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The fact that mol­ecular crystals exist as different polymorphic modifications and the identification of as many polymorphs as possible are important considerations for the pharmaceutic industry. The mol­ecule of N-benzyl-4-hy­droxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzo­thia­zine-3-carboxamide, C17H16N2O4S, does not contain a stereogenic atom, but intra­molecular hydrogen-bonding inter­actions engender enanti­omeric chiral conformations as a labile racemic mixture. The title compound crystallized in a solvent-dependent single chiral conformation within one of two conformationally polymorphic P212121 ortho­rhom­bic chiral crystals (denoted forms A and B). Each of these pseudo-enanti­omorphic crystals contains one of two pseudo-enanti­omeric diastereomers. Form A was obtained from methyl­ene chloride and form B can be crystallized from N,N-dimethyl­formamide, ethanol, ethyl acetate or xylene. Pharmacological studies with solid–particulate suspensions have shown that crystalline form A exhibits an almost fourfold higher anti­nociceptive activity compared to form B.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229616005453/fn3216sup1.cif
Contains datablocks I, II, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229616005453/fn3216Isup2.hkl
Contains datablock I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229616005453/fn3216IIsup3.hkl
Contains datablock II

CCDC references: 1471701; 1471700

Introduction top

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.

Experimental top

Synthesis and crystallization top

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.

Refinement top

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.

Pharmacological tests top

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.

Results and discussion top

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 C7C8 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.

Structure description top

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 C7C8 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.

Synthesis and crystallization top

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.

Refinement details top

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.

Computing details top

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).

