798
Vol. 55, No. 5
[5.2.1.02,6]dec-8-en-4-yl)-3-phenyl-thiourea (k1) Yield 3.18 g (83%). mp
191 °C. H-NMR (400 MHz, CDCl3) d: 0.62 (d, Jꢁ8 Hz, 3H, CH3), 1.35 (s,
3H, CH, CH2), 3.2 (s, 1H, CH), 3.79 (s, 3H, O-CH3), 5.7 (d, Jꢁ5.2 Hz, 1H,
CH), 6.81—6.88 (m, 3H, NH, Carom.), 7.22—7.24 (m, 2H, Carom.).
C22H27O4N3 (397.46): Calcd C 66.48, H 6.85, N 10.57; Found C 66.40, H
6.86, N 10.44.
1
6H, CH3), 1.48 (s, 6H, CH3), 1.61 (q, 1H, CH), 3.0 (s, 2H, CH), 7.27—7.38
(m, 5H, CHarom.), 7.71 (s, 1H, NH), 8.10 (s, 1H, NH). C21H25O2N3S
(383.50): Calcd C 65.77, H 6.57, N 10.96; Found C 65.74, H 6.5, N 10.84.
(1S,2R,6S,7R) 1-(1,7,8,9,10-Pentamethyl-3,5-dioxo-4-aza-tricyclo-
[5.2.1.02,6]dec-8-en-4-yl)-3-phenyl-urea (k1a) Yield 3.9 g (82%). mp
(1R,2S,6R,7R,10R) 1-Cyclohexyl-3-(10-isopropyl-8-methyl-3,5-dioxo-
4-aza-tricyclo[5.2.2.02,6]undec-8-en-4-yl)-thiourea (h3) Yield 2.8 g
(72%). mp 201 °C. 1H-NMR (400 MHz, CDCl3) d: 0.81 (d, Jꢁ6 Hz, 3H,
CH3), 0.92 (d, Jꢁ7.2 Hz, 3H, CH3), 1.07—1.15 (m, 6H, CH, CHcyclohexyl),
1.35—1.38 (m, 1H, CH), 1.62—1.86 (m, 4H, Ccyclohexyl), 1.78 (s, 3H, CH3),
1.98—12.05 (m, 1H, CH), 2.9—3.01 (m, 3H, CH, CH2), 3.2 (s, 1H, CH),
4.12 (s, 1H, NH), 5.72 (d, Jꢁ4 Hz, 1H, CH), 6.22 (s, 1H, NH). C21H31O2N3S
(389.55): Calcd C 64.75, H 7.02, N 10.79; Found C 65.02, H 7.07, N 10.95.
(1R,2S,6R,7R,10R) 1-Cyclohexyl-3-(10-isopropyl-8-methyl-3,5-dioxo-
4-aza-tricyclo[5.2.2.02,6]undec-8-en-4-yl)-urea (h3a) Yield 2.46 g (66%).
1
240 °C. H-NMR (400 MHz, CDCl3) d: 0.62 (d, Jꢁ6.4 Hz, 3H, CH3), 1.35
(s, 6H, CH3), 1.55 (s, 6H, CH3), 1.57—1.65 (m, 1H, CH), 3.07 (s, 2H, CH),
7.51—7.84 (m, 5H, CHarom.), 9.25 (s, 1H, NH), 11.82 (s, 1H, NH).
C21H25O3N3 (367.44): Calcd C 68.64, H 6.86, N 11.44; Found C 68.9, H
6.75, N 11.46.
(1S,2R,6S,7R) 1-(4-Methoxy-phenyl)-3-(1,7,8,9,10-pentamethyl-3,5-
dioxo-4-aza-tricyclo [5.2.1.02,6]dec-8-en-4-yl)-thiourea (k2) Yield 2.84 g
1
1
(69%). mp 127 °C. H-NMR (400 MHz, CDCl3) d: 0.61 (d, Jꢁ12 Hz, 3H,
mp 107 °C. H-NMR (400 MHz, CDCl3) d: 0.83 (d, Jꢁ6.8 Hz, 3H, CH3),
CH3), 1.34 (s, 6H, CH3), 1.53 (s, 6H, CH3), 1.6 (q, 1H, CH), 3.03 (s, 2H,
CH), 3.79 (s, 3H, O-CH3), 6.89 (d, Jꢁ12 Hz, 2H, CHarom.), 7.27 (d, Jꢁ12 Hz,
2H, CHarom.), 7.9 (s, 1H, NH), 8.12 (s, 1H, NH). C22H27O3N3S (413.53):
Calcd C 62.9, H 6.58, N 10.16; Found C 62.78, H 6.29, N 10.07.
