Chapter 5 5-(Sulfonyl)oxy-tryptamines and Ethylamino Side Chain Restricted Derivatives Abstract A number of 5-substituted sulfonic acid ester derivatives of 5- hydroxytryptamine (5-HT) were prepared and their affinities are compared to that of the reference compound 5-OSO2CF3-tryptamine (6). The structure-affinity relationships (SAFIR) are discussed in terms of in vitro binding for cloned human 5-HT1A, 5-HT1Dα and 5-HT1Dβ receptors. The 5-tosylated tryptamine (9) exhibited the best profile for 5- HT1Dα receptors (Ki = 4.8 nM) but still showed a comparatively lower affinity than compound 6. Other tryptamine derivatives displayed moderate binding to 5-HT1A and 5- − HT1Dβ receptors, along with Ki values ranging from 9 22 nM for the 5-HT1Dα sites. In addition, the syntheses of two ethylamino side chain restricted derivatives are described. The 6-triflated 3-aminotetrahydrocarbazole 19, as well as the 5-triflated indolepiperidines 22 and 23 induced a shift in affinity in favor of the 5-HT1Dβ receptors. The relatively longer N-O distance of 19, 22 and 23 as compared to tryptamines or 2- aminotetralins, is likely responsible for this observation. 5.1 Introduction The electron withdrawing aryl triflate group was previously shown to be a group 1 which (i) improves the pharmacokinetic properties of 5-HT1A receptor ligands and (ii) 2 enhances the affinity for 5-HT1D receptor ligands, compared to the hydroxy analogues. The latter improvement seemed to be more pronounced at 5-HT1Dα receptors relative to 5-HT1Dβ sites (see Chapter 2, Table 2.3 and Chapter 4, Table 4.1B). The question arises whether the triflate group is the optimal sulfonic acid ester for 5-HT1D affinity. Especially, the active site of both 5-HT1D receptor subtypes are known to contain a pocket which can accommodate large groups, located at the 5-position of indolealkylamines.3 The nature of this pocket may be explored by using sulfonate substituents with different electronic and steric properties. Thus, it was of interest to examine the effects of readily available sulfonic acid ester derivatives of 5-HT on the selectivity and affinity for the 5-HT1A and 5-HT1D receptors. 85 Chapter 5 H H2N O N S Me O O OTf Me H Me N N Me NH N 2 N H H (±)-cis-1 (±)-2 Naratriptan,3 Another approach which may improve the 5-HT1D versus 5-HT1A receptor affinity is rigidification of the tryptamine moiety. From the data presented in Chapters 2 and 4 it seems that ethylamino side chain restriction in the 2-aminotetralins produces marked effects on selectivity and affinity at 5-HT1 receptor subtypes. Recently, the enantiomers of 8-OH-DPAT were reported to have nanomolar affinities for the 5-HT1D receptor 4 subtypes. The affinity and agonist efficacy for the 5-HT1Dα and 5-HT1Dβ receptor were shown to reside in the R-enantiomer (Ki: 28.8 nM; EC50: 30 nM and Ki: 75.5; EC50: 415 nM, respectively). (±)-Cis-8-[[(trifluoromethyl)sulfonyl]oxy]-1-Methyl-2- (methylamino)tetralin (cis-1) displayed Ki values of 3.4 and 10 nM for 5-HT1Dα and 5- HT1Dβ receptors, respectively (Chapter 2). The antipodes of the monopropyl analogue of cis-1, like the enantiomers of 8-OH-DPAT, exhibited marked stereoselectivity for the 5- HT1D sites. Obviously, low nanomolar affinities of 2-aminotetralins for the 5-HT1D receptor subtypes are feasible when proper substituents are employed and, moreover, orientation A of 5-HT seems to be the active conformation (Figure 5.1). OH OH 8 1 NR2 7 2 NH2 6 3 5 4 N H OrientationA 2-aminotetralins OH OH 6 7 5 8 4 NH2 3 N 9 N NR2 H H 1 2 OrientationB 3-aminocarbazoles 86 5-(Sulfonyl)oxy-tryptamines and Ethylamino Side Chain Restricted Derivatives Figure 5.1. Ethylamino side chain orientations of 5-HT Orientation B of 5-HT is captured in the 3-aminocarbazole skeleton. King and co-workers reported aminocarbazole derivative (2) to have a Ki of 10 nM and high 5,* intrinsic activity for 5-HT1D receptors. This finding suggests that the binding conformation of the side chain of 5-CT at the 5-HT1D receptor may approximate orientation B. However, in the pharmacology experiments, the authors did not discriminate between the two 5-HT1D receptor subtypes, which makes it difficult to draw conclusions regarding the orientation of the ethyl amino group in each of these subtypes. Another type of indolealkylamine is represented by the semi-rigid Naratriptan (GR85548A, 3),6 which possesses a piperidine ring instead of