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

Lijun Zhang; Daxin Shi; Jiarong Li; Ling Zhang; Yanqiu Fan

doi:10.1107/S1600536808013366

. 2008 May 10;64(Pt 6):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

Lijun Zhang ^a, Daxin Shi ^a, Jiarong Li ^a,^*, Ling Zhang ^a, Yanqiu Fan ^a

PMCID: PMC2961386 PMID: 21202575

Abstract

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⋯π(arene) interactions.

Related literature

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 ▶).

Experimental

Crystal data

C₁₇H₁₈N₄
M _r = 278.35
Monoclinic,
a = 13.694 (13) Å
b = 6.888 (6) Å
c = 16.929 (16) Å
β = 112.417 (12)°
V = 1476 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 293 (2) K
0.24 × 0.18 × 0.10 mm

Data collection

Rigaku Saturn diffractometer
Absorption correction: multi-scan (Jacobson, 1998 ▶) T _min = 0.982, T _max = 0.992
10708 measured reflections
2593 independent reflections
2004 reflections with I > 2σ(I)
R _int = 0.045

Refinement

R[F ² > 2σ(F ²)] = 0.064
wR(F ²) = 0.162
S = 1.13
2593 reflections
190 parameters
H-atom parameters constrained
Δρ_max = 0.13 e Å⁻³
Δρ_min = −0.16 e Å⁻³

Data collection: CrystalClear (Rigaku, 2004 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; 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.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808013366/dn2339sup1.cif

e-64-o1056-sup1.cif^{(17.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808013366/dn2339Isup2.hkl

e-64-o1056-Isup2.hkl^{(127.4KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1B⋯N4ⁱ	0.86	2.28	3.139 (4)	175
N1—H1A⋯Cg1ⁱⁱ	0.86	2.84	3.608 (4)	150

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Symmetry codes: (i) Inline graphic ; (ii) . Cg1 is the centroid of the benzene ring.

Acknowledgments

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

supplementary crystallographic information

Comment

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).

Experimental

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.