Synthesis and biological activities of 2,6-diaryl-3-methyl-4-piperidone derivatives

Article abstract of DOI:10.1248/bpb.26.188

In the present study, a new series of 2,6-diaryl-3-methyl-4-piperidones was synthesized by Mannich reaction (condensation) of ethyl-methyl ketone, substituted aromatic aldehydes and ammonium acetate. Oximes and thiosemicarbazone derivatives of 2,6-diaryl-3-methyl-4-piperidones were synthesized by reaction with hydroxylamine hydrochloride and thiosemicarbazide respectively. The chemical structures were confirmed by means of IR, ¹H-, ¹³C-NMR and mass spectral data. The compounds were screened for acute toxicity, analgesic, local anaesthetic and antifungal activity. 2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-one 2 exhibited the highest analgesic and local anaesthetic activity. The oximes and thiosemicarbazones were completely devoid of analgesic and local anaesthetic activity. 2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)-piperidin-4-oxime 21 and 2-(4-methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 17 exhibited potent antifungal activity against Aspergillus niger. Antifungal activity against Candida albicans was observed only with 2-(4- dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 20. 2,6-Diaryl-3-methyl-4-piperidones did not exhibit antifungal property.

Full text of DOI:10.1248/bpb.26.188

188
Biol. Pharm. Bull. 26(2) 188—193 (2003)
Vol. 26, No. 2
Synthesis and Biological Activities of 2,6-Diaryl-3-methyl-4-piperidone
Derivatives
Natesh RAMESHKUMAR, ,a Anantharaman VEENA,a Raju ILAVARASAN,b Mandaleeswaran ADIRAJ,a
*
a
Pitchaimuthu SHANMUGAPANDIYAN,a and Seshaiah Krishnan SRIDHAR
b
a Department of Pharmaceutical Chemistry, C. L. Baid Metha College of Pharmacy; and Department of Pharmacology,
C. L. Baid Metha College of Pharmacy; Jyothi Nagar, Thorapakkam, Chennai 600096, India.
Received September 17, 2002; accepted November 11, 2002
In the present study, a new series of 2,6-diaryl-3-methyl-4-piperidones was synthesized by Mannich reaction
(condensation) of ethyl–methyl ketone, substituted aromatic aldehydes and ammonium acetate. Oximes and
thiosemicarbazone derivatives of 2,6-diaryl-3-methyl-4-piperidones were synthesized by reaction with hydroxyl-
amine hydrochloride and thiosemicarbazide respectively. The chemical structures were confirmed by means of
1
IR, H-, 13C-NMR and mass spectral data. The compounds were screened for acute toxicity, analgesic, local
anaesthetic and antifungal activity. 2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-one 2 exhibited
the highest analgesic and local anaesthetic activity. The oximes and thiosemicarbazones were completely devoid
of analgesic and local anaesthetic activity. 2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)-piperidin-4-oxime
21 and 2-(4-methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 17 exhibited potent antifungal activ-
ity against Aspergillus niger. Antifungal activity against Candida albicans was observed only with 2-(4-dimethyl-
aminophenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 20. 2,6-Diaryl-3-methyl-4-piperidones did not ex-
hibit antifungal property.
Key words piperidone; oxime; thiosemicarbazone; analgesic; local anaesthetic; antifungal
Piperidones were reported to possess analgesic,1,2) anti-in-
pounds gave satisfactory chemical analyses (Ϯ0.4%). The
flammatory,1) central nervous system (CNS),3—7) local anaes-
purity of the compounds were checked by TLC on SiO2 gel
thetic,3,8) anticancer9) and antimicrobial activity.10) Thiosemi-
(HF254, 200 mesh) coated glass plates using (4 : 1) CCl4: pe-
carbazones11—13) and oximes14) were reported to be associ-
troleum ether (40—60 °C) as mobile phase and visualized by
ated with antimicrobial activity. The earlier reports indicated
that the biological activities of piperidones were associated
with substitutions at 2, 3 and 6 positions.3,4) The biological
activity was found to be significant in compounds possessing
aromatic substituents in 2 and/or 6 positions.5,10) The pres-
ence of methyl substitution in 2 or 3 position5,6) was also at-
tributed to biological activities. Therefore, it was envisaged
that a new series of 2,6-diaryl-3-methyl-piperidones and their
corresponding, thiosemicarbazones and oximes would result
in compounds of potent biological activities.
iodine vapours. The spectral data are presented in Table 1.
General Procedure for 3-Methyl-2,6-diaryl-piperidin-4-
one (1—7) A mixture15) of ethyl methyl ketone (0.1 mol),
dried ammonium acetate (0.1 mol), p-chloro/p-hydroxy benz-
aldehyde (0.1 mol) and substituted benzaldehydes (0.1 mol)
in ethanol (30 ml) and heated to simmering carefully. It was
kept at room temperature for 12 h. Dry ether (50 ml) was
added followed by concentrated hydrochloric acid (30 ml)
and cooled in ice water. The precipitated hydrochloride was
filtered and washed repeatedly with ethanol–ether (1 : 5) mix-
ture. The hydrochloride was suspended in acetone, and made
In the present study, a new series of 2,6-diaryl-3-methyl-4-
piperidones was synthesized by Mannich reaction (condensa-
tion) of ethyl methyl ketone, substituted aromatic aldehydes
and ammonium acetate. Oxime and thiosemicarbazone deriv-
atives of 2,6-diaryl-3-methyl-4-piperidones were synthesized
by reaction with hydroxylamine hydrochloride and thiosemi-
carbazide respectively. The chemical structures were con-
1
firmed by means of IR, H-, 13C-NMR and mass spectral
data. The compounds were screened for acute oral toxicity,
analgesic, local anaesthetic and antifungal activity.
