CH 2 )i_ 6 CH 3 , - (CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 CH 3 , -(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 CH 3 , -
  • heteroalkyl groups include, but are not limited to, groups having different heteroatoms in a single group. Such examples of heteroalkyl groups include, but are not limited to, -(CH 2 ) 1 _ 6 S(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 , -(CH 2 ) !
  • heteroalkyl groups include, but are not limited to, polyoxyethylene groups, such as -(OCH 2 CH 2 -)i_ 5 CH 3 , for example, -0(CH 2 ) 2 0(CH 2 ) 2 OCH 3 ,
  • Heteroalkenyl groups include straight and branched chain heteroalkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • Heteroalkenyl groups have from 2 to 12 carbon atoms, e.g., from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, e.g., 2, 3, 4, 5, or 6 carbon atoms or any range therein (e.g., 2-4, 2-5, etc.), and further include 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from oxygen, sulfur, and nitrogen.
  • the heteroalkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to,
  • the heteroalkenyl group includes different heteroatoms in a single group. Heteroalkenyl groups may be substituted or unsubstituted.
  • Heteroalkynyl groups include straight and branched chain heteroalkyl groups as defined above, except that at least one triple bond exists between two carbon atoms.
  • Heteroalkynyl groups have from 2 to 12 carbon atoms, e.g., from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, e.g., 2, 3, 4, 5, or 6 carbon atoms or any range therein (e.g., 2-4, 2-5, etc.), and further including 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from oxygen, sulfur, and nitrogen.
  • the heteroalkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to
  • the heteroalkynyl group includes different heteroatoms in a single group. Heteroalkynyl groups may be substituted or unsubstituted.
  • alkylene refers to a divalent alkyl group, such as, but not limited to, - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, etc.
  • alkynylene refers to a divalent alkynyl group, such as, but not limited to, -C ⁇ C-, -C ⁇ CCH 2 -, - CH 2 C ⁇ CCH 2 -, etc.
  • heteroalkylene refers to a divalent heteroalkyl group, such as, but not limited to, -(CH 2 CH 2 0)i_ 6 -, -(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 -,-(CH 2 ) 1 _ 6 NR a (CH 2 ) 1 _ 6 -, -(CH 2 ) 1 _ 6 S(CH 2 ) 1 _ 6 -, -(CH 2 )i_ 6 0(CH 2 ) 1 _ 6 0(CH 2 ) 1 _ 6 -, -(CH 2 ) !
  • the heteroalkenylene group includes different heteroatoms in a single group.
  • heteroalkynylene refers to a divalent heteroalkynyl group, such as, but not limited to, -(OCH 2 CH 2 ) 2 _ 5 C ⁇ C-,
  • the heteroalkynyl group includes different heteroatoms in a single group.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl,
  • aryl groups contain 6-12 carbons, and in others from 6 to 10, e.g., 6, 7, 8, 9, or 10 carbon atoms, and any range therein, in the ring portions of the groups.
  • the aryl groups are phenyl or naphthyl.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as chlorophenyl or tolyl are referred to as substituted aryl groups. Alkyl substituted aryl groups may also be referred to as alkaryl groups. Phenyl groups are aryl groups ⁇ i.e., cyclic aromatic hydrocarbons that do not contain heteroatoms). Phenyl groups are cyclic -C63 ⁇ 4 systems with alternating carbon-carbon double bonds in which one or more bonds to a hydrogen(s) atom may be replaced by one or more bonds to an alkyl or substituent group as defined above.
  • fused aromatic-aliphatic ring systems e.g., indanyl, tetrahydr
  • Aralkyl groups are substituted aryl groups in which an alkyl group as defined above has a hydrogen or carbon bond of the alkyl group replaced with a bond to an aryl group as defined above.
  • aralkyl groups contain 7 to 14 carbon atoms, 7 to 10 carbon atoms, e.g., 7, 8, 9, or 10 carbon atoms or any range therein ⁇ e.g., 7-8).
  • Aralkyl groups may be substituted or unsubstituted. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group.
  • substituted and unsubstituted alkaryl groups include but are not limited to alkylphenyl such as methylphenyl, (chloromethyl)phenyl, chloro(chloromethyl)phenyl, or fused alkaryl groups such as 5-ethylnaphthalenyl.
  • Heterocyclyl groups are non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms.
  • heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members.
  • Heterocyclyl groups encompass partially unsaturated and saturated ring systems, such as, for example, imidazolinyl and imidazolidinyl groups.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • the phrase also includes heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members, referred to as "substituted heterocyclyl groups”.
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, pyrrolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and tetrahydrothiopyranyl groups.
  • Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.
  • the heteroatom(s) can also be in oxidized form, if chemically possible.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, be
  • Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3- dihydro indolyl groups.
  • the phrase "heteroaryl groups” includes fused ring compounds and also includes heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups, referred to as "substituted heteroaryl groups.”
  • Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
  • the heteroatom(s) can also be in oxidized form, if chemically possible.
  • carboxyl refers to a -C(0)OH group or to its ionized form, -C(0)0 .
  • carbonyl or "oxo" as used herein, when alone includes formyl [-C(0)H] and in combination is a -C(O)- group.
  • halogen refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • halide refers to the anion of a halogen, such as bromide, chloride, fluoride, and iodide. In some embodiments, the halide is chloride or iodide.
  • hydroxy or "hydroxyl” as used herein can refer to -OH.
  • aryloxy and arylalkoxy refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
  • alkanoyl and “alkanoyloxy” as used herein can refer, respectively, to -C(0)-alkyl groups and -0-C(0)-alkyl groups, each containing 2-5 carbon atoms.
  • esters refers to -C(0)OR 60 groups.
  • R 60 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • nitrile or "cyano” as used herein refers to the -CN group.
  • nitrate refers to an -ON0 2 group.
  • Urethane groups include N- and O-urethane groups, i.e., -NR 63 C(0)OR 64 and -OC(0)NR 63 R 64 groups, respectively.
  • R 63 and R 64 are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • R 63 may also be H.
  • amine refers to -NR 65 R 66 groups, wherein R 65 and R 66 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino.
  • the amine is NH 2 , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
  • sulfonamido includes S- and N-sulfonamide groups, i.e., -S0 2 NR 68 R 69 and -NR 68 S0 2 R 69 groups, respectively.
  • R 68 and R 69 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,
  • heterocyclylalkyl or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-S0 2 NH 2 ).
  • the sulfonamido is -NHS0 2 -alkyl and is referred to as the "alkylsulfonylamino" group.
  • thiol refers to -SH groups
  • sulfides include -SR 70 groups
  • sulfoxides include -S(0)R 71 groups
  • sulfones include -S0 2 R 72 groups
  • sulfonyls include
  • R , R , R' and R' J are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the sulfide is an alkylthio group, -S-alkyl.
  • urea refers to -NR 74 -C(0)-NR 75 R 76 groups.
  • R 74 , R 75 , and R 76 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to -C(NR 77 )NR 78 R 79 and -NR 77 C(NR 78 )R 79 , wherein R 77 , R 78 , and R 79 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to -NR 80 C(NR 81 )NR 82 R 83 , wherein R 80 , R 81 , R 82 and R 83 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • R 100 and R 101 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(0)NH 2 ) and formamide groups (-NHC(O)H).
  • the amide is -NR 100 C(O)-(Ci_ 5 alkyl) and the group is termed
  • imide refers to -C(0)NR 88 C(0)R 89 , wherein R 88 and R 89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term "imine” refers to -CR 90 (NR 91 ) and -N(CR 90 R 91 ) groups, wherein R 90 and R 91 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R 90 and R 91 are not both simultaneously hydrogen.
  • hydrazine refers to -NR 110 NR m R 112 groups where R 110 , R 111 , and R 112 are each independently selected from H or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • alkoxycarbonyl stands for a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.
  • solvate means a compound wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate.” The formation of solvates will vary depending on the compound and the solvent.
