US20190135741A1 - Methods of Making Deuterium-Enriched N-acetylcysteine Amide (D-NACA) and (2R, 2R')-3,3'-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress - Google Patents

Methods of Making Deuterium-Enriched N-acetylcysteine Amide (D-NACA) and (2R, 2R')-3,3'-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress Download PDF

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US20190135741A1
US20190135741A1 US16/180,984 US201816180984A US2019135741A1 US 20190135741 A1 US20190135741 A1 US 20190135741A1 US 201816180984 A US201816180984 A US 201816180984A US 2019135741 A1 US2019135741 A1 US 2019135741A1
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acetamidopropanamide
dinaca
disulfanediyl bis
pharmaceutical composition
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G. Michael Wall
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Nacuity Pharmaceuticals Inc
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Priority to US16/180,984 priority Critical patent/US20190135741A1/en
Priority to RU2019126848A priority patent/RU2019126848A/ru
Priority to CA3131442A priority patent/CA3131442A1/en
Priority to KR1020227002489A priority patent/KR20220016304A/ko
Priority to PCT/US2018/059446 priority patent/WO2019094383A1/en
Priority to KR1020207016592A priority patent/KR102357471B1/ko
Priority to JP2019535295A priority patent/JP2021502323A/ja
Priority to EP18876329.6A priority patent/EP3534890A4/en
Priority to CN201880047207.0A priority patent/CN111201017A/zh
Priority to AU2018365900A priority patent/AU2018365900B2/en
Priority to CA3046363A priority patent/CA3046363C/en
Assigned to NACUITY PHARMACEUTICALS, INC. reassignment NACUITY PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WALL, G. MICHAEL
Publication of US20190135741A1 publication Critical patent/US20190135741A1/en
Priority to US16/928,927 priority patent/US11753370B2/en
Assigned to NACUITY PHARMACEUTICALS, INC. reassignment NACUITY PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WALL, G. MICHAEL
Priority to AU2020227015A priority patent/AU2020227015B2/en
Priority to AU2022275499A priority patent/AU2022275499B9/en
Priority to US18/347,896 priority patent/US20230373913A1/en
Priority to US18/597,021 priority patent/US20240217927A1/en
Priority to AU2025200018A priority patent/AU2025200018A1/en
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Definitions

  • the present invention relates in general to the field of making (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA), pharmaceutical compositions, and methods of making and using NACA-d 3 to treat diseases associated with oxidative damage including, but not limited to, antivenom, beta-thallassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson's disease, platelet apoptosis, Tardive dyskinesia, Alzheimer disease, HIV-1-associated dementia, mitochondrial diseases, myocardial myopathy, neurodegenerative diseases, pulmonary fibrosis, retinitis pigmentosa, age-related macular degeneration, skin pigmentation, skin in need of rejuventation, antimicrobial infection, and/or Friedreich's ataxia.
  • diseases associated with oxidative damage
  • RP Retinitis Pigmentosa
  • Rods are the major consumers of oxygen in the retina and the loss of rods causes an increase in the tissue oxygen level in the outer retina. This activates NADPH oxidase causing accumulation of superoxide radicals in the cytosol and also increases their generation in mitochondria of cones.
  • the excess superoxide radicals overwhelm superoxide dismutase 1 and 2 (SOD1 and SOD2) and cause a chain reaction by which other free radicals are generated including some that are even more damaging than superoxide radicals, such as hydroxyl radicals and peroxynitrite.
  • the free radicals attack proteins, lipids, and DNA causing specific modifications that indicate that oxidative damage has occurred. Oxidative damage to lipids results in lipid hydroperoxides that break down to form 4-hydroxynonenal, malondialdehyde (MDA), and acrolein.
  • MDA malondialdehyde
  • the most common modification to proteins from oxidative damage is the formation of carbonyl adducts.
  • Measurements of these markers of oxidative damage provide a quantitative assessment of the amount of oxidative damage that has occurred in a tissue. These modifications can impair the function of macromolecules and while there are endogenous repair processes, they are overwhelmed by severe oxidative stress resulting in reduced cellular function and eventually apoptosis. After rods are eliminated from the photoreceptor layer, oxidative stress in the outer retina is severe and leads to gradual cone cell death usually starting in the midperiphery where cone density is low and then spreading peripherally and posteriorly (centrally). The posterior spread of cone death results in constriction of the visual field and eventually a central island of vision and its elimination causes blindness.
  • Argis II Retinal Prosthesis System was approved by FDA in 2013 as an implanted Humanitarian device (HUD) to treat adults with several RP, it only produces the sensation of light, thereby helping patients identify the location or movement of objects and people; the device is not disease modifying. Based on studies in animal models described below, NACA is able to treat RP in vivo.
  • the present invention includes a pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)(diNACA) and derivatives or solids thereof.
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) has the following formula:
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 0.1 mole percent (mol %) to 97 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 5 mol % to 95 mol % of the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 78 mol % to 95 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 88 mol % to 92 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 78 mol % to 82 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 90 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 10 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 80 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 20 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 85 mol % of (2R,2R′)-3, (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)N-acetyl cysteine amide.
  • the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and derivatives or solids thereof comprises 70 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 30 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant or additive.
  • the diNACA is enantiopure (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the diNACA is enantiopure (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the diNACA is a racemic mixture of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the diNACA is enantiopure (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the diNACA is enantiopure (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the diNACA is a racemic mixture of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the present invention includes a method of treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)(diNACA) to a patient in need thereof.
  • a pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)(diNACA) to a patient in need thereof.
  • the disease is an eye disease or disorder.
  • the disease is retinitis pigmentosa.
