US20140179779A1 - Deuterium Substituted Fumarate Derivatives - Google Patents

Deuterium Substituted Fumarate Derivatives Download PDF

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US20140179779A1
US20140179779A1 US14/136,990 US201314136990A US2014179779A1 US 20140179779 A1 US20140179779 A1 US 20140179779A1 US 201314136990 A US201314136990 A US 201314136990A US 2014179779 A1 US2014179779 A1 US 2014179779A1
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compound
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deuterium
disease
compounds
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Jianhua Chao
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Biogen MA Inc
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Biogen Idec MA Inc
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Definitions

  • BG-12 (dimethyl fumarate) is currently undergoing regulatory review as a potential oral treatment for multiple sclerosis (MS), following the completion of two large Phase 3 studies in patients with relapsing-remitting MS (RRMS).
  • CONFIRM which additionally evaluated subcutaneous glatiramer acetate as an active reference treatment (rater-blind). See, e.g., Fox R J, et al. N Engl J Med 2012; 367: 1087-97.
  • DMF dimethyl fumarate
  • Nrf2 is expressed ubiquitously in a range of tissues and, under normal basal conditions, is sequestered in the cytoplasm in a complex with Keap1 protein. However, when cells are under oxidative stress and overloaded with reactive oxygen or nitrogen species (ROS or RNS), or electrophilic entities, Nrf2 rapidly translocates to the nucleus, forms heterodimer with small protein Maf, then binds to the antioxidant response element, resulting in increased transcription of several antioxidant and detoxifying genes including NQO-1, HO-1, and SRXN1. See, e.g., Nguyen et al., Annu Rev Pharmacol Toxicol 2003; 43:233-260; McMahon et al., Cancer Res 2001; 61:3299-3307.
  • Sustained oxidative stress has been implicated in the pathogenesis of a variety of neurodegenerative diseases such as MS, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease.
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease For reviews, see, e.g., van Muiswinkel et al., Curr. Drug Targets CNS—Neurol. Disord, 2005; 4:267-281; Burton N. C. et al., Comprehensive Toxicology, 2010, 59-69.
  • DMF quickly gets absorbed in vivo and converted to MMF.
  • the half-life of MMF was shown to be approximately 1 hour (0.9 h in rat at 100 mg/Kg oral dose).
  • Both DMF and MMF are metabolized by esterases which are ubiquitous in the GI tract, blood and tissues.
  • BG-12 has demonstrated an acceptable safety profile in the DEFINE and CONFIRM studies.
  • tolerability issues such as flushing and gastrointestinal events were observed. While these events are generally mild to moderate in severity, there remains a desire to reduce such events to further increase patient compliance and improve patient's quality of life.
  • These mild adverse events could be the result of off-target events induced either by DMF or MMF and or the metabolites derived from them.
  • recent reports (Hanson et al., J. Clin. Invest. 2010, 120, 2910-2919; Hanson et al., Pharmacol. Ther. 2012, 136, 1-7.) indicate that MMF induced flushing is due to the activation of the G-protein-coupled receptor HCA2 (Hydroxy-carboxylic acid receptor 2, GPR109A).
  • each of R 1 and R 2 is hydrogen, deuterium, deuterated methyl, deuterated ethyl, C 1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
  • each of R 3 and R 4 is hydrogen or deuterium, provided that the compound of formula (I) contains at least one deuterium atom and that R 1 and R 2 are not hydrogen at the same time.
  • Also provided is a method of treating a neurodegenerative disease comprising administering to a subject in need of treatment for the neurodegenerative disease an effective amount of a compound of formula (I) described herein.
  • FIGS. 1( a )-( c ) describe the PD response of DMF and compounds of Examples 1 and 2.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups are optionally substituted and contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.
  • carbocyclic means a monocyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “ ”), that has a single point of attachment to the rest of the molecule.
  • carbocyclic groups are optionally substituted. Examples include cycloalkyl and cycloalkenyl.
  • aliphatic groups contain 3-7 aliphatic carbon atoms.
  • aliphatic groups contain 4-6 aliphatic carbon atoms.
  • aliphatic groups contain 5-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 6 aliphatic carbon atoms.
  • heteroaryl refers to groups having 5 to 6 ring atoms, sharing ⁇ electrons in a cyclic array; and having, in addition to carbon atoms, from 1-3 heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Unless otherwise specified, heteroaryl groups are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, 1-3 heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, and morpholinyl.
  • compounds of the invention may, when specified, contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • optionally substituted groups include halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —N(R)C(O)OR, —C(O)N(R) 2 , —OC(O)R, —N(R)C(O)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 .