Figures top
[Figure 1] Fig. 1. The molecular structures of the two pseudo-enantiomers of benzylamide (I), with form A at the bottom and form B at the top.
[Figure 2] Fig. 2. The molecular structures of (a) pseudo-enantiomer (1a) and (b) pseudo-enantiomer (1b), showing the atom-labelling schemes. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 3] Fig. 3. The crystal packing of pseudo-enantiomeric molecules (1a) (Form A) and (1b) (Form B).
(I) N-Benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide top
Crystal data top
C17H16N2O4SDx = 1.433 Mg m3
Mr = 344.39Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121Cell parameters from 3040 reflections
a = 5.4764 (3) Åθ = 3.6–30.6°
b = 15.9117 (8) ŵ = 0.23 mm1
c = 18.3228 (10) ÅT = 293 K
V = 1596.63 (15) Å3, colourless
Z = 40.2 × 0.02 × 0.02 mm
F(000) = 720
Data collection top
Xcalibur, Sapphire3
diffractometer
4658 independent reflections
Radiation source: Enhance (Mo) X-ray Source3004 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.055
Detector resolution: 16.1827 pixels mm-1θmax = 30.0°, θmin = 3.4°
ω scansh = 57
Absorption correction: multi-scan
(CrysAlis RED; Agilent, 2012)
k = 2022
Tmin = 0.979, Tmax = 1.000l = 2525
16369 measured reflections
Refinement top
Refinement on F2Hydrogen site location: mixed
Least-squares matrix: fullH 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 = 0.99Δρmax = 0.22 e Å3
4658 reflectionsΔρmin = 0.28 e Å3
226 parametersAbsolute structure: Flack x determined using 910 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
0 restraintsAbsolute structure parameter: 0.09 (5)
Crystal data top
C17H16N2O4SV = 1596.63 (15) Å3
Mr = 344.39Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 5.4764 (3) ŵ = 0.23 mm1
b = 15.9117 (8) ÅT = 293 K
c = 18.3228 (10) Å0.2 × 0.02 × 0.02 mm
Data collection top
Xcalibur, Sapphire3
diffractometer
4658 independent reflections
Absorption correction: multi-scan
(CrysAlis RED; Agilent, 2012)
3004 reflections with I > 2σ(I)
Tmin = 0.979, Tmax = 1.000Rint = 0.055
16369 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.051H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.094Δρmax = 0.22 e Å3
S = 0.99Δρmin = 0.28 e Å3
4658 reflectionsAbsolute structure: Flack x determined using 910 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
226 parametersAbsolute structure parameter: 0.09 (5)
0 restraints
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.30167 (14)0.70373 (4)0.12320 (4)0.04040 (18)
O10.1936 (5)0.88090 (14)0.26834 (12)0.0575 (6)
H10.319 (7)0.911 (3)0.243 (2)0.096 (14)*
O20.5263 (4)0.92725 (13)0.18735 (11)0.0532 (6)
O30.5295 (4)0.67251 (13)0.09536 (12)0.0556 (6)
O40.1137 (4)0.71866 (14)0.07081 (11)0.0521 (6)
N10.2068 (5)0.63746 (15)0.18639 (13)0.0485 (6)
N20.6795 (5)0.84615 (17)0.09810 (14)0.0463 (6)
H20.671 (5)0.797 (2)0.0768 (16)0.048 (8)*
C10.0244 (6)0.6630 (2)0.23545 (16)0.0454 (7)
C20.1351 (6)0.6048 (2)0.26687 (19)0.0611 (9)
