WO2016200364A1 - Compositions thérapeutiques contenant des composés skq et leurs utilisations - Google Patents

Compositions thérapeutiques contenant des composés skq et leurs utilisations Download PDF

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Publication number
WO2016200364A1
WO2016200364A1 PCT/US2015/034673 US2015034673W WO2016200364A1 WO 2016200364 A1 WO2016200364 A1 WO 2016200364A1 US 2015034673 W US2015034673 W US 2015034673W WO 2016200364 A1 WO2016200364 A1 WO 2016200364A1
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substituted
unsubstituted
carbon
alkyl
phe
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PCT/US2015/034673
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English (en)
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D. Travis Wilson
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Stealth Peptides International, Inc.
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Priority to PCT/US2015/034673 priority Critical patent/WO2016200364A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C07K5/06095—Arg-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B11/00—Diaryl- or thriarylmethane dyes
    • C09B11/04—Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
    • C09B11/10—Amino derivatives of triarylmethanes
    • C09B11/24—Phthaleins containing amino groups ; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B57/00—Other synthetic dyes of known constitution

Definitions

  • Disclosed herein are methods and compositions related to the treatment and/or amelioration of diseases and conditions comprising administration of SkQ compounds and/or naturally or artificially occurring derivatives, analogues, or 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 an SkQ compound 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 I:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R8 is a quaternary phosphonium, quaternary ammonium, or iminium group
  • Z " is a counterion
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula II:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R 9 at each occurrence independently is a substituted or unsubstituted Ci-C 6 alkyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a composition comprising Formula III:
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Rio and Rn independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C6 alkynyl group;
  • Ri2, Ri3, and Ri 4 independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C6 alkynyl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 . 0008]
  • the present disclosure provides a composition comprising Formula
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R9, Rio, and Rn independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a composition comprising Formula V:
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted C C 6 alkyl, C 2 -C 6
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Rio and R i3 independently are H, F, CI, Br, NR a R a , OR a , C ⁇ N, a substituted or
  • Ci-C 6 alkyl C 2 -C6 alkenyl, or C 2 -C6 alkynyl group
  • R11 and R i2 independently are H, F, CI, Br, NR b R b , OR b , C ⁇ N, C(0)OR b , phosphoric acid, sulfonic acid, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C6 alkynyl group;
  • Ri5 is O, S, N, or C
  • Ri6 and Ri7 independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, sulfonic acid, or absent;
  • Rig and Rig independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 alkynyl, aryl, or aralkyl group;
  • Ri 4 , R 2 o, R21, R 23 , R 24 , R 2 5, and R 26 independently are H, a substituted or unsubstituted
  • Ci-C 6 alkyl C 2 -C6 alkenyl, C 2 -C6 alkynyl, or sulfonic acid
  • Ri 8 and R 24 independently are CR b R b and linked together by 0-2 carbon atoms;
  • R 22 is O, S, or Se
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion; 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula VI:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and P 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Rio and Rn independently are H, F, CI, Br, a substituted or unsubstituted Ci-C 6 alkyl,
  • R12, Ri3, Ri4, Ri5, Rn, Ri8, Ri9, R 2 o, R 21 , R 22 , R 2 3, and R 24 independently are H, F, CI,
  • Ri3 and R14 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted C1-C2 alkyl group,
  • Rn and Ri8 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted C1-C2 alkyl group,
  • Rig and Rig are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted C1-C2 alkyl group, or any combination thereof;
  • Ri6 is a substituted or unsubstituted C1-C12 alkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C3-
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula VII:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, and R4 independently are H, F, CI, Br, OR a , NR b R b , a substituted or
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • R8 is a quaternary phosphonium, quaternary ammonium, or iminium group
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a composition comprising Formula VIII:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, andR 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • R 9 at each occurrence independently is a substituted or unsubstituted Ci-C 6 alkyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a composition comprising Formula
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R 3 , R4, and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C6 alkynyl group;
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • Rio and Rn independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C 6 alkynyl group;
  • R12, Ri3, and R14 independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C6 alkynyl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; R at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group;
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula X:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , P3, P , and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • R9, Rio, and Rn independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a composition comprising Formula
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , P3, P , and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • Re and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • Rio and R i3 independently are H, F, CI, Br, NR a R a , OR a , C ⁇ N, a substituted or
  • R11 and R i2 independently are H, F, CI, Br, NR b R b , OR b , C ⁇ N, C(0)OR b , phosphoric acid, sulfonic acid, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C6 alkynyl group;
  • Ri5 is O, S, N, or C
