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Here is reported the design and synthesis of a series of highly potent and selective α2C antagonists using benzodioxine methyl piperazine as a central scaffold by pharmacophoric analysis to improve the pharmacokinetics of suboptimal clinical candidate molecules.

In this manuscript, we report a series of benzodioxine methyl piperidine derivatives as highly potent and selective α2C antagonists by ligand design to improve the pharmacokinetics of a previous candidate molecule.

The need for effective solid-form screening approaches, especially designed for the early discovery phases, is well recognized within the pharmaceutical industry. Here we report on the early polymorphism and solvatomorphism evaluation of a new drug candidate for selective α2C-adrenoceptor antagonists ORM10921·HCl. The approach we use is based on the systematic batch-to-batch characterization of the solids generated during the salt synthesis optimization. Within this study three crystalline forms, two anhydrous and one hemihydrate, were discovered and identified by X-ray powder diffraction (XRPD), differential scanning calorimery (DSC), and thermal gravimetry (TGA). Moreover, coupling the gravimetric vapor sorption analysis with a conventional XRPD enabled the relative stability of these solid-state forms at ambient conditions to be established and the most stable form, the hemihydrate, to be selected for further development. Hence, the utilized approach has proven to be an effective and fast tool for init...

19S-Hydroxytacamine (3) and 19R-hydroxytacamine (4) were prepared from cis hydroxyesters 7 and 8 via corresponding O-TMS esters 9 and 22. Comparison of the spectral data of isomers 3 and 4 with those of 19-hydroxytacamine from Tabernaemontana eglandulosa confirms that isomer 3 represents the naturally occurring 19-hydroxytacamine.

Intramolecular aldol condensation of ketoaldehyde 8 affords three new compounds: enone 9 , hydroxyketone 10 , and enone 11 . Enone 9 possesses the ring system of (−)-voaketone ( 1 ), which is a skeletal rearrangement product of the indole alkaloid (−)-voacangine.

Base-catalysed epimerization of the easily accessible trans ester 3 at C-1 gives rise in good yield to the seemingly less stable cis ester 2, which can be converted into the indole alkaloid tacamonine (1) in three steps.

Total syntheses are described for seven tacamine-type indole alkaloids (1–7) found in Tabernaemontana eglandulosa. (±)-Tacamine (1), (±)-16-epitacamine (2), and (±)-apotacamine (3) were prepared from pentacyclic intermediates 18. Apotacamine (3) was also obtained from aldehyde 12 via epimerization of 20-epiapotacamine (19) by the Polonovski-Potier reaction. Homologation of ester 13 led to 20-epitacamonine (23), which was similarly converted to (±)-tacamonine (4). Reduction of 4 gave (±)-descarbomethoxytacamines 5 and 6. Aldehyde 11 was reacted with trimethylsilyl cyanide (TMSCN) to yield the two (±)-17-hydroxytacamonines (7), of which the isomer with an axial hydroxy group (17β-OH) was found to be identical with the natural compound. Finally, an attempt to prepare (±)-19S-hydroxytacamine (8) is described. As an intermediated for this, a new synthesis of the pyridine alkaloid methyl 5-(1′-hydroxyethyl)nicotinate (34) was achieved.

Methyl 3α-1,2,3,4,6,7,12,12bβ-cotahydroindolo[2,3- a ]quinolizine-1α-carboxylate ( 6 ), a key intermediate for the synthesis of tacamine-type indole alkaloids, was prepared in six simple steps from methyl 5-(1′-hydroxyethyl)nicotinate ( 7 ). The last step was the catalytic hydrogenation of the two ethylidene isomers 14 and 15 , both of which gave the target ester stereoselectively.

A simple and efficient method is described for the preparation of tacamonine (1) from the easily accessible ester 3. The method is based on the stereoselective synthesis of 20-epitacamonine (7), which is transformed to 1 using the Polonovski-Potier reaction.

The mixture of pentacyclic intermediates ( 4 ) was successfully converted into the pharmacologically interesting indole alkaloid (±)-tacamine ( 1 ). In a similar manner, the two unnatural isomers of 1 , (±)-14-epitacamine ( 9 ) and (±)-14-epi-16-epitacamine ( 10 ), were obtained from intermediate 7 . The key reaction, an acid-catalyzed displacement of the dimethylamino group with the hydroxyl group, is believed to take place via an iminium intermediate.

The synthesis of aldehyde intermediates suitable for the preparation of indole alkaloids of the tacamine (1) type is described. The four possible aldehydes 4–7 were prepared from methyl 5-ethylnicotinate (8) in a few simple steps using a base-catalyzed epimerization as the final step (Schemes 1 and 2). The key aldehyde 4, which is an analogue of the important vincamine intermediate 3 (‘Oppolzer's aldehyde’), was finally converted into the indole alkaloid (±)-apotacamine (21).

The HPLC enantiomeric separation of racemic indole alkaloids tacamonine, 17α-hydroxytacamonine, deethyleburnamonine, and vindeburnol was accomplished using Chiralpak AD and Chiralcel OD as chiral stationary phases. Small structural differences affect the enantioselectivity ability of these phases. Single enantiomers of tacamonine and vindeburnol were isolated by semipreparative HPLC and their CD spectra and optical rotations were measured. Chirality 13:691–693, 2001. © 2001 Wiley-Liss, Inc.

The synthesis of aldehyde intermediates suitable for the preparation of indole alkaloids of the tacamine (1) type is described. The four possible aldehydes 4–7 were prepared from methyl 5-ethylnicotinate (8) in a few simple steps using a base-catalyzed epimerization as the final step (Schemes 1 and 2). The key aldehyde 4, which is an analogue of the important vincamine intermediate 3 (‘Oppolzer's aldehyde’), was finally converted into the indole alkaloid (±)-apotacamine (21).

Both (±)-17α-hydroxytacamonine ( 3 ) and its 17β-isomer ( 4 ) were synthesized in two steps (one-pot) from aldehyde mixture 5/6 via the cyanohydrin reaction. NMR spectral characterization of isomer 3 revealed it to be unidentical with natural 17-hydroxytacamonine, whereas spectral data of isomer 4 were in agreement with those published for the natural isomer. The configuration at C-17 was confirmed by NOE difference spectroscopy.

A simple and efficient method is described for the preparation of tacamonine (1) from the easily accessible ester 3. The method is based on the stereoselective synthesis of 20-epitacamonine (7), which is transformed to 1 using the Polonovski-Potier reaction.

Base-catalysed epimerization of the easily accessible trans ester 3 at C-1 gives rise in good yield to the seemingly less stable cis ester 2, which can be converted into the indole alkaloid tacamonine (1) in three steps.

Intramolecular aldol condensation of ketoaldehyde 8 affords three new compounds: enone 9 , hydroxyketone 10 , and enone 11 . Enone 9 possesses the ring system of (−)-voaketone ( 1 ), which is a skeletal rearrangement product of the indole alkaloid (−)-voacangine.

(±)-20-Epiapotacamine (8) was synthesized in two steps from aldehyde 6 and was converted into the indole alkaloid (±)-apotacamine (2) by the Polonovski-Potier reaction.

Both (±)-17α-hydroxytacamonine ( 3 ) and its 17β-isomer ( 4 ) were synthesized in two steps (one-pot) from aldehyde mixture 5/6 via the cyanohydrin reaction. NMR spectral characterization of isomer 3 revealed it to be unidentical with natural 17-hydroxytacamonine, whereas spectral data of isomer 4 were in agreement with those published for the natural isomer. The configuration at C-17 was confirmed by NOE difference spectroscopy.