  • Each R is independently hydrogen or C 1-6 aliphatic; or two R groups attached to the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
  • Optionally substituted groups of aliphatic can further include phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • cycloalkyl)alkyl For example, cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl, heterocyclylalkyl.
  • Optionally substituted groups of phenyl, heterocycle, carbocycle, and heteroaryl can further include optionally substituted aliphatic groups.
  • deuterium enrichment factor means the ratio between the isotopic abundance and the natural abundance of deuterium.
  • a position designated as having deuterium when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • a position designated as having deuterium typically has a minimum isotopic enrichment factor of at least 3340 (50.1% deuterium incorporation) at each atom designated as deuterium in said compound.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • deuterated methyl and “deuterated ethyl,” as used herein, means that the methyl group and the ethyl group contain at least one deuterium atom.
  • deuterated methyl include —CDH 2 , —CD 2 H, and —CD 3 .
  • deuterated ethyl include —CHDCH 3 , —CD 2 CH 3 , —CHDCDH 2 ,
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • a “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent.
  • suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • activation and “upregulation,” when used in reference to the Nrf2 pathway, are used interchangeably herein.
  • a drug for treating a neurological disease refers to a compound that has a therapeutic benefit in a specified neurological disease as shown in at least one animal model of a neurological disease or in human clinical trials for the treatment of a neurological disease.
  • treatment refers to therapeutic as well as prophylactic/preventative measures.
  • those in need of treatment may include individuals already having a specified disease and those who are at risk for acquiring that disease.
  • terapéuticaally effective dose and “therapeutically effective amount” refer to that amount of a compound which results in prevention or delay of onset or amelioration of symptoms of a neurological disorder in a subject or an attainment of a desired biological outcome, such as reduced neurodegeneration (e.g., demyelination, axonal loss, and neuronal death), reduced inflammation of the cells of the CNS, or reduced tissue injury caused by oxidative stress and/or inflammation in a variety of cells.
  • a desired biological outcome such as reduced neurodegeneration (e.g., demyelination, axonal loss, and neuronal death), reduced inflammation of the cells of the CNS, or reduced tissue injury caused by oxidative stress and/or inflammation in a variety of cells.
  • each of R 1 and R 2 is hydrogen, deuterium, deuterated methyl, deuterated ethyl, C 1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
  • each of R 3 and R 4 is hydrogen or deuterium, provided that the compound of formula (I) contains at least one deuterium atom and that R 1 and R 2 are not hydrogen at the same time.
  • each of R 1 and R 2 is hydrogen, deuterium, deuterated methyl, deuterated ethyl, or C 1-6 aliphatic, and
  • each of R 3 and R 4 is hydrogen or deuterium, provided that the compound of formula (I) contains at least one deuterium atom and that R 1 and R 2 are not hydrogen at the same time.
  • R 1 is hydrogen or —CH 3 . In some embodiments, R 1 is —CD 3 . In some embodiments, R 1 is —CD 2 CD 3 .
  • R 2 is —CH 2 D, —CHD 2 , or —CD 3 . In some embodiments, R 2 is H, —CH 3 , —CH 2 D, —CHD 2 , or —CD 3 .
  • R 1 is hydrogen or —CH 3 and R 2 is —CH 2 D,
  • R 1 is —CD 3 and R 2 is —CH 2 D, —CHD 2 , or —CD 3 .
  • At least one of R 3 and R 4 is deuterium. In some embodiments, both of R 3 and R 4 are deuterium.
  • R 3 and R 4 are deuterium and R 2 is hydrogen, —CH 3 , —CH 2 D, —CHD 2 , or —CD 3 . In some embodiments, both of R 3 and R 4 are deuterium and R 2 is hydrogen, —CH 3 , —CH 2 D, —CHD 2 , or —CD 3 .
  • R 1 is —CD 2 CD 3 and R 2 is H, —CH 3 , —CH 2 D,
  • the compound of formula (I) is ( 2 H 6 )dimethyl fumaric acid ester, ( 2 H 3 )methyl fumaric acid ester, ( 2 H 3 )dimethyl fumaric acid ester, or dimethyl fumaric(2,3- 2 H 2 ) acid ester.
  • the compound of formula (I) is more resistant to CYP450 enzymes as compared with compounds of similar structure but lacking deuterium substitution.
  • the compound of formula (I) will have slightly altered and slower metabolism as compared with compounds of similar structure but lacking deuterium substitution.
  • the compound of formula (I) will have longer duration of action and/or improved side effect profile as compared with compounds of similar structure but lacking deuterium substitution.
  • fumaric acid 1 can be converted to the monohydrogen ( 2 H 3 )methyl fumaric acid ester 2 by reacting with deuterated methanol under the catalytic condition of p-toluenesulfonic acid at room temperature.
