Dorzolamide hydrochloride [systematic name: (4S)-trans-4-ethylammonio-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide chloride], C10H17N2O4S2+·Cl-, belongs to a class of drugs called carbonic anhydrase inhibitors. The ethylammonio side chain is in an extended conformation and is protonated at the N atom, which is hydrogen bonded to the Cl- anion. The dihedral angle between the planes of the thiophene ring and the sulfonamide group is 80.7 (1)°. A comparison is made with the dorzolamide bound in human carbonic anhydrase in the solid state. Hydrogen bonding is mediated by Cl- anions, resulting in indirect connectivity between the molecules.
Supporting information
CCDC reference: 638325
To obtain crystals suitable for X-ray studies, dorzolamide hydrochloride
(Pharmacology Department, IICT, Hyderabad) was dissolved in a methanol–water
solution (80:20 v/v) and the solvents were allowed to evaporate
slowly.
The H atoms attached to N atoms were located in a difference density map and
refined isotropically. All other H atoms were positioned geometrically and
were treated as riding on their parent C atoms, with C—H distances of
0.93–0.98 Å, and with Uiso(H) values of 1.5Ueq(C) for
methyl atoms and 1.2Ueq(C) for the other H atoms. The absolute
configuration of the procured material was known in advance and was confirmed
by unambiguous refinement of the absolute structure parameter (Flack &
Bernardinelli, 2000).
Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC (Sheldrick, 1990), DIAMOND (Brandenburg & Putz, 2005)
and Mercury
(Macrae et al., 2006); software used to prepare material for publication: SHELXL97.
(4
S)-
trans-4-ethylammonio-5,6-dihydro-6-methyl-4
H-thieno[2,3-
b]thiopyran- 2-sulfonamide 7,7-dioxide chloride
top
Crystal data top
C10H17N2O4S3+·Cl− | F(000) = 752 |
Mr = 360.89 | Dx = 1.606 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 8788 reflections |
a = 8.1272 (6) Å | θ = 2.2–28.0° |
b = 10.0646 (8) Å | µ = 0.69 mm−1 |
c = 18.2504 (14) Å | T = 293 K |
V = 1492.8 (2) Å3 | Block, colorless |
Z = 4 | 0.19 × 0.14 × 0.11 mm |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 2586 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.025 |
Graphite monochromator | θmax = 25.0°, θmin = 2.2° |
ω scans | h = −9→9 |
10633 measured reflections | k = −11→11 |
2630 independent reflections | l = −21→21 |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.024 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.065 | w = 1/[σ2(Fo2) + (0.0416P)2 + 0.2442P] where P = (Fo2 + 2Fc2)/3 |
S = 1.06 | (Δ/σ)max = 0.001 |
2630 reflections | Δρmax = 0.28 e Å−3 |
199 parameters | Δρmin = −0.17 e Å−3 |
0 restraints | Absolute structure: Flack & Bernardinelli (2000), 1098 Friedel pairs? |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −0.01 (6) |
Crystal data top
C10H17N2O4S3+·Cl− | V = 1492.8 (2) Å3 |
