Halide salts of anti­migraine agents eletriptan and naratriptan

Mol­ecules of eletriptan hydro­bromide monohydrate (system­atic name: (1S,2R)-1-methyl-2-{5-[2-(phenyl­sulfonyl)­ethyl]-1H-indol-3-yl­methyl}­pyrrolidinium bromide mono­hydrate), C₂₂H₂₇N₂O₂S⁺·Br^-·H₂O, (I), and naratriptan hydro­chloride (systematic name: 1-methyl-4-{5-[2-(methyl­sulfamoyl)­ethyl]-1H-indol-3-yl}­piperidinium chloride), C₁₇H₂₆N₃O₂S⁺·Cl^-, (II), adopt conformations similar to other triptans. The C-2 and C-5 substituents of the indole ring, both of which are in a region of conformational flexibility, are found to be oriented on either side of the indole ring plane in (I), whilst they are on the same side in (II). The N atom in the C-2 side chain is protonated in both structures and is involved in the hydrogen-bonding networks. In (I), the water mol­ecules create helical hydrogen-bonded chains along the c axis. In (II), the hydrogen bonding of the chloride ions results in macrocyclic R₄²(20) and R₄²(24) ring motifs that form sheets in the bc plane. This structural analysis provides an insight into the mol­ecular structure-activity relationships within this class of compound, which is of use for drug development.

S1. Comment

Migraine headache is a severe throbbing pain over one or both halves of the scalp and is accompanied by nausea, vomiting, photophobia and/or phonophobia. Triptans are the family of tryptamine-based drugs specifically designed to alleviate migraine headaches, which they do by blocking serotonin receptors in blood vessels in the brain (Saxena & Tfelt-Hansen, 2001). They are designer drugs obtained by modifying the serotonin molecule (Goadsby, 1998). Triptan drugs were first introduced during the 1990s and are now available in different types under a variety of commercial names: sumatriptan (Imitrex), zolimitriptan (Zomig), rizatriptan (Maxalt), almotriptan (Axert), naratriptan (Amerge), eletriptan (Relpax) and frovatriptan (Frova). All triptans share a basic indole ring, with the side chains being different. These side chains affect the pharmacokinetics of these agents in ways that may be clinically significant as they may make them more, or less, effective (Isaac & Slassi, 2001).

Eletriptan and naratriptan, the second-generation drugs of Pfizer and Glaxo Wellcome, respectively, are more lipophilic and have higher oral bioavailability than sumatriptan (Tepper et al., 2002). We have been studying the structural characteristics of a series of triptans (Ravikumar et al., 2004, 2006, 2007a,b and 2008), and the present study of eletriptan hydrobromide monohydrate, (I), and naratriptan hydrochloride, (II), is a continuation of our investigation into the three-dimensional structural correlation of triptans.

Pertinent bond lengths and angles for (I) and (II) are listed in Tables 1 and 4, and the molecular structures are depicted in Figs. 1 and 2, respectively. Protonation of the molecules occurs in both structures at atom N2 - of the pyrolidine ring in (I) and the piperidine ring in (II); the sum of the angles at this atom is 334.0 (2)° in (I) and 334.4 (1)° in (II). An overlay of the triptans superimposing the planar indole systems (Fig. 3) reveals the significant similarities and orientation differences.

The use of the substituents at C2 and C5 of the indole ring is believed to provide binding selectivity and affinity for 5-HT1D receptors (Slassi et al., 2000) and provides a region of conformational flexibility in the molecule. The conformational difference between the two structures, (I) and (II), is in the orientation of the substituents at C2 [methyl pyrrolidinyl in (I) and methylpiperidinyl in (II)] and C5 [phenylsulfonylethyl in (I) and ethanesulfonamide in (II)] of the indole ring (Fig. 3). In (I), the two substituents are oriented on either side of the indole ring plane, whereas in (II) they are on the same side. Furthermore, the orientation of the side chain at C2 can be visualized in terms of the torsion angle τ1, C1—C2—C9—C10 [24.5 (2) in (I) and 4.3 (3)° in (II)], synperiplanar in both. The corresponding angles in other triptans are listed in Table 3, from which the two principal orientations - synperiplanar and anticlinal - can be noted in the solid-state structures.

An interesting comparison between the structures of (I) and (II) is the position of the protonated atom N2 relative to the indole ring system. In (I) it is intra, being almost coplanar with the indole ring plane [0.080 (2) Å], whereas in (II) it is extra, 1.123 (2) Å above the plane. The distance between atom N2 and the centroid of the C3–C8 aromatic ring remains almost equal in both structures [6.48 Å in (I) and 6.76 Å in (II)]. The corresponding distances - a parameter correlating the 5-HT1B-like [5-HT1D ?] receptor model (Moloney et al., 1999) - deduced for other triptans are listed in Table 3, which also indicates whether atom N2 is coplanar or not.

The ethanesulfonyl side chains of both (I) and (II) show a similar orientation, as indicated by the torsion angles τ2 (C6—C5—C15—C16) = 65.8 (2) and 67.0 (2)° and τ3 (C5—C15—C16—S1) = 168.7 (2) and -168.5 (1)°, respectively. It is interesting to note that the corresponding torsion angles found in other triptans (Table 3) all favour a similar synclinal orientation for τ2 but only some of them do for τ3. The terminal groups, phenyl in (I) and amide in (II), attached with this chain are antiperiplanar [C15—C16—S1—C17 = -175.9 (2)°] and synclinal [C15—C16—S1—N3 = 56.4 (2)°], respectively.

The conformation of the pyrolidine ring in (I) can be best described as an envelope, with the twofold axis through atom C13. The piperidine ring in (II) adopts a chair conformation. The dihedral angles of the mean plane of the pyrolidine or phenyl ring with the mean plane of the indole ring are 82.8 (1) and 71.1 (1)°, respectively, indicating near perpendicularity in (I).