  • Ri6 and Ri7 independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 alkynyl, sulfonic acid, or absent;
  • Rig and Rig independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, aryl, or aralkyl group;
  • Ri4, R 2 o, R21, R 23 , R 2 4, R 2 5, and R 26 independently are H, a substituted or unsubstituted
  • Ci-C 6 alkyl C 2 -C6 alkenyl, C 2 -C6 alkynyl, or sulfonic acid
  • Rig and R 24 independently are CR b R b and linked together by 0-2 carbon atoms;
  • R 22 is O, S, or Se
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XII:
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • Rio and Rn independently are H, F, CI, Br, a substituted or unsubstituted Ci-C 6 alkyl,
  • R12, Ri3, Ri4, Ri5, Rn, Ri8, Ri9, R 2 o, R 21 , R 22 , R 2 3, and R 24 independently are H, F, CI,
  • Ri3 and R14 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted C1-C2 alkyl group, Ri7 and Ris are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted C1-C2 alkyl group,
  • Ris and Ri9 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group, or any combination thereof;
  • Ri6 is a substituted or unsubstituted C1-C12 alkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C3-
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XIII:
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 at each occurrence independently is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • Rg is a quaternary phosphonium, quaternary ammonium, or iminium group
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XIV:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 at each occurrence independently is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • R 9 at each occurrence independently is a substituted or unsubstituted Ci-C 6 alkyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion; 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XV:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and P4 independently are O, S, NR b , or absent;
  • R 5 at each occurrence independently is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • Rio and Rn independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group;
  • R12, Ri3, and R14 independently are a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, or C 2 -C 6 alkynyl group;
  • R a at each occurrence is independently H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence is independently H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XVI:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 at each occurrence independently is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • R9, Rio, and Rn independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, cycloalkyl, or aryl group;
  • R a at each occurrence is independently H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence is independently H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion; and 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XVII:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and P 4 independently are O, S, NR b , or absent;
  • R 5 at each occurrence independently is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group;
  • 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • Rio and R i3 independently are H, F, CI, Br, NR a R a , OR a , C ⁇ N, a substituted or
  • R11 and R i2 independently are H, F, CI, Br, NR b R b , OR b , C ⁇ N, C(0)OR b , phosphoric acid, sulfonic acid, a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group;
  • Ri5 is O, S, N, or C
  • Ri6 and Ri7 independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, sulfonic acid, or absent;
  • Rig and Rig independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or aralkyl group;
  • Ri4, R 2 o, R21, R 23 , R 2 4, R 2 5, and R 26 independently are H, a substituted or unsubstituted
  • Ci-C 6 alkyl C2-C6 alkenyl, C2-C6 alkynyl, or sulfonic acid
  • Rig and R24 independently are CR b R b and linked together by 0-2 carbon atoms;
  • R22 is O, S, or Se
  • R a at each occurrence is independently H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence is independently H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 .
  • composition comprising Formula XVIII:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 at each occurrence independently is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • Rio and Rn independently are H, F, CI, Br, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • Ri3 and Ri 4 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group,
  • Ri7 and Ris are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group,
  • Ris and R19 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted C1-C2 alkyl group, or any combination thereof;
  • Ri6 is a substituted or unsubstituted C1-C12 alkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C 3 -
  • R a at each occurrence is independently H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence is independently H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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
  • SkQ* collectively refers to derivatives, variants or analogues of the SkQ compounds of the present technology, such as but not limited to as Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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.
  • an ophthalmic disease or condition such as dry eye, diabetic retinopathy, cataracts, retinitis pigmentosa
  • 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or 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 SkQ
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl- Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe- D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl- Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys- NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl- Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl- Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 ,Phe-D-Arg-Phe-Lys-NH 2 , or 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 SkQ compounds and/or SkQ*, 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 . .
  • the composition comprises SkQ compounds and/or SkQ*. [0047] In some embodiments, 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.
  • the present technology provides compositions comprising an aromatic-cationic peptide of the present technology conjugated to an SkQ compound and/or SkQ*as well as methods for their use. Such molecules are referred to hereinafter as "peptide conjugates.” At least one SkQ compound and/or SkQ*and at least one aromatic-cationic peptide associate to form a peptide conjugate.
