Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229616005453/fn3216sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S2053229616005453/fn3216Isup2.hkl | |
Structure factor file (CIF format) https://doi.org/10.1107/S2053229616005453/fn3216IIsup3.hkl |
CCDC references: 1471701; 1471700
The possibility of molecular crystals existing as different polymorphic modifications is very important for the pharmaceutic industry. Significant differences in the properties of drug substances from different manufacturers, a sharp decline in biological activity, rapid loss of storage stability, increased water absorption, the sudden appearance of the chemical incompatibility of the ingredients in the multicomponent dosage forms, the deterioration of solubility and changes of flow ability are just some of considerable pharmaceutical, pharmacological and technological problems caused namely by polymorphism (Brittain, 1999; Brüning & Schmidt, 2015; Gunn et al., 2012; Luźnik et al., 2014; Nyström et al., 2015; Saurabh & Kaushal, 2011) that producers have to face. Therefore, the activity of the pharmaceutical companies in detecting and describing as many polymorphs as possible increases sharply in addition to purely scientific interest and such researches are patented for their intellectual property protection (Brittain, 1999; Bernstein, 2002; Hilfiker, 2006).
Taking into account the obtained biological activity of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, (I), in the state of aqueous suspensions of the crystals, we studied the possibility to their forming different crystal structures depending on the nature of the solvent.
The title compoundsw were synthesized according to the known methodology of Ukrainets et al. (2015). The crystals of (1a) crystallized from methylene chloride and the crystals of (1b) crystallized from N,N-dimethylformamide.
Crystal data, data collection and structure refinement details are summarized in Table 1. The positions of the H atoms were located from electron-density difference maps and refined using a riding model, with Uiso = nUeq of the carrier atom, with n = 1.5 for the methyl group and 1.2 otherwise. H atoms of hydroxy and amide groups were refined using isotropic approximation.
The antinociception activity of benzylamides (1a)–(1e) which is the animal parallel of analgesic activity in humans have been studied on the standard model of the thermal irritation of the tail tip (Tail Immersion Test) in 12 adult white male rats weighing 190–200 g. All biological experiments were carried out in full accordance with the European Convention on the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (Vogel, 2008) and the Ukrainian Law No. 3447-IV `On protection of animals from severe treatment' (2006). The tail tip of the experimental animal was immersed in a water bath heated to 327 K, and the initial length of the latent period of immersion (withdrawal) of the tail expressed in seconds was determined. The antinociceptive effect (in %) was assessed by changing the duration of the latent period in 1 h after introduction of the substances studied. All tested substances and the reference drug (Piroxicam) were introduced orally in the form of fine aqueous suspensions stabilized with Tween-80 in the dose of 20 mg kg-1. The animals of the control group received an equivalent amount of water with Tween-80. The results of biological testing can be significantly affected by the particle size of the substances under study (Lin et al., 2014; Alvarez, 2014). Therefore, all five samples of benzylamides (1a)–(1e) have been studied in the form of powder fractions with the particle size of 0.211–0.178 mm selected using the corresponding sieves. Seven experimental animals were involved to obtain statistically reliable results (the significance level of the confidence interval accepted in this work was p ≤ 0.05) in testing each of benzylamides (1a)–(1e), reference drug and control.
The precondition for choosing of benzylamide (I) as the object of studying was its high analgesic activity under low toxicity in the first place (Ukrainets et al., 2015). In this case, the fact that benzylamide (I) was undergone biological testing as water suspension and hence, drug form was applied as the solid dispersed phase is very important.
We have tried to obtain different crystal forms of the benzylamide (I) by a simple crystallization from the solvents that are widely used and necessarily pharmaceutically acceptable (European Pharmacopoeia, 2007): methylene chloride, (1a), N,N-dimethylformamide, (1b), ethanol, (1c), ethyl acetate, (1d), and xylene, (1e). Contrary to our expectations, quite similar colourless outward crystals have been obtained in all cases and passed the pharmacological tests (see Experimental). The obtained results proved to be unexpected (Table 2).
For some incomprehensible reasons, only one sample of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, (1a), crystallized from methylene chloride has revealed high antinociception activity. Biological properties of the samples crystallized from other solvents proved to be about four times lower.
To study this fact, X-ray diffraction measurements have been carried out for all crystal samples of benzylamide, i.e. (1a)–(1e), taking into account the application of this compound in solid state. The results have shown that benzylamide crystallized in the P212121 orthorhombic chiral space group from all used in our study solvents. It indicates the existence of one enantiomer in crystal phase. The presence of the S atom has allowed the use of the Flack parameter to determine molecule types (A and B) in crystals which are the mirror reflections of each other (Fig. 1). The N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide molecule does not contain any stereogenic chirotopic atom. It can be assumed to some measure that the sulfur atom can be considered as asymmetric due to the formation of an N2—H2···O4 intramolecular hydrogen bond with the participation of one O atom of the sulfonyl group (the characteristics of this hydrogen bond are H···O = 2.18 (2) Å and N—H···O = 137 (2)° in compound (1a) and H···O = 2.14 (4) Å and N—H···O = 138 (3)° in compound (1b). On the other hand, chirality relative to a plane is known (Flack, 2003) and the planar fragment of the benzothiazine bicycle can be such plane.
It was obtained also that the crystals from the methylene solution (1a) contain only molecules A, and the crystals from all other solutions (1b)–(1e) consist of pseudo-enantiomeric molecules B. This is confirmed additionally by X-ray study of some crystals benzylamides (1a) and (1b) which are chosen randomly from the total mass. Moreover, the dissolution of (1a) crystals in N,N-dimethylformamide and its recrystallization from this solvent has not changed the form A of the 2λ6,1-benzothiazine-3-carboxamide molecule as well as similar experiment with (1b) crystals dissolved in methylene chloride. On this basis, it can be argued that we observed the formation of two crystal phases which have to be formed in a spontaneous resolution of a conglomerate of pseudo-enantiomeric chiral molecules.
The unit-cell parameters for all studied crystal structures are close enough. At that the values of Flack parameter (Parsons et al., 2013) [it is 0.09 (5) for structure (1a) and -0.16 (9) for (1b)] have determined unambiguously the pseudo-enantiomeric type of molecule in these crystals. In both pseudo-enantiomers, the dihydrothiazine ring adopts the conformation which is intermediate between a twist-boat and a sofa (the puckering parameters are given in Table 2). Deviations of the S1 and C8 atoms from the mean plane of the remaining atoms of the ring are -0.81 and -0.23 Å, respectively, in molecule A and 0.81 and 0.23 Å, respectively, in molecule B. The cyclic N atom has almost planar configuration where the sum of bond angles centred at this atom is 358° in both molecules. The carbamide substituent at the C8 atom is coplanar to the C7═C8 endocyclic double bond (the C7—C8—C9—O2 torsion angle; Table 3). Such conformation is stabilized by the formation of the O1—H···O2 intramolecular hydrogen bond (Table 4). Additionally, the formation of strong enough hydrogen bond causes the redistribution of the electron density within this fragment: the C9—O2 and C7—C8 bonds are elongated (Table 3) as compared to their mean values (Burgi & Dunitz, 1994) for such bond types (1.210 and 1.326 Å, respectively). The C7—O1 bond is shortened (mean value = 1.362 Å). The benzyl substituent has the antiperiplanar conformation relative to the C8—C9 bond (the C10—N2—C9—C8 torsion angle; Table 3) and its aromatic ring is located in a -sc position relative to the C9—N2 bond and is turned due to rotation around the N2—C10 bond (the C9—N2—C10—C11 and N2—C10—C11—C12 torsion angles). At that the H12···N2 shortened intramolecular contact [the distance is 2.59 Å in both molecules as compared to van der Waals radii sum (Zefirov, 1997) 2.67 Å] is observed. The steric repulsion between methyl substituent and bicyclic fragment (the shortened intramolecular contacts are: H2···C17 = 2.57 Å in A and 2.58 Å in B (the van der Waals radii sum is 2.87 Å), H17c···C2 = 2.74 Å in A and 2.71 Å in B (2.87 Å), H2···H17c = 2.32 Å in A and 2.29 Å in B (2.34 Å), H17b···O4 = 2.36 Å in A and 2.37 Å in B (2.46 Å) causes the elongation of the C1—N1 bond (Table 2) as compared to its mean value 1.371 Å.
