Large-scale synthesis of new cyclazines, 5-thia-1,8b-diazaacenaphthylene-3-carboxylic acid derivatives having the peripheral 12π-electron ring system

Ikemoto, Tomomi; Kawamoto, Tadashi; Wada, Hiroki; Ishida, Toru; Itô, Tatsuya; Isogami, Yasushi; Miyano, Yoshiko; Mizuno, Yukio; Tomimatsu, Kiminori; Hamamura, Kazumasa; Takatani, Muneo; Wakimasu, Mitsuhiro

doi:10.1016/s0040-4020(01)01171-1

Cited by 18 publications

(8 citation statements)

References 8 publications

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“…Since an attempted direct oxidation of 2‐amino‐6‐chloropyridine18 with m ‐chloroperbenzoic acid ( m ‐CPBA) according to the protocol of Pentimalli19 unexpectedly did not give the desired N ‐oxide 20 , it was prepared from 2‐acetamido‐6‐chloropyridine ( 16 )20 or alternatively from 2,6‐dichloropyridine N ‐oxide21 ( 21 ) (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

et al. 2004

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An efficient and scalable synthesis of enantiomerically pure N-Boc-protected 4-(Z)-propenylproline (15) using the conventional Wittig reaction to construct the double bond has been developed [11% yield over 8 steps from N-Boc-pro- (29)] was prepared along a reasonably efficient synthetic route applying the thermal rearrangement of 2-azido-6-chloropyridine N-oxide (22) as a key step in fairly good overall yield [9% over 7 steps from easily accessible 2,6-dichloro-

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Section: Resultsmentioning

confidence: 99%

Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

et al. 2004

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“…The group also found an efficient synthesis of another cyclazine derivative, 236 , through imidazopyridine 232 derived from 2,6-dichloropyridine, ammonia, and chloroacetaldehyde, as shown in Scheme . The key step in the process includes an S N Ar reaction of 232 with ethyl 2-mercaptoacetate followed by an unpredicted cyclization with hexamethylenetetramine (HMT)/TFA to give 235 in an excellent yield.…”

Section: Pyridine Derivativesmentioning

confidence: 99%

Efficient Azacycle Formations Developed in Japanese Pharmaceutical Industries: Elegancy, Logistics, and Training (ELT) “Sandwich” for Process Chemists

Mizufune¹

2019

Org. Process Res. Dev.

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Efficient azacycle (nitrogen-containing heterocycle) formations developed by chemists in Japanese pharmaceutical industries have been selected from the published articles since the year 2000. The selected examples have been classified by the nitrogen source in the raw materials and have been reviewed from the following process chemistry perspectives; elegancy to establish the active pharmaceutical ingredient synthetic processes, logistics to procure/transform the required raw materials, and training for process chemists to consider azacycle formations according to a systematic approach. This mini-review also focuses on the molecular diversity created by the azacycle formations.

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“…19 Hydroxyimidazo pyridine 8 was coupled with pyrimidinone 9 using modified peptide coupling conditions (PyBOP, DBU) 20 to give intermediate 10. After basic hydrolysis of the ethyl ester, the isoxazole amide was formed using standard conditions.…”

mentioning

confidence: 99%

Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG

Mainolfi¹,

Powers²,

Meredith³

et al. 2016

ACS Med. Chem. Lett.

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Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6−5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds. KEYWORDS: Vascular endothelial growth factor receptor 2, VEGF, KDR, bicyclic core, scaffold morphing, AMD T he current approved therapies for the treatment of wet or neovascular AMD are the anti-VEGF-A antibody ranibizumab, the anti-VEGF-A aptamer pegaptanib, and the anti-VEGF-A trap fusion protein aflibercept. Each of these wet-AMD treatments must be delivered by intravitreal injections, and 60 percent of patients do not experience a clinically significant gain of visual acuity (≥15 letters). 1 Based on this we have envisioned an opportunity for orally available inhibitor of the receptor tyrosine kinase (RTK) VEGFR-2 (KDR, Flt-1) to provide an alternative wet-AMD treatment paradigm. The role of VEGF-A in the regulation of angiogenesis is well established, and although, new vessel growth and maturation are highly complex processes, requiring the sequential activation of a series of receptors by numerous ligands, VEGF-A signaling often represents a critical rate-limiting step. 2 VEGF-A promotes growth of vascular endothelial cells and is also known to induce vascular leakage. Ocular VEGF-A levels are increased in neovascular diseases of the retina such as neovascular AMD. 3,4 We have recently disclosed the medicinal chemistry efforts around the indole-pyrimidine series of VEGFR-2 inhibitors 5 where several approaches were taken toward modulation of ontarget potency, solubility, pk, and in vivo efficacy. This was accomplished by focusing on the optimization of the two extremities of the molecules: the urea and the pyrimidine. 5 Herein, we focus on the modification/replacement of the

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Large-scale synthesis of new cyclazines, 5-thia-1,8b-diazaacenaphthylene-3-carboxylic acid derivatives having the peripheral 12π-electron ring system

Cited by 18 publications

References 8 publications

Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

Convergent Syntheses of N‐Boc‐Protected (2S,4R)‐4‐(Z)‐Propenylproline and 5‐Chloro‐1‐(methoxymethoxy)pyrrol‐2‐carboxylic Acid − Two Essential Building Blocks for the Signal Metabolite Hormaomycin

Efficient Azacycle Formations Developed in Japanese Pharmaceutical Industries: Elegancy, Logistics, and Training (ELT) “Sandwich” for Process Chemists

Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG

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