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The crystal structure of the title compound, C11H16N4O2S·H2O, a pancreatic B-cell selective KATP channel opener, reveals that that the N-alkyl­sulfonyl­guanidine moiety of the drug containing the two guanidine NH groups in the same spatial orientation (in parallel) is closely related to the N-alkyl­cyano­guanidine moiety of pinacidil in the solid state. The results confirm that the title drug may be considered as a hybrid compound between pinacidil and diazo­xide. The crystal packing involves four hydrogen bonds which link the drug and water mol­ecules.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536801016622/ob6078sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S1600536801016622/ob6078Isup2.hkl
Contains datablock I

CCDC reference: 176014

Key indicators

  • Single-crystal X-ray study
  • T = 293 K
  • Mean [sigma](C-C) = 0.011 Å
  • R factor = 0.077
  • wR factor = 0.251
  • Data-to-parameter ratio = 11.7

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


Amber Alert Alert Level B:
THETM_01 Alert B The value of sine(theta_max)/wavelength is less than 0.575 Calculated sin(theta_max)/wavelength = 0.5619
Author response: we couldn't obtain samples of better quality (without disorder). Several set of measurements were undertaken (cf '_publ_section_exptl_refinement'). We have selected the set which gives the best results. We think it is important to publish them because the compound is the best representative of its class in relation with its biological activity and therapeutic potentiality.
PLAT_030  Alert B Refined Extinction parameter within range ....       2.36 Sigma
Author response: see above

Yellow Alert Alert Level C:
RFACR_01 Alert C The value of the weighted R factor is > 0.25 Weighted R factor given 0.251 PLAT_352 Alert C Short N-H Bond (0.87A) N(4) - H(4) = 0.71 Ang. PLAT_353 Alert C Long N-H Bond (0.87A) N(11) - H(11) = 1.01 Ang. PLAT_354 Alert C Short O-H Bond (0.82A) O(3) - H(32) = 0.68 Ang. PLAT_360 Alert C Short C(sp3)-C(sp3) Bond C(12) - C(13) = 1.41 Ang. PLAT_601 Alert C Structure Contains Solvent Accessible VOIDS of 31.00 A   3
0 Alert Level A = Potentially serious problem
2 Alert Level B = Potential problem
6 Alert Level C = Please check

Comment top

The crystal structure of the title compound, (I), was determined in order to confirm that the best representative of pancreatic B-cell selective KATP channel openers belonging to the class of pyridothiadiazine dioxides was structurally related to both diazoxide (a benzothiadiazine dioxide KATP channel opener; Bandoli & Nicolini, 1977) and pinacidil (a pyridylalkylcyanoguanidine KATP channel opener; Pirotte, Dupont et al., 1993).

The crystal packing of (I) is dominated by four hydrogen bonds (Table 2). The water molecule is an acceptor in two N—H···O bonds and a donor in O—H···N(pyridinic) and OH···O(sulfoxide) bonds. This scheme confirms the 4H-tautomeric form as N4 is engaged in an hydrogen bond, whereas N2 is not included in any close intermolecular contact. The same orientation of N4—H and N11—H is similar to that of the two guanidic NH groups observed in pinacidil.

Experimental top

The synthesis of the title compound, (I), has been described by Pirotte, de Tullio et al. (1993). Crystals of (I) were obtained by slow evaporation of a methanol solution.

Refinement top

All H atoms (with the exception of the nitrogen-bound atoms H4 and H11, and the water H atoms H31 and H32) were included in the refinement as riding, with isotropic displacement parameters fixed at 1.2Ueq of the parent atom (1.5Ueq for methyl H atoms). Atoms H4, H11, H31 and H32 were refined isotropically, their displacement parameters being fixed at 1.2Ueq of the N– or O-bound atom. H32 was nevertheless kept fixed in the last cycles of least-squares refinement. The large value (1/4) of wR2 at the end of the refinement could be related with a slight disorder of the N-alkylsulfonylguanidine moiety. Some of its atoms exhibit indeed rather large values of anisotropic displacement parameters. Various data collections undertaken with Mo Kα radiation on different samples mounted on the Stoe four-circle diffractometer and also on a MAR345 image-plate diffractometer yielded similar results.