  • the SkQ compound and/or SkQ*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-SkQ compound
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-SkQ compound
  • the type of association between the SkQ compound and/or SkQ* and aromatic- cationic peptides typically depends on, for example, functional groups available on the SkQ compound and/or SkQ* 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 SkQ compound and/or SkQ* conjugated to an aromatic-cationic peptide, wherein the aromatic- cationic peptide is selected from the group consisting of: 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys- NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 , or any peptide described in Section II; and wherein the SkQ compound and/or SkQ* is a compound described in Section I.
  • the SkQ compound and/or SkQ* is conjugated to the aromatic-cationic peptide by a linker.
  • the SkQ compound and/or SkQ* and aromatic-cationic peptide are chemically bonded.
  • the SkQ compound and/or SkQ* and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the SkQ compound and/or SkQ* are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic- cationic peptide and the SkQ compound and/or SkQ*.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for delivering an aromatic-cationic peptide and/or SkQ compound and/or SkQ* to a cell, the method comprising contacting the cell with a peptide conjugate, wherein the peptide conjugate comprises the SkQ compound and/or SkQ* conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: 2 ',6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 , or any peptide described in Section II; and wherein the SkQ compound and/or SkQ* is a compound described in Section I.
  • the SkQ compound and/or SkQ* is conjugated to the aromatic-cationic peptide by a linker.
  • the SkQ compound and/or SkQ* and aromatic-cationic peptide are chemically bonded.
  • the SkQ compound and/or SkQ* and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the SkQ compound and/or SkQ* are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the SkQ compound and/or SkQ*.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for treating,
  • 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 an SkQ compound and/or SkQ*.
  • the present technology provides methods for treating,
  • 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.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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 an SkQ compound and/or SkQ*.
  • 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
  • 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 , and R 11 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 an SkQ compound and/or SkQ*.
  • 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 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or 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 an SkQ compound and/or SkQ* 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 an SkQ compound and/or SkQ* containing a pendant OH group.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to an SkQ compound and/or SkQ*.
  • Such molecules are referred to hereinafter as peptide conjugates.
  • At least one SkQ compound and/or SkQ*as described in Section I and at least one aromatic-cationic peptide as described in Section II associate to form a peptide conjugate.
  • the SkQ compound and/or SkQ* 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-SkQ compound
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-SkQ compound
  • the type of association between the SkQ compound and/or SkQ* and aromatic- cationic peptides typically depends on, for example, functional groups available on the SkQ compound and/or SkQ* 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 term "about” encompasses the range of experimental error that may occur in a measurement and will be clear to the skilled artisan.
  • 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.
  • Aliphatic refers to non-aromatic compounds.
  • Aliphatic compounds include straight-chained, branched, and non-aromatic rings.
  • Aliphatic compounds include alkyl, alkenyl, and alkynyl groups and may include atoms other than carbon and hydrogen.
  • aliphatic compounds may include oxygen, nitrogen, sulfur, or halogen atoms.
  • Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, e.g., from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1, 2, 3, 4, 5, or 6 carbon atoms.
  • 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. Representative 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, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.
  • (Ci-C 6 )alkyl refer, unless otherwise provided, to any straight or branched Ci-C 6 alkyl group, hence comprehensive of a “(Ci-C4)alkyl” group and 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, 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 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 may be substituted or unsubstituted. Representative substituted alkenyl 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.
  • 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, 2 to 5, 2 to 4, or 2, 3, 4, 5, or 6 carbon atoms.
  • the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to - C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CCH 3 , -C ⁇ CCH 2 CH(CH 2 CH 3 ) 2 , among others.
  • 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.
  • amidine refers to -C(NR°)NR p R q and -NR°C(NR p )R q , wherein R°, R p , and R q are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • 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.
  • 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, 5-8, or 6, 7, 8, 9, or 10 carbon atoms in the ring portions of the groups. In some embodiments, 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 -C 6 H 5 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, tetrahydrona
  • 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.
  • 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, 7 to 8, or 7, 8, 9, or 10 carbon atoms.
  • 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.
  • Representative substituted and unsubstituted alkaryl groups include but are not limited to alkylphenyl such as methylphenyl,
  • 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.
  • carbonyl or "oxo" as used herein, when alone includes formyl [-C(0)H] and in combination is a -C(O)- group.
  • carboxyl refers to a -C(0)OH group or to its ionized form, -C(0)0-.
  • control is an alternative sample used in an experiment for comparison purpose.
  • a control can be "positive” or “negative.”
  • a positive control a compound or composition known to exhibit the desired therapeutic effect
  • a negative control a subject or a sample that does not receive the therapy or receives a placebo
  • 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.
