SUBSTITUTED 1-(2-THIENYL)CYCLOHEXYLAMINES AND RELATED COMPOUNDS AS POTENTIAL NMDA ANTAGONISTS

Article abstract of DOI:10.1135/cccc19950894

Reactions of bisulfite addition compounds prepared in situ from cyclohexanone or 3,4,5,6-tetrahydro-2H-thiopyran-3-one with potassium cyanide and corresponding amines resulted with high yields in amino nitriles type of V and VI.These compounds were subjected to reactions with 2-thienylmagnesium bromide and in the case of the amino nitriles Vc and Vf with 5-bromo-2-thienylmagnesium bromide.Only in the case of compound Vf, a by-product X was isolated in addition to the desired 1-<1-(5-bromo-2-thienyl)-1-cyclohexyl>piperidine (VIIf).Compound VIIf was used for the synthesis of the carboxylic acid XI.The compounds prepared were tested by some methods of biochemical and behavioural pharmacology.

Full text of DOI:10.1135/cccc19950894

894
Sindelar, Dobrovsky, Krejci, Polivka:
SUBSTITUTED 1-(2-THIENYL)CYCLOHEXYLAMINES AND RELATED
COMPOUNDS AS POTENTIAL NMDA ANTAGONISTS
Karel SINDELAR, Karel DOBROVSKY, Ivan KREJCI and Zdenek POLIVKA
Research Institute for Pharmacy and Biochemistry,
130 60 Prague 3, The Czech Republic
Received January 18, 1995
Accepted February 16, 1995
Reactions of bisulfite addition compounds prepared in situ from cyclohexanone or 3,4,5,6-tetrahydro-
2H-thiopyran-3-one with potassium cyanide and corresponding amines resulted with high yields in
amino nitriles type of V and VI. These compounds were subjected to reactions with 2-thienylmagne-
sium bromide and in the case of the amino nitriles Vc and Vf with 5-bromo-2-thienylmagnesium bro-
mide. Only in the case of compound Vf, a by-product X was isolated in addition to the desired
1-[1-(5-bromo-2-thienyl)-1-cyclohexyl]piperidine (VIIf). Compound VIIf was used for the synthesis
of the carboxylic acid XI. The compounds prepared were tested by some methods of biochemical and
behavioural pharmacology.
Searching for excitatory amino acid antagonists belongs presently to the first line of our
endeavour. For noncompetitive antagonists of the NMDA-receptor complex, anticon-
vulsant and antipsychotic effects and further favourable influence on learning and
memory processes are to be expected. Some compounds with this mechanism of action
were synthesized in the 50th already.
Tiletamine (I, Telazol) is a structural analog of ketamine (II) and phencyclidine (III,
PCP). The last named compound was originally synthesized in 1957 by Parke Davis
Pharmaceutical Company and was supposed to be a dissociate anesthetic1. In clinical
trials however, PCP was really found to be a valuable anesthetic, but its action was
accompanied by producing post-anesthetic hallucinations2,3 which was the reason of
discontinuation of its administration to humans. Later, PCP was approved for use as a
veterinary anesthetic; the mentioned tiletamine (I) is being used in the same indication.
For humans, PCP is the drug of abuse (“angel dust”). In central nervous system, PCP
interacts with various receptors including the σ- and µ-opioid, muscarinic and sero-
tonergic4–6, but it predominantly binds with high affinity to its own PCP binding site,
which has been shown to be associated with the ion channel linked to the NMDA
subtype of excitatory amino acid receptor7–9. There, PCP and its analog including tilet-
amine (I) and tenocyclidine10,11 (IV, TCP) act as noncompetitive NMDA antagonists, so
called “open-channel blockers”.
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Sindelar, Dobrovsky, Krejci, Polivka:
A number of new compounds, whose structures were derived from those of I – III,
has recently been prepared. The aim of such investigations is the research for similar
substances with antagonistic effect on the NMDA receptor in which the undesired hal-
lucinogenic effect would be suppressed.
