Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807033971/lh2454sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S1600536807033971/lh2454Isup2.hkl |
CCDC reference: 657779
Key indicators
- Single-crystal X-ray study
- T = 293 K
- Mean (C-C) = 0.005 Å
- R factor = 0.058
- wR factor = 0.208
- Data-to-parameter ratio = 17.1
checkCIF/PLATON results
No syntax errors found
Alert level C PLAT230_ALERT_2_C Hirshfeld Test Diff for C33 - C34 .. 5.18 su PLAT241_ALERT_2_C Check High Ueq as Compared to Neighbors for C12 PLAT322_ALERT_2_C Check Hybridisation of S1 in Main Residue . ? PLAT340_ALERT_3_C Low Bond Precision on C-C Bonds (x 1000) Ang ... 5
Alert level G PLAT199_ALERT_1_G Check the Reported _cell_measurement_temperature 293 K PLAT200_ALERT_1_G Check the Reported _diffrn_ambient_temperature . 293 K
0 ALERT level A = In general: serious problem 0 ALERT level B = Potentially serious problem 4 ALERT level C = Check and explain 2 ALERT level G = General alerts; check 2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 3 ALERT type 2 Indicator that the structure model may be wrong or deficient 1 ALERT type 3 Indicator that the structure quality may be low 0 ALERT type 4 Improvement, methodology, query or suggestion 0 ALERT type 5 Informative message, check
For background information, see Malinka et al. (2005); Allen et al. (1987); Cremer & Pople (1975); Nardelli (1983); Spek (2003). For related structures, see: Karczmarzyk & Malinka (1998, 2004, 2005).
The title compound was prepared from 2-hydroxymethyl-4,6-dimethylisothiazolo[5,4-b]pyridin-3(2H)-one and commercially available N-(2-fluorophenyl)piperazine, according to the method of Malinka et al. (2005). Crystals suitable for X-ray diffraction analysis were grown by slow evaporation of a hexane solution of the title compound.
All H atoms were located in a difference Fourier map and subsequently treated as riding with C—H distances of 0.93 (aromatic), 0.97 (CH2) and 0.96 Å (CH3) and Uiso = 1.5Ueq(C).
Recently we described synthesis, structure, conformation and analgesic action of a series of derivatives of 2-(4-arylpiperazin-1-ylmethyl)isothiazolo[5,4-b]pyridin-3(2H)-one (Malinka et al., 2005). In our SAR studies we found that the potency of the analgesic effect is highly influenced by the nature of the substituent present at aromatic ring of the 4-arylpiperazine substructure. The best analgesic results were obtained for phenylpiperazine derivatives of isothiazolopyridine with electron-withdrawing substituents (o-Cl, o-F, p-NO2, m-CF3), while the derivatives with o-electron-donating groups (o-OCH3, o-CH3) and compound with unsubstituted phenyl ring were inactive in the analgesic tests. As a continuation of our investigations, in this paper we report the results of the X-ray structure determination of title compound which proved to be the most active as an analgesic agent in the analyzed series of arylpiperazine derivatives of isothiazolopyridine.
The bond lengths and angles do not differ significantly from those reported for other related structures (e.g. Karczmarzyk & Malinka, 2005). The pyridine and isothiazole rings are planar to within 0.005 (3) and 0.029 (3) Å, respectively, and they are inclined at an angle of 0.96 (7)°.
The 4-(2-fluorophenyl)piperazin-1-ylmethyl substituent has a cis-gauche-trans conformation with the torsion angles S1—N2—C12—N21 of 25.7 (4)°, N2—C12—N21—C22 of 86.5 (4)° and N2—C12—N21—C26 of -146.9 (3)°. These torsion angles indicates a similar spatial orientation of the substituent in relation to the fused bicyclic system in the title compound and unsubstituted-phenylpiperazine derivative of isothiazolopyridine [the torsion angles are 24.5 (2), 77.9 (2) and -159.3 (2)°, respectively; Karczmarzyk & Malinka, 1998]. The piperazine ring adopts a chair conformation with puckering parameters of Q = 0.582 (4) Å and θ = 180.0 (4)° (Cremer & Pople, 1975). The N24—C31 bond length of 1.406 (4) Å, shorter than an average non-conjugated Car—N (Nsp3, pyramidal) single bond of 1.426 (11) Å (Allen et al., 1987), and the sum of the bond angles around N24 of 342.00° are typical for conjugation of the lone pair at N24 with the π system of the benzene ring. This conjugation is characteristic for meta and para electron-attracting substitution (Karczmarzyk & Malinka, 2005) and in the unsubstituted-phenylpiperazine system it is diminished by the steric effect of the 2-F group of the benzene ring. It is confirmed by the change of the dihedral angle between the mean planes of the aromatic and piperazine rings from 6.15 (6)° for the unsubstituted benzene ring in the phenylpiperazine derivative of isothiazolopyridine to 37.72 (13)° in the title compound. It is worthy to mention that this dihedral angle is close to 60° for other 2-substituted phenylpiperazine derivatives (Karczmarzyk & Malinka, 2004). In conclusion, the observed similarity of the structural features at crystals of the title compound and its unsubstituted analogue may suggest that within series of analgesic isothiazolopyridines fluorine does not resemble other halogens but mimics a hydrogen atom.
