YC-1, an activation inductor of soluble guanylyl cyclase

The crystal structure of 1-benzyl-3-(5-hydroxy­methyl-2-furyl)­indazole, C₁₉H₁₆N₂O₂, showed that the furan O and indazole N atoms lie on the same face of the mol­ecule. The crystal packing consists of intermolecular hydrogen bonding, and indazole-indazole and indazole-phenyl interactions.

S1. Comment

The benzyl indazole-derivative YC-1 (1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole) has been described as an inhibitor of platelet aggregation (Ko et al., 1994; Wu et al., 1995) and smooth muscle cell proliferation (Yu et al., 1995). Recently, it has been demonstrated that YC-1 induced activation of soluble guanylyl cyclase (sGC) probably by binding to an allosteric site which sensitizes the sGC enzyme toward its gaseous activators (NO, CO) by reducing the ligand dissociation rate from the heme group (Friebe & Koesling, 1998; Denninger et al., 1999; Kharitonov et al., 1999; Fribe et al., 1999; Schelvis et al., 1999). Considering YC-1 as a lead to design new sGC activators with potential therapeutic interest in cardiovascular diseases, we are engaged in a program aiming to synthetize new analogues possessing the same structural features as YC-1 and in particular having the same spatial arrangement of the 3 putative interaction centers with the enzyme: two N atoms of the indazole ring, oxygen of the furane ring and oxygen of the alcohol group. In order to model these interactions we needed to determine the three-dimensional structure of a stable conformation of YC-1. The first molecular modeling trials were unable to define the relative orientation of the furane and indazole rings, i.e. if the oxygen of the furane lies cis or trans with respect to nitrogen N9 of the indazole nucleus with certainty. \sch

In the resulting crystal structure, the furane and the indazole rings are quasi coplanar (Fig. 1). The ring heteroatoms, furane oxygen (O7) and indazole N atoms (N9, N10), lie on the same face of the molecule, i.e. in the cis conformation. The angle between the planes of the two rings is about 5.4 (1)°. The third ring, the phenyl of the benzyl group, adopts an approximately perpendicular position with respect to the two rings mentioned above. The angle between benzyl and the plane of two rings is about 77.87 (4)°.

The crystal packing is stabilized by intermolecular hydrogen bonding and interactions between the aromatic rings of the molecule. An intermolecular hydrogen bond forms between nitrogen N9 of the indazole ring and the O1—H1 of hydroxymethyl group of the furane ring of a neighbouring molecule [N9···H1(1/2 − x, −1/2 + y, 1/2 − z) = 1.93 (3) Å] (Table 1, Fig. 2). The intermolecular distances observed between the aromatic rings of neighbouring molecules suggest two interactions as the most important: indazole···indazole and indazole···phenyl (see Fig. 2), for which a T-shaped arrangement was observed. Such an arrangement has been shown to result in favourable intermolecular attractive forces (Koch & Egert, 1995). For indazole···indazole T-shaped arrangements the shortest distance corresponds to a C13—H13···Cg1 interaction with a H13···Cg1 distance of 3.18 Å (Cg1 is the centroid of the indazole phenyl ring with symmetry code 3/2 − x, y − 1/2, 1/2 − z). For indazole···phenyl T-shaped arrangement the shortest distance corresponds to a C14—H14···Cg2 interaction with H14···Cg2 distance of 3.07 Å (Cg2 is the centroid of the phenyl ring with symmetry code 3/2 − x, 1/2 + y, 1/2 − z).

S2. Experimental

Suitable red transparent crystals of the compound synthetized according to Collot et al. (1999) were grown by slow evaporation from hexane solution at room temperature.

S3. Refinement

All hydrogen atoms were found in the difference electron-density map with bond lengths and angles close to well established geometrical criteria. They were refined with isotropic displacment factors.