  • the present technology relates to compounds of general formula (I):
  • L is a linker comprising 1 to 10 optionally substituted backbone atoms selected from carbon, nitrogen and oxygen;
  • R 1 and R 2 are each independently selected from hydrogen and Ci-C 6 alkyl, or R 1 and R 2 are joined together to form a second linker between the amide nitrogen atom and the cationic nitrogen atom, or R 1 is joined with a backbone atom of the linker L in a cyclic structure and/or R 2 is joined with a backbone atom of the linker L in a cyclic structure; and
  • R 3 is selected from hydrogen and Ci-C 6 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties, or R 3 is absent when the cationic nitrogen atom is part of an imine moiety; and
  • R 4 is selected from hydrogen and Ci-C 6 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties;
  • X is a pharmaceutically acceptable anion.
  • the compound according to the present technology is a compound wherein:
  • the compound according to the present technology is a compound wherein:
  • the compound according to the present technology is a compound wherein:
  • the compound of the present technology is a compound wherein:
  • the compound is a compound wherein:
  • the compound according to the present technology is a compound wherein:
  • the present technology pertains to a compound which is a derivative of 6-hydroxy- 2,5,7,8-tetramethylchroman-2-carboxylic acid, which is also known as TROLOXTM.
  • the carboxylic acid moiety is replaced by an amide moiety, wherein the nitrogen atom of the amide moiety is connected via a linker to a cationic nitrogen atom.
  • this cationic nitrogen atom formally originates from protonation or alkylation, e.g., protonation or methylation of a trivalent nitrogen atom.
  • the trivalent nitrogen atom is an amine moiety, either primary, secondary or tertiary, or an imine moiety, either primary or secondary.
  • the counter ion (X ) of the cationic nitrogen atom is a negatively charged ion.
  • X is a monovalent negatively charged ion, e.g., an anion as indicated herein below.
  • the synthesis of the compounds of the present technology does not encompass the protonation or alkylation of an amine or imine nitrogen atom.
  • the cationic nitrogen atom may also be formed via a different route. As such, the cationic nitrogen atom only "formally" originates from the protonation or alkylation of an amine or imine nitrogen atom.
  • L is a linker between the amide nitrogen atom and the cationic nitrogen atom
  • R 1 and R 2 are each independently selected from hydrogen (H) or Ci-C 6 alkyl, or R 1 and R 2 are joined together and thus form a second linker between the amide nitrogen atom and the cationic nitrogen atom, or R 1 is joined with a backbone atom of the linker L in a cyclic structure and/or R 2 is joined with a backbone atom of the linker L in a cyclic structure; and - R 3 is selected from hydrogen (H) or Ci-C 6 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties, or R3 is absent when the cationic nitrogen atom is part of an imine moiety; and
  • R 4 is selected from hydrogen (H) or Ci-C 6 alkyl, wherein the alkyl moiety may be
  • X is a pharmaceutically acceptable anion.
  • the compound identified by general formula (I) comprises at least one chiral carbon atom (stereocenter), i.e., the atom at the 2-position of the TROLOXTM-moiety.
  • stereocenter i.e., the atom at the 2-position of the TROLOXTM-moiety.
  • Both the compound having an ⁇ -configuration and the compound having an ⁇ -configuration of the carbon atom at the 2-position are encompassed in the present technology, as well as mixtures of the different stereoisomers.
  • Such a mixture may have one of the configurations in enantiomeric excess, or may be racemic.
  • an additional stereocenter is present in the compound according to the present technology, for example in the linker, it may exists as the ⁇ -configuration, as the ⁇ -configuration, or as a mixture of both configurations.
  • Such a mixture may have one of the configurations in enantiomeric excess, or may be racemic. If more than one stereocenter is present in the compound according to the present
  • the linker L comprises at least one double bond, located between the cationic nitrogen atom and the adjacent backbone atom of the linker.
  • R 3 is absent.
  • the cationic nitrogen atom is part of an amine moiety, it is connected to the linker via a single bond, and R 3 is present.
  • R 3 is selected from hydrogen (H) or Ci- C 6 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • R 3 is H or C 1 -C4 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • R 3 is H or Ci -C 2 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • Halogen atoms include fluorine (F), chlorine (CI), bromine (Br), iodine (I), and astatine (At).
  • the halogen atom is fluorine (F).
  • alkoxy moieties include methoxy and ethoxy.
  • haloalkoxy moieties at least one hydrogen atom of an alkoxy moiety is replaced by a halogen atom, such as F.
  • suitable moieties for R 3 include H, methyl (Me), trifluoromethyl (— CF 3 ), ethyl (Et), isopropyl (iPr), cyclopropyl (-cPr), methylene cyclopropyl (— CH 2 cPr), n-propyl (n-Pr), 2,2,2- trifluoroethyl (— CH 2 CF 3 ), methoxymethyl (— CH 2 OCH 3 ).
  • R 3 is H or methyl (Me).
  • R 3 is H.
  • R 3 is C 1 -C4 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • R 3 is C 1 -C 2 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • the compound contains moieties comprising an imine moiety including guanidine and amidine, wherein one of the nitrogen atoms is substituted to form the connection with the amide nitrogen atom via linker L.
  • R 4 is the substituent on the cationic nitrogen atom, which originates from formal protonation or alkylation of the amine or imine moiety.
  • the compound according to the present technology in view of the presence of the cationic nitrogen atom and X " , is a salt, such as a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals.
  • the pharmaceutically acceptable salts of the amine or imine moiety of the compound according to the present technology are known to those skilled in the art, and originate from formal treatment of the compound with an acid or an alkylating agent. Examples of suitable acids include organic acids or inorganic acids.
  • inorganic acids include, but are not limited to, hydrochloric acid (HC1), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H 2 S0 4 ), nitric acid (HN0 3 ), trifluoroacetic acid (TFAH or CF 3 C0 2 H) and phosphoric acid (H 3 P0 4 ).
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids and salicylic acid.
  • R 4 is hydrogen, and the type of acid determines counter ion X.
  • the salt can be formed by formal treatment with an alkylating agent.
  • Suitable alkylating agents include, but are not limited to, Ci-C 6 alkyl halides (such as methyl iodide, ethyl iodide, propyl iodide, butyl chloride, butyl fluoride, butyl bromide), dimethyl sulfate, dimethyl carbonate, methyl triflate, methyl fluorosulfonate, methyl chlorosulfonate, methyl
  • R 4 is selected from hydrogen (H) or Ci-C 6 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties. In some embodiments, R 4 is H or C 1 -C4 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • R 4 is H or Ci-C 2 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties.
  • Halogen atoms include fluorine (F), chlorine (CI), bromine (Br), iodine (I), and astatine (At).
  • the halogen atom is fluorine (F).
  • alkoxy moieties include methoxy and ethoxy. In haloalkoxy moieties, at least one hydrogen atom of an alkoxy moiety is replaced by a halogen atom, such as F.
  • R 4 examples include, H, methyl (Me), trifluoromethyl (— CF 3 ), ethyl (Et), isopropyl (iPr), cyclopropyl (-cPr), methylene cyclopropyl (— CH 2 cPr), n-propyl (n-Pr), 2,2,2-trifluoroethyl (— CH 2 CF 3 ), methoxymethyl (— CH 2 OCH 3 ).
  • R 4 is H or methyl (Me).
  • R 4 is H.
  • X can be any anion.
  • X is a physiologically or pharmaceutically acceptable anion.
  • X is a monovalent anion.
  • X is selected from a group consisting of F, CI, Br, I, HSO 4 , N0 3 , TFA (CF 3 C0 2 ), formate, acetate, propionate, glycolate, pyruvate, oxalate, maleate, malonate, succinate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, sulfonate, and salicylate.
  • X is CI, I, TFA or formate.
  • X is CI, I or TFA.
  • X is CI .
  • cationic nitrogen atom originates from formal protonation
  • this protonation is accomplished with hydrogen chloride (HC1), trifluoroacetic acid (TFAH or CF 3 C0 2 H) or formic acid (HCOOH).
  • protonation is accomplished with HC1 or TFAH.
  • formal methylation is accomplished with methyl iodide (Mel).
  • R 1 and R 2 are each independently selected from hydrogen (H) or Ci-C 6 alkyl.
  • R 1 is H or C 1 -C 2 alkyl.
  • R 1 is H or methyl (Me).
  • R 1 is H.
  • R 2 is H or C 1 -C 2 alkyl.
  • R 2 is H or methyl (Me).
  • R 2 is Me.
  • the amide nitrogen atom is connected to the cationic nitrogen atom via a second linker.
