{4(S)-(Piperidin-1-ylcarbonyl)-4-[3-(trifluoro­methyl)phenylsulfon­amido]butyl}guanidinium chloride: a model of a graftable thrombin inhibitor

In the title compound, C₁₈H₂₇F₃N₅O₃S⁺·Cl⁻, the guanidine group forms N—H...Cl hydrogen bonds, with four N...Cl distances in the range 3.164 (3)–3.337 (4) Å. In the crystal packing, the cations are further linked by N—H...O and C—H...O inter­actions. The structure is compared with that of argatroban complexed with thrombin and is the subject of docking studies in the active site of thrombin.

S1. Comment

Thrombin is a key enzyme in the blood coagulation system and represents a main target in medicinal chemistry (Weitz, 2003). Recently, we became interested in designing thrombin inhibitors for the biocompatibilization of polymer materials (Salvagnini et al., 2005). Our strategy relies upon the covalent grafting of biologically active molecules, via a spacer arm, on the surface of polymer devices. In this way, we can selectively confer specific properties on the material surface, while the physico-chemical and mechanical properties of the bulk remain unchanged (Marchand-Brynaert, 1999). Graftable thrombin inhibitors are derived from L-arginine and have a piperazinyl amide moiety bearing a spacer arm at site 4 (X in the scheme) for surface grafting. The replacement of the classically used piperidine with a piperazine ring, in order to use the atom at position 4 as an anchor for various spacer arms, had to be validated. Thus, a small library of thrombin inhibitors with different groups at position 4 was synthesized. Of these, the title compound with a CH₂ substituent, (I) (with a piperidine moiety), is presented here. Four other compounds, with O, N—H, N—Et and N—Ac substituents, will be published shortly (Salvagnini et al., 2006).

The elucidation of the structure of (I) (Fig. 1) and its interactions in crystal packing can help to determine its position and orientation when docked in the thrombin active site. Bond lengths and angles are as expected, e.g. the S═O bond lengths in the sulfonamide group are similar to the expected value of 1.43 Å for C—SO₂—N systems (Allen, 2002). The N atom of the amide bond, involved in the piperidine ring, is sp², with bond angles close to 120° (total of 358°) [C13—N5—C18 = 126.9 (3), C13—N5—C14 = 118.3 (3) and C18—N5—C14 = 112.7 (3)°].

In compound (I), the guanidine group interacts with the Cl⁻ anions (Table 1) via strong donor–weak acceptor N—H···Cl⁻ interactions (Desiraju & Steiner, 1999) that can also be described as `chelated' (Giacovazzo et al., 1992). In the Cambridge Structural Database (CSD, Version?; Allen, 2002), 36 entries have such interactions (ISOSTAR; Bruno et al., 1997), but only a few possess the chelated geometry, where the Cl⁻ anion interacts with two N—H moieties, N—H···Cl bond distances in the range 2.2–2.8 Å. In the crystal packing, (N/C)—H···O interactions are present and link symmetry-related cations (Table 1). An intramolecular C—H···π(arene) interaction (C10—H10B···Cg2, where Cg2 is the centroid of the phenyl ring C2–C7; Table 1) and weaker C—H···O contacts constrain the conformations of the guanidine, piperidine and trifluoromethylphenyl moieties.

The amide and sulfonamide groups of (I) were modelled superimposed on argatroban (a reference thrombin inhibitor) co-crystallized with human thrombin (Fig. 2a) (Banner & Hadvary, 1991). The piperidine moiety of each compound fits well, in contrast with the other groups. Indeed, the guanidine function is oriented so as to form either an ionic interaction with Asp189 in thrombin or an N—H···Cl interaction in the crystal packing. Moreover, the sulfonamide group of aragtroban interacts with the backbone of Gly216, orienting the tetrahydroquinoline in a different way than the trifluorophenyl group of (I).

