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FG-4592  

2015-07-13 16:36:16|  分类: 合成化学 |  标签: |举报 |字号 订阅

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FG-4592 - zliming2004 - zliming2004的博客
 
FG-4592 is a new-generation hypoxia-inducible factor prolyl hydroxylase inhibitor in early clinical trials at FibroGen for the oral treatment of iron deficiency anemia and renal failure anemia. Preclinical studies are ongoing for the treatment of sickle cell anemia.

The investigational therapy is designed to restore balance to the body's natural process of erythropoiesis through mechanisms including: natural EPO production, suppression of the effects of inflammation, downregulation of the iron sequestration hormone hepcidin, and an upregulation of other iron genes, ensuring efficient mobilization and utilization of the body's own iron stores. In April 2006, FG-4592 was licensed to Astellas Pharma by originator FibroGen in Asia, Europe and South Africa for the treatment of anemia. FibroGen retains rights in the rest of the world. In 2007, the FDA put the trial on clinical hold due to one case of death by fulminant hepatitis during a phase II clinical trial for patients with anemia associated with chronic kidney disease and not requiring dialysis. However, in 2008, the FDA informed the company that clinical trials could be resumed. Phase II/III clinical trials for this indication resumed in 2012. In 2013, the compound was licensed to AstraZeneca by FibroGen for development and marketing in US, CN and all major markets excluding JP, Europe, the Commonwealth of Independent States, the Middle East and South Africa, for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
Phase Organization Condition
Phase IIIAstellas Pharma
AstraZeneca
FibroGen
Anemia, renal failure
FG-4592 - zliming2004 - zliming2004的博客

Condensation of 5-bromophthalide (I) with phenol (II) in the presence of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (III), which upon lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene yields 2-chloromethyl-4-phenoxybenzoyl chloride (IV). Esterification of acid chloride (IV) with MeOH at 50 °C furnishes the methyl ester (V), which is then condensed with methyl N-tosylglycinate (VI) in the presence of K2CO3 and NaI in DMF at 50 °C to afford N-substituted aminoester (VII). Cyclization of the intermediate diester (VII) using NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (VIII), which is submitted to Mannich reaction with bis-dimethylaminomethane (IX) in the presence of AcOH at 57 °C to provide the dimethylaminomethyl compound (X). Treatment of amine (X) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-acetoxymethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XI). Hydrogenolysis of the benzylic acetate (XII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XII), which finally couples with glycine (XIII) in the presence of NaOMe in MeOH at 110 °C to afford the target roxadustat (1-3).

 FG-4592 - zliming2004 - zliming2004的博客
 
Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which upon esterification with MeOH and H2SO4 at reflux yields methyl ester (IV). Subsequent rearrangement of phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of intermediate (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxy-isoquinoline-2-carboxylate (VI), which upon hydrolysis with NaOH in refluxing H2O/EtOH furnishes carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at -78 °C, followed by alkylation with PhCH2Br in the presence of K2CO3 in refluxing acetone affords the 2-methyl isoquinoline (VIII). Ester hydrolysis in intermediate (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by coupling with benzyl glycinate hydrochloride (X) to yield benzylated roxadustat (XI). Finally, debenzylation of intermediate (XI) with H2 over Pd/C in EtOAc/MeOH provides the title compound (1).
FG-4592 - zliming2004 - zliming2004的博客

Condensation of 4-nitro-ortho-phthalonitrile (I) with phenol (II) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (III) (1), which upon hydrolysis with NaOH (1) or KOH (2) in refluxing MeOH yields 4-phenoxyphthalic acid (IV) (1,2). Dehydration of dicarboxylic acid (IV) using Ac2O and AcOH at reflux furnishes the phthalic anhydride (V), which is then condensed with methyl 2-isocyanoacetate (VI) using DBU in THF to provide oxazole derivative (VII). Rearrangement of intermediate (VII) with HCl in MeOH at 60 °C leads to isoquinoline derivative (VIII), which is partially chlorinated by means of POCl3 at 70 °C to afford 1-chloro-isoquinoline derivative (IX). Substitution of chlorine in intermediate (IX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxy-3-carboxylate (X), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (XI). Coupling of carboxylic acid (XI) with methyl glycinate hydrochloride (XII) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields roxadustat methyl ester (XII), which is finally hydrolyzed with aqueous NaOH in THF to afford the target roxadustat (1).
Patent NumberApplicantTitleConditionSubject Matter
EP 1644336
US 8278325
JP 2006527200
JP 2010111697
CN 102977015
US 2014343094
CN 102977016
US 7323475
US 8765956
US 2013310565
CN 103145616
US 2013178417
CN 102718708
WO 2004108681
US 2004254215
JP 2011148810
EP 2357175
US 8017625
US 2012029011
US 8916585
 
FibroGen, Inc. Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietinFG-4592 - zliming2004 - zliming2004的博客  
Anemia
Injury
Neurological Disorders
FG-4592 - zliming2004 - zliming2004的博客  
Drug Substances
 
WO 2013013609
EP 2734504
CN 104024227
US 2015031721
 
Zhejiang Beta Pharma Inc.  Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereofFG-4592 - zliming2004 - zliming2004的博客  
Anemia
Cancer
Diabetes
Inflammation
Ischemia
Thalassemia
Transplantation
FG-4592 - zliming2004 - zliming2004的博客  
Polymorphs
Drug Substances
 

Patent NumberApplicantTitleConditionSubject Matter
WO 2014014834
CN 103435546
 
FibroGen, Inc.  Process for making isoquinoline compoundsFG-4592 - zliming2004 - zliming2004的博客  
Anemia
Injury, tissue
FG-4592 - zliming2004 - zliming2004的博客  
Synthesis
Synthesis Intermediates
 
CN 103539735
US 2014024676
WO 2014014835
US 2014303202
US 2015038529
EP 2872488
 
FibroGen, Inc.  Crystalline forms of a prolyl hydroxylase inhibitorFG-4592 - zliming2004 - zliming2004的博客  
Anemia
FG-4592 - zliming2004 - zliming2004的博客  
Drug Substances
Polymorphs
 
US 2014024675
US 8883823
KR 2015058147
US 2015175550
 
FibroGen, Inc.  Crystalline forms of a prolyl hydroxylase inhibitorFG-4592 - zliming2004 - zliming2004的博客  
Anemia
Hypoxia
Ischemia
FG-4592 - zliming2004 - zliming2004的博客  
Polymorphs
Drug Substances
 

Patent NumberApplicantTitleConditionSubject Matter
EP 1644336
US 8278325
JP 2006527200
JP 2010111697
CN 102977015
US 2014343094
CN 102977016
US 7323475
US 8765956
US 2013310565
CN 103145616
US 2013178417
CN 102718708
WO 2004108681
US 2004254215
JP 2011148810
EP 2357175
US 8017625
US 2012029011
US 8916585
 
FibroGen, Inc.  Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietinFG-4592 - zliming2004 - zliming2004的博客  
Anemia
Injury
Neurological Disorders
FG-4592 - zliming2004 - zliming2004的博客  
Drug Substances
 
 
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