(1S,2R,6S,7R) 1-(4-Methoxy-phenyl)-3-(1,7,8,9,10-pentamethyl-3,5-
dioxo-4-aza-tricyclo[5.2.1.02,6]dec-8-en-4-yl)-urea (k2a) Yield 3.13 g
(79%). mp 205 °C. 1H-NMR (400 MHz, CDCl3) d: 0.62 (d, Jꢁ8 Hz, 3H,
CH3), 1.33 (s, 6H, CH3), 1.54 (s, 6H, CH3), 1.65 (s, 1H, CH), 2.95 (s, 2H,
CH), 3.74 (s, 3H, O-CH3), 4.81 (s, 1H, NH), 6.75 (d, 2H, CHarom.), 7.17 (s,
1H, NH), 7.17—7.23 (m, 2H, CHarom.). C22H27O4N3 (397.46): Calcd C
66.48, H 6.85, N 10.57; Found C 66.52, H 6.47, N 10.47.
(1S,2R,6S,7R) 1-Cyclohexyl-3-(1,7,8,9,10-pentamethyl-3,5-dioxo-4-
aza-tricyclo[5.2.1.02,6]dec-8-en-4-yl)-thiourea (k3) Yield 3.07 g (72%).
mp 127 °C. 1H-NMR (400 MHz, CDCl3) d: 0.61 (d, Jꢁ8 Hz, 3H, CH3),
1.15—1.27 (m, 6H, CHcyclohexyl), 1.37 (s, 6H, CH3), 1.53 (s, 6H, CH3),
1.58 (q, 1H, CH), 1.70—1.73 (m, 2H, CHcyclohexyl), 2.03—12.06 (m, 2H,
CHcyclohexyl), 3.02 (s, 2H, CH), 4.13 (s, 1H, NH), 6.13 (s, 1H, NH).
C21H31O2N3S (389.55): Calcd C 64.75, H 8.02, N 10.79; Found C 64.96;
H 8.02, N 10.72.
0.93 (d, Jꢁ8 Hz, 3H, CH3), 1.08—1.14 (m, 6H, CH, CHcyclohexyl), 1.26—1.34
(m, 5H, CH, CHcyclohexyl), 1.84 (s, 3H, CH3), 1.86—1.92 (m, 1H, CH), 2.95
(m, 1H, CH), 3.02 (s, 2H, CH2), 3.23 (s, 1H, CH), 4.93 (s, 1H, NH), 5.77 (d,
Jꢁ4 Hz, 1H, CH), 8.66 (s, 1H, NH). C21H31O3N3 (373.48): Calcd C 67.53, H
8.37, N 11.25; Found C 67.94, H 8.39, N 10.88.
(1S,2R,6S,7S) 1-(1-Isopropyl-7-methyl-3,5-dioxo-4-aza-tricyclo-
[5.2.2.02,6]undec-8-en-4-yl)-3-phenyl-thiourea (d1) Yield 2.87 g (75%).
1
mp 108 °C. H-NMR (400 MHz, CDCl3) d: 0.98 (d, Jꢁ6.8 Hz, 3H, CH3),
1.12 (d, Jꢁ6.4 Hz, 3H, CH3), 1.26—1.37 (m, 2H, CH2), 1.49 (s, 3H, CH3),
1.51—1.57 (m, 2H, CH2), 2.53—2.58 (m, 1H, CH), 2.76 (d, Jꢁ8 Hz, 1H,
CH), 3.12 (d, Jꢁ8.4 Hz, 1H, CH), 5.95 (d, Jꢁ8.4 Hz, 1H, CHꢁ), 6.03 (d,
Jꢁ8.4 Hz, 1H, CHꢁ), 7.28—7.43 (m, 5H, CHarom.), 7.53 (s, 1H, NH), 8.17
(s, 1H, NH). C21H25O2N3S (383.50): Calcd C 65.77, H 6.57, N 10.96; Found
C 65.93, H 6.55, N 10.97.