The structure of (I) was subjected to a docking study in the active site of human thrombin [Protein Data Bank (PDB; Berman et al., 2000) code 1DWC] using GOLD (Jones et al., 2001). The binding mode of (I) is similar to that of argatroban (r.m.s deviation = 0.28 Å) (Fig. 2b). The guanidyl functional group, which binds the S-pocket and interacts with Asp189, is in an extended conformation and also interacts with the C═O bond of Gly219 and Ala190. The piperidine and trifluorophenyl groups occupy the P– and D– pockets, respectively. A weak O—H···F bond is observed between the CF₃ group and Tyr60A of the D-pocket (Desiraju & Steiner, 1999). This type of interaction is not common, but eight entries in the PDB involve a CF₃ group interacting with a tyrosine (ISOSTAR), with O···F distances in the range 2.9–3.4 Å.

In conclusion, the crystal structure of the thrombin inhibitor, (I), was determined in order to highlight its structural properties. Moreover, it has proved to be a useful starting point for thrombin docking studies.

S2. Experimental

The synthesis of (I) has been described previously (Salvagnini et al., 2005). Crystals were obtained by slow evaporation of an ethanol solution of (I), to produce colourless crystals suitable for X-ray analysis.

S3. Refinement

All H atoms were calculated and fixed in geometrically idealized positions using the SHELXL97 defaults (at 293 K) (Sheldrick, 1997), with N—H = 0.86 Å and C—H = 0.93–0.98 Å, and with U_iso(H) = 1.2U_eq(C,N). The CF₃ group is disordered over two rotational occupancies with site-occupancy factors of 0.58 and 0.42.

The stereochemistry of (I) has already been determined (Salvagnini et al., 2005, 2006), and therefore no Friedel reflections were collected. The refined value of the Flack parameter (Flack, 1983) of 0.00 (3) with R = 0.046 confirmed the S configuration, whereas the inverted conformation (R configuration) gave a Flack parameter of 0.93 (2) for R = 0.059.

The docking studies were performed using the program GOLD (Jones et al., 2001), which is a genetic algorithm for protein–ligand docking with full ligand and partial protein flexibility. The active site was defined as all protein atoms within 15 Å of any ligand atom in the experimental protein–ligand complex (1DWC). A maximum of ten docking solutions were generated for each structure. The default software settings were used for the parameters controlling the genetic algorithm. The scoring function used to rank the dockings was GOLDSCORE and it is partly based on conformational and non-bonded contact information from the CSD.

Computing details

Data collection: CAD-4 MACH3 (Nonius, 2000); cell refinement: CAD-4 MACH3; data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: enCIFer (Allen et al., 2004).

Figures

	Fig. 1. A view of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. Thin dashed lines indicate the hydrogen bonds. Heavy dashed lines indicate the disordered CF3 group (Which disorder component is shown?)
	Fig. 2. (a) The conformation of the crystal structure of (I). (b) The conformation after docking in thrombin. These conformations are superimposed on the cocrystallized structure of argatroban (A) in the active site of human thrombin.

{4(S)-(Piperidin-1-ylcarbonyl)-4-[3- (trifluoromethyl)benzenesulfonamido]butyl}guanidinium chloride

Crystal data

C18H27F3N5O3S^+·Cl^−	F(000) = 1016
Mr = 485.96	Dx = 1.395 Mg m^−3
Orthorhombic, P212121	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 23 reflections
a = 8.371 (1) Å	θ = 17.7–31.2°
b = 9.351 (1) Å	µ = 2.79 mm^−1
c = 29.554 (3) Å	T = 293 K
V = 2313.4 (4) Å^3	Prism, colourless
Z = 4	0.45 × 0.21 × 0.04 mm

Data collection

Enraf–Nonius CAD-4 diffractometer	2579 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.000
Graphite monochromator	θmax = 75.0°, θmin = 3.0°
θ/2θ scans	h = 0→10
Absorption correction: analytical (de Meulenaer & Tompa, 1965)	k = −11→0
Tmin = 0.367, Tmax = 0.897	l = 0→37
2740 measured reflections	3 standard reflections every 200 reflections
2740 independent reflections	intensity decay: 2%