Computing details top

Data collection: DIF4 (Stoe & Cie, 1987); cell refinement: DIF4; data reduction: REDU4 (Stoe & Cie, 1987); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-III (Burnett & Johnson, 1996); software used to prepare material for publication: SHELXL97.

Figures top
[Figure 1] Fig. 1. The molecular structure of (I) with the atom-labelling scheme. Displacement ellipsoids are shown at the 50% probability level.
(R/S)-3-(3-Methyl-2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide hydrate top
Crystal data top
C11H16N4O2S·H2ODx = 1.306 Mg m3
Mr = 286.35Cu Kα radiation, λ = 1.54180 Å
Trigonal, R3Cell parameters from 30 reflections
a = 26.198 (5) Åθ = 20.7–40.7°
c = 11.024 (7) ŵ = 2.08 mm1
V = 6552 (4) Å3T = 293 K
Z = 18Prism, colourless
F(000) = 27360.57 × 0.38 × 0.34 mm
Data collection top
Stoe-Siemens AED four-circle
diffractometer
1429 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.049
Graphite monochromatorθmax = 60.0°, θmin = 3.4°
ω scansh = 2925
Absorption correction: ψ scan
(EMPIR; Stoe & Cie, 1987)
k = 029
Tmin = 0.351, Tmax = 0.493l = 1212
6653 measured reflections2 standard reflections every 60 min
2166 independent reflections intensity decay: 5%
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: H atoms were placed at standard calculated positions, except atoms H(N4), H(N11) and H(water), which were obtained from difference map.
R[F2 > 2σ(F2)] = 0.077H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.251 w = 1/[σ2(Fo2) + (0.1779P)2 + 0.4536P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max < 0.001
2166 reflectionsΔρmax = 0.44 e Å3
185 parametersΔρmin = 0.27 e Å3
0 restraintsExtinction correction: SHELXL97, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.00026 (11)
Crystal data top
C11H16N4O2S·H2OZ = 18
Mr = 286.35Cu Kα radiation
Trigonal, R3µ = 2.08 mm1
a = 26.198 (5) ÅT = 293 K
c = 11.024 (7) Å0.57 × 0.38 × 0.34 mm
V = 6552 (4) Å3
Data collection top
Stoe-Siemens AED four-circle
diffractometer
1429 reflections with I > 2σ(I)
Absorption correction: ψ scan
(EMPIR; Stoe & Cie, 1987)
Rint = 0.049
Tmin = 0.351, Tmax = 0.493θmax = 60.0°
6653 measured reflections2 standard reflections every 60 min
2166 independent reflections intensity decay: 5%
Refinement top
R[F2 > 2σ(F2)] = 0.0770 restraints
wR(F2) = 0.251H atoms treated by a mixture of independent and constrained refinement
S = 1.05Δρmax = 0.44 e Å3
2166 reflectionsΔρmin = 0.27 e Å3
185 parameters
Special details top

