Maikel
Wijtmans
*a,
Frédéric
Denonne
b,
Sylvain
Célanire‡
b,
Michel
Gillard
b,
Saskia
Hulscher
a,
Christel
Delaunoy
b,
Nathalie
Van houtvin
b,
Remko A.
Bakker§
a,
Sabine
Defays
b,
Julien
Gérard
b,
Luc
Grooters
b,
Delphine
Hubert
b,
Henk
Timmerman
a,
Rob
Leurs
a,
Patrice
Talaga
b,
Iwan J. P.
de Esch
a and
Laurent
Provins
*b
aLeiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Exact Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. E-mail: wijtmans@few.vu.nl
bUCB Pharma, UCB NewMedicines, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. E-mail: Laurent.Provins@ucb.com
First published on 18th June 2010
Antagonists/inverse agonists for the COMPOUND LINKS
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Download mol file of compoundhistamine H3 receptor (H3R) are subject to intensive research. Many chemical classes contain a 3-propoxy linker to connect an aromatic moiety and a basic amine. Rigidifying this linker by several moieties has proven successful. However, so far, a 3-cyclobutoxy constraint has not been disclosed in H3R research. Here, we present novel synthetic methodology toward compounds with this functionality. A condensation between COMPOUND LINKS
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Download mol file of compoundpiperidine and COMPOUND LINKS
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Download mol file of compound1,3-cyclobutanedione followed by a reduction furnishes a versatile cis-3-piperidino-COMPOUND LINKS
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Download mol file of compoundcyclobutanol building block which allows ready access to constrained compounds having a 3-piperidino-cyclobutoxy moiety. Pharmacological studies reveal that this particular rigidification leads to a significant increase in H3R affinity compared to the non-constrained counterpart. In all, the constrained 3-cyclobutoxy linker emerges as a novel, versatile and attractive motif for H3R ligands.
An inspection of published and patented antagonists/inverse agonists shows the widespread occurrence of a 3-propoxy linker as part of the general pharmacophore, connecting an aromatic moiety and a basic amine (Fig. 1 and 2A).3,4 In fact, it has been demonstrated that incorporation of a 3-piperidino-propoxy-based unit in known COMPOUND LINKS
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Download mol file of compoundserotonin transporter inhibitors and dopaminergic agents was sufficient to induce considerable H3R affinity.5,6 Structurally varying examples of H3R ligands with the classical 3-propoxy linker (i.e. bearing a 3-aminopropoxy moiety, Fig. 1) include 1,7 JNJ-5207852 (2),8 biphenyls such as A-423579 (3),9 and naphthalenes (4).10 The list also includes the COMPOUND LINKS
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Download mol file of compoundoxazoline and COMPOUND LINKS
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Download mol file of compoundoxazole classes, exemplified by 5 and 6, respectively.11,12 Several research groups have rigidified the 3-propoxy linker using e.g. a piperidine (7, 8),13,14 COMPOUND LINKS
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Download mol file of compoundfuran (COMPOUND LINKS
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Download mol file of compound9),15 COMPOUND LINKS
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Download mol file of compoundpyridine (COMPOUND LINKS
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Download mol file of compound10)16 or morpholino constraint (11).17
Fig. 1 Selected H3R antagonists/inverse agonists. The 3-aminopropoxy unit, be it unconstrained or derivatized to a constrained analogue, is depicted in red. |
Fig. 2 (A) A general pharmacophore for H3R antagonists/inverse agonists showing the classical 3-propoxy linker and its rigidification by means of a cyclobutyl constraint. (B) Retrosynthetic approach. |
We were interested in the possibility of rigidifying the 3-propoxy linker by means of a cyclobutyl constraint (Fig. 2A). To us, the resulting 3-cyclobutoxy linker presented several distinct advantages: (1) it is a highly compact cyclo-constraint, yet fully incorporates the three-carbon linker; (2) in contrast to e.g. the piperidine and morpholino constraints (i.e.7, 8, 11), a cyclobutyl group leaves the N-terminus free for attachment of secondary amines, some of which are known to be privileged in H3R antagonists;18 (3) directional fine-tuning can be achieved by the relative stereochemistry of the cyclobutyl substituents. Although the cyclobutyl moiety has been used for some H3R ligands either as a side-chain (e.g.8 and clinical candidate 12, GSK189254)19 or as part of a non-classical linker (e.g.13 and Phase II candidate 14, PF-03654746),20,21 the incorporation of a 3-cyclobutoxy constraint into the classical and widely applied 3-aminopropoxy pharmacophoric element (i.e. to 15) has hitherto not been disclosed. In this article, we report on efficient synthetic methodologies and pharmacological studies related to H3R ligands incorporating this 3-amino-cyclobutoxy unit.
Interestingly, a search revealed that COMPOUND LINKS
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Download mol file of compound1,3-cyclobutanedione existed as its COMPOUND LINKS
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Download mol file of compounddicyclohexylammonium salt (16).24 Mono-amination of free COMPOUND LINKS
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Download mol file of compound1,3-cyclobutanedione to a cyclobutylenaminone has been described by Wasserman et al.25,26 and we postulated this to be an excellent way to selectively install our single amine moiety. A second step involving the reduction27 of the enaminone to the COMPOUND LINKS
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Download mol file of compoundaminoalcohol, a reaction not described in the literature so far for a cyclobutylenaminone, was envisaged (Fig. 2B).
