WO2010112092A1 - Composés pour le traitement de la dystrophie musculaire de duchenne - Google Patents

Composés pour le traitement de la dystrophie musculaire de duchenne Download PDF

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WO2010112092A1
WO2010112092A1 PCT/EP2009/065128 EP2009065128W WO2010112092A1 WO 2010112092 A1 WO2010112092 A1 WO 2010112092A1 EP 2009065128 W EP2009065128 W EP 2009065128W WO 2010112092 A1 WO2010112092 A1 WO 2010112092A1
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alkyl
compound
optionally substituted
muscular dystrophy
halo
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PCT/EP2009/065128
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English (en)
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Stephen Paul Wren
Graham Michael Wynne
Francis Xavier Wilson
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Biomarin Iga, Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • DMD Duchenne muscular dystrophy
  • X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene.
  • the gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons.
  • Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements.
  • Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein.
  • the high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
  • Dogs offer the best phenocopy for human disease, and are considered a high benchmark for preclinical studies. Unfortunately, breeding these animals is expensive and difficult, and the clinical time course can be variable among litters. [0005] The mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulf ⁇ eld et al., X Chromosome-Linked Muscular Dystrophy (max) in the Mouse, Proc. Natl. Acad. Sci. USA 81, 1189-92 (1984)). [0006] Since the discovery of the DMD gene about 20 years ago, varying degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which are being followed up in humans.
  • Gene- and cell-based therapies offer the fundamental advantage of obviating the need to separately correct secondary defects/pathology (for example, contractures), especially if initiated early in the course of the disease.
  • secondary defects/pathology for example, contractures
  • these approaches face a number of technical hurdles.
  • Immunological responses against viral vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery.
  • Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein.
  • the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment. These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies.
  • Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein.
  • Upregulation of utrophin an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins et al., Neuromuscul. Disord., Sl :S78-S89 (2002); Khurana et al, Nat. Rev. Drug Discov., 2:379-90 (2003)).
  • utrophin When utrophin is over- expressed in transgenic mdx mice, it localizes to the sarcolemma of muscle cells and restores the components of the dystrophin-associated protein complex (DAPC), which prevents the dystrophic development and in turn leads to functional improvement of skeletal muscle.
  • DAPC dystrophin-associated protein complex
  • Adenoviral delivery of utrophin in the dog has been shown to prevent pathology. Commencement of increased utrophin expression shortly after birth in the mouse model can be effective, and no toxicity is observed when utrophin is ubiquitously expressed, which is promising for the translation of this therapy to humans. Upregulation of endogenous utrophin to sufficient levels to decrease pathology might be achieved by the delivery of small diffusible compounds.
  • 0901417.6 disclosed compounds which upregulate endogenous utrophin in predictive screens, and thus, may be useful in the treatment of DMD.
  • compositions comprising the compounds, and methods of use thereof.
  • compounds that upregulate endogenous utrophin and are useful in the treatment or prophylaxis of muscular dystrophy, including DMD.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of cachexia.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy, or Becker muscular dystrophy.
  • compositions comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers or excipients.
  • the method treats, prevents, and/or manages one or more symptoms of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method treats, prevents, and/or manages one or more symptoms of Duchenne muscular dystrophy.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In another embodiment, the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted.
  • the alkyl is a linear saturated monovalent hydrocarbon radical of 1 to 20 (Ci-C 20 ), 1 to 15 (Ci-Ci 5 ), 1 to 10 (Ci-Ci 0 ), 1 to 6 (Ci-C 6 ), or 1 to 5 (C 1 - C 5 ) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3 - C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), 3 to 6 (C 3 -C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • Ci-C 6 alkyl refers to an optionally substituted linear or branched saturated monovalent hydrocarbon radical having one to six carbon atoms, such as, e.g. , methyl, ethyl, n-propyl, isopropyl, t-butyl, and n-hexyl.
  • the Ci-C 6 alkyl is optionally substituted with one or more halo, such as, e.g., trifluoromethyl and 1,2- dichloroethyl.
  • Ci-C 6 haloalkyl refers to a Ci-C 6 alkyl group as defined herein elsewhere substituted by one or more halo.
  • Ci-C 3 alkyl and “Ci-Ci 0 alkyl” have similar meanings except that they contain respectively from one to three and from one to ten carbon atoms.
  • the alkyl may be optionally substituted as described herein.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bond(s), wherein the alkenyl is optionally substituted.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, "E” and "Z” configurations.
  • alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and A- methylbutenyl.
  • C 2 -C 6 alkenyl refers to an optionally substituted linear or branched monovalent hydrocarbon radical having from two to six carbon atoms and containing at least one carbon-carbon double bond, such as, e.g., ethenyl, 2-propenyl, and 3-hexenyl.
  • the C 2 -C 6 alkenyl is optionally substituted with one or more halo, such as, e.g., chloroethenyl and fluoroethenyl.