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

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

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.54453 (5)0.03102 (6)0.24676 (11)0.0792 (6)
O10.5508 (2)0.0180 (2)0.2836 (6)0.164 (3)
O20.5676 (2)0.0532 (3)0.1332 (4)0.171 (3)
N20.57457 (19)0.0802 (2)0.3424 (4)0.0950 (14)
C30.5445 (2)0.0903 (2)0.4269 (4)0.0764 (13)
N40.4854 (2)0.0640 (2)0.4300 (4)0.0856 (14)
H40.474 (3)0.079 (3)0.465 (6)0.103*
C50.4484 (2)0.0277 (2)0.3420 (4)0.0717 (12)
C60.3878 (2)0.0073 (2)0.3426 (5)0.0813 (14)
H60.37110.01830.40440.098*
C70.3543 (2)0.0281 (3)0.2535 (5)0.0876 (15)
H70.31410.04140.25710.105*
N80.37385 (19)0.0461 (2)0.1584 (4)0.0907 (13)
C90.4319 (2)0.0264 (2)0.1572 (5)0.0832 (14)
H90.44740.03700.09240.100*
C100.47038 (19)0.0090 (2)0.2478 (4)0.0655 (12)
N110.5734 (2)0.1293 (2)0.5140 (4)0.0945 (14)
H110.543 (3)0.130 (3)0.569 (6)0.113*
C120.6380 (2)0.1602 (3)0.5307 (6)0.109 (2)
H120.65050.13190.50900.131*
C130.6664 (5)0.2076 (6)0.4488 (10)0.219 (6)
H13A0.65570.19330.36730.329*
H13B0.70830.22560.45830.329*
H13C0.65450.23620.46500.329*
C140.6517 (3)0.1736 (4)0.6632 (7)0.137 (3)
H140.62670.13810.71080.164*
C150.7165 (4)0.1937 (6)0.6889 (8)0.192 (5)
H15A0.72580.16520.65740.288*
H15B0.72330.19750.77490.288*
H15C0.74110.23110.65070.288*
C160.6377 (4)0.2237 (5)0.6992 (9)0.188 (5)
H16A0.66150.24520.76750.283*
H16B0.59680.20620.72010.283*
H16C0.64640.25000.63180.283*
O30.5306 (2)0.1266 (2)0.3735 (4)0.1110 (15)
H310.553 (3)0.101 (3)0.320 (7)0.133*
H320.54600.13600.40750.133*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0728 (9)0.0991 (10)0.0752 (9)0.0500 (7)0.0040 (6)0.0165 (6)
O10.129 (4)0.119 (3)0.288 (8)0.096 (3)0.040 (4)0.045 (4)
O20.085 (3)0.273 (7)0.073 (3)0.029 (4)0.006 (2)0.011 (3)
N20.070 (3)0.123 (4)0.092 (3)0.049 (3)0.000 (2)0.031 (3)
C30.077 (3)0.090 (3)0.073 (3)0.050 (3)0.003 (2)0.012 (3)
N40.071 (3)0.104 (3)0.084 (3)0.045 (2)0.010 (2)0.023 (2)
C50.067 (3)0.084 (3)0.069 (3)0.041 (2)0.003 (2)0.003 (2)
C60.068 (3)0.095 (3)0.083 (3)0.043 (3)0.010 (3)0.000 (3)
C70.064 (3)0.101 (4)0.095 (4)0.039 (3)0.002 (3)0.010 (3)
N80.071 (3)0.111 (3)0.083 (3)0.040 (3)0.010 (2)0.000 (2)
C90.083 (3)0.096 (4)0.069 (3)0.044 (3)0.002 (3)0.006 (3)
C100.066 (3)0.073 (3)0.061 (3)0.038 (2)0.002 (2)0.000 (2)
N110.078 (3)0.116 (4)0.090 (3)0.050 (3)0.007 (2)0.035 (3)
C120.077 (4)0.125 (5)0.102 (4)0.033 (4)0.002 (3)0.039 (4)
C130.138 (8)0.239 (13)0.195 (11)0.030 (8)0.020 (8)0.061 (10)
C140.093 (5)0.164 (7)0.119 (6)0.039 (5)0.019 (4)0.008 (5)
C150.127 (7)0.266 (14)0.160 (9)0.082 (8)0.032 (6)0.019 (8)
C160.138 (7)0.238 (12)0.181 (9)0.088 (8)0.015 (6)0.115 (9)
O30.126 (4)0.159 (4)0.093 (3)0.105 (3)0.021 (2)0.008 (3)
Geometric parameters (Å, º) top