CHEMISTRY
The melting points were taken in open capillary tube and
are uncorrected. The IR spectra of the compounds were
recorded on ABB Bomem FTIR spectrometer MB104 with
1
KBr pellets. H-NMR spectra and 13C-NMR were recorded
on 400 MHz-Joel GSX 400 using DMSO-d6 as solvent. The
chemical shifts are reported as parts per million downfield
from tetra methyl silane (Me4Si). Mass spectra were recorded
on Finningan MAT 8230. Microanalyses for C, H, N were
performed in Heraeus CHN Rapid Analyzer. All the com-
Fig. 1. Synthetic Scheme
* To whom correspondence should be addressed. e-mail: clbmcpl@md4.vsnl.net.in
© 2003 Pharmaceutical Society of Japan

February 2003
189
Table 1. Spectral Data of the Synthesized Compounds
Compd IR (KBr) cmϪ1
1H-NMR (DMSO-d6) d ppm
13C-NMR (DMSO-d6) d ppm
EI-MS m/z
1
2
3
4
5
6
3025 (O–H),
2930 (N–H),
11.21 (s, 1H; 4Ј-OH), 9.74 (s, 1H; NH),
203.5, 191.1, 163.5, 158.3, 134.1,
315 (Mϩ) (Calcd for C18H18ClNO2: 315.8),
298, 279, 262, 244, 240, 227, 208, 199, 180,
167, 149, 138(B), 117, 103, 91, 77, 57, 51
6.62—7.87(m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 133.7, 132.1, 131.2, 130.3, 128.5,
125.5, 115.6, 95.5, 64, 58.7, 46.1,
2.28 (m, 3H; 3,5-H), 0.81 (s, 3H; 3-CH3) 44.4, 40.1, 39.5, 38.8, 10.3
9.81 (s, 1H; NH), 7.12—8.06 (m, 8H; 203.3, 138.9, 134.1, 131.2, 130.6,
1722 (CϭO), H), 3.25—3.28 (m, 2H; 2,6-H), 2.04—
828 (Ar–H)
2919 (N–H),
1722 (CϭO), 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 3.54—3.62 (m, 129.3, 128.8, 93.2, 63.9, 58.6, 46.1, 293, 276, 261, 244, 242, 221, 208, 199, 181,
817 (Ar–H)
313 (Mϩ) (Calcd for C19H20ClNO: 313.8),
2H; 2,6-H), 2.62 (s, 3H; 4Ј-CH3), 2.22— 44.6, 40.1, 39.9, 38.8, 20.8, 10.3
2.45 (m, 3H; 3,5-H), 0.84 (s, 3H; 3-CH3)
9.81 (s, 1H; NH), 7.45—7.91 (m, 8H;
168, 167, 146, 138, 118(B), 115, 91, 89, 77,
55, 52
2936 (N–H),
203, 131.1, 130.5, 128.9, 114.1, 64, 329 (Mϩ) (Calcd for C19H20ClNO2: 329.8),
55.4, 40.1, 39.9, 38.8, 10.4
1722 (CϭO), 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 4.1 (s, 3H; 4Ј-
829 (Ar–H)
311, 277, 261, 257, 241, 227, 208, 190, 176,
162, 148, 134(B), 117, 103, 91, 77, 56, 52
OCH3), 3.5—3.64 (m, 2H; 2,6-H), 2.51—
2.60 (m, 3H; 3,5-H), 0.83 (s, 3H; 3-CH3)
9.63 (s, 1H; NH), 7.55—8.07 (m, 7H;
2934 (N–H),
203.4, 134.3, 133.7, 131.2, 130.5,
359 (Mϩ) (Calcd for C20H22ClNO3: 359.8),
1721 (CϭO), 2Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 3.91 (s, 6H; 3Ј,4Ј- 128.8, 63.9, 58.6, 46.1, 44.3, 40.1, 335, 333, 303, 288, 279, 262, 240, 227, 220,
824 (Ar–H)
OCH3), 3.64—3.79 (m, 2H; 2,6-H), 2.54— 39.9, 38.8, 10.3
2.68 (m, 3H; 3,5-H), 0.75 (s, 3H; 3-CH3)
9.81 (s, 1H; NH), 7.49—7.78 (m, 6H;
2Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 4.02 (s, 9H; 3Ј,4Ј,5Ј- 63.9, 58.6, 46.1, 44.3, 40.1, 39.9,
OCH3), 3.56—3.77 (m, 2H; 2,6-H), 2.45— 38.8, 10.3
2.69 (m, 3H; 3,5-H), 0.75 (s, 3H; 3-CH3)
192, 180, 167, 140, 138(B), 117, 103, 77, 57,
55
2934 (N–H),
1721(CϭO),
824 (Ar–H)
203.4, 134.2, 131.2, 130.5, 128.8,
390 (Mϩ) (Calcd for C21H24ClNO4: 389.8),
355, 332, 316, 294, 279, 262, 242, 228, 194,
168, 149(B), 138, 113, 112, 83, 71, 57
2938 (N–H),
9.91 (s, 1H; NH), 7.18—8.04 (m, 8H;
203.4, 134.3, 133.7, 131.3, 130.6,
342 (Mϩ) (Calcd for C20H23ClN2O: 342.8),
1722 (CϭO), 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ, 6Љ-H), 3.67—3.78 (m, 128.9, 111.2, 64.0, 58.7, 46.2, 44.4, 332, 288, 275, 263, 245, 226, 202, 199, 180,
822 (Ar–H)
2H; 2,6-H), 3.08 (s, 6H; 4Ј-N[CH3]2),
2.51—2.84 (m, 3H; 3,5-H), 0.75 (s, 3H;
3-CH3)
10.51 (s, 1H; 4Љ-OH), 9.64 (s, 1H; NH),