  • halo such as, e.g., chloroethenyl and fluoroethenyl.
  • the terms "C 2 -Ci 0 alkenyl" has similar meanings except that they contain from two to ten carbon atoms.
  • the alkenyl may be optionally substituted as described herein.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bond(s), wherein the alkynyl is optionally substituted.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -Ci 5 ), 2 to 10 (C 2 -Ci 0 ), 2 to 6 (C 2 -C 6 ), or 2 to 5 (C 2 -C 5 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (Cs-C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), 3 to 6 (C 3 -C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • C 2 -C 6 alkynyl refers to an optionally substituted linear or branched monovalent hydrocarbon radical having from two to six carbon atoms and containing at least one carbon-carbon triple bond, such as, e.g., ethynyl, 2-propynyl, and 3-hexynyl.
  • the C 2 -C 6 alkynyl is optionally substituted with one or more halo.
  • C 2 -Ci 0 alkynyl has similar meanings except that they contain from two to ten carbon atoms.
  • the alkynyl may be optionally substituted as described herein.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon radical, wherein the alkylene is optionally substituted.
  • the alkylene is a saturated linear divalent hydrocarbon radical of 1 to 20 (Ci-C 20 ), 1 to 15 (Ci-Ci 5 ), 1 to 10 (Ci-Ci 0 ), 1 to 6 (Ci-C 6 ), or 1 to 5 (C 1 - C 5 ) carbon atoms, or a saturated branched divalent hydrocarbon radical of 3 to 20 (Cs-C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), 3 to 6 (C 3 -C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • linear Ci-C 6 and branched C 3 -C 6 alkylene groups are also referred to as "lower alkylene.”
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms).
  • Ci-C 6 alkylene refers to a saturated optionally substituted linear divalent hydrocarbon radical of 1 to 6 carbon atoms or a saturated optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • Ci-C 3 alkylene refers to a saturated optionally substituted linear divalent hydrocarbon radical of 1 to 3 carbon atoms or a saturated optionally substituted branched divalent hydrocarbon radical of 3 carbon atoms, such as, e.g., -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, and -CH(CH 3 )-(CH 2 )-.
  • the alkylene may be optionally substituted as described herein.
  • alkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bond(s), wherein the alkenylene is optionally substituted.
  • alkenylene also embraces radicals having "cis” and “trans” configurations, or alternatively, "E” and "Z” configurations.
  • the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -Ci 5 ), 2 to 10 (C 2 -Ci 0 ), or 2 to 6 (C 2 -C 6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3 -C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), or 3 to 6 (C 3 -C 6 ) carbon atoms.
  • alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.
  • C 2 -C 6 alkenylene refers to an optionally substituted linear divalent hydrocarbon radical of 2 to 6 carbon atoms or an optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms, which contains one or more carbon-carbon double bond.
  • the alkenylene may be optionally substituted as described herein.
  • alkynylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bond(s), wherein the alkynylene is optionally substituted.
  • the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -C 15 ), 2 to 10 (C 2 -Ci 0 ), or 2 to 6 (C 2 -C 6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3 -C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), or 3 to 6 (C 3 -C 6 ) carbon atoms.
  • C 2 -C 6 alkynylene refers to an optionally substituted linear divalent hydrocarbon radical of 2 to 6 carbon atoms or an optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms, which contains one or more carbon-carbon triple bond.
  • the alkynylene may be optionally substituted as described herein.
  • the term “carbocyclic” refers to an optionally substituted aromatic or non-aromatic ring system wherein all of the ring atoms are carbon atoms.
  • the carbocyclic ring system is monocyclic or multicyclic.
  • the carbocyclic is optionally substituted with one or more halo.
  • the carbocyclic is an optionally substituted non-aromatic ring system having from 3 to 8 ring atoms, all of which are carbon atoms.
  • the carbocyclic contains one or more carbon-carbon double bond.
  • carbocyclic ring systems include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • carbocyclic ring systems also include, but are not limited to, phenyl, naphthyl, or indanyl. In certain embodiments, the carbocyclic may be optionally substituted as described herein.
  • heterocyclic refers to an optionally substituted aromatic or non-aromatic ring system wherein one or more of the ring atom(s) is a hetero atom independently selected from N, O, and S.
  • the heterocyclic ring system is monocyclic or multicyclic.
  • the heterocyclic is an optionally substituted non-aromatic ring system having 3 to 8 ring atoms, one or more of which is a hetero atom independently selected from N, O, and S.
  • Examples include, but are not limited to, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, imidazolinyl, dioxanyl, and pyrrolidinyl. Examples also include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, and benzimidazolyl.
  • Examples also include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzimidazolinyl, benzodioxolyl, benzodioxanyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, thiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, and imidazolyl.
  • the heterocyclic may be optionally substituted as described herein.
