supplementary materials


HTML versionpdf versioncif file3d viewstructure factorssupplementary materialsCIF check reportsimilar papers Open access

dn2339 scheme

Acta Cryst. (2008). E64, o1056    [ doi:10.1107/S1600536808013366 ]

1-Phenyl-6,7,8,9-hexahydro-1H,5H-cyclohepta[1',2':2,3]pyrido[6,5-c]pyrazol-4-amine: a new tacrine analogue

L. Zhang, D. Shi, J. Li, L. Zhang and Y. Fan

Abstract top

The title compound, C17H18N4, contains a pyrazolopyridine system fused with a seven-membered carbocyclic ring. The pyrazole ring is coplanar with the pyridine ring, while the phenyl ring is twisted by a dihedral angle of 14.38 (14)° with respect to the pyridine ring. The seven-membered ring displays a chair conformation. The packing is stabilized by N-H...N hydrogen bonds and N-H...[pi](arene) interactions.

Comment top

Tacrine (9-amino-1,2,3,4-tetrahydroacridine, THA) was the first acetylcholinesterase inhibitor approved for the palliative treatment of Alzheimer's disease (AD) (Gracon et al., 1998). But due to its undesirable side effects, especially its hepatotoxicity, the clinical usefulness is limited (Stachlewitz et al., 1997), and the research on seeking new AChE inhibitors with improved activity and reduced adverse side effects are progressing (Haviv et al., 2005). In view of the considerable biological and medicinal activities of pyrazole ring compounds, such as important adenosine antagonist (Zocchi et al., 1996), antifungals (Kim et al., 1996), plant growth regulators (Erast et al., 1987), anti-tumor agents (Lin et al., 2007), anticonvulsant agents (Kelley et al., 1988), etc. we designed and synthesized the compound 11-phenyl-1,5,6,7,8,9- hexahydrocyclohepta[b]pyrazolo[4,3-e]-pyridin-4-amine (a new Tacrine analogue) (Scheme 1).

In the title compound, the fused pyrazolopyridine moiety is roughly coplanar, with an angle of 1.4° between the pyrazole and the pyridine rings (Fig. 1), The largest deviation from the mean plane being 0.014 (2)Å at C5. Both the C3—N2 [1.345 (3) Å] and the C4—N2 [1.348 (3) Å] bond lengths of pyridine are much shorter than those observed in the pyrazole ring [C3—N3 1.378 (3) Å and N3—N4 1.380 (3) Å], indicating higher aromatic nature of the pyridine ring than the pyrazole. The amino group is sligthly twisted by 1.71 (8)° with respect to the pyrazolopyridine moiety The benzene is also twisted and make a dihedral angle of 14.38 (14)\% with the pyrazolopyridine moiety, The seven-membered ring displays a chair conformation.

There are strong intermolecular N—H···N hydrogen bonds between the amino group and one N atom of the pyrazole ring (Table 1, Fig. 2). The packing is further stabilized by N—H···π(benzene) interactions (Table 1).

Related literature top

For related literature, see: Gracon et al. (1998); Haviv et al. (2005); Kelley et al. (1988); Kim et al. (1996); Lin et al. (2007); Stachlewitz et al. (1997); Zocchi et al. (1996); Erast et al. (1987). Cg1 is the centroid of the benzene ring.

Experimental top

A solution of 0.2 g of 5-amino-4-cyanopyrazole (1.1 mmol,), 0.16 g of AlCl3 (1.2 mmol,) in 5 ml of 1,2-dichloroethane was refluxed for 4 h (monitored by TLC). The reaction mixture was cooled, dispersed into THF/water (2:1 vol.) and titrated to pH=7 by 20% sodium hydroxide. Then, the mixture was stirred for 30 min. and extracted three times with dichloromethane, the organic layers were dried and evaporated at reduced pressure to give the solid product (Fig. 3). The title compound 1 was purified by silica gel column chromatography eluting with ethyl acetate/light petroleum in 40% yield.

Its single-crystal was cultured from a solution of ethanol by slow evaporation at room temperature.