  • This second linker is defined by joining together R 1 on the amide nitrogen atom and R 2 on the cationic nitrogen atom.
  • the amide nitrogen atom, the cationic nitrogen atom, the first linker and the second linker together form a cyclic structure.
  • the cyclic structure is a 4-10-membered cyclic structure.
  • the cyclic structure is a 5-8-membered cyclic structure.
  • another linker is defined by joining together R 1 on the amide nitrogen atom and R 2 on the cationic nitrogen atom.
  • the cyclic structure is a 6-membered cyclic structure.
  • the second linker is a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — bridge, wherein two or three carbon atoms are present between the amide nitrogen atom and the cationic nitrogen atom.
  • the second linker is a— CH 2 — CH 2 — bridge.
  • the amide nitrogen atom is connected to a backbone atom of the linker, thereby forming a cyclic structure.
  • the resulting cyclic structure is a 4-10-membered cyclic structure.
  • the resulting cyclic structure is a 5-8-membered cyclic structure.
  • the resulting cyclic structure is a 6-membered cyclic structure.
  • the backbone atom of the linker to which the nitrogen atom is connected in this respect has a substituent R 1 , which is joined together with R 1 on the amide nitrogen atom.
  • the cationic nitrogen atom is not included in the cyclic structure, but instead only part of the backbone of the linker is included.
  • this connection between the amide nitrogen atom and a backbone atom of the linker is a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — bridge, wherein two or three carbon atoms are present between the amide nitrogen atom and the backbone atom of the linker.
  • this connection between the amide nitrogen atom and a backbone atom of the linker is a— CH 2 — CH 2 — bridge.
  • the cationic nitrogen atom is connected to a backbone atom of the linker, thereby forming a cyclic structure.
  • the resulting cyclic structure is a 4-10-membered cyclic structure.
  • the resulting cyclic structure is a 5-8-membered cyclic structure.
  • the resulting cyclic structure is a 6-membered cyclic structure.
  • the backbone atom of the linker to which the nitrogen atom is connected in this respect has a substituent R 2 , which is joined together with R 2 on the cationic nitrogen atom.
  • the amide nitrogen atom is not included in the cyclic structure, but instead only part of the backbone of the linker is included.
  • this connection between the cationic nitrogen atom and a backbone atom of the linker is a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — bridge, wherein two or three carbon atoms are present between the cationic nitrogen atom and the backbone atom of the linker.
  • this connection between the cationic nitrogen atom and a backbone atom of the linker is a— CH 2 — CH 2 — bridge. It is also possible that a connection exists between R 1 on the amide nitrogen atom and an R 1 substituent on the linker and between R 2 on the cationic nitrogen atom and an R 2 substituent on the linker.
  • the solubility of the compound of the present technology in water is between 2.0 and 5.0, between 2.5 and 4.5, or between 3.0 and 4.0.
  • Log(P ow ) the logarithm of the partition coefficient between 1-octanol and water, is a well-known measure of water solubility.
  • Compounds having a log(P ow ) value between 3 and 4 are ideally balanced between sufficient water solubility for preparation of aqueous solutions or suspensions and sufficient lipophilicity to ensure efficient transport of the compound over the cellular membrane.
  • Appropriate linkers L to connect the amide nitrogen atom to the cationic nitrogen atom are linkers comprising 1 to 10 optionally substituted backbone atoms.
  • L can thus comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 optionally substituted backbone atoms.
  • L represents linkers comprising 1 to 8 optionally substituted backbone atoms.
  • backbone atoms are those atoms which make up the shortest chain between the amide nitrogen atom and the cationic nitrogen atom.
  • the backbone may be a linear structure, but may also be part of a cyclic structure.
  • the backbone is defined as the shortest chain between the amide nitrogen atom and the cationic nitrogen atom.
  • one of the backbone atoms comprises a substituent R 5
  • one of the backbone atoms comprises a substituent R 5
  • preferably two different backbone atoms comprise the substituents R 5 and R 5 , wherein R 5 and R 5 are joined to form a cyclic structure.
  • the resulting cyclic structure is a 4-10-membered cyclic structure.
  • the resulting cyclic structure is a 5-8-membered cyclic structure.
  • the resulting cyclic structure is a 6-membered cyclic structure.
  • the amide nitrogen atom and the cationic nitrogen atom are not included in the cyclic structure, but instead only part of the backbone of the linker is included.
  • this connection between the backbone atom(s) of the linker, bearing the R 5 and R 5 substituents is a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — CH 2 — bridge.
  • the backbone atoms are selected from carbon, nitrogen and oxygen. In some embodiments, the backbone atoms are selected from carbon and nitrogen.
  • the carbon and nitrogen backbone atoms of the linker may bear hydrogen atoms, may be substituted, or double or triple bonds may be present between adjacent backbone atoms, as will be understood by a person skilled in the art.
  • hydrogen is not regarded a substituent.
  • an oxygen atom is present as a backbone atom in the linker
  • the oxygen backbone atom bears no hydrogen atoms, substituents or double or triple bonds. Triple bonds may be present between two carbon atoms of the backbone.
  • "optionally substituted" is used to indicate that a (backbone) atom may bear one or more substituents, or may bear no substituents and 0- 3 hydrogen atoms may be present instead, to fulfill the valence requirements of said
  • oxo 0
  • two substituents on the same atom or on different atoms may be joined to form cyclic structures. If two substituents on a single backbone atom are joined in a cyclic structure, this cyclic structure may be regarded as being connected via a spiro junction to the backbone.
  • a cyclic structure may also be formed by joining one substituent on a backbone atom with R 1 on the amide nitrogen atom or with R 2 on the cationic nitrogen atom.
  • the cyclic structures formed as such may be all-carbon or may comprise 0-3 heteroatoms ⁇ e.g., N, O, S and/or P), and may comprise 0-3 double bonds. All atoms in these cyclic structures may optionally be substituted.
  • each R 6 is independently an alkyl moiety.
  • each R 6 is independently a Ci-C 6 alkyl moiety.
  • each R 6 is independently a C 1 -C 2 alkyl moiety.
  • one or more CH 2 moieties may each independently be replaced by one of O, S or NH, and/or one or more CH moieties may be replaced by N.
  • the dashed bond at the left side of each of the structures for L 1 to L 26 indicates the bond between the linker and the amide nitrogen atom
  • the dashed bond at the right side of each of the structures for L 1 to L 26 indicates the bond between the linker and the cationic nitrogen atom.
  • the linkers depicted as chemical formulas are oriented in the same direction, i.e., the pendant bond at the left side of each of the chemical formulas for L 1 to L 26 indicates the bond between the linker and the amide nitrogen atom
  • the dashed bond at the right side of each of the chemical formulas for L 1 to L 26 indicates the bond between the linker and the cationic nitrogen atom.
  • Each occurrence of R 1 is a bridge between the linker and the amide nitrogen atom, wherein R 1 is joined with R 1 via said bridge, thus forming a 4-10-membered cyclic structure, a 5-8-membered cyclic structure, or a 6-membered cyclic structure, which is built up from the amide nitrogen atom, 1-4 atoms of the backbone of the linker, and 1-4 atoms which make up the bridge joining R 1 and R 1 .
  • each occurrence of R 2 is a bridge between the linker and the cationic nitrogen atom, wherein R 2 is joined with R 2 via said bridge, thus forming a 4-10- membered cyclic structure, a 5-8-membered cyclic structure, or a 6-membered cyclic structure, which is built up from the cationic nitrogen atom, 1-4 atoms of the backbone of the linker, and 1-4 atoms which make up the bridge joining R 2 and R 2 .
  • each occurrence of R 5 and R 5 is a bridge between one backbone atom of the linker, bearing R 5 , and another backbone atom of the linker, bearing R 5 , wherein R 5 is joined with R 5 via said bridge, thus forming a 4-10- membered cyclic structure, a 5-8-membered cyclic structure, or a 6-membered cyclic structure, which is built up from 2-5 atoms of the backbone of the linker, and 1-5 atoms which make up the bridge joining R 5 and R 5 .
  • R 1 ' is joined to R 1 via a bridge.
  • R 1 is joined to R 1 via a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — bridge.
  • R 1 is joined to R 1 via a— CH 2 — CH 2 — bridge.
