ABSTRACT
The triene-containing C17-benzene ansamycins trienomycins A and F were prepared in 16 steps (longest linear sequence, LLS) and 28 total steps. The C11-C13 stereotriad was generated via enantioselective Ru-catalyzed alcohol CH syn crotylation followed by chelation-controlled carbonyl dienylation. Enantioselective Rh-catalyzed acetylene-aldehyde reductive coupling mediated by gaseous H2 was used to form a diene that ultimately was subjected to diene-diene ring closing metathesis to form the macrocycle. The present approach is 14 steps shorter (LLS) than the prior syntheses of trienomycins A and F, and 8 steps shorter than any prior synthesis of a triene-containing C17-benzene ansamycin.
Subject(s)
Alanine/analogs & derivatives , Carbon/chemistry , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/chemical synthesis , Alanine/chemical synthesis , Alanine/chemistry , Chemistry Techniques, Synthetic , HydrogenationABSTRACT
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/toxicity , Aniline Compounds/chemical synthesis , Aniline Compounds/toxicity , Cardiovascular System/drug effects , Enzyme Inhibitors/toxicity , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/toxicity , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guinea Pigs , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Myocytes, Cardiac/drug effects , RatsABSTRACT
3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.
Subject(s)
Amides/chemical synthesis , Aniline Compounds/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Amides/chemistry , Aniline Compounds/chemistry , Animals , Dogs , Heterocyclic Compounds, 2-Ring/chemistry , Mice , Molecular Structure , Protein Kinase Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core.
Subject(s)
Rifamycins/chemical synthesis , Alcohols/chemistry , Aldehydes/chemistry , Catalysis , Cyclization , Iridium/chemistry , Molecular Structure , Oxidation-Reduction , Rhodium/chemistry , Rifamycins/chemistryABSTRACT
Unstable? We're able! 1,n-Glycols serve as synthetic equivalents to unstable dialdehydes in two-directional carbonyl allylation from the alcohol oxidation level under iridium-catalyzed transfer hydrogenation conditions. Iterative asymmetric allylation employing 1,3-propanediol enables the rapid assembly of protected 1,3-polyol substructures with exceptional levels of stereocontrol.
Subject(s)
Aldehydes/chemistry , Iridium/chemistry , Polymers/chemical synthesis , Catalysis , Hydrogenation , Oxidation-Reduction , Polymers/chemistry , StereoisomerismABSTRACT
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.