H2A0.12480.54850.25380.073*
C30.3071 (7)0.6301 (3)0.31677 (19)0.0686 (10)
H30.40890.59030.33810.082*
C40.3315 (6)0.7139 (3)0.33592 (18)0.0651 (10)
H40.45360.73070.36800.078*
C50.1721 (6)0.7720 (2)0.30673 (16)0.0539 (8)
H50.18480.82820.32030.065*
C60.0088 (5)0.7477 (2)0.25688 (15)0.0424 (7)
C70.1879 (6)0.80883 (18)0.23153 (14)0.0419 (6)
C80.3466 (5)0.79382 (18)0.17493 (14)0.0380 (6)
C90.5262 (5)0.85844 (19)0.15301 (15)0.0410 (7)
C100.8384 (5)0.91339 (19)0.07288 (18)0.0501 (8)
H10A0.95410.89050.03810.060*
H10B0.93060.93480.11410.060*
C110.7033 (6)0.98542 (19)0.03742 (16)0.0474 (7)
C120.4874 (6)0.9725 (2)0.00051 (18)0.0581 (9)
H120.42090.91880.00250.070*
C130.3684 (8)1.0381 (3)0.0355 (2)0.0782 (12)
H130.22291.02820.06030.094*
C140.4641 (10)1.1164 (4)0.0337 (2)0.0904 (15)
H140.38511.15990.05790.108*
C150.6761 (10)1.1322 (3)0.0035 (2)0.0859 (13)
H150.74041.18630.00470.103*
C160.7967 (8)1.0657 (2)0.0400 (2)0.0675 (10)
H160.93951.07630.06590.081*
C170.2715 (7)0.54813 (19)0.17761 (18)0.0624 (10)
H17A0.28140.52200.22470.094*
H17B0.42650.54370.15340.094*
H17C0.14870.52050.14890.094*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0524 (4)0.0280 (3)0.0408 (3)0.0002 (3)0.0009 (4)0.0027 (3)
O10.0768 (15)0.0414 (13)0.0544 (13)0.0090 (13)0.0192 (13)0.0139 (10)
O20.0731 (14)0.0353 (13)0.0513 (13)0.0123 (11)0.0100 (12)0.0109 (10)
O30.0602 (13)0.0395 (14)0.0670 (14)0.0056 (10)0.0099 (12)0.0113 (10)
O40.0684 (14)0.0469 (15)0.0409 (11)0.0023 (10)0.0115 (10)0.0006 (10)
N10.0650 (15)0.0286 (13)0.0519 (14)0.0022 (13)0.0009 (14)0.0047 (11)
N20.0531 (14)0.0342 (15)0.0516 (15)0.0036 (13)0.0099 (14)0.0048 (12)
C10.0535 (18)0.043 (2)0.0398 (16)0.0064 (15)0.0076 (15)0.0089 (14)
C20.072 (2)0.050 (2)0.061 (2)0.0174 (18)0.0059 (18)0.0107 (17)
C30.069 (2)0.075 (3)0.061 (2)0.029 (2)0.003 (2)0.017 (2)
C40.060 (2)0.084 (3)0.0520 (19)0.009 (2)0.0059 (17)0.0091 (19)
C50.0578 (19)0.059 (2)0.0454 (17)0.0040 (17)0.0034 (17)0.0039 (15)
C60.0450 (16)0.0448 (19)0.0374 (15)0.0061 (14)0.0018 (14)0.0068 (13)
C70.0527 (16)0.0345 (17)0.0384 (14)0.0010 (15)0.0025 (15)0.0016 (12)
C80.0486 (16)0.0277 (14)0.0377 (14)0.0025 (13)0.0030 (12)0.0013 (12)
C90.0505 (18)0.0335 (17)0.0389 (15)0.0007 (14)0.0030 (14)0.0012 (13)
C100.0486 (18)0.045 (2)0.0565 (18)0.0043 (15)0.0084 (15)0.0005 (15)
C110.0558 (18)0.0400 (18)0.0464 (16)0.0045 (15)0.0210 (17)0.0030 (13)
C120.057 (2)0.056 (2)0.062 (2)0.0039 (17)0.0090 (19)0.0002 (18)
C130.077 (3)0.091 (4)0.066 (2)0.027 (3)0.014 (2)0.003 (2)
C140.114 (4)0.078 (4)0.080 (3)0.032 (3)0.031 (3)0.018 (3)
C150.130 (4)0.038 (2)0.090 (3)0.007 (3)0.042 (3)0.005 (2)
C160.082 (2)0.050 (2)0.071 (2)0.011 (2)0.024 (2)0.0060 (18)
C170.094 (3)0.0308 (17)0.063 (2)0.0028 (17)0.007 (2)0.0060 (15)
Geometric parameters (Å, º) top
S1—O31.437 (2)C5—C61.402 (4)
S1—O41.427 (2)C6—C71.457 (4)
S1—N11.650 (2)C7—C81.374 (4)
S1—C81.736 (3)C8—C91.479 (4)
O1—H10.95 (4)C10—H10A0.9700
O1—C71.331 (3)C10—H10B0.9700
O2—C91.263 (3)C10—C111.511 (4)