  • ester 2 can react with a variety of alcohols R 1 OH (e.g., CH 3 OH, CH 2 DOH, CHD 2 OH, CD 3 OH, CD 3 CH 2 OH, or other deuterated alcohols) to provide deuterated fumaric acid esters of Formula Ia.
  • compounds of Formula 1b can be prepared in two steps by first reacting with CD 3 OD at room temperature under, e.g., the catalytic condition of p-toluene sulfonic acid followed by subsequent esterification with alcohol R 1 OH (e.g., CH 3 OH, CH 2 DOH, CHD 2 OH, CD 3 OH, CD 3 CH 2 OH, or other deuterated alcohols) using either Method A or B.
  • CD 3 OD e.g., the catalytic condition of p-toluene sulfonic acid
  • R 1 OH e.g., CH 3 OH, CH 2 DOH, CHD 2 OH, CD 3 OH, CD 3 CH 2 OH, or other deuterated alcohols
  • Compounds of Formula Ic can be prepared by reacting 3 with a variety of alcohol R 1 OH under catalytic acid condition at ambient temperature. Treatment of compounds of Formula Ic under the conditions of HOBT, EDCI, and DiPEA will generate diester compounds of Formula Id.
  • compositions comprising a compound of formula (I) or a compound of formula (I) in combination with a pharmaceutically acceptable excipient (e.g., carrier).
  • a pharmaceutically acceptable excipient e.g., carrier
  • Compounds of formula (I) can be administered by any method that permits the delivery of the compound to a subject in need thereof.
  • compounds of formula (I) can be administered by orally, intranasally, transdermally, subcutaneously, intradermally, vaginally, intraaurally, intraocularly, intramuscularly, buccally, rectally, transmucosally, or via inhalation, or intravenous administration.
  • compounds of formula (I) can be administered via pills, tablets, microtablets, pellets, micropellets, capsules (e.g., containing microtablets), suppositories, liquid formulations for oral administration, and in the form of dietary supplements.
  • Oral formulations e.g., tablets and microtablets
  • the mean diameter of a microtablet is about 1-5 mm, e.g., about 1-3 mm or about 2 mm.
  • compositions can include well-known pharmaceutically acceptable excipients, e.g., if the composition is an aqueous solution containing the active agent, it can be an isotonic saline, 5% glucose, or others. Solubilizing agents such as cyclodextrins, or other solubilizing agents well known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compound. See, e.g., U.S. Pat. Nos. 6,509,376 and 6,436,992 for some formulations containing DMF and/or MMF.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • Carriers or excipients generally serve as fillers, disintegrants, lubricants, and glidants.
  • suitable carriers include magnesium carbonate, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, talc, silica, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil.
  • co-solvents can be employed at a level between about 0.01% and about 2% by weight.
  • Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing.
  • Such agents can be employed at a level between about 0.01% and about 2% by weight.
  • compositions of formula (I) can be administered in the form of a sustained or controlled release pharmaceutical formulation.
  • a sustained or controlled release pharmaceutical formulation can be prepared by various technologies by a skilled person in the art.
  • the formulation can contain the therapeutic compound, a rate-controlling polymer (i.e., a material controlling the rate at which the therapeutic compound is released from the dosage form) and optionally other excipients.
  • rate-controlling polymers are hydroxy alkyl cellulose, hydroxypropyl alkyl cellulose (e.g., hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropyl isopropyl cellulose, hydroxypropyl butyl cellulose and hydroxypropyl hexyl cellulose), poly(ethylene)oxide, alkyl cellulose (e.g., ethyl cellulose and methyl cellulose), carboxymethyl cellulose, hydrophilic cellulose derivatives, and polyethylene glycol, and compositions as described in WO 2006/037342, WO 2007/042034, WO 2007/042035, WO 2007/006308, WO 2007/006307, and WO 2006/050730.
  • Nrf2 Nuclear Factor-Erythroid 2-related factor 2; for sequence of the Nrf2, see Accession No. AAB32188
  • ARE antioxidant response element
  • the Nrf2/ARE pathway a major determinant of phase II gene induction, has been well characterized for its role in hepatic detoxification and chemoprevention through the activation of phase II gene expression.
  • ARE-regulated genes may also contribute to the maintenance of redox homeostasis by serving as endogenous anti-oxidant systems.
