Deaza Derivatives of Anpirtoline
17
General procedure forpreparationof 4-phenylsulfanylpiperidine derivatives
Hydrochloride of 4-(4-Chlorophenylsulfanyl)piperidine (3j)
3
Yield 39%, mp 259–266 °C. 1H-NMR (DMSO-d6): δ = 1.86 (m, 2H, H-3,
H-5), 2.08 (m, 2H, H-3, H-5), 2.89 (m, 2H, H-2, H-6), 3.33 (m, 2H, H-2,
H-6), 3.68 (m, 1H, H-4), 7.80 (AA′BB′ system, 4H, H-2′, H-3′, H-5′, H-6′),
9.29 (bs, 2H, N+H2). Anal. (C11H15Cl2NS) C, H, Cl, N, S.
1-Ethoxycarbonylpiperidin-4-ylsulfanyl derivative 2 (5 mmol) was dis-
solved in a mixture of acetic acid (10 mL) and concentrated hydrochloric
acid (10 mL) and the mixture was refluxed for 24–48 h (TLC). Then the
mixture was evaporated to dryness and the residue was crystallized from
2-propanol (if not otherwise stated).
Hydrochloride of 4-(3,4-Dichlorophenylsulfanyl)piperidine (3k)
Yield 28%, mp 182–185 °C. 1H-NMR (DMSO-d6): δ = 1.68–1.88 (m, 2H,
H-3, H-5), 2.09 (m, 2H, H-3, H-5), 2.97 (m, 2H, H-2, H-6), 3.25 (m, 2H, H-2,
H-6), 3.64 (m, 1H, H-4), 7.41 (dd, J = 8.5 Hz, 2.2 Hz, 1H, H-6′), 7.60 (d, J
= 8.5 Hz, 1H, H-5′), 7.68 (d, J = 2.2 Hz, 1H, H-2′), 9.29 (bs, 2H, N+H2). Anal.
(C11H14Cl3NS) C, H, Cl, N, S.
Hydrochloride of 4-Phenylsulfanylpiperidine (3a)
Yield 64%, mp 158–159 °C. 1H-NMR (DMSO-d6): δ = 1.65-1.85 (m, 2H,
H-3, H-5), 2.07 (m, 2H, H-3, H-5), 2.96 (m, 2H, H-2, H-6), 3.24 (m, 2H, H-2,
H-6), 3.50 (m, 1H, H-4), 7.24–7.48 (m, 5H, H-2′, H-3′, H-4′, H-5′, H-6′),
9.22 (bs, 2H, N+H2). Anal. (C11H16ClNS) C, H, Cl, N, S.
Hydrochloride of 4-(3,5-Dichlorophenylsulfanyl)piperidine (3l)
Hydrochloride of 4-(4-Fluorophenylsulfanyl)piperidine (3b)
Yield 35%, mp 171–174 °C (ethanol). 1H-NMR (DMSO-d6): δ = 1.80 (m,
2H, H-3, H-5), 2.11 (m, 2H, H-3, H-5), 3.01 (m, 2H, H-2, H-6), 3.26 (m, 2H,
H-2, H-6), 3.75 (m, 1H, H-4), 7.46 m, 3H, H-2′, H-4′, H-6′), 9.38 (bs, 2H,
N+H2). Anal. (C11H14Cl3NS) C, H, Cl, N, S.
Yield 52%, mp 168–169 °C. 1H-NMR (DMSO-d6): δ = 1.65–1.85 (m, 2H,
H-3, H-5), 2.05 (m, 2H, H-3, H-5), 2.94 (m, 2H, H-2, H-6), 3.30 (m, 2H, H-2,
H-6), 3.43 (m, 1H, H-4), 7.21 (tt, J = 8.8 Hz, 2.2 Hz, 2H, H-2′, H-6′), 7.51
(m, 2H, H-3′, H-5′), 9.34 (bs, 2H, N+H2). Anal. (C11H15ClFNS) C, H, Cl, F,
N, S.
Hydrochloride of 4-(3-Fluorophenylsulfanyl)piperidine (3m)
Yield 61%, mp 121–126 °C. 1H-NMR (DMSO-d6): δ = 1.60–1.75 (m, 2H,
H-3, H-5), 2.00-2.15 (m, 2H, H-3, H-5), 2.85 (m, 2H, H-2, H-6), 3.15 (m,
2H, H-2, H-6), 3.35 (m, 1H, H-4), 7.10-7.35 (m, 4H, H-2′, H-4′, H-5′, H-6′),
9.38 (bs, 2H, N+H2). Anal. (C11H15ClFNS) C, H, Cl, F, N, S.