  • the disease is antivenom, beta-thallassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson's disease, platelet apoptosis, Tardive dyskinesia, Alzheimer disease, HIV-1-associated dementia, mitochondrial diseases, myocardial myopathy, neurodegenerative diseases, pulmonary fibrosis, Friedreich's ataxia.
  • the present invention includes a method of making (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (DiNACA) comprising the steps of: forming L-Cystine Dimethylester Dihydrochloride from L-cystine by the following reaction:
  • the methods further comprises the step of purifying the DiNACA by the following reaction:
  • the purified diNACA comprises 0.1 mol % to 97 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the purified diNACA comprises 5 mol % to 95 mol % of the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the purified diNACA comprises 78 mol % to 95 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the purified diNACA comprises 88 mol % to 92 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the purified DiNACA comprises 78 mol % to 82 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the purified diNACA comprises 90 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 10 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). In another aspect, the purified diNACA comprises 80 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 20 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the purified diNACA comprises 85 mol % of (2R,2R′)-3, (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)N-acetyl cysteine amide.
  • the purified DiNACA comprises 70 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 30 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • the method further comprises the step of formulating a pharmaceutical composition by mixing the diNACA with a pharmaceutically acceptable adjuvant or additive.
  • the present invention includes a pharmaceutical composition comprising deuterated N-acetylcysteine amide (NACA-d 3 ), or a physiologically acceptable salt thereof, having a deuterium enrichment above the natural abundance of deuterium; and D 3 -N-acetyl cysteine amide, or a physiologically acceptable derivative thereof, having a deuterium enrichment above the natural abundance of deuterium.
  • NACA-d 3 deuterated N-acetylcysteine amide
  • D 3 -N-acetyl cysteine amide or a physiologically acceptable derivative thereof, having a deuterium enrichment above the natural abundance of deuterium.
  • the deuterated N-acetylcysteine amide has the following formula:
  • the pharmaceutical composition may comprise 0.1 mole/percent (mol %) to 97 mol % of the D 3 -N-acetyl cysteine amide. In another aspect, the pharmaceutical composition may comprise 5 mol % to 95 mol % of the D 3 -N-acetyl cysteine amide. In another aspect, the pharmaceutical composition may comprise 78 mol % to 95 mol % of the D 3 -N-acetyl cysteine amide. In another aspect, the pharmaceutical composition may comprise 88 mol % to 92 mol % of the D 3 -N-acetyl cysteine amide.
  • the pharmaceutical composition may comprise 78 mol % to 82 mol % of the D 3 -N-acetyl cysteine amide. In another aspect, the pharmaceutical composition may comprise 90 mol % of the D 3 -N-acetyl cysteine and 10 mol % of the N-acetyl cysteine amide. In another aspect, the pharmaceutical composition may comprise 80 mol % of the D 3 -N-acetyl cysteine and 20 mol % of the N-acetyl cysteine amide. In another aspect, the pharmaceutical composition may comprise 85 mol % of the D 3 -N-acetyl cysteine amide and 15 mol % of the N-acetyl cysteine amide.
  • the pharmaceutical composition may comprise 70 mol % of the D 3 -N-acetyl cysteine amide and 30 mol % of the N-acetyl cysteine amide.
  • the deuterium enrichment in D3-position in the D 3 -N-acetyl cysteine amide is about 90 mol % to 98 mol %.
  • the difference in the deuterium enrichment in the D3-positions in the D 3 -N-acetyl cysteine is about 8 to 10 percentage points.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant or additive.
  • the pharmaceutical composition may comprise deuterium enrichment above the natural abundance of deuterium is within a predefined range of 0.02 mol % to 100 mol % deuterium, as determined by NMR spectroscopy in d 6 -dimethyl sulfoxide using a 500 MHz spectrometer.
  • the NACA-d 3 is enantiopure (R)-2-acetylamino-3-mercapto-propamide.
  • the NACA-d 3 is enantiopure (S)-2-acetylamino-3-mercapto-propamide.
  • the NACA-d 3 is a racemic mixture of (R)-2-acetylamino-3-mercapto-propamide and (S)-2-acetylamino-3-mercapto-propamide.
  • the present invention includes a method of treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition of claim 1 to a patient in need thereof.
  • the disease is a disease of the eye.
  • the disease is retinitis pigmentosa.
  • the disease is antivenom, beta-thallassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson's disease, platelet apoptosis, Tardive dyskinesia, Alzheimer disease, HIV-1-associated dementia, mitochondrial diseases, myocardial myopathy, neurodegenerative diseases, pulmonary fibrosis, or Friedreich's ataxia.
  • the present invention includes a method of making deuterium enriched N-acetylcysteine amide (NACA-d 3 ) comprising the steps of:
  • the present invention includes a method of making deuterium enriched N-acetylcysteine amide (NACA-d 3 ) comprising the steps of:
  • FIG. 1 is an X-Ray Powder Diffractogram for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 2 shows proton nuclear magnetic spectrum for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 3 shows heteronuclear single quantum correlation spectrum for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 4 shows heteronuclear multiple-bond correlation spectrum for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 5 shows a combination thermogravimetric and differential thermal analysis for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 6 shows liquid chromatographic mass spectrometric data for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 7 shows chemical shift data for one batch of the N-2-acetyl-L-cysteineamide-d 3 (NACA-d 3 ) of the present invention.
  • FIG. 8 shows additional chemical shift data for another batch of the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • FIG. 9 shows MS results the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • FIG. 10 shows additional MS results the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • This invention pertains to (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide), which is also known as diNACA, diNaca, di-NACA, DiNACA, Di-NACA, dimer of NACA, NACA dimer, NACA disulfide, each of which is used interchangeably herein.