Mr = 360.89 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 8.1272 (6) Å | µ = 0.69 mm−1 |
b = 10.0646 (8) Å | T = 293 K |
c = 18.2504 (14) Å | 0.19 × 0.14 × 0.11 mm |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 2586 reflections with I > 2σ(I) |
10633 measured reflections | Rint = 0.025 |
2630 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.024 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.065 | Δρmax = 0.28 e Å−3 |
S = 1.06 | Δρmin = −0.17 e Å−3 |
2630 reflections | Absolute structure: Flack & Bernardinelli (2000), 1098 Friedel pairs? |
199 parameters | Absolute structure parameter: −0.01 (6) |
0 restraints | |
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. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
Cl1 | 0.49736 (7) | 0.80253 (5) | 0.55773 (3) | 0.04711 (16) | |
S1 | −0.02864 (6) | 0.33887 (5) | 0.71283 (3) | 0.03103 (13) | |
S2 | 0.23296 (6) | 0.44375 (5) | 0.81026 (2) | 0.03023 (13) | |
S3 | 0.49183 (6) | 0.64654 (5) | 0.84373 (3) | 0.03204 (13) | |
O1 | 0.0230 (2) | 0.20851 (14) | 0.69111 (9) | 0.0459 (4) | |
O2 | −0.12865 (19) | 0.35001 (17) | 0.77731 (9) | 0.0464 (4) | |
O3 | 0.3980 (2) | 0.65343 (17) | 0.90997 (8) | 0.0456 (4) | |
O4 | 0.5431 (3) | 0.76538 (16) | 0.80865 (10) | 0.0577 (5) | |
N1 | 0.2692 (2) | 0.55688 (18) | 0.54350 (9) | 0.0296 (3) | |
H1N1 | 0.222 (3) | 0.567 (2) | 0.5001 (13) | 0.040 (6)* | |
H2N1 | 0.326 (3) | 0.628 (3) | 0.5522 (14) | 0.049 (7)* | |
N2 | 0.6498 (2) | 0.5598 (3) | 0.86097 (12) | 0.0458 (5) | |
H1N2 | 0.719 (4) | 0.565 (3) | 0.8278 (16) | 0.071 (10)* | |
H2N2 | 0.629 (4) | 0.485 (3) | 0.8832 (17) | 0.060 (9)* | |
C1 | 0.3642 (2) | 0.56555 (18) | 0.78043 (10) | 0.0262 (4) | |
C2 | 0.3390 (2) | 0.60074 (18) | 0.70979 (10) | 0.0259 (4) | |
H2 | 0.3993 | 0.6658 | 0.6856 | 0.031* | |
C3 | 0.2099 (2) | 0.52701 (18) | 0.67698 (10) | 0.0242 (4) | |
C4 | 0.1386 (2) | 0.54867 (19) | 0.60185 (10) | 0.0261 (4) | |
H4 | 0.0811 | 0.6342 | 0.6026 | 0.031* | |
C5 | 0.0130 (2) | 0.4425 (2) | 0.57939 (10) | 0.0338 (4) | |
H5A | −0.0380 | 0.4690 | 0.5336 | 0.041* | |
H5B | 0.0705 | 0.3595 | 0.5708 | 0.041* | |
C6 | −0.1217 (2) | 0.4189 (2) | 0.63623 (11) | 0.0328 (4) | |
H6 | −0.2006 | 0.3564 | 0.6149 | 0.039* | |
C7 | 0.1430 (2) | 0.44002 (18) | 0.72613 (10) | 0.0251 (4) | |
C8 | −0.2167 (3) | 0.5421 (3) | 0.65870 (14) | 0.0464 (5) | |
H8A | −0.1479 | 0.5978 | 0.6885 | 0.070* | |
H8B | −0.3123 | 0.5164 | 0.6861 | 0.070* | |
H8C | −0.2500 | 0.5900 | 0.6157 | 0.070* | |
C9 | 0.3833 (3) | 0.4402 (2) | 0.53811 (13) | 0.0418 (5) | |
H9A | 0.4345 | 0.4251 | 0.5854 | 0.050* | |
H9B | 0.3206 | 0.3615 | 0.5255 | 0.050* | |
C10 | 0.5143 (3) | 0.4621 (3) | 0.48168 (13) | 0.0529 (6) | |
H10A | 0.4652 | 0.4643 | 0.4338 | 0.079* | |
H10B | 0.5929 | 0.3911 | 0.4840 | 0.079* | |
H10C | 0.5687 | 0.5451 | 0.4910 | 0.079* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