N1—C11.404 (4)C11—C121.387 (5)
N1—C171.474 (4)C11—C161.377 (4)
N2—H20.88 (3)C12—H120.9300
N2—C91.325 (3)C12—C131.388 (5)
N2—C101.454 (4)C13—H130.9300
C1—C21.397 (4)C13—C141.351 (6)
C1—C61.407 (4)C14—H140.9300
C2—H2A0.9300C14—C151.369 (6)
C2—C31.373 (5)C15—H150.9300
C3—H30.9300C15—C161.416 (6)
C3—C41.385 (5)C16—H160.9300
C4—H40.9300C17—H17A0.9600
C4—C51.380 (4)C17—H17B0.9600
C5—H50.9300C17—H17C0.9600
O3—S1—N1107.55 (14)C7—C8—C9120.3 (3)
O3—S1—C8110.87 (13)C9—C8—S1121.3 (2)
O4—S1—O3116.43 (13)O2—C9—N2120.4 (3)
O4—S1—N1110.57 (13)O2—C9—C8117.9 (3)
O4—S1—C8109.38 (13)N2—C9—C8121.7 (3)
N1—S1—C8100.90 (13)N2—C10—H10A108.8
C7—O1—H1102 (2)N2—C10—H10B108.8
C1—N1—S1119.2 (2)N2—C10—C11113.7 (3)
C1—N1—C17121.3 (3)H10A—C10—H10B107.7
C17—N1—S1117.7 (2)C11—C10—H10A108.8
C9—N2—H2116 (2)C11—C10—H10B108.8
C9—N2—C10120.8 (3)C12—C11—C10121.4 (3)
C10—N2—H2123 (2)C16—C11—C10120.5 (3)
N1—C1—C6120.0 (3)C16—C11—C12118.1 (3)
C2—C1—N1121.2 (3)C11—C12—H12119.3
C2—C1—C6118.8 (3)C11—C12—C13121.4 (4)
C1—C2—H2A119.7C13—C12—H12119.3
C3—C2—C1120.7 (4)C12—C13—H13120.0
C3—C2—H2A119.7C14—C13—C12119.9 (4)
C2—C3—H3119.4C14—C13—H13120.0
C2—C3—C4121.1 (3)C13—C14—H14119.6
C4—C3—H3119.4C13—C14—C15120.7 (4)
C3—C4—H4120.5C15—C14—H14119.6
C5—C4—C3119.1 (3)C14—C15—H15120.2
C5—C4—H4120.5C14—C15—C16119.5 (4)
C4—C5—H5119.5C16—C15—H15120.2
C4—C5—C6121.0 (3)C11—C16—C15120.3 (4)
C6—C5—H5119.5C11—C16—H16119.9
C1—C6—C7120.6 (3)C15—C16—H16119.9
C5—C6—C1119.3 (3)N1—C17—H17A109.5
C5—C6—C7120.0 (3)N1—C17—H17B109.5
O1—C7—C6115.4 (3)N1—C17—H17C109.5
O1—C7—C8121.2 (3)H17A—C17—H17B109.5
C8—C7—C6123.4 (3)H17A—C17—H17C109.5
C7—C8—S1117.8 (2)H17B—C17—H17C109.5
S1—N1—C1—C2151.6 (2)C2—C3—C4—C53.1 (5)
S1—N1—C1—C632.0 (4)C3—C4—C5—C61.6 (5)
S1—C8—C9—O2170.6 (2)C4—C5—C6—C11.2 (4)
S1—C8—C9—N27.9 (4)C4—C5—C6—C7174.8 (3)
O1—C7—C8—S1172.4 (2)C5—C6—C7—O111.9 (4)
O1—C7—C8—C90.8 (4)C5—C6—C7—C8169.8 (3)
O3—S1—N1—C1163.6 (2)C6—C1—C2—C31.2 (5)
O3—S1—N1—C1731.4 (3)C6—C7—C8—S19.4 (4)
O3—S1—C8—C7149.4 (2)C6—C7—C8—C9179.0 (3)
O3—S1—C8—C939.1 (3)C7—C8—C9—O20.7 (4)
O4—S1—N1—C168.3 (2)C7—C8—C9—N2179.2 (3)
O4—S1—N1—C1796.7 (3)C8—S1—N1—C147.4 (2)
O4—S1—C8—C780.9 (2)C8—S1—N1—C17147.6 (2)
O4—S1—C8—C990.6 (2)C9—N2—C10—C1167.5 (4)
N1—S1—C8—C735.7 (3)C10—N2—C9—O24.4 (4)
N1—S1—C8—C9152.8 (2)C10—N2—C9—C8174.0 (3)
N1—C1—C2—C3177.6 (3)C10—C11—C12—C13177.4 (3)
N1—C1—C6—C5179.1 (3)C10—C11—C16—C15176.7 (3)
N1—C1—C6—C73.1 (4)C11—C12—C13—C140.6 (5)
N2—C10—C11—C1231.2 (4)C12—C11—C16—C151.3 (5)
N2—C10—C11—C16151.0 (3)C12—C13—C14—C151.0 (6)
C1—C2—C3—C41.7 (5)C13—C14—C15—C160.3 (6)
C1—C6—C7—O1164.0 (3)C14—C15—C16—C110.9 (6)
C1—C6—C7—C814.3 (4)C16—C11—C12—C130.5 (5)
C2—C1—C6—C52.5 (4)C17—N1—C1—C212.9 (4)
C2—C1—C6—C7173.4 (3)C17—N1—C1—C6163.6 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O30.88 (3)2.15 (3)2.883 (3)140 (3)
O1—H1···O20.961.55 (4)2.463 (3)158 (4)
C17—H17a···O2i0.962.453.324 (4)152
C17—H17c···C12ii0.962.863.614 (5)136
C17—H17c···C13ii0.962.753.679 (5)164