7.24—7.82 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 129.5, 128.6, 125.9, 115.6, 65.2,
40.1, 39.9, 38.8, 10.3
167, 151, 138(B), 117, 103, 89, 77, 57, 52
7
8
3025 (O–H),
2930 (N–H),
204.6, 158.5, 139.1, 132.8, 130.7,
295 (Mϩ) (Calcd for C19H21NO2: 295.4),
293, 272, 262, 236, 222, 207, 195, 188, 174,
160, 147, 132, 118(B), 115, 91, 89, 77, 56, 52
1722 (CϭO), H), 3.47—3.61 (m, 2H; 2,6-H), 2.62 (s,
64.8, 59.4, 46.6, 44.9, 40.3, 39.9,
828 (Ar–H)
3H; 4Ј-CH3), 2.51—2.74 (m, 3H; 3,5-H), 21.1, 15.4, 10.6
0.74 (s, 3H; 3-CH3)
3461 (NH2),
3161 (O–H),
2976 (N–H),
1493 (CϭS),
11.21 (s, 1H; 4Ј-OH), 9.78 (s, 1H; NH),
158, 134.3, 133.9, 131.2, 130.6,
389 (Mϩ) (Calcd for C19H21ClN4OS: 388.9),
8.15 (s, 1H; ϭN–NH), 7.01-7.98 (m, 8H; 129.3, 128.8, 115.7, 86.2, 84.1, 63.9, 381, 333, 316, 297, 278, 261, 240, 239, 210,
2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 6.73 (s, 2H; 58.6, 56.1, 46.1, 44.3, 40.9, 39.9, 200, 168, 149, 148(B), 113, 112, 83, 70, 57
NH2), 3.61—3.74 (m, 2H; 2,6-H), 2.53— 38.8, 18.6, 12.2, 10.3
1091 (N–C–N), 2.76 (m, 3H; 3,5-H), 0.76 (s, 3H; 3-CH3)
828 (Ar–H)
9
10
11
12
13
14
3424 (NH2),
2974 (N–H),
1494 (CϭS),
9.69 (s, 1H; NH), 8.13 (s, 1H; ϭN–NH), 161, 131, 128.9, 79.3, 78.9, 64, 46, 386 (Mϩ) (Calcd for C20H23ClN4S: 386.9),
7.49—7.81 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 40.1, 39.9, 38.8
H), 7.34 (s, 2H; NH2), 3.44—3.61 (m, 2H;
361, 346, 321, 303, 289, 275, 261, 243, 232,
215, 191, 177, 167, 149, 128, 117, 91(B), 77,
57, 56
1091 (N–C–N), 2,6-H), 2.55 (s, 3H; 4Ј-CH3), 2.42—2.51
816 (Ar–H)
3420 (NH2),
2935 (N–H),
1495 (CϭS),
(m, 3H; 3,5-H), 0.81 (s, 3H; 3-CH3)
9.81 (s, 1H; NH), 8.04 (s, 1H; ϭN–NH), 158, 130.9, 129.8, 128.6, 113.9,
402 (Mϩ) (Calcd for C20H23ClN4OS: 402.9),
7.36—7.91 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 79.1, 78.8, 64, 55.1, 40, 39.8, 38.9, 333, 329, 308, 279, 262, 258, 227, 209, 190,
H), 6.96 (s, 2H; NH2), 3.74 (s, 3H; 4Ј-
10.1
167, 162, 134(B), 117, 103, 77, 76, 55
1092 (N–C–N), OCH3), 3.42—3.51 (m, 2H; 2,6-H), 2.51—
828(Ar–H)
3421 (NH2),
2935 (N–H),
1495 (CϭS),
2.80 (m, 3H; 3,5-H), 0.75 (s, 3H; 3-CH3)
9.77 (s, 1H; NH), 8.17 (s, 1H; ϭN–NH), 160, 130.9, 128.7, 79.3, 78.9, 64,
7.41—8.01 (m, 7H; 2Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 50, 40.1, 39.9, 38.8, 10.2
7.28 (s, 2H; NH2), 3.81 (s, 6H; 3Ј,4Ј-OCH3),
432 (Mϩ) (Calcd for C21H25ClN4O2S: 432.9),
359, 333, 279, 262, 240, 228, 199, 183, 167,
149(B), 138, 113, 103, 71, 57
1092 (N–C–N), 3.39—3.48 (m, 2H; 2,6-H), 2.47—2.55
827 (Ar–H)
3442 (NH2),
2940 (N–H),
1495 (CϭS),
(m, 3H; 3,5-H), 0.80 (s, 3H; 3-CH3)
9.81 (s, 1H; NH), 8.28 (s, 1H; ϭN–NH), 157, 131, 130.4, 128.7, 100, 79.3,
7.36—7.79 (m, 6H; 2Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H),
7.19 (s, 2H; NH2), 3.96 (s, 9H; 3Ј,4Ј,5Ј-
463 (Mϩ) (Calcd for C22H27ClN4O3S: 463.1),
440, 424, 412, 368, 353, 334, 309, 280, 262,
253, 213, 188, 167, 149, 138(B), 105, 76, 57
78.9, 65.2, 47.5, 40.1, 39.9, 38.8,
21.8, 10.2
1092 (N–C–N), OCH3), 3.42—3.66 (m, 2H; 2,6-H), 2.54—
828 (Ar–H)
3347 (NH2),
2945 (N–H),
1495 (CϭS),
2.77 (m, 3H; 3,5-H), 0.81 (s, 3H; 3-CH3)
9.82 (s, 1H; NH), 8.25 (s, 1H; ϭN–NH), 162, 134, 133.8, 131, 130.4, 128.6, 415 (Mϩ), (Calcd for C21H26ClN5S: 415.9),
7.42—7.86 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 79.2, 78.9, 63.8, 58.5, 45.9, 44.2,
H), 6.72 (s, 2H; NH2), 3.56—3.74 (m, 2H; 40, 39.8, 38.8, 10.1
411, 393, 369, 367, 333, 316, 299, 278, 262,
256, 222, 205, 188, 168, 165, 138(B), 117,
103, 77, 76, 51