  • This invention pertains to deuterated N-acetylcysteine amide, also known as deuterated NPI-001, deuterated NACA, deuterated AD4, deuterated BB-001, deuterated (R)-2-acetylamino)-3-mercapto-propamide, deuterated N-acetyl-L-cysteinamide, or deuterated acetylcysteineamide.
  • This invention pertains to deuterated N-acetylcysteine amide, deuterated NPI-001, deuterated NACA, deuterated AD4, deuterated BB-001, deuterated (R)-2-acetylamino-3-mercapto-propamide, deuterated N-acetyl-L-cysteinamide, or deuterated acetylcysteineamide, all of which are used interchangeably.
  • This invention also pertains to NACA-d3 treatment of eye diseases associated with oxidative damage, but also other diseases associated with oxidative damage including, but not limited to, antivenom, beta-thallassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson's disease, platelet apoptosis, Tardive dyskinesia, Alzheimer disease, HIV-1-associated dementia, mitochondrial diseases, myocardial myopathy, neurodegenerative diseases, pulmonary fibrosis, Friedreich's ataxia.
  • diseases associated with oxidative damage including, but not limited to, antivenom, beta-thallassemia, cataract, chronic obstructive pulmonary disease, macular degeneration, contrast-induced nephropathy, asthma, lung contusion, methamphetamine-induced oxidative stress, multiple sclerosis, Parkinson's disease, platelet apoptosis, Tard
  • the term “deuterium-enriched” refers to the feature that the compound has a quantity of deuterium that is greater than in naturally occurring compounds or synthetic compounds prepared from substrates having the naturally occurring distribution of isotopes.
  • the invention provides deuterium-enriched, deuterated-N-acetyl cysteine amide, pharmaceutical compositions, and methods of treating eye disorders, and other medical disorders using, e.g., an enantiopure or enantio-enriched deuterium-enriched D 3 -N-acetyl cysteine amide (NACA-d 3 ).
  • NACA-d 3 an enantiopure or enantio-enriched deuterium-enriched D 3 -N-acetyl cysteine amide
  • the threshold amount of deuterium enrichment is specified in certain instances in this disclosure, and all percentages given for the amount of deuterium present are mole percentages.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the eye condition, eye disease, eye disorder, and the like, or ameliorating a symptom thereof.
  • the term “therapeutically effective amount” refers to an amount of a compound of the invention that is effective when administered alone or in combination to treat the desired condition or disorder.
  • a “therapeutically effective amount” includes an amount of the combination of compounds claimed that is effective to treat the desired condition or disorder.
  • the combination of compounds can be additive and is preferably a synergistic combination. Synergy occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower incidence of adverse side effects and/or toxicity, increased efficacy, or some other beneficial effect of the combination compared with the individual components.
  • DiNACA is typically administered in admixture with suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) selected based on the intended form of administration and as consistent with conventional pharmaceutical practices.
  • a pharmaceutically acceptable carrier or carrier materials selected based on the intended form of administration and as consistent with conventional pharmaceutical practices.
  • diNACA may be formulated to provide, e.g., maximum and/or consistent dosing for the particular form for oral, rectal, topical (including ophthalmic), inhalation, intranasal, injection (intravenous or intraocular) or parenteral administration. While diNACA may be administered alone, it will generally be provided in a stable form mixed with a pharmaceutically acceptable carrier.
  • the carrier may be solid or liquid, depending on the type and/or location of administration selected.
  • DiNACA may be included in a tablet.
  • Tablets may contain, e.g., suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and/or melting agents.
  • oral administration may be in a dosage unit form of a tablet, gelcap, caplet or capsule, the active drug component being combined with an non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, mixtures thereof, and the like.
  • an non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, mixtures thereof, and the like.
  • Suitable binders for use with the present invention include: starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants for use with the invention may include: sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, mixtures thereof, and the like.
  • Disintegrators may include: starch, methyl cellulose, agar, bentonite, xanthan gum, mixtures thereof, and the like.
  • DiNACA may be administered in the form of liposome delivery systems, e.g., small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles, whether charged or uncharged.
  • Liposomes may include one or more: phospholipids (e.g., cholesterol), stearylamine and/or phosphatidylcholines, mixtures thereof, and the like.
  • DiNACA may also be coupled to one or more soluble, biodegradable, bioacceptable polymers as drug carriers or as a prodrug.
  • polymers may include: polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, mixtures thereof, and the like.
  • diNACA may be coupled one or more biodegradable polymers to achieve controlled release of the diNACA
  • biodegradable polymers for use with the present invention include: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels, mixtures thereof, and the like.
  • the term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds, wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
  • the pharmaceutically acceptable salts include the conventional quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, bisulfonic, carbonic, citric, edetic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauric, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, naphthylic, nitric, oleic, oxalic,
  • a dosage unit for use of the deuterated-N-acetyl cysteine amide of the present invention may be a single compound or mixtures thereof with other compounds, e.g., a potentiator.
  • the compounds may be mixed together, form ionic or even covalent bonds.
  • the deuterated-N-acetyl cysteine amide of the present invention may be administered in oral, intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • different dosage forms e.g., tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, gels, solutions, and emulsions may be used to provide the deuterated-N-acetyl cysteine amide of the present invention to a patient in need of therapy that includes D 3 -N-acetyl cysteine amide.
  • Deuterated-N-acetyl cysteine amide is typically administered in admixture with suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) selected based on the intended form of administration and as consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials
  • the deuterated-N-acetyl cysteine amide may be formulated to provide, e.g., maximum and/or consistent dosing for the particular form for oral, rectal, topical (including ophthalmic), inhalation, intranasal, injection (intravenous or intraocular) or parenteral administration.
