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3.12 LLAMA Analysis
Having constructed a small library of 2-spiropiperidines utilising a diverse range of chemistry to introduce new functional groups, the lead-likeness and the relative three-dimensionality of the 2-spiropiperidines was of interest. The 18 functionalised 2-spiropiperidines were analysed through LLAMA to gauge their lead-likeness and three-dimensionality.
3.12.1 Lead-Likeness
It has been determined that the lipophilicity of a molecule is a defining characteristic for its potential success as a drug candidate.34 In order to facilitate delivery of a drug candidate to the desired pharmacological target as well as participate in subsequent interactions, aqueous solubility is a necessity.155 If the molecule is too hydrophobic, it has the ability to interact with other biological environments and consequently have potentially undesired toxic effects.1,156 It has therefore been determined that a low lipophilicity is required for lead compounds prior to lead optimization. It has also been deduced that during the lead optimisation process, an increase in both molecular weight and lipophilicity is observed, as extra complexity and size are added to the molecules.157 Tentative limits are therefore installed to deduce whether a compound can be described as ‘lead-like’, based on its molecular weight and lipophilicity.
80 Whilst not all drugs are administered orally, these guidelines that describe molecules as ‘lead- like’ represents the best starting points to allow maximum flexibility through optimisation.1 Churcher described an area of chemical space in which lead compounds reside, in which there is a potential for the development into a drug candidate.1 This area of chemical space, coined as ‘lead-like space’, defines compounds as having AlogP values in the range of -1 to +3 and a molecular weight in the range of 200-350 (14-26 non-hydrogen atoms) (Figure 25). The orange oval described as optimal drug-like space gives a broad representation of the properties of oral drug candidates (Figure 25), and typically as molecular weight increases, the associated lipophilicity also increases.
Figure 25. Molecular weight vs AlogP for identification of ‘lead-like’ space.
Whilst a compound may exhibit the desirable properties to describe it as ‘lead-like’, it may also possess certain properties and functionalities that impose a negative impact on its overall ‘lead-likeness’. Consequently, a ‘lead-likeness’ penalty was introduced by Marsden and Nelson.14 The penalty is an integer value calculated by analysing the key properties of the molecule; the AlogP value, the heavy atom count, the number of aromatic rings, and the
81 number of undesirable functional groups. The AlogP value should ideally be between -1 and +3,1 the heavy atom count should be between 17-24,1 the number of aromatic rings present should not exceed two,38 and there should be no reactive functional groups that can interfere with potential bindings.14,113 Penalty points are awarded based upon how far outside the ideal space the molecule lies, and the further away from the ideal space, the larger the penalty. The largest penalty that can be imposed is for the presence of a bad functional group. The closer the penalty to zero, the greater the ‘lead-likeness’ of a compound. Using the LLAMA online software, an example of the calculation of the penalty is described for 2- spiropiperidine 138a (Figure 26).47 Both the heavy atom count and the AlogP value fit within the desired guidelines, however, the lack of an aromatic group and a presence of a methyl ester (undesirable functional group, as defined by LLAMA) gives 2-spiropiperidine 138a a ‘lead-likeness’ score of six. 2-Spiropiperidine 138a is therefore not described as ‘lead-like’.
Figure 26. Calculation of the ‘lead-likeness’ score of 2-spiropiperidine 138a.
The ‘lead-likeness’ of the functionalised 2-spiropiperidines were analysed using the LLAMA online software.47 An example calculation of the lead-likeness of 2-spiropiperidine 163 is described below (Figure 27). As well as satisfying the guidelines for the heavy atom count and AlogP value, 2-spiropiperidine 163 also has an aromatic ring, and has been decarboxylated so the bad functional group has been removed. As a result, 2-spiropiperidine 163 has a ‘lead- likeness’ score of zero, deeming the compound to be ‘lead-like’.
82 Figure 27. Calculation of the ‘lead-likeness’ score of 2-spiropiperidine 163.
LLAMA analysis of the functionalised 2-spiropiperidines has shown that over half of the compounds have an excellent ‘lead-likeness’ score of zero (Figure 28).47 The higher-scoring amides 150a and 150b have earnt their penalty from the number of heavy atoms, exceeding the desired number for a ‘lead-like’ compound. The remaining 2-spiropiperidines all have ‘lead-likeness’ scores of five and six. This is because of the presence of the ester group, and in the case of 2-spiropiperidine 148a, the lack of an aromatic group. Removal or manipulation of the ester group of the 2-spiropiperidines would consequently improve the ‘lead-likeness’ of all compounds.
