Spiro Compounds. Группа авторов
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medications and represent attractive synthetic targets included in chemical libraries for diversity‐oriented synthesis within drug discovery projects. In this context, the spiro moiety has been and can be employed both as core structure and as an activity modulator, appended to decorate the peripheral part of the molecule [13].
The major advantage of spirocycles in biological applications as core structure or pharmacophores originates from their 3‐D nature and the associated conformational features that allow for a better ability to interact with the target protein enzyme. The tetrahedral feature of the spiro atom renders the two ring planes nearly perpendicular to each other with a limited number of potential conformations. When added in the periphery of the molecule, the spirocycle acts as a modulator of physicochemical properties such as log P and water solubility, as well as affecting the metabolic stability of the molecule. Not least, from an intellectual property perspective, the introduction of spirocycles offers the possibility of obtaining a free patent space in a me‐too research approach.
Prominent examples of marketed spirocompounds, illustrating these concepts, include fluspirilene 12, spiraprilat 13, and cevimeline 14, while experimental compounds in different stages of clinical development are ETX0914 15, a DNA gyrase inhibitor; tofoglifozin CSG452 16, an inhibitor of hSGLT2 for the treatment of Type 2 diabetes; AZD1979 17, an antagonist of melanin‐concentrating hormone receptor; and rolapitant 18, a neurokinine 1 receptor antagonist [13, 14] (Figure 1.6).
We wish once more to draw the attention of the readers on the potential usefulness and uniqueness of the spiro motif in the interaction with a specific biological target spanning from drugs to agrochemicals.
The enzyme Acetyl‐coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms, among which include humans, insects, and plants. The experimental ACC inhibitor compounds for the treatment of human metabolic disease contain a spirocyclic moiety as in Takeda compound 19 [15] and in Pfizer PF‐05221304 20. The last one is currently in phase II clinical trials for the treatment of Non‐Alcoholic Steatohepatitis (NASH) [16] (Figure 1.7).
Figure 1.6 Examples of marketed spiro compound drugs.
Sources: Based on Zheng and Tice [13]; Zheng et al. [14].
Figure 1.7 ACC inhibitors of pharmaceutical interest.
Sources: Based on Bourbeau and Bartberger [16a]; Esler and Bence [16b].
The commercial insecticide/acaricide products spirotetramat 21, spiromesifen 22, and spirodiclofen 23 from Bayer CS and spiropidion 24 from Syngenta, acting as insect ACC inhibitors, all have spirocyclic structures [17] (Figure 1.8).
New spirocyclic herbicide compounds with the representative formula 25 have been recently patented [18]. It is noteworthy that compounds 21 and 24, sharing similar molecular features with 25, do not show any phytotoxic effect (Figure 1.9).
Figure 1.8 Commercial spirocyclic insecticide/acaricide products.
Source: Jeschke et al. [17].
Figure 1.9 Recently patented spiro compound of agrochemical interest.
Figure 1.10 Example of numbering of spirocyclic compounds.
As presented in this chapter, spirocyclic scaffolds find application in a large number of sectors for their own peculiar architecture characteristics, displaying valuable application properties, or simply because of the introduction of structural novelty that guarantee patentability and intellectual property rights.
1.1 Notes on IUPAC Rules for Spiro Compounds
Naming spirocycles could be quite complex. The accepted rules are collected in the IUPAC blue book [1, 19].
Simplifying with two examples, the structure 26 is numbered starting from the smallest cycle (Figure 1.10). The name comes from the prefix spiro followed by square brackets containing the number of atoms of the two cycles starting from the smallest and excluding the spirocenter. In this case, the functional group is an alkane so that the name became spiro[4,5]decane.
Figure 1.11 Example of naming chiral spiro compounds.
When the compound is chiral because it contains a chiral center, the CIP rules are followed. In the case in which the substituents on the spirocenter are the same, but the structures display an axial chirality as in Figure 1.11, we assign arbitrarily the priority to one of the cycles and then, within each cycle the order follows the CIP rules: a>a′>b>b′.
References
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8 8