  • the amide nitrogen atom is embedded in a six-membered cyclic structure, which is built up from the amide nitrogen atom, two carbon atoms and one nitrogen atom of the backbone of the linker, and two more carbon atoms which make up the bridge of R 1 and R 1 .
  • linker L 10 1 18 19 21 2' 2 linker L may be represented as L .
  • R is joined to R via a bridge.
  • R 2 is joined to R 2 via a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — bridge.
  • R 2 is joined to R 2 via a— CH 2 — CH 2 — CH 2 — bridge.
  • linker L 20 and L 26 R 5 is joined to R 5 via a bridge.
  • R 5 is joined to R 5 via a— CH 2 — CH 2 — or— CH 2 — CH 2 — CH 2 — bridge. In some embodiments, R 5 is joined to R 5 via a— CH 2 — CH 2 — bridge.
  • Linkers L 11 , L 12 , L 13 , L 14 , L 15 , L 18 (as long as R 2 — R 2 is not— C(O)— ), L 19 (as long as R 2 — R 2' is not— CH 2 — ), L 20 (as long as R 5 — R 5 is not— CH 2 — ), L 21 (as long as R 2 — R 2' is not— CH 2 — CH 2 — ), L 22 (as long as R 1 — R 1 ' is not— CH 2 — CH 2 — ), L 23 (as long as R 1 — R 1 ' is not— CH 2 — CH 2 — ), L 24 (as long as R 1 — R 1 ' is not— CH 2 — ) and L 25 (as long as R 1 — R 1 is not— CH 2 — ) comprise an additional stereocenter.
  • Linker L 26 comprises a disubstituted cycloalkyl moiety, and may thus occur in either the czs-form or the trans-fovm.
  • LLiinnkkeerr LL 26 ccoommpprriis seess aa ddiissuubbistituted cyclohexyl moiety.
  • Linker L may occur in the trans-fovm.
  • the linkers are L 5 , L 8 , L 11 and L 12 . In some embodiments, the linkers are L 8 and L u . In some embodiments, the linker is L 11 . In
  • the linkers are L , L , L , L and L .
  • the linkers are L 16 and L 19 .
  • the preferred linkers are L 5 , L 8 , L 11 , L 12 , L 16 , L 17 , L 19 , L 21 and L 26 , more preferably L 8 , L 11 , L 16 , L 17 , L 19 , L 21 and L 26 , most preferably L 16 and L 19 .
  • L 19 is combined with R 2 —
  • R 3 Me, Et, iPr or CH 2 CF 3 .
  • the linkers are L 7 and L 1 , and an even more preferred linker is L 7 .
  • compounds according to the present technology are identified here below as compounds A to O, which are defined by general formula (I), wherein:
  • R 4 H
  • X " CI " ;
  • the compound of the present technology is not compound D, and is selected from the group consisting of compounds A to C and E to AH. In some embodiments, the compound is selected from the group consisting of compounds A to C and E to P.
  • the compounds are compounds F, K, N and O. In some embodiments, the compounds according to the present technology are compounds K and N. In some embodiments, the compound of the present technology is compound N. In some embodiments, the compounds according to the present technology are compounds U, V, T, X, Z, AE, AF, AG and AH. In some embodiments, the compounds according to the present technology are compounds U, V, X, Z, AE, AF and AH. In some embodiments, the compounds according to the present technology are compounds V, X and AF.
  • the preferred compounds are F, K, N, O, U, V, T, X, Z, AE, AF, AG and AH, more preferably K, N, U, V, X, Z, AE, AF and AH, most preferably V, X and AF.
  • Compound F may have the ⁇ -configuration, the ⁇ -configuration or a mixture thereof. In some embodiments, compound F is a mixture of the R- and S-enantiomers, e.g., a racemic mixture. Compound K may have the ⁇ -configuration, the ⁇ -configuration or a mixture thereof. In some embodiments, compound K is a mixture of the R- and S- enantiomers, e.g., a racemic mixture. Compound N may have the i?J?-configuration, Reconfiguration, ⁇ -configuration, ⁇ -configuration or any mixture thereof. In some embodiments, compound N is a mixture of the R,S- and ⁇ S-diastereomers, e.g., a 1/1
  • Compound O may have the i?,i?-configuration, ⁇ -configuration, S,R- configuration, ⁇ -configuration or any mixture thereof.
  • compound O is a mixture of the R,S- and ⁇ S-diastereomers, e.g., a 1/1 (mol/mol) mixture.
  • Compound U may have the R-configuration, the S- configuration or a mixture thereof.
  • compound U has the ⁇ -configuration or the ⁇ -configuration.
  • Compound V may have the ⁇ -configuration, the ⁇ -configuration or a mixture thereof.
  • compound V has the ⁇ -configuration.
  • Compound T may have the R- configuration, the ⁇ -configuration or a mixture thereof. In some embodiments, compound T has the ⁇ -configuration or the ⁇ -configuration.
  • Compound X may have the R,R- configuration, ⁇ -configuration, ⁇ -configuration, ⁇ -configuration or any mixture thereof. In some embodiments, compound X has the ⁇ -configuration.
  • Compound Z may have the ⁇ -configuration, the ⁇ -configuration or a mixture thereof. In some embodiments, compound Z is a mixture of the R- and S-enantiomers, e.g., a racemic mixture.
  • Compound AE may have the R, trans-configuration, i?,czs-configuration, ⁇ transconfiguration, the iSlcz ' s-configuration or any mixture thereof. In some embodiments, compound AE has the R, trans-configuration or the iS*, trans-configuration.
  • Compound AF may have the i?,i?-configuration, ⁇ -configuration, ⁇ -configuration, the S, S- configuration or any mixture thereof. In some embodiments, compound AF has the S,R- configuration.
  • Compound AG may have the i?,i?-configuration, ⁇ -configuration, ⁇ -configuration, the S,S- configuration or any mixture thereof.
  • compound AG has the S,S- configuration or the S,R- configuration.
  • Compound AH may have the R- configuration, the ⁇ -configuration or a mixture thereof.
  • compound AH has the S- configuration.
  • the first designator (R or S) of the configuration is for the 2-position of the TROLOXTM moiety, and in case an additional stereocenter is present in the compound according to the present technology, the configuration of which is defined by the second designator.
  • the compounds are compound V in the ⁇ -configuration (i?-V), compound X in the ⁇ -configuration (S,R-X) and compound AF in the S,R- configuration (S,R- AF).
  • the compounds are compounds I and J. In some embodiments, the compound is compound J.
  • the present technology also includes all stereoisomers and geometric isomers of the compounds, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
  • the present technology also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures.
  • the compound according to the present technology is not the compound represented by formula (I), wherein:
  • the compounds can be administered in prodrug form.
  • Prodrugs are derivatives of the compounds which are themselves relatively inactive, but which convert into the active compound when introduced into the subject in which they are used, by a chemical or biological process in vivo, such as an enzymatic conversion. Further discussion of suitable prodrugs is provided in H. Bundgaard, Design of Prodrugs (New York: Elsevier, 1985); in R. Silverman, The Organic Chemistry of Drug Design and Drug Action (Boston: Elsevier, 2004); in R. L. Juliano , Biological Approaches to the Controlled Delivery of Drugs (Annals of the New York Academy of Sciences, volume 507, New York: N. Y. Academy of Sciences, 1987); and in E. B. Roche, Design of Biopharmaceutical Properties Through Prodrugs and Analogs (Symposium sponsored by Medicinal Chemistry Section, APhA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Florida), published by The Academy in Washington, 1977.
  • compounds of the present technology are compounds wherein the linkers are L 5 , L 8 , L 11 , L 12 , L 16 , L 17 , L 19 , L 21 and L 26 . In some embodiments, compounds of the present technology are compounds wherein the linkers are
  • compounds wherein the linkers are L 16 and L 19 . More specifically, compounds of the present technology having one or more of these effects are compounds F, K, N, O, U, V, T, X, Z, AE, AF, AG and AH. In some embodiments, compounds according to the present technology having one or more of these effects are compounds K, N, U, V, X, Z, AE, AF and AH. In some embodiments, compounds according to the present technology having one or more of these effects are compounds V, X and AF.
  • compounds of the present technology are compounds wherein the linkers are L 7 and L 1 . In some embodiments, compounds of the present technology are compounds wherein the linker is L 7 . In some embodiments, compounds of the present technology are compounds I and J. In some embodiments, the compound of the present technology is compound J.