  • Nrf2-regulated genes contains over 200 genes encoding proteins and enzymes involved in detoxification and antioxidant response (Kwak et al., J. Biol. Chem., 2003, 278:8135) such as, e.g., glutathione peroxidase, glutathione-S-transferases (GSTs), NAD(P)H:quinone oxidoreductases, now commonly known as nicotinamide quinone oxidoreductase 1 (NQO1; EC 1.6.99.2; also known as DT diaphorase and menadione reductase), NQO2, g-glutamylcysteine synthase (g-GCS), glucuronosyltransferase, ferritin, and heme oxygenase-1 (HO-1), as well as any one of the enzymes proteins listed in Table 1 in Chen & Kunsch, Curr. Pharm. Designs, 2004, 10:879-8
  • the Nrf2-regulated gene which is used to assess the activation of the Nrf2 pathway is a phase II detoxification enzyme, an anti-oxidant enzyme, an enzyme of the NADPH generating system, and/or Nrf2 itself.
  • phase II detoxification enzymes include NQO1, NQO2, GST-Ya, GST-pi, GST-theta 2, GST-mu (1,2,3), microsomal GST 3, catalytic y-GCS, regulatory-GCS, microsomal epoxide hydrolase, UDP-glucuronosyltransferase, transaldolase, transketolase, and drug-metabolizing enzyme.
  • anti-oxidant enzymes examples include HO-1, ferritin (L), glutathione reductase, glutathione peroxidase, metallothionein I, thioredoxin, thioredoxin reductase, peroxiredoxin MSP23, Cu/Zn superoxide dismutase, and catalase.
  • the enzymes of the NADPH generating system include malic enzyme, UDP-glucose dehydrogenase, malate oxidoreductase, and glucose-6-phosphate dehydrogenase.
  • Nrf2 is sequestered in the cytoplasm to the actin-bound Kelch-like ECH-associated protein 1 (Keap1; Accession No. NP — 987096 for human Keap1), a Cullin3 ubiquitin ligase adaptor protein. More specifically, the N-terminal domain of Nrf2, known as Neh2 domain, is thought to interact with the C-terminal Kelch-like domain of Keap1. In response to xenobiotics or oxidative stress, Nrf2 is released from the Keap1/Nrf2 complex, thereby promoting nuclear translocation of Nrf2 and concomitant activation of ARE-mediated gene transcription.
  • Kelch-like ECH-associated protein 1 Kelch-like ECH-associated protein 1
  • Keap1 function requires association with Cullin3, a scaffold protein that positions Keap1 and its substrate in proximity to the E3 ligase Rbx1, allowing the substrate (Nrf2) to be polyubiquitinated and thus targeted for degradation.
  • the exact mechanism of how the Keap1/Nrf2 complex senses oxidative stress remains poorly understood.
  • Human Keap1 contains 25 cysteine residues that were hypothesized to function as sensors of oxidative stress; 9 of the cysteines are thought to be highly reactive (Dinkova-Kostova et al., PNAS, 2005, 102(12):4584-9).
  • DMF is neuroprotective in animal models of neuroinflammation and neurodegeneration and that it defends against oxidative stress-induced injury.
  • Linker R. A. et al. and Scannevin R. H. et al., supra see also Ellrichmann C, et al. PLoS One 2011; 6:e16172.
  • the neuroprotective effects of compounds of formula (I) can be evaluated in similar studies.
  • the neuroprotective effects of compounds of formula (I) can be investigated in the malonate striatal lesion model of excitotoxicity.
  • Malonate is a succinate dehydrogenase inhibitor, which is a mitochondrial enzyme that plays a central role in neuronal energy metabolism.
  • Injection of malonate into the striatal region of the brain produces a lesion that is excitotoxic in character, as it can be blocked by systemic administration of N-methyl-D-aspartate (NMDA) receptor antagonists and has little inflammatory involvement.
  • NMDA N-methyl-D-aspartate
  • Intrastriatal malonate injection has been used as a model for acute neurodegeneration, and the potential therapeutic effects of test compounds of formula (I) can be explored in this setting. See, e.g., Scannevin R. H.
  • cuprizone is a neurotoxicant that when administered chronically to mice results in demyelination in the central nervous system, and has been used as a model to investigate modulation of remyelination.
  • rapamycin in addition to cuprizone results in more robust and consistent demyelination, presumably due to the anti-proliferative effect of stimulating the mammalian target of rapamycin (mTOR) receptor and pathway.
  • mTOR mammalian target of rapamycin
  • ROS/RNS are most damaging in the brain and neuronal tissue, where they attack post-mitotic (i.e., non-dividing) cells such as glial cells and neurons, which are particularly sensitive to free radicals, leading to neuronal damage.
  • Oxidative stress has been implicated in the pathogenesis of a variety of neurodegenerative diseases, including MS, ALS, Alzheimer's disease, Huntington disease, and Parkinson's disease.
  • MS post-mitotic
  • glial cells and neurons which are particularly sensitive to free radicals, leading to neuronal damage.