In (I), the water molecule plays a key role in the hydrogen-bonding network. It acts as both donor and acceptor, creating a helical chain along the c axis (Fig. 4, Table 2). The sulfonyl O and Br atoms participate in the hydrogen-bonding network. In (II), the Cl^- ion plays a central role in the hydrogen-bonding network (Fig. 5, Table 5). All three N atoms (N1, N2 and N3) form hydrogen bonds only with the Cl atom, even though the sulfonyl O atoms are available. The N2—H···Cl and N3—H···Cl hydrogen bonds link the molecules into a chain running along the c axis. The N1—H···Cl hydrogen bond links to a chain related by centrosymmetry, along the b axis, resulting in a supramolecular macrocycle that may be described in graph-set notation as R₄²(20) and R₄²(24) (Etter, 1990; Etter et al., 1990; Bernstein et al., 1995), forming sheets in the bc plane. Since these two rings are edge fused, they form an overall macrocylic R₆³(37) ring in the sheets.

In conclusion, such crystal structures provide useful information on the overall conformation of molecules, the orientations of the two indole ring substituents and the molecular interactions influencing crystal packing. A word of caution may be exercised regarding the C2 side-chain orientation, since in solid-state structures it is probably governed largely by the position of the counterions, viz. halide, succinate, malate, benzoate etc. and may not be significant for activity, in view of the flexibility of the chain.

Related literature

For related literature, see: Bernstein et al. (1995); Etter (1990); Etter, MacDonald & Bernstein (1990); Flack & Bernardinelli (2000); Goadsby (1998); Isaac & Slassi (2001); Moloney et al. (1999); Ravikumar et al. (2004, 2006, 2007a, 2007b, 2008); Saxena & Tfelt-Hansen (2001); Slassi et al. (2000); Tepper et al. (2002).

S2. Experimental

Crystals of eletriptan hydrobromide monohydrate and naratriptan hydrochloride (SMS Pharma Research Centre, Hyderabad) suitable for X-ray diffraction were obtained from solutions in a mixture of methanol and water [Solvent ratio?] by the method of slow evaporation.

S3. Refinement

All N-bound and O-bound H atoms of both (I) and (II) were located in a difference density map and refined isotropically. All other H atoms were positioned geometrically and were treated as riding on their parent C atoms, with C—H = 0.93–0.98 Å, and with U_iso(H) = 1.5U_eq(C) for methyl H and 1.2U_eq(C) for other H atoms. The methyl groups were allowed to rotate but not to tip. The absolute configuration of the procured material was known in advance and was confirmed by unambiguous refinement of the absolute structure parameter (Flack & Bernardinelli, 2000).

Computing details

For both compounds, data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg & Putz, 2005) and PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The asymmetric unit of (I), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. Dashed lines indicate hydrogen bonds.
	Fig. 2. The asymmetric unit of (II), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. The dashed line indicates the hydrogen bond.
	Fig. 3. A superposition of the molecular conformations of triptans; the overlay was made by making a least-squares fit through the indole ring of eletriptan, (I). For naratriptan, (II), the r.m.s deviation is 0.022 Å; for zolmitriptan (labelled 3), r.m.s deviation = 0.028 Å; for sumatriptan (labelled 4), r.m.s deviation = 0.017 Å; for almotriptan (labelled 5), r.m.s deviation = 0.19 Å; for rizatriptan benzoate (labelled 6), r.m.s deviation = 0.013 Å; for sumatriptan succinate (labelled 7), r.m.s deviation = 0.017 Å; and for almotriptan malate (labelled 8), r.m.s deviation = 0.023 Å.
	Fig. 4. A view of part of the crystal structure of (I), showing the formation of helical chain along the c axis. Hydrogen bonds are drawn as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity. [Symmetry codes: (i) -x + 1, -y + 2, -z + 1; (ii) x - 1, y, z + 1].
	Fig. 5. A view of part of the crystal structure of (II), showing the aggregation of R4^2(20) and R4^2(24) ring hydrogen-bonding motifs forming sheets in the bc plane. H atoms not involved in hydrogen bonding have been omitted for clarity. Dashed lines indicate hydrogen bonds. [Symmetry codes: (i) x - 1/2, -y + 3/2, -z + 1; (ii) -x + 1/2, -y + 1, z + 1/2].

(I) (1S,2R)-1-methyl-2-{5-[2-(phenylsulfonyl)ethyl]-1H-indol-3- ylmethyl}pyrrolidinium bromide monohydrate

Crystal data

C22H27N2O2S^+·Br^−·H2O	F(000) = 1000
Mr = 481.44	Dx = 1.408 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 6588 reflections
a = 9.4019 (6) Å	θ = 2.4–27.1°
b = 13.4089 (8) Å	µ = 1.93 mm^−1
c = 18.0173 (11) Å	T = 294 K
V = 2271.4 (2) Å^3	Block, colourless
Z = 4	0.16 × 0.12 × 0.07 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer	3984 independent reflections
Radiation source: fine-focus sealed tube	3761 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.066
ω scans	θmax = 25.0°, θmin = 1.9°
Absorption correction: multi-scan (SADABS; Bruker, 2001)	h = −11→11
Tmin = 0.75, Tmax = 0.86	k = −15→15
21861 measured reflections	l = −21→21