The crystal packing of two pseudo-enantiomeric molecules has very similar type and differs from each other as mirror reflection (Fig. 3).
In the crystal phase, molecules (1a) and (1b) form a network of weak intermolecular hydrogen bonds (Table 3). Hydrogen bonds of the same type have very close geometric characteristics and inverse-symmetry operations. Thus, two pseudo-enantiomeric crystal structures are mirroring each to other. Taking into account almost complete identity of all factors except this one it could be argued that such unequality for two structures is the reason of different antinociception activity.
The possibility of molecular crystals existing as different polymorphic modifications is very important for the pharmaceutic industry. Significant differences in the properties of drug substances from different manufacturers, a sharp decline in biological activity, rapid loss of storage stability, increased water absorption, the sudden appearance of the chemical incompatibility of the ingredients in the multicomponent dosage forms, the deterioration of solubility and changes of flow ability are just some of considerable pharmaceutical, pharmacological and technological problems caused namely by polymorphism (Brittain, 1999; Brüning & Schmidt, 2015; Gunn et al., 2012; Luźnik et al., 2014; Nyström et al., 2015; Saurabh & Kaushal, 2011) that producers have to face. Therefore, the activity of the pharmaceutical companies in detecting and describing as many polymorphs as possible increases sharply in addition to purely scientific interest and such researches are patented for their intellectual property protection (Brittain, 1999; Bernstein, 2002; Hilfiker, 2006).
Taking into account the obtained biological activity of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, (I), in the state of aqueous suspensions of the crystals, we studied the possibility to their forming different crystal structures depending on the nature of the solvent.
The antinociception activity of benzylamides (1a)–(1e) which is the animal parallel of analgesic activity in humans have been studied on the standard model of the thermal irritation of the tail tip (Tail Immersion Test) in 12 adult white male rats weighing 190–200 g. All biological experiments were carried out in full accordance with the European Convention on the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (Vogel, 2008) and the Ukrainian Law No. 3447-IV `On protection of animals from severe treatment' (2006). The tail tip of the experimental animal was immersed in a water bath heated to 327 K, and the initial length of the latent period of immersion (withdrawal) of the tail expressed in seconds was determined. The antinociceptive effect (in %) was assessed by changing the duration of the latent period in 1 h after introduction of the substances studied. All tested substances and the reference drug (Piroxicam) were introduced orally in the form of fine aqueous suspensions stabilized with Tween-80 in the dose of 20 mg kg-1. The animals of the control group received an equivalent amount of water with Tween-80. The results of biological testing can be significantly affected by the particle size of the substances under study (Lin et al., 2014; Alvarez, 2014). Therefore, all five samples of benzylamides (1a)–(1e) have been studied in the form of powder fractions with the particle size of 0.211–0.178 mm selected using the corresponding sieves. Seven experimental animals were involved to obtain statistically reliable results (the significance level of the confidence interval accepted in this work was p ≤ 0.05) in testing each of benzylamides (1a)–(1e), reference drug and control.
The precondition for choosing of benzylamide (I) as the object of studying was its high analgesic activity under low toxicity in the first place (Ukrainets et al., 2015). In this case, the fact that benzylamide (I) was undergone biological testing as water suspension and hence, drug form was applied as the solid dispersed phase is very important.
We have tried to obtain different crystal forms of the benzylamide (I) by a simple crystallization from the solvents that are widely used and necessarily pharmaceutically acceptable (European Pharmacopoeia, 2007): methylene chloride, (1a), N,N-dimethylformamide, (1b), ethanol, (1c), ethyl acetate, (1d), and xylene, (1e). Contrary to our expectations, quite similar colourless outward crystals have been obtained in all cases and passed the pharmacological tests (see Experimental). The obtained results proved to be unexpected (Table 2).
For some incomprehensible reasons, only one sample of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, (1a), crystallized from methylene chloride has revealed high antinociception activity. Biological properties of the samples crystallized from other solvents proved to be about four times lower.
To study this fact, X-ray diffraction measurements have been carried out for all crystal samples of benzylamide, i.e. (1a)–(1e), taking into account the application of this compound in solid state. The results have shown that benzylamide crystallized in the P212121 orthorhombic chiral space group from all used in our study solvents. It indicates the existence of one enantiomer in crystal phase. The presence of the S atom has allowed the use of the Flack parameter to determine molecule types (A and B) in crystals which are the mirror reflections of each other (Fig. 1). The N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide molecule does not contain any stereogenic chirotopic atom. It can be assumed to some measure that the sulfur atom can be considered as asymmetric due to the formation of an N2—H2···O4 intramolecular hydrogen bond with the participation of one O atom of the sulfonyl group (the characteristics of this hydrogen bond are H···O = 2.18 (2) Å and N—H···O = 137 (2)° in compound (1a) and H···O = 2.14 (4) Å and N—H···O = 138 (3)° in compound (1b). On the other hand, chirality relative to a plane is known (Flack, 2003) and the planar fragment of the benzothiazine bicycle can be such plane.
It was obtained also that the crystals from the methylene solution (1a) contain only molecules A, and the crystals from all other solutions (1b)–(1e) consist of pseudo-enantiomeric molecules B. This is confirmed additionally by X-ray study of some crystals benzylamides (1a) and (1b) which are chosen randomly from the total mass. Moreover, the dissolution of (1a) crystals in N,N-dimethylformamide and its recrystallization from this solvent has not changed the form A of the 2λ6,1-benzothiazine-3-carboxamide molecule as well as similar experiment with (1b) crystals dissolved in methylene chloride. On this basis, it can be argued that we observed the formation of two crystal phases which have to be formed in a spontaneous resolution of a conglomerate of pseudo-enantiomeric chiral molecules.
The unit-cell parameters for all studied crystal structures are close enough. At that the values of Flack parameter (Parsons et al., 2013) [it is 0.09 (5) for structure (1a) and -0.16 (9) for (1b)] have determined unambiguously the pseudo-enantiomeric type of molecule in these crystals. In both pseudo-enantiomers, the dihydrothiazine ring adopts the conformation which is intermediate between a twist-boat and a sofa (the puckering parameters are given in Table 2). Deviations of the S1 and C8 atoms from the mean plane of the remaining atoms of the ring are -0.81 and -0.23 Å, respectively, in molecule A and 0.81 and 0.23 Å, respectively, in molecule B. The cyclic N atom has almost planar configuration where the sum of bond angles centred at this atom is 358° in both molecules. The carbamide substituent at the C8 atom is coplanar to the C7═C8 endocyclic double bond (the C7—C8—C9—O2 torsion angle; Table 3). Such conformation is stabilized by the formation of the O1—H···O2 intramolecular hydrogen bond (Table 4). Additionally, the formation of strong enough hydrogen bond causes the redistribution of the electron density within this fragment: the C9—O2 and C7—C8 bonds are elongated (Table 3) as compared to their mean values (Burgi & Dunitz, 1994) for such bond types (1.210 and 1.326 Å, respectively). The C7—O1 bond is shortened (mean value = 1.362 Å). The benzyl substituent has the antiperiplanar conformation relative to the C8—C9 bond (the C10—N2—C9—C8 torsion angle; Table 3) and its aromatic ring is located in a -sc position relative to the C9—N2 bond and is turned due to rotation around the N2—C10 bond (the C9—N2—C10—C11 and N2—C10—C11—C12 torsion angles). At that the H12···N2 shortened intramolecular contact [the distance is 2.59 Å in both molecules as compared to van der Waals radii sum (Zefirov, 1997) 2.67 Å] is observed. The steric repulsion between methyl substituent and bicyclic fragment (the shortened intramolecular contacts are: H2···C17 = 2.57 Å in A and 2.58 Å in B (the van der Waals radii sum is 2.87 Å), H17c···C2 = 2.74 Å in A and 2.71 Å in B (2.87 Å), H2···H17c = 2.32 Å in A and 2.29 Å in B (2.34 Å), H17b···O4 = 2.36 Å in A and 2.37 Å in B (2.46 Å) causes the elongation of the C1—N1 bond (Table 2) as compared to its mean value 1.371 Å.