The product 1, white crystal, m.p. 194–195°C, was characterized by 1H NMR, 13C NMR, ESI, IR, EA. IR (KBr) (cm-1): 3482 and 3350 (NH), 2922 (CH), 1638 and 1594 (C=N), 1501, 1358; 1H NMR (400 MHz, CDCl3, δp.p.m.): 1.62–1.90 (m, 6H, alkyl-H), 2.66–2.69 (t, 2H, alkyl-H), 3.08–3.01 (t, 2H, alkyl-H), 4.60 (s, 2H, NH2), 7.22–7.26 (t, J=7.4 Hz, 1H), 7.46–7.50 (t, J=7.5 Hz, 2H), 7.98 (s, 1H), 8.30–8.32 (d, J=7.6 Hz, 2H); 13C NMR (400 MHz, CDCl3, δp.p.m.): 25.40, 26.79, 27.56, 32.16, 39.81, 106.11, 113.24, 120.91 (2 C), 125.37, 128.89 (2 C), 130.61, 140.02, 143.69, 149.52, 165.25; ESI [M+H]+: 279.1; Anal. Calcd. for C17H18N4: C, 73.35; H, 6.52; N, 20.13. Found: C, 73.17; H, 6.52; N, 19.99.

Refinement top

All H atoms attached to C atoms were fixed geometrically and treated as riding with C—H = 0.93 Å (aromatic) or 0.98 Å (methine) with Uiso(H) = 1.2Ueq(C). H atoms attached to N were located in difference Fourier maps but introduced in calculated positions and treated as riding on the N atoms with N-H = 0.86 Å and Uiso(H) = 1.2Ueq(N).

Computing details top

Data collection: CrystalClear (Rigaku, 2004); cell refinement: CrystalClear (Rigaku, 2004); data reduction: CrystalClear (Rigaku, 2004); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEPIII (Burnett & Johnson, 1996), ORTEP-3 for Windows (Farrugia, 1997) and PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound, with the atom- labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. H atoms are represented as small spheres of arbitrary radii.
[Figure 2] Fig. 2. Partial packing view showing as dashed lines the N-H···N hydrogen bondings. H atoms not involved in hydrogen bonds have been omitted for clarity. [Symmetry code: (i) -x+1/2, y-1/2, -z]
[Figure 3] Fig. 3. Reaction pathway for the synthesis of the title compound.
1-Phenyl-6,7,8,9-hexahydro-1H,5H-cyclohepta[1',2':2,3]pyrido[6,5-c]pyrazol- 4-amine top
Crystal data top
C17H18N4F000 = 592
Mr = 278.35Dx = 1.252 Mg m−3
Monoclinic, P21/aMo Kα radiation
λ = 0.71070 Å
Hall symbol: -P 2yabCell parameters from 2169 reflections
a = 13.694 (13) Åθ = 2.6–27.9º
b = 6.888 (6) ŵ = 0.08 mm−1
c = 16.929 (16) ÅT = 293 (2) K
β = 112.417 (12)ºPlatelet, colorless
V = 1476 (2) Å30.24 × 0.18 × 0.10 mm
Z = 4
Data collection top
Rigaku Saturn
diffractometer		2593 independent reflections
Radiation source: rotating anode2004 reflections with I > 2σ(I)
Monochromator: confocalRint = 0.045
Detector resolution: 7.31 pixels mm-1θmax = 25.0º
T = 293(2) Kθmin = 1.3º
ω scansh = −16→16
Absorption correction: multi-scan
(Jacobson, 1998)		k = −8→8
Tmin = 0.982, Tmax = 0.992l = −20→20
10708 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.064H-atom parameters constrained
wR(F2) = 0.162  w = 1/[σ2(Fo2) + (0.0737P)2 + 0.1595P]
where P = (Fo2 + 2Fc2)/3
S = 1.13(Δ/σ)max = 0.001
2593 reflectionsΔρmax = 0.13 e Å−3
190 parametersΔρmin = −0.16 e Å−3
Primary atom site location: structure-invariant direct methodsExtinction correction: none
Crystal data top
C17H18N4V = 1476 (2) Å3
Mr = 278.35Z = 4
Monoclinic, P21/aMo Kα
a = 13.694 (13) ŵ = 0.08 mm−1
b = 6.888 (6) ÅT = 293 (2) K
c = 16.929 (16) Å0.24 × 0.18 × 0.10 mm
β = 112.417 (12)º
Data collection top
Rigaku Saturn
diffractometer		2593 independent reflections
Absorption correction: multi-scan
(Jacobson, 1998)		2004 reflections with I > 2σ(I)
Tmin = 0.982, Tmax = 0.992Rint = 0.045
10708 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.064190 parameters
wR(F2) = 0.162H-atom parameters constrained
S = 1.13Δρmax = 0.13 e Å−3
2593 reflectionsΔρmin = −0.16 e Å−3
Special details top