S1—O21.386 (5)N11—H111.00 (6)
S1—O11.433 (5)C12—C131.410 (12)
S1—N21.542 (4)C12—C141.504 (10)
S1—C101.728 (4)C12—H120.9800
N2—C31.330 (6)C13—H13A0.9600
C3—N111.329 (6)C13—H13B0.9600
C3—N41.343 (6)C13—H13C0.9600
N4—C51.365 (6)C14—C151.531 (11)
N4—H40.72 (6)C14—C161.579 (12)
C5—C101.388 (6)C14—H140.9800
C5—C61.399 (7)C15—H15A0.9600
C6—C71.335 (7)C15—H15B0.9600
C6—H60.9300C15—H15C0.9600
C7—N81.351 (7)C16—H16A0.9600
C7—H70.9300C16—H16B0.9600
N8—C91.340 (7)C16—H16C0.9600
C9—C101.392 (6)O3—H310.86 (7)
C9—H90.9300O3—H320.68
N11—C121.476 (7)
O2—S1—O1114.3 (4)C13—C12—N11111.0 (7)
O2—S1—N2109.5 (3)C13—C12—C14117.2 (8)
O1—S1—N2108.4 (3)N11—C12—C14108.9 (5)
O2—S1—C10109.1 (3)C13—C12—H12106.4
O1—S1—C10108.2 (3)N11—C12—H12106.4
N2—S1—C10107.0 (2)C14—C12—H12106.4
C3—N2—S1122.7 (4)C12—C13—H13A109.5
N11—C3—N2119.5 (5)C12—C13—H13B109.5
N11—C3—N4116.4 (4)H13A—C13—H13B109.5
N2—C3—N4124.1 (5)C12—C13—H13C109.5
C3—N4—C5125.1 (4)H13A—C13—H13C109.5
C3—N4—H4115 (5)H13B—C13—H13C109.5
C5—N4—H4115 (5)C12—C14—C15110.8 (7)
N4—C5—C10120.1 (4)C12—C14—C16108.0 (7)
N4—C5—C6122.5 (4)C15—C14—C16110.2 (8)
C10—C5—C6117.4 (5)C12—C14—H14109.3
C7—C6—C5119.3 (5)C15—C14—H14109.3
C7—C6—H6120.4C16—C14—H14109.3
C5—C6—H6120.4C14—C15—H15A109.5
C6—C7—N8125.5 (5)C14—C15—H15B109.5
C6—C7—H7117.3H15A—C15—H15B109.5
N8—C7—H7117.3C14—C15—H15C109.5
C9—N8—C7115.4 (5)H15A—C15—H15C109.5
N8—C9—C10123.6 (5)H15B—C15—H15C109.5
N8—C9—H9118.2C14—C16—H16A109.5
C10—C9—H9118.2C14—C16—H16B109.5
C5—C10—C9118.8 (4)H16A—C16—H16B109.5
C5—C10—S1118.8 (4)C14—C16—H16C109.5
C9—C10—S1122.3 (4)H16A—C16—H16C109.5
C3—N11—C12124.6 (5)H16B—C16—H16C109.5
C3—N11—H11108 (4)H31—O3—H32111
C12—N11—H11128 (4)
O2—S1—N2—C3133.6 (5)C6—C5—C10—S1177.7 (4)
O1—S1—N2—C3101.2 (5)N8—C9—C10—C53.3 (8)
C10—S1—N2—C315.4 (6)N8—C9—C10—S1177.1 (4)
S1—N2—C3—N11173.2 (5)O2—S1—C10—C5130.8 (5)
S1—N2—C3—N47.9 (8)O1—S1—C10—C5104.3 (5)
N11—C3—N4—C5172.6 (5)N2—S1—C10—C512.4 (5)
N2—C3—N4—C56.3 (9)O2—S1—C10—C948.8 (6)
C3—N4—C5—C108.8 (8)O1—S1—C10—C976.1 (5)
C3—N4—C5—C6171.9 (5)N2—S1—C10—C9167.3 (4)
N4—C5—C6—C7179.9 (5)N2—C3—N11—C124.9 (9)
C10—C5—C6—C70.7 (8)N4—C3—N11—C12176.1 (6)
C5—C6—C7—N81.1 (9)C3—N11—C12—C1379.4 (10)
C6—C7—N8—C90.7 (8)C3—N11—C12—C14150.1 (7)
C7—N8—C9—C101.6 (8)C13—C12—C14—C1564.8 (13)
N4—C5—C10—C9177.9 (5)N11—C12—C14—C15168.2 (8)
C6—C5—C10—C92.7 (7)C13—C12—C14—C1656.0 (11)
N4—C5—C10—S11.7 (7)N11—C12—C14—C1671.0 (8)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N4—H4···O3i0.72 (6)2.21 (6)2.872 (6)154 (6)
N11—H11···O3i1.00 (6)1.99 (6)2.961 (6)161 (5)
O3—H31···N8ii0.86 (7)2.27 (7)2.997 (6)141 (7)
O3—H31···O10.86 (7)2.24 (8)2.801 (7)122 (6)
O3—H32···O2iii0.682.122.771 (6)161
Symmetry codes: (i) x+1, y, z+1; (ii) y+2/3, x+y+1/3, z+1/3; (iii) y+2/3, xy2/3, z+1/3.