  • one or more ring N atom(s) may be replaced with N(O) to form an oxide.
  • one or more ring S atom(s) may be replaced with S(O) or S(O) 2 to form an oxide.
  • aromatic refers to an optionally substituted carbocyclic or heterocyclic ring system which contains at least one aromatic ring.
  • the aromatic ring system is monocyclic or multicyclic.
  • the aromatic ring is monocyclic or bicyclic and has from 5 to 10 ring atoms.
  • the aromatic is bicyclic with two fused rings, wherein one of the rings is aromatic and the other may be aromatic or partially saturated. Examples of aromatic ring systems include, but are not limited to, phenyl, naphthalenyl, and indanyl.
  • aromatic ring systems may also include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzimidazolinyl, benzodioxyl, benzodioxanyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, thiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, and imidazolyl.
  • the aromatic ring system may be optionally substituted as described herein.
  • non-aromatic refers to an optionally substituted carbocyclic or heterocyclic ring system which may be fully or partially saturated.
  • the non-aromatic ring system is monocyclic or multicyclic.
  • the non-aromatic ring is monocyclic or bicyclic and has from 3 to 12 ring atoms.
  • Examples of non-aromatic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and pyrrolidinyl.
  • the non-aromatic ring system may be optionally substituted as described herein.
  • cycloalkyl or non- aromatic carbocyclic refers to a saturated bridged or non-bridged monovalent cyclic hydrocarbon radical, wherein the cycloalkyl or non-aromatic carbocyclic is optionally substituted.
  • the cycloalkyl or non-aromatic carbocyclic is monocyclic or multicyclic.
  • the cycloalkyl or non-aromatic carbocyclic is optionally substituted with one or more halo.
  • the cycloalkyl or non-aromatic carbocyclic has from 3 to 20 (C 3 -C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), 3 to 8 (C 3 -C 8 ), 3 to 7 (C 3 -Cy), or 3 to 6 (C 3 -C 6 ) carbon atoms.
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
  • the cycloalkyl or non-aromatic carbocyclic may be optionally substituted as described herein.
  • aryl or “aromatic carbocyclic” refers to a monovalent monocyclic or multicyclic hydrocarbon radical that contains at least one aromatic ring, wherein the aryl or aromatic carbocyclic is optionally substituted.
  • the aryl has from 6 to 20 (C 6 -C 20 ), from 6 to 15 (C 6 - C 15 ), or from 6 to 10 (C 6 -Ci 0 ) ring atoms.
  • the aryl has a single ring or two fused rings and from 6 to 10 ring carbon atoms.
  • the aryl or aromatic carbocyclic is bicyclic, i.e., having two rings, wherein one of the rings is aromatic and the other ring may be aromatic or partially saturated.
  • the aryl or aromatic carbocyclic is bicyclic or tricyclic, wherein one of the rings is aromatic and the other of the ring(s) may be saturated, partially unsaturated, and/or aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and indanyl.
  • aryl groups also include, but are not limited to fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.
  • aryl groups also include, but are not limited to, dihydronaphthyl, indenyl, or tetrahydronaphthyl (tetralinyl).
  • the aryl or aromatic carbocyclic may be optionally substituted as described herein.
  • aralkyl or “aryl-alkyl” refers to a monovalent alkyl group substituted with aryl. In certain embodiments, the alkyl and aryl moieties are optionally substituted with one or more substituents as described herein.
  • heteroaryl or “heteroaromatic” refers to a monovalent monocyclic or multicyclic radical that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N, and wherein the heteroaryl is optionally substituted.
  • each ring of the heteroaryl can contain one to two O atoms, one to two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • the heteroaryl or heteroaromatic has a single ring or two fused rings and from 5 to 10 ring atoms, at least one of which is a heteroatom selected from N, O, and S.
  • the heteroaryl or heteroaromatic is bicyclic, i.e., having two rings, wherein one of the rings is aromatic and the other ring may be aromatic or partially saturated.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzo furanyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl may be optionally substituted as described herein.
  • heterocyclyl refers to a monovalent monocyclic or multicyclic radical that contains at least one non-aromatic ring, wherein at least one non-aromatic ring contains one or more heteroatoms independently selected from O, S, and N, and wherein the heterocyclyl is optionally substituted.
  • the heterocyclyl has from 3 to 20, from 3 to 15, from 3 to 12, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system.
  • the nitrogen or sulfur atom(s) in the heterocyclyl is optionally oxidized. In certain embodiments, the nitrogen atom(s) in the heterocyclyl is optionally quaternized. In certain embodiments, some of the rings in the heterocyclyl may be partially or fully saturated, or aromatic. In certain embodiments, the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyl examples include, but are not limited to, azepinyl, benzimidazolinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ⁇ -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • the term "optionally substituted” is intended to mean that a group, including but not limited to, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently selected from, e.g., (a) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C 6-14 aryl, C 7 -Is aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q 1 ; and (b) halo, cyano (-CN), nitro (-NO 2 ), -C(O)R a , -C(O)OR a , -C(O)NR
  • the terms “optically active” and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
  • the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • a chiral center or another form of isomeric center is present in a compound provided herein, all forms of such isomer or isomers, including stereoisomers, enantiomers and diastereoisomers, are intended to be within the scope of this disclosure.