  • deuterated-N-acetyl cysteine amide may be administered alone, it will generally be provided in a stable form or derivatives thereof mixed with a pharmaceutically acceptable carrier.
  • the carrier may be solid or liquid, depending on the type and/or location of administration selected.
  • deuterium ( 2 H) is a stable, non-radioactive isotope of 1 H hydrogen and has an atomic weight of 2.014. Hydrogen naturally occurs as a mixture of the isotopes: hydrogen ( 1 H), deuterium ( 2 H), and tritium ( 3 H). The skilled artisan recognizes that in all chemical compounds with an H atom, the H atom actually represents a mixture of 1 H, 2 H, and 3 H, where about 0.015% is deuterium. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% are considered unnatural and, as a result, novel over their non-enriched counterparts.
  • the deuterium-enriched D 3 -N-acetyl cysteine amide described herein includes deuterium enrichment for D 3 -N-acetyl cysteine amide and optionally in other locations in the compound. Deuterium-enrichment reduces the rate at which the two enantiomers of D 3 -N-acetyl cysteine amide may interconvert. Further, the deuterium-enriched D 3 -N-acetyl cysteine amide described herein is provided in enantiomerically pure form.
  • This enantiomerically pure, deuterium-enriched D 3 -N-acetyl cysteine amide provides for a better therapeutic agent than non-deuterated D 3 -N-acetyl cysteine amide and/or racemic mixtures of the compound.
  • the present invention provides deuterium-enriched compounds for use in the therapeutic methods and pharmaceutical compositions described herein.
  • the deuterium-enriched compounds are provided in high enantiomeric purity in order to maximize therapeutic benefit, such as maximal potency per dose of therapeutic agent and minimize adverse side effects, such as off-target effects.
  • gelatin capsules may include deuterated-N-acetyl cysteine amide, diNACA, or both and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • diluents may be used to make compressed tablets. Both tablets and capsules may be manufactured as immediate-release, mixed-release or sustained-release formulations to provide for a range of release of medication over a period of minutes to hours.
  • Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere.
  • An enteric coating may be used to provide selective disintegration in, e.g., the gastrointestinal tract.
  • the deuterated-N-acetyl cysteine amide, diNACA, or both may be administered in the form of liposome delivery systems, e.g., small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles, whether charged or uncharged.
  • Liposomes may include one or more: phospholipids (e.g., cholesterol), stearylamine and/or phosphatidylcholines, mixtures thereof, and the like.
  • the deuterated-N-acetyl cysteine amide, diNACA, or both may also be coupled to one or more soluble, biodegradable, bioacceptable polymers as drug carriers or as a prodrug.
  • Such polymers may include: polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, mixtures thereof, and the like.
  • the deuterated-N-acetyl cysteine amide may be coupled one or more biodegradable polymers to achieve controlled release of the deuterated-N-acetyl cysteine amide
  • biodegradable polymers for use with the present invention include: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels, mixtures thereof, and the like.
  • the oral drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, surfactants, coloring agents, and melting agents, mixtures thereof, and the like.
  • Liquid dosage forms for oral administration may also include coloring and flavoring agents that increase patient acceptance and therefore compliance with a dosing regimen.
  • Solutions for parenteral administration include generally, a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering salts.
  • suitable stabilizing agents e.g., water, a suitable oil, saline, aqueous dextrose (e.g., glucose, lactose and related sugar solutions) and glycols (e.g., propylene glycol or polyethylene glycols) may be used as suitable carriers for parenteral solutions.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite and/or ascorbic acid, either alone or in combination, are suitable stabilizing agents.
  • Citric acid and its salts and sodium EDTA may also be included to increase stability.
  • parenteral solutions may include pharmaceutically acceptable preservatives, e.g., benzalkonium chloride, methyl- or propyl-paraben, and/or chlorobutanol.
  • pharmaceutically acceptable preservatives e.g., benzalkonium chloride, methyl- or propyl-paraben, and/or chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field, relevant portions incorporated herein by reference.
  • Topical Lotions, Gels, Creams, Solutions or Suspensions For topical administration in a liquid dosage form, the drug components may be combined with numerous non-toxic, pharmaceutically acceptable inert excipients such as ethanol, glycerol, water, and some non-aqueous moieties. Formulations may be sterile or non-sterile. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, thickeners, viscosity-modifiers, surfactants, coloring agents, and melting agents, mixtures thereof, and the like.
  • Capsules may be prepared by filling standard two-piece hard gelatin or hydroxypropyl methylcellulose capsules each with 10 to 500 milligrams of powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose and 6 milligrams magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient is dissolved in a digestible oil such as soybean oil, cottonseed oil or olive oil. The active ingredient is prepared and injected by using a positive displacement pump into gelatin to form soft gelatin capsules containing, e.g., 100-500 milligrams of the active ingredient. The capsules are washed and dried.
  • a digestible oil such as soybean oil, cottonseed oil or olive oil.
  • the active ingredient is prepared and injected by using a positive displacement pump into gelatin to form soft gelatin capsules containing, e.g., 100-500 milligrams of the active ingredient. The capsules are washed and dried.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100-500 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • effervescent tablet appropriate amounts of, e.g., monosodium citrate and sodium bicarbonate, are blended together and then roller compacted, in the absence of water, to form flakes that are then crushed to give granulates.
  • the granulates are then combined with the active ingredient, drug and/or salt thereof, conventional beading or filling agents and, optionally, sweeteners, flavors and lubricants.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in deionized water and mixed with, e.g., up to 10% by volume propylene glycol and water.