Symmetry codes: (i) x+1, y1/2, z+1/2; (ii) x1/2, y+3/2, z.
(II) N-Benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide top
Crystal data top
C17H16N2O4SDx = 1.453 Mg m3
Mr = 344.39Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121Cell parameters from 2803 reflections
a = 5.4469 (3) Åθ = 3.4–28.2°
b = 15.8455 (10) ŵ = 0.23 mm1
c = 18.2412 (9) ÅT = 293 K
V = 1574.38 (15) Å3Stick, colourless
Z = 40.2 × 0.02 × 0.02 mm
F(000) = 720.8596
Data collection top
Agilent Xcalibur Sapphire3
diffractometer
2777 independent reflections
Radiation source: Enhance (Mo) X-ray Source2296 reflections with I 2u(I)
Graphite monochromatorRint = 0.068
Detector resolution: 16.1827 pixels mm-1θmax = 25.0°, θmin = 3.4°
ω scansh = 67
Absorption correction: multi-scan
(CrysAlis RED; Agilent, 2012)
k = 2322
Tmin = 0.775, Tmax = 1.000l = 2725
16325 measured reflections
Refinement top
Refinement on F225 constraints
Least-squares matrix: fullH 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 = 0.84Δρmax = 0.20 e Å3
2777 reflectionsΔρmin = 0.21 e Å3
225 parametersAbsolute structure: Flack x determined using 839 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
0 restraintsAbsolute structure parameter: 0.16 (9)
Crystal data top
C17H16N2O4SV = 1574.38 (15) Å3
Mr = 344.39Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 5.4469 (3) ŵ = 0.23 mm1
b = 15.8455 (10) ÅT = 293 K
c = 18.2412 (9) Å0.2 × 0.02 × 0.02 mm
Data collection top
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 = 1.000Rint = 0.068
16325 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.040H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.124Δρmax = 0.20 e Å3
S = 0.84Δρmin = 0.21 e Å3
2777 reflectionsAbsolute structure: Flack x determined using 839 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
225 parametersAbsolute structure parameter: 0.16 (9)
0 restraints
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.69864 (14)0.79616 (4)0.37664 (4)0.0416 (2)
O10.8053 (5)0.61912 (14)0.23171 (13)0.0597 (6)
H10.683 (7)0.592 (3)0.257 (2)0.092 (15)*
O20.4734 (4)0.57292 (14)0.31270 (12)0.0550 (6)
O30.8868 (4)0.78152 (15)0.42918 (12)0.0537 (6)
O40.4709 (4)0.82769 (14)0.40441 (14)0.0575 (6)
N10.7926 (5)0.86279 (15)0.31387 (15)0.0495 (6)
N20.3199 (5)0.65392 (17)0.40157 (14)0.0476 (6)
H20.326 (6)0.704 (2)0.4243 (19)0.054 (9)*
C10.9743 (6)0.8371 (2)0.26440 (17)0.0466 (8)
C21.1358 (7)0.8951 (2)0.2331 (2)0.0624 (10)
H2a1.1265 (7)0.9517 (2)0.2462 (2)0.0748 (12)*
C31.3080 (7)0.8692 (3)0.1833 (2)0.0677 (10)
H31.4117 (7)0.9090 (3)0.1622 (2)0.0812 (12)*
C41.3316 (7)0.7859 (3)0.1636 (2)0.0676 (11)
H41.4533 (7)0.7692 (3)0.1310 (2)0.0811 (13)*
C51.1718 (7)0.7275 (2)0.19318 (17)0.0573 (9)
H51.1846 (7)0.6711 (2)0.17971 (17)0.0688 (11)*
C60.9913 (6)0.7522 (2)0.24306 (17)0.0442 (7)
C70.8119 (6)0.69118 (18)0.26832 (16)0.0434 (7)
C80.6530 (5)0.70668 (19)0.32516 (15)0.0402 (7)
C90.4747 (6)0.64221 (19)0.34671 (16)0.0417 (7)