  • Compounds provided herein containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or a diastereomerically enriched mixture, or the racemic mixture may be separated using known techniques and an individual enantiomer may be used alone.
  • solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the bound solvent is water
  • the solvate is a hydrate.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids, organic acids, inorganic bases, and organic bases.
  • pharmaceutically acceptable salt When the compound provided herein contains an acidic or basic moiety, it may be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley- VCH and VHCA: Zurich, Switzerland, 2002.
  • suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohe
  • suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, sodium hydroxide, and primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, JV-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)
  • prodrug refers to a covalently bonded compound comprising a parent drug moiety and a pro-moiety, which undergoes bond cleavage reaction in vivo to release the active parent drug.
  • prodrug refers to a functional derivative of a parent compound, for example, a compound of formula (I), and is readily convertible into the parent compound in vivo.
  • a prodrug may be converted to the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • the term "subject” refers to an animal, including but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • the terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • the terms “manage,” “managing,” and “management” refer to preventing, reducing, or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a complete cure of the disease or disorder. In this regard, the term “manage,” “managing,” or “management” encompasses treating a patient who had suffered from a particular disease to prevent, minimize, or slow the progression or recurrence of the disease.
  • the term “therapeutically effective amount” refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • the term “therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • prophylactically effective amount refers to the amount of a compound sufficient to prevent a disease or disorder, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • prophylactically effective amount can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the term "pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • active ingredient and active substance refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or managing one or more symptoms of a condition, disorder, or disease.
  • active ingredient and active substance may be an optically active isomer of a compound described herein.
  • drug or “therapeutic agent” refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or managing one or more symptoms of a condition, disorder, or disease.
  • L 1 is -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(NR 7 )-, -C(O)NR 7 -, -NR 7 C(O)-, -NR 7 SO 2 -, or -P(O)OR 7 -;
  • R 1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more halo, OH, CN, Ci-C 6 alkyl, 0(Ci-C 6 alkyl), C(O)(Ci-C 6 alkyl), C(O)NH(Ci-C 6 alkyl), NHC(O)(Ci-C 6 alkyl), NHS(O) 2 (Ci-C 6 alkyl), Or NR 5 R 6 ;
  • R 2 is hydrogen, halo, cyano, or 0(Ci-C 6 alkyl);
  • R 3 is (i) Ci-C 6 alkyl; or (ii) cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, CN, Ci-C 6 alkyl, 0(Ci-C 6 alkyl), C(O)(Ci-C 6 alkyl), C(O)NR 7 (Ci-C 6 alkyl), NHS(O) 2 (Ci-C 6 alkyl), Or NR 5 R 6 ; each occurrence of R 4 is independently halo or optionally substituted C 1 -C 4 alkyl;
  • R 5 and R 6 are each independently hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen or C 1 -C 4 alkyl; and n is 0, 1, or 2; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • n is 0, 1, or 2; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • L 1 is -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(NR 7 )-, -C(O)NR 7 -, -NR 7 C(O)-, or -P(O)OR 7 -;
  • R 1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more halo, OH, CN, Ci-C 6 alkyl, 0(Ci-C 6 alkyl), C(O)(Ci-C 6 alkyl), C(O)NH(Ci-C 6 alkyl), NHC(O)(Ci-C 6 alkyl), NHS(O) 2 (Ci-C 6 alkyl), Or NR 5 R 6 ;
  • R 2 is hydrogen, halo, cyano, or 0(Ci-C 6 alkyl);
  • R 3 is (i) Ci-C 6 alkyl; or (ii) cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, CN, Ci-C 6 alkyl, 0(Ci-C 6 alkyl), C(O)(Ci-C 6 alkyl), C(O)NR 7 (Ci-C 6 alkyl), NHS(O) 2 (Ci-C 6 alkyl), Or NR 5 R 6 ; each occurrence of R 4 is independently halo or optionally substituted C1-C4 alkyl;
  • R 5 and R 6 are each independently hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen or Ci-C 4 alkyl; and n is O, 1, or 2; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • L 1 is -O-. In one embodiment, L 1 is -S-. In one embodiment, L 1 is -SO-. In one embodiment, L 1 is -SO 2 -. In one embodiment, L 1 is -SO 2 NR 7 -. In one embodiment, L 1 is -C(O)-. In one embodiment, L 1 is -C(NR 7 )-. In one embodiment, L 1 is -C(O)NR 7 -. In one embodiment, L 1 is -P(O)OR 7 -.