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.024	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.066	w = 1/[σ^2(Fo^2) + (0.0416P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max = 0.001
3984 reflections	Δρmax = 0.36 e Å^−3
279 parameters	Δρmin = −0.25 e Å^−3
0 restraints	Absolute structure: Flack & Bernardinelli (2000), with how many Friedel pairs?
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.007 (5)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.7115 (3)	0.75178 (16)	0.51628 (11)	0.0462 (5)
H1	0.7705	0.8022	0.5339	0.055*
C2	0.6300 (2)	0.69147 (14)	0.55980 (11)	0.0397 (4)
C3	0.5553 (2)	0.62645 (13)	0.50994 (11)	0.0371 (4)
C4	0.4560 (2)	0.54997 (14)	0.52014 (11)	0.0388 (4)
H4	0.4281	0.5317	0.5678	0.047*
C5	0.3992 (2)	0.50151 (14)	0.45886 (12)	0.0422 (5)
C6	0.4469 (3)	0.52790 (16)	0.38693 (12)	0.0494 (5)
H6	0.4099	0.4944	0.3461	0.059*
C7	0.5461 (3)	0.60153 (16)	0.37568 (11)	0.0485 (5)
H7	0.5768	0.6177	0.3281	0.058*
C8	0.5993 (2)	0.65118 (14)	0.43741 (11)	0.0407 (4)
C9	0.6250 (3)	0.68641 (15)	0.64310 (12)	0.0474 (5)
H9A	0.6859	0.6325	0.6599	0.057*
H9B	0.5286	0.6713	0.6586	0.057*
C10	0.6721 (3)	0.78258 (17)	0.67974 (12)	0.0517 (5)
H10	0.7591	0.8059	0.6552	0.062*
C11	0.5627 (4)	0.8667 (2)	0.67850 (17)	0.0783 (8)
H11A	0.4752	0.8446	0.6553	0.094*
H11B	0.5991	0.9237	0.6513	0.094*
C12	0.5369 (4)	0.8941 (2)	0.75973 (16)	0.0841 (10)
H12A	0.5234	0.9654	0.7653	0.101*
H12B	0.4538	0.8599	0.7789	0.101*
C13	0.6687 (4)	0.8604 (2)	0.79898 (15)	0.0791 (9)
H13A	0.7447	0.9087	0.7934	0.095*
H13B	0.6508	0.8497	0.8514	0.095*
C14	0.8507 (3)	0.7292 (3)	0.77544 (17)	0.0925 (11)
H14A	0.9182	0.7751	0.7547	0.139*
H14B	0.8625	0.6649	0.7528	0.139*
H14C	0.8660	0.7237	0.8280	0.139*
C15	0.2883 (2)	0.42176 (14)	0.46794 (13)	0.0458 (5)
H15A	0.2054	0.4386	0.4385	0.055*
H15B	0.2594	0.4183	0.5196	0.055*
C16	0.3456 (2)	0.32015 (14)	0.44345 (12)	0.0412 (4)
H16A	0.4385	0.3094	0.4655	0.049*
H16B	0.3568	0.3197	0.3899	0.049*
C17	0.3211 (2)	0.11320 (15)	0.44297 (11)	0.0410 (4)
C18	0.3585 (3)	0.04389 (17)	0.49625 (14)	0.0547 (6)
H18	0.3348	0.0535	0.5459	0.066*
C19	0.4327 (3)	−0.04101 (18)	0.47362 (17)	0.0679 (7)
H19	0.4575	−0.0895	0.5082	0.081*
C20	0.4691 (3)	−0.05295 (17)	0.40044 (17)	0.0701 (8)
H20	0.5200	−0.1091	0.3859	0.084*
C21	0.4316 (3)	0.01650 (19)	0.34864 (16)	0.0683 (7)
H21	0.4578	0.0072	0.2993	0.082*
C22	0.3556 (3)	0.09999 (16)	0.36842 (13)	0.0542 (6)
H22	0.3280	0.1465	0.3329	0.065*
N1	0.6947 (2)	0.72792 (14)	0.44290 (10)	0.0482 (5)
H1N	0.720 (2)	0.7617 (15)	0.4086 (12)	0.039 (6)*
N2	0.7039 (2)	0.76611 (17)	0.76130 (11)	0.0543 (5)