Computing details

Data collection: CAD-4-PC (Enraf-Nonius, 1994); cell refinement: CAD-4-PC; data reduction: Xtal (Hall et al., 1992); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. View of YC-1 showing the labelling of the non-hydrogen atoms. Displacement ellipsoids are shown at 50% probability levels; hydrogen atoms are drawn as a small circles of arbitrary radius.
	Fig. 2. Crystal packing of YC-1 molecules projected on the ac plane. H atoms are omitted for clarity. Dashed lines indicate the hydrogen bonds and interactions between aromatic rings.

'1-Benzyl-3-(5'-hydroxymethyl-2-furyl)indazole'

Crystal data

C19H16N2O2	Dx = 1.331 Mg m^−3
Mr = 304.34	Melting point: 112° K
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 14.345 (1) Å	Cell parameters from 25 reflections
b = 5.6905 (7) Å	θ = 8–14°
c = 18.714 (1) Å	µ = 0.09 mm^−1
β = 96.064 (9)°	T = 293 K
V = 1519.1 (2) Å^3	Prism, translucent pale red
Z = 4	0.6 × 0.4 × 0.3 mm
F(000) = 646

Data collection

Enraf-Nonius CAD4 diffractometer	Rint = 0.012
Radiation source: fine-focus sealed tube	θmax = 27.0°, θmin = 2.2°
Graphite monochromator	h = −18→18
θ/2θ scans	k = 0→7
3412 measured reflections	l = 0→23
3314 independent reflections	3 standard reflections every 60 min
2522 reflections with I > 2σ(I)	intensity decay: 3%