83 Figure 28. LLAMA analysis of the functionalised 2-spiropiperidines.
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3.12.2 PMI Analysis
Having assessed the ‘lead-likeness’ of the 2-spiropiperidines, the 18 functionalised 2- spiropiperidines were next plotted onto a PMI plot using the LLAMA software, with the 75% line from the ZINC database plot still shown for reference (Figure 29).47,14
Figure 29. PMI plot for the functionalized 2-spiropiperidines.
It can be seen that a greater proportion of the functionalised 2-spiropiperidines lie to the left of the ZINC 75% line than the respective 2-spiropiperidine scaffolds. This is a consequence of numerous factors. All of the examples were performed on 2-spiropiperidines with aromatic C-6 substituents (except the reduction of 138a), which consequently adds planarity to the structure. Approximately one half of the structures underwent decarboxylation, which in turn removed the C-3 tether, which was a vector to point into and explore three-dimensional
85 space. Adding to this, the introduction of alkenes and alkynes reduces the fsp3 in the molecules and ultimately reduces three-dimensionality.
Interestingly, the most three-dimensional structure was hydrazone 151 (Figure 29, A), presumably a consequence of the hydrazone functional group, with the amine providing an extra vector for elaboration and exploration. It also exhibits a plane of best fit of 1.468 Å, compared to approximately 1-1.2 Å for the other functionalised 2-spiropiperidines.47,14 The other three-dimensional 2-spiropiperidine was alcohol 148a (Figure 29, B). The reduction was performed on an aliphatic C-6 substituent (methyl group), the C-3 ester remained, and the sp2 ketone was reduced to an sp3 alcohol. Understandably, two of the most two-dimensional was 2-spiropiperidine 161 (Figure 29, C) and 147d (Figure 29, D). Amine 161 exhibits all three of the negative impacting factors described above; an aromatic C-6 substituent, C-3 decarboxylation, and introduction of an alkyne. Ketone 147d possesses similar properties but contains a linear nitrile on the aromatic ring.
The synthesis of a library of functionalised 2-spiropiperidines that exhibit greater three- dimensionality can be achieved by careful design of substrate, reaction and reagent. Aliphatic and substituted aromatic C-6 substituents on the parent 2-spiropiperidine scaffold aid in giving three-dimensionality to the functionalised 2-spiropiperidine. Reactions that remove substituents such as the C-3 ester or the C-4 ketone increases two-dimensionality, so functional group interconvention is preferential. Choice of the coupling reagent is also essential, as the introduction of alkynes, alkenes and aromatics will reduce three- dimensionality. Examples of functionalised 2-spiropiperidines that all lie to the right of the 75% ZINC line on the PMI plot that have been designed with the above rules are demonstrated below (Figure 30, 164, 165 and 166).
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4. One-Pot Synthesis of 2-Spiropiperidines
4.1 Preliminary Studies
A stepwise procedure for the synthesis of 2-spiropiperidines had been successfully developed, and it was next deemed desirable to synthesise 2-spiropiperidines in one-pot.
In preliminary studies, diketene 168 was used to be consistent with the previous one-pot piperidine synthesis reported from within the group.95 Due to its commercial unavailability, diketene 168 had to be prepared through treatment of acetyl chloride 167 with triethylamine (Scheme 67).158,159 Under the reaction conditions, ketene was formed which spontaneously dimerised to diketene 168. Aqueous work-up of the reaction mixture would result in hydrolysis of diketene 168, so the solvent choice was crucial. Diketene 168 has a high volatility, so would be used as a solution in subsequent reactions. Toluene was chosen as the solvent due to the insolubility of the by-product triethylamine hydrochloride. The preferred solvent would have been Et2O, however, the subsequent reaction would require the use of TiCl4 which is incompatible with Et2O.160 Upon filtration of triethylamine hydrochloride, diketene 168 was retrieved as a 4.91 wt% solution in a moderate 50% yield (Scheme 67), and was prepared freshly for each reaction. The formation of diketene was confirmed by 1H NMR spectroscopy.