  • esteer refers to -C(0)OR a groups.
  • R a is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • guanidine refers to -NR r C(NR s )NR l R u , wherein R r , R s , R l and R u are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • halogen refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • 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.
  • hydrazine refers to -NR NR gg R groups where R , R gg , and R hh are each independently selected from H or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • hydroxyl as used herein can refer to -OH or its ionized form, -0-.
  • imide refers to -C(0)NR bb C(0)R cc , wherein R bb and R cc 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 dd (NR ee ) and -N(CR dd R ee ) groups, wherein R dd and R ee 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 dd and R ee are not both simultaneously hydrogen.
  • Iminium groups include any of a class of salts derived from iminium, wherein the nitrogen atom is attached to three groups.
  • the three groups include single bonds to one organic group and a hydrogen or two independent organic groups, and a double bond to a third independent organic group.
  • organic groups may include groups having from 10 to 35 carbon atoms, e.g., from 12 to 30, 14 to 28, 15 to 26, 18 to 25, or 20 to 24, carbon atoms.
  • Organic groups may include aliphatic and aromatic groups including groups containing fused rings.
  • Organic groups also include substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups, or combinations thereof.
  • Representative organic groups include, but are not limited to, rhodamine, berberine, palmatine, and derivatives thereof.
  • 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.
  • Such 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.
  • nitrile or "cyano” as used herein refers to the -CN group.
  • nitro refers to an -N0 2 group.
  • 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
  • Quaternary phosphonium groups include any of a class of salts derived from phosphonium, wherein the phosphorus atom is attached to four independent organic groups such as substituted or unsubstituted alkyl, cycloalkyl, or aryl groups as defined above.
  • organic groups include, but are not limited to, n-dodecyl, n-decyl, n-octyl, n- hexyl, n-butyl, tetramethyldecyl, tetraethyldecyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, biphenyl, methylphenyl, methoxyphenyl, or aminophenyl.
  • three of the organic groups may be aryl groups, e.g., triphenylphosphonium.
  • Quaternary ammonium groups include any of a class of salts derived from ammonium, wherein the nitrogen atom is attached to four independent organic groups such as substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or aryl groups as defined above.
  • Organic groups include, but are not limited to, carnitine, n- dodecyl, n-decyl, n-octyl, n-hexyl, n-butyl, tetramethyldecyl, tetraethyldecyl, decenyl, hexenyl, decynyl, hexynyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, biphenyl, methylphenyl, methoxyphenyl, or aminophenyl.
  • three of the four organic groups may be Ci-C 6 alkyl groups, e.g., tributylammonium and trimethylammonium.
  • the quaternary ammonium group is a carnitine derivative.
  • 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.
  • SkQ compound includes at least an oxidized or reduced quinone derivative that is conjugated to a membrane penetrating cation via a linker.
  • Quinone derivatives include Coenzyme Q (ubiquinone), demethoxyubiquinone, plastoquinone, methylplastoquinone, vitamin K ls vitamin E, and structural analogs thereof that retain the antioxidant activity of a quinone itself (“quinone derivatives").
  • Membrane penetrating cations include phosphonium derivatives and cationic nitrogen derivatives, such as, alkyltriphenylphosphonium, quaternary ammoniums and iminiums, methylcarnitine,
  • SkQ* collectively refers to derivatives, variants or analogues of the SkQ compounds of the present technology, such as but not limited to as Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof.
  • 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 terms "subject,” “individual,” or “patient” can be an individual organism, a vertebrate, a mammal, or a human.
  • sulfonamido includes S- and N-sulfonamide groups, i.e., -S0 2 NR f R g and -NR f S0 2 R g groups, respectively.
  • R f and R g 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.
  • 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.
  • thiol refers to -SH groups
  • sulfides include -SR h groups
  • sulfoxides include -S(0)R' groups
  • sulfones include -S0 2 R J groups
  • sulfonyls include - S0 2 OR k R h , R R j , and R k 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
  • 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.
  • urea refers to -NR 1 -C(0)-NR m R n groups.
  • R 1 , R m , and R n groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • Urethane groups include N- and O-urethane groups, i.e., -NR b C(0)OR c and
  • R b and R c are independently a substituted or
  • R b may also be H.
  • 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.
  • SkQ compounds comprise a quinone derivative conjugated with a membrane penetrating cation.
  • the quinone derivative of the SkQ compound is conjugated with a membrane penetrating cation via a linker.