  • the present technology provides compounds of Formula (II):
  • Z is absent, -NR 10 -, -S-, or -0-;
  • L is absent, -C(0)0-, -C(0)N(R a ) -, or L is a substituted or unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group;
  • Y is absent, -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen, amino, carboxyl, cyano, hydroxyl, halogen, nitro, or perhaloalkyl group, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, -C(0)-alkyl, -C(0)-aryl, -C(0)-aralkyl, ester, or amide group,
  • R 8 is a hydrogen, halogen, -Si(R a ) 3 , -C(0)R a , a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl group; wherein at least one of R 5 , R6, R 7 , and Rg is a group other than hydrogen, provided that R 8 is halogen only when Y is absent, and R 8 is -Si(R a ) 3 only when Y is absent or -0-;
  • R 9 is a hydrogen, halogen, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl group;
  • R 10 and R 11 are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, or aryl group, wherein
  • R 10 and R 11 are divalent groups joined together by -C(0)0- or
  • R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is connected to an atom of L in a cyclic structure
  • R 12 is absent, hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl,
  • cycloalkylalkyl alkenyl, alkynyl, aryl, or aralkyl group, wherein when R 12 is absent, the dashed line indicates that R 11 is connected to N by a double bond or when R 12 is absent, L is connected to N by a double bond;
  • R 13 is a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl group;
  • n 1, 2, 3, 4, or 5;
  • X " is an anion
  • Z is -NR 10 - or -0-;
  • L is a substituted or unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group;
  • Y is -0-, -S-, -NR -;
  • R 5 , R 6 , R 7 , and R 8 are each independently a hydrogen, -C(0)R a , or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R 5 , R 6 , R 7 , and R 8 is a group other than hydrogen
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl, alkenyl, or alkynyl group
  • R 10 and R 11 are each independently selected from a substituted or unsubstituted alkyl , wherein
  • R 10 and R 11 are divalent groups joined together by a substituted or unsubstituted alkylene or alkenylene group; or
  • R 10 is joined with an atom of L in a cyclic structure, and/or
  • R 11 is joined with an atom of L in a cyclic structure;
  • R is absent, hydrogen, or a substituted or unsubstituted alkyl group, wherein when R 12 is absent, the dashed line indicates that R 11 is connected to N by a double bond;
  • R 13 is a hydrogen or substituted or unsubstituted alkyl group
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted
  • X " is an anion
  • Z is -0-
  • L is a substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl group;
  • Y is -0-, -S-, -NR -;
  • R 5 , R 6 , R 7 , and R 8 are each independently a hydrogen or a substituted or unsubstituted alkyl group
  • R 5 , R 6 , R 7 , and R 8 is a group other than hydrogen;
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl group;
  • R 10 is absent
  • R 11 is a substituted or unsubstituted alkyl, wherein
  • R 11 is divalent and is joined with an atom of L in a cyclic structure;
  • R 12 is absent, hydrogen, or a substituted or unsubstituted alkyl group, wherein when R 12 is absent, the dashed line indicates that R 11 is connected to N by a double bond;
  • R 13 is a hydrogen or substituted or unsubstituted alkyl group
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted -
  • X " is an anion
  • Z is -NR 10 -;
  • L is a substituted or unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group;
  • Y is -0-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, -C(0)R a , or alkoxy group; and R 8 is a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, or -C(0)R a group;
  • R 5 , R 6 , R 7 , and R 8 is a group other than hydrogen;
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl group;
  • R 10 and R 11 are each independently a hydrogen or substituted or unsubstituted alkyl group
  • R 10 and R 11 are divalent groups joined together by a substituted or unsubstituted alkylene or alkenylene; or
  • R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is connected to an atom of L in a cyclic structure
  • R 12 is absent, hydrogen, or a substituted or unsubstituted alkyl group, wherein when R 12 is absent and the dotted line indicates R 11 is connected to the N by a double bond;
  • R 13 is a hydrogen or substituted or unsubstituted alkyl group
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted
  • X " is an anion
  • the present technology provides compounds of Formula (IIA):
  • Z is -NR 10 - or -0-;
  • L is absent, -C(0)0-,- C(0)N(R a )-, or L is a substituted or unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group;
  • Y is absent, -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino, alkylamino, dialkylamino, aralkyl, cyano, - C(0)-alkyl, -C(0)-aryl, -C(0)-aralkyl, carboxyl, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl group;
  • R 8 is a hydrogen, halogen, -Si(R a ) 3 , -C(0)R a , a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group; wherein at least one of R 5 , R 6 , R 7 , and R 8 is a group other than hydrogen, provided that R 8 is halogen only when Y is absent, and R 8 is -Si(R a ) 3 only when Y is absent or -0-;
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl, alkenyl, or alkynyl group
  • R 10 and R 11 are each independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, or aryl, wherein
  • R 10 and R 11 are divalent groups joined together by -C(0)0- or
  • R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is joined with an atom of L in a cyclic structure
  • R 12 is a hydrogen, substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R 13 is a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl group;
  • X " is an anion.
  • Z is -NR 10 - or -0-;
  • L is -C(0)0-, -C(0)N(R a )-, or an unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene, group;
  • Y is -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen, -C(0)R a , or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, or alkoxy group;
  • R 8 is a hydrogen, -C(0)R a , or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R 5 , R 6 , R 7 , and R 8 is a group other than hydrogen;
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl group;
  • R 10 and R 11 are each independently a hydrogen or substituted or unsubstituted alkyl group, wherein
  • R 10 and R 11 are divalent groups joined together by a substituted or unsubstituted alkylene, alkenylene, or alkynylene group; or R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is connected to an atom of L in a cyclic structure
  • R 12 is a hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R 13 is a hydrogen or substituted or unsubstituted alkyl group
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted alkyl group
  • X " is an anion.
  • Z is -NR 10 -;
  • L is a -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,-(CH 2 ) 6 -, -(CH 2 ) 2 NH(CO)CH 2 -,
  • R 31 is an alkylene, alkenylene, alkynylene, heteroalkyl, or
  • R 32 is an alkylene, alkenylene, alkynylene, heteroalkyl, or heteroalkenyl, or heteroalkynyl bridge having a total of 1 to 5 atoms connecting L to R 11 ;
  • R 33 and R 34 are both substituents of L and are connected together by an alkylene, alkenylene, alkynylene, heteroalkyl, or heteroalkenyl, or heteroalkynyl bridge having a total of 1 to 5 atoms;
  • Y is -0-
  • R J , R°, R', R°, R R , and R 1J are each independently a hydrogen or a substituted or unsubstituted Ci-C 6 alkyl group;
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from a hydrogen or substituted or
  • R 10 and R 11 are divalent groups joined together by a substituted or unsubstituted alkylene, alkenylene, or alkynylene group; or R 10 is joined with an atom of L in a cyclic structure, and/or
  • R 11 is joined with an atom of L in a cyclic structure
  • X " is an anion
  • the present technology provides compounds of Formula (IIB):
  • Z is -NR 10 - or -0-;
  • L is absent, -C(0)0-, -C(0)N(R a ) -, or L is a substituted or unsubstituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene group;
  • Y is absent, -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino, alkylamino, dialkylamino, aralkyl, cyano, - C(0)-alkyl, -C(0)-aryl, -C(0)-aralkyl, carboxyl, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl group,
  • R 8 is a hydrogen, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, or -Si(R a ) 3 , -C(0)R a group; wherein at least one of R 5 , 5, R7, and Rg is a group other than hydrogen, provided that R 8 is halogen only when Y is absent, and R 8 is Si(R a ) 3 only when Y is absent or -0-;
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl, alkenyl, or alkynyl group
  • R 10 is a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, or aryl group
  • R 11 is a substituted or unsubstituted alkyl or alkenyl group, optionally
  • R 10 and R 11 are divalent groups joined together by a substituted or unsubstituted alkenylene or heteroalkenylene group; or R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is connected to an atom of L in a cyclic structure
  • R 13 is a hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl group;
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl group;
  • X " is an anion.