  • the solution is made isotonic with sodium chloride and sterilized using, e.g., ultrafiltration.
  • aqueous suspension is prepared for oral administration so that each 5 ml contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin.
  • An inhalation or intranasal formulation includes a solution, suspension, semi-solid formulation, dry powder, or other formulation administered intranasally.
  • a sterile injectable formulation includes a solution or suspension that is suitable for intramuscular, intravenous, intraocular (including intravitreal or intracameral) or subcutaneous administration.
  • injectable formulations are isosmotic, usually with osmaolarity similar to isotonic 0.9% saline solution, and pH balanced, usually with a neutral pH.
  • the active ingredient is compressed into a hardness in the range 6 to 12 Kp.
  • the hardness of the final tablets is influenced by the linear roller compaction strength used in preparing the granulates, which are influenced by the particle size of, e.g., the monosodium hydrogen carbonate and sodium hydrogen carbonate. For smaller particle sizes, a linear roller compaction strength of about 15 to 20 KN/cm may be used.
  • chewable refers to semi-soft, palatable and stable chewable treat without addition of water. It should be appreciated to the skilled artisan that a chewable composition will be stable and palatable, fast disintegrating, semi-soft medicated chewable tablets (treats) by extrusion without the addition of extraneous water. A soft chewable tablets does not harden on storage and are resistant to microbial contamination.
  • a semi-soft chewable contain a blend of any one or more of binders, flavors, palatability enhancers, humectants, disintegrating agents, non-aqueous solvents, and diluents that are plasticized with liquid plasticizers, such as glycols and polyols to make them ductile and extrudable.
  • the chewable can be made by extrusion, e.g., including fats or lipids as plasticizers and binding agents, is manufactured in the absence of added water, uses plasticizers to replace water in extrudable matrices, contains humectants to maintain the extrudable chew in a pliant and soft state during its shelf life, or any combination thereof.
  • the chewable form may be provided in conjunction with one or more flavorings and/or taste masking agents that improve the taste of the formulation greater than 10, 20, 30, 40, 50, 60, 70, 80, or 90%.
  • the chewable can include the active agent and the ion exchange resin to enhance taste masking.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorings and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Enantiopurity covers both the R and S enantiomers of diNACA.
  • the natural enantiomer i.e., the enantiomer found in nature for cysteine is L-cysteine.
  • L-cysteine When L-cysteine is converted by chemical synthesis to diNACA with no racemization, the result is di-L-NACA which is equivalent to (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide).
  • Enantiopurity covers both the R and S enantiomers of NACA-d3.
  • the natural enantiomer i.e., the enantiomer found in nature for cysteine is L-cysteine.
  • L-cysteine When L-cysteine is converted by chemical synthesis to NACA with no racemization, the result is N-acetyl-L-cysteine amide, which is equivalent to (R)-2-acetylamino-3-mercapto-propamide.
  • NACA N-acetylsysteine amide
  • NACA-d3 is the reduction in metabolism rate compared to the non-deuterated NACA.
  • Non-deuterated NACA has a plasma half-life of approximately 2 hours in fasting subjects and approximately 6 hours in fed subjects.
  • the major metabolite of NACA is N-acetylcysteine (NAC) afforded by deamidation of the primary amide functional group of NACA by tissue (e.g., plasma or other tissue) amidase.
  • NACA cysteine afforded by (a) deamidation of the primary amide functional group of NACA by tissue (e.g., plasma or other tissue) amidase and (b) de-acetylation of the secondary amide functional group of NACA by tissue (e.g., plasma or other tissue) amidase.
  • tissue e.g., plasma or other tissue
  • replacement of the acetyl methyl group hydrogen atoms with deuterium atoms slows down the action of tissue amidases on both (primary and secondary) amide functional groups of NACA-d3, thereby prolonging its residence time in the body, i.e., increasing the half-life in the body.
  • Step 1 (01NPI01-01) was performed in a 2000L glass-lined reactor using 67 kg of L-cystine.
  • the material was treated with methanol (1323 kg, 25 vol) and thionyl chloride (80 kg, 2.41 eq) and agitated for 1 hour before heating to reflux.
  • IPC In-Process Control
  • the reaction was deemed complete.
  • the methanol was exchanged with methyl t-butylether and the product isolated by filtration. Due to the scale, the isolation occurred in three portions with the first and some of the second portion being carried forward without drying. The remainder of the material was dried under vacuum to yield L-cystine dimethylester dihydrochloride.
  • Step 2 was carried out in a 2000L glass-lined reactor by treating 44 kg of L-cystine dimethylester dihydrochloride with acetonitrile (799 kg, 23 vol), cooling to 0 ⁇ 5° C. and sparging with nitrogen for 30 minutes. Triethylamine (55 kg, 4.2 eq) was added followed by slow addition of acetic anhydride (28 kg, 2.1 eq) while maintaining the internal temperature at ⁇ 5° C. The reaction was stirred for 30 minutes and then sampled until the IPC met the criteria for completion, less than 1% of L-cystine dimethylester dihyrochloride remaining.
  • Step 3 was performed by first sparging 28-30% ammonium hydroxide (244 kg, 8.44 eq) with nitrogen for 30 minutes. The solution was then cooled to 0 ⁇ 5° C. and 87.1 kg of DiNACMe added. The solution was stirred at 0 ⁇ 5° C. for 4 hours before sampling. The IPC showed 0.1% DiNACMe remaining and was deemed complete.
  • the ammonium hydroxide was distilled to ⁇ 87L and exchanged with degassed ethanol (3 ⁇ 344 kg) to a volume of ⁇ 87L. Upon completion of the solvent exchanges, degassed ethanol (344 kg, 4 vol) was added and the slurry stirred for 1 hour at 0 ⁇ 5° C. The material was filtered, washed with degassed ethanol and dried under vacuum to yield 50.25 kg (63%) of diNACA.