C100.1612 (6)0.5863 (2)0.42677 (19)0.0518 (8)
H10a0.0438 (6)0.6092 (2)0.46145 (19)0.0621 (10)*
H10b0.0697 (6)0.5644 (2)0.38530 (19)0.0621 (10)*
C110.2976 (6)0.51444 (19)0.46283 (17)0.0482 (7)
C120.5141 (7)0.5282 (2)0.5008 (2)0.0587 (9)
H120.5805 (7)0.5822 (2)0.5029 (2)0.0705 (11)*
C130.6323 (9)0.4623 (3)0.5356 (2)0.0819 (14)
H130.7783 (9)0.4724 (3)0.5606 (2)0.0983 (16)*
C140.5392 (11)0.3841 (4)0.5340 (3)0.0900 (15)
H140.6198 (11)0.3406 (4)0.5583 (3)0.1080 (18)*
C150.3267 (12)0.3678 (3)0.4968 (3)0.0900 (15)
H150.2635 (12)0.3133 (3)0.4956 (3)0.1080 (18)*
C160.2029 (9)0.4338 (2)0.4602 (2)0.0678 (10)
H160.0589 (9)0.4230 (2)0.4344 (2)0.0813 (12)*
C170.7284 (8)0.9518 (2)0.3220 (2)0.0646 (11)
H17a0.571 (3)0.9565 (2)0.3451 (14)0.0969 (16)*
H17b0.850 (3)0.9794 (4)0.3517 (13)0.0969 (16)*
H17c0.723 (5)0.9780 (5)0.2745 (2)0.0969 (16)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0541 (4)0.0299 (4)0.0407 (4)0.0002 (3)0.0005 (4)0.0021 (3)
O10.0801 (16)0.0392 (13)0.0598 (14)0.0082 (13)0.0200 (14)0.0139 (10)
O20.0749 (15)0.0385 (13)0.0517 (13)0.0132 (11)0.0090 (12)0.0101 (10)
O30.0719 (14)0.0486 (15)0.0407 (11)0.0024 (11)0.0109 (10)0.0016 (10)
O40.0620 (13)0.0425 (14)0.0679 (15)0.0054 (11)0.0087 (13)0.0111 (11)
N10.0670 (16)0.0280 (13)0.0535 (14)0.0032 (13)0.0010 (15)0.0027 (11)
N20.0575 (15)0.0322 (15)0.0532 (15)0.0034 (13)0.0098 (14)0.0032 (11)
C10.0541 (18)0.0446 (19)0.0413 (16)0.0048 (15)0.0054 (15)0.0085 (14)
C20.078 (2)0.050 (2)0.059 (2)0.0199 (18)0.0064 (19)0.0110 (17)
C30.071 (2)0.075 (3)0.057 (2)0.025 (2)0.005 (2)0.0142 (19)
C40.060 (2)0.092 (3)0.051 (2)0.014 (2)0.0073 (17)0.008 (2)
C50.063 (2)0.065 (2)0.0437 (17)0.0002 (17)0.0054 (18)0.0027 (15)
C60.0510 (17)0.0405 (18)0.0412 (15)0.0049 (14)0.0041 (14)0.0063 (14)
C70.0542 (16)0.0364 (16)0.0394 (15)0.0017 (15)0.0009 (15)0.0002 (12)
C80.0521 (17)0.0324 (15)0.0362 (14)0.0009 (13)0.0009 (13)0.0002 (12)
C90.0537 (18)0.0300 (16)0.0414 (15)0.0004 (13)0.0012 (15)0.0014 (13)
C100.0502 (18)0.050 (2)0.0547 (18)0.0044 (15)0.0065 (15)0.0000 (15)
C110.0580 (18)0.0385 (17)0.0482 (17)0.0009 (15)0.0190 (17)0.0038 (13)
C120.060 (2)0.054 (2)0.063 (2)0.0032 (17)0.0113 (19)0.0036 (18)
C130.082 (3)0.093 (4)0.071 (3)0.027 (3)0.013 (2)0.003 (3)
C140.113 (4)0.075 (4)0.083 (3)0.029 (3)0.023 (3)0.010 (3)
C150.140 (4)0.038 (2)0.092 (3)0.008 (3)0.050 (3)0.003 (2)
C160.080 (2)0.050 (2)0.073 (2)0.0096 (19)0.022 (2)0.0078 (18)
C170.096 (3)0.0346 (17)0.063 (2)0.0026 (18)0.010 (2)0.0065 (15)
Geometric parameters (Å, º) top
S1—O31.422 (2)C5—C61.396 (5)
S1—O41.430 (2)C6—C71.450 (4)
S1—N11.639 (3)C7—C81.373 (4)
S1—C81.719 (3)C8—C91.463 (4)
O1—H10.92 (4)C10—H10a0.9700
O1—C71.323 (4)C10—H10b0.9700
O2—C91.261 (4)C10—C111.510 (5)
N1—C11.400 (4)C11—C121.385 (5)
N1—C171.461 (4)C11—C161.378 (5)
N2—H20.90 (4)C12—H120.9300
N2—C91.322 (4)C12—C131.381 (6)
N2—C101.451 (4)C13—H130.9300
C1—C21.395 (5)C13—C141.340 (7)
C1—C61.403 (5)C14—H140.9300
C2—H2a0.9300C14—C151.366 (7)