Cl1 | 0.0541 (3) | 0.0391 (3) | 0.0482 (3) | −0.0142 (3) | 0.0073 (3) | 0.0053 (2) |
S1 | 0.0295 (2) | 0.0276 (2) | 0.0360 (2) | −0.00838 (19) | −0.00087 (19) | 0.00171 (19) |
S2 | 0.0330 (2) | 0.0305 (2) | 0.0272 (2) | −0.0059 (2) | −0.00170 (19) | 0.00394 (18) |
S3 | 0.0341 (3) | 0.0306 (2) | 0.0314 (2) | −0.0051 (2) | −0.0067 (2) | −0.00322 (18) |
O1 | 0.0487 (9) | 0.0249 (7) | 0.0642 (10) | −0.0071 (7) | −0.0051 (8) | −0.0019 (7) |
O2 | 0.0420 (8) | 0.0558 (10) | 0.0414 (8) | −0.0155 (8) | 0.0075 (7) | 0.0042 (8) |
O3 | 0.0502 (9) | 0.0526 (9) | 0.0341 (8) | 0.0069 (8) | −0.0050 (7) | −0.0140 (7) |
O4 | 0.0783 (13) | 0.0401 (9) | 0.0547 (10) | −0.0281 (9) | −0.0218 (10) | 0.0064 (8) |
N1 | 0.0279 (8) | 0.0328 (9) | 0.0280 (8) | −0.0008 (8) | −0.0030 (7) | 0.0060 (7) |
N2 | 0.0298 (10) | 0.0638 (14) | 0.0437 (11) | −0.0010 (10) | −0.0040 (9) | 0.0024 (11) |
C1 | 0.0246 (9) | 0.0243 (8) | 0.0297 (9) | −0.0002 (7) | −0.0009 (7) | −0.0024 (8) |
C2 | 0.0248 (8) | 0.0204 (8) | 0.0325 (10) | −0.0014 (7) | 0.0016 (8) | 0.0000 (7) |
C3 | 0.0243 (8) | 0.0197 (8) | 0.0286 (9) | 0.0023 (7) | 0.0017 (7) | 0.0000 (7) |
C4 | 0.0255 (9) | 0.0247 (9) | 0.0280 (9) | −0.0008 (7) | −0.0012 (7) | −0.0002 (8) |
C5 | 0.0347 (10) | 0.0356 (9) | 0.0310 (9) | −0.0088 (9) | −0.0028 (8) | −0.0030 (8) |
C6 | 0.0253 (9) | 0.0369 (11) | 0.0361 (11) | −0.0059 (8) | −0.0049 (8) | −0.0022 (9) |
C7 | 0.0247 (9) | 0.0221 (8) | 0.0286 (9) | −0.0001 (7) | −0.0010 (7) | −0.0009 (8) |
C8 | 0.0323 (10) | 0.0494 (13) | 0.0573 (13) | 0.0080 (10) | −0.0029 (10) | −0.0003 (11) |
C9 | 0.0409 (11) | 0.0373 (11) | 0.0474 (12) | 0.0055 (10) | 0.0044 (10) | −0.0041 (10) |
C10 | 0.0441 (13) | 0.0700 (16) | 0.0445 (12) | 0.0094 (13) | 0.0072 (10) | −0.0055 (11) |
Geometric parameters (Å, º) top
S1—O1 | 1.4333 (16) | C3—C7 | 1.366 (3) |
S1—O2 | 1.4345 (16) | C3—C4 | 1.504 (2) |
S1—C7 | 1.7440 (19) | C4—C5 | 1.534 (3) |
S1—C6 | 1.782 (2) | C4—H4 | 0.9800 |
S2—C7 | 1.7008 (18) | C5—C6 | 1.526 (3) |
S2—C1 | 1.7135 (19) | C5—H5A | 0.9700 |
S3—O4 | 1.4193 (17) | C5—H5B | 0.9700 |
S3—O3 | 1.4312 (16) | C6—C8 | 1.517 (3) |
S3—N2 | 1.584 (2) | C6—H6 | 0.9800 |
S3—C1 | 1.7538 (18) | C8—H8A | 0.9600 |
N1—C9 | 1.499 (3) | C8—H8B | 0.9600 |
N1—C4 | 1.505 (2) | C8—H8C | 0.9600 |
N1—H1N1 | 0.88 (2) | C9—C10 | 1.497 (3) |
N1—H2N1 | 0.87 (3) | C9—H9A | 0.9700 |
N2—H1N2 | 0.83 (3) | C9—H9B | 0.9700 |
N2—H2N2 | 0.87 (3) | C10—H10A | 0.9600 |
C1—C2 | 1.352 (3) | C10—H10B | 0.9600 |
C2—C3 | 1.418 (3) | C10—H10C | 0.9600 |
C2—H2 | 0.9300 | | |
| | | |
O1—S1—O2 | 117.67 (10) | N1—C4—H4 | 107.3 |
O1—S1—C7 | 109.80 (9) | C5—C4—H4 | 107.3 |
O2—S1—C7 | 107.06 (9) | C6—C5—C4 | 113.81 (16) |
O1—S1—C6 | 108.73 (10) | C6—C5—H5A | 108.8 |
O2—S1—C6 | 111.58 (10) | C4—C5—H5A | 108.8 |
C7—S1—C6 | 100.63 (9) | C6—C5—H5B | 108.8 |
C7—S2—C1 | 89.80 (9) | C4—C5—H5B | 108.8 |
O4—S3—O3 | 119.79 (11) | H5A—C5—H5B | 107.7 |
O4—S3—N2 | 108.44 (13) | C8—C6—C5 | 114.96 (18) |