In the crystal structure, molecules are linked into chains parallel to [010] direction via short intermolecular C—H···X (X = N, O) contacts (Table 1; Spek, 2003; Nardelli, 1983). Additionally, pairs of pyridine rings belonging to inversion-related molecules overlap, with a centroid-to-centroid separation of 3.5908 (18) Å. The shortest intermolecular contact [N7···C4i = 3.586 (4) Å; symmetry code: (i) = 1 - x, -y, -z] is characteristic of π···π interactions.
For background information, see Malinka et al. (2005); Allen et al. (1987); Cremer & Pople (1975); Nardelli (1983); Spek (2003). For related structures, see: Karczmarzyk & Malinka (1998, 2004, 2005).
Data collection: KM4B8 (Gałdecki et al., 1996); cell refinement: KM4B8; data reduction: DATAPROC (Gałdecki et al., 1995); program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: SHELXL97 and WinGX (Farrugia, 1999).
C19H21FN4OS | F(000) = 784 |
Mr = 372.46 | Dx = 1.311 Mg m−3 |
Monoclinic, P21/n | Cu Kα radiation, λ = 1.54178 Å |
Hall symbol: -P 2yn | Cell parameters from 25 reflections |
a = 8.118 (1) Å | θ = 20.6–39.7° |
b = 10.551 (2) Å | µ = 1.74 mm−1 |
c = 22.054 (2) Å | T = 293 K |
β = 92.13 (1)° | Prism, colourless |
V = 1887.7 (5) Å3 | 0.35 × 0.20 × 0.10 mm |
Z = 4 |
Kuma KM-4 four-circle diffractometer | 2273 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.038 |
Graphite monochromator | θmax = 80.2°, θmin = 4.0° |
ω–2θ scans | h = −10→10 |
Absorption correction: ψ scan (North et al., 1968) | k = −13→1 |
Tmin = 0.582, Tmax = 0.842 | l = −28→1 |
4806 measured reflections | 2 standard reflections every 100 reflections |
4034 independent reflections | intensity decay: 0.3% |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.058 | H-atom parameters constrained |
wR(F2) = 0.208 | w = 1/[σ2(Fo2) + (0.1364P)2] where P = (Fo2 + 2Fc2)/3 |
S = 0.98 | (Δ/σ)max < 0.001 |
4034 reflections | Δρmax = 0.42 e Å−3 |
236 parameters | Δρmin = −0.29 e Å−3 |
0 restraints | Extinction correction: SHELXL97, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.0028 (7) |
C19H21FN4OS | V = 1887.7 (5) Å3 |
Mr = 372.46 | Z = 4 |
Monoclinic, P21/n | Cu Kα radiation |
a = 8.118 (1) Å | µ = 1.74 mm−1 |
b = 10.551 (2) Å | T = 293 K |
c = 22.054 (2) Å | 0.35 × 0.20 × 0.10 mm |
β = 92.13 (1)° |
Kuma KM-4 four-circle diffractometer | 2273 reflections with I > 2σ(I) |
Absorption correction: ψ scan (North et al., 1968) | Rint = 0.038 |
Tmin = 0.582, Tmax = 0.842 | 2 standard reflections every 100 reflections |
4806 measured reflections | intensity decay: 0.3% |
4034 independent reflections |
R[F2 > 2σ(F2)] = 0.058 | 0 restraints |
wR(F2) = 0.208 | H-atom parameters constrained |
S = 0.98 | Δρmax = 0.42 e Å−3 |
4034 reflections | Δρmin = −0.29 e Å−3 |
236 parameters |