The crystal packing of two pseudo-enantiomeric molecules has very similar type and differs from each other as mirror reflection (Fig. 3).
In the crystal phase, molecules (1a) and (1b) form a network of weak intermolecular hydrogen bonds (Table 3). Hydrogen bonds of the same type have very close geometric characteristics and inverse-symmetry operations. Thus, two pseudo-enantiomeric crystal structures are mirroring each to other. Taking into account almost complete identity of all factors except this one it could be argued that such unequality for two structures is the reason of different antinociception activity.
The title compoundsw were synthesized according to the known methodology of Ukrainets et al. (2015). The crystals of (1a) crystallized from methylene chloride and the crystals of (1b) crystallized from N,N-dimethylformamide.
Crystal data, data collection and structure refinement details are summarized in Table 1. The positions of the H atoms were located from electron-density difference maps and refined using a riding model, with Uiso = nUeq of the carrier atom, with n = 1.5 for the methyl group and 1.2 otherwise. H atoms of hydroxy and amide groups were refined using isotropic approximation.
For both compounds, data collection: CrysAlis CCD (Agilent, 2012); cell refinement: CrysAlis RED (Agilent, 2012); data reduction: CrysAlis RED (Agilent, 2012). Program(s) used to solve structure: SHELXS97 (Sheldrick, 2008) for (I); SHELXT (Sheldrick, 2015b) for (II). Program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015a) for (I); olex2.refine (Bourhis et al., 2015) for (II). Molecular graphics: Olex2 (Dolomanov et al., 2009) for (I); OLEX2 (Dolomanov et al., 2009) for (II). Software used to prepare material for publication: Olex2 (Dolomanov et al., 2009) for (I); OLEX2 (Dolomanov et al., 2009) for (II).
C17H16N2O4S | Dx = 1.433 Mg m−3 |
Mr = 344.39 | Mo Kα radiation, λ = 0.71073 Å |
Orthorhombic, P212121 | Cell parameters from 3040 reflections |
a = 5.4764 (3) Å | θ = 3.6–30.6° |
b = 15.9117 (8) Å | µ = 0.23 mm−1 |
c = 18.3228 (10) Å | T = 293 K |
V = 1596.63 (15) Å3 | , colourless |
Z = 4 | 0.2 × 0.02 × 0.02 mm |
F(000) = 720 |
Xcalibur, Sapphire3 diffractometer | 4658 independent reflections |
Radiation source: Enhance (Mo) X-ray Source | 3004 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.055 |
Detector resolution: 16.1827 pixels mm-1 | θmax = 30.0°, θmin = 3.4° |
ω scans | h = −5→7 |
Absorption correction: multi-scan (CrysAlis RED; Agilent, 2012) | k = −20→22 |
Tmin = 0.979, Tmax = 1.000 | l = −25→25 |
16369 measured reflections |
Refinement on F2 | Hydrogen site location: mixed |
Least-squares matrix: full | H atoms treated by a mixture of independent and constrained refinement |
R[F2 > 2σ(F2)] = 0.051 | w = 1/[σ2(Fo2) + (0.035P)2] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.094 | (Δ/σ)max = 0.001 |
S = 0.99 | Δρmax = 0.22 e Å−3 |
4658 reflections | Δρmin = −0.28 e Å−3 |
226 parameters | Absolute structure: Flack x determined using 910 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
0 restraints | Absolute structure parameter: 0.09 (5) |
C17H16N2O4S | V = 1596.63 (15) Å3 |
Mr = 344.39 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 5.4764 (3) Å | µ = 0.23 mm−1 |
b = 15.9117 (8) Å | T = 293 K |
c = 18.3228 (10) Å | 0.2 × 0.02 × 0.02 mm |
Xcalibur, Sapphire3 diffractometer | 4658 independent reflections |
Absorption correction: multi-scan (CrysAlis RED; Agilent, 2012) | 3004 reflections with I > 2σ(I) |
Tmin = 0.979, Tmax = 1.000 | Rint = 0.055 |
16369 measured reflections |
R[F2 > 2σ(F2)] = 0.051 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.094 | Δρmax = 0.22 e Å−3 |
S = 0.99 | Δρmin = −0.28 e Å−3 |
4658 reflections | Absolute structure: Flack x determined using 910 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
226 parameters | Absolute structure parameter: 0.09 (5) |
0 restraints |
Experimental. Absorption correction: CrysAlis RED, Agilent Technologies, Version 1.171.36.24 (release 03-12-2012 CrysAlis171 .NET) (compiled Dec 3 2012,18:21:49) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Intensities of 15460 reflections (4595 independent, Rint = 0.039) for structure (1a) and 15538 reflections (4583 independent, Rint = 0.066) for structure (1b) have been measured on the «Xcalibur-3» diffractometer (graphite monochromated MoKα radiation, CCD detector, ω-scans, 2Θmax = 60?). The structures were solved by direct method using SHELXTL package [Sheldrick, 2015]. Positions of the hydrogen atoms were located from electron density difference maps and refined by ?riding? model with