  • Z is -N(R 10 )- or -0-;
  • L is -C(0)0-, -C(0)N(R a )-, or L is a substituted or unsubstituted alkylene
  • Y is -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , and R 7 are each independently a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, -C(0)R a , or alkoxy group;
  • R 8 is a hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, -C(0)R a , wherein at least one of R 5 , R 6 , R 7 , and R 8 is a group other than hydrogen;
  • R 9 is a hydrogen or a substituted or unsubstituted alkyl group
  • R 10 and R 11 are each independently selected from a hydrogen or substituted or
  • R 10 and R 11 are divalent groups connected together by a substituted or unsubstituted alkylene group
  • R 10 is connected to an atom of L in a cyclic structure, and/or
  • R 11 is connected to an atom of L in a cyclic structure
  • R 13 is a hydrogen or substituted or unsubstituted alkyl group
  • R a at each occurrence is independently a hydrogen or a substituted or unsubstituted alkyl group
  • X " is an anion.
  • Z is -NR 10 -;
  • L is a -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,-(CH 2 ) 6 -, -(CH 2 ) 2 NH(CO)CH 2 -,
  • (-R 35 -) is an alkylene, alkenylene, alkynylene, heteroalkyl, or
  • heteroalkenyl, or heteroalkynyl bridge having a total of 1 to 5 atoms connecting L to R 10 ;
  • -R 36 - is an alkylene, alkenylene, alkynylene, heteroalkyl, or heteroalkenyl, or heteroalkynyl bridge having a total of
  • Y is -0-
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 13 are each independently a hydrogen or a substituted or unsubstituted Ci-C 6 alkyl group;
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from a hydrogen or substituted or
  • R 10 and R 11 are divalent groups joined together by a substituted or unsubstituted alkylene, alkenylene, or alkynylene group; or
  • R 10 is joined with an atom of L in a cyclic structure, and/or
  • R 11 is joined with an atom of L in a cyclic structure
  • X " is an anion
  • Z is -NR 10 -;
  • L is a substituted or unsubstituted Ci-C 6 alkylene or heteroalkylene
  • L is optionally connected to R 10 or R 11 with a substituted or
  • Y is -0-, -S-, or -N(R a )-;
  • R 5 , R 6 , R 7 , and R 9 are each independently Ci-C 6 alkyl group
  • R 8 is hydrogen
  • R 10 and R 11 are each independently a hydrogen or Ci-C 6 alkyl group
  • R 12 and R 13 are each independently a hydrogen, Ci-C 6 alkyl or heteroalkyl group, C 3 _ 6 cyloalkyl, or C 4 -8 cycloalkylalkyl group, wherein the alkyl, cycloalkyl, cycloalkylalkyl, and heteroalkyl groups are optionally substituted with one or more halogen atoms;
  • R a at each occurrence is a hydrogen or a substituted or unsubstituted alkyl group; and X " is a halide, sulfate, sulfonate, nitrate, formate, or substituted or unsubstituted
  • Z is -NR 10 -;
  • L is a straight or branched C 1 -C 12 heteroalkylene comprising 1, 2, or 3 nitrogen atoms and substituted with 1 to 6 substituents selected from the group consisting of oxo, -COOR b , and -NR b 2 ;
  • L is joined to R 10 or R 11 by a substituted or unsubstituted C 2 -C 4 alkylene via the backbone of L or a substituent of L;
  • Y is O
  • R 5 , R 6 , R 7 , and R 9 are each independently methyl; R 8 is hydrogen;
  • R 10 and R 11 are each independently a hydrogen or Ci-C 6 alkyl
  • R 12 is absent, a hydrogen, or Ci-C 6 alkyl substituted with one or more halogen atoms, -CF 3 , methyl, ethyl, isopropyl, cyclopropyl, methylenecyclopropyl, n-propyl, -CH 2 CF 3 , or -CH 2 OCH 3 ;
  • R 13 is independently a hydrogen or Ci-C 6 alkyl substituted with one or more halogen atoms, trifluoromethyl, methyl, ethyl, isopropyl, cyclopropyl, methylene cyclopropyl, n-propyl, 2,2,2-trifluoroethyl, or methoxymethyl;
  • R a at each occurrence is a hydrogen or a substituted or unsubstituted alkyl group
  • X " is a F “ , CI “ , Br “ , ⁇ , HS0 4 ⁇ , N0 3 “ , CF 3 C0 2 " , formate, acetate, propionate, glycolate, pyruvate, oxalate, maleate, malonate, succinate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, sulfonate, or salicylate.
  • Formulas (II), (IIA), and (IIB) are examples of Formulas (II), (IIA), and (IIB),
  • Z is -NR 10 -;
  • L is independently a straight or branched Ci-C 6 heteroalkylene comprising 1 , 2, or 3 nitrogen atoms and substituted with 1 , 2, or 3 substituents selected from the group consisting of oxo, -COOR b , and -NR b ;
  • L is connected to R 10 or R 11 with a substituted or unsubstituted C 2 -C 4 alkylene via the backbone of L or a substituent of L;
  • Y is O
  • R 5 , R 6 , R 7 , and R 9 are each independently a methyl
  • R 8 is hydrogen
  • R 10 and R 11 are each independently a hydrogen or methyl
  • R 12 is absent, a hydrogen, or methyl
  • R 13 is independently a hydrogen or methyl
  • R b at each occurrence is a hydrogen or a substituted or unsubstituted Ci-C 6 alkyl;
  • X is a CI " , ⁇ , CF 3 C0 2 " , or formate.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently a hydrogen or a substituted or unsubstituted Ci-C 6 alkyl group;
  • R 5 , R ⁇ , R 7 , and R 8 is a substituted or unsubstituted Ci- C 6 alkyl group
  • R 12 and R 13 are each independently a hydrogen or C 1 -C 12 alkyl, wherein the alkyl group may be substituted with one or more halogen atoms or (halo)alkoxy groups;
  • R a at each occurrence is independently a hydrogen or Ci-C 6 alkyl group
  • G at each occurrence is independently C 1 -C 7 alkylene, C 1 -C 7 alkenylene, C 1 -C 7 alkynylene, C 1 -C 7 heteroalkylene, C 1 -C 7 heteroalkenylene, or C 1 -C 7 heteroalkynylene;
  • M at each occurrence is independently Ci-C 6 alkylene, Ci-C 6 alkenylene, Ci-C 6
  • alkynylene Ci-C 6 heteroalkylene, Ci-C 6 heteroalkenylene, or Ci-C 6 heteroalkynylene;
  • T and J are each independently 1, 2, or 3 carbon atoms
  • X " is an anion
  • aromatic-cationic peptides of the present technology are water-soluble, highly polar, and can readily penetrate cell membranes.
  • aromatic-cationic peptides of the present technology include a minimum of three amino acids, covalently joined by peptide bonds.
  • the maximum number of amino acids present in the aromatic-cationic peptides of the present technology is about twenty amino acids covalently joined by peptide bonds. In some embodiments, the maximum number of amino acids is about twelve. In some embodiments, the maximum number of amino acids is about nine. In some embodiments, the maximum number of amino acids is about six. In some embodiments, the maximum number of amino acids is four.
  • the present technology provides an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof such as acetate salt or trifluoroacetate salt.
  • the peptide comprises at least one net positive charge; a minimum of three amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1 ; and
  • the peptide comprises the amino acid sequence Phe-D-Arg- Phe-Lys-NH 2 or D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
  • the peptide comprises one or more of the peptides of Table A:
  • the aromatic-cationic peptide is defined by Formula A:
  • R 1 and R 2 are each independently selected from
  • R 3 and R 4 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from (i) hydrogen;
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • the peptide is defined by Formula B:
  • R 1 and R 2 are each independently selected from
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
  • the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
  • the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
  • Aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), and Trp (W).
  • the Aromatic residue may be substituted with cyclohexylalanine (Cha).
  • the Cationic residue is a residue selected from the group consisting of: Arg (R), Lys (K), and His (H).
  • the Cationic residue may be substituted with norleucine (Nle) or 2-amino-heptanoic acid (Ahe).
  • amino acids of the aromatic-cationic peptides of the present technology can be any amino acid.
  • amino acid is used to refer to any organic molecule that contains at least one amino group and at least one carboxyl group. In some embodiments, at least one amino group is at the a position relative to the carboxyl group.
  • the amino acids may be naturally occurring.