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.045	Hydrogen site location: difference Fourier map
wR(F^2) = 0.140	All H-atom parameters refined
S = 1.06	w = 1/[σ^2(Fo^2) + (0.0797P)^2 + 0.1614P] where P = (Fo^2 + 2Fc^2)/3
3314 reflections	(Δ/σ)max = 0.002
272 parameters	Δρmax = 0.17 e Å^−3
0 restraints	Δρmin = −0.26 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
O1	0.17746 (9)	0.5018 (3)	0.14774 (8)	0.0605 (4)
H1	0.1485 (18)	0.479 (4)	0.1909 (14)	0.081 (8)*
C2	0.26647 (12)	0.6012 (3)	0.16676 (11)	0.0477 (4)
H2A	0.2753 (13)	0.626 (3)	0.2180 (11)	0.047 (5)*
H2B	0.2708 (16)	0.760 (4)	0.1467 (14)	0.077 (7)*
C3	0.34246 (11)	0.4527 (3)	0.14267 (9)	0.0411 (4)
C4	0.39309 (13)	0.4583 (4)	0.08684 (11)	0.0530 (5)
H4	0.3881 (14)	0.570 (4)	0.0468 (11)	0.061 (6)*
C5	0.45655 (14)	0.2643 (4)	0.09424 (10)	0.0513 (5)
H5	0.5057 (15)	0.225 (4)	0.0636 (12)	0.060 (6)*
C6	0.44100 (11)	0.1537 (3)	0.15560 (9)	0.0382 (4)
O7	0.37037 (8)	0.26462 (19)	0.18630 (6)	0.0400 (3)
C8	0.48337 (11)	−0.0478 (3)	0.19403 (8)	0.0360 (3)
N9	0.44752 (9)	−0.1291 (2)	0.25180 (7)	0.0381 (3)
N10	0.49974 (9)	−0.3194 (2)	0.27504 (7)	0.0390 (3)
C11	0.56862 (11)	−0.3617 (3)	0.23180 (9)	0.0378 (4)
C12	0.63615 (12)	−0.5397 (3)	0.23502 (10)	0.0466 (4)
H12	0.6409 (14)	−0.657 (4)	0.2741 (11)	0.056 (6)*
C13	0.69657 (14)	−0.5360 (4)	0.18323 (12)	0.0563 (5)
H13	0.7420 (15)	−0.653 (4)	0.1850 (12)	0.061 (6)*
C14	0.69198 (14)	−0.3617 (4)	0.13005 (12)	0.0592 (5)
H14	0.7368 (14)	−0.365 (4)	0.0949 (11)	0.059 (6)*
C15	0.62560 (13)	−0.1868 (4)	0.12678 (11)	0.0507 (4)
H15	0.6229 (14)	−0.067 (4)	0.0893 (11)	0.055 (5)*
C16	0.56145 (11)	−0.1870 (3)	0.17839 (9)	0.0384 (4)
C17	0.47221 (12)	−0.4644 (3)	0.33327 (10)	0.0431 (4)
H17A	0.4168 (14)	−0.388 (4)	0.3515 (10)	0.049 (5)*
H17B	0.4518 (16)	−0.626 (4)	0.3140 (12)	0.071 (7)*
C18	0.54777 (11)	−0.4963 (3)	0.39462 (8)	0.0358 (3)
C19	0.54818 (13)	−0.7009 (3)	0.43514 (10)	0.0436 (4)
H19	0.5017 (14)	−0.824 (4)	0.4186 (11)	0.058 (6)*
C20	0.61380 (15)	−0.7326 (3)	0.49372 (10)	0.0509 (5)
H20	0.6139 (15)	−0.874 (4)	0.5220 (12)	0.065 (6)*
