US2019135741A1PendingUtilityA1

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

50
Assignee: NACUITY PHARMACEUTICALS INCPriority: Nov 9, 2017Filed: Nov 5, 2018Published: May 9, 2019
Est. expiryNov 9, 2037(~11.3 yrs left)· nominal 20-yr term from priority
Inventors:G. Michael Wall
A61P 27/02C07C 319/12C07C 319/22A61K 31/16A61K 9/0048A61P 39/06C07D 277/12C07C 319/24C07B 2200/07A61K 9/08C07C 323/41C07C 319/28A61K 31/185A61K 47/10C07B 2200/05A61P 27/12A61P 17/00A61P 11/00A61P 9/00A61P 25/28A61K 31/00
50
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention includes pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)(diNACA) or D 3 -N-acetyl cysteine amide, or a physiologically acceptable salt thereof, having a deuterium enrichment above the natural abundance of deuterium, and derivatives or solids thereof, and methods of using diNACA to treat eye diseases and other diseases associated with oxidative damage including, e.g., 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, skin pigmentation, skin in need of rejuventation, antimicrobial infection, Friedreich's ataxia.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediylbis(2-acetamidopropanamide)(diNACA) and derivatives or solids thereof. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical composition of  claim 1 , comprising 0.1 mole percent (mol %) to 97 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 5 mol % to 95 mol % of the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 78 mol % to 95 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 88 mol % to 92 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); or 78 mol % to 82 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         4 . The pharmaceutical composition of  claim 1 , comprising 90 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 10 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 80 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 20 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 85 mol % of (2R,2R′)-3, (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)N-acetyl cysteine amide; or 70 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 30 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         5 . The pharmaceutical composition of  claim 1 , further comprising one or more pharmaceutically acceptable salts, excipients, adjuvants, or additives. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the diNACA is enantiopure (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the diNACA is enantiopure (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the diNACA is a racemic mixture of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the diNACA is enantiopure (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the diNACA is enantiopure (2S,2S′)-3,3′-disulfanediylbis(2-acetamidopropanamide). 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the diNACA is a racemic mixture of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and (2S,2S′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         12 . A method of treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition comprising (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) to a patient in need thereof. 
     
     
         13 . The method of  claim 12 , wherein the disease is an eye disease or disorder. 
     
     
         14 . The method of  claim 12 , wherein the disease is retinitis pigmentosa. 
     
     
         15 . The method of  claim 12 , wherein 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, skin pigmentation, skin in need of rejuventation, antimicrobial infection, Friedreich's ataxia. 
     
     
         16 . A method of making (2R,2R′)-3,3′-disulfanediylbis(2-acetamidopropanamide) (diNACA) comprising the steps of:
 forming L-Cystine Dimethylester Dihydrochloride from L-cystine by the following reaction: 
 
       
         
           
           
               
               
           
         
       
       forming Di-NACMe from L-Cystine Dimethylester Dihydrochloride by the following reaction: 
       
         
           
           
               
               
           
         
         generating DiNACA from Di-NACMe by the following reaction: 
       
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 16 , further comprising the step of purifying the DiNACA by the following reaction: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 16 , wherein the purified diNACA comprises 0.1 mol % to 97 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 5 mol % to 95 mol % of the (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 78 mol % to 95 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 88 mol % to 92 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); or 78 mol % to 82 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         19 . The method of  claim 16 , wherein 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); 80 mol % of (2R,2R′)-3,3′-disulfanediylbis(2-acetamidopropanamide) and 20 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide); 85 mol % of (2R,2R′)-3, (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide)N-acetyl cysteine amide; or 70 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) and 30 mol % of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide). 
     
     
         20 . The method of  claim 16 , further comprising the step of formulating a pharmaceutical composition by mixing the diNACA with a pharmaceutically acceptable adjuvant or additive. 
     
     
         21 . 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. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the deuterated N-acetylcysteine amide has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The pharmaceutical composition of  claim 21 , comprising 0.1 mole/percent (mol %) to 97 mol % of the D 3 -N-acetyl cysteine amide; 5 mol % to 95 mol % of the D 3 -N-acetyl cysteine amide; 78 mol % to 95 mol % of the D 3 -N-acetyl cysteine amide; 88 mol % to 92 mol % of the D 3 -N-acetyl cysteine amide; or 78 mol % to 82 mol % of the D 3 -N-acetyl cysteine amide. 
     
     
         24 . The pharmaceutical composition of  claim 21 , comprising 90 mol % of the D 3 -N-acetyl cysteine and 10 mol % of the N-acetyl cysteine amide; 80 mol % of the D 3 -N-acetyl cysteine and 20 mol % of the N-acetyl cysteine amide; 85 mol % of the D 3 -N-acetyl cysteine amide and 15 mol % of the N-acetyl cysteine amide; or 70 mol % of the D 3 -N-acetyl cysteine amide and 30 mol % of the N-acetyl cysteine amide. 
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein the deuterium enrichment in D3-position in the D 3 -N-acetyl cysteine amide is about 90 mol % to 98 mol %. 
     
     
         26 . The pharmaceutical composition of  claim 21 , wherein the difference in the deuterium enrichment in the D3-positions in the D 3 -N-acetyl cysteine is about 8 to 10 percentage points. 
     
     
         27 . The pharmaceutical composition of  claim 21 , further comprising a pharmaceutically acceptable adjuvant or additive. 
     
     
         28 . The pharmaceutical composition of  claim 21 , wherein the 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. 
     
     
         29 . The pharmaceutical composition of  claim 21 , wherein NACA-d 3  is enantiopure (R)-2-acetylamino-3-mercapto-propamide. 
     
     
         30 . The pharmaceutical composition of  claim 21 , wherein NACA-d 3  is enantiopure (S)-2-acetylamino-3-mercapto-propamide. 
     
     
         31 . The pharmaceutical composition of  claim 21 , wherein NACA-d 3  is a racemic mixture of (R)-2-acetylamino-3-mercapto-propamide and (S)-2-acetylamino-3-mercapto-propamide. 
     
     
         32 . A method of treating a disease associated with oxidative damage, comprising administering a pharmaceutical composition of  claim 21  to a patient in need thereof. 
     
     
         33 . The method of  claim 32 , wherein the disease is a disease of the eye. 
     
     
         34 . The method of  claim 32 , wherein the disease is retinitis pigmentosa. 
     
     
         35 . The method of  claim 32 , wherein 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. 
     
     
         36 . A method of making deuterium enriched N-acetylcysteine amide (NACA-d 3 ) comprising the steps of: 
       
         
           
           
               
               
           
         
       
     
     
         37 . A method of making deuterium enriched N-acetylcysteine amide (NACA-d 3 ) comprising the steps of:

Cited by (0)

No later patents cite this yet.

References (0)

No backward citations on record.