  • Naturally occurring amino acids include, for example, the twenty most common levorotatory (L,) amino acids normally found in mammalian proteins, i.e., alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (He), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan, (Trp), tyrosine (Tyr), and valine (Val).
  • L levorotatory amino acids normally found in mammalian proteins
  • alanine (Ala) amino acids normally found in mammalian proteins i.e., alanine (Ala), arginine (Arg), asparag
  • amino acids include, for example, amino acids that are synthesized in metabolic processes not associated with protein synthesis.
  • amino acids ornithine and citrulline are synthesized in mammalian metabolism during the production of urea.
  • the peptides useful in the present technology can contain one or more non-naturally occurring amino acids.
  • the non-naturally occurring amino acids may be (L-), dextrorotatory (D-), or mixtures thereof.
  • the peptide has no amino acids that are naturally occurring.
  • Non-naturally occurring amino acids are those amino acids that typically are not synthesized in normal metabolic processes in living organisms, and do not naturally occur in proteins.
  • the non-naturally occurring amino acids useful in the present technology are also not recognized by common proteases.
  • the non-naturally occurring amino acid can be present at any position in the peptide.
  • the non-naturally occurring amino acid can be at the N terminus, the C-terminus, or at any position between the N-terminus and the C-terminus.
  • the non-natural amino acids may, for example, comprise alkyl, aryl, or alkylaryl groups.
  • alkyl amino acids include a-aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminovaleric acid, and ⁇ -aminocaproic acid.
  • aryl amino acids include ortho-, meta, and para-aminobenzoic acid.
  • alkylaryl amino acids include ortho-, meta-, and para-aminophenyl acetic acid, and ⁇ -phenyl- ⁇ -aminobutyric acid.
  • Non-naturally occurring amino acids also include derivatives of naturally occurring amino acids.
  • the derivatives of naturally occurring amino acids may, for example, include the addition of one or more chemical groups to the naturally occurring amino acid.
  • one or more chemical groups can be added to one or more of the 2', 3', 4', 5', or 6' position of the aromatic ring of a phenylalanine or tyrosine residue, or the 4', 5', 6', or 7' position of the benzo ring of a tryptophan residue.
  • the group can be any chemical group that can be added to an aromatic ring.
  • Some examples of such groups include branched or unbranched C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, or t-butyl, C 1 -C 4 alkyloxy (i.e., alkoxy), amino, C 1 -C 4 alkylamino and C 1 -C 4 dialkylamino (e.g., methylamino, dimethylamino), nitro, hydroxyl, halo (i.e., fluoro, chloro, bromo, or iodo).
  • Some specific examples of non-naturally occurring derivatives of naturally occurring amino acids include norvaline (Nva), norleucine (Nle), and hydroxyproline (Hyp).
  • Another example of a modification of an amino acid in a peptide useful in the present methods is the derivatization of a carboxyl group of an aspartic acid or a glutamic acid residue of the peptide.
  • derivatization is amidation with ammonia or with a primary or secondary amine, e.g., methylamine, ethylamine, dimethylamine or diethylamine.
  • Another example of derivatization includes esterification with, for example, methyl or ethyl alcohol.
  • Another such modification includes derivatization of an amino group of a lysine, arginine, or histidine residue.
  • amino groups can be acylated.
  • suitable acyl groups include, for example, a benzoyl group or an alkanoyl group comprising any of the C 1 -C4 alkyl groups mentioned above, such as an acetyl or propionyl group.
  • the non-naturally occurring amino acids are resistant, and in some embodiments insensitive, to common proteases.
  • non-naturally occurring amino acids that are resistant or insensitive to proteases include the dextrorotatory (D-) form of any of the above-mentioned naturally occurring L-amino acids, as well as L- and/or D non- naturally occurring amino acids.
  • D-amino acids do not normally occur in proteins, although they are found in certain peptide antibiotics that are synthesized by means other than the normal ribosomal protein synthetic machinery of the cell, as used herein, the D-amino acids are considered to be non-naturally occurring amino acids.
  • the peptides useful in the methods of the present technology should have less than five, less than four, less than three, or less than two contiguous L-amino acids recognized by common proteases, irrespective of whether the amino acids are naturally or non-naturally occurring.
  • the peptide has only D-amino acids, and no L-amino acids.
  • the peptide contains protease sensitive sequences of amino acids, at least one of the amino acids is a non-naturally-occurring D-amino acid, thereby conferring protease resistance.
  • An example of a protease sensitive sequence includes two or more contiguous basic amino acids that are readily cleaved by common proteases, such as endopeptidases and trypsin. Examples of basic amino acids include arginine, lysine and histidine.
  • the aromatic-cationic peptides have a minimum number of net positive charges at physiological pH in comparison to the total number of amino acid residues in the peptide.
  • the minimum number of net positive charges at physiological pH is referred to below as (p m ).
  • the total number of amino acid residues in the peptide is referred to below as (r).
  • physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
  • physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
  • physiological pH of a human is normally approximately 7.4, but normal physiological pH in mammals may be any pH from about 7.0 to about 7.8.
  • a peptide has a positively charged N-terminal amino group and a negatively charged C-terminal carboxyl group. The charges cancel each other out at physiological pH.
  • the peptide Tyr-Arg-Phe-Lys- Glu-His-Trp-Arg has one negatively charged amino acid (i.e., Glu) and four positively charged amino acids (i.e., two Arg residues, one Lys, and one His). Therefore, the above peptide has a net positive charge of three.
  • the aromatic-cationic peptides have a relationship between the minimum number of net positive charges at physiological pH (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1.
  • the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
  • the aromatic-cationic peptides have a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 2p m is the largest number that is less than or equal to r + 1.
  • the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
  • the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) are equal.
  • the peptides have three or four amino acid residues and a minimum of one net positive charge, or a minimum of two net positive charges, or a minimum of three net positive charges.
  • aromatic-cationic peptides have a minimum number of aromatic groups in comparison to the total number of net positive charges (p t ).
  • the minimum number of aromatic groups will be referred to below as (a).
  • Naturally-occurring amino acids that have an aromatic group include the amino acids histidine, tryptophan, tyrosine, and phenylalanine.
  • the hexapeptide Lys-Gln-Tyr-D-Arg-Phe-Trp has a net positive charge of two (contributed by the lysine and arginine residues) and three aromatic groups (contributed by tyrosine, phenylalanine and tryptophan residues).
  • the aromatic-cationic peptides should also have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges at physiological pH (p t ) wherein 3 a is the largest number that is less than or equal to p t + 1, except that when p t is 1 , a may also be 1.
  • the relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) is as follows:
  • the aromatic-cationic peptides have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a is the largest number that is less than or equal to p t + 1.
  • the number of aromatic groups (a) and the total number of net positive charges (pt) are equal.
  • carboxyl groups are amidated with, for example, ammonia to form the C-terminal amide.
  • the terminal carboxyl group of the C-terminal amino acid may be amidated with any primary or secondary amine.
  • the primary or secondary amine may, for example, be an alkyl, especially a branched or unbranched C1-C4 alkyl, or an aryl amine.
  • amino acid at the C-terminus of the peptide may be converted to an amido, N-methylamido, N-ethylamido, N,N-dimethylamido, ⁇ , ⁇ -diethyl amido, N-methyl-N- ethylamido, N-phenylamido or N-phenyl-N-ethylamido group.
  • the free carboxylate groups of the asparagine, glutamine, aspartic acid, and glutamic acid residues not occurring at the C-terminus of the aromatic-cationic peptides of the present technology may also be amidated wherever they occur within the peptide.
  • the amidation at these internal positions may be with ammonia or any of the primary or secondary amines described herein.
  • the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and at least one aromatic amino acid.
  • the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and two aromatic amino acids.
  • Aromatic-cationic peptides useful in the methods of the present technology include, but are not limited to, the following peptide examples:
  • the aromatic-cationic peptide is a peptide having:
  • 2p m is the largest number that is less than or equal to r+1, and a may be equal to p t .
  • the aromatic-cationic peptide may be a water-soluble peptide having a minimum of two or a minimum of three positive charges.
  • the peptide comprises one or more non-naturally occurring amino acids, for example, one or more D-amino acids.
  • the C-terminal carboxyl group of the amino acid at the C-terminus is amidated.
  • the peptide has a minimum of four amino acids. The peptide may have a maximum of about 6, a maximum of about 9, or a maximum of about 12 amino acids.