H2N	0.644 (3)	0.7245 (19)	0.7712 (14)	0.049 (7)*
S1	0.23056 (6)	0.22216 (3)	0.46994 (3)	0.04000 (12)
O1	0.10076 (16)	0.22946 (11)	0.42758 (9)	0.0522 (4)
O2	0.2173 (2)	0.22161 (12)	0.54933 (8)	0.0598 (4)
Br1	0.73101 (3)	0.83875 (2)	0.269612 (12)	0.06036 (10)
O1W	0.5203 (2)	0.63364 (14)	0.82638 (13)	0.0600 (5)
H1W	0.454 (4)	0.639 (2)	0.8011 (19)	0.083 (12)*
H2W	0.494 (4)	0.663 (2)	0.861 (2)	0.087 (12)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0510 (12)	0.0479 (11)	0.0396 (11)	−0.0102 (9)	0.0005 (10)	0.0010 (9)
C2	0.0429 (11)	0.0422 (10)	0.0340 (10)	−0.0021 (8)	0.0005 (9)	−0.0001 (8)
C3	0.0396 (10)	0.0357 (9)	0.0360 (10)	0.0029 (8)	−0.0004 (8)	0.0025 (8)
C4	0.0429 (11)	0.0393 (10)	0.0341 (10)	0.0017 (8)	0.0015 (9)	0.0017 (8)
C5	0.0433 (11)	0.0385 (10)	0.0449 (12)	0.0034 (9)	−0.0030 (9)	−0.0010 (9)
C6	0.0593 (14)	0.0495 (11)	0.0393 (12)	−0.0004 (10)	−0.0092 (10)	−0.0060 (9)
C7	0.0612 (13)	0.0518 (12)	0.0326 (11)	0.0027 (11)	0.0004 (10)	0.0028 (9)
C8	0.0452 (11)	0.0403 (10)	0.0367 (11)	0.0021 (9)	0.0012 (8)	0.0035 (9)
C9	0.0501 (12)	0.0531 (12)	0.0390 (11)	−0.0088 (10)	0.0014 (9)	0.0012 (9)
C10	0.0583 (13)	0.0647 (13)	0.0322 (11)	−0.0175 (12)	0.0021 (10)	−0.0017 (10)
C11	0.109 (2)	0.0614 (15)	0.0644 (17)	0.0016 (16)	−0.0042 (17)	−0.0035 (13)
C12	0.128 (3)	0.0530 (14)	0.0713 (19)	0.0089 (16)	0.027 (2)	−0.0010 (14)
C13	0.122 (3)	0.0697 (16)	0.0460 (14)	−0.0244 (17)	0.0039 (16)	−0.0135 (12)
C14	0.0512 (16)	0.176 (3)	0.0505 (16)	−0.0029 (19)	−0.0087 (13)	−0.0027 (19)
C15	0.0409 (11)	0.0454 (11)	0.0511 (12)	−0.0010 (9)	−0.0010 (10)	−0.0061 (9)
C16	0.0353 (10)	0.0434 (11)	0.0448 (12)	−0.0026 (9)	−0.0006 (8)	0.0007 (8)
C17	0.0393 (11)	0.0423 (10)	0.0415 (11)	−0.0041 (8)	0.0011 (9)	0.0005 (9)
C18	0.0608 (15)	0.0509 (12)	0.0524 (14)	−0.0057 (11)	−0.0078 (12)	0.0055 (10)
C19	0.0728 (17)	0.0473 (13)	0.083 (2)	0.0039 (12)	−0.0138 (15)	0.0120 (13)
C20	0.0679 (17)	0.0519 (14)	0.090 (2)	0.0083 (12)	0.0085 (15)	−0.0053 (14)
C21	0.0816 (19)	0.0587 (14)	0.0645 (17)	0.0029 (14)	0.0239 (15)	−0.0061 (13)
C22	0.0683 (15)	0.0461 (12)	0.0481 (13)	0.0009 (12)	0.0077 (12)	0.0029 (10)
N1	0.0569 (12)	0.0495 (10)	0.0383 (10)	−0.0093 (9)	0.0045 (8)	0.0079 (8)
N2	0.0526 (11)	0.0731 (13)	0.0371 (10)	−0.0191 (10)	0.0035 (9)	−0.0035 (9)
S1	0.0387 (3)	0.0444 (2)	0.0369 (2)	−0.0026 (2)	0.0023 (2)	0.00044 (19)
O1	0.0362 (8)	0.0609 (9)	0.0597 (9)	−0.0026 (7)	−0.0047 (7)	0.0012 (7)
O2	0.0786 (12)	0.0636 (9)	0.0373 (8)	−0.0024 (9)	0.0105 (8)	−0.0009 (7)
Br1	0.05458 (15)	0.08405 (18)	0.04246 (13)	0.00331 (12)	0.00418 (10)	0.00765 (10)
O1W	0.0602 (12)	0.0659 (11)	0.0538 (11)	−0.0052 (9)	−0.0015 (10)	−0.0001 (9)