C21	0.68007 (14)	−0.5633 (4)	0.51245 (10)	0.0530 (5)
H21	0.7261 (16)	−0.585 (4)	0.5507 (13)	0.072 (7)*
C22	0.68042 (14)	−0.3594 (4)	0.47233 (11)	0.0536 (5)
H22	0.7255 (16)	−0.245 (4)	0.4832 (13)	0.067 (6)*
C23	0.61447 (13)	−0.3254 (3)	0.41408 (10)	0.0446 (4)
H23	0.6144 (13)	−0.180 (3)	0.3849 (11)	0.050 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0433 (7)	0.0856 (11)	0.0525 (8)	−0.0119 (7)	0.0050 (6)	−0.0113 (7)
C2	0.0442 (9)	0.0393 (9)	0.0579 (11)	0.0000 (7)	−0.0032 (8)	−0.0004 (9)
C3	0.0404 (8)	0.0333 (8)	0.0475 (9)	−0.0038 (7)	−0.0044 (7)	0.0071 (7)
C4	0.0507 (10)	0.0518 (11)	0.0561 (11)	0.0016 (8)	0.0047 (8)	0.0210 (9)
C5	0.0509 (10)	0.0552 (11)	0.0487 (10)	0.0054 (9)	0.0105 (8)	0.0144 (9)
C6	0.0399 (8)	0.0353 (8)	0.0391 (8)	−0.0015 (6)	0.0022 (6)	0.0005 (7)
O7	0.0447 (6)	0.0340 (6)	0.0411 (6)	0.0027 (5)	0.0040 (5)	0.0040 (5)
C8	0.0396 (8)	0.0331 (8)	0.0352 (8)	−0.0023 (6)	0.0028 (6)	−0.0005 (6)
N9	0.0402 (7)	0.0356 (7)	0.0382 (7)	0.0035 (6)	0.0030 (5)	0.0027 (6)
N10	0.0402 (7)	0.0373 (7)	0.0398 (7)	0.0047 (6)	0.0055 (5)	0.0067 (6)
C11	0.0379 (8)	0.0359 (8)	0.0394 (8)	−0.0013 (6)	0.0032 (6)	−0.0011 (6)
C12	0.0446 (9)	0.0402 (9)	0.0545 (11)	0.0060 (7)	0.0036 (8)	0.0026 (8)
C13	0.0486 (10)	0.0522 (11)	0.0695 (13)	0.0129 (9)	0.0124 (9)	−0.0009 (10)
C14	0.0534 (11)	0.0647 (13)	0.0634 (12)	0.0079 (9)	0.0245 (10)	−0.0001 (10)
C15	0.0515 (10)	0.0516 (10)	0.0508 (10)	0.0017 (8)	0.0141 (8)	0.0057 (9)
C16	0.0393 (8)	0.0357 (8)	0.0399 (8)	−0.0025 (7)	0.0030 (6)	−0.0011 (7)
C17	0.0423 (9)	0.0421 (9)	0.0448 (9)	−0.0031 (7)	0.0045 (7)	0.0093 (7)
C18	0.0404 (8)	0.0299 (7)	0.0383 (8)	0.0018 (6)	0.0101 (6)	0.0006 (6)
C19	0.0550 (10)	0.0332 (8)	0.0434 (9)	0.0005 (8)	0.0085 (7)	0.0031 (7)
C20	0.0706 (12)	0.0398 (9)	0.0428 (10)	0.0088 (9)	0.0086 (9)	0.0087 (8)
C21	0.0596 (11)	0.0581 (12)	0.0392 (9)	0.0123 (9)	−0.0044 (8)	−0.0005 (8)
C22	0.0544 (10)	0.0497 (11)	0.0547 (11)	−0.0079 (9)	−0.0039 (8)	−0.0054 (9)
C23	0.0533 (10)	0.0329 (8)	0.0478 (9)	−0.0036 (7)	0.0061 (8)	0.0030 (7)