  • Step 3A the recrystallization of diNACA from water, was performed in a 200L glass-lined reactor.
  • Batch 01NPI03A-01 involved the recrystallization of 25.1 kg of diNACA from degassed water (151 kg, 6 vol) to yield 17.05 kg of diNACA.
  • the remaining 25.1 kg of diNACA was recrystallized in batch 01NPI03A-02 to give 17.5 kg of diNACA.
  • Both lots of recrystallized diNACA were combined (34.55 kg) and recrystallized a final time in batch 01NPI03A-03 to give 28.3 kg of purified diNACA.
  • FIG. 1 is an X-Ray Powder Diffractogram for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 2 shows proton nuclear magnetic spectrum for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 3 shows heteronuclear single quantum correlation spectrum for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 4 shows heteronuclear multiple-bond correlation spectrum for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 5 shows a combination thermogravimetric and differential thermal analysis for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • FIG. 6 shows liquid chromatographic mass spectrometric data for (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) of the present invention.
  • Sodium phosphate, propylene glycol, Pluronic F127, edetate disodium benzalkonium chloride are dissolved in 800 ml of water.
  • the pH is adjusted with dilue HCl or NaOH.
  • DiNACA is added.
  • the osmolarity is within 250 to 350 mOsm Kg.
  • Solution is q.s. with water to a total of 1 liter.
  • the formulation is sterilized by autoclave. This is only one ophthalmic formulation and does not exclude other solution formulations.
  • Isolated or purified compounds are a group of compounds that have been separated from their environment, such as from a crude reaction mixture if made in a laboratory setting or removed from their natural environment if naturally occurring.
  • Examples of the purity of the isolated compound include, for example, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, to 100% by weight.
  • Another aspect of the invention provides a unit quantum of a compound described herein, such as an amount of at least (a) one microgram of a disclosed compound, (b) one mg, or (c) one gram.
  • the quantum is, for example, at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, or 1 mole of the compound.
  • the present amounts also cover lab-scale (e.g., gram scale including 1, 2, 3, 4, 5 g, etc.), kilo-lab scale (e.g., kilogram scale including 1, 2, 3, 4, 5 kg, etc.), and industrial or commercial scale (e.g., multi-kilogram or above scale including 100, 200, 300, 400, 500 kg, etc.) quantities as these will be more useful in the actual manufacture of a pharmaceutical.
  • Industrial/commercial scale refers to the amount of product that would be produced in a batch that was designed for clinical testing, formulation, sale/distribution to the public, etc.
  • Doses of a compound provided herein, or a pharmaceutically acceptable salt thereof vary depending on factors such as: specific indication to be treated; age and condition of a patient; and amount of a second active agent used, if any.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof may be used in an amount of from about 0.1 mg to about 1 g per day, or from about 0.1 mg to about 500 mg per day, and can be adjusted in a conventional fashion (e.g., the same amount administered each day of the treatment), in cycles (e.g., one week on, one week off), or in an amount that increases or decreases over the course of treatment.
  • the dose can be from about 1 mg to 1000 mg, from about 1 mg to about 450 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 300 mg, from about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg.
  • the daily dose can be from about 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, 275 mg to 300 mg, 300 mg to 325 mg, 325 mg to 350 mg, 350 mg to 375 mg, 375 mg to 400 mg, 400 mg to 425 mg, or 425 mg to 450 mg.
  • (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) is administered at a daily dosage in the range of about 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, or 275 mg to 300 mg.
  • (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) is administered at a daily dosage in the range of about 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, or 275 mg to 300 mg.
  • (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) is administered at a daily dosage in the range of about 125 mg to 150 mg or 150 mg to 175 mg.
  • (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) is administered at a daily dosage in the range of about 125 mg to 175 mg. In certain embodiments, (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) is administered at a daily dosage in the range of about 140 mg to 160 mg. In yet other embodiments, (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) is administered at a daily dosage in the range of about 50 mg to 175 mg, or about 125 mg to 175 mg.
  • the daily dose is less than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, or 450 mg. In yet other embodiments, the daily dose is less than about 125 mg, 150 mg, or 175 mg.
  • the formulation may also exclude non-active ingredients, in which case the formulation will “consist essentially” of the active agents claimed herein, as non-active ingredients.
  • the formulation may also exclude all other ingredients, in which case the formulation will “consist” of the active agents. Each of these variants are contemplated herein.
  • NACA-d 3 A process for preparing 10 mg of D 3 -N-acetyl cysteine amide 5 (NACA-d 3 ) is described.
  • the inventors used various approaches to make D 3 -N-acetyl cysteine amide by using the chemistry shown in Scheme 1. In each case, the inventors observed a mixture of compounds while forming the methyl ester 3 and LCMS suggests that several other compounds were made, including 4 in addition to the desired 3. Treatment of this mixture with ammonium hydroxide gave 6, with no observation of the desired 5 by LCMS.
  • Cysteine methyl ester 7 (Scheme 2) allows the elimination of the problematic transformation of 2 to 3. Acetylation affords 3 directly from 7 and then reaction with ammonium hydroxide provides the target compound 5.
  • FIG. 7 shows chemical shift data for one batch of the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • FIG. 8 shows chemical shift data for another batch of the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • FIG. 9 shows MS results the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • FIG. 10 shows MS results the N-2-acetyl-L-cysteineamide-d 3 of the present invention.
  • NACA-d 3 is dissolved in a mixture of water and Ora-Sweet®.
