Stereoselective Synthesis of cis-1,3-Disubstituted Cyclobutyl Kinase Inhibitors

Abstract

Two synthetic routes to a series of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane are described. The first route utilized addition of 3-aminocyclobutanol to 1,4-dinitroimidazole 5 as the crucial step in preparing 1, whereas the second route employed a novel 1,4-addition of 4-nitroimidazole 18 to in situ generated cyclobutenone 17 as the key reaction. This allowed for a stereoselective and shorter synthesis that eliminated the use of potentially explosive 1,4-dinitroimidazole 5. [structure: see text]

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

“…This suggests that inhibitors of Cdk5 activity may be effective candidates for therapeutic development (25,70,71). Although several potent chemical inhibitors of Cdk5 have been identified and studied (26,72,73), most compete with ATP at the catalytic binding site. Accordingly, these compounds are relatively nonspecific because other cyclin-dependent kinases (as well as other kinases) are equally dependent on ATP binding.…”

1,4-Dinitro-1H-imidazoles

“…48 The products served as starting materials in syntheses of adenines. Two other compounds, the (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) N)adenine and (1-3 H)ribose, were also prepared. The compounds were then enzymatically coupled to isotopically modified ribosyl groups to give respectively substituted adenosines (31, Figure 5).…”

“…N)imidazol-1′-yl]acetic acid was obtained. The latter acid with bromine and phosphorus trichloride in anhydrous benzene formed a product that was subjected to hydrolysis to afford 2-methyl-4(5)-nitro-1H- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) N)imidazole in 40% yield. Starting compound 2 was also treated with ( 15 N)ammonia to produce a mixture of isotopically modified and natural nitrous oxide.…”

“…1-Cycloalkyl-4-nitro-1H-imidazoles, obtained in an ANRORC reaction of dinitroimidazole 1 with 3-amino-1-benzyloxycyclobutane, were used in the synthesis of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane moiety. 7 Later, the same approach was applied to the synthesis of 4-acylamino derivatives of 1-cyclopentyl-1H-imidazole and 3-(1H-imidazol-1-yl)cyclobutanol. The treatment of dinitroimidazole 1 with the respective primary amines afforded nitroimidazoles of type 13.…”

“…15 Similar results were obtained while heating dinitroimidazoles 1 and 2 in concentrated sulfuric acid at 120 o C for around 2.5 hours. The 1-nitro group migrated to the 5-position of the imidazole ring, yielding over 30% of the respective 4,5-dinitro-1H-imidazoles (9, 61) together with the respective 1-denitration products (7,62) in 50% or 25% yields. 18 Compound 3 under similar conditions gave 5(4)-methyl-4(5)-nitro-1H-imidazole (63) in 60% yield as the only identified product (Scheme 29).…”