Hydrochloride of 4-(2-Nitrophenylsulfanyl)piperidine (3c)
Yield 64%, mp 264–268 °C. 1H-NMR (DMSO-d6): δ = 1.85 (m, 2H, H-3,
H-5), 2.16 (m, 2H, H-3, H-5), 3.06 (m, 2H, H-2, H-6), 3.28 (m, 2H, H-2,
H-6), 3.84 (m, 1H, H-4), 7.47 (ddd, J = 8.2 Hz, 7.0 Hz, 1.4 Hz, 1H, H-4′ or
H-5′), 7.73 (ddd, J = 8.2 Hz, 7.0 Hz, 1.4 Hz, 1H, H-4′ or H-5′), 7.82 (dd, J =
8.2 Hz, 1.4 Hz, 1H, H-6′), 8.11 (dd, J = 8.2 Hz, 1.4 Hz, 1H, H-3′), 9.33 (bs,
2H, N+H2). Anal. (C11H15ClN2O2S) C, H, Cl, N, S.
Hydrochloride of 4-(3-Methylphenylsulfanyl)piperidine (3n)
Yield 56%, mp 150–152 °C. 1H-NMR (DMSO-d6): δ = 1.77 (m, 2H, H-3,
H-5), 2.06 (m, 2H, H-3, H-5), 2.31 (s, 3H, CH3), 2.96 (m, 2H, H-2, H-6),
3.24 (m, 2H, H-2, H-6), 3.49 (m, 1H, H-4), 7.11-7.25 (m, 4H, H-2′, H-4′,
H-5′, H-6′), 9.29 (bs, 2H, N+H2). Anal. (C12H18ClNS) C, H, Cl, N, S.
Hydrochloride of 4-(4-Nitrophenylsulfanyl)piperidine (3d)
Yield 80%, mp 219–222 °C (ethanol). 1H-NMR (DMSO-d6): δ = 1.86 (m,
2H, H-3, H-5), 2.18 (m, 2H, H-3, H-5), 3.05 (m, 2H, H-2, H-6), 3.28 (m, 2H,
H-2, H-6), 3.87 (m, 1H, H-4), 7.62 (dt, J = 8.9 Hz, 2.2 Hz, 2H, H-2′, H-6′),
8.15 (dt, J = 8.9 Hz, 2.2 Hz, 2H, H-3′, H-5′), 9.36 (bs, 2H, N+H2). Anal.
(C11H15ClN2O2S) C, H, Cl, N, S.
Hydrochloride of 4-(3-Trifluoromethylphenylsulfanyl)piperidine (3o)
Yield 25%, mp 105–106 °C. 1H-NMR (DMSO-d6): δ = 1.78 (m, 2H, H-3,
H-5), 2.10 (m, 2H, H-3, H-5), 2.99 (m, 2H, H-2, H-6), 3.25 (m, 2H, H-2,
H-6), 3.68 (m, 1H, H-4), 7.57–7.66 (m, 2H, H-5′, H-6′), 7.68-7.80 (m, 2H,
H-2′, H-4′), 9.29 (bs, 2H, N+H2). Anal. (C12H15ClF3NS) C, H, Cl, F, N, S.
Hydrochloride of 4-(2,4-Dinitrophenylsulfanyl)piperidine (3e)
1
Yield 33%, mp 279–287 °C (decomp.). H-NMR (DMSO-d6): δ = 1.87
(m, 2H, H-3, H-5), 2.22 (m, 2H, H-3, H-5), 3.08 (m, 2H, H-2, H-6), 3.31 (m,
2H, H-2, H-6), 4.01 (m, 1H, H-4), 8.04 (d, J = 9.1 Hz, 1H, H-6′), 8.42 (dd, J
= 9.1 Hz, 2.6 Hz , 1H, H-5′), 8.86 (d, J = 2.6 Hz, 1H, H-3′), 9.26 (bs, 2H,
N+H2). Anal. (C11H14ClN3O4S) C, H, Cl, N, S.