Our synthesis of compounds of type VII and VIII started from the corresponding
bisulfite addition compounds prepared in situ from cyclohexanone or 3,4,5,6-tetra-
hydro-2H-thiopyran-3-one. Their reactions with potassium cyanide and the correspond-
ing amine resulted with high yields in the amino nitriles V and VI. These compounds
were subjected to reactions with 2-thienylmagnesium bromide and in the case of the
amino nitriles Vb and Vf with 5-bromo-2-thienylmagnesium bromide. Only in the case
of compound Vf, a by-product was isolated in addition to the desired 1-[1-(5-bromo-2-
thienyl)-1-cyclohexyl]piperidine (VIIf). This by-product X resulted from reaction of the
amino nitrile Vf with 2,5-bis(bromomagnesium)thiophene which was formed as a by-
product of the preparation of the Grignard reagent mentioned. Compound VIIf was used
for the synthesis of the carboxylic acid XI (preparation of the organometallic reagent by
means of butyllithium and reaction with solid carbon dioxide).
The compounds prepared were tested by some methods of biochemical and beha-
vioural pharmacology. Inhibition of binding of 1 nM [3H]MK-801 in rat brain cortex
membranes, IC50 (µM): VIIa, 6.2; VIIb, 26; VIIc, 5.3; VIId, 4.1; VIIe, 40.7; VIIf, 1.1; IX,
0.23; X, 100. Compounds VIIb, VIIc, VIId and VIIf in concentrations 1 000 nM inhibied
the binding of 10 nM [3H] kainate in membranes, isolated from rat brains (subpopula-
tion of the glutamate receptors), to 50% of the original values (this finding is being
further studied). Inhibition of binding of 1 nM [3H] glycine to compound in a concen-
tration of 1 000 nM, % of inhibition of the original binding: VIIb, 44; VIIc, 55; VIIe, 89;
VIIf, 87; X, 76. Anticonvulsant effect in the electroshock test in female mice, i.p. dose
of 20 mg/kg, number of protected mice in groups by 6 animals: VIIb, 5/6; VIIc, 5/6;
VIId, 3/6; VIIe, 3/6; VIIIa, and X, indication of effect. Protection from acute anoxia
brought about by potassium cyanide in mice, the i.p. doses of 20 mg/kg used, survival
in sec (in the control group survival of 30 – 36 s): VIIb, 60; VIIc, 61; VIId, 48; VIIe, 48.
More detailed results of the pharmacological testing will be published elsewhere.
EXPERIMENTAL
The melting points of analytical samples were determined with the Mettler FP-5 melting point re-
corder and they are not corrected; the samples were dried in vacuo of about 40 Pa at a room tempera-
ture or at a suitably elevated temperature. IR spectra were recorded with the Unicam SP 2000 or
Perkin–Elmer 298 spectrophotometers, NMR spectra on a Tesla BS 567A (1H at 100 MHz, 13C at
25.14 MHz) in CD3SOCD3 unless stated otherwise, chemical shifts are given in ppm (δ-scale), coup-
ling constants (J) in Hz; mass spectra (m/z, %) were measured on a Varian-MAT 44S (GC-MS) spec-
trometer. The homogeneity of the products and composition of the mixtures were checked by
thin-layer chromatography (TLC) on silica gel (Silufol UV254). Preparative chromatographic separ-
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ations were carried out on columns of silica gel (Fluka 60). The extracts were dried with K2CO3 and
evaporated under reduced pressure on a rotary evaporator.
[2-(3,4-Dimethoxyphenyl)ethyl]methylamine
N-[2-(3,4-Dimethoxyphenyl)ethyl]formamide12 (35.5 g, 0.17 mol) was dissolved in tetrahydrofuran
(340 ml), the solution was treated with NaBH4 (14.1 g, 0.37 mol) and at 20 – 27 °C under stirring
dropwise with BF3 etherate (50.7 g, 0.36 mol). The mixture was stirred for 1 h at room temperature
and then refluxed for 3 h. After cooling it was made alkaline with 20% NaOH (300 ml), the aqueous
layer was separated and extracted with benzene (300 ml). The organic layers were combined, the
solvents were evaporated and the residue was distilled in vacuo; 29.7 g (90%), b.p. 115 – 117 °C/50 Pa.
