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. 2019 Jul 18;10(8):1198-1204.
doi: 10.1021/acsmedchemlett.9b00248. eCollection 2019 Aug 8.

Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a log D Lowering Twist

Sébastien L Degorce  1 , Michael S Bodnarchuk  1 , James S Scott  1
Affiliations

Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a log D Lowering Twist

Sébastien L Degorce et al. ACS Med Chem Lett. .

Abstract

We have conducted an analysis of azaspiro[3.3]heptanes used as replacements for morpholines, piperidines, and piperazines in a medicinal chemistry context. In most cases, introducing a spirocyclic center lowered the measured logD 7.4 of the corresponding molecules by as much as -1.0 relative to the more usual heterocycle. This may seem counterintuitive, as the net change in the molecule is the addition of a single carbon atom, but it may be rationalized in terms of increased basicity. An exception to this was found with N-linked 2-azaspiro[3.3]heptane, where logD 7.4 increased by as much as +0.5, consistent with the addition of carbon. During our investigation, we also concluded that azaspiro[3.3]heptanes are most likely not suitable bioisosteres for morpholines, piperidines, and piperazines, when not used as terminal groups, due to significant changes in their geometry.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Azaspiroheptane analogues of piperidine, morpholine, and piperazine.
Figure 2
Figure 2
Comparison of QM-minimized conformations for spiro-variants (orange) of morpholines and piperazines (cyan). aDistance (Å) between the two heteroatoms in the ring. bVolume (Å3).
Figure 3
Figure 3
Selected examples of azaspiro[3.3]heptanes used as morpholine/piperazine replacements.
Figure 4
Figure 4
X-ray structures of 2,6-diazaspiro[3.3]heptanes used as piperazine replacements: (A) 17a (cyan) and 17b (orange); (B) 18a (cyan), 18b (orange). The azaspiroheptane base is shifted by ∼1.2–1.5 Å relative to the piperazine, consistent with Figure 2.
Figure 5
Figure 5
QM-minimized geometries of a 2,6-diazaspiro[3.3]heptane 21b (orange) used as a replacement of piperazine 21a (cyan). aGPR119 potency (μM). bIncubation at 10 μM (10–6 cm/s).
Figure 6
Figure 6
Selected examples of 2,6-diazaspiro[3.3]heptanes used as replacements for nonterminal piperazines.
Figure 7
Figure 7
Selected examples of 2-azaspiro[3.3]heptanes used as piperidine replacements.
Figure 8
Figure 8
ΔlogD7.4 relative to parent: (A) 2-oxa-6-azaspiro[3.3]heptanes and 2-azaspiro[3.3]heptanes; (B) 2,6-diazaspiro[3.3]heptanes. Error bars are shown for ±SD.
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