O3—S3—N2 | 106.91 (11) | C8—C6—S1 | 111.93 (15) |
O4—S3—C1 | 105.56 (9) | C5—C6—S1 | 107.41 (13) |
O3—S3—C1 | 105.29 (9) | C8—C6—H6 | 107.4 |
N2—S3—C1 | 110.73 (11) | C5—C6—H6 | 107.4 |
C9—N1—C4 | 116.06 (16) | S1—C6—H6 | 107.4 |
C9—N1—H1N1 | 107.4 (15) | C3—C7—S2 | 114.05 (14) |
C4—N1—H1N1 | 109.7 (15) | C3—C7—S1 | 126.94 (14) |
C9—N1—H2N1 | 109.0 (17) | S2—C7—S1 | 118.84 (10) |
C4—N1—H2N1 | 107.1 (17) | C6—C8—H8A | 109.5 |
H1N1—N1—H2N1 | 107 (2) | C6—C8—H8B | 109.5 |
S3—N2—H1N2 | 112 (2) | H8A—C8—H8B | 109.5 |
S3—N2—H2N2 | 115 (2) | C6—C8—H8C | 109.5 |
H1N2—N2—H2N2 | 121 (3) | H8A—C8—H8C | 109.5 |
C2—C1—S2 | 113.33 (14) | H8B—C8—H8C | 109.5 |
C2—C1—S3 | 126.57 (15) | C10—C9—N1 | 111.7 (2) |
S2—C1—S3 | 119.43 (11) | C10—C9—H9A | 109.3 |
C1—C2—C3 | 112.18 (17) | N1—C9—H9A | 109.3 |
C1—C2—H2 | 123.9 | C10—C9—H9B | 109.3 |
C3—C2—H2 | 123.9 | N1—C9—H9B | 109.3 |
C7—C3—C2 | 110.64 (16) | H9A—C9—H9B | 107.9 |
C7—C3—C4 | 122.55 (16) | C9—C10—H10A | 109.5 |
C2—C3—C4 | 126.45 (17) | C9—C10—H10B | 109.5 |
C3—C4—N1 | 112.42 (15) | H10A—C10—H10B | 109.5 |
C3—C4—C5 | 113.51 (15) | C9—C10—H10C | 109.5 |
N1—C4—C5 | 108.56 (15) | H10A—C10—H10C | 109.5 |
C3—C4—H4 | 107.3 | H10B—C10—H10C | 109.5 |
| | | |
C7—S2—C1—C2 | 0.11 (15) | C4—C5—C6—S1 | −70.06 (19) |
C7—S2—C1—S3 | 171.29 (12) | O1—S1—C6—C8 | 165.84 (15) |
O4—S3—C1—C2 | 8.1 (2) | O2—S1—C6—C8 | 34.44 (18) |
O3—S3—C1—C2 | 135.72 (18) | C7—S1—C6—C8 | −78.85 (15) |
N2—S3—C1—C2 | −109.1 (2) | O1—S1—C6—C5 | −67.08 (15) |
O4—S3—C1—S2 | −161.83 (13) | O2—S1—C6—C5 | 161.52 (13) |
O3—S3—C1—S2 | −34.18 (14) | C7—S1—C6—C5 | 48.24 (15) |
N2—S3—C1—S2 | 81.02 (15) | C2—C3—C7—S2 | −0.7 (2) |
S2—C1—C2—C3 | −0.5 (2) | C4—C3—C7—S2 | −174.16 (13) |
S3—C1—C2—C3 | −170.92 (14) | C2—C3—C7—S1 | 174.42 (14) |
C1—C2—C3—C7 | 0.7 (2) | C4—C3—C7—S1 | 0.9 (3) |
C1—C2—C3—C4 | 173.92 (17) | C1—S2—C7—C3 | 0.33 (15) |
C7—C3—C4—N1 | −137.54 (18) | C1—S2—C7—S1 | −175.18 (12) |
C2—C3—C4—N1 | 50.0 (2) | O1—S1—C7—C3 | 96.48 (18) |
C7—C3—C4—C5 | −13.8 (2) | O2—S1—C7—C3 | −134.72 (17) |
C2—C3—C4—C5 | 173.72 (18) | C6—S1—C7—C3 | −18.03 (19) |
C9—N1—C4—C3 | 56.4 (2) | O1—S1—C7—S2 | −88.66 (13) |
C9—N1—C4—C5 | −70.0 (2) | O2—S1—C7—S2 | 40.15 (14) |
C3—C4—C5—C6 | 51.1 (2) | C6—S1—C7—S2 | 156.83 (11) |
N1—C4—C5—C6 | 176.88 (16) | C4—N1—C9—C10 | −176.49 (17) |
C4—C5—C6—C8 | 55.2 (2) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N1···Cl1i | 0.89 (2) | 2.48 (2) | 3.2088 (17) | 139 (2) |
N1—H2N1···Cl1 | 0.87 (3) | 2.24 (3) | 3.1016 (19) | 170 (2) |
N2—H1N2···O1ii | 0.83 (3) | 2.57 (3) | 3.197 (3) | 133 (3) |
N2—H2N2···Cl1iii | 0.87 (3) | 2.37 (3) | 3.215 (3) | 165 (3) |
C2—H2···Cl1 | 0.93 | 2.82 | 3.672 (2) | 152 |
C9—H9A···O4iii | 0.97 | 2.52 | 3.358 (3) | 144 |
Symmetry codes: (i) x−1/2, −y+3/2, −z+1; (ii) −x+1, y+1/2, −z+3/2; (iii) −x+1, y−1/2, −z+3/2. |
Experimental details
Crystal data |
Chemical formula | C10H17N2O4S3+·Cl− |