Treatment of salt 16 with 1.1 equiv. of CF3COOH in COMPOUND LINKS
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Download mol file of compounddioxane (to liberate the parent dione) and subsequent stirring with 1.3 equiv. of piperidine at room temperature for 18 h furnished enaminone 17 in 66% yield (Fig. 3). Compound 17 proved remarkably resistant toward a variety of reductive conditions, including hydrogenation with platinum or palladium catalysts (room temperature or 50 °C) or NaBH4 in COMPOUND LINKS
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Download mol file of compoundacetic acid or COMPOUND LINKS
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Download mol file of compoundmethanol (at room temperature). Treatment with LiAlH4 provided some degree of success, but this protocol was plagued by low yields. Gratifyingly, though, we found that 17 can be smoothly reduced by heating it with NaBH4 in EtOH for 12 h (Fig. 3), affording COMPOUND LINKS
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Download mol file of compound3-(piperidin-1-yl)cyclobutanol 18 in high yield (78% isolated). The cis-architecture of 18 was established through 2D-NMR (see ESI†). The relative stereochemistry of 18 could be readily inverted by a classical Mitsunobu inversion (Fig. 3). That is, treatment of 18 with diisopropylazodicarboxylate, COMPOUND LINKS
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Download mol file of compoundtriphenylphosphine and COMPOUND LINKS
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Download mol file of compoundbenzoic acid followed by hydrolysis of intermediate 19 cleanly delivered trans-isomer 20 in 60% yield from 18.
Fig. 3 Synthetic routes to cis- and trans-3-piperidino-cyclobutanols 18 and 20 and to compounds COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound22, 24 and 25. |
Having the required 3-piperidino-cyclobutanols 18 and 20 at hand, the stage was set for coupling to the aromatic core of the COMPOUND LINKS
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Download mol file of compoundoxazoline or oxazole part. As outlined earlier, alkylation of the corresponding COMPOUND LINKS
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Download mol file of compoundphenol was the strategy of choice, requiring an activation of the alcohol group of the 3-piperidino-cyclobutanols. Toward this end, two strategies were pursued, both of which are accompanied by inversion at the O-bound carbon. The first approach used Mitsunobu conditions, with which we were able to successfully couple 18 and phenol 2111 to afford the trans-constrained COMPOUND LINKS
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Download mol file of compoundoxazoline ligand COMPOUND LINKS
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Download mol file of compound22 in 27% yield (Fig. 3). Analogously, we performed Mitsunobu couplings on spiro-oxazolino-phenol 2311 with both cis- and trans-3-piperidino-COMPOUND LINKS
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Download mol file of compoundcyclobutanol 18 and 20 to give trans- and cis-compounds 24 and 25 in 23% and 18% isolated yield, respectively (Fig. 3).
The second approach toward activation of the alcohol moiety comprised conversion of 18 to versatile building block COMPOUND LINKS
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Download mol file of compoundcis-tosylate COMPOUND LINKS
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Download mol file of compound26 by reaction with TsCl in 55% yield. The 3-piperidino-cyclobutyl group was then introduced by displacement of the COMPOUND LINKS
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Download mol file of compoundtosylate by the desired COMPOUND LINKS
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Download mol file of compoundphenolate. Two illustrations of this approach are shown in Fig. 4. Starting phenol 28 was obtained by a condensation between COMPOUND LINKS
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Download mol file of compound4-hydroxybenzamide and COMPOUND LINKS
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Download mol file of compound1,3-dichloropropan-2-one (to give 27) followed by substitution with piperidine. The COMPOUND LINKS
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Download mol file of compoundphenolate of 28 was then reacted with COMPOUND LINKS
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Download mol file of compound26 to give trans-compound 29. A similar reaction type but with different reaction conditions was applied to phenol 30, affording ester-substituted COMPOUND LINKS
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Download mol file of compoundtrans-oxazole COMPOUND LINKS
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Fig. 4 Synthetic routes to compounds COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound26, 29 and COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound31. |
Compound | pKi ± SD a | pEC50inv ± SD b | ||
---|---|---|---|---|
a Binding affinities (pKi) were assessed by displacement of [3H]-Nα-methylhistamine on membranes from CHO cells stably expressing the human H3R. The results are presented as the mean of two to six experiments. b [35S]GTPγS binding assay was performed on membranes from CHO cells stably expressing the human H3R. The results are presented as the mean of three to six experiments. c Already reported by us.11 d Already reported by us.12 SD = standard deviation. | ||||
Thioperamide | — | — | 6.8 ± 0.1 | 7.0 ± 0.1 |
5 | 6.8 ± 0.1 | 7.8 ± 0.1 | ||
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8.1 ± 0.3 | 9.2 ± 0.1 | ||
32 | 7.1 ± 0.1 | 8.1 ± 0.1 | ||
24 | 8.7 ± 0.1 | 8.7 ± 0.1 | ||
25 | 6.6 ± 0.1 | 7.1 ± 0.1 | ||
6 | 8.2 ± 0.3 | 8.8 ± 0.2 | ||
29 | 8.9 ± 0.1 | 8.5 ± 0.1 | ||
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compound31 |
8.7 ± 0.1 | 8.8 ± 0.1 |
Footnotes |
† Electronic supplementary information (ESI) available: Gradient programs, compound purities, pharmacological procedures, computational studies, synthetic procedures and NMR spectra. See DOI: 10.1039/c0md00056f |
‡ Present address: Addex Pharma, Geneva, Switzerland. |
§ Present address: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. |
This journal is © The Royal Society of Chemistry 2010 |