C2—C31.369 (6)C15—H150.9300
C3—H30.9300C15—C161.412 (7)
C3—C41.373 (6)C16—H160.9300
C4—H40.9300C17—H17a0.9600
C4—C51.380 (5)C17—H17b0.9600
C5—H50.9300C17—H17c0.9600
O4—S1—O3116.33 (14)C9—C8—S1121.7 (2)
N1—S1—O3110.54 (15)C9—C8—C7119.8 (3)
N1—S1—O4107.04 (15)N2—C9—O2119.4 (3)
C8—S1—O3109.74 (14)C8—C9—O2118.6 (3)
C8—S1—O4110.88 (14)C8—C9—N2121.9 (3)
C8—S1—N1101.23 (13)H10a—C10—N2108.82 (17)
C7—O1—H199 (3)H10b—C10—N2108.82 (18)
C1—N1—S1118.9 (2)H10b—C10—H10a107.7
C17—N1—S1118.5 (2)C11—C10—N2113.7 (3)
C17—N1—C1121.0 (3)C11—C10—H10a108.82 (17)
C9—N2—H2117 (2)C11—C10—H10b108.82 (18)
C10—N2—H2122 (2)C12—C11—C10121.2 (3)
C10—N2—C9121.1 (3)C16—C11—C10120.0 (3)
C2—C1—N1121.2 (3)C16—C11—C12118.8 (3)
C6—C1—N1120.3 (3)H12—C12—C11119.7 (2)
C6—C1—C2118.5 (3)C13—C12—C11120.5 (4)
H2a—C2—C1119.8 (2)C13—C12—H12119.7 (3)
C3—C2—C1120.4 (4)H13—C13—C12119.6 (3)
C3—C2—H2a119.8 (2)C14—C13—C12120.8 (5)
H3—C3—C2119.1 (2)C14—C13—H13119.6 (3)
C4—C3—C2121.7 (3)H14—C14—C13119.8 (3)
C4—C3—H3119.1 (2)C15—C14—C13120.5 (5)
H4—C4—C3120.6 (2)C15—C14—H14119.8 (3)
C5—C4—C3118.9 (4)H15—C15—C14120.0 (3)
C5—C4—H4120.6 (2)C16—C15—C14120.0 (4)
H5—C5—C4119.6 (2)C16—C15—H15120.0 (3)
C6—C5—C4120.7 (4)C15—C16—C11119.4 (4)
C6—C5—H5119.6 (2)H16—C16—C11120.3 (2)
C5—C6—C1119.7 (3)H16—C16—C15120.3 (3)
C7—C6—C1120.4 (3)H17a—C17—N1109.5
C7—C6—C5119.7 (3)H17b—C17—N1109.5
C6—C7—O1115.7 (3)H17b—C17—H17a109.5
C8—C7—O1121.2 (3)H17c—C17—N1109.5
C8—C7—C6123.1 (3)H17c—C17—H17a109.5
C7—C8—S1118.0 (2)H17c—C17—H17b109.5
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O40.90 (3)2.14 (3)2.874 (3)138 (3)
O1—H1···O20.92 (4)1.56 (4)2.447 (3)162 (4)
C17—H17c···O2iiii0.962.443.306 (4)150
C17—H17b···C12ivii0.962.843.601 (5)137
C17—H17b···C13ivii0.962.733.666 (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 formulaC17H16N2O4SC17H16N2O4S
Mr344.39344.39
Crystal system, space groupOrthorhombic, P212121Orthorhombic, P212121
Temperature (K)293293
a, b, c (Å)5.4764 (3), 15.9117 (8), 18.3228 (10)5.4469 (3), 15.8455 (10), 18.2412 (9)
V3)1596.63 (15)1574.38 (15)
Z44
Radiation typeMo KαMo Kα
µ (mm1)0.230.23
Crystal size (mm)0.2 × 0.02 × 0.020.2 × 0.02 × 0.02
Data collection
DiffractometerXcalibur, Sapphire3Agilent Xcalibur Sapphire3
Absorption correctionMulti-scan
(CrysAlis RED; Agilent, 2012)
Multi-scan
(CrysAlis RED; Agilent, 2012)
Tmin, Tmax0.979, 1.0000.775, 1.000
No. of measured, independent and
observed reflections
16369, 4658, 3004 [I > 2σ(I)]16325, 2777, 2296 [I 2u(I)]
Rint0.0550.068
(sin θ/λ)max1)0.7030.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.051, 0.094, 0.99 0.040, 0.124, 0.84
No. of reflections46582777
No. of parameters226225
H-atom treatmentH atoms treated by a mixture of independent and constrained refinementH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.22, 0.280.20, 0.21
Absolute structureFlack 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 parameter0.09 (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).