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. Weighted least-squares planes through the starred atoms (Nardelli, Musatti, Domiano & Andreetti Ric.Sci.(1965),15(II—A),807). Equation of the plane: m1*X+m2*Y+m3*Z=d Plane 1 m1 = 0.39138(0.00077) m2 = -0.44517(0.00107) m3 = -0.80539(0.00071) D = -0.19003(0.00587) Atom d s d/s (d/s)**2 S1 * 0.0019 0.0008 2.259 5.103 N2 * -0.0253 0.0026 - 9.692 93.931 C3 * 0.0286 0.0031 9.244 85.443 C9 * -0.0035 0.0028 - 1.250 1.564 C8 * -0.0110 0.0027 - 4.097 16.782 C12 0.2009 0.0042 48.095 2313.111 O3 0.1087 0.0026 42.553 1810.724 ============ Sum((d/s)**2) for starred atoms 202.821 Chi-squared at 95% for 2 degrees of freedom: 5.99 The group of atoms deviates significantly from planarity Plane 2 m1 = 0.40648(0.00105) m2 = -0.44475(0.00112) m3 = -0.79811(0.00082) D = -0.11803(0.00486) Atom d s d/s (d/s)**2 C4 * 0.0047 0.0031 1.512 2.285 C5 * -0.0029 0.0032 - 0.891 0.795 C6 * 0.0015 0.0030 0.495 0.245 N7 * -0.0017 0.0025 - 0.712 0.507 C8 * 0.0039 0.0027 1.443 2.081 C9 * -0.0049 0.0028 - 1.737 3.017 C10 0.0178 0.0041 4.334 18.785 C11 - 0.0208 0.0038 - 5.476 29.989 ============ Sum((d/s)**2) for starred atoms 8.931 Chi-squared at 95% for 3 degrees of freedom: 7.81 The group of atoms deviates significantly from planarity Plane 3 m1 = 0.39562(0.00050) m2 = -0.44354(0.00065) m3 = -0.80421(0.00028) D = -0.16267(0.00293) Atom d s d/s (d/s)**2 S1 * 0.0040 0.0008 4.776 22.809 N2 * -0.0286 0.0026 - 10.988 120.734 C3 * 0.0190 0.0031 6.160 37.941 C4 * 0.0135 0.0031 4.303 18.512 C5 * 0.0110 0.0032 3.402 11.573 C6 * 0.0041 0.0030 1.346 1.813 N7 * -0.0157 0.0024 - 6.395 40.891 C8 * -0.0149 0.0027 - 5.543 30.723 C9 * -0.0134 0.0028 - 4.733 22.399 C10 0.0388 0.0041 9.426 88.842 C11 - 0.0125 0.0038 - 3.284 10.784 C12 0.1995 0.0042 47.777 2282.667 O3 0.0948 0.0026 37.134 1378.943 N21 - 0.1758 0.0027 - 66.314 4397.555 N24 - 1.1240 0.0025 - 452.430 204693.344 F37 - 0.0215 0.0022 - 9.734 94.749 ============ Sum((d/s)**2) for starred atoms 307.394 Chi-squared at 95% for 6 degrees of freedom: 12.60 The group of atoms deviates significantly from planarity Plane 4 m1 = -0.01782(0.00194) m2 = 0.68699(0.00140) m3 = -0.72645(0.00130) D = -5.64159(0.01863) Atom d s d/s (d/s)**2 C22 * 0.0050 0.0035 1.415 2.003 C23 * -0.0045 0.0033 - 1.342 1.800 C25 * 0.0052 0.0036 1.445 2.087 C26 * -0.0064 0.0040 - 1.607 2.584 N21 0.6619 0.0026 250.471 62735.781 N24 - 0.6719 0.0025 - 265.708 70600.602 ============ Sum((d/s)**2) for starred atoms 8.474 Chi-squared at 95% for 1 degrees of freedom: 3.84 The group of atoms deviates significantly from planarity Plane 5 m1 = 0.51053(0.00123) m2 = 0.32124(0.00143) m3 = -0.79760(0.00090) D = -1.41382(0.01995) Atom d s d/s (d/s)**2 C31 * 0.0049 0.0030 1.662 2.762 C32 * -0.0091 0.0033 - 2.733 7.467 C33 * 0.0057 0.0038 1.469 2.159 C34 * 0.0048 0.0040 1.202 1.445 C35 * -0.0083 0.0040 - 2.076 4.312 C36 * 0.0012 0.0035 0.334 0.111 F37 - 0.0514 0.0022 - 23.295 542.672 ============ Sum((d/s)**2) for