(1S,2R,6S,7S) 1-(1-Isopropyl-7-methyl-3,5-dioxo-4-aza-tricyclo-
[5.2.2.02,6]undec-8-en-4-yl)-3-phenyl-urea (d1a) Yield 2.71 g (74%). mp
1
171 °C. H-NMR (400 MHz, CDCl3) d: 1.03 (d, Jꢁ6.8 Hz. 3H, CH3), 1.14
(d, Jꢁ6.8 Hz, 3H, CH3), 1.36—1.46 (m, 2H, CH2), 1.54 (s, 3H, CH3),
1.56—1.69 (m, 2H, CH2), 2.52—2.59 (m, 1H, CH), 2.89 (d, Jꢁ8 Hz, 1H,
CH), 3.28 (d, Jꢁ8,4 Hz, 1H, CH), 6.21 (d, Jꢁ8.4 Hz, 1H, CHꢁ), 6.29 (d,
Jꢁ8.4 Hz, 1H, CHꢁ), 7.05—7.47 (m, 7H, CHarom., NH). C21H25O3N3
(367.44): Calcd C 68.64, H 6.86, N 11.44; Found C 68.50, H 6.71, N 11.37.
(1S,2R,6S,7S) 1-(1-Isopropyl-7-methyl-3,5-dioxo-4-aza-tricyclo-
[5.2.2.02,6]undec-8-en-4-yl)-3-(4-methoxy-phenyl)-thiourea (d2) Yield
2.56 g (62%). mp 126 °C. 1H-NMR (400 MHz, CDCl3) d: 0.98 (d, Jꢁ3.6 Hz,
3H, CH3), 1.11 (d, Jꢁ3.6 Hz, 3H, CH3), 1.27—1.40 (m, 2H, CH2), 1.49 (s,
3H, CH3), 1.58—1.53 (m, 2H, CH2), 2.55—2.57 (m, 1H, CH), 2.75 (d,
Jꢁ6 Hz, 1H, CH), 3.11 (d, Jꢁ6 Hz, 1H, CH), 3.81 (s, 3H, O-CH3), 5.93 (d,
1H, CHꢁ), 5.99 (d, 1H, CHꢁ), 6.91—6.93 (m, 2H, CHarom.), 7.30—7.36 (m,
3H, CHarom., NH), 8.0 (s, 1H, NH). C22H27O3N3S (413.53): Calcd C 63.9, H
6.58, N 10.16; Found C 64.26, H 6.64, N 10.14.
(1S,2R,6S,7R) 1-Cyclohexyl-3-(1,7,8,9,10-pentamethyl-3,5-dioxo-4-
aza-tricyclo[5.2.1.02,6]dec-8-en-4-yl)-urea (k3a) Yield 2.72 g (73%). mp
1
256 °C. H-NMR (400 MHz, CDCl3) d: 0.62 (d, Jꢁ8 Hz, 3H, CH3), 1.09—
1.14 (m, 6H, CHcyclohexyl), 1.33 (s, 6H, CH3), 1.51 (s, 6H, CH3), 1.60 (q, 1H,
CH), 1.67—1.7 (m, 2H, CHcyclohexyl), 1.90—1.93 (m, 2H, CHcyclohexyl), 2.96
(s, 2H, CH), 4.77 (s, 1H, NH), 6.38 (s, 1H, NH). C21H31O3N3 (373.48):
Calcd C 67.53, H 8.37, N 11.25; Found C 67.62, H 8.17, N 11.23.
Pharmacology The experiments were performed on male Albino Swiss
mice (18—30 g). 8—10 animals were kept in a cage, at room temp. of
20ꢃ1 °C, on a 12 : 12 h dark–light cycle. Standard food (Bacutil, Motycz)
and water were available ad libitum. The investigated substance, marked as
k1a, was administered i.p. in the volume of 10 ml/kgꢀ1 as suspensions in
aqueosus solution of 0.5% methylcellulose (tylose). The compounds were
injected 60 min before the test. Controls received the equivalent volume of
the solvent.
(1S,2R,6S,7S) 1-(1-Isopropyl-7-methyl-3,5-dioxo-4-aza-tricyclo-
[5.2.2.02,6]undec-8-en-4-yl)-3-(4-methoxy-phenyl)-urea (d2a) Yield
1
3.13 g. mp 145 °C. H-NMR (400 MHz, CDCl3) d: 1.02 (d, Jꢁ6.8 Hz, 3H,
All performed tests, suggested by Vogel and Vogel29) are generally ac-
cepted as basic in investigation of the central activity by behavioral methods.
The acute toxicity of the compound was assessed in mice according to
Litchfield and Wilcoxon method,30) as the LD50 calculated from mortality
within 48 h. In addition, the activity of compounds was assessed in the fol-
lowing test:
• Locomotor activity was measured in photoresistor actometers for single
mice for 30 min as a) spontaneous activity and b) amphetamine-induced hy-
peractivity: mice received subcutaneusly (s.c.) 5 mg/kg of amphetamine
30 min before the test.