  • the peptides have a tyrosine residue or a tyrosine derivative at the N-terminus (i.e., the first amino acid position).
  • Suitable derivatives of tyrosine include 2'- methyltyrosine (Mmt); 2',6'-dimethyltyrosine (2'6'-Dmt); 3 ',5 '-dimethyltyrosine (3'5'Dmt); N,2',6'-trimethyltyrosine (Tmt); and 2'-hydroxy-6'-methyltyrosine (Hmt).
  • a peptide has the formula Tyr-D-Arg-Phe-Lys-NH 2 .
  • Tyr-D- Arg-Phe-Lys-NH 2 has a net positive charge of three, contributed by the amino acids tyrosine, arginine, and lysine and has two aromatic groups contributed by the amino acids
  • the tyrosine of Tyr-D-Arg-Phe-Lys-NH 2 can be a modified derivative of tyrosine such as in 2',6'-dimethyltyrosine to produce the compound having the formula 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 .
  • 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 has a molecular weight of 640 and carries a net three positive charge at physiological pH.
  • the aromatic-cationic peptide does not have a tyrosine residue or a derivative of tyrosine at the N-terminus (i.e., amino acid position 1).
  • the amino acid at the N-terminus can be any naturally-occurring or non-naturally-occurring amino acid other than tyrosine.
  • the amino acid at the N-terminus is phenylalanine or its derivative.
  • Exemplary derivatives of phenylalanine include 2'- methylphenylalanine (Mmp), 2',6'-dimethylphenylalanine (2',6'-Dmp), N,2',6'- trimethylphenylalanine (Tmp), and 2'-hydroxy-6'-methylphenylalanine (Hmp).
  • an aromatic-cationic peptide that does not have a tyrosine residue or a derivative of tyrosine at the N-terminus is a peptide with the formula Phe-D-Arg-Phe-Lys- NH 2 .
  • the N-terminal phenylalanine can be a derivative of phenylalanine such as 2',6'-dimethylphenylalanine (2'6'-Dmp).
  • the amino acid sequence of 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 is rearranged such that Dmt is not at the N-terminus.
  • An example of such an aromatic-cationic peptide is a peptide having the formula of D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • Suitable substitution variants of the peptides listed herein include conservative amino acid substitutions.
  • Amino acids may be grouped according to their physicochemical characteristics as follows:
  • Non-polar amino acids Ala(A) Ser(S) Thr(T) Pro(P) Gly(G) Cys (C);
  • Aromatic amino acids Phe(F) Tyr(Y) Trp(W) His (H).
  • substitutions of an amino acid in a peptide by another amino acid in the same group are referred to as a conservative substitution and may preserve the physicochemical characteristics of the original peptide.
  • substitutions of an amino acid in a peptide by another amino acid in a different group are generally more likely to alter the
  • Examples of peptides that have a tyrosine residue or a tyrosine derivative at the N- terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 6.
  • Tmt N, 2',6'-trimethyltyrosine
  • Examples of peptides that do not have a tyrosine residue or a tyrosine derivative at the N-terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 7. TABLE 7. Peptide Analogs Lacking Mu-Opioid Activity

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Abstract

La présente invention concerne des méthodes et des compositions pour le traitement et/ou la prévention de maladies ou d'états pathologiques consistant à administrer des composés chromanyle, et/ou des dérivés, des analogues, des stéréoisomères, des tautomères, des solvates et des sels pharmaceutiquement acceptables de ceux-ci, d'origine naturelle ou artificielle, seuls ou en association avec un ou plusieurs agents actifs (par exemple un peptide aromatique-cationique). La présente technologie fournit des compositions associées à des peptides aromatiques-cationiques liés à des composés chromanyle ou à des dérivés, des analogues, des stéréoisomères, des tautomères, des solvates et des sels pharmaceutiquement acceptables de ceux-ci, et des utilisations de celles-ci. Dans certains modes de réalisation, le peptide aromatique-cationique comprend le D-Arg-2'6'-Dmt-Lys-Phe-NH2.
PCT/US2015/032440 2015-05-26 2015-05-26 Compositions thérapeutiques comprenant des composés chromanyle, des variants et des analogues associés, et leurs utilisations Ceased WO2016190852A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019070917A1 (fr) * 2017-10-03 2019-04-11 The Schepens Eye Research Institute, Inc. Composés et compositions pour inhiber la dégénérescence de l'épithélium pigmentaire rétinien et procédés les utilisant
WO2023023256A1 (fr) * 2021-08-18 2023-02-23 Oculogenex Inc. Transfert de gènes médié par aav pour une rétinopathie

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US20040259763A1 (en) * 2000-07-12 2004-12-23 Maria Koufaki Bifunctional agents possessing antioxidant and antiarrhythmic activity
US20060193797A1 (en) * 2005-02-25 2006-08-31 Galileo Pharmaceuticals, Inc Chroman derivatives as lipoxygenase inhibitors
WO2010106209A1 (fr) * 2009-03-20 2010-09-23 Consejo Superior De Investigaciones Científicas (Csic) Utilisation d'un composé pour le traitement d'une lésion produite par une reperfusion post-ischémique
US20110136898A1 (en) * 2008-08-05 2011-06-09 University College Cork, National University Of Ireland, Cork Treatment of retinal degeneration
US20110280805A1 (en) * 2008-10-31 2011-11-17 Neurodyn, Inc. Neurotoxic sterol glycosides
US20130158106A1 (en) * 2010-06-02 2013-06-20 The United States Of America As Represented By The Department Of Veteran Affairs Tocopherol derivatives and methods of use
US20130303436A1 (en) * 2012-12-06 2013-11-14 Stealth Peptides Internatioanl, Inc. Peptide therapeutics and methods for using same
WO2014011047A1 (fr) * 2012-07-12 2014-01-16 Khondrion B.V. Dérivés de chromanyle destinés au traitement de la maladie mitochondriale
WO2014022552A1 (fr) * 2012-08-02 2014-02-06 Stealth Peptides International, Inc. Methodes de traitement de l'atherosclerose

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US20040259763A1 (en) * 2000-07-12 2004-12-23 Maria Koufaki Bifunctional agents possessing antioxidant and antiarrhythmic activity
US20030187059A1 (en) * 2002-02-22 2003-10-02 Levin Robert M. Methods and compounds useful in inhibiting oxidative and/or free radical damage and in the treatment and prevention of disease
US20060193797A1 (en) * 2005-02-25 2006-08-31 Galileo Pharmaceuticals, Inc Chroman derivatives as lipoxygenase inhibitors
US20110136898A1 (en) * 2008-08-05 2011-06-09 University College Cork, National University Of Ireland, Cork Treatment of retinal degeneration
US20110280805A1 (en) * 2008-10-31 2011-11-17 Neurodyn, Inc. Neurotoxic sterol glycosides
WO2010106209A1 (fr) * 2009-03-20 2010-09-23 Consejo Superior De Investigaciones Científicas (Csic) Utilisation d'un composé pour le traitement d'une lésion produite par une reperfusion post-ischémique
US20130158106A1 (en) * 2010-06-02 2013-06-20 The United States Of America As Represented By The Department Of Veteran Affairs Tocopherol derivatives and methods of use
WO2014011047A1 (fr) * 2012-07-12 2014-01-16 Khondrion B.V. Dérivés de chromanyle destinés au traitement de la maladie mitochondriale
WO2014022552A1 (fr) * 2012-08-02 2014-02-06 Stealth Peptides International, Inc. Methodes de traitement de l'atherosclerose
US20130303436A1 (en) * 2012-12-06 2013-11-14 Stealth Peptides Internatioanl, Inc. Peptide therapeutics and methods for using same

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019070917A1 (fr) * 2017-10-03 2019-04-11 The Schepens Eye Research Institute, Inc. Composés et compositions pour inhiber la dégénérescence de l'épithélium pigmentaire rétinien et procédés les utilisant
US11260048B2 (en) 2017-10-03 2022-03-01 The Schepens Eye Research Institute, Inc. Compounds and compositions for inhibiting retinal pigment epithelium degeneration and methods using the same
WO2023023256A1 (fr) * 2021-08-18 2023-02-23 Oculogenex Inc. Transfert de gènes médié par aav pour une rétinopathie

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