Mr | 360.89 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 293 |
a, b, c (Å) | 8.1272 (6), 10.0646 (8), 18.2504 (14) |
V (Å3) | 1492.8 (2) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.69 |
Crystal size (mm) | 0.19 × 0.14 × 0.11 |
|
Data collection |
Diffractometer | Bruker SMART APEX CCD area-detector diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 10633, 2630, 2586 |
Rint | 0.025 |
(sin θ/λ)max (Å−1) | 0.595 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.024, 0.065, 1.06 |
No. of reflections | 2630 |
No. of parameters | 199 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.28, −0.17 |
Absolute structure | Flack & Bernardinelli (2000), 1098 Friedel pairs? |
Absolute structure parameter | −0.01 (6) |
Selected geometric parameters (Å, º) topS1—O1 | 1.4333 (16) | S3—O4 | 1.4193 (17) |
S1—O2 | 1.4345 (16) | S3—O3 | 1.4312 (16) |
S1—C7 | 1.7440 (19) | S3—N2 | 1.584 (2) |
S1—C6 | 1.782 (2) | S3—C1 | 1.7538 (18) |
S2—C1 | 1.7135 (19) | | |
| | | |
C7—S1—C6 | 100.63 (9) | C3—C4—N1 | 112.42 (15) |
C7—S2—C1 | 89.80 (9) | C8—C6—C5 | 114.96 (18) |
C9—N1—C4 | 116.06 (16) | | |
| | | |
C7—C3—C4—N1 | −137.54 (18) | C7—S1—C6—C8 | −78.85 (15) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N1···Cl1i | 0.89 (2) | 2.48 (2) | 3.2088 (17) | 139 (2) |
N1—H2N1···Cl1 | 0.87 (3) | 2.24 (3) | 3.1016 (19) | 170 (2) |
N2—H1N2···O1ii | 0.83 (3) | 2.57 (3) | 3.197 (3) | 133 (3) |
N2—H2N2···Cl1iii | 0.87 (3) | 2.37 (3) | 3.215 (3) | 165 (3) |
C2—H2···Cl1 | 0.93 | 2.82 | 3.672 (2) | 152 |
C9—H9A···O4iii | 0.97 | 2.52 | 3.358 (3) | 144 |
Symmetry codes: (i) x−1/2, −y+3/2, −z+1; (ii) −x+1, y+1/2, −z+3/2; (iii) −x+1, y−1/2, −z+3/2. |
Dorzolamide hydrochloride is one of a number of topical medications used to treat glaucoma (Baldwin et al., 1989). Glaucoma is a potentially devastating eye disease, caused by the build-up of abnormally high pressure in the eye. Dorzolamide belongs to a class of drugs called carbonic anhydrase inhibitors and has become commercially available since 1995 for topical ophthalmic use (Seong et al., 2001). It is thought to reduce the raised intraocular pressure by the same mechanism as that of carbonic anhydrase-II in the ciliary body. It is an effective second line agent for patients of open angle glaucoma and ocular hypertension who are unable to tolerate ophthalmic β blockers (Balfour & Wilde, 1997). The United States Food and Drug Administration has granted marketing clearance to Merck & Co. Inc. in the brand names Trusopt (contains only dorzolamide) and Cosopt, the first eye drop that combines a topical carbonic anhydrase inhibitor (dorzolamide) and a topical β-blocking agent (timolol maleate). In a continuation of our ongoing programmes for the structural elucidation of drug molecules and structure–activity relationships, the crystal structure of dorzolamide hydrochloride, (I), has been determined.