  • Ora-Sweet is a commercially available syrup vehicle containing water, sucrose, glycerin, sorbitol, flavoring, buffering agents (citric acid and/or sodium phosphate), methyl paraben and potassium sorbate, pH 4.2 manufactured by Paddock Laboratories, Inc., Minneapolis, Minn.
  • ORA-SWEET has a cherry syrup flavor.
  • Neat NACA-d3 has a mild sulfur odor. When mixed with ORA-SWEET there is no odor and the taste is that of ORA-SWEET only.
  • ORA-SWEET is a pale pink clear solution. The lowest concentration of NACA-d3 (250 mg/100 ml ORA-SWEET) is a pale pink clear solution while the highest concentration of NACA-d3 (4,000 mg/100 ml ORA-SWEET) is a very pale pink clear solution.
  • Sodium phosphate, propylene glycol, Pluronic F127, edetate disodium benzalkonium chloride are dissolved in 800 ml of water.
  • the pH is adjusted with dilute HCl or NaOH.
  • NACA-d3 is added.
  • the osmolarity is within 250 to 350 mOsm Kg.
  • Solution is q.s. with water to a total of 1 liter.
  • the formulation is sterilized by autoclave. This is only one ophthalmic formulation and does not exclude other solution formulations.
  • Isolated or purified compounds are a group of compounds that have been separated from their environment, such as from a crude reaction mixture if made in a laboratory setting or removed from their natural environment if naturally occurring.
  • Examples of the purity of the isolated compound include, for example, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% by weight.
  • Another aspect of the invention provides a unit quantum of a deuterium-enriched compound described herein, such as an amount of at least (a) one microgram of a disclosed deuterium-enriched compound, (b) one mg, or (c) one gram.
  • the quantum is, for example, at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, or 1 mole of the compound.
  • the present amounts also cover lab-scale (e.g., gram scale including 1, 2, 3, 4, 5 g, etc.), kilo-lab scale (e.g., kilogram scale including 1, 2, 3, 4, 5 kg, etc.), and industrial or commercial scale (e.g., multi-kilogram or above scale including 100, 200, 300, 400, 500 kg, etc.) quantities as these will be more useful in the actual manufacture of a pharmaceutical.
  • Industrial/commercial scale refers to the amount of product that would be produced in a batch that was designed for clinical testing, formulation, sale/distribution to the public, etc.
  • Doses of a compound provided herein, or a pharmaceutically acceptable salt thereof vary depending on factors such as: specific indication to be treated; age and condition of a patient; and amount of a second active agent used, if any.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof may be used in an amount of from about 0.1 mg to about 1 g per day, or from about 0.1 mg to about 500 mg per day, and can be adjusted in a conventional fashion (e.g., the same amount administered each day of the treatment), in cycles (e.g., one week on, one week off), or in an amount that increases or decreases over the course of treatment.
  • the dose can be from about 1 mg to 1000 mg, from about 1 mg to about 450 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 300 mg, from about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg.
  • the daily dose can be from about 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, 275 mg to 300 mg, 300 mg to 325 mg, 325 mg to 350 mg, 350 mg to 375 mg, 375 mg to 400 mg, 400 mg to 425 mg, or 425 mg to 450 mg.
  • the deuterium-enriched D 3 -N-acetyl cysteine amide is administered at a daily dosage in the range of about 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, or 275 mg to 300 mg.
  • the deuterium-enriched D 3 -N-acetyl cysteine amide is administered at a daily dosage in the range of about 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, or 275 mg to 300 mg.
  • the deuterium-enriched D 3 -N-acetyl cysteine amide is administered at a daily dosage in the range of about 125 mg to 150 mg or 150 mg to 175 mg.
  • the deuterium-enriched D 3 -N-acetyl cysteine amide is administered at a daily dosage in the range of about 125 mg to 175 mg. In certain embodiments, the deuterium-enriched D 3 -N-acetyl cysteine amide is administered at a daily dosage in the range of about 140 mg to 160 mg. In yet other embodiments, the D 3 -N-acetyl cysteine amide-enriched D 3 -N-acetyl cysteine amide is administered at a daily dosage in the range of about 50 mg to 175 mg, or about 125 mg to 175 mg.
  • the daily dose is less than about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, or 450 mg. In yet other embodiments, the daily dose is less than about 125 mg, 150 mg, or 175 mg.
  • the formulation may also exclude non-active ingredients, in which case the formulation will “consist essentially” of the active agents claimed herein, as non-active ingredients.
  • the formulation may also exclude all other ingredients, in which case the formulation will “consist” of the active agents. Each of these variants are contemplated herein.
  • compositions of the invention can be used to achieve methods of the invention.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • “comprising” may be replaced with “consisting essentially of” or “consisting of”.
  • the phrase “consisting essentially of” requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention.
  • the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), property(ies), method/process steps or limitation(s)) only.
  • A, B, C, or combinations thereof refers to all permutations and combinations of the listed items preceding the term.
  • “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.
  • expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth.
  • BB BB
  • AAA AAA
  • AB BBC
  • AAABCCCCCC CBBAAA
  • CABABB CABABB
  • words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
  • the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skill in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
  • a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
  • each dependent claim can depend both from the independent claim and from each of the prior dependent claims for each and every claim so long as the prior claim provides a proper antecedent basis for a claim term or element.