Geometric parameters (Å, º)

O1—C2	1.408 (2)	C12—H12	0.99 (2)
O1—H1	0.96 (3)	C13—C14	1.402 (3)
C2—C3	1.487 (3)	C13—H13	0.93 (2)
C2—H2A	0.96 (2)	C14—C15	1.374 (3)
C2—H2B	0.98 (2)	C14—H14	0.97 (2)
C3—C4	1.334 (3)	C15—C16	1.403 (2)
C3—O7	1.3796 (19)	C15—H15	0.97 (2)
C4—C5	1.428 (3)	C17—C18	1.504 (2)
C4—H4	0.98 (2)	C17—H17A	1.00 (2)
C5—C6	1.349 (2)	C17—H17B	1.02 (2)
C5—H5	0.98 (2)	C18—C23	1.386 (2)
C6—O7	1.370 (2)	C18—C19	1.389 (2)
C6—C8	1.452 (2)	C19—C20	1.379 (3)
C8—N9	1.328 (2)	C19—H19	0.99 (2)
C8—C16	1.427 (2)	C20—C21	1.373 (3)
N9—N10	1.3616 (18)	C20—H20	0.96 (2)
N10—C11	1.363 (2)	C21—C22	1.382 (3)
N10—C17	1.455 (2)	C21—H21	0.93 (2)
C11—C12	1.398 (2)	C22—C23	1.380 (3)
C11—C16	1.406 (2)	C22—H22	0.92 (2)
C12—C13	1.367 (3)	C23—H23	0.99 (2)
C2—O1—H1	107.8 (15)	C14—C13—H13	120.8 (14)
O1—C2—C3	111.68 (15)	C15—C14—C13	121.63 (19)
O1—C2—H2A	109.3 (11)	C15—C14—H14	119.3 (13)
C3—C2—H2A	111.2 (11)	C13—C14—H14	119.1 (13)
O1—C2—H2B	111.4 (14)	C14—C15—C16	118.09 (18)
C3—C2—H2B	109.3 (14)	C14—C15—H15	120.7 (12)
H2A—C2—H2B	103.7 (19)	C16—C15—H15	121.2 (12)
C4—C3—O7	109.51 (15)	C15—C16—C11	119.08 (16)
C4—C3—C2	134.51 (17)	C15—C16—C8	136.65 (16)
O7—C3—C2	115.97 (15)	C11—C16—C8	104.27 (14)
C3—C4—C5	107.43 (16)	N10—C17—C18	114.16 (14)
C3—C4—H4	127.8 (12)	N10—C17—H17A	107.2 (11)
C5—C4—H4	124.7 (12)	C18—C17—H17A	109.1 (11)
C6—C5—C4	106.40 (17)	N10—C17—H17B	109.7 (13)
C6—C5—H5	126.0 (13)	C18—C17—H17B	108.5 (13)
C4—C5—H5	127.4 (13)	H17A—C17—H17B	107.9 (17)
C5—C6—O7	109.75 (15)	C23—C18—C19	118.80 (16)
C5—C6—C8	133.79 (16)	C23—C18—C17	122.55 (14)
O7—C6—C8	116.45 (14)	C19—C18—C17	118.60 (15)
C6—O7—C3	106.89 (13)	C20—C19—C18	120.44 (17)
N9—C8—C16	110.71 (14)	C20—C19—H19	122.3 (12)
N9—C8—C6	120.01 (14)	C18—C19—H19	117.2 (12)
C16—C8—C6	129.27 (15)	C21—C20—C19	120.47 (17)
C8—N9—N10	106.83 (13)	C21—C20—H20	119.1 (13)
N9—N10—C11	111.08 (12)	C19—C20—H20	120.5 (13)
N9—N10—C17	120.46 (13)	C20—C21—C22	119.52 (17)
C11—N10—C17	128.01 (14)	C20—C21—H21	121.2 (15)
N10—C11—C12	130.13 (15)	C22—C21—H21	119.3 (15)
N10—C11—C16	107.10 (14)	C23—C22—C21	120.35 (18)
C12—C11—C16	122.77 (16)	C23—C22—H22	118.7 (14)
C13—C12—C11	116.52 (17)	C21—C22—H22	120.9 (14)
C13—C12—H12	122.4 (12)	C22—C23—C18	120.41 (17)
C11—C12—H12	121.0 (12)	C22—C23—H23	120.9 (11)
C12—C13—C14	121.90 (18)	C18—C23—H23	118.7 (11)
C12—C13—H13	117.3 (14)
O1—C2—C3—C4	99.3 (2)	C11—C12—C13—C14	0.7 (3)
O1—C2—C3—O7	−81.4 (2)	C12—C13—C14—C15	−0.8 (3)
O7—C3—C4—C5	0.3 (2)	C13—C14—C15—C16	−0.2 (3)
C2—C3—C4—C5	179.68 (19)	C14—C15—C16—C11	1.2 (3)
C3—C4—C5—C6	−0.9 (2)	C14—C15—C16—C8	−178.8 (2)
C4—C5—C6—O7	1.1 (2)	N10—C11—C16—C15	179.03 (15)
C4—C5—C6—C8	−177.86 (18)	C12—C11—C16—C15	−1.4 (3)
C5—C6—O7—C3	−0.93 (18)	N10—C11—C16—C8	−0.95 (17)
C8—C6—O7—C3	178.23 (13)	C12—C11—C16—C8	178.66 (15)
C4—C3—O7—C6	0.36 (18)	N9—C8—C16—C15	−179.33 (19)
C2—C3—O7—C6	−179.14 (14)	C6—C8—C16—C15	2.2 (3)
C5—C6—C8—N9	−174.71 (18)	N9—C8—C16—C11	0.65 (18)
O7—C6—C8—N9	6.4 (2)	C6—C8—C16—C11	−177.86 (15)
C5—C6—C8—C16	3.7 (3)	N9—N10—C17—C18	−125.77 (16)
O7—C6—C8—C16	−175.21 (15)	C11—N10—C17—C18	62.7 (2)
C16—C8—N9—N10	−0.09 (17)	N10—C17—C18—C23	31.4 (2)
C6—C8—N9—N10	178.59 (13)	N10—C17—C18—C19	−151.32 (15)
C8—N9—N10—C11	−0.55 (17)	C23—C18—C19—C20	0.1 (2)
C8—N9—N10—C17	−173.37 (14)	C17—C18—C19—C20	−177.22 (16)
N9—N10—C11—C12	−178.61 (17)	C18—C19—C20—C21	−0.5 (3)
C17—N10—C11—C12	−6.5 (3)	C19—C20—C21—C22	0.3 (3)
N9—N10—C11—C16	0.97 (17)	C20—C21—C22—C23	0.3 (3)
C17—N10—C11—C16	173.11 (15)	C21—C22—C23—C18	−0.7 (3)
N10—C11—C12—C13	179.89 (17)	C19—C18—C23—C22	0.5 (3)
C16—C11—C12—C13	0.4 (3)	C17—C18—C23—C22	177.73 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N9^i	0.96 (3)	1.93 (3)	2.831 (2)	156 (2)

Symmetry code: (i) −x+1/2, y+1/2, −z+1/2.