  • L 1 is -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(NR 7 )-, -C(O)NR 7 -, -NR 7 C(O)-, -NR 7 SO 2 -, or -P(O)OR 7 -.
  • L 1 is -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(NR 7 )-, -C(O)NR 7 -, or -P(O)OR 7 -.
  • L 1 is -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(O)NR 7 -, -NR 7 C(O)-, -NR 7 SO 2 -, or -P(O)OR 7 -. In one embodiment, L 1 is -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(O)NR 7 -, -NR 7 C(O)-, or -P(O)OR 7 -.
  • L 1 is -SO 2 -, -SO 2 NR 7 -, -C(O)-, -C(O)NR 7 -, or -P(O)OR 7 -. In one embodiment, L 1 is -SO 2 - or -P(O)OR 7 -. In one embodiment, L 1 is -P(O)OCH 3 - or -P(O)OH-. In one embodiment, L 1 is -P(O)OCH 3 -.
  • R 1 is optionally substituted aryl. In one embodiment, R 1 is optionally substituted heteroaryl. In one embodiment, R 1 is optionally substituted cycloalkyl. In one embodiment, R 1 is optionally substituted heterocyclyl. In one embodiment, R 1 is optionally substituted with halo. In one embodiment, R 1 is optionally substituted with OH. In one embodiment, R 1 is optionally substituted with CN. In one embodiment, R 1 is optionally substituted with Ci-C 6 alkyl. In one embodiment, R 1 is optionally substituted with 0(Ci-C 6 alkyl). In one embodiment, R 1 is optionally substituted with C(O)(Ci-C 6 alkyl).
  • R 1 is optionally substituted with C(O)NH(Ci-C 6 alkyl). In one embodiment, R 1 is optionally substituted with NHC(O)(Ci-C 6 alkyl). In one embodiment, R 1 is optionally substituted with NHS(O) 2 (Ci-C 6 alkyl). In one embodiment, R 1 is optionally substituted with NR 5 R 6 . In one embodiment, R 1 is unsubstituted aryl. In one embodiment, R 1 is unsubstituted heteroaryl. In one embodiment, R 1 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 1 is optionally substituted with one or more halo, OH, C 1 -C 4 alkyl, or 0(Ci-C 4 alkyl).
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, OH, Ci-C 4 alkyl, or 0(Ci-C 4 alkyl).
  • R 1 is phenyl.
  • R 1 is unsubstituted phenyl.
  • R 1 is optionally substituted phenyl.
  • R 1 is phenyl optionally substituted with one or more halo, OH, C 1 -C 4 alkyl, or 0(Ci-C 4 alkyl).
  • R 2 is hydrogen. In one embodiment, R 2 is halo. In one embodiment, R 2 is cyano. In one embodiment, R 2 is 0(Ci-C 6 alkyl).
  • R 3 is Ci-C 6 alkyl. In one embodiment, R 3 is optionally substituted Ci-C 6 alkyl. In one embodiment, R 3 is Ci-C 6 alkyl optionally substituted with one or more halo. In one embodiment, R 3 is optionally substituted cycloalkyl. In one embodiment, R is optionally substituted heterocyclyl. In one embodiment, R is optionally substituted aryl. In one embodiment, R 3 is optionally substituted heteroaryl. In one embodiment, R 3 is optionally substituted with halo. In one embodiment, R 3 is optionally substituted with OH. In one embodiment, R 3 is optionally substituted with CN. In one embodiment, R 3 is optionally substituted with Ci-C 6 alkyl.
  • R 3 is optionally substituted with 0(Ci-C 6 alkyl). In one embodiment, R 3 is optionally substituted with C(O)(Ci-C 6 alkyl). In one embodiment, R 3 is optionally substituted with C(O)NR 7 (Ci-
  • R is optionally substituted with NHS(O) 2 (Ci-C 6 alkyl).
  • R 3 is optionally substituted with NR 5 R 6 .
  • R 4 is halo. In one embodiment, R 4 is optionally substituted
  • R 4 is Ci-C 4 alkyl optionally substituted with one or more halo.
  • R 4 is fluoro.
  • R 4 is methyl.
  • R 4 is methyl substituted with one or more halo.
  • R 4 is methyl substituted with one or more fluoro.
  • R 4 is halo or methyl optionally substituted with one or more halo.
  • R 4 is fluoro, methyl, or trifluoromethyl.
  • R 5 is hydrogen. In one embodiment, R 5 is C 1 -C 3 alkyl.
  • R 6 is hydrogen. In one embodiment, R 6 is C 1 -C 3 alkyl.
  • R 7 is hydrogen. In one embodiment, R 7 is Ci-C 4 alkyl. In one embodiment, R 7 is methyl. In one embodiment, R 7 is hydrogen or methyl.
  • n is 0. In one embodiment, n is 1. In one embodiment, n is 2.