1092 (N–C–N), 2,6-H), 2.72 (s, 6H; 4Ј-N[CH3]2), 2.45—
828 (Ar–H)
3467 (NH2),
3421 (O–H),
2922 (N–H),
1512 (CϭS),
2.67 (m, 3H; 3,5-H), 0.82 (s, 3H; 3-CH3)
11.51 (s, 1H; 4Љ-OH), 9.54 (s, 1H; NH),
160, 131.1, 130.5, 128.9, 114.1, 65, 368 (Mϩ) (Calcd for C20H24N4OS: 368.5),
8.15 (s, 1H; ϭN–NH), 6.94—7.34 (m, 8H; 55.4, 40.1, 39.9, 38.8, 10.4
2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 6.68 (s, 2H; NH2),
332, 320, 297, 278, 262, 256, 227, 208, 192,
168, 166, 148(B), 113, 105, 83, 70, 57
3.51—3.76 (m, 2H; 2,6-H), 2.78 (s, 3H;
1069 (N–C–N), 4Ј-CH3), 2.62—2.75 (m, 3H; 3,5-H), 0.89
816 (Ar–H) (s, 3H; 3-CH3)

190
Vol. 26, No. 2
Table 1. Continued
Compd IR (KBr) cmϪ1
1H-NMR (DMSO-d6) d ppm
13C-NMR (DMSO-d6) d ppm
EI-MS m/z
15
16
17
18
19
20
21
3243 (NO–H), 11.12 (s, 1H; NOH), 10.26 (s, 1H; 4Ј-OH), 153.2, 135.1, 134.6, 131.8, 130.9,
2920 (N–H), 9.81 (s, 1H; NH), 6.46—7.98 (m, 8H; 129.1, 128.9, 120.9, 115.6, 79.7,
1652 (CϭN), 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 3.62—3.86 (m, 66.1, 64.3, 59.2, 46.4, 44.7, 40.5,
330 (Mϩ) (Calcd for C18H19ClN2O2: 330.8),
316, 302, 299, 282, 263, 254, 239, 227, 208,
194, 176, 167, 142, 140(B), 115, 111, 89, 77,
57, 51
828 (Ar–H)
2H; 2,6-H), 2.47—2.56 (m, 3H; 3,5-H),
0.85 (s, 3H; 3-CH3)
39.9, 38.2, 28.2, 12.3, 10.6
3229 (NO–H), 11.21 (s, 1H; NOH), 9.69 (s, 1H; NH),
2922 (N–H),
145, 131.1, 130.4, 128.9, 79.3, 78.9, 328 (Mϩ) (Calcd for: 328.8), 308, 291, 279,
7.17—7.75 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 65, 50, 40.1, 39.9, 38.8 263, 255, 243, 222, 208, 191, 172, 167, 149,
1652 (CϭN), H), 3.52—3.65 (m, 2H; 2,6-H), 2.75 (s,
140, 120(B), 105, 91, 77, 69, 54
814 (Ar–H)
3H; 4Ј-CH3), 2.51—2.65 (m, 3H; 3,5-H),
0.83 (s, 3H; 3-CH3)
3306 (NO–H), 11.23 (s, 1H; NOH), 9.71 (s, 1H; NH),
2936 (N–H),
1613 (CϭN), H), 3.84 (s, 3H; 4Ј-OCH3), 3.48—3.56 (m, 59.2, 58.8, 55.2, 40.1, 39.9, 38.8,
159.8, 153.2, 134.9, 134, 133, 131.1, 344 (Mϩ) (Calcd for C19H21ClN2O2: 344.8),
7.37—7.98 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 130.5, 128.6, 113.9, 79.3, 78.6, 65.7, 331, 312, 293, 279, 262, 244, 227, 205, 188,
177, 167, 140(B), 134, 115, 103, 77, 68, 55
829 (Ar–H)
2H; 2,6-H), 2.52—2.78 (m, 3H; 3,5-H),
0.85 (s, 3H; 3-CH3)
37.9, 28, 12, 11.9
3217 (NO–H), 11.17 (s, 1H; NOH), 9.76 (s, 1H; NH),
2938 (N–H),
1599 (CϭN), 3.92 (s, 6H; 3Ј,4Ј-OCH3), 3.52—3.76 (m, 38.1, 37.8, 36.8, 35.9, 25.8, 9.9, 8.2 209, 192, 177, 166, 140(B), 138, 115, 103, 77,
150.8, 132, 131.9, 129.1, 128.4,
374 (Mϩ) (Calcd for C20H23ClN2O3: 374.8),
7.41—8.1 (m, 7H; 2Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 126.6, 77.3, 76.6, 63.7, 56.8, 54.2, 352, 348, 331, 302, 288, 276, 262, 240, 227,
826 (Ar–H)
2H; 2,6-H), 2.48—2.66 (m, 3H; 3,5-H),
0.86 (s, 3H; 3-CH3)
68, 55
3334 (NO–H), 11.12 (s, 1H; NOH), 9.82 (s, 1H; NH),
2938 (N–H), 7.31—7.86 (m, 6H; 2Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H),
1598 (CϭN), 3.91 (s, 9H; 3Ј,4Ј,5Ј-OCH3), 3.61—3.82
150.8, 132, 131.9, 129.1, 128.4,
126.6, 77.3, 76.6, 63.7, 56.8, 54.2, 350, 347, 330, 279, 262, 248, 226, 209, 192,
38.1, 37.8, 36.8, 35.9, 25.8, 9.9, 8.2 167, 166, 140(B), 115, 103, 77, 68, 55
404 (Mϩ) (Calcd for C21H25ClN2O4: 404.9),
827 (Ar–H)
(m, 2H; 2,6-H), 2.53—2.66 (m, 3H; 3,5-
H), 0.85 (s, 3H; 3-CH3)
3335 (NO–H), 11.14 (s, 1H; NOH), 9.82 (s, 1H; NH),
2979 (N–H), 7.32—7.88 (m, 8H; 2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ- 128.9, 115.9, 96.2, 91.6, 79.4, 78.7, 351, 349, 333, 317, 298, 276, 264, 227, 208,
1599 (CϭN), H), 3.47—3.64 (m, 2H; 2,6-H), 2.81 (s,