  • Oxidative stress has been implicated in the pathogenesis of a variety of neurodegenerative diseases, including MS, ALS, Alzheimer's disease, Huntington disease, and Parkinson's disease.
  • van Muiswinkel et al. Curr. Drug Targets CNS—Neurol. Disord., 2005, 4:267-281.
  • Nrf2 An anti-oxidative enzyme under control of Nrf2, NQO1 (NAD(P)H dehydrogenase, quinone 1), was reported to be substantially upregulated in the brain tissues of AD and PD subjects (Muiswinkel et al., Neurobiol. Aging, 2004, 25:1253). Similarly, increased expression of NQO1 was reported in the ALS subjects' spinal cord (Muiswinkel et al., Curr. Drug Targets—CNS. Neurol. Disord., 2005, 4:267-281) and in active and chronic lesions in the brains of patients suffering from MS (van Horssen et al., Free Radical Biol . & Med., 2006, 41:311-311). These observations indicate that the Nr12 pathway may be activated in neurodegenerative and neuroinflammatory diseases as an endogenous protective mechanism.
  • the invention provides methods of treating, slowing, or preventing a neurological disease by treating (e.g., orally administering to) a subject in need thereof one or more compounds of formula (I).
  • neurological diseases include MS, ALS, Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • the subject is mammalian, and can be a rodent or another laboratory animal, e.g., a non-human primate. In preferred embodiments, the subject is human.
  • neurodegenerative diseases include acute haemorrhagic leucoencephalomyelitis, Hurst's disease, acute disseminated encephalomyelitis, optic neuritis, spinal cord lesions, acute necrotizing myelitis, transverse myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy (PML), radiation myelopathy, HTLV-1 associated myelopathy, monophasic isolated demyelination, central pontine myelinolysis, and leucodystrophy (e.g., adrenoleucodystrophy, metachromatic leucodystrophy, Krabbe's disease, Canavan's disease, Alexander's disease, Pelizaeus-Merbacher disease, vanishing white matter disease, oculodentodigital syndrome), chronic inflammatory demyelinating polyneuritis (CIDP), and acute inflammatory demyelinating polyneuropathy (AIDP).
  • CIDP chronic inflammatory
  • GBS Guillain-Barre syndrome
  • MG myasthenia gravis
  • ELS Eaton Lambert Syndrome
  • encephalomyelitis e.g., encephalomyelitis
  • Other diseases for which compounds of formula (I) may be therapeutically effective include inflammatory bowel disease, Crohn's disease, lupus, asthma, and other inflammatory diseases.
  • Nrf2 pathway Activation of the Nrf2 pathway has demonstrated protective benefits in several neurodegenerative disease models. See, e.g., Calkins M J et al., Toxicoi Sci 2010; 115:557-568.
  • EAE Experimental Autoimmune Encephalomyelitis
  • MS animal model such as Experimental Autoimmune Encephalomyelitis (EAE) (Tuohy et al., J. Immunol., 1988, 141:1126-1130, Sobel et al. J. Immunol., 1984, 132:2393-2401, and Traugott, Cell Immunol., 1989 119:114-129).
  • EAE Experimental Autoimmune Encephalomyelitis
  • Chronic relapsing EAE provides a well established experimental model for testing agents that would be useful for the treatment of MS.
  • the mouse EAE is an induced autoimmune demyelinating disease with many similarities to human MS in its clinical manifestations.
  • TMEV Thieler's murine encephalomyelitis virus
  • MHV murine hepatitis virus
  • Sindbis virus Sindbis virus as described in, e.g., Ercoli et al., J. immunol., 2006, 175:3293-3298.
  • ALS is a progressive neurodegenerative disease characterized by loss of both upper and lower motor neurons leading to body and facial muscle weakness. Life expectancy is approximately 3 years post diagnosis. The unmet need is extremely high as Rilutek (riluzole) is the only approved disease modifier and offers only a modest benefit (extends survival by about 3 months).
  • a commonly used animal model is the mouse model with ALS-linked SOD1 G93A mutation. It has been shown recently that activation of the Nrf2 pathway via genetic overexpression or pharmacological induction conferred benefit in an hSOD1 G93A animal model. See Vargas M. R., et al., J. Neurosci., 2008, 28(50):1357-13581.
  • AD Alzheimer's disease
  • Ab extracellular amyloid-beta
  • NFT neurofibrillary tangles
  • AD patients display prominent cognitive deficits such as memory loss, executive dysfunctioning, and behavior and psychological symptoms associated with dementia including paranoid and elusional behavior, hallucinations, anxieties and phobias.
  • AD animal models commonly used include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents.
  • spontaneous models in various species including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents.