  • the quinone derivative of the SkQ compound is conjugated with a membrane penetrating cation via an alkyl residue on the linker.
  • the SkQ compound comprises an aliphatic -(CH 2 ) n linker that conjugates the quinone derivative of the SkQ compound to a membrane penetrating cation, wherein n is 4 to 12.
  • the SkQ compound comprises an aliphatic decyl linker that links the quinone derivative of the SkQ compound to a membrane penetrating cation. In some embodiments, the SkQ compound comprises an aliphatic pentyl linker that links the quinone derivative of the SkQ compound to a membrane penetrating cation.
  • the length of the aliphatic linker in the SkQ compound is chosen based on its octanol: water distribution coefficient.
  • the octanol: water distribution coefficients are estimated using a method based on correlation of this parameter with retention time in a reversed-phase high performance liquid chromatography (HPLC) column. See Lombardo F. et al., J Med Chem. 44:2490-7 (2001).
  • the length of the aliphatic linker of the SkQ compound is chosen based on an octanol: water distribution ratio of at least 500:1, at least 1000:1, at least 2000:1, at least 2100:1, at least 2200:1, at least 2300:1, at least 2400:1, at least 2500:1, at least 2600:1, at least 2700:1, at least 2800:1, at least 2900:1, at least 3000:1, at least 4000:1, at least 5000:1, at least 6000:1, at least 7000:1, at least 8000:1, at least 9000:1, at least 10,000:1, at least 11,000:1, at least 12,000:1, or at least 13000:1.
  • the quinone derivative of the SkQ compound is selected from the group consisting of Coenzyme Q (ubiquinone), demethoxyubiquinone, plastoquinone, methylplastoquinone, vitamin K ls vitamin E and derivatives or analogues thereof.
  • the quinone derivative of the SkQ compound is ubiquinone. In some embodiments, the quinone derivative of the SkQ compound is
  • the quinone derivative of the SkQ compound is plastoquinone. In some embodiments, the quinone derivative of the SkQ compound is methylplastoquinone. In some embodiments, the quinone derivative of the SkQ compound is vitamin Ki. In some embodiments, the quinone derivative of the SkQ compound is vitamin E. In another embodiment, the quinone derivative of the SkQ compound is a redox-active /?ara-benzoquinone.
  • the membrane penetrating cation of the SkQ compound can be naturally occurring or synthesized.
  • the membrane penetrating cation of the SkQ compound is a cationic plant alkaloid.
  • the membrane penetrating cation of the SkQ compound is an isoquinoline alkaloid derived from plants of the
  • the membrane penetrating cation of the SkQ compound is berberine or a metabolite, analogue, or derivative thereof. In other embodiments, the membrane penetrating cation of the SkQ compound is palmatine or a metabolite, analogue, or derivative thereof.
  • the membrane penetrating cation of the SkQ compound comprises a phosphonium derivative.
  • the membrane penetrating cation of the SkQ compound is alkyltriphenylphosphonium (or an analogue or derivative thereof).
  • the membrane penetrating cation of the SkQ compound comprises an ionized nitrogen atom.
  • the membrane penetrating cation of the SkQ compound is methylcarnitine (or an analogue or derivative thereof).
  • the membrane penetrating cation of the SkQ compound is tributylammonium (or an analogue or derivative thereof).
  • the membrane penetrating cation of the SkQ compound is Rhodamine 19 (or an analogue or derivative thereof).
  • the membrane penetrating cation of the SkQ compound is fluorescent.
  • the membrane penetrating cation of the SkQ compound is selected from the group consisting of alkyl triphenylphosphonium, methylcarnitine, tributylammonium, Rhodamine 19, berberine, palmatine, and a metabolite, analogue, or derivative thereof.
  • SkQ compounds of the present technology include SkQ compounds selected from the group consisting of SkQ 1, SkQ2M, SkQ3, SkQ4, SkQ5, SkQRl, MitoQ, and DMQ.