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.

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
N10.22712 (17)−0.0370 (3)0.14030 (12)0.0759 (7)
H1A0.2063−0.12880.16450.091*
H1B0.2046−0.03150.08550.091*
N20.43578 (14)0.4015 (3)0.28441 (11)0.0555 (5)
N30.41678 (14)0.5193 (3)0.14393 (11)0.0561 (5)
N40.36441 (16)0.4614 (3)0.06027 (11)0.0659 (6)
C10.29571 (17)0.0997 (3)0.18869 (13)0.0520 (6)
C20.32949 (16)0.2498 (3)0.14847 (13)0.0506 (6)
C30.39672 (16)0.3917 (3)0.19859 (13)0.0497 (5)
C40.40415 (17)0.2541 (3)0.32127 (13)0.0536 (6)
C50.33628 (16)0.1021 (3)0.27801 (13)0.0517 (6)
C60.31279 (19)0.3022 (4)0.06373 (14)0.0633 (7)
H60.27030.23250.01590.076*
C70.47904 (17)0.6919 (3)0.16101 (15)0.0553 (6)
C80.5064 (2)0.7724 (4)0.09698 (17)0.0709 (7)
H80.48370.71540.04320.085*
C90.5679 (2)0.9391 (4)0.1146 (2)0.0841 (9)
H90.58620.99380.07190.101*
C100.6020 (2)1.0244 (4)0.1935 (2)0.0856 (9)
H100.64341.13590.20450.103*
C110.5746 (2)0.9436 (4)0.25592 (19)0.0801 (8)
H110.59731.00130.30960.096*
C120.51355 (18)0.7772 (4)0.24043 (16)0.0650 (7)
H120.49590.72320.28360.078*
C130.4445 (2)0.2642 (4)0.41739 (14)0.0737 (8)
H13A0.49700.36650.43710.088*
H13B0.47910.14260.44090.088*
C140.3584 (2)0.3027 (4)0.45167 (17)0.0882 (9)
H14A0.39080.35920.50820.106*
H14B0.31000.39820.41520.106*
C150.2955 (2)0.1271 (5)0.45736 (17)0.0860 (9)
H15A0.24470.16770.48120.103*
H15B0.34330.03590.49710.103*
C160.2365 (2)0.0213 (4)0.37396 (15)0.0755 (8)
H16A0.18360.10810.33590.091*
H16B0.1997−0.08860.38560.091*
C170.3059 (2)−0.0518 (4)0.32817 (15)0.0671 (7)
H17A0.3699−0.10660.37020.081*
H17B0.2689−0.15520.28940.081*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0947 (16)0.0801 (15)0.0543 (12)−0.0340 (12)0.0301 (12)−0.0143 (10)
N20.0539 (11)0.0634 (12)0.0483 (11)−0.0081 (9)0.0185 (9)−0.0006 (9)
N30.0578 (12)0.0610 (12)0.0471 (11)−0.0037 (9)0.0173 (9)0.0050 (9)
N40.0722 (14)0.0747 (14)0.0465 (11)−0.0064 (11)0.0178 (10)0.0053 (10)
C10.0523 (13)0.0573 (13)0.0484 (12)−0.0041 (11)0.0214 (11)−0.0058 (10)
C20.0503 (13)0.0581 (14)0.0429 (12)0.0013 (11)0.0171 (10)0.0002 (10)
C30.0476 (13)0.0577 (13)0.0447 (12)−0.0002 (11)0.0186 (10)0.0035 (10)
C40.0493 (13)0.0676 (15)0.0439 (12)−0.0047 (11)0.0177 (10)0.0006 (10)
C50.0530 (13)0.0555 (13)0.0485 (12)−0.0017 (11)0.0217 (10)0.0010 (10)
C60.0683 (16)0.0724 (16)0.0447 (13)−0.0090 (13)0.0166 (11)−0.0012 (11)
C70.0480 (13)0.0531 (13)0.0633 (14)0.0038 (11)0.0195 (11)0.0097 (11)
C80.0694 (16)0.0731 (17)0.0712 (16)0.0035 (14)0.0278 (14)0.0164 (13)
C90.081 (2)0.0758 (19)0.103 (2)−0.0069 (16)0.0428 (18)0.0252 (17)
C100.081 (2)0.0668 (18)0.110 (2)−0.0146 (15)0.0371 (18)0.0020 (17)
C110.0773 (19)0.0689 (17)0.096 (2)−0.0126 (14)0.0348 (16)−0.0040 (15)