starred atoms 18.256 Chi-squared at 95% for 3 degrees of freedom: 7.81 The group of atoms deviates significantly from planarity Dihedral angles formed by LSQ-planes Plane - plane angle (s.u.) angle (s.u.) 1 2 0.96 (0.07) 179.04 (0.07) 1 3 0.27 (0.06) 179.73 (0.06) 1 4 74.20 (0.10) 105.80 (0.10) 1 5 45.64 (0.10) 134.36 (0.10) 2 3 0.72 (0.07) 179.28 (0.07) 2 4 74.51 (0.11) 105.49 (0.11) 2 5 45.48 (0.10) 134.52 (0.10) 3 4 74.19 (0.10) 105.81 (0.10) 3 5 45.50 (0.09) 134.50 (0.09) 4 5 37.72 (0.13) 142.28 (0.13) |
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. |
x | y | z | Uiso*/Ueq | ||
S1 | 0.75858 (9) | 0.00660 (7) | 0.14207 (4) | 0.0852 (3) | |
F37 | 1.3924 (3) | −0.3219 (2) | 0.34144 (10) | 0.1181 (8) | |
O3 | 0.4193 (3) | −0.2394 (2) | 0.14045 (12) | 0.1003 (7) | |
N7 | 0.5886 (3) | 0.1699 (2) | 0.07058 (11) | 0.0799 (6) | |
N2 | 0.6544 (3) | −0.1274 (2) | 0.16009 (12) | 0.0843 (7) | |
N21 | 0.8861 (3) | −0.1781 (2) | 0.22261 (12) | 0.0897 (7) | |
N24 | 1.1390 (3) | −0.1550 (3) | 0.31417 (11) | 0.0820 (7) | |
C3 | 0.5003 (4) | −0.1421 (3) | 0.13382 (14) | 0.0801 (7) | |
C4 | 0.3158 (3) | 0.0006 (3) | 0.06429 (14) | 0.0832 (8) | |
C5 | 0.3164 (4) | 0.1154 (3) | 0.03479 (14) | 0.0880 (8) | |
H51 | 0.2234 | 0.1396 | 0.0118 | 0.132* | |
C6 | 0.4515 (4) | 0.1965 (3) | 0.03820 (13) | 0.0833 (8) | |
C8 | 0.5869 (3) | 0.0578 (3) | 0.09931 (12) | 0.0725 (6) | |
C9 | 0.4580 (3) | −0.0282 (3) | 0.09857 (13) | 0.0730 (7) | |
C10 | 0.1704 (4) | −0.0873 (4) | 0.05983 (19) | 0.1168 (13) | |
H101 | 0.1227 | −0.0850 | 0.0194 | 0.175* | |
H102 | 0.0897 | −0.0612 | 0.0880 | 0.175* | |
H103 | 0.2058 | −0.1721 | 0.0693 | 0.175* | |
C11 | 0.4497 (5) | 0.3222 (3) | 0.00618 (17) | 0.1058 (11) | |
H111 | 0.4093 | 0.3111 | −0.0350 | 0.159* | |
H112 | 0.5594 | 0.3560 | 0.0064 | 0.159* | |
H113 | 0.3790 | 0.3798 | 0.0267 | 0.159* | |
C12 | 0.7451 (5) | −0.2303 (3) | 0.1903 (2) | 0.1081 (11) | |
H121 | 0.6747 | −0.2735 | 0.2182 | 0.162* | |
H122 | 0.7803 | −0.2912 | 0.1605 | 0.162* | |
C22 | 0.8501 (4) | −0.1351 (3) | 0.28346 (16) | 0.0929 (9) | |
H221 | 0.8205 | −0.2073 | 0.3080 | 0.139* | |
H222 | 0.7571 | −0.0775 | 0.2813 | 0.139* | |
C23 | 0.9964 (4) | −0.0693 (3) | 0.31254 (15) | 0.0869 (9) | |
H231 | 1.0217 | 0.0063 | 0.2897 | 0.130* | |
H232 | 0.9717 | −0.0440 | 0.3535 | 0.130* | |
C25 | 1.1750 (4) | −0.1964 (4) | 0.25276 (15) | 0.0974 (10) | |
H251 | 1.2689 | −0.2533 | 0.2542 | 0.146* | |
H252 | 1.2025 | −0.1235 | 0.2283 | 0.146* | |
C26 | 1.0277 (5) | −0.2630 (4) | 0.22462 (18) | 0.1053 (11) | |
H261 | 1.0516 | −0.2900 | 0.1838 | 0.158* | |
H262 | 1.0029 | −0.3377 | 0.2482 | 0.158* | |
C31 | 1.2764 (4) | −0.1165 (3) | 0.35029 (13) | 0.0808 (8) | |
C32 | 1.4039 (4) | −0.2024 (3) | 0.36426 (15) | 0.0899 (9) | |
C33 | 1.5384 (5) | −0.1744 (4) | 0.39968 (17) | 0.1053 (11) | |
H331 | 1.6207 | −0.2344 | 0.4067 | 0.158* | |