  • an SkQ compound of the present technology is SkQBer having the following structure:
  • SkQl is 10-(6'-plastoquinonyl) decyltriphenylphosphonium
  • SkQ2M is methylated 10-(6'-plastoquinonyl) decylcarnitine
  • SkQ3 is 10-(6'-methylplastoquinonyl) decyltriphenylphosphonium
  • SkQ4 is 10-(6'-plastoquinonyl) decyltributylammonium
  • SkQ5 is 5-(6'-plastoquinonyl) amyltriphenylphosphonium
  • SkQRl is lO-(plastoquinonyl) decylrhodamine 19;
  • MitoQ is 10-(6-ubiquinonyl) decyltriphenylphosphonium
  • DMQ is a demethoxy-derivative of ubiquinone lacking one of the two methoxy groups
  • SkQBer is 13-[9-(4,5-dimethyl-3,6-dioxocyclohexa-l,4-dien-l-yl)nonyloxycarbonyl- methyljberberine;
  • SkQPalm is 13-[9-(4,5-dimethyl-3,6-dioxocyclohexa-l,4-dien-l- yl)nonyloxycarbonyl-methyl]palmatine.
  • the SkQ compounds accumulate in the inner mitochondrial membrane.
  • the SkQ compounds are able to penetrate through planar phospholipid bilayer membranes (BLM).
  • the concentration gradients of the SkQ compounds generate Nernst diffusion potential with the "plus" sign in the compartment with the lower concentration of the (membrane penetrating) cation in the range of 5 x 1(T 12 - 5 x 1(T 10 M, 5 x ⁇ 11 - 5 x 10 9 M, 5 x 1(T 10 - 5 x 1(T 8 M, 5 x 1(T 8 - 5 x 1(T 6 M, 5 x 1(T 6 - 5 x 10 5 M, 5 x 1(T 6 - 5 x 10 4 M, or 5 x 10 5 - 5 x 10 4 M.
  • the SkQ compounds of the present technology are reduced by the mitochondrial respiratory chain to SkQH 2 .
  • the rate of oxidation of SkQH2 is lower than the rate of SkQ reduction.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • P i and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R8 is a quaternary phosphonium, quaternary ammonium, or iminium group
  • Z " is a counterion
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted C C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R 9 at each occurrence independently is a substituted or unsubstituted Ci-C 6 alkyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 3 , and R 5 independently are H or a substituted or unsubstituted Ci-C 6 alkyl
  • R 2 and R 4 independently are O or absent
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • R 9 at each occurrence independently is a substituted or unsubstituted aryl group; n is from 4-6; and
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R3, and R 5 independently are H or methyl
  • R 2 and R 4 independently are O or absent
  • Re and R 7 at each occurrence are H;
  • R 9 at each occurrence is a phenyl group
  • n 5;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl, or C2-C6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Rio and Rn independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group;
  • R12, Ri3, and Ri 4 independently are a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, or C 2 -C 6 alkynyl group;
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 3 , R 5 , Rio, and R u independently are H or a substituted or unsubstituted Ci-C 6 alkyl group
  • R 2 and R 4 independently are O or absent
  • Re and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R 12 , Ri 3 , and Ri 4 independently are a substituted or unsubstituted Ci-C 6 alkyl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R3, R12, Ri3, and Ri 4 are methyl
  • R 2 and R 4 independently are O or absent;
  • R 5 is H or methyl;
  • n 5;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • R9, Rio, and Rn independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 3 , and R 5 independently are H or a substituted or unsubstituted Ci-C 6 alkyl; R 9 , Rio, and Rn independently are a substituted or unsubstituted Ci-C 6 alkyl;
  • R 2 and R 4 independently are O or absent
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 are methyl
  • R 2 and R 4 independently are O or absent
  • R 5 is H or methyl
  • Re and R 7 at each occurrence are H;
  • R 9 , Rio, and Rn are butyl
  • n 5;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • ⁇ and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Rio and R i3 independently are H, F, CI, Br, NR a R a , OR a , C ⁇ N, a substituted or
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group
  • Rii and R i2 independently are H, F, CI, Br, NR b R b , OR b , C ⁇ N, C(0)OR b , phosphoric acid, sulfonic acid, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • Ri 5 is O, S, N, or C; Ri6 and Rn independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, sulfonic acid, or absent;
  • Rig and Rig independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, aryl, or aralkyl group;
  • Ri4, R20, R21, R23, R24, R25, and R 26 independently are H, a substituted or unsubstituted
  • Ci-C 6 alkyl C2-C6 alkenyl, C2-C6 alkynyl, or sulfonic acid
  • Rig and R24 independently are CR b R b and linked together by 0-2 carbon atoms;
  • R22 is O, S, or Se
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 3 , R 5 , Rn, Rn, R 2 o, and R 2 i independently are H or a substituted or unsubstituted
  • R2 and R 4 independently are O or absent
  • Re and R 7 at each occurrence are H;
  • Ri6 is absent
  • R22 is O
  • n is from 4-6;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 3 , Ri4, and R21 are methyl
  • R 2 and R 4 independently are O or absent
  • R 5 is H or methyl
  • Ri6 is absent
  • Ri7 and R 2 o are ethyl
  • R 22 is O
  • n 5;
  • Z " is a counterion.