  • Parkinson's disease is characterized by the loss of ⁇ 50-70% of the dopaminergic neurons in the substantia nigra pars compacta (SNc), a profound loss of dopamine (DA) in the striatum, and the presence of intracytoplasmic inclusions called Lewy bodies (LB), which are composed mainly of ⁇ -synuclein and ubiquitin.
  • SNc substantia nigra pars compacta
  • DA dopamine
  • LB Lewy bodies
  • PD animal models can typically be divided into toxin-based (those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP) rotenone, and paraquat) or genetic models such as those utilizing the in vivo expression of PD-related mutations (e.g., those related to alpha-synuclein, PINK1, Parkin and LRRK2).
  • 6-OHDA 6-hydroxydopamine
  • MPTP 1-methyl-1,2,3,6-tetrahydropiridine
  • paraquat paraquat
  • genetic models such as those utilizing the in vivo expression of PD-related mutations (e.g., those related to alpha-synuclein, PINK1, Parkin and LRRK2).
  • HD Huntington's disease
  • IT15 cognitive dysfunction and abnormal body movements
  • HD is characterized by progressive neurodegeneration of the striatum but also involves other regions, primarily the cerebral cortex.
  • HD animal models are typically either toxin-induced models or genetic models.
  • Toxin-induced models e.g., those based on 3-nitropropionic acid and quinolinic acid
  • mitochondrial impairment and excitotoxicity-induced cell death are both mechanisms of degeneration seen in the HD brain.
  • transgenic and knock-out mice include transgenic and knock-out mice, as well as a model that uses a viral vector to encode the gene mutation in certain areas of the brain.
  • a model that uses a viral vector to encode the gene mutation in certain areas of the brain See, e.g., Ramaswamy et al., ILAR J 2007; 48(9):356-373.
  • a compound may be optionally tested in at least one additional animal model (see, generally, Immunologic Defects in Laboratory Animals, eds. Gershwin et al., Plenum Press, 1981), for example, such as the following: the SWR X NZB (SNF1) mouse model (Uner et al., J. Autoimmune Disease, 1998, 11(3):233-240), the KRN transgenic mouse (K/BxN) model (Ji et al., Immunol.
  • SNF1 SWR X NZB
  • K/BxN KRN transgenic mouse
  • NZB X NZW mice a model for SLE (Riemekasten et al., Arthritis Rheum., 2001,) 44(10):2435-2445); the NOD mouse model of diabetes (Baxter et al., Autoimmunity, 1991, 9(1):61-67), etc.).
  • the invention further includes treating a subject having a neurodegenerative disease by combination therapy.
  • the method includes treating (e.g., orally administering to) a subject having or at risk of developing a neurodegenerative disease with a compound of formula (I) and one or more other compounds of formula (I) or one or more other therapeutic agents.
  • the one or more other therapeutic agents is a disease modifying agent.
  • the one or more other therapeutic agents alleviate the side effects of the compound of formula (I).
  • the one or more other therapeutic agent can be a therapeutic agent that can reduce the flushing (e.g., aspirin) or GI disturbance (e.g., loperamide).
  • the combination therapy requires orally administering two compounds wherein at least one of the two compounds is a compound of formula (I).
  • the subject can be treated with two compounds of formula (I).
  • the subject can be treated with a compound of formula (I) and DMF, MMF, or a DMF/MMF prodrug
  • the first compound and the second compound may be administered concurrently (as separate compositions or together in a single dosage form) or consecutively over overlapping or non-overlapping intervals.
  • the first compound and the second compound can be administered in any order.
  • the length of an overlapping interval is more than 2, 4, 6, 12, 24, 48 weeks or longer.
  • the compound of formula (I) and the one or more other therapeutic agents can be used to treat MS.
  • the one or more other therapeutic agents can be, e.g., interferon beta-1a (Avonex®, Rebif®), glatiramer (Copaxone®), modafinil, azathioprine, predisolone, mycophenolate, mofetil, mitoxantrone, natalizumab (Tysabri®), sphinogosie-1 phosphate modulator e.g., fingolimod (Gilenya®), and other drugs useful for MS treatment such as teriflunomide (Aubagio®), piroxicam, and phenidone.
  • interferon beta-1a Avonex®, Rebif®
  • glatiramer Copaxone®
  • modafinil modafinil
  • azathioprine predisolone
  • mycophenolate mofetil
  • mitoxantrone natalizuma
  • the compound of formula (I) and the one or more other therapeutic agents can be used to treat ALS.
  • the one or more other therapeutic agents is an agent or agents known or believe to be effective for ALS treatment, e.g., riluzole and dexpramipexole.
  • the compound of formula (I) and the one or more other therapeutic agents can be used to treat AD.