Uiso = nUeq of the carrier atom (n = 1.5 for methyl group and 1.2 for other atoms). Hydrogen atoms of hydroxyl and amide groups were refined using isotropic approximation. Full-matrix least-squares refinement of the structures against F2 in anisotropic approximation for non-hydrogen atoms using 4552 ((1a)), 4533 ((1b)) reflections was converged to: wR2 = 0.096 (R1 = 0.040 for 3608 reflections with F>4σ(F), S = 0.992) for structure (1a) and wR2 = 0.097 (R1 = 0.050 for 2816 reflections with F>4σ(F), S = 0.957) for structure (1b). The final atomic coordinates, and crystallographic data for molecules (1a) and (1b) have been deposited to with the Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and are available on request quoting the deposition numbers CCDC 1430997 for (1a) and CCDC 1430998 for (1b)). |
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
x | y | z | Uiso*/Ueq | ||
S1 | 0.30167 (14) | 0.70373 (4) | 0.12320 (4) | 0.04040 (18) | |
O1 | 0.1936 (5) | 0.88090 (14) | 0.26834 (12) | 0.0575 (6) | |
H1 | 0.319 (7) | 0.911 (3) | 0.243 (2) | 0.096 (14)* | |
O2 | 0.5263 (4) | 0.92725 (13) | 0.18735 (11) | 0.0532 (6) | |
O3 | 0.5295 (4) | 0.67251 (13) | 0.09536 (12) | 0.0556 (6) | |
O4 | 0.1137 (4) | 0.71866 (14) | 0.07081 (11) | 0.0521 (6) | |
N1 | 0.2068 (5) | 0.63746 (15) | 0.18639 (13) | 0.0485 (6) | |
N2 | 0.6795 (5) | 0.84615 (17) | 0.09810 (14) | 0.0463 (6) | |
H2 | 0.671 (5) | 0.797 (2) | 0.0768 (16) | 0.048 (8)* | |
C1 | 0.0244 (6) | 0.6630 (2) | 0.23545 (16) | 0.0454 (7) | |
C2 | −0.1351 (6) | 0.6048 (2) | 0.26687 (19) | 0.0611 (9) | |
H2A | −0.1248 | 0.5485 | 0.2538 | 0.073* | |
C3 | −0.3071 (7) | 0.6301 (3) | 0.31677 (19) | 0.0686 (10) | |
H3 | −0.4089 | 0.5903 | 0.3381 | 0.082* | |
C4 | −0.3315 (6) | 0.7139 (3) | 0.33592 (18) | 0.0651 (10) | |
H4 | −0.4536 | 0.7307 | 0.3680 | 0.078* | |
C5 | −0.1721 (6) | 0.7720 (2) | 0.30673 (16) | 0.0539 (8) | |
H5 | −0.1848 | 0.8282 | 0.3203 | 0.065* | |
C6 | 0.0088 (5) | 0.7477 (2) | 0.25688 (15) | 0.0424 (7) | |
C7 | 0.1879 (6) | 0.80883 (18) | 0.23153 (14) | 0.0419 (6) | |
C8 | 0.3466 (5) | 0.79382 (18) | 0.17493 (14) | 0.0380 (6) | |
C9 | 0.5262 (5) | 0.85844 (19) | 0.15301 (15) | 0.0410 (7) | |
C10 | 0.8384 (5) | 0.91339 (19) | 0.07288 (18) | 0.0501 (8) | |
H10A | 0.9541 | 0.8905 | 0.0381 | 0.060* | |
H10B | 0.9306 | 0.9348 | 0.1141 | 0.060* | |
C11 | 0.7033 (6) | 0.98542 (19) | 0.03742 (16) | 0.0474 (7) | |
C12 | 0.4874 (6) | 0.9725 (2) | −0.00051 (18) | 0.0581 (9) | |
H12 | 0.4209 | 0.9188 | −0.0025 | 0.070* | |
C13 | 0.3684 (8) | 1.0381 (3) | −0.0355 (2) | 0.0782 (12) | |
H13 | 0.2229 | 1.0282 | −0.0603 | 0.094* | |
C14 | 0.4641 (10) | 1.1164 (4) | −0.0337 (2) | 0.0904 (15) | |
H14 | 0.3851 | 1.1599 | −0.0579 | 0.108* | |
C15 | 0.6761 (10) | 1.1322 (3) | 0.0035 (2) | 0.0859 (13) | |
H15 | 0.7404 | 1.1863 | 0.0047 | 0.103* | |
C16 | 0.7967 (8) | 1.0657 (2) | 0.0400 (2) | 0.0675 (10) | |
H16 | 0.9395 | 1.0763 | 0.0659 | 0.081* | |
C17 | 0.2715 (7) | 0.54813 (19) | 0.17761 (18) | 0.0624 (10) | |
H17A | 0.2814 | 0.5220 | 0.2247 | 0.094* | |
H17B | 0.4265 | 0.5437 | 0.1534 | 0.094* | |
H17C | 0.1487 | 0.5205 | 0.1489 | 0.094* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0524 (4) | 0.0280 (3) | 0.0408 (3) | 0.0002 (3) | −0.0009 (4) | −0.0027 (3) |
O1 | 0.0768 (15) | 0.0414 (13) | 0.0544 (13) | −0.0090 (13) | 0.0192 (13) | −0.0139 (10) |
O2 | 0.0731 (14) | 0.0353 (13) | 0.0513 (13) | −0.0123 (11) | 0.0100 (12) | −0.0109 (10) |
O3 | 0.0602 (13) | 0.0395 (14) | 0.0670 (14) | 0.0056 (10) | 0.0099 (12) | −0.0113 (10) |
O4 | 0.0684 (14) | 0.0469 (15) | 0.0409 (11) | −0.0023 (10) | −0.0115 (10) | 0.0006 (10) |
N1 | 0.0650 (15) | 0.0286 (13) | 0.0519 (14) | −0.0022 (13) | −0.0009 (14) | 0.0047 (11) |
N2 | 0.0531 (14) | 0.0342 (15) | 0.0516 (15) | −0.0036 (13) | 0.0099 (14) | −0.0048 (12) |
C1 | 0.0535 (18) | 0.043 (2) | 0.0398 (16) | −0.0064 (15) | −0.0076 (15) | 0.0089 (14) |
C2 | 0.072 (2) | 0.050 (2) | 0.061 (2) | −0.0174 (18) | −0.0059 (18) | 0.0107 (17) |
C3 | 0.069 (2) | 0.075 (3) | 0.061 (2) | −0.029 (2) | 0.003 (2) | 0.017 (2) |
C4 | 0.060 (2) | 0.084 (3) | 0.0520 (19) | −0.009 (2) | 0.0059 (17) | 0.0091 (19) |
C5 | 0.0578 (19) | 0.059 (2) | 0.0454 (17) | −0.0040 (17) | 0.0034 (17) | 0.0039 (15) |
C6 | 0.0450 (16) | 0.0448 (19) | 0.0374 (15) | −0.0061 (14) | −0.0018 (14) | 0.0068 (13) |
C7 | 0.0527 (16) | 0.0345 (17) | 0.0384 (14) | −0.0010 (15) | −0.0025 (15) | −0.0016 (12) |
C8 | 0.0486 (16) | 0.0277 (14) | 0.0377 (14) | −0.0025 (13) | −0.0030 (12) | −0.0013 (12) |
C9 | 0.0505 (18) | 0.0335 (17) | 0.0389 (15) | 0.0007 (14) | −0.0030 (14) | −0.0012 (13) |