C120.0638 (16)0.0633 (16)0.0712 (16)−0.0039 (12)0.0294 (13)0.0000 (12)
C130.0709 (17)0.098 (2)0.0462 (13)−0.0243 (15)0.0163 (12)−0.0020 (13)
C140.111 (2)0.102 (2)0.0664 (17)−0.0358 (18)0.0502 (17)−0.0252 (15)
C150.098 (2)0.106 (2)0.0694 (17)−0.0220 (18)0.0490 (17)−0.0144 (15)
C160.0798 (18)0.0903 (19)0.0643 (16)−0.0226 (15)0.0364 (14)−0.0022 (14)
C170.0829 (18)0.0652 (16)0.0568 (14)−0.0123 (13)0.0305 (13)−0.0004 (12)
Geometric parameters (Å, °) top
N1—C11.361 (3)C9—C101.368 (4)
N1—H1A0.8600C9—H90.9300
N1—H1B0.8600C10—C111.369 (4)
N2—C31.345 (3)C10—H100.9300
N2—C41.347 (3)C11—C121.383 (3)
N3—C31.377 (3)C11—H110.9300
N3—N41.380 (3)C12—H120.9300
N3—C71.427 (3)C13—C141.523 (4)
N4—C61.318 (3)C13—H13A0.9700
C1—C51.398 (3)C13—H13B0.9700
C1—C21.410 (3)C14—C151.508 (4)
C2—C31.388 (3)C14—H14A0.9700
C2—C61.411 (3)C14—H14B0.9700
C4—C51.406 (3)C15—C161.519 (4)
C4—C131.507 (3)C15—H15A0.9700
C5—C171.512 (3)C15—H15B0.9700
C6—H60.9300C16—C171.523 (3)
C7—C121.375 (3)C16—H16A0.9700
C7—C81.390 (3)C16—H16B0.9700
C8—C91.388 (4)C17—H17A0.9700
C8—H80.9300C17—H17B0.9700
C1—N1—H1A120.0C11—C10—H10120.4
C1—N1—H1B120.0C10—C11—C12121.0 (3)
H1A—N1—H1B120.0C10—C11—H11119.5
C3—N2—C4113.38 (18)C12—C11—H11119.5
C3—N3—N4110.27 (19)C7—C12—C11119.8 (2)
C3—N3—C7130.71 (19)C7—C12—H12120.1
N4—N3—C7119.02 (18)C11—C12—H12120.1
C6—N4—N3105.81 (18)C4—C13—C14113.6 (2)
N1—C1—C5123.9 (2)C4—C13—H13A108.8
N1—C1—C2119.7 (2)C14—C13—H13A108.8
C5—C1—C2116.4 (2)C4—C13—H13B108.8
C3—C2—C1118.98 (19)C14—C13—H13B108.8
C3—C2—C6104.73 (19)H13A—C13—H13B107.7
C1—C2—C6136.3 (2)C15—C14—C13115.4 (2)
N2—C3—N3126.5 (2)C15—C14—H14A108.4
N2—C3—C2126.41 (19)C13—C14—H14A108.4
N3—C3—C2107.11 (19)C15—C14—H14B108.4
N2—C4—C5125.8 (2)C13—C14—H14B108.4
N2—C4—C13114.5 (2)H14A—C14—H14B107.5
C5—C4—C13119.6 (2)C14—C15—C16116.1 (2)
C1—C5—C4118.92 (19)C14—C15—H15A108.3
C1—C5—C17121.2 (2)C16—C15—H15A108.3
C4—C5—C17119.9 (2)C14—C15—H15B108.3
N4—C6—C2112.1 (2)C16—C15—H15B108.3
N4—C6—H6124.0H15A—C15—H15B107.4
C2—C6—H6124.0C15—C16—C17114.7 (2)
C12—C7—C8119.8 (2)C15—C16—H16A108.6
C12—C7—N3120.7 (2)C17—C16—H16A108.6
C8—C7—N3119.5 (2)C15—C16—H16B108.6
C9—C8—C7119.0 (3)C17—C16—H16B108.6
C9—C8—H8120.5H16A—C16—H16B107.6
C7—C8—H8120.5C5—C17—C16114.4 (2)
C10—C9—C8121.2 (3)C5—C17—H17A108.7
C10—C9—H9119.4C16—C17—H17A108.7
C8—C9—H9119.4C5—C17—H17B108.7
C9—C10—C11119.2 (3)C16—C17—H17B108.7
C9—C10—H10120.4H17A—C17—H17B107.6
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N1—H1B···N4i0.862.283.139 (4)175
N1—H1A···Cg1ii0.862.843.608 (4)150
Symmetry codes: (i) −x+1/2, y−1/2, −z; (ii) x−3/2, −y−1/2, z.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N1—H1B···N4i0.862.283.139 (4)175
N1—H1A···Cg1ii0.862.843.608 (4)150
Symmetry codes: (i) −x+1/2, y−1/2, −z; (ii) x−3/2, −y−1/2, z.
Acknowledgements top