827 (Ar–H)
152.9, 134.8, 133.7, 131.2, 130.6,
357 (Mϩ) (Calcd for C20H24ClN3O: 357.9),
65.9, 64.2, 59.8, 58.8, 46.2, 44.5, 41, 192, 179, 166, 140(B), 138, 115, 103, 77, 68,
10.4, 6.8
6H; 4Ј-N[CH3]2), 2.48—2.68 (m, 3H; 3,5- 40.3, 39.9, 38, 35.5, 27.9, 19.7, 12.1, 55
H), 0.8 (s, 3H; 3-CH3)
3215 (NO–H), 11.09 (s, 1H; NOH), 10.15 (s, 1H; 4Ј-OH), 153.2, 138.5, 132.9, 129.8, 128.9,
310 (Mϩ) (Calcd for C19H22N2O2: 310.4), 308,
291, 279, 262, 256, 236, 222, 207, 189, 172,
167, 149(B), 132, 120, 105, 91, 71, 57, 54
3010 (O–H),
2938 (N–H),
9.68 (s, 1H; NH), 6.59—7.55 (m, 8H;
2Ј,3Ј,5Ј,6Ј,2Љ,3Љ,5Љ,6Љ-H), 3.49—3.68 (m, 38.9, 37.9, 27.9, 20.7, 11.9
115.1, 79.2, 78.8, 66.2, 40, 39.7,
1600 (CϭN), 2H; 2,6-H), 2.72 (s, 3H; 4Ј-CH3), 2.48—
818 (Ar–H) 2.64 (m, 3H; 3,5-H), 0.84 (s, 3H; 3-CH3)
alkaline using strong ammonia solution. On dilution with ex- 8.17. Found: C, 69.88; H, 6.51; N, 8.29.
cess of water, the base was precipitated which was filtered,
vacuum dried and recrystallized from absolute alcohol.
2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)-
piperidin-4-one 7: Yieldϭ53.4%, mp 196—198 °C, Rf
2-(4-Hydroxyphenyl)-3-methyl-6-(4-chlorophenyl)-pi- valueϭ0.83. Anal. Calcd for C19H21NO2: C, 79.25; H, 7.17;
peridin-4-one 1: Yieldϭ73.4%, mp 218—220 °C, Rf valueϭ N, 4.74. Found: C, 79.44; H, 7.02; N, 4.57.
0.84. Anal. Calcd for C18H18ClNO2: C, 68.46; H, 5.74; N,
4.44. Found: C, 68.51; H, 5.89; N, 4.71.
General Procedure for 3-Methyl-2,6-diaryl-piperidin-4-
thiosemicarbazone (8—14) A mixture of 3-methyl-2,6-di-
aryl-piperidin-4-one (0.01 mol) and thiosemicarbazide (0.01
2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin
-
4-one 2: Yieldϭ94.4%, mp 250—252 °C, Rf valueϭ0.82. mol) dissolved in ethanol (30 ml) was refluxed on a steam
Anal. Calcd for C19H20ClNO: C, 72.72; H, 6.42; N, 4.46. bath for 3 h with continuous stirring. The contents were
Found: C, 73.04; H, 6.26; N, 4.22.
cooled and poured into crushed ice. The precipitate obtained
2-(4-Methoxyphenyl)-3-methyl-6-(4-chlorophenyl)- was filtered, washed with water, vacuum dried and recrystal-
piperidin-4-one 3: Yieldϭ86.1%, mp 230—232 °C, Rf lized from absolute alcohol.
valueϭ0.82. Anal. Calcd for C19H20ClNO2: C, 69.20; H,
2-(4-Hydroxyphenyl)-3-methyl-6-(4-chlorophenyl)-
6.11; N, 4.25. Found: C, 69.48; H, 5.99; N, 4.18.
piperidin-4-thiosemicarbazone 8: Yieldϭ52.5%, mp 170—
2-(3Ј,4-Dimethoxyphenyl)-3-methyl-6-(4-chlorophenyl)- 172 °C, Rf valueϭ0.66. Anal. Calcd for C19H21ClN4OS: C,
piperidin-4-one 4: Yieldϭ48.9%, mp 264—266 °C, Rf 58.68; H, 5.44; N, 14.41. Found: C, 58.92; H, 5.09; N, 14.27.
valueϭ0.91. Anal. Calcd for C20H22ClNO3: C, 66.76; H,
2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-
6.16; N, 3.89. Found: C, 66.61; H, 6.34; N, 3.66.
4-thiosemicarbazone 9: Yieldϭ64.7%, mp 206—208 °C, Rf
2-(3,4,5-Trimethoxyphenyl)-3-methyl-6-(4-chlorophenyl)- valueϭ0.78. Anal. Calcd for C20H23ClN4S: C, 62.09; H, 5.99;
piperidin-4-one 5: Yieldϭ32.5%, mp 250—252 °C, Rf N, 14.48. Found: C, 61.91; H, 6.22; N, 14.56.
valueϭ0.62. Anal. Calcd for C21H24ClNO4: C, 64.71; H,
2-(4-Methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-
6.21; N, 7.19. Found: C, 64.60; H, 6.36; N, 7.31.
piperidin-4-thiosemicarbazone 10: Yieldϭ73.6%, mp 218—
2-(4-Dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)- 220 °C, Rf valueϭ0.91. Anal. Calcd for C20H23ClN4OS: C,
piperidin-4-one 6: Yieldϭ43.9%, mp 198—200 °C, Rf valueϭ 59.62; H, 5.75; N, 13.91. Found: C, 59.88; H, 5.91; N, 13.67.