  • the one or more other therapeutic agents is an agent or agents known or believe to be effective for AD treatment, e.g., rosiglitazone, roloxifene, vitamin E, donepezil, tacrine, rivastigmine, galantamine, and memantine.
  • the compound of formula (I) and the one or more other therapeutic agents can be used to treat PD.
  • the one or more other therapeutic agents is an agent or agents known or believe to be effective for PD treatment include dopamine precursors such levodopa, dopamine agonists such as bromocriptine, pergolide, pramipexole, and ropinirole, MAO-B inhibitors such as selegiline, anticholinergic drugs such as benztropine, trihexyphenidyl, tricyclic antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, amantadine, and trimipramine, some antihistamines such as diphenhydramine; antiviral drugs such as amantadine.
  • dopamine precursors such levodopa
  • dopamine agonists such as bromocriptine
  • Useful drugs for treating symptoms of Huntington's disease further include selective serotonin reuptake inhibitors (SSRI) such as fluoxetine, paroxetine, sertraline, escitalopram, citalopram, fluvosamine; norepinephrine and serotoiun reuptake inhibitors (NSR1) such as venlafaxine and duloxetine.
  • SSRI selective serotonin reuptake inhibitors
  • NSR1 serotonin reuptake inhibitors
  • compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose (reduce or prevent neurodegeneration or neuroinflammation).
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose (reduce or prevent neurodegeneration or neuroinflammation).
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • the dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to Nrf2 activation); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents, as mentioned above, can be used in conjunction with the methods and compounds of the invention.
  • At least one compound of formula (I) or pharmaceutically acceptable salt thereof is administered in an amount and for a period of time sufficient to reduce or prevent neurodegeneration and neuroinflammation in the subject. In one embodiment, at least one compound is administered in an amount and for a period of time sufficient to reduce astrogliosis, demyelination, axonal loss, and/or neuronal death in the subject. In one embodiment, the at least one compound or pharmaceutically acceptable salt thereof is administered in an amount and for a period of time sufficient to provide neuroprotection (e.g., restoring or increasing myelin content) to the subject.
  • neuroprotection e.g., restoring or increasing myelin content
  • Methods of the invention may include treating the subject having a neurodegenerative disease with a therapeutically effective amount of at least one compound of formula (I), which can range from about 1 mg/kg to about 50 mg/kg (e.g., from about 2.5 mg/kg to about 20 mg/kg or from about 2.5 mg/kg to about 15 mg/kg). Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents.
  • a therapeutically effective amount of at least one compound of formula (I) can range from about 1 mg/kg to about 50 mg/kg (e.g., from about 2.5 mg/kg to about 20 mg/kg or from about 2.5 mg/kg to about 15 mg/kg).
  • Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents.
  • an effective dose of a compound of formula (I) to be administered to a subject can be from about 0.1 g to about 1 g per day, for example, from about 200 mg to about 800 mg per day (e.g., from about 240 mg to about 720 mg per day; or from about 480 mg to about 720 mg per day; or about 480 mg per day; or about 720 mg per day).
  • the daily doses may be administered in separate administrations of 2, 3, 4, or 6 equal doses.
  • the effective daily dose is about 720 mg per day and is administered in 3 equal doses to a subject in need thereof (i.e., three times a day, TID).
  • the effective daily dose is about 480 mg per day and is administered in 2 equal doses to a subject in need thereof (i.e., two times a day, BID).
  • the therapeutically effective dose of a compound of formula (I) is administered to a subject in need thereof for a period of time sufficient to reduce neurodegeneration and/or neuroinflammation, e.g., by at least 30%, 50%, 100% or higher over a control over a period of at least 5, 10, 12, 20, 40, 52, 100, or 200 weeks.
  • the pharmaceutical composition is administered at least one hour before or after food is consumed by the subject in need thereof.
  • the subject experiences side effects (e.g., flushing or GI discomfort)
  • the subject can consume food shortly (e.g., 30 mins to an hour) before administered the pharmaceutical composition.
  • the subject administered a compound of formula (I) may take one or more non-steroidal anti-inflammatory drugs (e.g., aspirin) before (for example, 10 minutes to an hour, e.g., 30 minutes before) taking the pharmaceutical composition.
  • the subject administered the pharmaceutical composition takes the one or more non-steroidal anti-inflammatory drugs (e.g., aspirin) to control side effects (e.g., flushing).
  • the one or more non-steroidal anti-inflammatory drugs is selected from a group consisting of aspirin, ibuprofen, naproxen, ketoprofen, celecoxib, MK-0524, and combinations thereof.
  • the one or more non-steroidal anti-inflammatory drugs can be administered in an amount of about 50 mg to about 500 mg before taking the dosage form described above.