We thank Beijing Institute of Technology for financial support and Naikai University for X-ray diffraction analysis.

references
References top

Burnett, M. N. & Johnson, C. K. (1996). ORTEPIII. Report ORNL-6895. Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.

Erast, B., Bend, Z. & Norbert, M. (1987). German Patent DE 3 604 569.

Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.

Gracon, S. I., Knapp, M. J., Berghoff, W. G., Pierce, M., DeJong, R., Lobbestael, S. J., Symons, J., Dombey, S. L., Luscombe, F. A. & Kraemer, D. (1998). Alzheimer Dis. Assoc. Disord. 12, 93–101.

Haviv, H., Wong, D. M., Greenblatt, H. M., Carlier, P. R., Han, Y. F., Pang, Y. P., Silman, I. & Sussman, J. L. (2005). J. Am. Chem. Soc. 127, 11029–11036.

Jacobson, R. (1998). Private communication to the Rigaku Corporation, Tokyo, Japan.

Kelley, J. L., Krochmal, M. P., Linn, J. A., McLean, E. W. & Soroko, F. E. (1988). J. Med. Chem. 31, 1005-1009.

Kim, Y. C., Ji, X. D. & Jacobson, K. A. (1996). J. Med. Chem. 39, 4142-4148.

Lin, R., Connolly, P., Chiu, G., Yu, Y., Li, S., Emanuel, S. & Greenberger, L. (2007). 234th ACS National Meeting, Boston, August 19–23.

Rigaku (2004). CrystalClear. Rigaku Corporation, Tokyo, Japan.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Spek, A. L. (2003). J. Appl. Cryst. 36, 7–13.

Stachlewitz, R. F., Arteel, G. E., Raleigh, J. A., Connor, H. D., Mason, R. P. & Thurman, R. G. J. (1997). J. Pharmacol. Exp. Ther. 282, 1591–1599.

Zocchi, C., Ongini, E., Conti, A., Monopoli, A., Negretti, A., Baraldi, P. G. & Dionisotti, S. (1996). J. Pharmacol. Exp. Ther. 276, 398-404.