Factors influencing the interconversion of a new class of dibenzodiazepine sulfonamide atropisomers

Abstract

A novel family of atropisomers based on a conformationally constrained seven membered ring system is investigated using a combination of preparative chiral chromatography, circular dichroism, and other analytical techniques. The influence of structure on the rate of atropisomer interconversion was explored with a series of analogs showing a range of interconversion rates ranging from very fast (undetectable on the HPLC timescale) to very slow (half life of many days).

Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

“…This was accomplished by inserting a bulkier substituent adjacent to the sulphonamide moiety and resulted in an atropisomer specific preparation of several new derivatives, MMK‐7725, ( 33 ), and subsequently the cyclobutyl analog 34 (IC 50 1.4 nM against hBRS‐3 receptor) and the gem–dimethyl analogs 35 (0.6 nM) and 36 (0.5 nM), all being of the same S form as 32 . These analogs displayed excellent BRS‐3 binding potencies with half‐lives of over 250 hours at 60 °C in ethanol as monitored by circular dichroism by measuring the decrease in the positive CD signal at 260 nm versus time . The CD of the ( S )‐form of 32 exhibits a negative exciton couplet with opposite signals at −330 nm and +260 nm.…”

“…Atropisomerism resulting from planar chirality 5 is a key feature of some sulphonamide substituted dibenzodiazepines synthesized by Merck chemists to combat obesity. [27][28][29] Bombesin Receptor Subtype 3 (BRS-3), an orphan G-protein coupled receptor (GPCR), has been shown to regulate energy homeostasis in animals by reducing food intake. 28,29 It was thus reasoned that BRS-3 agonists could be useful in controlling obesity.…”

“…30 These analogs displayed excellent BRS-3 binding potencies with half-lives of over 250 hours at 60 C in ethanol as monitored by circular dichroism by measuring the decrease in the positive CD signal at 260 nm versus time. 27,30 The CD of the (S)-form of 32 exhibits a negative exciton couplet with opposite signals at À330 nm and +260 nm. This resolved the atropisomerism problem and made these leads promising for further biological evaluation and development efforts.…”

9.06 The Use of Preparative Chiral Chromatography for Accessing Enantiopurity in Pharmaceutical Discovery and Development

“…64 In the example presented in Figure 13, rapid application of preparative chiral chromatography and a variety of other analytical techniques allowed fine tuning of the rate of atropisomerization of a family of selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists during lead optimization, simply by adjusting a single 'R' group substituent. 65,66 Understanding gained during these studies allowed medicinal chemists to design molecules at will that would be locked into a single atropisomeric form or that would be rapidly interconverting during the course of treatment.…”

Conformational Restriction and Steric Hindrance in Medicinal Chemistry

“…As the rate of obesity is increasing, so too is the need for an effective anti-obesity drug. In a BRS-3 HTS screen, Merck chemists discovered the compound shown in Figure 11.7 (A) [44,45]. In a BRS-3 HTS screen, Merck chemists discovered the compound shown in Figure 11.7 (A) [44,45].…”