C34 | 1.5514 (5) | −0.0558 (5) | 0.42506 (17) | 0.1141 (12) | |
H341 | 1.6429 | −0.0347 | 0.4496 | 0.171* | |
C35 | 1.4283 (5) | 0.0317 (4) | 0.41392 (17) | 0.1094 (11) | |
H351 | 1.4364 | 0.1115 | 0.4317 | 0.164* | |
C36 | 1.2938 (5) | 0.0027 (3) | 0.37695 (15) | 0.0916 (9) | |
H361 | 1.2128 | 0.0637 | 0.3696 | 0.137* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0741 (4) | 0.0758 (5) | 0.1050 (6) | −0.0140 (3) | −0.0071 (3) | 0.0038 (4) |
F37 | 0.1243 (16) | 0.1012 (15) | 0.1289 (16) | 0.0506 (13) | 0.0062 (13) | −0.0048 (12) |
O3 | 0.1020 (16) | 0.0845 (14) | 0.1152 (17) | −0.0338 (12) | 0.0147 (13) | 0.0025 (12) |
N7 | 0.0837 (14) | 0.0740 (14) | 0.0821 (14) | −0.0071 (12) | 0.0060 (11) | −0.0042 (12) |
N2 | 0.0807 (14) | 0.0686 (14) | 0.1033 (17) | −0.0096 (11) | −0.0016 (13) | 0.0046 (13) |
N21 | 0.0961 (17) | 0.0767 (15) | 0.0960 (18) | 0.0080 (13) | −0.0023 (14) | 0.0006 (13) |
N24 | 0.0857 (14) | 0.0824 (16) | 0.0787 (14) | 0.0255 (13) | 0.0125 (11) | 0.0030 (12) |
C3 | 0.0801 (17) | 0.0766 (18) | 0.0845 (17) | −0.0113 (14) | 0.0153 (13) | −0.0085 (15) |
C4 | 0.0680 (14) | 0.102 (2) | 0.0800 (17) | −0.0075 (15) | 0.0084 (12) | −0.0106 (16) |
C5 | 0.0776 (17) | 0.106 (2) | 0.0805 (18) | 0.0051 (16) | 0.0025 (14) | −0.0052 (17) |
C6 | 0.096 (2) | 0.084 (2) | 0.0699 (15) | 0.0073 (16) | 0.0070 (14) | −0.0067 (14) |
C8 | 0.0725 (14) | 0.0696 (15) | 0.0756 (15) | −0.0086 (13) | 0.0070 (11) | −0.0073 (13) |
C9 | 0.0691 (14) | 0.0775 (17) | 0.0728 (15) | −0.0066 (12) | 0.0101 (11) | −0.0107 (13) |
C10 | 0.0724 (18) | 0.147 (4) | 0.130 (3) | −0.029 (2) | −0.0076 (18) | 0.004 (3) |
C11 | 0.128 (3) | 0.091 (2) | 0.098 (2) | 0.006 (2) | 0.001 (2) | 0.0080 (19) |
C12 | 0.113 (3) | 0.075 (2) | 0.135 (3) | 0.0018 (18) | −0.013 (2) | 0.005 (2) |
C22 | 0.0853 (19) | 0.087 (2) | 0.107 (2) | 0.0202 (16) | 0.0153 (17) | 0.0086 (18) |
C23 | 0.0853 (18) | 0.088 (2) | 0.0878 (19) | 0.0295 (16) | 0.0047 (14) | −0.0015 (16) |
C25 | 0.094 (2) | 0.112 (3) | 0.0863 (19) | 0.028 (2) | 0.0123 (16) | −0.0109 (19) |
C26 | 0.110 (3) | 0.101 (3) | 0.105 (2) | 0.027 (2) | 0.004 (2) | −0.015 (2) |
C31 | 0.0869 (18) | 0.085 (2) | 0.0710 (16) | 0.0260 (15) | 0.0123 (14) | 0.0117 (14) |
C32 | 0.092 (2) | 0.096 (2) | 0.0824 (18) | 0.0322 (17) | 0.0139 (15) | 0.0046 (16) |
C33 | 0.099 (2) | 0.125 (3) | 0.091 (2) | 0.034 (2) | 0.0041 (18) | 0.011 (2) |
C34 | 0.101 (2) | 0.148 (4) | 0.092 (2) | 0.015 (3) | −0.0056 (19) | 0.013 (3) |
C35 | 0.125 (3) | 0.117 (3) | 0.086 (2) | 0.005 (2) | −0.006 (2) | 0.005 (2) |
C36 | 0.104 (2) | 0.084 (2) | 0.0873 (19) | 0.0227 (17) | 0.0080 (16) | 0.0102 (16) |
S1—N2 | 1.702 (3) | C11—H111 | 0.9600 |
S1—C8 | 1.739 (3) | C11—H112 | 0.9600 |
F37—C32 | 1.360 (4) | C11—H113 | 0.9600 |
O3—C3 | 1.231 (3) | C12—H121 | 0.9700 |
N7—C8 | 1.342 (4) | C12—H122 | 0.9700 |
N7—C6 | 1.330 (4) | C22—C23 | 1.499 (5) |