  • Ri and R 3 independently are H, C(0)R a , a substituted or unsubstituted Ci-C 6 alkyl,
  • R 2 and R 4 independently are O, S, NR b , or absent;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted C C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Rio and Rn independently are H, F, CI, Br, a substituted or unsubstituted Ci-C 6 alkyl,
  • R12, Ri 3 , Ri 4 , Ri5, Rn, Ri8, Ri9, R 2 o, R 2 i, R 22 , R 23 , and R 24 independently are H, F, CI,
  • Ri 3 and Ri 4 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group,
  • Rn and Rig are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group,
  • Ri 8 and Ri 9 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group, or any combination thereof;
  • Ri 6 is a substituted or unsubstituted alkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C 3 -
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 3 , and R 5 independently are H or a substituted or unsubstituted Ci-C 6 alkyl; R 2 and R 4 independently are O or absent;
  • R7, Rio, R11, Ri 2 , Ri5, Ri6, Ri9, R 2 o, R 2 i, R 22 , R 2 3, and R 24 are H;
  • Ri3, Ri 4 , Ri7, and Rig independently are OR a ;
  • Ri3 and Ri 4 are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group,
  • Ri7 and Ris are linked together by a -O-alkyl-0- group, wherein alkyl is a substituted or unsubstituted Ci-C 2 alkyl group, or any combination thereof;
  • R a is a substituted or unsubstituted Ci-C 6 alkyl
  • n is from 4-6;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri and R3 are methyl
  • R 2 and R 4 independently are O or absent
  • R 5 is H or methyl
  • R 7 Rio, R11, Ri 2 , R15, Ri6, R19, R 2 o, R 2 i, R 22 , R 2 3, and R 24 are H;
  • Ri3, Ri 4 , Ri7, and R i8 are OCH 3 ;
  • R13 and Ri 4 are linked together by -0-CH 2 -0-;
  • n 5;
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, and R4 independently are H, F, CI, Br, OR a , NR b R b , a substituted or
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • R 5 is H, F, CI, Br, OR b , NR b R b , a substituted or unsubstituted C C 6 alkyl, C 2 -C 6
  • alkenyl or C 2 -C 6 alkynyl group
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • Rg is a quaternary phosphonium, quaternary ammonium, or iminium group
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, andR 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • R 9 at each occurrence independently is a substituted or unsubstituted Ci-C 6 alkyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R 3 , R4, and R 5 independently are H or a substituted or unsubstituted Ci-C 6 alkyl group;
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • R 9 at each occurrence independently is a substituted or unsubstituted aryl group; n is from 4-6; and
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R 3 , and R4 are H;
  • R 5 is H or methyl
  • R 2 and R 4 independently are O or absent
  • R5 is H or methyl
  • Re and R 7 at each occurrence are H;
  • R 9 at each occurrence is a phenyl group
  • n 5;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • Re and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • Rio and R u independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • Ri 2 , Ri3, and R14 independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, R5, Rio, and Ru independently are H or a substituted or unsubstituted Ci-C 6 alkyl group; Re and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci-
  • Ri 2 , Ri 3 , and Ri 4 independently are a substituted or unsubstituted Ci-C 6 alkyl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R 4 , Re, R7 Rio, and Rn are H;
  • R 5 is H or methyl
  • R12, Ri3, and Ri 4 are methyl
  • n 5;
  • Z " is a counterion.
  • the present technology provides compounds of Formula X:
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;
  • R9, Rio, and Rn independently are a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or aryl group;
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 4-6;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R 3 , R 4 , and R 5 independently are H or a substituted or unsubstituted Ci-C 6 alkyl group;
  • R 9 , Rio, and R u are each a substituted or unsubstituted Ci-C 6 alkyl
  • n is from 4-6;
  • Z " is a counterion.
  • C x and C y are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R 3 , and R 4 are H;
  • R 5 is H or methyl
  • Re and R 7 at each occurrence are H;
  • R9, Rio, and Ru are butyl
  • n 5;
  • Z " is a counterion.