  • n is 0 or 1.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof wherein L 1 is -S(O) 2 - or -P(O)OR 7 -, R 1 is optionally substituted aryl or optionally substituted heteroaryl, R 2 is hydrogen, R 3 is Ci-C 6 alkyl, each occurrence of R 4 is independently halo or methyl optionally substituted with one or more halo, and n is 0 or 1.
  • R 4 is fluoro, methyl or trifluoromethyl.
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, OH, C 1 -C 4 alkyl, or
  • R 1 is optionally substituted phenyl. In one embodiment, R 1 is phenyl optionally substituted with one or more halo, OH, Ci-C 4 alkyl, or
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a method of making a compound of formula (I) is provided herein.
  • the compounds of formula (I) can be synthesized from commercially available starting materials using the following methods.
  • compounds of formula (I) may be prepared from a compound of formula (II):
  • the reaction may be conducted in an organic solvent, such as, e.g., dioxane, at elevated temperature, such as, e.g., between about 17O 0 C and about 25O 0 C, for example, with microwave irradiation.
  • an example of this reaction is provided as Procedure A in the Examples below.
  • the reaction is carried out to yield a compound of formula (I), wherein L 1 is - SO 2 -.
  • compounds of formulae (II) are readily available or may be synthesized using known methods from commercially available starting materials.
  • a compound of formula (II) may be synthesized from a compound of formula (IX):
  • a compound of formula (IX) is reacted with a dealkylating reagent, such as, e.g., boron tribromide, under an inert atmosphere.
  • a dealkylating reagent such as, e.g., boron tribromide
  • 2-amino- 4-iodophenol an example of a compound of formula (II)
  • 5-iodo-2-methoxyaniline by a reaction with boron tribromide is described in the Examples below.
  • compounds of formula (III) may be prepared from the corresponding carboxylic acid of formula (IV) using standard methods:
  • compounds of formula (I) may also be prepared from a compound of formula (V):
  • the reaction of a compound of formula (V) and a compound of formula (VI) yields a compound of formula (I), wherein L 1 is -P(O)OR 7 -.
  • An example of this reaction is provided as Example 2 below.
  • X is a leaving group.
  • X is halo.
  • X is iodo.
  • Compounds of formula (VI) are well known, and are readily available, or may be prepared by known methods.
  • compounds of formula (V) may be prepared from a compound of formula (VII):
  • R 8 is Ci-C 6 alkyl.
  • a compound of formula (VIII) is reacted with a dealkylating reagent, such as, e.g., boron tribromide, as illustrated in the Examples below.
  • a dealkylating reagent such as, e.g., boron tribromide, as illustrated in the Examples below.
  • suitable protecting groups may be used, as understood by one of ordinary skills in the art. One skilled in the art would also be able to choose the appropriate protecting groups and the conditions to introduce and remove such protecting groups. Information concerning protecting groups is available, for example, in Theodora W. Greene and Peter G. M. Wuts, "Protecting Groups in Organic Synthesis", 4 th Edition, Wiley Interscience, 2006.
  • the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is administered in the form of a pharmaceutical composition.
  • the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia is administered in the form of a pharmaceutical composition.
  • the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy is administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises less than about 80% w/w, less than about 50% w/w, less than about 20% w/w, or between about 0.1 and about 20% w/w, of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in admixture with at least one pharmaceutically acceptable excipient, diluent, or carrier.
  • a process for the production of a pharmaceutical composition provided herein, which comprises mixing the ingredients.
  • examples of pharmaceutical formulations or compositions, and suitable diluents or carriers include, but are not limited to, the following: for intravenous injection or infusion — purified water or saline solution; for inhalation compositions — coarse lactose; for tablets, capsules, and dragees — microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; and for suppositories — natural or hardened oils or waxes.
  • the compound provided herein is used in aqueous solution, e.g., for intravenous infusion
  • the pharmaceutical composition containing the compound provided herein may further comprise one or more excipients.
  • the excipients include, but are not limited to, chelating or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents, and buffering agents.
  • solutions containing a compound of formula (I) may, if desired, be evaporated, e.g., by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
  • the compound provided herein is not used in a solution.
  • the compound of formula (I) is in a form having a mass median diameter of from about 0.01 to about 10 ⁇ m.
  • the pharmaceutical composition comprising the compound of formula (I) may further contain one or more preserving, stabilizing, and/or wetting agents, solubilisers, e.g., a water soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water soluble glycol such as propylene glycol, sweetening and/or coloring agents, and/or flavorings.
  • the compositions may be formulated in sustained release form.
  • the pharmaceutical composition comprises a compound of formula (I) in between about 0.01% and about 99.9% w/w, relative to the entire preparation. In certain embodiments, the pharmaceutical composition comprises a compound of formula (I) in between about 0.1% and about 50% w/w, relative to the entire preparation. [0092] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I), and at least one pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser is non-toxic and does not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral or by injection, such as cutaneous, subcutaneous, or intravenous injection.