Hydrochloride of 4-(3-Methoxyphenylsulfanyl)piperidine (3p)
Yield 61%, mp 222–225 °C. 1H-NMR (DMSO-d6): δ = 1.64 (m, 2H, H-3,
H-5), 2.11 (m, 2H, H-3, H-5), 2.83 (m, 2H, H-2, H-6), 3.31 (m, 2H, H-2,
H-6), 3.36 (m, 1H, H-4), 3.74 (s, 3H, CH3), 6.62 (d, J = 2.2 Hz, 1H, H-2′),
6.85 (dd, J = 9.0 Hz, 1H, 2.0 Hz, H-4′), 6.92 (m, 1H, H-5′ or H-6′), 7.24 (m,
1H, H-5′ or H-6′), 9.36 (bs, 2H, N+H2). Anal. (C12H18ClNOS) C, H, Cl, N,
S.
Hydrochloride of 4-(4-Chloro-2-nitrophenylsulfanyl)piperidine (3f)
Yield 55%, mp 250–252 °C. 1H-NMR (DMSO-d6): δ = 1.84 (m, 2H, H-3,
H-5), 2.15 (m, 2H, H-3, H-5), 3.04 (m, 2H, H-2, H-6), 3.28 (m, 2H, H-2,
H-6), 3.84 (m, 1H, H-4), 7.77 (dd, J = 8.6 Hz, 2.4 Hz , 1H, H-5′), 7.85 (d, J
= 8.6 Hz, 1H, H-6′), 8.19 (d, J = 2.4 Hz, 1H, H-3′), 9.25 (bs, 2H, N+H2). Anal.
(C11H14Cl2N2O2S) C, H, Cl, N, S.
Hydrochloride of 4-(4-Methoxyphenylsulfanyl)piperidine (3q)
Yield 47%, mp 168–171 °C. 1H-NMR (DMSO-d6): δ = 1.67 (m, 2H, H-3,
H-5), 2.00 (m, 2H, H-3, H-5), 2.90 (m, 2H, H-2, H-6), 3.23 (m, 2H, H-2,
H-6), 3.32 (m, 1H, H-4), 3.78 (s, 3H, CH3), 6.95 (d, J = 9.1 Hz, 2H, H-2′,
H-6′ or H-3′, H-5′), 7.41 (d, J = 9.1 Hz, 2H, H-2′, H-6′ or H-3′, H-5′), 9.30
(bs, 2H, N+H2). Anal. (C12H18ClNOS) C, H, Cl, N, S.
Hydrochloride of 4-(5-Chloro-2-nitrophenylsulfanyl)piperidine (3g)
Yield 39%, mp 235–238 °C. 1H-NMR (DMSO-d6): δ = 1.83 (m, 2H, H-3,
H-5), 2.16 (m, 2H, H-3, H-5), 3.07 (m, 2H, H-2, H-6), 3.21 (m, 2H, H-2,
H-6), 3.95 (m, 1H, H-4), 7.50 (dd, J = 8.8 Hz, 2.1 Hz, 1H, H-4′), 7.81 (d, J
= 2.1 Hz, 1H, H-6′), 8.16 (d, J = 8.8 Hz, 1H, H-3′), 9.34 (bs, 2H, N+H2). Anal.
(C11H14Cl2N2O2S) C, H, Cl, N, S.
Biological Experiments
Acetic Acid-Induced Writhing
Hydrochloride of 4-(3-Chlorophenylsulfanyl)piperidine (3i)
Writhing was induced by intraperitoneal injection of 0.2 mL of 0.7%
solution of acetic acid to male NMRI mice 30 min after the administration
of 30mg/kg of the tested compound[8]. Writhings were counted for 20 min,
compared with the control and expressed as decrease of the stretching
movements (%).
Yield 53%, mp 161–165 °C. 1H-NMR (DMSO-d6): δ = 1.82 (m, 2H, H-3,
H-5), 2.05 (m, 2H, H-3, H-5), 3.00 (m, 2H, H-2, H-6), 3.26 (m, 2H, H-2,
H-6), 3.95 (m, 1H, H-4), 7.51–7.75 (m, 4H, H-2′, H-4′, H-5′, H-6′), 11.2 (bs,
2.0H, N+H2). Anal. (C11H15Cl2NS) C, H, Cl, N, S.
Arch. Pharm. Pharm. Med. Chem. 332, 13–18 (1999)