Experimental details

Crystal data
Chemical formulaC11H16N4O2S·H2O
Mr286.35
Crystal system, space groupTrigonal, R3
Temperature (K)293
a, c (Å)26.198 (5), 11.024 (7)
V3)6552 (4)
Z18
Radiation typeCu Kα
µ (mm1)2.08
Crystal size (mm)0.57 × 0.38 × 0.34
Data collection
DiffractometerStoe-Siemens AED four-circle
diffractometer
Absorption correctionψ scan
(EMPIR; Stoe & Cie, 1987)
Tmin, Tmax0.351, 0.493
No. of measured, independent and
observed [I > 2σ(I)] reflections
6653, 2166, 1429
Rint0.049
θmax (°)60.0
(sin θ/λ)max1)0.562
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.077, 0.251, 1.05
No. of reflections2166
No. of parameters185
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.44, 0.27

Computer programs: DIF4 (Stoe & Cie, 1987), DIF4, REDU4 (Stoe & Cie, 1987), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), ORTEP-III (Burnett & Johnson, 1996), SHELXL97.

Selected geometric parameters (Å, º) top
S1—O21.386 (5)C3—N111.329 (6)
S1—O11.433 (5)C3—N41.343 (6)
S1—N21.542 (4)N11—C121.476 (7)
N2—C31.330 (6)
N2—S1—C10107.0 (2)N2—C3—N4124.1 (5)
C3—N2—S1122.7 (4)C3—N4—C5125.1 (4)
N11—C3—N2119.5 (5)C3—N11—C12124.6 (5)
N11—C3—N4116.4 (4)
C10—S1—N2—C315.4 (6)N2—S1—C10—C512.4 (5)
S1—N2—C3—N11173.2 (5)N2—C3—N11—C124.9 (9)
S1—N2—C3—N47.9 (8)C3—N11—C12—C1379.4 (10)
N11—C3—N4—C5172.6 (5)C3—N11—C12—C14150.1 (7)
N2—C3—N4—C56.3 (9)N11—C12—C14—C15168.2 (8)
C3—N4—C5—C108.8 (8)N11—C12—C14—C1671.0 (8)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N4—H4···O3i0.72 (6)2.21 (6)2.872 (6)154 (6)
N11—H11···O3i1.00 (6)1.99 (6)2.961 (6)161 (5)
O3—H31···N8ii0.86 (7)2.27 (7)2.997 (6)141 (7)
O3—H31···O10.86 (7)2.24 (8)2.801 (7)122 (6)
O3—H32···O2iii0.682.122.771 (6)161
Symmetry codes: (i) x+1, y, z+1; (ii) y+2/3, x+y+1/3, z+1/3; (iii) y+2/3, xy2/3, z+1/3.
 

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