CH3), 1.14 (d, Jꢁ6.8 Hz, 3H, CH3), 1.34—1.45 (m, 2H, CH2), 1.53 (s, 3H,
CH3), 1.59—1.65 (m, 2H, CH2), 2.52—2.57 (m, 1H, CH), 2.87 (d,
Jꢁ8.4 Hz, 1H, CH), 3.27 (d, Jꢁ8.8 Hz, 1H, CH), 3.81 (s, 3H, O-CH3), 5.95
(d, Jꢁ8.4 Hz, 1H, CHꢁ), 6.25 (d, Jꢁ8.4 Hz, 1H, CHꢁ), 6.81—6.92 (m, 3H,
CHarom., NH), 7.20—7.37 (m, 2H, CHarom.), 10.65 (s, 1H, NH). C22H27O4N3
(397.46): Calcd C 66.48, H 6.85, N 10.57; Found C 66.76, H 6.58, N 10.47.
(1S,2R,6S,7S) 1-Cyclohexyl-3-(1-isopropyl-7-methyl-3,5-dioxo-4-aza-
tricyclo[5.2.2.02,6]undec-8-en-4-yl)-thiourea (d3) Yield 2.56 g (66%). mp
1
112 °C. H-NMR (200 MHz, DMSO) d: 1.01 (d, Jꢁ6.8 Hz, 3H, CH3), 1.11
(d, Jꢁ6.4 Hz, 3H, CH3), 1.15—1.43 (m, 10H, CH2 cyclohexyl), 1.49 (s, 3H,
CH3), 1.52—1.57 (m, 2H, CH2), 1.7—1.74 (m, 2H, CHcyclohexyl), 2.50—2.55
(m, 1H, CH), 2.71 (d, Jꢁ8.4 Hz, 1H, CH), 3.08 (d, Jꢁ4 Hz, 1H, CH), 4.0 (s,
1H, NH), 5.98 (d, Jꢁ8 Hz, 1H, CHꢁ), 6.08 (d, Jꢁ8 Hz, 1H, CHꢁ), 7.32 (s,
1H, NH). C21H31O2N3S (389.55): Calcd C 67.75, H 8.02, N 10.79; Found C
67.69, H 7.80, N 11.24.
• Nociceptive reactions were studied in 0.6% acetic acid-induced
writhing test.31) The number of writhing episodes was measured for 10 min
starting 5 min after i.p. administration of acid solution.
• Motor coordination was evaluated in rota rod test32) and chimney test.33)
• Body temperatue in normothermic mice was measured in the rectum by
thermistor thermometer.
(1S,2R,6S,7S) 1-Cyclohexyl-3-(1-isopropyl-7-methyl-3,5-dioxo-4-aza-
tricyclo[5.2.2.02,6]undec-8-en-4-yl)-urea (d3a) Yield 2.31 g (62%). mp
• Pentylenetetrazole (110 mg/kg, s.c.)-induced convulsions were evalu-
ated as the number of mice with clonic seizures, tonic convulsions and dead
animals.
• “Head twitch” responses after 5-hydroxytryptophan (5-HTP), according
to Corne et al.34) Mice received 5-HTP (180 mg/kg, i.p.) and the number of
head twitches was recorded in 6 two-minute intervals (4—6, 14—16, 24—
26, 34—36, 44—46, 54—56 min).
1
203 °C. H-NMR (400 MHz, CDCl3) d: 0.98 (d, Jꢁ6.8 Hz, 3H, CH3), 1.10
(d, Jꢁ6.4 Hz, 3H, CH3), 1.06—1.34 (m, 4H, CH2 CHcyclohexyl), 1.28—1.38
(m, 6H, CH2 CHcyclohexyl), 1.35 (s, 3H, CH3), 1.59—1.7 (m, 2H, CH2), 1.91—
1.94 (m, 2H, Ccyclohexyl), 2.52—2.59 (m, 1H, CH), 2.67 (d, Jꢁ8 Hz, 1H, CH),
3.05 (d, Jꢁ8 Hz, 1H, CH), 4.80 (s, 1H, NH), 5.97 (d, Jꢁ8.4 Hz, 1H, CHꢁ),
6.05 (d, Jꢁ8.4 Hz, 1H, CHꢁ), 6.35 (s, 1H, NH). C21H31O3N3 (373.48):
Calcd C 67.53, H 8.37, N 11.25; Found C 67.67, H 8.32, N 11.22.
The compound was injected in doses equivalent to 0.1 LD50 (200 mg/kg).
Statistics Obtained data were calculated by Student’s t-test and c2 test
(1S,2R,6S,7R) 1-(1,7,8,9,10-Pentamethyl-3,5-dioxo-4-aza-tricyclo-