N2—C3 | 1.368 (4) | C22—H221 | 0.9700 |
N2—C12 | 1.458 (4) | C22—H222 | 0.9700 |
N21—C12 | 1.436 (4) | C23—H231 | 0.9700 |
N21—C26 | 1.457 (4) | C23—H232 | 0.9700 |
N21—C22 | 1.456 (4) | C25—C26 | 1.501 (5) |
N24—C31 | 1.406 (4) | C25—H251 | 0.9700 |
N24—C25 | 1.463 (4) | C25—H252 | 0.9700 |
N24—C23 | 1.468 (3) | C26—H261 | 0.9700 |
C3—C9 | 1.465 (4) | C26—H262 | 0.9700 |
C4—C5 | 1.375 (5) | C31—C36 | 1.393 (5) |
C4—C9 | 1.390 (4) | C31—C32 | 1.401 (4) |
C4—C10 | 1.502 (4) | C32—C33 | 1.351 (5) |
C5—C6 | 1.391 (4) | C33—C34 | 1.373 (6) |
C5—H51 | 0.9300 | C33—H331 | 0.9300 |
C6—C11 | 1.503 (5) | C34—C35 | 1.376 (5) |
C8—C9 | 1.384 (4) | C34—H341 | 0.9300 |
C10—H101 | 0.9600 | C35—C36 | 1.373 (5) |
C10—H102 | 0.9600 | C35—H351 | 0.9300 |
C10—H103 | 0.9600 | C36—H361 | 0.9300 |
N2—S1—C8 | 89.40 (13) | N2—C12—H122 | 109.9 |
C8—N7—C6 | 114.6 (3) | H121—C12—H122 | 108.3 |
C3—N2—C12 | 123.2 (3) | N21—C22—C23 | 110.8 (3) |
C3—N2—S1 | 116.7 (2) | N21—C22—H221 | 109.5 |
C12—N2—S1 | 118.6 (2) | C23—C22—H221 | 109.5 |
C12—N21—C26 | 113.1 (3) | N21—C22—H222 | 109.5 |
C12—N21—C22 | 113.2 (3) | C23—C22—H222 | 109.5 |
C26—N21—C22 | 110.4 (3) | H221—C22—H222 | 108.1 |
C31—N24—C25 | 115.4 (2) | N24—C23—C22 | 109.7 (3) |
C31—N24—C23 | 116.4 (3) | N24—C23—H231 | 109.7 |
C25—N24—C23 | 110.2 (2) | C22—C23—H231 | 109.7 |
O3—C3—N2 | 121.9 (3) | N24—C23—H232 | 109.7 |
O3—C3—C9 | 129.2 (3) | C22—C23—H232 | 109.7 |
N2—C3—C9 | 108.9 (2) | H231—C23—H232 | 108.2 |
C5—C4—C9 | 115.6 (3) | N24—C25—C26 | 109.8 (3) |
C5—C4—C10 | 122.0 (3) | N24—C25—H251 | 109.7 |
C9—C4—C10 | 122.4 (3) | C26—C25—H251 | 109.7 |
C4—C5—C6 | 122.2 (3) | N24—C25—H252 | 109.7 |
C4—C5—H51 | 118.9 | C26—C25—H252 | 109.7 |
C6—C5—H51 | 118.9 | H251—C25—H252 | 108.2 |
N7—C6—C5 | 122.8 (3) | N21—C26—C25 | 109.9 (3) |
N7—C6—C11 | 115.6 (3) | N21—C26—H261 | 109.7 |
C5—C6—C11 | 121.6 (3) | C25—C26—H261 | 109.7 |
N7—C8—C9 | 126.3 (3) | N21—C26—H262 | 109.7 |
N7—C8—S1 | 120.5 (2) | C25—C26—H262 | 109.7 |
C9—C8—S1 | 113.1 (2) | H261—C26—H262 | 108.2 |
C8—C9—C4 | 118.4 (3) | C36—C31—C32 | 115.4 (3) |
C8—C9—C3 | 111.7 (3) | C36—C31—N24 | 124.5 (3) |
C4—C9—C3 | 129.9 (3) | C32—C31—N24 | 120.1 (3) |
C4—C10—H101 | 109.5 | F37—C32—C33 | 117.4 (3) |
C4—C10—H102 | 109.5 | F37—C32—C31 | 118.6 (3) |
H101—C10—H102 | 109.5 | C33—C32—C31 | 124.1 (4) |
C4—C10—H103 | 109.5 | C32—C33—C34 | 118.9 (3) |
H101—C10—H103 | 109.5 | C32—C33—H331 | 120.6 |
H102—C10—H103 | 109.5 | C34—C33—H331 | 120.6 |
C6—C11—H111 | 109.5 | C35—C34—C33 | 119.6 (4) |
C6—C11—H112 | 109.5 | C35—C34—H341 | 120.2 |
H111—C11—H112 | 109.5 | C33—C34—H341 | 120.2 |
C6—C11—H113 | 109.5 | C34—C35—C36 | 120.9 (4) |
H111—C11—H113 | 109.5 | C34—C35—H351 | 119.6 |
H112—C11—H113 | 109.5 | C36—C35—H351 | 119.6 |
N21—C12—N2 | 108.7 (3) | C35—C36—C31 | 121.2 (3) |
N21—C12—H121 | 109.9 | C35—C36—H361 | 119.4 |