0.66. Anal. Calcd for C20H23ClN2O: C, 70.08; H, 6.76; N,
2-(3,4-Dimethoxyphenyl)-3-methyl-6-(4-chlorophenyl)-

February 2003
191
piperidin-4-thiosemicarbazone 11: Yieldϭ78.9%, mp 188— compounds and the standard drugs were administered in the
190 °C, Rf valueϭ0.68. Anal. Calcd for C21H25ClN4O2S: C, form of a suspension (1% carboxy methyl cellulose as vehi-
58.27; H, 5.82; N, 12.94. Found: C, 57.98; H, 5.98; N, 13.24. cle) in the same route of administration.
2-(3,4,5-Trimethoxyphenyl)-3-methyl-6-(4-chlorophenyl)-
Animals Inbred wistar albino mice (20—30 g) was used.
piperidin-4-thiosemicarbazone 12: Yieldϭ76.4%, mp 172— They were kept in colony cages at 25Ϯ2 °C, relative humid-
175 °C, Rf valueϭ0.89. Anal. Calcd for C22H27ClN4O3S: C, ity 45—55% under 12 h light and dark cycle. The animals
57.07; H, 5.88; N, 12.10. Found: C, 57.29; H, 6.12; N, 11.98. were fed with standard animal feed and water ad libitum. All
2-(4-Dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)- the animals were acclimatized for a week before use. Small
piperidin-4-thiosemicarbazone 13: Yieldϭ63.5%, mp 216— frogs (Rana tigrina; 100—150 g) was procured locally and
218 °C, Rf valueϭ0.41. Anal. Calcd for C21H26ClN5S: C, used on the same day.
60.65; H, 6.30; N, 16.84. Found: C, 60.41; H, 6.15; N, 16.99.
Acute Oral Toxicity Acute oral toxicity16) was per-
2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)- formed as per OECD-423 guidelines (acute toxic class
piperidin-4-thiosemicarbazone 14: Yieldϭ50.9%, mp 152— method). Wistar albino mice (nϭ3) of either sex selected by
154 °C, Rf valueϭ0.75. Anal. Calcd for C20H24N4OS: C, random sampling technique was used for the study. The ani-
65.19; H, 6.56; N, 15.20. Found: C, 64.91; H, 6.47; N, 15.38. mals were kept fasting for 3—4 h providing only water, after
General Procedure for 3-Methyl-2,6-diaryl-piperidin-4- which the test compounds (suspended in olive oil) were ad-
oxime (15—21) A mixture of 3-methyl-2,6-diaryl-piperidin- ministered orally at the dose level of 5 mg/kg by intragastric
4-one (0.01 mol) and hydroxylamine hydrochloride (0.01 tube and observed for 3 d. If mortality was observed in 2—3
mol) dissolved in ethanol (30 ml) was refluxed on a steam animals, then the dose administered was assigned as toxic
bath for 30 min. The contents were cooled and poured into dose. If mortality was observed in one animal, then the same
crushed ice. The precipitated obtained was filtered, washed dose was repeated again to confirm the toxic dose. If mortal-
with water, vacuum dried and recrystallized from absolute al- ity was not observed, the procedure was repeated for further
cohol.
2-(4-Hydroxyphenyl)-3-methyl-6-(4-chlorophenyl)-
higher doses such as 50, 300 and 2000 mg/kg.
Analgesic Activity The analgesic activity17) was deter-
piperidin-4-oxime 15: Yieldϭ57.5%, mp 196—198 °C, Rf mined by tail immersion method. Wistar albino mice (nϭ6)
valueϭ0.82. Anal. Calcd for C18H19ClN2O2: C, 65.36; H, of either sex selected by random sampling technique was
5.79; N, 8.47. Found: C, 65.44; H, 5.85; N, 8.63.
used for the study. Diclofenac sodium at the dose of 20
2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin- mg/kg was administered as standard drug for comparison.
4-oxime 16: Yieldϭ64.7%, mp 238—240 °C, Rf valueϭ0.72. The test compounds at 2 dose levels (30 and 60 mg/kg) were
Anal. Calcd for C19H21ClN2O: C, 69.41; H, 6.44; N, 8.52. administered orally by intragastric tube. The animals were
Found: C, 69.29; H, 6.58; N, 8.77.
held in position by a suitable restrainer with the tail extend-
2-(4-Methoxyphenyl)-3-methyl-6-(4-chlorophenyl)- ing out and the tail (up to 5 cm) was then dipped in a beaker
piperidin-4-oxime 17: Yieldϭ73.6%, mp 230—232 °C, Rf of water maintained at 55Ϯ0.5 °C. The time in seconds taken
valueϭ0.62. Anal. Calcd for C19H21ClN2O2: C, 66.19; H, to withdraw the tail clearly out of water was taken as the re-
6.14; N, 8.13. Found: C, 65.89; H, 6.30; N, 8.29.
action time. The first reading (0 min) was taken immediately
2-(3,4-Dimethoxyphenyl)-3-methyl-6-(4-chlorophenyl)- after the administration of the test compound and subsequent
piperidin-4-oxime 18: Yieldϭ75.4%, mp 236—238 °C, Rf reaction time was recorded at 30, 60, 120 and 180 min after
valueϭ0.48. Anal. Calcd for C20H23ClN2O3: C, 64.09; H, the administration of compounds. A cut off point of 15 s was
6.18; N, 7.48. Found: C, 63.82; H, 6.37; N, 7.33.
observed to prevent the tail damage. The data are presented
2-(3,4,5-Trimethoxyphenyl)-3-methyl-6-(4-chlorophenyl)- in Table 2.
piperidin-4-oxime 19: Yieldϭ69.3%, mp 238—240 °C, Rf
Local Anaesthetic Activity The local anaesthetic activ-
valueϭ0.41. Anal. Calcd for C21H25ClN2O4: C, 62.29; H, ity18) was determined by nerve block anaesthesia in frogs
6.22; N, 6.92. Found: C, 62.19; H, 6.38; N, 7.09.