C10 | 0.0486 (18) | 0.045 (2) | 0.0565 (18) | −0.0043 (15) | 0.0084 (15) | 0.0005 (15) |
C11 | 0.0558 (18) | 0.0400 (18) | 0.0464 (16) | −0.0045 (15) | 0.0210 (17) | −0.0030 (13) |
C12 | 0.057 (2) | 0.056 (2) | 0.062 (2) | 0.0039 (17) | 0.0090 (19) | 0.0002 (18) |
C13 | 0.077 (3) | 0.091 (4) | 0.066 (2) | 0.027 (3) | 0.014 (2) | 0.003 (2) |
C14 | 0.114 (4) | 0.078 (4) | 0.080 (3) | 0.032 (3) | 0.031 (3) | 0.018 (3) |
C15 | 0.130 (4) | 0.038 (2) | 0.090 (3) | −0.007 (3) | 0.042 (3) | 0.005 (2) |
C16 | 0.082 (2) | 0.050 (2) | 0.071 (2) | −0.011 (2) | 0.024 (2) | −0.0060 (18) |
C17 | 0.094 (3) | 0.0308 (17) | 0.063 (2) | 0.0028 (17) | −0.007 (2) | 0.0060 (15) |
S1—O3 | 1.437 (2) | C5—C6 | 1.402 (4) |
S1—O4 | 1.427 (2) | C6—C7 | 1.457 (4) |
S1—N1 | 1.650 (2) | C7—C8 | 1.374 (4) |
S1—C8 | 1.736 (3) | C8—C9 | 1.479 (4) |
O1—H1 | 0.95 (4) | C10—H10A | 0.9700 |
O1—C7 | 1.331 (3) | C10—H10B | 0.9700 |
O2—C9 | 1.263 (3) | C10—C11 | 1.511 (4) |
N1—C1 | 1.404 (4) | C11—C12 | 1.387 (5) |
N1—C17 | 1.474 (4) | C11—C16 | 1.377 (4) |
N2—H2 | 0.88 (3) | C12—H12 | 0.9300 |
N2—C9 | 1.325 (3) | C12—C13 | 1.388 (5) |
N2—C10 | 1.454 (4) | C13—H13 | 0.9300 |
C1—C2 | 1.397 (4) | C13—C14 | 1.351 (6) |
C1—C6 | 1.407 (4) | C14—H14 | 0.9300 |
C2—H2A | 0.9300 | C14—C15 | 1.369 (6) |
C2—C3 | 1.373 (5) | C15—H15 | 0.9300 |
C3—H3 | 0.9300 | C15—C16 | 1.416 (6) |
C3—C4 | 1.385 (5) | C16—H16 | 0.9300 |
C4—H4 | 0.9300 | C17—H17A | 0.9600 |
C4—C5 | 1.380 (4) | C17—H17B | 0.9600 |
C5—H5 | 0.9300 | C17—H17C | 0.9600 |
O3—S1—N1 | 107.55 (14) | C7—C8—C9 | 120.3 (3) |
O3—S1—C8 | 110.87 (13) | C9—C8—S1 | 121.3 (2) |
O4—S1—O3 | 116.43 (13) | O2—C9—N2 | 120.4 (3) |
O4—S1—N1 | 110.57 (13) | O2—C9—C8 | 117.9 (3) |
O4—S1—C8 | 109.38 (13) | N2—C9—C8 | 121.7 (3) |
N1—S1—C8 | 100.90 (13) | N2—C10—H10A | 108.8 |
C7—O1—H1 | 102 (2) | N2—C10—H10B | 108.8 |
C1—N1—S1 | 119.2 (2) | N2—C10—C11 | 113.7 (3) |
C1—N1—C17 | 121.3 (3) | H10A—C10—H10B | 107.7 |
C17—N1—S1 | 117.7 (2) | C11—C10—H10A | 108.8 |
C9—N2—H2 | 116 (2) | C11—C10—H10B | 108.8 |
C9—N2—C10 | 120.8 (3) | C12—C11—C10 | 121.4 (3) |
C10—N2—H2 | 123 (2) | C16—C11—C10 | 120.5 (3) |
N1—C1—C6 | 120.0 (3) | C16—C11—C12 | 118.1 (3) |
C2—C1—N1 | 121.2 (3) | C11—C12—H12 | 119.3 |
C2—C1—C6 | 118.8 (3) | C11—C12—C13 | 121.4 (4) |
C1—C2—H2A | 119.7 | C13—C12—H12 | 119.3 |
C3—C2—C1 | 120.7 (4) | C12—C13—H13 | 120.0 |
C3—C2—H2A | 119.7 | C14—C13—C12 | 119.9 (4) |
C2—C3—H3 | 119.4 | C14—C13—H13 | 120.0 |
C2—C3—C4 | 121.1 (3) | C13—C14—H14 | 119.6 |
C4—C3—H3 | 119.4 | C13—C14—C15 | 120.7 (4) |
C3—C4—H4 | 120.5 | C15—C14—H14 | 119.6 |
C5—C4—C3 | 119.1 (3) | C14—C15—H15 | 120.2 |
C5—C4—H4 | 120.5 | C14—C15—C16 | 119.5 (4) |
C4—C5—H5 | 119.5 | C16—C15—H15 | 120.2 |
C4—C5—C6 | 121.0 (3) | C11—C16—C15 | 120.3 (4) |
C6—C5—H5 | 119.5 | C11—C16—H16 | 119.9 |
C1—C6—C7 | 120.6 (3) | C15—C16—H16 | 119.9 |
C5—C6—C1 | 119.3 (3) | N1—C17—H17A | 109.5 |
C5—C6—C7 | 120.0 (3) | N1—C17—H17B | 109.5 |
O1—C7—C6 | 115.4 (3) | N1—C17—H17C | 109.5 |
O1—C7—C8 | 121.2 (3) | H17A—C17—H17B | 109.5 |
C8—C7—C6 | 123.4 (3) | H17A—C17—H17C | 109.5 |
C7—C8—S1 | 117.8 (2) | H17B—C17—H17C | 109.5 |
S1—N1—C1—C2 | 151.6 (2) | C2—C3—C4—C5 | −3.1 (5) |
S1—N1—C1—C6 | −32.0 (4) | C3—C4—C5—C6 | 1.6 (5) |
S1—C8—C9—O2 | 170.6 (2) | C4—C5—C6—C1 | 1.2 (4) |
S1—C8—C9—N2 | −7.9 (4) | C4—C5—C6—C7 | −174.8 (3) |
O1—C7—C8—S1 | −172.4 (2) | C5—C6—C7—O1 | 11.9 (4) |
O1—C7—C8—C9 | −0.8 (4) | C5—C6—C7—C8 | −169.8 (3) |
O3—S1—N1—C1 | 163.6 (2) | C6—C1—C2—C3 | 1.2 (5) |
O3—S1—N1—C17 | −31.4 (3) | C6—C7—C8—S1 | 9.4 (4) |
O3—S1—C8—C7 | −149.4 (2) | C6—C7—C8—C9 | −179.0 (3) |
O3—S1—C8—C9 | 39.1 (3) | C7—C8—C9—O2 | −0.7 (4) |
O4—S1—N1—C1 | −68.3 (2) | C7—C8—C9—N2 | −179.2 (3) |
O4—S1—N1—C17 | 96.7 (3) | C8—S1—N1—C1 | 47.4 (2) |
O4—S1—C8—C7 | 80.9 (2) | C8—S1—N1—C17 | −147.6 (2) |
O4—S1—C8—C9 | −90.6 (2) | C9—N2—C10—C11 | −67.5 (4) |
N1—S1—C8—C7 | −35.7 (3) | C10—N2—C9—O2 | −4.4 (4) |
N1—S1—C8—C9 | 152.8 (2) | C10—N2—C9—C8 | 174.0 (3) |
N1—C1—C2—C3 | 177.6 (3) | C10—C11—C12—C13 | −177.4 (3) |
N1—C1—C6—C5 | −179.1 (3) | C10—C11—C16—C15 | 176.7 (3) |
N1—C1—C6—C7 | −3.1 (4) | C11—C12—C13—C14 | 0.6 (5) |
N2—C10—C11—C12 | −31.2 (4) | C12—C11—C16—C15 | −1.3 (5) |
N2—C10—C11—C16 | 151.0 (3) | C12—C13—C14—C15 | −1.0 (6) |
C1—C2—C3—C4 | 1.7 (5) | C13—C14—C15—C16 | 0.3 (6) |
C1—C6—C7—O1 | −164.0 (3) | C14—C15—C16—C11 | 0.9 (6) |
C1—C6—C7—C8 | 14.3 (4) | C16—C11—C12—C13 | 0.5 (5) |
C2—C1—C6—C5 | −2.5 (4) | C17—N1—C1—C2 | −12.9 (4) |
C2—C1—C6—C7 | 173.4 (3) | C17—N1—C1—C6 | 163.6 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O3 | 0.88 (3) | 2.15 (3) | 2.883 (3) | 140 (3) |
O1—H1···O2 | 0.96 | 1.55 (4) | 2.463 (3) | 158 (4) |