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)] = 0.046	H-atom parameters constrained
wR(F^2) = 0.132	w = 1/[σ^2(Fo^2) + (0.0927P)^2 + 0.4728P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max < 0.001
2740 reflections	Δρmax = 0.39 e Å^−3
289 parameters	Δρmin = −0.40 e Å^−3
15 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.00 (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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
S1	0.39669 (13)	1.09592 (11)	0.12816 (3)	0.0602 (3)
O1	0.3543 (5)	1.1662 (4)	0.08651 (11)	0.0804 (10)
O2	0.5278 (5)	1.1435 (5)	0.15489 (14)	0.0905 (12)
O3	0.0142 (4)	1.2935 (2)	0.17744 (8)	0.0564 (7)
N1	0.2435 (4)	1.0976 (3)	0.16049 (9)	0.0457 (6)
H1	0.2564	1.1140	0.1889	0.055*
N2	0.0874 (4)	0.5785 (3)	0.20864 (10)	0.0466 (6)
H2	0.0326	0.5085	0.1979	0.056*
N3	0.3201 (4)	0.6491 (3)	0.24318 (12)	0.0600 (8)
H3A	0.2821	0.7337	0.2469	0.072*
H3B	0.4148	0.6291	0.2525	0.072*
N4	0.2924 (5)	0.4194 (3)	0.21811 (14)	0.0652 (9)
H4A	0.3867	0.3995	0.2278	0.078*
H4B	0.2360	0.3545	0.2051	0.078*
N5	−0.1210 (4)	1.2419 (3)	0.11389 (10)	0.0488 (6)
C1	0.3239 (9)	0.6488 (6)	0.0252 (2)	0.0982 (19)
F1	0.312 (2)	0.7409 (19)	−0.0085 (6)	0.171 (6)	0.42
F2	0.2026 (17)	0.5646 (13)	0.0264 (8)	0.139 (3)	0.42
F3	0.445 (2)	0.5610 (18)	0.0078 (5)	0.163 (5)	0.42
F1'	0.1971 (15)	0.7198 (14)	0.0063 (4)	0.171 (6)	0.58
F2'	0.2730 (13)	0.5094 (9)	0.0290 (5)	0.139 (3)	0.58
F3'	0.4308 (17)	0.6423 (14)	−0.0090 (3)	0.163 (5)	0.58
C2	0.3826 (7)	0.7103 (5)	0.06713 (16)	0.0725 (12)
C3	0.3705 (6)	0.8581 (5)	0.07559 (14)	0.0615 (10)
H3	0.3214	0.9180	0.0547	0.074*
C4	0.4318 (5)	0.9127 (5)	0.11504 (13)	0.0596 (10)
C5	0.5058 (7)	0.8251 (7)	0.14616 (17)	0.0795 (15)
H5	0.5496	0.8633	0.1725	0.095*
C6	0.5143 (8)	0.6794 (7)	0.1378 (2)	0.0941 (19)
H6	0.5628	0.6194	0.1588	0.113*
C7	0.4519 (8)	0.6236 (6)	0.0989 (2)	0.0914 (18)
H7	0.4565	0.5254	0.0939	0.110*
C8	0.0821 (4)	1.0722 (3)	0.14327 (10)	0.0404 (7)
H8	0.0873	1.0376	0.1120	0.048*
C9	−0.0055 (4)	0.9629 (3)	0.17287 (11)	0.0434 (7)
H9A	−0.0036	0.9954	0.2040	0.052*
H9B	−0.1163	0.9579	0.1634	0.052*
C10	0.0673 (5)	0.8130 (3)	0.17050 (11)	0.0462 (8)
H10A	0.0370	0.7683	0.1422	0.055*
H10B	0.1829	0.8206	0.1711	0.055*
C11	0.0127 (4)	0.7199 (3)	0.20947 (12)	0.0447 (7)
H11A	0.0386	0.7669	0.2378	0.054*
H11B	−0.1024	0.7090	0.2081	0.054*
C12	0.2337 (4)	0.5508 (3)	0.22332 (12)	0.0455 (7)
C13	−0.0107 (4)	1.2147 (3)	0.14510 (10)	0.0417 (7)
C14	−0.2066 (5)	1.3805 (4)	0.11595 (13)	0.0580 (9)
H14A	−0.1967	1.4215	0.1460	0.070*
H14B	−0.3191	1.3664	0.1095	0.070*
C15	−0.1340 (6)	1.4801 (4)	0.08127 (15)	0.0683 (11)
H15A	−0.0239	1.5004	0.0893	0.082*
H15B	−0.1923	1.5698	0.0810	0.082*
C16	−0.1398 (9)	1.4127 (6)	0.03440 (16)	0.0881 (16)
H16A	−0.2500	1.4080	0.0244	0.106*