The molecular framework (Fig. 1) consists of a central thienothiopyran bicyclic ring system with a sulfonamide and an ethylamino substituent. The bond distances and angles (Table 1) are in normal ranges (Allen et al., 1987) and are comparable to those of similar structures. Owing to the high basicity of ethylamine, the protonation, as anticipated, occurs at atom N1 preferentially over the sulfonamide atom N2.
The arrangement of bonds around atom S3 is distorted tetrahedral, a structural feature commonly found in sulfonamide compounds (Liu et al., 1994; Pedregosa et al., 1993; Lisgarten & Palmer, 1988). The largest deviation is in the angle O3—S3—O4, 119.8 (1)°, while the other angles are in the range, 105.3 (1) – 110.7 (1)°. The S3—N2 bond length (Table 1) is intermediate between the values found in actazolamide [1.594 (3) Å; Mathew & Palenik, 1974] and methazolamide [1.575 (2) Å; Alzuet et al., 1991]. The crystal structures of the complex dorzolamide–human carbonic anhydrase (HCAII) [dHCA; Smith et al., 1994; Protein Data Bank (Berman et al., 2000) entry 1cil] and brinzolamide–HCAII (bHCA; Stams et al., 1998; Protein Data Bank entry 1a42) are available and the extracted ligand structures are used here for comparison.
The sulfonamide group plays an anchoring role at the active site through coordination of its N atom with the Zn atom of HCAII (Greer et al., 1994). Here its orientation with respect to the thiophene ring, defined by the torsion angle N2—S3—C1—S2, is 81.0 (2)°. The corresponding angle observed in the dHCA complex structure is 144°, while it is 152° in bHCA. It is interesting that the ab initio molecular orbital calculations at the 3–21G* level (Greer et al., 1994) suggest that the preferred torsion angle is 72°, which is close to that found here. Recently, Zou et al. (2005) reported the crystal structure of a key intermediate of the carbonic anhydrase inhibitor similar to the title compound (having an acetamide instead of an ethylamino side chain), where this angle is -74.9 (1)°. Given the potential importance of a C3 substituent in triggering the conformational change of His64 (a key residue in the enzymatic active site of HCAII), the orientation of the ethylamino chain is considered to be significant (Smith et al., 1994). Here it is in an extended conformation, with C9—N1 bound cis to C4—C3 [C9—N1—C4—C3 = 56.4 (2)°], whereas in both dHCA and bHCA, it is found to be trans (168 and 165°, respectively; see Fig. 2). It is noteworthy to mention that the methyl group C8, introduced into the thienothiopyran ring system, stabilizes the alkylamino substituent in what would otherwise be a less favorable pseudo-axial conformation (Davis et al., 2003). Considering the torsion angles N1—C4—C3—C7 and C8—C6—S1—C7 (Table 1), the ethylamino group and the methyl prefer pseudoequatorial and pseudoaxial conformations, respectively. Conversely, the corresponding torsion angles are -103 and -171° in dHCA, and -131 and -163° in bHCA.
The six-membered thiopyran ring adopts a half-chair conformation in both (I) and the dHCA complex. However, atom C6 in the ring is `flipped' up and down in both (Fig. 3), which may allow the methyl group and the ethylamino group to adopt their preferred orientations. This flip in (I) may be attributed to the involvement of the protonated N1 of the ethylamino group in hydrogen bonding with Cl atoms (Table 2). The structure–activity distances between the center of the thiophene ring and the two N atoms (the interaction sites) are 3.625 Å for N1 and 3.894 Å for N2, and to the methyl atom occupying the lipophillic groove the distance is 4.145 Å. The corresponding distances in dHCA are 3.460, 3.878 and 5.212 Å, and those in bHCA are 3.592, 3.777 and 4.913 Å, respectively.
The crystal structure is stabilized by a network of hydrogen bonds, largely mediated by the Cl atoms. Each Cl1 atom bridges three molecules via N—H···Cl hydrogen bonds. An intermolecular hydrogen bond is found between the sulfonamide N2 and O1 of the sulfoxide (Fig. 4); weaker C—H···Cl and C—H···O interactions are also present (Table 2).