C17—H17a···O2i | 0.96 | 2.45 | 3.324 (4) | 152 |
C17—H17c···C12ii | 0.96 | 2.86 | 3.614 (5) | 136 |
C17—H17c···C13ii | 0.96 | 2.75 | 3.679 (5) | 164 |
Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) x−1/2, −y+3/2, −z. |
C17H16N2O4S | Dx = 1.453 Mg m−3 |
Mr = 344.39 | Mo Kα radiation, λ = 0.71073 Å |
Orthorhombic, P212121 | Cell parameters from 2803 reflections |
a = 5.4469 (3) Å | θ = 3.4–28.2° |
b = 15.8455 (10) Å | µ = 0.23 mm−1 |
c = 18.2412 (9) Å | T = 293 K |
V = 1574.38 (15) Å3 | Stick, colourless |
Z = 4 | 0.2 × 0.02 × 0.02 mm |
F(000) = 720.8596 |
Agilent Xcalibur Sapphire3 diffractometer | 2777 independent reflections |
Radiation source: Enhance (Mo) X-ray Source | 2296 reflections with I ≥ 2u(I) |
Graphite monochromator | Rint = 0.068 |
Detector resolution: 16.1827 pixels mm-1 | θmax = 25.0°, θmin = 3.4° |
ω scans | h = −6→7 |
Absorption correction: multi-scan (CrysAlis RED; Agilent, 2012) | k = −23→22 |
Tmin = 0.775, Tmax = 1.000 | l = −27→25 |
16325 measured reflections |
Refinement on F2 | 25 constraints |
Least-squares matrix: full | H atoms treated by a mixture of independent and constrained refinement |
R[F2 > 2σ(F2)] = 0.040 | w = 1/[σ2(Fo2) + (0.1P)2] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.124 | (Δ/σ)max < 0.001 |
S = 0.84 | Δρmax = 0.20 e Å−3 |
2777 reflections | Δρmin = −0.21 e Å−3 |
225 parameters | Absolute structure: Flack x determined using 839 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
0 restraints | Absolute structure parameter: −0.16 (9) |
C17H16N2O4S | V = 1574.38 (15) Å3 |
Mr = 344.39 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 5.4469 (3) Å | µ = 0.23 mm−1 |
b = 15.8455 (10) Å | T = 293 K |
c = 18.2412 (9) Å | 0.2 × 0.02 × 0.02 mm |
Agilent Xcalibur Sapphire3 diffractometer | 2777 independent reflections |
Absorption correction: multi-scan (CrysAlis RED; Agilent, 2012) | 2296 reflections with I ≥ 2u(I) |
Tmin = 0.775, Tmax = 1.000 | Rint = 0.068 |
16325 measured reflections |
R[F2 > 2σ(F2)] = 0.040 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.124 | Δρmax = 0.20 e Å−3 |
S = 0.84 | Δρmin = −0.21 e Å−3 |
2777 reflections | Absolute structure: Flack x determined using 839 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
225 parameters | Absolute structure parameter: −0.16 (9) |
0 restraints |
Experimental. Absorption correction: CrysAlis RED, Agilent Technologies, Version 1.171.36.24 (release 03-12-2012 CrysAlis171 .NET) (compiled Dec 3 2012,18:21:49) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. |
x | y | z | Uiso*/Ueq | ||
S1 | 0.69864 (14) | 0.79616 (4) | 0.37664 (4) | 0.0416 (2) | |
O1 | 0.8053 (5) | 0.61912 (14) | 0.23171 (13) | 0.0597 (6) | |
H1 | 0.683 (7) | 0.592 (3) | 0.257 (2) | 0.092 (15)* | |
O2 | 0.4734 (4) | 0.57292 (14) | 0.31270 (12) | 0.0550 (6) | |
O3 | 0.8868 (4) | 0.78152 (15) | 0.42918 (12) | 0.0537 (6) | |
O4 | 0.4709 (4) | 0.82769 (14) | 0.40441 (14) | 0.0575 (6) | |
N1 | 0.7926 (5) | 0.86279 (15) | 0.31387 (15) | 0.0495 (6) | |
N2 | 0.3199 (5) | 0.65392 (17) | 0.40157 (14) | 0.0476 (6) | |
H2 | 0.326 (6) | 0.704 (2) | 0.4243 (19) | 0.054 (9)* | |
C1 | 0.9743 (6) | 0.8371 (2) | 0.26440 (17) | 0.0466 (8) | |
C2 | 1.1358 (7) | 0.8951 (2) | 0.2331 (2) | 0.0624 (10) | |
H2a | 1.1265 (7) | 0.9517 (2) | 0.2462 (2) | 0.0748 (12)* | |
C3 | 1.3080 (7) | 0.8692 (3) | 0.1833 (2) | 0.0677 (10) | |
H3 | 1.4117 (7) | 0.9090 (3) | 0.1622 (2) | 0.0812 (12)* | |
C4 | 1.3316 (7) | 0.7859 (3) | 0.1636 (2) | 0.0676 (11) | |
H4 | 1.4533 (7) | 0.7692 (3) | 0.1310 (2) | 0.0811 (13)* | |
C5 | 1.1718 (7) | 0.7275 (2) | 0.19318 (17) | 0.0573 (9) | |
H5 | 1.1846 (7) | 0.6711 (2) | 0.17971 (17) | 0.0688 (11)* | |
C6 | 0.9913 (6) | 0.7522 (2) | 0.24306 (17) | 0.0442 (7) | |
C7 | 0.8119 (6) | 0.69118 (18) | 0.26832 (16) | 0.0434 (7) | |
C8 | 0.6530 (5) | 0.70668 (19) | 0.32516 (15) | 0.0402 (7) | |
C9 | 0.4747 (6) | 0.64221 (19) | 0.34671 (16) | 0.0417 (7) | |
C10 | 0.1612 (6) | 0.5863 (2) | 0.42677 (19) | 0.0518 (8) | |
H10a | 0.0438 (6) | 0.6092 (2) | 0.46145 (19) | 0.0621 (10)* | |
H10b | 0.0697 (6) | 0.5644 (2) | 0.38530 (19) | 0.0621 (10)* | |
C11 | 0.2976 (6) | 0.51444 (19) | 0.46283 (17) | 0.0482 (7) | |
C12 | 0.5141 (7) | 0.5282 (2) | 0.5008 (2) | 0.0587 (9) | |
H12 | 0.5805 (7) | 0.5822 (2) | 0.5029 (2) | 0.0705 (11)* | |
C13 | 0.6323 (9) | 0.4623 (3) | 0.5356 (2) | 0.0819 (14) | |
H13 | 0.7783 (9) | 0.4724 (3) | 0.5606 (2) | 0.0983 (16)* | |
C14 | 0.5392 (11) | 0.3841 (4) | 0.5340 (3) | 0.0900 (15) | |
H14 | 0.6198 (11) | 0.3406 (4) | 0.5583 (3) | 0.1080 (18)* | |
C15 | 0.3267 (12) | 0.3678 (3) | 0.4968 (3) | 0.0900 (15) | |