an ethylamino side chain. Naratriptan is reported to be clinically effective in the treatment of migraine, with superior potency as compared to sumatriptan (24) in binding and functional studies.7 This compound showed a Ki of approximately 8 nM for 5-HT1D receptors, measured in guinea pig striatal membranes. In the present study we describe the synthesis and SAR of sulfonic acid ester substituted tryptamines. In addition, the influence of rigidification of tryptamine analogues on selectivity for the 5-HT1A and 5-HT1D receptor subtypes is examined, which is the second objective of this chapter. Throughout this series of compounds, the aryl triflate group is used as the reference substituent. 5.2 Chemistry Preparation of 5-Sulfonyloxytryptamines. The sulfonic acid ester derivatives were prepared in moderate to high yields by treating N,N-phthalimido protected 5-HT (see Section 4.5) with the appropriate sulfonyl or sulfamoyl chloride. The coupling was effected using; Et3N as a base and dioxane as the solvent (method A); phase-transfer conditions with tetrabutyl ammonium iodide as the phase-transfer catalyst (method B); or NaH as the base and DMF as the solvent (method C). The phthalimides were converted into the primary amines upon treatment with hydrazine in ethanol (Scheme 5.1). * Measured in Piglet caudate. 87 Chapter 5 O O OH O O Me S S N O F3C O NH2 Me NH2 NH2 N H 4 N N 12 H 6 H a h b O O O O Me S S N O OH Me O H NH2 g NPhth c NH2 N N N H 11 H 5 H 7 f d O O e O O S S S O O O O S NH2 O NH2 Me NH N 2 N H 10 H 8 N H 9 Scheme 5.1. (a) N-Et-CO2-phth, 10% NaHCO3 (pH 8), THF/H2O; (b) PhN(SO2CF3)2, Et3N, CH2Cl2; (c) MeSO2Cl, method A; ; (d) PhSO2Cl, method A; (e) p-TolSO2Cl, method A; (f) 2-ThSO2Cl, method B; (g) MeNHSO2Cl, method A; (h) (Me)2NSO2Cl, method C. Steps b-h were succeeded by deprotection with hydrazine in abs. ethanol. Upon crystallization from H2O/MeOH, the mesylate derivative 7 yielded crystals that were suitable for a single crystal X-ray spectroscopy determination (Figure 5.2). The compound crystallized as the hemi-oxalate in a monoclinic C2/c spacegroup with 8 molecules per unit cell (a = 22.158; b = 5.791; c = 24.172 Å). In Table 5.1, selected bond distances, bond angles and torsional angles are listed. The crystal structure is stabilized by complexation between the NH of the indole portion and the oxalic acid via H-bonds at a distance of 1.834 Å (Figure 5.2B). This distance is comparable with that of the normal ionic interaction of the primary amine and the oxalic acid, being 1.826 Å. Furthermore, clear intermolecular H-bonds (2.034 Å) can be observed between O16 of one molecule and the ethylamino N+H of another molecule. This is also reflected by the 88 5-(Sulfonyl)oxy-tryptamines and Ethylamino Side Chain Restricted Derivatives relative long bond length of S14-O16 (1.426 Å) as compared that of S14-O17 (1.359 Å). Figure 5.2A. Molecular structure of7 . Figure 5.2B. Stereoview of the intermolecular interactions of7 (indicated by a dashed line). 89 Chapter 5 16 17 O O 15 S 13 Me 14 O 10 9 11 1 2 NH2 8 12 4 7 3 6 N 5 H Figure 5.2C. Numbering of the atoms of3 . Table 5.1. Selected interatomic distances, angles and torsional angles of compound3 Distance (Å) Angle (deg) Torsional Angle (deg) N1-C2 1.498 N1-C2-C3 110.2 N1-C2-C3-C4 178.4 S14-C15 1.744 C2-C3-C4 110.3 C2-C3-C4-C5 108.9 O13-S14 1.550 C10-O13-S14 120.9 C11-C10-O13- −97.3 C10-O13 1.486 O13-S14-C15 101.1 C10-O13-S14- −84.7 S14-O16 1.426 O13-S14-O16 104.9 C10-O13-S14- 28.2 S14-O17 1.359 O13-S14-O17 114.3 C10-O13-S14- 158.9 OMe OMe NPhth a b + O NPhth 15 NHNH2.HCl N H d 13 14 16 OH OSO2CF3 OSO2CF3 c d N NPhth N NPhth N NH2 H H H 17 18 19 Scheme 5.2. (a) EtOH, ∆; (b) BBr3, CH2Cl2, –78 °C–rt; (c) PhN(SO2CF3)2, Et3N, CH2Cl2; (d) H2NNH2.H2O, EtOH. Preparation of 3-Aminocarbazoles. N-Phthalimido protected 4- aminocyclohexanol was oxidized with pyridinium chlorochromate to give the 90 5-(Sulfonyl)oxy-tryptamines and Ethylamino Side Chain Restricted Derivatives cyclohexanone derivative 14. The 3-aminocarbazole skeleton was prepared via the Fischer-indole synthesis by refluxing 14 with p-methoxyphenylhydrazine (13) in ethanol (83%).8 Intermediate 15 was either N-deprotected to give 16, or O-demethylated to give 17 (31%), which subsequently was triflated and converted into the primary amine to yield carbazole derivative 19 employing conditions described as above (Scheme 5.2).