- Development of a Factory Process for Omecamtiv Mecarbil, a Novel Cardiac Myosin Activator
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The development of a factory process to manufacture the novel cardiac myosin activator omecamtiv mecarbil (1) is described. Omecamtiv mecarbil is prepared via the convergent synthesis and coupling of two key fragments, aniline 2 and carbamate 4-HCl, which serves as a masked isocyanate. To enable practical access to aniline 2, reduction of the corresponding nitroaromatic was designed to control potential mutagenic impurities. Key to the efficient preparation of 2 was the benzylic bromination of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5-phosphate. Overall, the longest linear sequence consists of six steps, including a final salt formation step to afford the drug substance in 55% overall yield. Because of poor performance of the original free-base form of the drug substance in modified-release formulations, an improved dihydrochloride hydrate form was developed to aid drug product performance and manufacturability.
- Caille, Seb,Allgeier, Alan M.,Bernard, Charles,Correll, Tiffany L.,Cosbie, Andrew,Crockett, Richard D.,Cui, Sheng,Faul, Margaret M.,Hansen, Karl B.,Huggins, Seth,Langille, Neil,Mennen, Steven M.,Morgan, Bradley P.,Morrison, Henry,Muci, Alexander,Nagapudi, Karthik,Quasdorf, Kyle,Ranganathan, Krishnakumar,Roosen, Philipp,Shi, Xianqing,Thiel, Oliver R.,Wang, Fang,Tvetan, Justin T.,Woo, Jacqueline C. S.,Wu, Steven,Walker, Shawn D.
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p. 1558 - 1567
(2019/09/04)
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- SYNTHESIS OF OMECAMTIV MECARBIL
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Provided herein is a synthesis for omecamtiv mecarbil dihydrochloride hydrate and various intermediates. (I)
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- HETEROCYCLIC COMPOUNDS AND THEIR USES
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Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.
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- HETEROCYCLIC COMPOUNDS AND THEIR USES
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Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.
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Paragraph 0118; 0119; 0120
(2014/10/04)
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- Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac myosin
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We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.
- Morgan, Bradley P.,Muci, Alexander,Lu, Pu-Ping,Qian, Xiangping,Tochimoto, Todd,Smith, Whitney W.,Garard, Marc,Kraynack, Erica,Collibee, Scott,Suehiro, Ion,Tomasi, Adam,Valdez, S. Corey,Wang, Wenyue,Jiang, Hong,Hartman, James,Rodriguez, Hector M.,Kawas, Raja,Sylvester, Sheila,Elias, Kathleen A.,Godinez, Guillermo,Lee, Kenneth,Anderson, Robert,Sueoka, Sandra,Xu, Donghong,Wang, Zhengping,Djordjevic, Nebojsa,Malik, Fady I.,Morgans, David J.
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scheme or table
p. 472 - 477
(2011/03/20)
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- COMPOUNDS, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 46-48
(2010/11/28)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives modulate diskeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T, and skeletal muscle, including fragments and isoforms thereof, as well as the skeletal sarcomere, and are useful in the treatment of obesity, sarcopenia, wasting syndrome, frailty, muscle spasm, cachexia, neuromuscular diseases (e.g., amyotrophic lateral sclerosis, spinal muscular atrophy, familial or acquired myopathies or muscular dystrophies), post-surgical and post-traumatic muscle weakness, and other conditions.
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Page/Page column 59-60
(2008/06/13)
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS
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Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
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Page/Page column 46-47
(2010/11/27)
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