Geometric parameters (Å, º)

C1—C2	1.362 (3)	C13—H13B	0.9700
C1—N1	1.369 (3)	C14—N2	1.488 (4)
C1—H1	0.9300	C14—H14A	0.9600
C2—C3	1.436 (3)	C14—H14B	0.9600
C2—C9	1.503 (3)	C14—H14C	0.9600
C3—C4	1.399 (3)	C15—C16	1.530 (3)
C3—C8	1.410 (3)	C15—H15A	0.9700
C4—C5	1.388 (3)	C15—H15B	0.9700
C4—H4	0.9300	C16—S1	1.7674 (19)
C5—C6	1.416 (3)	C16—H16A	0.9700
C5—C15	1.503 (3)	C16—H16B	0.9700
C6—C7	1.373 (3)	C17—C18	1.381 (3)
C6—H6	0.9300	C17—C22	1.393 (3)
C7—C8	1.389 (3)	C17—S1	1.759 (2)
C7—H7	0.9300	C18—C19	1.396 (4)
C8—N1	1.369 (3)	C18—H18	0.9300
C9—C10	1.515 (3)	C19—C20	1.372 (4)
C9—H9A	0.9700	C19—H19	0.9300
C9—H9B	0.9700	C20—C21	1.365 (4)
C10—N2	1.516 (3)	C20—H20	0.9300
C10—C11	1.527 (4)	C21—C22	1.375 (3)
C10—H10	0.9800	C21—H21	0.9300
C11—C12	1.528 (4)	C22—H22	0.9300
C11—H11A	0.9700	N1—H1N	0.80 (2)
C11—H11B	0.9700	N2—H2N	0.81 (3)
C12—C13	1.496 (5)	S1—O2	1.4358 (15)
C12—H12A	0.9700	S1—O1	1.4427 (16)
C12—H12B	0.9700	O1W—H1W	0.78 (4)
C13—N2	1.473 (3)	O1W—H2W	0.78 (4)
C13—H13A	0.9700
C2—C1—N1	110.60 (19)	H13A—C13—H13B	109.1
C2—C1—H1	124.7	N2—C14—H14A	109.5
N1—C1—H1	124.7	N2—C14—H14B	109.5
C1—C2—C3	106.01 (18)	H14A—C14—H14B	109.5
C1—C2—C9	128.25 (19)	N2—C14—H14C	109.5
C3—C2—C9	125.59 (18)	H14A—C14—H14C	109.5
C4—C3—C8	119.34 (18)	H14B—C14—H14C	109.5
C4—C3—C2	133.61 (19)	C5—C15—C16	110.99 (17)
C8—C3—C2	107.06 (17)	C5—C15—H15A	109.4
C5—C4—C3	119.7 (2)	C16—C15—H15A	109.4
C5—C4—H4	120.2	C5—C15—H15B	109.4
C3—C4—H4	120.2	C16—C15—H15B	109.4
C4—C5—C6	119.3 (2)	H15A—C15—H15B	108.0
C4—C5—C15	120.9 (2)	C15—C16—S1	111.65 (14)
C6—C5—C15	119.81 (19)	C15—C16—H16A	109.3
C7—C6—C5	122.0 (2)	S1—C16—H16A	109.3
C7—C6—H6	119.0	C15—C16—H16B	109.3
C5—C6—H6	119.0	S1—C16—H16B	109.3
C6—C7—C8	118.1 (2)	H16A—C16—H16B	108.0
C6—C7—H7	121.0	C18—C17—C22	121.7 (2)
C8—C7—H7	121.0	C18—C17—S1	119.31 (18)
N1—C8—C7	130.84 (19)	C22—C17—S1	118.98 (16)
N1—C8—C3	107.58 (17)	C17—C18—C19	118.2 (2)
C7—C8—C3	121.58 (19)	C17—C18—H18	120.9
C2—C9—C10	112.80 (17)	C19—C18—H18	120.9
C2—C9—H9A	109.0	C20—C19—C18	120.0 (2)
C10—C9—H9A	109.0	C20—C19—H19	120.0
C2—C9—H9B	109.0	C18—C19—H19	120.0
C10—C9—H9B	109.0	C21—C20—C19	120.9 (2)
H9A—C9—H9B	107.8	C21—C20—H20	119.6
C9—C10—N2	110.86 (18)	C19—C20—H20	119.6
C9—C10—C11	115.2 (2)	C20—C21—C22	120.8 (2)
N2—C10—C11	104.73 (19)	C20—C21—H21	119.6
C9—C10—H10	108.6	C22—C21—H21	119.6
N2—C10—H10	108.6	C21—C22—C17	118.3 (2)
C11—C10—H10	108.6	C21—C22—H22	120.8