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US16/180,984 2017-11-09 2018-11-05 Methods of Making Deuterium-Enriched N-acetylcysteine Amide (D-NACA) and (2R, 2R')-3,3'-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress Abandoned US20190135741A1 (en)

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US16/180,984 US20190135741A1 (en) 2017-11-09 2018-11-05 Methods of Making Deuterium-Enriched N-acetylcysteine Amide (D-NACA) and (2R, 2R')-3,3'-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress
AU2018365900A AU2018365900B2 (en) 2017-11-09 2018-11-06 Methods of making deuterium-enriched N-acetylcysteine amide (d-NACA) and (2R,2R')-3,3' -disulfanediyl bis(2-acetamidopropanamide) (diNACA) and using d-NACA and diNACA to treat diseases involving oxidative stress
CA3046363A CA3046363C (en) 2017-11-09 2018-11-06 Methods of making deuterium-enriched n-acetylcysteine amide (d-naca) and (2r,2r')-3,3'-disulfanediyl bis(2-acetamidopropanamide) (dinaca) and using d-naca and dinaca to treat diseases involving oxidative stress
KR1020227002489A KR20220016304A (ko) 2017-11-09 2018-11-06 중수소 농축 N-아세틸시스테인 아미드(D-NACA) 및 (2R,2R')-3,3'-디설판디일 비스(2-아세트아미도프로판아미드)(Di-NACA)의 제조방법 및 산화 스트레스를 포함하는 질환을 치료하기 위한 D-NACA 및 Di-NACA의 사용방법
PCT/US2018/059446 WO2019094383A1 (en) 2017-11-09 2018-11-06 Methods of making deuterium-enriched n-acetylcysteine amide (d-naca) and (2r,2r')-3,3' -disulfanediyl bis(2-acetamidopropanamide) (dinaca) and using d-naca and dinaca to treat diseases involving oxidative stress
KR1020207016592A KR102357471B1 (ko) 2017-11-09 2018-11-06 중수소 농축 N-아세틸시스테인 아미드(D-NACA) 및 (2R,2R')-3,3'-디설판디일 비스(2-아세트아미도프로판아미드)(Di-NACA)의 제조방법 및 산화 스트레스를 포함하는 질환을 치료하기 위한 D-NACA 및 Di-NACA의 사용방법
JP2019535295A JP2021502323A (ja) 2017-11-09 2018-11-06 重水素濃縮ｎ−アセチルシステインアミド（ｄ−ｎａｃａ，ｄｅｕｔｅｒｉｕｍ−ｅｎｒｉｃｈｅｄ ｎ−ａｃｅｔｙｌｃｙｓｔｅｉｎｅ ａｍｉｄｅ）及び（２ｒ，２ｒ’）−３，３’−ジスルファンジイルビス（２−アセトアミドプロパンアミド）（ｄｉｎａｃａ）を作製する、並びに酸化ストレスが関与する疾患を治療するためにｄ−ｎａｃａ及びｄｉｎａｃａを使用する方法
EP18876329.6A EP3534890A4 (en) 2017-11-09 2018-11-06 METHOD FOR THE PRODUCTION OF DEUTERIUM-REFINED N-ACETYLCYSTEINAMIDE (D-NACA) AND (2R, 2R ') - 3,3'-DISULFANDIYL-BIS (2-ACETAMIDOPROPANAMIDE) (DINACA) AND USE OF D-NACA AND DINACA FOR THE TREATMENT OF ILLNESSES IN CONNECTION WITH OXIDATIVE STRESS
CN201880047207.0A CN111201017A (zh) 2017-11-09 2018-11-06 制备富含氘的n-乙酰基半胱氨酸酰胺(d-naca)和(2r,2r′)-3,3′-二硫烷二基双(2-乙酰氨基丙酰胺)(dinaca)及使用d-naca和dinaca治疗涉及氧化应激的疾病的方法
RU2019126848A RU2019126848A (ru) 2017-11-09 2018-11-06 Способы производства дейтерий-обогащённого N-ацетилцистеин амида (D-NACA) и (2R,2R')-3,3'-дисульфанедиил бис(2-ацетамидопропанамида) (DINACA) и применение D-NACA и DINACA для лечения заболеваний, включающих окислительный стресс
CA3131442A CA3131442A1 (en) 2017-11-09 2018-11-06 Methods of making deuterium-enriched n-acetylcysteine amide (d-naca) and (2r,2r')-3,3'-disulfanediyl bis(2-acetamidopropanamide) (dinaca) and using d-naca and dinaca to treat diseases involving oxidative stress
US16/928,927 US11753370B2 (en) 2017-11-09 2020-07-14 Methods of making deuterium-enriched N-acetylcysteine amide (d-NACA) and (2R, 2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA) and using d-NACA and diNACA to treat diseases involving oxidative stress
AU2020227015A AU2020227015B2 (en) 2017-11-09 2020-09-01 Methods of making deuterium-enriched n-acetylcysteine amide (d-naca) and (2r,2r’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (dinaca) and using d-naca and dinaca to treat diseases involving oxidative stress
AU2022275499A AU2022275499B9 (en) 2017-11-09 2022-11-25 Methods of making deuterium-enriched n-acetylcysteine amide (d-naca) and (2r,2r’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (dinaca) and using d-naca and dinaca to treat diseases involving oxidative stress
US18/347,896 US20230373913A1 (en) 2017-11-09 2023-07-06 Methods of Making Deuterium-Enriched N-Acetylcysteine Amide (D-NACA) and (2R,2R)-3,3-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress
US18/597,021 US20240217927A1 (en) 2017-11-09 2024-03-06 Methods of Making Deuterium-Enriched N-Acetylcysteine Amide (D-NACA) and (2R,2R)-3,3-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress
AU2025200018A AU2025200018A1 (en) 2017-11-09 2025-01-02 Methods of making deuterium-enriched n-acetylcysteine amide (d-naca) and (2r,2r’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (dinaca) and using d-naca and dinaca to treat diseases involving oxidative stress

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