  • Ri, R 2 , R3, R4, and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • R 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group
  • Rio and R i3 independently are H, F, CI, Br, NR a R a , OR a , C ⁇ N, a substituted or
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • R11 and R i2 independently are H, F, CI, Br, NR b R b , OR b , C ⁇ N, C(0)OR b , phosphoric acid, sulfonic acid, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl group;
  • Ri5 is O, S, N, or C
  • Ri6 and Ri7 independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, sulfonic acid, or absent;
  • Rig and Rig independently are H, a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or aralkyl group;
  • Ri4, R 2 o, R 2 i, R 23 , R 2 4, R 2 5, and R 26 independently are H, a substituted or unsubstituted
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or sulfonic acid
  • Rig and R 24 independently are CR b R b and linked together by 0-2 carbon atoms;
  • R 22 is O, S, or Se
  • R a at each occurrence independently is H, a substituted or unsubstituted Ci-C 6 alkyl,
  • R b at each occurrence independently is H or a substituted or unsubstituted Ci-C 6 alkyl group
  • n is from 2-6;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond; provided that when C x and C y are connected by a carbon-carbon double bond Re is absent;
  • Ri, R 2 , R3, R4, R5, Ri4, Ri7, R20, and R 2 i independently are H or a substituted or unsubstituted Ci-C 6 alkyl;
  • Re and R 7 at each occurrence are H;
  • Ri6 is absent
  • R22 is O
  • n is from 4-6;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, Re, and R 7 are H;
  • R 5 is H or methyl
  • Ri4 and R 2 i are methyl
  • Ri6 is absent
  • Ri 7 and R 2 o are ethyl
  • R22 is O
  • n 5;
  • Z " is a counterion.
  • C x and Cy are connected by a carbon-carbon single bond or a carbon-carbon double bond;
  • Ri, R 2 , R3, R4, and R 5 independently are H, F, CI, Br, OR a , NR b R b , a substituted or unsubstituted Ci-C 6 alkyl, C 2 -C6 alkenyl, or C 2 -C6 alkynyl group; 5 and R 7 at each occurrence independently are H or a substituted or unsubstituted Ci- C 6 alkyl group;

Abstract

L'invention concerne des méthodes et des compositions de traitement et/ou de prévention de maladies ou de troubles consistant à administrer des composés SkQ, et/ou des dérivés, des analogues ou des sels pharmaceutiquement acceptables de ceux-ci, d'origine naturelle ou artificielle, seuls ou associés à un ou plusieurs agents actifs (par exemple, un peptide aromatique-cationique). La présente technologie porte sur des compositions associées à des peptides aromatiques-cationiques liés à des composés SkQ et sur des utilisations de ceux-ci. Dans certains modes de réalisation, le peptide aromatique-cationique comprend du 2',6'-diméthyl-Tyr-D-Arg-Phé-Lys-NH2,du Phé-D-Arg-Phé-Lys-NH2, ou du D-Arg-2',6'-Dmt-Lys-Phé-NH2.
PCT/US2015/034673 2015-06-08 2015-06-08 Compositions thérapeutiques contenant des composés skq et leurs utilisations WO2016200364A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
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US11807674B2 (en) 2013-03-15 2023-11-07 Protagonist Therapeutics, Inc. Hepcidin analogues and uses thereof
US11840581B2 (en) 2014-05-16 2023-12-12 Protagonist Therapeutics, Inc. α4β7 thioether peptide dimer antagonists
US10941183B2 (en) 2014-07-17 2021-03-09 Protagonist Therapeutics, Inc. Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases
US11884748B2 (en) 2014-07-17 2024-01-30 Protagonist Therapeutics, Inc. Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases
US11111272B2 (en) 2014-10-01 2021-09-07 Protagonist Therapeutics, Inc. α4α7 peptide monomer and dimer antagonists
US10787490B2 (en) 2015-07-15 2020-09-29 Protaganist Therapeutics, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
US11472842B2 (en) 2015-12-30 2022-10-18 Protagonist Therapeutics, Inc. Analogues of hepcidin mimetics with improved in vivo half lives
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US11753443B2 (en) 2018-02-08 2023-09-12 Protagonist Therapeutics, Inc. Conjugated hepcidin mimetics
US11041000B2 (en) 2019-07-10 2021-06-22 Protagonist Therapeutics, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
US11845808B2 (en) 2020-01-15 2023-12-19 Janssen Biotech, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
US11939361B2 (en) 2020-11-20 2024-03-26 Janssen Pharmaceutica Nv Compositions of peptide inhibitors of Interleukin-23 receptor

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