H15 | 0.2635 (12) | 0.3133 (3) | 0.4956 (3) | 0.1080 (18)* | |
C16 | 0.2029 (9) | 0.4338 (2) | 0.4602 (2) | 0.0678 (10) | |
H16 | 0.0589 (9) | 0.4230 (2) | 0.4344 (2) | 0.0813 (12)* | |
C17 | 0.7284 (8) | 0.9518 (2) | 0.3220 (2) | 0.0646 (11) | |
H17a | 0.571 (3) | 0.9565 (2) | 0.3451 (14) | 0.0969 (16)* | |
H17b | 0.850 (3) | 0.9794 (4) | 0.3517 (13) | 0.0969 (16)* | |
H17c | 0.723 (5) | 0.9780 (5) | 0.2745 (2) | 0.0969 (16)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0541 (4) | 0.0299 (4) | 0.0407 (4) | −0.0002 (3) | −0.0005 (4) | −0.0021 (3) |
O1 | 0.0801 (16) | 0.0392 (13) | 0.0598 (14) | −0.0082 (13) | 0.0200 (14) | −0.0139 (10) |
O2 | 0.0749 (15) | 0.0385 (13) | 0.0517 (13) | −0.0132 (11) | 0.0090 (12) | −0.0101 (10) |
O3 | 0.0719 (14) | 0.0486 (15) | 0.0407 (11) | −0.0024 (11) | −0.0109 (10) | −0.0016 (10) |
O4 | 0.0620 (13) | 0.0425 (14) | 0.0679 (15) | 0.0054 (11) | 0.0087 (13) | −0.0111 (11) |
N1 | 0.0670 (16) | 0.0280 (13) | 0.0535 (14) | −0.0032 (13) | −0.0010 (15) | 0.0027 (11) |
N2 | 0.0575 (15) | 0.0322 (15) | 0.0532 (15) | −0.0034 (13) | 0.0098 (14) | −0.0032 (11) |
C1 | 0.0541 (18) | 0.0446 (19) | 0.0413 (16) | −0.0048 (15) | −0.0054 (15) | 0.0085 (14) |
C2 | 0.078 (2) | 0.050 (2) | 0.059 (2) | −0.0199 (18) | −0.0064 (19) | 0.0110 (17) |
C3 | 0.071 (2) | 0.075 (3) | 0.057 (2) | −0.025 (2) | 0.005 (2) | 0.0142 (19) |
C4 | 0.060 (2) | 0.092 (3) | 0.051 (2) | −0.014 (2) | 0.0073 (17) | 0.008 (2) |
C5 | 0.063 (2) | 0.065 (2) | 0.0437 (17) | −0.0002 (17) | 0.0054 (18) | 0.0027 (15) |
C6 | 0.0510 (17) | 0.0405 (18) | 0.0412 (15) | −0.0049 (14) | −0.0041 (14) | 0.0063 (14) |
C7 | 0.0542 (16) | 0.0364 (16) | 0.0394 (15) | 0.0017 (15) | −0.0009 (15) | −0.0002 (12) |
C8 | 0.0521 (17) | 0.0324 (15) | 0.0362 (14) | −0.0009 (13) | −0.0009 (13) | 0.0002 (12) |
C9 | 0.0537 (18) | 0.0300 (16) | 0.0414 (15) | −0.0004 (13) | −0.0012 (15) | −0.0014 (13) |
C10 | 0.0502 (18) | 0.050 (2) | 0.0547 (18) | −0.0044 (15) | 0.0065 (15) | 0.0000 (15) |
C11 | 0.0580 (18) | 0.0385 (17) | 0.0482 (17) | −0.0009 (15) | 0.0190 (17) | −0.0038 (13) |
C12 | 0.060 (2) | 0.054 (2) | 0.063 (2) | 0.0032 (17) | 0.0113 (19) | −0.0036 (18) |
C13 | 0.082 (3) | 0.093 (4) | 0.071 (3) | 0.027 (3) | 0.013 (2) | 0.003 (3) |
C14 | 0.113 (4) | 0.075 (4) | 0.083 (3) | 0.029 (3) | 0.023 (3) | 0.010 (3) |
C15 | 0.140 (4) | 0.038 (2) | 0.092 (3) | −0.008 (3) | 0.050 (3) | 0.003 (2) |
C16 | 0.080 (2) | 0.050 (2) | 0.073 (2) | −0.0096 (19) | 0.022 (2) | −0.0078 (18) |
C17 | 0.096 (3) | 0.0346 (17) | 0.063 (2) | 0.0026 (18) | −0.010 (2) | 0.0065 (15) |
S1—O3 | 1.422 (2) | C5—C6 | 1.396 (5) |
S1—O4 | 1.430 (2) | C6—C7 | 1.450 (4) |
S1—N1 | 1.639 (3) | C7—C8 | 1.373 (4) |
S1—C8 | 1.719 (3) | C8—C9 | 1.463 (4) |
O1—H1 | 0.92 (4) | C10—H10a | 0.9700 |
O1—C7 | 1.323 (4) | C10—H10b | 0.9700 |
O2—C9 | 1.261 (4) | C10—C11 | 1.510 (5) |
N1—C1 | 1.400 (4) | C11—C12 | 1.385 (5) |
N1—C17 | 1.461 (4) | C11—C16 | 1.378 (5) |
N2—H2 | 0.90 (4) | C12—H12 | 0.9300 |
N2—C9 | 1.322 (4) | C12—C13 | 1.381 (6) |
N2—C10 | 1.451 (4) | C13—H13 | 0.9300 |
C1—C2 | 1.395 (5) | C13—C14 | 1.340 (7) |
C1—C6 | 1.403 (5) | C14—H14 | 0.9300 |
C2—H2a | 0.9300 | C14—C15 | 1.366 (7) |
C2—C3 | 1.369 (6) | C15—H15 | 0.9300 |
C3—H3 | 0.9300 | C15—C16 | 1.412 (7) |
C3—C4 | 1.373 (6) | C16—H16 | 0.9300 |
C4—H4 | 0.9300 | C17—H17a | 0.9600 |
C4—C5 | 1.380 (5) | C17—H17b | 0.9600 |
C5—H5 | 0.9300 | C17—H17c | 0.9600 |
O4—S1—O3 | 116.33 (14) | C9—C8—S1 | 121.7 (2) |
N1—S1—O3 | 110.54 (15) | C9—C8—C7 | 119.8 (3) |
N1—S1—O4 | 107.04 (15) | N2—C9—O2 | 119.4 (3) |
C8—S1—O3 | 109.74 (14) | C8—C9—O2 | 118.6 (3) |
C8—S1—O4 | 110.88 (14) | C8—C9—N2 | 121.9 (3) |
C8—S1—N1 | 101.23 (13) | H10a—C10—N2 | 108.82 (17) |
C7—O1—H1 | 99 (3) | H10b—C10—N2 | 108.82 (18) |
C1—N1—S1 | 118.9 (2) | H10b—C10—H10a | 107.7 |
C17—N1—S1 | 118.5 (2) | C11—C10—N2 | 113.7 (3) |
C17—N1—C1 | 121.0 (3) | C11—C10—H10a | 108.82 (17) |
C9—N2—H2 | 117 (2) | C11—C10—H10b | 108.82 (18) |
C10—N2—H2 | 122 (2) | C12—C11—C10 | 121.2 (3) |
C10—N2—C9 | 121.1 (3) | C16—C11—C10 | 120.0 (3) |
C2—C1—N1 | 121.2 (3) | C16—C11—C12 | 118.8 (3) |
C6—C1—N1 | 120.3 (3) | H12—C12—C11 | 119.7 (2) |
C6—C1—C2 | 118.5 (3) | C13—C12—C11 | 120.5 (4) |
H2a—C2—C1 | 119.8 (2) | C13—C12—H12 | 119.7 (3) |
C3—C2—C1 | 120.4 (4) | H13—C13—C12 | 119.6 (3) |
C3—C2—H2a | 119.8 (2) | C14—C13—C12 | 120.8 (5) |
H3—C3—C2 | 119.1 (2) | C14—C13—H13 | 119.6 (3) |
C4—C3—C2 | 121.7 (3) | H14—C14—C13 | 119.8 (3) |
C4—C3—H3 | 119.1 (2) | C15—C14—C13 | 120.5 (5) |
H4—C4—C3 | 120.6 (2) | C15—C14—H14 | 119.8 (3) |
C5—C4—C3 | 118.9 (4) | H15—C15—C14 | 120.0 (3) |
C5—C4—H4 | 120.6 (2) | C16—C15—C14 | 120.0 (4) |