H16B	−0.0817	1.4729	0.0133	0.106*
C17	−0.0691 (8)	1.2641 (6)	0.03361 (14)	0.0841 (15)
H17A	0.0456	1.2702	0.0378	0.101*
H17B	−0.0888	1.2207	0.0043	0.101*
C18	−0.1414 (6)	1.1697 (5)	0.07085 (14)	0.0664 (11)
H18A	−0.2540	1.1540	0.0650	0.080*
H18B	−0.0881	1.0776	0.0715	0.080*
Cl1	0.67475 (10)	0.49136 (9)	0.24053 (3)	0.0492 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0606 (5)	0.0570 (5)	0.0629 (5)	−0.0121 (5)	0.0108 (4)	0.0115 (4)
O1	0.107 (3)	0.0658 (18)	0.0685 (17)	−0.0053 (19)	0.0214 (19)	0.0261 (15)
O2	0.0653 (19)	0.106 (3)	0.100 (3)	−0.033 (2)	0.0090 (19)	0.001 (2)
O3	0.0822 (18)	0.0317 (11)	0.0552 (12)	0.0069 (12)	−0.0128 (13)	−0.0098 (10)
N1	0.0527 (15)	0.0385 (13)	0.0461 (13)	−0.0020 (13)	−0.0006 (12)	0.0022 (11)
N2	0.0498 (15)	0.0236 (11)	0.0662 (16)	−0.0025 (12)	−0.0060 (13)	0.0043 (11)
N3	0.0561 (17)	0.0348 (14)	0.089 (2)	−0.0009 (13)	−0.0181 (18)	−0.0012 (15)
N4	0.0625 (19)	0.0296 (13)	0.104 (2)	0.0034 (14)	−0.0162 (19)	−0.0030 (16)
N5	0.0619 (17)	0.0338 (12)	0.0508 (14)	0.0074 (13)	−0.0054 (13)	0.0022 (11)
C1	0.133 (5)	0.062 (3)	0.100 (4)	0.009 (4)	0.005 (4)	−0.009 (3)
F1	0.212 (13)	0.136 (6)	0.164 (9)	0.061 (10)	−0.099 (10)	−0.065 (6)
F2	0.141 (8)	0.084 (6)	0.191 (5)	−0.016 (5)	−0.007 (8)	−0.031 (7)
F3	0.199 (7)	0.193 (14)	0.097 (7)	−0.053 (10)	0.035 (7)	−0.050 (7)
F1'	0.212 (13)	0.136 (6)	0.164 (9)	0.061 (10)	−0.099 (10)	−0.065 (6)
F2'	0.141 (8)	0.084 (6)	0.191 (5)	−0.016 (5)	−0.007 (8)	−0.031 (7)
F3'	0.199 (7)	0.193 (14)	0.097 (7)	−0.053 (10)	0.035 (7)	−0.050 (7)
C2	0.078 (3)	0.059 (2)	0.080 (3)	0.015 (2)	0.016 (2)	0.002 (2)
C3	0.066 (2)	0.060 (2)	0.059 (2)	0.010 (2)	0.0123 (18)	0.0122 (18)
C4	0.056 (2)	0.063 (2)	0.059 (2)	0.0114 (19)	0.0183 (17)	0.0144 (18)
C5	0.071 (3)	0.103 (4)	0.065 (2)	0.035 (3)	0.011 (2)	0.011 (2)
C6	0.097 (4)	0.098 (4)	0.088 (3)	0.056 (4)	0.019 (3)	0.025 (3)
C7	0.105 (4)	0.071 (3)	0.098 (4)	0.042 (3)	0.029 (3)	0.012 (3)
C8	0.0503 (17)	0.0272 (14)	0.0435 (14)	0.0012 (13)	−0.0017 (13)	0.0007 (11)
C9	0.0471 (16)	0.0268 (13)	0.0564 (17)	0.0007 (13)	0.0023 (14)	0.0059 (12)
C10	0.060 (2)	0.0258 (13)	0.0529 (17)	0.0022 (14)	0.0012 (15)	0.0011 (12)
C11	0.0450 (16)	0.0286 (14)	0.0606 (17)	0.0011 (13)	0.0029 (14)	0.0050 (14)
C12	0.0530 (18)	0.0287 (14)	0.0550 (16)	−0.0007 (14)	−0.0020 (15)	0.0059 (13)
C13	0.0553 (17)	0.0266 (13)	0.0431 (14)	−0.0007 (14)	0.0005 (14)	0.0024 (11)
C14	0.063 (2)	0.0435 (18)	0.067 (2)	0.0149 (18)	−0.0030 (18)	0.0110 (16)
C15	0.080 (3)	0.048 (2)	0.077 (2)	0.004 (2)	−0.001 (2)	0.0171 (19)
C16	0.122 (5)	0.078 (3)	0.064 (2)	0.006 (3)	−0.011 (3)	0.026 (2)
C17	0.112 (4)	0.089 (3)	0.051 (2)	0.005 (3)	−0.012 (2)	−0.005 (2)
C18	0.084 (3)	0.052 (2)	0.063 (2)	0.005 (2)	−0.029 (2)	−0.0061 (18)
Cl1	0.0538 (4)	0.0415 (4)	0.0522 (4)	0.0021 (3)	−0.0081 (3)	0.0037 (3)