N2—C12—H121 | 109.9 | C31—C36—H361 | 119.4 |
N21—C12—H122 | 109.9 | ||
C8—S1—N2—C3 | 3.4 (2) | C22—N21—C12—N2 | 86.5 (4) |
C8—S1—N2—C12 | 169.7 (3) | C3—N2—C12—N21 | −168.9 (3) |
C12—N2—C3—O3 | 9.2 (5) | S1—N2—C12—N21 | 25.7 (4) |
S1—N2—C3—O3 | 174.9 (2) | C12—N21—C22—C23 | −174.0 (3) |
C12—N2—C3—C9 | −169.9 (3) | C26—N21—C22—C23 | 58.1 (4) |
S1—N2—C3—C9 | −4.3 (3) | C31—N24—C23—C22 | −168.1 (3) |
C9—C4—C5—C6 | 1.0 (4) | C25—N24—C23—C22 | 58.0 (4) |
C10—C4—C5—C6 | −179.2 (3) | N21—C22—C23—N24 | −57.4 (3) |
C8—N7—C6—C5 | 0.6 (4) | C31—N24—C25—C26 | 166.6 (3) |
C8—N7—C6—C11 | 179.3 (3) | C23—N24—C25—C26 | −59.0 (4) |
C4—C5—C6—N7 | −0.8 (5) | C12—N21—C26—C25 | 173.6 (3) |
C4—C5—C6—C11 | −179.4 (3) | C22—N21—C26—C25 | −58.5 (4) |
C6—N7—C8—C9 | −0.9 (4) | N24—C25—C26—N21 | 59.0 (4) |
C6—N7—C8—S1 | 178.3 (2) | C25—N24—C31—C36 | 122.2 (3) |
N2—S1—C8—N7 | 179.2 (2) | C23—N24—C31—C36 | −9.3 (4) |
N2—S1—C8—C9 | −1.4 (2) | C25—N24—C31—C32 | −61.2 (4) |
N7—C8—C9—C4 | 1.2 (4) | C23—N24—C31—C32 | 167.3 (3) |
S1—C8—C9—C4 | −178.1 (2) | C36—C31—C32—F37 | 177.8 (3) |
N7—C8—C9—C3 | 178.7 (3) | N24—C31—C32—F37 | 1.0 (4) |
S1—C8—C9—C3 | −0.6 (3) | C36—C31—C32—C33 | −1.6 (5) |
C5—C4—C9—C8 | −1.2 (4) | N24—C31—C32—C33 | −178.5 (3) |
C10—C4—C9—C8 | 179.0 (3) | F37—C32—C33—C34 | −177.9 (3) |
C5—C4—C9—C3 | −178.1 (3) | C31—C32—C33—C34 | 1.5 (6) |
C10—C4—C9—C3 | 2.1 (5) | C32—C33—C34—C35 | −0.1 (6) |
O3—C3—C9—C8 | −176.1 (3) | C33—C34—C35—C36 | −1.1 (6) |
N2—C3—C9—C8 | 3.0 (3) | C34—C35—C36—C31 | 0.9 (6) |
O3—C3—C9—C4 | 1.0 (5) | C32—C31—C36—C35 | 0.3 (5) |
N2—C3—C9—C4 | −180.0 (3) | N24—C31—C36—C35 | 177.1 (3) |
C26—N21—C12—N2 | −146.9 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
C33—H331···N7i | 0.93 | 2.60 | 3.486 (5) | 160 |
C36—H361···O3ii | 0.93 | 2.34 | 3.240 (4) | 161 |
Symmetry codes: (i) −x+5/2, y−1/2, −z+1/2; (ii) −x+3/2, y+1/2, −z+1/2. |
Experimental details
Crystal data | |
Chemical formula | C19H21FN4OS |
Mr | 372.46 |
Crystal system, space group | Monoclinic, P21/n |
Temperature (K) | 293 |
a, b, c (Å) | 8.118 (1), 10.551 (2), 22.054 (2) |
β (°) | 92.13 (1) |
V (Å3) | 1887.7 (5) |
Z | 4 |
Radiation type | Cu Kα |
µ (mm−1) | 1.74 |
Crystal size (mm) | 0.35 × 0.20 × 0.10 |
Data collection | |
Diffractometer | Kuma KM-4 four-circle |
Absorption correction | ψ scan (North et al., 1968) |
Tmin, Tmax | 0.582, 0.842 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4806, 4034, 2273 |
Rint | 0.038 |
(sin θ/λ)max (Å−1) | 0.639 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.058, 0.208, 0.98 |
No. of reflections | 4034 |
No. of parameters | 236 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.42, −0.29 |
Computer programs: KM4B8 (Gałdecki et al., 1996), KM4B8, DATAPROC (Gałdecki et al., 1995), SIR92 (Altomare et al., 1993), SHELXL97 (Sheldrick, 1997), ORTEP-3 for Windows (Farrugia, 1997), SHELXL97 and WinGX (Farrugia, 1999).