C10—C11—C12	105.7 (2)	C17—C22—H22	120.8
C10—C11—H11A	110.6	C8—N1—C1	108.75 (17)
C12—C11—H11A	110.6	C8—N1—H1N	124.4 (16)
C10—C11—H11B	110.6	C1—N1—H1N	125.2 (15)
C12—C11—H11B	110.6	C13—N2—C14	114.5 (3)
H11A—C11—H11B	108.7	C13—N2—C10	106.1 (2)
C13—C12—C11	104.4 (3)	C14—N2—C10	113.4 (2)
C13—C12—H12A	110.9	C13—N2—H2N	109.6 (17)
C11—C12—H12A	110.9	C14—N2—H2N	112.0 (17)
C13—C12—H12B	110.9	C10—N2—H2N	100.2 (18)
C11—C12—H12B	110.9	O2—S1—O1	116.99 (11)
H12A—C12—H12B	108.9	O2—S1—C17	108.23 (10)
N2—C13—C12	103.1 (2)	O1—S1—C17	108.64 (10)
N2—C13—H13A	111.1	O2—S1—C16	109.02 (10)
C12—C13—H13A	111.1	O1—S1—C16	108.92 (10)
N2—C13—H13B	111.1	C17—S1—C16	104.28 (9)
C12—C13—H13B	111.1	H1W—O1W—H2W	99 (3)
N1—C1—C2—C3	−1.0 (3)	C6—C5—C15—C16	65.9 (3)
N1—C1—C2—C9	174.7 (2)	C5—C15—C16—S1	168.71 (15)
C1—C2—C3—C4	−179.2 (2)	C22—C17—C18—C19	0.0 (3)
C9—C2—C3—C4	5.0 (4)	S1—C17—C18—C19	−178.76 (19)
C1—C2—C3—C8	1.0 (2)	C17—C18—C19—C20	1.3 (4)
C9—C2—C3—C8	−174.9 (2)	C18—C19—C20—C21	−1.1 (4)
C8—C3—C4—C5	−1.8 (3)	C19—C20—C21—C22	−0.4 (5)
C2—C3—C4—C5	178.3 (2)	C20—C21—C22—C17	1.7 (4)
C3—C4—C5—C6	2.3 (3)	C18—C17—C22—C21	−1.5 (4)
C3—C4—C5—C15	−177.66 (18)	S1—C17—C22—C21	177.3 (2)
C4—C5—C6—C7	−1.2 (3)	C7—C8—N1—C1	179.3 (2)
C15—C5—C6—C7	178.8 (2)	C3—C8—N1—C1	0.0 (2)
C5—C6—C7—C8	−0.4 (3)	C2—C1—N1—C8	0.6 (3)
C6—C7—C8—N1	−178.3 (2)	C12—C13—N2—C14	164.8 (2)
C6—C7—C8—C3	1.0 (3)	C12—C13—N2—C10	38.9 (3)
C4—C3—C8—N1	179.53 (18)	C9—C10—N2—C13	−148.7 (2)
C2—C3—C8—N1	−0.6 (2)	C11—C10—N2—C13	−23.9 (3)
C4—C3—C8—C7	0.2 (3)	C9—C10—N2—C14	84.7 (3)
C2—C3—C8—C7	−179.97 (19)	C11—C10—N2—C14	−150.4 (3)
C1—C2—C9—C10	24.5 (3)	C18—C17—S1—O2	3.2 (2)
C3—C2—C9—C10	−160.6 (2)	C22—C17—S1—O2	−175.67 (18)
C2—C9—C10—N2	−164.60 (19)	C18—C17—S1—O1	−124.82 (18)
C2—C9—C10—C11	76.7 (3)	C22—C17—S1—O1	56.3 (2)
C9—C10—C11—C12	121.9 (3)	C18—C17—S1—C16	119.14 (19)
N2—C10—C11—C12	−0.2 (3)	C22—C17—S1—C16	−59.7 (2)
C10—C11—C12—C13	23.6 (3)	C15—C16—S1—O2	−60.44 (18)
C11—C12—C13—N2	−38.4 (3)	C15—C16—S1—O1	68.29 (17)
C4—C5—C15—C16	−114.1 (2)	C15—C16—S1—C17	−175.86 (15)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···Br1	0.80 (2)	2.71 (2)	3.4747 (19)	159 (2)
N2—H2N···O1W	0.81 (3)	1.96 (3)	2.740 (3)	162 (2)
O1W—H1W···Br1^i	0.78 (4)	2.47 (4)	3.244 (2)	175 (3)
O1W—H2W···O1^ii	0.78 (4)	2.08 (4)	2.827 (3)	162 (3)

Symmetry codes: (i) x−1/2, −y+3/2, −z+1; (ii) −x+1/2, −y+1, z+1/2.