  • the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions may comprise a liquid carrier, such as water, petroleum, animal or vegetable oils, or mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such as gelatin.
  • the pharmaceutical compositions are provided in a dosage form for parenteral administration, and one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions may be formulated for intravenous, cutaneous or subcutaneous injection
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • isotonic vehicles such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection.
  • Preservatives, stabilisers, buffers, antioxidants, and/or other additives may be included as required.
  • compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, e.g., Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al, Eds., Marcel Dekker, Inc.: New York, NY, 2008).
  • the pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • the pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. [00100] In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I) in another embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy. In certain embodiments, the medicament is in tablet, capsule, powder, or liquid form. In certain embodiments, the medicament is formulated as described herein.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • binders fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 200 (W.R.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB- O-SIL ® (Cabot Co. of Boston, MA), and asbestos-free talc.
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in- oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly- alkylene glycol including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene
  • formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the dosage forms provided herein.
  • compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (See, Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, NN-dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propylparabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • cyclodextrins including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • the pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions provided herein can be administered topically to the skin, orifices, or mucosa.
  • topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR).
  • electroporation iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in- water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (See, Remington: The Science and Practice of Pharmacy, supra).
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single -phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
  • the pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane.
  • atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer
  • a suitable propellant such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane.
  • the pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • the powder can comprise a bioadhesive agent, including chitosan or cyclod
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /- leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
  • compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • modified release dosage form refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
  • modified release examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
  • compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art (See, Takada et ⁇ l. in “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).
  • the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose
  • the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate -methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plastic
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semi-permeable membrane with at least one delivery port, which encapsulates the core.
  • the semi-permeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water- swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic mono
  • PEO polyethylene oxide
  • PEG poly
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffmose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEM TM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semi-permeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119.
  • Such hydrophobic but water- vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semi-permeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semi-permeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • the pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 55, 1-21; Verma et ah, Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).
  • the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to about 1 mm in diameter.
  • multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores.
  • Multiparticulate Oral Drug Delivery Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.
  • Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Patent Nos.
  • kits that upregulate endogenous utrophin, and therefore, are useful in the treatment or prophylaxis of muscular dystrophy, including DMD, and other similar conditions.
  • a compound of formula (I) for use in medicine, for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the dose of the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is determined with consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment for, and other factors. In one embodiment, the dose varies depending on the target disease, condition, subject of administration, administration method, and the like.
  • the pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered orally as a therapeutic agent for the treatment or prophylaxis of Duchenne muscular dystrophy in a patient suffering from such a disease.
  • a therapeutic agent for the treatment or prophylaxis of Duchenne muscular dystrophy in a patient suffering from such a disease.
  • from about 0.01 mg to about 1O g of the compound is administered.
  • from about 0.1 mg to about 100 mg of the compound is administered.
  • the compound is administered in a single dose per day.
  • the compound is administered in 2 or 3 portions per day.
  • a method of treating, preventing, and/or managing a disorder or symptoms related to Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • a method of treating, preventing, and/or managing a disorder or symptoms related to Duchenne muscular dystrophy or Becker muscular dystrophy comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • provided herein is a method of treating, preventing, and/or managing Duchenne muscular dystrophy. In another embodiment, provided herein is a method of treating, preventing, and/or managing Becker muscular dystrophy. In another embodiment, provided herein is a method of treating, preventing, and/or managing cachexia. [00178] In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy or Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the manufacturing of a medicament for the treatment, prevention, and/or management of Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the manufacturing of a medicament for the treatment, prevention, and/or management of cachexia.
  • the method comprises administering to a subject (e.g., a human) a therapeutically or prophylactically effective amount of a composition of a compound of formula (I).
  • a subject e.g., a human
  • the subject is a human.
  • the subject is a mammal.
  • the subject is a non- human primate, a farm animal, such as cattle, a sport animal, or a pet such as a horse, dog, or cat.
  • compound activity can be assessed by functional assays described herein elsewhere.
  • the efficacious concentration of the compounds provided herein is less than about 0.1 nM, less than about 1 nM, less than about 10 nM, less than about 100 nM, less than about 1 ⁇ M, less than about 10 ⁇ M, less than about 100 ⁇ M, or less than about 1 mM.
  • compounds' activity may be assessed in various art-recognized animal models as described herein elsewhere.
  • the compounds provided herein are active in at least one model, which can be used to measure the activity of the compounds and estimate their efficacy in treating Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the compounds are active in, for example, the mdx mouse model, when compared to the effect of a vehicle.
  • the compounds provided herein are active in a dose-dependent manner.
  • the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration, and can be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is administration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period.