D—H···A | D—H | H···A | D···A | D—H···A |
C33—H331···N7i | 0.93 | 2.60 | 3.486 (5) | 160 |
C36—H361···O3ii | 0.93 | 2.34 | 3.240 (4) | 161 |
Symmetry codes: (i) −x+5/2, y−1/2, −z+1/2; (ii) −x+3/2, y+1/2, −z+1/2. |
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Recently we described synthesis, structure, conformation and analgesic action of a series of derivatives of 2-(4-arylpiperazin-1-ylmethyl)isothiazolo[5,4-b]pyridin-3(2H)-one (Malinka et al., 2005). In our SAR studies we found that the potency of the analgesic effect is highly influenced by the nature of the substituent present at aromatic ring of the 4-arylpiperazine substructure. The best analgesic results were obtained for phenylpiperazine derivatives of isothiazolopyridine with electron-withdrawing substituents (o-Cl, o-F, p-NO2, m-CF3), while the derivatives with o-electron-donating groups (o-OCH3, o-CH3) and compound with unsubstituted phenyl ring were inactive in the analgesic tests. As a continuation of our investigations, in this paper we report the results of the X-ray structure determination of title compound which proved to be the most active as an analgesic agent in the analyzed series of arylpiperazine derivatives of isothiazolopyridine.
The bond lengths and angles do not differ significantly from those reported for other related structures (e.g. Karczmarzyk & Malinka, 2005). The pyridine and isothiazole rings are planar to within 0.005 (3) and 0.029 (3) Å, respectively, and they are inclined at an angle of 0.96 (7)°.
The 4-(2-fluorophenyl)piperazin-1-ylmethyl substituent has a cis-gauche-trans conformation with the torsion angles S1—N2—C12—N21 of 25.7 (4)°, N2—C12—N21—C22 of 86.5 (4)° and N2—C12—N21—C26 of -146.9 (3)°. These torsion angles indicates a similar spatial orientation of the substituent in relation to the fused bicyclic system in the title compound and unsubstituted-phenylpiperazine derivative of isothiazolopyridine [the torsion angles are 24.5 (2), 77.9 (2) and -159.3 (2)°, respectively; Karczmarzyk & Malinka, 1998]. The piperazine ring adopts a chair conformation with puckering parameters of Q = 0.582 (4) Å and θ = 180.0 (4)° (Cremer & Pople, 1975). The N24—C31 bond length of 1.406 (4) Å, shorter than an average non-conjugated Car—N (Nsp3, pyramidal) single bond of 1.426 (11) Å (Allen et al., 1987), and the sum of the bond angles around N24 of 342.00° are typical for conjugation of the lone pair at N24 with the π system of the benzene ring. This conjugation is characteristic for meta and para electron-attracting substitution (Karczmarzyk & Malinka, 2005) and in the unsubstituted-phenylpiperazine system it is diminished by the steric effect of the 2-F group of the benzene ring. It is confirmed by the change of the dihedral angle between the mean planes of the aromatic and piperazine rings from 6.15 (6)° for the unsubstituted benzene ring in the phenylpiperazine derivative of isothiazolopyridine to 37.72 (13)° in the title compound. It is worthy to mention that this dihedral angle is close to 60° for other 2-substituted phenylpiperazine derivatives (Karczmarzyk & Malinka, 2004). In conclusion, the observed similarity of the structural features at crystals of the title compound and its unsubstituted analogue may suggest that within series of analgesic isothiazolopyridines fluorine does not resemble other halogens but mimics a hydrogen atom.
In the crystal structure, molecules are linked into chains parallel to [010] direction via short intermolecular C—H···X (X = N, O) contacts (Table 1; Spek, 2003; Nardelli, 1983). Additionally, pairs of pyridine rings belonging to inversion-related molecules overlap, with a centroid-to-centroid separation of 3.5908 (18) Å. The shortest intermolecular contact [N7···C4i = 3.586 (4) Å; symmetry code: (i) = 1 - x, -y, -z] is characteristic of π···π interactions.