(II) 1-methyl-4-{5-[2-(methylsulfamoyl)ethyl]-1H-indol-3-yl}piperidinium chloride

Crystal data

C17H26N3O2S^+·Cl^−	Z = 2
Mr = 371.92	F(000) = 396
Triclinic, P1	Dx = 1.319 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 6.1914 (5) Å	Cell parameters from 5193 reflections
b = 12.2298 (10) Å	θ = 2.6–28.0°
c = 12.9948 (11) Å	µ = 0.33 mm^−1
α = 78.348 (1)°	T = 294 K
β = 76.338 (1)°	Block, colourless
γ = 86.033 (1)°	0.18 × 0.15 × 0.08 mm
V = 936.18 (13) Å^3

Data collection

Burker SMART APEX CCD area-detector diffractometer	3006 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.018
Graphite monochromator	θmax = 25.0°, θmin = 1.6°
ω scans	h = −7→7
9097 measured reflections	k = −14→14
3301 independent reflections	l = −15→15

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.036	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.097	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0486P)^2 + 0.3147P] where P = (Fo^2 + 2Fc^2)/3
3301 reflections	(Δ/σ)max = 0.001
231 parameters	Δρmax = 0.24 e Å^−3
0 restraints	Δρmin = −0.34 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.5449 (3)	0.98809 (16)	0.65005 (17)	0.0562 (5)
H1	0.6528	1.0189	0.5901	0.067*
C2	0.5646 (3)	0.88617 (14)	0.71365 (14)	0.0441 (4)
C3	0.3612 (3)	0.87256 (14)	0.79556 (14)	0.0418 (4)
C4	0.2735 (3)	0.78710 (14)	0.88254 (13)	0.0422 (4)
H4	0.3556	0.7214	0.8966	0.051*
C5	0.0654 (3)	0.80058 (16)	0.94706 (14)	0.0460 (4)
C6	−0.0569 (3)	0.90060 (17)	0.92507 (16)	0.0543 (5)
H6	−0.1959	0.9094	0.9696	0.065*
C7	0.0218 (3)	0.98533 (16)	0.84045 (17)	0.0553 (5)
H7	−0.0617	1.0506	0.8268	0.066*
C8	0.2305 (3)	0.97032 (14)	0.77583 (15)	0.0483 (4)
C9	0.7580 (3)	0.80530 (14)	0.70112 (14)	0.0420 (4)
H9	0.8091	0.7900	0.7686	0.050*
C10	0.9532 (3)	0.85169 (14)	0.60995 (15)	0.0473 (4)
H10A	0.9037	0.8719	0.5430	0.057*
H10B	1.0040	0.9188	0.6250	0.057*
C11	1.1431 (3)	0.76844 (15)	0.59688 (16)	0.0500 (4)
H11A	1.2626	0.8001	0.5376	0.060*
H11B	1.1995	0.7517	0.6621	0.060*
C12	0.8864 (3)	0.61234 (15)	0.66696 (15)	0.0464 (4)
H12A	0.9404	0.5932	0.7328	0.056*
H12B	0.8386	0.5445	0.6520	0.056*
C13	0.6933 (3)	0.69450 (14)	0.68115 (15)	0.0445 (4)
H13A	0.5770	0.6617	0.7415	0.053*
H13B	0.6336	0.7085	0.6169	0.053*
C14	1.2579 (3)	0.58442 (16)	0.55097 (17)	0.0547 (5)
H14A	1.3259	0.5650	0.6116	0.082*
H14B	1.3653	0.6187	0.4887	0.082*
H14C	1.2047	0.5182	0.5370	0.082*
C15	−0.0332 (3)	0.70945 (17)	1.03972 (15)	0.0515 (5)
H15A	−0.0777	0.7399	1.1051	0.062*
H15B	0.0791	0.6516	1.0502	0.062*
C16	−0.2340 (3)	0.65810 (16)	1.02022 (14)	0.0479 (4)
H16A	−0.1838	0.6150	0.9637	0.057*
H16B	−0.3320	0.7176	0.9951	0.057*
C17	−0.6003 (4)	0.7424 (2)	1.2136 (2)	0.0837 (8)
H17A	−0.7250	0.7243	1.1886	0.126*
H17B	−0.5170	0.8001	1.1608	0.126*
H17C	−0.6525	0.7681	1.2805	0.126*
N1	0.3461 (3)	1.03869 (14)	0.68603 (15)	0.0601 (5)
H1N	0.297 (4)	1.105 (2)	0.6619 (18)	0.064 (6)*
N2	1.0693 (2)	0.66347 (12)	0.57513 (12)	0.0420 (3)
H2N	1.013 (3)	0.6777 (16)	0.5170 (17)	0.053 (6)*
N3	−0.4582 (3)	0.64332 (17)	1.23026 (14)	0.0608 (5)
H3N	−0.358 (4)	0.6518 (19)	1.2550 (18)	0.062 (7)*
O1	−0.5847 (2)	0.54093 (13)	1.11255 (11)	0.0635 (4)
O2	−0.2388 (3)	0.48404 (12)	1.17328 (12)	0.0682 (4)
S1	−0.38571 (7)	0.57068 (4)	1.13655 (4)	0.04786 (15)
Cl1	0.83672 (9)	0.71229 (4)	0.38363 (4)	0.05522 (16)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0587 (12)	0.0429 (10)	0.0590 (12)	−0.0056 (9)	−0.0049 (9)	0.0001 (9)
C2	0.0478 (10)	0.0388 (9)	0.0450 (10)	−0.0050 (7)	−0.0108 (8)	−0.0050 (7)
C3	0.0451 (9)	0.0394 (9)	0.0439 (9)	−0.0011 (7)	−0.0146 (7)	−0.0092 (7)
C4	0.0425 (9)	0.0438 (9)	0.0419 (9)	−0.0002 (7)	−0.0146 (7)	−0.0063 (7)
C5	0.0443 (10)	0.0544 (10)	0.0421 (9)	−0.0038 (8)	−0.0136 (8)	−0.0105 (8)
C6	0.0475 (11)	0.0599 (12)	0.0568 (11)	0.0039 (9)	−0.0081 (9)	−0.0203 (9)
C7	0.0560 (11)	0.0440 (10)	0.0682 (13)	0.0094 (8)	−0.0160 (10)	−0.0173 (9)
C8	0.0549 (11)	0.0380 (9)	0.0544 (11)	0.0004 (8)	−0.0160 (9)	−0.0108 (8)
C9	0.0431 (9)	0.0431 (9)	0.0395 (9)	−0.0051 (7)	−0.0116 (7)	−0.0030 (7)
C10	0.0475 (10)	0.0397 (9)	0.0531 (10)	−0.0116 (8)	−0.0078 (8)	−0.0059 (8)
C11	0.0397 (9)	0.0509 (10)	0.0584 (11)	−0.0120 (8)	−0.0077 (8)	−0.0082 (9)
C12	0.0424 (9)	0.0410 (9)	0.0517 (10)	−0.0069 (7)	−0.0068 (8)	−0.0015 (8)
C13	0.0378 (9)	0.0414 (9)	0.0508 (10)	−0.0075 (7)	−0.0075 (7)	−0.0015 (8)
C14	0.0471 (10)	0.0516 (11)	0.0615 (12)	0.0044 (8)	−0.0095 (9)	−0.0068 (9)
C15	0.0424 (10)	0.0691 (12)	0.0414 (9)	−0.0055 (9)	−0.0104 (8)	−0.0046 (9)
C16	0.0496 (10)	0.0560 (11)	0.0379 (9)	−0.0042 (8)	−0.0126 (8)	−0.0047 (8)
C17	0.0595 (14)	0.111 (2)	0.0876 (18)	0.0127 (14)	−0.0122 (13)	−0.0464 (16)
N1	0.0664 (11)	0.0363 (9)	0.0695 (11)	0.0036 (8)	−0.0111 (9)	0.0019 (8)
N2	0.0390 (8)	0.0431 (8)	0.0437 (8)	−0.0023 (6)	−0.0133 (6)	−0.0031 (6)
N3	0.0491 (10)	0.0898 (14)	0.0458 (9)	−0.0096 (9)	−0.0105 (8)	−0.0160 (9)
O1	0.0580 (8)	0.0756 (10)	0.0605 (9)	−0.0186 (7)	−0.0204 (7)	−0.0076 (7)
O2	0.0711 (10)	0.0586 (9)	0.0723 (10)	−0.0023 (7)	−0.0276 (8)	0.0071 (7)
S1	0.0467 (3)	0.0543 (3)	0.0422 (3)	−0.0076 (2)	−0.01441 (19)	−0.0012 (2)
Cl1	0.0698 (3)	0.0475 (3)	0.0532 (3)	0.0039 (2)	−0.0278 (2)	−0.0064 (2)