The antinociception activity of benzylamides (1a)–(1e) and Pyroxicam top
CompoundThe 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
Pyroxicam9.45±0.74+ 25.3
Control7.54±0.82
Selected geometric parameters (Å, °) for molecules (1a) and (1b) top
ParameterForm AForm B
Ring-puckering parameters (Zefirov et al., 1990)
S0.590.59
Θ50.550.9
Ψ20.620.2
Bond lengths
C9—O21.263 (4)1.261 (4)
O1—C71.331 (4)1.323 (4)
C7—C81.374 (4)1.373 (4)
N1—C11.404 (4)1.400 (4)
Torsion angles
C1—N1—S1—C847.4 (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—C8174.0 (3)-173.9 (3)
Geometric characteristics (Å, °) of the intra- and intermolecular hydrogen bonds for (1a) and (1b) top
InteractionSymmetry codeH···AD—H···A
Molecule A
O1—H···O21.55 (4)158 (4)
C17—H17c···O2-x+1, y-1/2, -z+1/22.43152
C17—H17a···C12' (π)x-1/2, -y+1/2, -z2.86135
C17—H17a···C13' (π)x-1/2, -y+1/2,- z2.74163
Molecule B
O1—H···O21.56 (4)162 (4)
C17—H17c···O2'-x, y+1/2, -z+3/22.44150
C17—H17a···C12' (π)x+1/2, -y+1/2, -z+22.83138
C17—H17a···C13' (π)x+1/2, -y+1/2, -z+22.73166
Hydrogen-bond geometry (Å, º) for (I) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O30.88 (3)2.15 (3)2.883 (3)140 (3)
O1—H1···O20.961.55 (4)2.463 (3)158 (4)
C17—H17a···O2i0.962.453.324 (4)152
C17—H17c···C12ii0.962.863.614 (5)136
C17—H17c···C13ii0.962.753.679 (5)164
Symmetry codes: (i) x+1, y1/2, z+1/2; (ii) x1/2, y+3/2, z.
Hydrogen-bond geometry (Å, º) for (II) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O40.90 (3)2.14 (3)2.874 (3)138 (3)
O1—H1···O20.92 (4)1.56 (4)2.447 (3)162 (4)
C17—H17c···O2iiii0.962.443.306 (4)150
C17—H17b···C12ivii0.962.843.601 (5)137
C17—H17b···C13ivii0.962.733.666 (6)165
Symmetry codes: (i) x+1, y+1/2, z+1/2; (ii) x+1/2, y+1, z+3/2.
 

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