Spiro Compounds. Группа авторов

Чтение книги онлайн.

СКАЧАТЬ their spirocyclic counterparts (Figure 2.6a). Similarly, the C–O distance in an oxetane is around 2 Å, while the C–O distance in the parent carbonyl group is approximately 1.2 Å. Another important difference is the introduction of exit vectors “out‐of‐plan” in these isosteres compared with the parent groups (Figure 2.6b). Nevertheless, such differences also contribute to the unique properties of the spiro analogues and make them interesting structural features for bioisosteric replacement (Figure 2.6c). For example, incorporation of morpholine rings into drug scaffolds is an established strategy for improving aqueous solubility. However, oxidative metabolism is a known inactivation pathway of morpholines, most often resulting from ring opening. Spiro‐oxetanes 26 and 29 (Table 2.3) were proposed as replacements for morpholine 31, due to the similar relative spatial disposition of their hydrophobic and polar features. Interestingly, 29 displays higher solubility and lower logP than the parent morpholine, while also remaining stable to oxidative metabolism. A number of other potential spirocyclic morpholine mimics based on [3.3], [3.4], and [3.5] motifs have been reported by Carreira, displaying a range of unique dipoles and exit vectors for tunable properties [55].

Another illustrative successful example is the bioisosteric replacement of the metabolically labile morpholine unit of BTK inhibitor 32 (Figure 2.7). This led to the development of 2‐oxa‐6‐azaspiro[3.3]heptane functionalized analogue 33, which displays enhanced stability and solubility while retaining similar potency to its target compared with the parent molecule [57].

Thalidomide 34 (Figure 2.8) was introduced on the market in the late 1950s–early 1960s as an antiemetic and sedative, and banned a few years later due to its shattering side‐effects. Overall, thalidomide is thought to have caused numerous and severe birth defects in more than 10 000 children during that time [25]. While thalidomide was initially administered as a racemic mixture, it has since been shown that the (R) enantiomer has sedative effects and the (S) enantiomer is teratogenic. It is also known that racemization spontaneously takes place in vivo due to the acidity of H_a (Figure 2.8), although as of today the exact mechanism underlying the teratogenicity of thalidomide is still under investigation. In 2013, Carreira and coworkers reported derivative 35 where one of the imide carbonyls is replaced by an oxetane [56], with the goal of limiting in vivo metabolism and racemization, and potentially altering teratogenicity (Figure 2.8). Not unexpectedly, 35 displayed higher pK _a, lower lipophilicity, and increased solubility. It displayed similar intrinsic clearance rates in human microsomes compared with 34; however, showed much improved plasma stability after five hours. Pleasingly, 35 was configurationally stable to racemization in human blood plasma after five hours, thereby showing that a carbonyl to oxetane switch can be a viable approach to mitigate epimerization at adjacent stereocenters.

Table 2.2 Physicochemical and biochemical properties of selected oxetanes, and their carbonylated and gem‐dimethyl counterparts.

      Source: Based on Wuitschik et al. [55].

Solubility (μg ml−1)	4000	1400	220	4100	730	40	n.d.	24 000	290
Lipophilicity logD (logP)	1.2 (1.6)	1.0 (2.0)	2.3 (4.4)	−0.1 (−0.1)	0.7 (1.5)	1.4 (3.7)	n.d.	0.5 (1.2)	0.8 (3.1)
hCLint (min−1 mg−1 μl)	120	6	23	100	2	10	n.d.	3	0
mCLint (min−1 mg−1 μl)	88	22	31	580	27	39	n.d.	7	16
pK a amine	7.5	СКАЧАТЬ В начало < 14 15 16 17 18 19 20 21 22 23 > В конец