(nϭ6). The animal was decerebrated and the upper part of
2-(4-Dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)- the spinal cord was destroyed with a pithing needle. The ab-
piperidin-4-oxime 20: Yieldϭ71.3%, mp 222—224 °C, Rf domen was cut open and all the abdominal organs was re-
valueϭ0.52. Anal. Calcd for C20H24ClN3O: C, 67.12; H, moved, so that a pouch (sac) was made to expose the spinal
6.76; N, 11.74. Found: C, 66.94; H, 6.99; N, 11.66.
nerves. The animal was fixed on a frog board with two of its
2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)- hind legs hanging free from the board. The right leg was im-
piperidin-4-oxime 21: Yieldϭ45.2%, mp 152—154 °C, Rf mersed in a beaker containing 0.1 N hydrochloric acid and the
valueϭ0.74. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; time taken for the absence of withdrawal was noted. The
N, 9.03. Found: C, 73.81; H, 7.22; N, 9.31.
same procedure was repeated for the left leg also. The sac
was filled with 2 ml of the test compounds at 0.5, 1, 2% w/v
(suspended in 1% carboxy methyl cellulose) and the absence
of withdrawal reflex was observed at the interval of 30 s. The
PHARMACOLOGY
The synthesized compounds were evaluated for analgesic, leg was washed with normal saline between exposure to acid.
local anaesthetic and antifungal activity. Acute oral toxicity Lignocaine (0.5, 1, 2% w/v) was taken as the standard drug
test was performed for all the synthesized compounds as per for comparison. The data are presented in Table 3.
organization of economic co-operation and development
Antifungal Activity The antifungal activity19) of the
(OECD) guidelines. Statistical analysis (ANOVA followed by compounds was tested against C. albicans and A. niger using
Dunnett’s t-test) was performed for analgesic activity to as- sabourand dextrose agar medium. The sterilized (antoclaved
certain the significance of the exhibited activity. The test at 120° for 30 min) medium (40—50°) was inoculated

192
Vol. 26, No. 2
Table 2. Analgesic Activity of the Compounds by Tail Immersion Method
Pain reaction time in s (meanϮS.E.M.)
Compound
Dose (mg/kg)
0 min
30 min
60 min
90 min
120 min
180 min
1
2
3
4
5
6
7
30
60
30
60
30
60
30
60
30
60
30
60
30
60
—
20
3.8Ϯ0.61
3.1Ϯ0.45
3Ϯ0.43
2.6Ϯ0.55
3Ϯ0.62
2.8Ϯ0.31
2.6Ϯ0.21
2.6Ϯ0.34
2.8Ϯ0.31
2.3Ϯ0.47
2.6Ϯ0.21
2.6Ϯ0.21
3Ϯ0.25
4.6Ϯ0.43b)
6.3Ϯ0.43b)
6.6Ϯ0.16b)
8.5Ϯ0.56b)
4.3Ϯ0.43b)
4.8Ϯ0.31b)
3.8Ϯ0.31b)
5.3Ϯ0.43b)
4.6Ϯ0.34b)
3.8Ϯ0.3b)
4.3Ϯ0.21b)
4.6Ϯ0.21b)
4.8Ϯ0.3b)
5.8Ϯ0.3b)
2.6Ϯ0.21
6.8Ϯ0.3b)
7.6Ϯ0.43b)
10.3Ϯ0.43b)
9.6Ϯ0.22b)
10.3Ϯ0.43b)
6Ϯ0.58b)
7.6Ϯ0.22b)
10.6Ϯ0.16b)
10.1Ϯ0.32b)
12.8Ϯ0.61b)
7Ϯ0.26b)
6Ϯ0.22b)
5.8Ϯ0.17b)
6.8Ϯ0.61b)
10Ϯ0.59b)
4.8Ϯ0.31b)
7.3Ϯ0.22b)
7Ϯ0.53b)
3.5Ϯ0.22
5.8Ϯ0.32b)
4.6Ϯ0.22b)
5.6Ϯ0.5b)
3.6Ϯ0.43
4.6Ϯ0.43b)
4Ϯ0.53a)
8.8Ϯ0.61b)
5.6Ϯ0.34b)
7.1Ϯ0.32b)
4.8Ϯ0.61b)
5.5Ϯ0.34b)
4.5Ϯ0.34b)
5.8Ϯ0.3b)
9Ϯ0.26b)
6Ϯ0.28b)
9.3Ϯ0.43b)
6.3Ϯ0.35b)
6.8Ϯ0.3b)
5.6Ϯ0.33b)
8Ϯ0.25b)
10.6Ϯ0.68b)
7.6Ϯ0.34b)
7.3Ϯ0.61b)
6.5Ϯ0.28b)
6.3Ϯ0.61b)
5.3Ϯ0.31b)
5.8Ϯ0.56b)
2.3Ϯ0.16
7Ϯ0.53b)
4.6Ϯ0.53b)
5Ϯ0.22b)
3.8Ϯ0.58
3.6Ϯ0.21
3.8Ϯ0.68
4.3Ϯ0.55a)
2.6Ϯ0.36
12.3Ϯ0.43b)
5.8Ϯ0.16b)
7.3Ϯ0.33b)
2.8Ϯ0.16
6.3Ϯ0.43b)
8.5Ϯ0.22b)
2.6Ϯ0.21
3.1Ϯ0.25
2.6Ϯ0.21
2.8Ϯ0.16
Control
Diclofenac
10Ϯ0.25b)
11.8Ϯ0.3b)
14Ϯ0.16b)
Significance levels: a) pϽ0.01, b) pϽ0.001 compared to control.