Geometric parameters (Å, º)

S1—O1	1.440 (3)	C5—C6	1.387 (9)
S1—O2	1.424 (4)	C5—H5	0.9300
S1—N1	1.599 (3)	C6—C7	1.366 (9)
S1—C4	1.781 (4)	C6—H6	0.9300
O3—C13	1.225 (4)	C7—H7	0.9300
N1—C8	1.463 (4)	C8—C9	1.532 (4)
N1—H1	0.8600	C8—C13	1.543 (4)
N2—C12	1.325 (5)	C8—H8	0.9800
N2—C11	1.463 (4)	C9—C10	1.530 (4)
N2—H2	0.8600	C9—H9A	0.9700
N3—C12	1.309 (5)	C9—H9B	0.9700
N3—H3A	0.8600	C10—C11	1.514 (4)
N3—H3B	0.8600	C10—H10A	0.9700
N4—C12	1.332 (4)	C10—H10B	0.9700
N4—H4A	0.8600	C11—H11A	0.9700
N4—H4B	0.8600	C11—H11B	0.9700
N5—C13	1.330 (4)	C14—C15	1.513 (5)
N5—C18	1.450 (5)	C14—H14A	0.9700
N5—C14	1.482 (4)	C14—H14B	0.9700
C1—F2	1.285 (14)	C15—C16	1.523 (7)
C1—F1	1.318 (16)	C15—H15A	0.9700
C1—F3'	1.352 (11)	C15—H15B	0.9700
C1—F1'	1.370 (11)	C16—C17	1.510 (8)
C1—F2'	1.377 (10)	C16—H16A	0.9700
C1—F3	1.402 (15)	C16—H16B	0.9700
C1—C2	1.453 (8)	C17—C18	1.535 (7)
C2—C7	1.369 (7)	C17—H17A	0.9700
C2—C3	1.408 (6)	C17—H17B	0.9700
C3—C4	1.372 (6)	C18—H18A	0.9700
C3—H3	0.9300	C18—H18B	0.9700
C4—C5	1.378 (6)
O2—S1—O1	121.4 (2)	C13—C8—H8	109.9
O2—S1—N1	106.48 (19)	C10—C9—C8	113.2 (3)
O1—S1—N1	108.0 (2)	C10—C9—H9A	108.9
O2—S1—C4	107.1 (3)	C8—C9—H9A	108.9
O1—S1—C4	107.1 (2)	C10—C9—H9B	108.9
N1—S1—C4	105.78 (17)	C8—C9—H9B	108.9
C8—N1—S1	122.1 (2)	H9A—C9—H9B	107.8
C8—N1—H1	119.0	C11—C10—C9	111.8 (3)
S1—N1—H1	119.0	C11—C10—H10A	109.3
C12—N2—C11	124.5 (3)	C9—C10—H10A	109.3
C12—N2—H2	117.7	C11—C10—H10B	109.3
C11—N2—H2	117.7	C9—C10—H10B	109.3
C12—N3—H3A	120.0	H10A—C10—H10B	107.9
C12—N3—H3B	120.0	N2—C11—C10	112.2 (3)
H3A—N3—H3B	120.0	N2—C11—H11A	109.2
C12—N4—H4A	120.0	C10—C11—H11A	109.2
C12—N4—H4B	120.0	N2—C11—H11B	109.2
H4A—N4—H4B	120.0	C10—C11—H11B	109.2
C13—N5—C18	126.9 (3)	H11A—C11—H11B	107.9
C13—N5—C14	118.3 (3)	N3—C12—N2	121.3 (3)