Geometric parameters (Å, º)

C1—N1	1.363 (3)	C12—C13	1.509 (2)
C1—C2	1.365 (3)	C12—H12A	0.9700
C1—H1	0.9300	C12—H12B	0.9700
C2—C3	1.439 (2)	C13—H13A	0.9700
C2—C9	1.499 (2)	C13—H13B	0.9700
C3—C4	1.406 (2)	C14—N2	1.480 (2)
C3—C8	1.411 (2)	C14—H14A	0.9600
C4—C5	1.380 (3)	C14—H14B	0.9600
C4—H4	0.9300	C14—H14C	0.9600
C5—C6	1.409 (3)	C15—C16	1.525 (3)
C5—C15	1.506 (3)	C15—H15A	0.9700
C6—C7	1.370 (3)	C15—H15B	0.9700
C6—H6	0.9300	C16—S1	1.7679 (18)
C7—C8	1.388 (3)	C16—H16A	0.9700
C7—H7	0.9300	C16—H16B	0.9700
C8—N1	1.366 (2)	C17—N3	1.458 (3)
C9—C13	1.527 (2)	C17—H17A	0.9600
C9—C10	1.527 (2)	C17—H17B	0.9600
C9—H9	0.9800	C17—H17C	0.9600
C10—C11	1.503 (3)	N1—H1N	0.87 (2)
C10—H10A	0.9700	N2—H2N	0.89 (2)
C10—H10B	0.9700	N3—S1	1.6116 (19)
C11—N2	1.492 (2)	N3—H3N	0.78 (2)
C11—H11A	0.9700	O1—S1	1.4272 (14)
C11—H11B	0.9700	O2—S1	1.4301 (15)
C12—N2	1.502 (2)
N1—C1—C2	110.95 (18)	C12—C13—C9	112.80 (14)
N1—C1—H1	124.5	C12—C13—H13A	109.0
C2—C1—H1	124.5	C9—C13—H13A	109.0
C1—C2—C3	105.67 (16)	C12—C13—H13B	109.0
C1—C2—C9	127.22 (17)	C9—C13—H13B	109.0
C3—C2—C9	127.11 (15)	H13A—C13—H13B	107.8
C4—C3—C8	118.36 (16)	N2—C14—H14A	109.5
C4—C3—C2	134.72 (16)	N2—C14—H14B	109.5
C8—C3—C2	106.91 (15)	H14A—C14—H14B	109.5
C5—C4—C3	120.04 (16)	N2—C14—H14C	109.5
C5—C4—H4	120.0	H14A—C14—H14C	109.5
C3—C4—H4	120.0	H14B—C14—H14C	109.5
C4—C5—C6	119.39 (17)	C5—C15—C16	112.07 (15)
C4—C5—C15	120.92 (17)	C5—C15—H15A	109.2
C6—C5—C15	119.68 (17)	C16—C15—H15A	109.2
C7—C6—C5	122.34 (18)	C5—C15—H15B	109.2
C7—C6—H6	118.8	C16—C15—H15B	109.2
C5—C6—H6	118.8	H15A—C15—H15B	107.9
C6—C7—C8	117.64 (18)	C15—C16—S1	113.24 (12)
C6—C7—H7	121.2	C15—C16—H16A	108.9
C8—C7—H7	121.2	S1—C16—H16A	108.9
N1—C8—C7	130.05 (18)	C15—C16—H16B	108.9
N1—C8—C3	107.73 (17)	S1—C16—H16B	108.9
C7—C8—C3	122.22 (18)	H16A—C16—H16B	107.7
C2—C9—C13	111.95 (14)	N3—C17—H17A	109.5
C2—C9—C10	112.59 (14)	N3—C17—H17B	109.5
C13—C9—C10	108.55 (14)	H17A—C17—H17B	109.5
C2—C9—H9	107.9	N3—C17—H17C	109.5
C13—C9—H9	107.9	H17A—C17—H17C	109.5
C10—C9—H9	107.9	H17B—C17—H17C	109.5
C11—C10—C9	111.80 (14)	C1—N1—C8	108.74 (16)
C11—C10—H10A	109.3	C1—N1—H1N	128.8 (15)
C9—C10—H10A	109.3	C8—N1—H1N	122.4 (15)
C11—C10—H10B	109.3	C14—N2—C11	111.69 (14)
C9—C10—H10B	109.3	C14—N2—C12	112.41 (14)
H10A—C10—H10B	107.9	C11—N2—C12	110.27 (14)
N2—C11—C10	110.57 (14)	C14—N2—H2N	105.4 (13)
N2—C11—H11A	109.5	C11—N2—H2N	110.6 (13)
C10—C11—H11A	109.5	C12—N2—H2N	106.2 (13)
N2—C11—H11B	109.5	C17—N3—S1	119.18 (16)
C10—C11—H11B	109.5	C17—N3—H3N	114.2 (17)
H11A—C11—H11B	108.1	S1—N3—H3N	111.8 (17)
N2—C12—C13	109.36 (14)	O1—S1—O2	119.03 (9)
N2—C12—H12A	109.8	O1—S1—N3	107.23 (10)
C13—C12—H12A	109.8	O2—S1—N3	106.20 (10)
N2—C12—H12B	109.8	O1—S1—C16	107.89 (9)
C13—C12—H12B	109.8	O2—S1—C16	108.31 (9)
H12A—C12—H12B	108.3	N3—S1—C16	107.69 (10)
N1—C1—C2—C3	0.1 (2)	C2—C9—C10—C11	−178.59 (15)
N1—C1—C2—C9	−179.73 (17)	C13—C9—C10—C11	−54.06 (19)
C1—C2—C3—C4	177.9 (2)	C9—C10—C11—N2	58.1 (2)
C9—C2—C3—C4	−2.3 (3)	N2—C12—C13—C9	−57.48 (19)
C1—C2—C3—C8	−0.6 (2)	C2—C9—C13—C12	179.30 (14)
C9—C2—C3—C8	179.18 (16)	C10—C9—C13—C12	54.40 (19)
C8—C3—C4—C5	−0.8 (2)	C4—C5—C15—C16	−112.37 (19)
C2—C3—C4—C5	−179.24 (18)	C6—C5—C15—C16	67.0 (2)
C3—C4—C5—C6	−0.2 (3)	C5—C15—C16—S1	−168.50 (14)
C3—C4—C5—C15	179.14 (16)	C2—C1—N1—C8	0.5 (2)
C4—C5—C6—C7	0.9 (3)	C7—C8—N1—C1	180.0 (2)
C15—C5—C6—C7	−178.44 (18)	C3—C8—N1—C1	−0.9 (2)
C5—C6—C7—C8	−0.5 (3)	C10—C11—N2—C14	174.23 (15)
C6—C7—C8—N1	178.3 (2)	C10—C11—N2—C12	−60.02 (19)
C6—C7—C8—C3	−0.7 (3)	C13—C12—N2—C14	−175.61 (15)
C4—C3—C8—N1	−177.86 (16)	C13—C12—N2—C11	59.04 (19)
C2—C3—C8—N1	0.9 (2)	C17—N3—S1—O1	−54.9 (2)
C4—C3—C8—C7	1.3 (3)	C17—N3—S1—O2	176.81 (17)
C2—C3—C8—C7	−179.87 (17)	C17—N3—S1—C16	60.96 (19)
C1—C2—C9—C13	−118.4 (2)	C15—C16—S1—O1	171.84 (14)
C3—C2—C9—C13	61.9 (2)	C15—C16—S1—O2	−58.07 (17)
C1—C2—C9—C10	4.3 (3)	C15—C16—S1—N3	56.39 (17)
C3—C2—C9—C10	−175.50 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···Cl1^i	0.87 (2)	2.34 (2)	3.2045 (18)	173 (2)
N2—H2N···Cl1	0.89 (2)	2.21 (2)	3.0978 (16)	174 (2)
N3—H3N···Cl1^ii	0.78 (2)	2.53 (2)	3.2601 (19)	157 (2)

Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) x−1, y, z+1.