H5—C5—C4 | 119.6 (2) | C16—C15—H15 | 120.0 (3) |
C6—C5—C4 | 120.7 (4) | C15—C16—C11 | 119.4 (4) |
C6—C5—H5 | 119.6 (2) | H16—C16—C11 | 120.3 (2) |
C5—C6—C1 | 119.7 (3) | H16—C16—C15 | 120.3 (3) |
C7—C6—C1 | 120.4 (3) | H17a—C17—N1 | 109.5 |
C7—C6—C5 | 119.7 (3) | H17b—C17—N1 | 109.5 |
C6—C7—O1 | 115.7 (3) | H17b—C17—H17a | 109.5 |
C8—C7—O1 | 121.2 (3) | H17c—C17—N1 | 109.5 |
C8—C7—C6 | 123.1 (3) | H17c—C17—H17a | 109.5 |
C7—C8—S1 | 118.0 (2) | H17c—C17—H17b | 109.5 |
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O4 | 0.90 (3) | 2.14 (3) | 2.874 (3) | 138 (3) |
O1—H1···O2 | 0.92 (4) | 1.56 (4) | 2.447 (3) | 162 (4) |
C17—H17c···O2iiii | 0.96 | 2.44 | 3.306 (4) | 150 |
C17—H17b···C12ivii | 0.96 | 2.84 | 3.601 (5) | 137 |
C17—H17b···C13ivii | 0.96 | 2.73 | 3.666 (6) | 165 |
Symmetry codes: (i) −x+1, y+1/2, −z+1/2; (ii) −x+1/2, −y+1, z+3/2. |
Experimental details
(I) | (II) | |
Crystal data | ||
Chemical formula | C17H16N2O4S | C17H16N2O4S |
Mr | 344.39 | 344.39 |
Crystal system, space group | Orthorhombic, P212121 | Orthorhombic, P212121 |
Temperature (K) | 293 | 293 |
a, b, c (Å) | 5.4764 (3), 15.9117 (8), 18.3228 (10) | 5.4469 (3), 15.8455 (10), 18.2412 (9) |
V (Å3) | 1596.63 (15) | 1574.38 (15) |
Z | 4 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.23 | 0.23 |
Crystal size (mm) | 0.2 × 0.02 × 0.02 | 0.2 × 0.02 × 0.02 |
Data collection | ||
Diffractometer | Xcalibur, Sapphire3 | Agilent Xcalibur Sapphire3 |
Absorption correction | Multi-scan (CrysAlis RED; Agilent, 2012) | Multi-scan (CrysAlis RED; Agilent, 2012) |
Tmin, Tmax | 0.979, 1.000 | 0.775, 1.000 |
No. of measured, independent and observed reflections | 16369, 4658, 3004 [I > 2σ(I)] | 16325, 2777, 2296 [I ≥ 2u(I)] |
Rint | 0.055 | 0.068 |
(sin θ/λ)max (Å−1) | 0.703 | 0.595 |
Refinement | ||
R[F2 > 2σ(F2)], wR(F2), S | 0.051, 0.094, 0.99 | 0.040, 0.124, 0.84 |
No. of reflections | 4658 | 2777 |
No. of parameters | 226 | 225 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.22, −0.28 | 0.20, −0.21 |
Absolute structure | Flack x determined using 910 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) | Flack x determined using 839 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
Absolute structure parameter | 0.09 (5) | −0.16 (9) |
Computer programs: CrysAlis CCD (Agilent, 2012), CrysAlis RED (Agilent, 2012), SHELXS97 (Sheldrick, 2008), SHELXT (Sheldrick, 2015b), SHELXL2014 (Sheldrick, 2015a), olex2.refine (Bourhis et al., 2015), Olex2 (Dolomanov et al., 2009), OLEX2 (Dolomanov et al., 2009).
Compound | The latent period in 1 h after introduction of the compound (s) | Change of the latent period compared to control (%)% |
(1a) | 16.07±0.95 | + 113.1 |
(1b) | 9.92±0.73 | + 31.6 |
(1c) | 9.46+0.77 | + 25.5 |
(1d) | 9.40±0.80 | + 24.7 |
(1e) | 9.67±0.74 | + 25.3 |
Pyroxicam | 9.45±0.74 | + 25.3 |
Control | 7.54±0.82 |
Parameter | Form A | Form B |
Ring-puckering parameters (Zefirov et al., 1990) | ||
S | 0.59 | 0.59 |
Θ | 50.5 | 50.9 |
Ψ | 20.6 | 20.2 |
Bond lengths | ||
C9—O2 | 1.263 (4) | 1.261 (4) |
O1—C7 | 1.331 (4) | 1.323 (4) |
C7—C8 | 1.374 (4) | 1.373 (4) |
N1—C1 | 1.404 (4) | 1.400 (4) |
Torsion angles | ||
C1—N1—S1—C8 | 47.4 (3) | -47.1 (3) |
N1—S1—C8—C7 | -35.7 (3) | 36.0 (3) |
C9—N2—C10—C11 | -67.5 (4) | 67.7 (4) |
N2—C10—C11—C12 | -31.2 (4) | 30.8 (4) |
C7—C8—C9—O2 | -0.7 (4) | 0.8 (4) |
C10—N2—C9—C8 | 174.0 (3) | -173.9 (3) |
Interaction | Symmetry code | H···A | D—H···A |
Molecule A | |||
O1—H···O2 | 1.55 (4) | 158 (4) | |
C17—H17c···O2 | -x+1, y-1/2, -z+1/2 | 2.43 | 152 |
C17—H17a···C12' (π) | x-1/2, -y+1/2, -z | 2.86 | 135 |
C17—H17a···C13' (π) | x-1/2, -y+1/2,- z | 2.74 | 163 |
Molecule B | |||
O1—H···O2 | 1.56 (4) | 162 (4) | |
C17—H17c···O2' | -x, y+1/2, -z+3/2 | 2.44 | 150 |
C17—H17a···C12' (π) | x+1/2, -y+1/2, -z+2 | 2.83 | 138 |
C17—H17a···C13' (π) | x+1/2, -y+1/2, -z+2 | 2.73 | 166 |
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O3 | 0.88 (3) | 2.15 (3) | 2.883 (3) | 140 (3) |
O1—H1···O2 | 0.96 | 1.55 (4) | 2.463 (3) | 158 (4) |
C17—H17a···O2i | 0.96 | 2.45 | 3.324 (4) | 152 |
C17—H17c···C12ii | 0.96 | 2.86 | 3.614 (5) | 136 |
C17—H17c···C13ii | 0.96 | 2.75 | 3.679 (5) | 164 |
Symmetry codes: (i) −x+1, y−1/2, −z+1/2; (ii) x−1/2, −y+3/2, −z. |
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O4 | 0.90 (3) | 2.14 (3) | 2.874 (3) | 138 (3) |
O1—H1···O2 | 0.92 (4) | 1.56 (4) | 2.447 (3) | 162 (4) |
C17—H17c···O2iiii | 0.96 | 2.44 | 3.306 (4) | 150 |
C17—H17b···C12ivii | 0.96 | 2.84 | 3.601 (5) | 137 |
C17—H17b···C13ivii | 0.96 | 2.73 | 3.666 (6) | 165 |
Symmetry codes: (i) −x+1, y+1/2, −z+1/2; (ii) −x+1/2, −y+1, z+3/2. |