  • an appropriate dosage level in the treatment, prevention, and/or management of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level generally is ranging from about 0.001 to about 1000 mg per kg subject body weight per day (mg/kg per day), from about 0.001 to about 300 mg/kg per day, from about 0.001 to about 100 mg/kg per day, from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, from about 1 to about 20 mg/kg per day, from about 0.01 to about 1000 mg/kg per day, from about 0.1 to about 1000 mg/kg per day, from about 1 to about 1000 mg/kg per day, from about 10 to about 1000 mg/kg per day, from about 100 to about 1000 mg/kg per day, or from about 100 to about 300 mg/kg per day, which can be administered in single or multiple doses per day.
  • the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, from about 1 to about 50, from about 5 to about 50, from about 10 to about 100, from about 20 to about 200, from about 30 to about 300, or from about 50 to about 500 mg/kg per day.
  • an appropriate dosage level is less than about 0.001 mg/kg per day, less than about 0.01 mg/kg per day, less than about 0.1 mg/kg per day, less than about 0.5 mg/kg per day, less than about 1 mg/kg per day, less than about 5 mg/kg per day, less than about 10 mg/kg per day, less than about 15 mg/kg per day, less than about 20 mg/kg per day, less than about 25 mg/kg per day, less than about 50 mg/kg per day, less than about 75 mg/kg per day, less than about 100 mg/kg per day, less than about 200 mg/kg per day, less than about 500 mg/kg per day, less than about 1 g/kg per day, less than about 3 g/kg per day, less than about 5 g/kg per day, or less than about 10 g/kg per day.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, or about 1,000 mg, of the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy, which may be determined by a physician treating the particular patient.
  • the compounds provided herein can be combined or used in combination with other agents or therapies useful in the treatment, prevention, and/or management of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • Suitable other therapeutic agents include, but are not limited to, corticosteroids, such as, e.g., prednisone and deflazacort.
  • other therapies that may be used in combination with the compounds provided herein include, but are not limited to, physical therapy, gene therapy, and/or orthopedic appliances, such as, e.g., braces and wheelchairs.
  • such other agents or drugs can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compounds provided herein, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • a pharmaceutical composition containing such other drugs in addition to the compound provided herein can be utilized, but is not required.
  • the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.
  • the weight ratio of a compound provided herein to the second active ingredient can be varied, and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound provided herein to the corticosteroid can range from about 1 ,000: 1 to about 1 : 1 ,000, from about 200: 1 to about 1 :200, from about 100:1 to about 1 :100, from about 10:1 to about 1 :10, from about 5:1 to about 1 :5, or from about 2:1 to about 1 :2.
  • combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein.
  • the kit includes a container comprising a dosage form of the compound provided herein, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.
  • kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. [00194] In one embodiment, kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles, including but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles including but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles including but not limited to, ethyl alcohol
  • HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionization mode. A Phenomenex Gemini Cl 8 150x4.6 mm HPLC column was used.
  • 1 H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained in CDCI3 or DMSO-d ⁇ solutions (reported in ppm), using deuterated chloroform (7.25 ppm) or DMSO-d ⁇ (2.50 ppm) as the reference standard.
  • Tetrakis(triphenylphosphine)palladium(0) (0.14 mmol) was added in one portion to a stirred solution of (Z)-2-(l-fluoro-2-phenylvinyl)-5-iodobenzo[d]oxazole (2.8 mmol) and methyl ethylphosphinate (1.4 mmol) (prepared using known method described in Patel, D.V. et ah, Journal of Medicinal Chemistry, 1995, 38, 4557-69) in toluene (10 mL) in the presence of triethylamine (4.2 mmol) and the resulting mixture was heated in a sealed tube at 100 0 C for 3 hr under an atmosphere of dry nitrogen.
  • the cell line used for the screen was an immortalized mdx mouse H2K cell line that had been stably transfected with a plasmid containing ⁇ 5kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene.
  • the cells Under conditions of low temperature and interferon containing media, the cells remained as myoblasts. These were plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase was then determined by cell lysis and reading of the light output from the expressed luciferase gene utilizing a plate luminometer.

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Abstract

La présente invention concerne des composés représentés par la formule (I) dans laquelle R1, R2, R3, R4, L1, et n sont tels que définis dans la description, lesquels composés sont utiles pour le traitement ou la prophylaxie d'états pathologiques tels que la dystrophie musculaire de Duchenne, la dystrophie musculaire de Becker et la cachexie.
PCT/EP2009/065128 2009-04-02 2009-11-13 Composés pour le traitement de la dystrophie musculaire de duchenne WO2010112092A1 (fr)

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WO2016001682A1 (fr) 2014-07-04 2016-01-07 Summit Therapeutics Plc Traitement de l'hypertransaminasémie
WO2023075491A1 (fr) * 2021-10-29 2023-05-04 중앙대학교 산학협력단 Composition pour prévenir, atténuer ou traiter la dystrophie musculaire

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