The literature13 gave b.p. 159 °C/1.48 kPa.
The hydrochloride was obtained by neutralization of the base with the solution of HCl in ether,
m.p. 134 – 136 °C (ethanol–acetone). 1H NMR spectrum: 2.56 s, 3 H (CH3N); 3.00 m, 4 H
(CH2CH2); 3.74 s and 3.76 s, 2 × 3 H (2 × OCH3); 6.77 dd, 1 H, J(2′,6′) = 2.5, J (5′,6′) = 9 (H-6′);
6.88 d, 1 H, J(2′,6′) = 2.5 (H-2′); 6.96 d, 1 H, J(5′,6′) = 9 (H-5′). 13C NMR spectrum: 30.92 t (Ar-CH2);
32.19 q (N−CH3); 49.22 t (CH2N); 2 × 55.50 q (2 × OCH3); 112.04 d (C-5′); 112.58 d (C-2′); 120.56 d
(C-6′); 129.60 s (C-1′); 147.67 s (C-4′); 148.87 s (C-3′). For C11H18ClNO2 + 0.5 H2O (240.7) calcu-
lated: 54.88% C, 7.96% H, 14.73% Cl, 5.82% N; found: 55.10% C, 7.99% H, 14.83% Cl, 5.29% N.
General Procedure for Preparation of Aminonitriles Va – Vf, VIa and VIb
A solution of Na2S2O5 (10.4 g, 0.1 mol) in water (40 ml) was added to cyclohexanone (11.6 g, 0.1
mol) or 3,4,5,6-tetrahydro-2H-thiopyran-3-one14 (11.6 g, 0.1 mol) and the mixture was stirred for 2 h. It
was then treated over 5 min with a solution of KCN (6.6 g, 0.1 mol) in water (15 ml) and with the
corresponding amine (0.11 mol) at 20 – 30 °C. After 4 h of stirring, the mixture was extracted with
ether, the extract was processed, and the residue was either distilled in vacuo or crystallized.
N′-(1-Cyano-1-cyclohexyl)-N,N-diethylethylenediamine (Va): Reaction of cyclohexanone with N,N-
diethylethylenediamine (12.7 g, 0.11 mol) gave 20.5 g (92%) of Va, b.p. 130 °C/0.5 kPa. Literature15
gave the b.p. of 120 °C/0.5 kPa. Dihydrochloride hemihydrate was obtained by neutralization of the
base with HCl in ether and crystallization from ethanol–acetone, m.p. 110 – 113 °C. For
C13H27Cl2N3 + 0.5 H2O (305.3) calculated: 51.14% C, 9.24% H, 23.23% Cl, 13.76% N; found:
51.17% C, 8.91% H, 23.48% Cl, 14.07% N.
N-(1-Cyano-1-cyclohexyl)-N-benzylmethylamine (Vb): Reaction of cyclohexanone with N-benzyl-
methylamine (13.3 g, 0.11 mol) afforded 16.0 g (70%) of Vb, b.p. 156 – 158 °C/30 Pa (in agreement
with ref.16).
N-(1-Cyano-1-cyclohexyl)-N-(2-phenylethyl)methylamine (Vc): Reaction of cyclohexanone with
N-(2-phenylethyl)methylamine (14.9 g, 0.11 mol) resulted in 19.9 g (82%) of Vc, b.p. 168 – 172 °C/0.2 kPa.
For C16H22N2 (242.4) calculated: 79.29% C, 9.15% H, 11.56% N; found: 79.03% C, 9.05% H,
11.75% N.
N-(1-Cyano-1-cyclohexyl)-N-(3-phenylpropyl)methylamine (Vd): Cyclohexanone and N-(3-phenyl-
propyl)methylamine (16.4 g, 0.11 mol) gave by similar procedure 21.6 g (84%) of Vd, b.p. 175 – 178 °C/0.2 kPa.
For C17H24N2 (256.4) calculated: 79.64% C, 9.44% H, 10.93% N; found: 79.49% C, 9.67% H,
10.87% N.