  • a patient takes 325 mg aspirin before taking each dosage form described above.
  • the pharmaceutical preparation further comprises administering to the patient a first dose of the pharmaceutical preparation for a first dosing period; and administering to the patient a second dose of the pharmaceutical preparation for a second dosing period.
  • the first dose is lower than the second dose (e.g., the first dose is about half of the second dose).
  • the first dosing period is at least one week (e.g., 1-4 weeks).
  • the first dose of the pharmaceutical preparation comprises about 120 mg of a compound of formula (I) and the pharmaceutical preparation is administered to the patient BID or TID (e.g., BID) for the first dosing period.
  • the second dose of the first pharmaceutical preparation comprises about 240 mg of a compound of formula (I) and the first pharmaceutical preparation is administered to the patient BID or TID (e.g., BID) for the second dosing period.
  • the subject after being administered the dose at the second dosing period, experiences more than expected level of side effects (e.g., flushing or a gastrointestinal disturbance), the subject can use a lower dose (e.g., the dose at the first dosing period) for a period (e.g., 1-4 weeks or more) sufficient to allow the side effects to decrease before returning to the dose at the second dosing period.
  • Example 1 was dosed in 0.5% HPMC suspension @ 104 mg/kg (90 mg/kg MMF-eq) to male SD rats via oral gavage. Plasma samples were collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 12 hours and processed according to the above procedure. The concentration of D-MMF was determined by LC/MS/MS. Brain and CSF samples were collected at 30 min, 2 hr, 4 hr and 6 hr. The concentration of D-MMF was determined by LC/MS/MS.
  • Human cancer cell line DLD-1 and breast cancer cell line MCF7 reporter stable cell lines were generated by transfection with a firefly luciferase reporter construct harboring the luciferase cDNA cloned downstream of eight catenated copies of the antioxidant response element (ARE) (GACAAAGCACCCGT; SEQ ID NO.:1). See Wang et al. Cancer Res. 2006; 66:10983-94.
  • ARE antioxidant response element
  • the cells were plated in 96-well plates at 20-50 k cells/well 24 hours prior to stimulation with the test compounds.
  • the test compounds were prepared in dimethylsulfoxide (DMSO) and diluted with culture media to required concentrations (final DMSO concentrations ⁇ 0.3%).
  • DMSO dimethylsulfoxide
  • the reporter cells were harvested 24 hours-48 hours after addition of the compounds and lysed for detection of luciferase activity. Luciferase activity in the lysates was monitored using the Bright-Glo Luciferase Assay System of Promega and Tecan Genios Pro plate reader.
  • Luciferase induction in the compound-treated cells was calculated as fold change over the baseline activity detected in control cultures treated with DMSO-containing media.
  • Nrf2 Activation in DLD-1 and MCF-7 ARE-Luc Reporter Cell Line
  • Test compounds were dosed either in suspension of 0.8% HPMC or corn oil via oral gavage to male SD rats (average weight of 250 mg, 6 animals per group, two groups), at a dose of 100 mg/kg equivalent of DMF (dosing volume: 5 ml/kg). After 30 minutes, the first group of animals was sacrificed via CO2 asphyxiation. 1.0 mL blood sample via cardiac bleed pipetted into chilled lithium heparin tubes with 10 mg sodium fluoride. Samples were centrifuged within 30 minutes at 4° C. for 15 minutes at 1500 G and plasma was transferred to chilled tubes and immediately frozen on dry ice, further kept at ⁇ 70° C. until shipment for analysis. Brain was removed; sections were weighed and frozen until analysis.

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  • Dermatology (AREA)
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  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
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US14/136,990 2012-12-21 2013-12-20 Deuterium Substituted Fumarate Derivatives Abandoned US20140179779A1 (en)

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US10940117B2 (en) 2012-08-22 2021-03-09 Arbor Pharmaceuticals, Llc Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
US10945984B2 (en) 2012-08-22 2021-03-16 Arbor Pharmaceuticals, Llc Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects
US9597292B2 (en) 2012-08-22 2017-03-21 Xenoport, Inc. Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof
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US10105337B2 (en) 2014-02-28 2018-10-23 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
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US10959972B2 (en) 2014-11-17 2021-03-30 Biogen Ma Inc. Methods of treating multiple sclerosis
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US20180064653A1 (en) * 2015-03-17 2018-03-08 Hetero Labs Limited Pharmaceutical compositions of dimethyl fumarate
WO2016153957A3 (en) * 2015-03-20 2016-11-10 Biogen Ma Inc. Methods and compositions for the intravenous administration of fumarates for the treatment of neurological diseases
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US20140194427A1 (en) 2014-07-10

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