Table 3. Local Anaesthetic Activity of the Compounds by Nerve Block Table 4. Antifungal Activity of the Compounds by Disc Diffusion Method
Anaesthesia
Zone of inhibition (mm)
Mean absence of foot
withdrawal reflex in s
Compound
Compound
Lignocaine
Concentration
Aspergillus niger
Candida albicans
0.5%
1%
2%
0.5%
1%
2%
0.5%
1%
2%
0.5%
1%
2%
0.5%
1%
2%
0.5%
1%
2%
0.5%
1%
2%
0.5%
1%
2%
82.50
75
60
405
345
300
112.50
90
67.50
270
225
8
9
10
11
12
13
15
16
17
18
19
20
21
9
11
10
10
9
9.5
13
17
19
11
14
16
19
19
—
—
—
—
—
—
—
—
—
—
—
19
—
20
1
2
3
4
5
6
7
210
195
150
135
Ketoconazole
135
112.50
82.50
345
225
210
330
240
210
up to 2000 mg/kg and were considered as safe (x-unclassi-
fied). Compounds 5—7, 13, 17, 18 and 21 produced mortal-
ity at 2000 mg/kg and they were considered as class-4 com-
pounds.
Compounds 1—7 exhibited significant analgesic and local
anaesthetic activity. Graded dose response was observed for
the active compounds. 2-(4-Methylphenyl)-3-methyl-6-(4-
chlorophenyl)-piperidin-4-one 2 exhibited the highest anal-
(1 ml/100 ml of medium) with the suspension of the microor- gesic and local anaesthetic activity. It was observed that
ganism (matched to McFarland barium sulphate standard) when the 4-keto functionality was condensed to form
and poured into a petridish to give a depth of 3—4 mm. The thiosemicarbazones (8—14) or oximes (15—21), the result-
paper impregnated with the test compounds (1 mg/ml in di- ing compounds did not exhibit analgesic and local anaes-
methyl sulphoxide) was placed on the solidified medium. thetic activity. The predominant and stable configuration20) of
The plates were preincubated for 1 h at room temperature and 2,6-diaryl-3-substituted-piperidones is chair form with the
incubated at 37 °C for 48 h for antifungal activity. Ketocona- substituents in the equatorial positions. The analgesic and
zole (100 mg/disc) was used as standard. The observed zone local anaesthetic activity of compounds 1—7 may be attrib-
of inhibition is presented in Table 4.
uted to this favourable configuration. The introduction of
thiosemicarbazino (8—14) or oxime (15—21) substitution
probably leads to unfavourable configuration of the mole-
cules resulting in compounds completely devoid of analgesic
RESULTS AND DISCUSSION
Compounds 1—4, 8—12, 14—20 did not cause mortality and local anaesthetic activity. Therefore, the 4-keto moiety of

February 2003
193
Fernando. Spen., 47, 168—172 (1979).
2) Jerom B. R., Spencer K. H., Eur. Pat. Appl. EP 277794 (1988).
3) Perumal R. V., Adiraj M., Shanmugapandiyan P., Indian Drugs, 38,
156—159 (2001).
the present series of piperidones seems to play a vital role in
the analgesic and local anaesthetic activity of the com-
pounds.
Compounds 8—13, 15—21 exhibit antifungal activity
against A. niger. Antifungal activity against C. albicans was
only observed with 2-(4-dimethylaminophenyl)-3-methyl-6-
(4-chlorophenyl)-piperidin-4-oxime 20. 2-(4-Methylphenyl)-
3-methyl-6-(4-hydroxyphenyl)-piperidin-4-oxime 21 and 2-
(4-methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-
4-oxime 17 was found to exhibit equivalent antifungal activ-
ity against A. niger compared to ketoconazole. The com-
pounds with 4-keto group (1—7) did not exhibit antifungal
activity.
In the present series of compounds, the oxime substitution
at the 4 position and 4-dimethylamino phenyl substitution at
the 2 position seems to play a vital role in the activity against
C. albicans. The activity against A. niger was significantly
higher for oximes (15—21) than the corresponding thiosemi-
carbazones (8—14). The presence of thiosemicarbazino or
oxime functionality at the 4-position of the present series of
piperidones seems to possess an important role in the anti-
fungal activity of the compounds.
4) Bochringer C. F., Shochne G. M. B. H., Brit. Pat. Appl. BP866488
(1961).
5) Ganellin C. R., Spickett R. G., J. Med. Chem., 8, 619—625 (1965).
6) Nikolov M., Stefanora D., Chardanov D., Acta Nerv. Super., 16, 264—
267 (1974).
7) Kathleen B., Jean-Peirre C., Andre H., Eur. Pat. Appl. EP 169139
(1986).
8) Hagenbach R. E., Gysin H., Experentia, 8, 184—188 (1952).
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674 (1985).
10) Mobio I. G., Soldatenkov A. T., Federov V. O., Ageev E. A., Sergeeva
N. D., Lin S., Stashenko E. E., Prostakov N. S., Andreeva E. I., Khim.
Farm. Zh., 23, 421—427 (1989).
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1349—1354 (1981).
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York, 1977, pp. 43—86.
Acknowledgement The authors are thankful to the prin- 17) Palanichamay S., Nagarajan S., J. Ethnopharmacol., 29, 73—79
(1990).
cipal and the management of C. L. Baid Metha College of
Pharmacy, Chennai for their generous support for the work.
18) Laurence D. R., Bacharach A. L. (ed.), “Evaluation of Drug Activities:
Pharmacometrics,” Academic Press, New York, 1964, p. 207.
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