C18—N5—C14	112.7 (3)	N3—C12—N4	119.7 (3)
F2—C1—F1	111.3 (13)	N2—C12—N4	118.9 (3)
F3'—C1—F1'	103.4 (9)	O3—C13—N5	122.9 (3)
F3'—C1—F2'	102.9 (9)	O3—C13—C8	117.5 (3)
F1'—C1—F2'	104.6 (10)	N5—C13—C8	119.4 (3)
F2—C1—F3	102.8 (10)	N5—C14—C15	108.4 (3)
F1—C1—F3	99.2 (10)	N5—C14—H14A	110.0
F2—C1—C2	119.1 (11)	C15—C14—H14A	110.0
F1—C1—C2	114.2 (9)	N5—C14—H14B	110.0
F3'—C1—C2	115.6 (8)	C15—C14—H14B	110.0
F1'—C1—C2	114.7 (7)	H14A—C14—H14B	108.4
F2'—C1—C2	114.2 (8)	C14—C15—C16	110.4 (4)
F3—C1—C2	107.4 (9)	C14—C15—H15A	109.6
C7—C2—C3	119.3 (5)	C16—C15—H15A	109.6
C7—C2—C1	119.6 (5)	C14—C15—H15B	109.6
C3—C2—C1	121.0 (5)	C16—C15—H15B	109.6
C4—C3—C2	119.3 (4)	H15A—C15—H15B	108.1
C4—C3—H3	120.4	C17—C16—C15	112.5 (4)
C2—C3—H3	120.4	C17—C16—H16A	109.1
C3—C4—C5	120.9 (5)	C15—C16—H16A	109.1
C3—C4—S1	118.8 (3)	C17—C16—H16B	109.1
C5—C4—S1	120.0 (4)	C15—C16—H16B	109.1
C4—C5—C6	119.2 (6)	H16A—C16—H16B	107.8
C4—C5—H5	120.4	C16—C17—C18	111.3 (5)
C6—C5—H5	120.4	C16—C17—H17A	109.4
C7—C6—C5	120.4 (5)	C18—C17—H17A	109.4
C7—C6—H6	119.8	C16—C17—H17B	109.4
C5—C6—H6	119.8	C18—C17—H17B	109.4
C6—C7—C2	120.8 (5)	H17A—C17—H17B	108.0
C6—C7—H7	119.6	N5—C18—C17	108.4 (3)
C2—C7—H7	119.6	N5—C18—H18A	110.0
N1—C8—C9	110.6 (3)	C17—C18—H18A	110.0
N1—C8—C13	108.2 (2)	N5—C18—H18B	110.0
C9—C8—C13	108.4 (3)	C17—C18—H18B	110.0
N1—C8—H8	109.9	H18A—C18—H18B	108.4
C9—C8—H8	109.9

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Cl1^i	0.86	2.45	3.164 (3)	141
N2—H2···O3^ii	0.86	2.11	2.886 (4)	151
N3—H3A···Cl1^i	0.86	2.46	3.237 (3)	150
N3—H3B···Cl1	0.86	2.55	3.316 (3)	148
N4—H4A···Cl1	0.86	2.59	3.337 (4)	146
N4—H4B···O3^ii	0.86	2.11	2.873 (5)	148
C10—H10B···Cg2	0.97	2.93	3.688 (5)	136
C11—H11A···O3^iii	0.97	2.56	3.420 (4)	148

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