N-(1-Cyano-1-cyclohexyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]methylamine (Ve): Reaction of cy-
clohexanone with [2-(3,4-dimethoxyphenyl)ethyl]methylamine (21.5 g, 0.11 mol) afforded 24.2 g
(80%) of Ve, m.p. 66 – 68 °C (cyclohexane). IR spectrum (Nujol): 810, 816, 880 (Ar-H); 1 140, 1 153,
1 227, 1 255 (ArOR); 1 511, 1 590, 1 604, 3 010 (Ar); 2 210 (CN); 2 785 (N−CH3). 1H NMR
spectrum (CDCl3): 1.30 – 2.20 m, 10 H (5 × CH2 of cyclohexyl); 2.40 s, 3 H (NCH3); 2.75 m, 4 H
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Sindelar, Dobrovsky, Krejci, Polivka:
(ArCH2CH2N); 3.84 s and 3.85 s, 2 × 3 H (2 × OCH3); 6.75 m, 3 H (Ar-H). 13C NMR spectrum
(CDCl3): 2 × 22.18 t (C-3, C-5); 24.80 t (C-4); 34.43 t (ArCH2); 2 × 34.66 t (C-2, C-6); 36.15 q
(N−CH3); 53.71 t (CH2N); 2 × 55.80 q (2 × OCH3); 61.62 s (C-1); 111.30 d (ArC-6); 112.19 d (ArC-2);
119.96 s (CN); 120.63 d (ArC-5); 132.66 s (ArC-1); 147.45 s (ArC-4); 148.79 s (ArC-3).
3-Cyano-3-(1-piperidinyl)-3,4,5,6-tetrahydro-2H-thiopyran (VIa): Reaction of 3,4,5,6-tetrahydro-
2H-thiopyran-3-one with piperidine (9.4 g, 0.11 mol) afforded 19.3 g (92%) of VIa, m.p. 97 – 99 °C
(benzene–light petroleum). 13C NMR spectrum (CDCl3): 24.05 t (C-5); 24.65 t (C-4′); 2 × 26.14 t
(C-3′ and C-5′); 27.71 t (C-6); 33.99 t (C-4); 34.88 t (C-2); 2 × 47.51 t (C-2′ and C-6′); 61.25 s
(C-3); 118.09 s (CN). For C11H18N2S (210.3) calculated: 62.81% C, 8.63% H, 13.32% N, 15.24% S;
found: 62.78% C, 8.57% H, 13.54% N, 15.26% S.
3-Cyano-3-[4-(2-hydroxyethyl)-1-piperazinyl]-3,4,5,6-tetrahydro-2H-thiopyran (VIb): Similar re-
action of 3,4,5,6-tetrahydro-2H-thiopyran-3-one with 1-(2-hydroxyethyl)piperazine (14.3 g, 0.11 mol)
gave 23.2 g (91%) of oily VIb. Neutralization of the base with a solution of maleic acid in acetone
gave hydrogen maleate, m.p. 118 – 123 °C (acetone). 13C NMR spectrum: 24.55 t (C-5); 26.44 t (C-6);
32.64 t (C-4); 33.24 t (C-2); 2 × 43.40 t (C-2′ and C-6′); 2 × 51.47 t (C-3′ and C-5′); 55.05 t (N−CH2);
57.37 s (C-3); 60.35 t (CH2OH); 117.65 s (CN); 2 × 135.72 d (CH=CH of maleate); 2 × 167.24 s
(COOH). For C16H25N3O5S (371.5) calculated: 51.73% C, 6.78% H, 11.31% N, 8.63% S; found:
51.61% C, 6.72% H, 11.01% N, 8.30% S.
General Procedure for Preparation of Cyclohexanes VIIa – VIIf and Thiopyranes VIIIa and IX
Grignard reagent was prepared either from 2-bromothiophene (13.0 g, 0.08 mol) or 2,5-dibromothio-
phene (19.4 g, 0.08 mol) and Mg (2.0 g, 0.08 mol) in ether (60 ml). After 1 h of refluxing, the
solution of the reagent was treated dropwise under stirring with solution of aminonitriles Va – Vf,
VIa, and VIb in ether (40 ml). The mixture was refluxed for further 5 h, decomposed with 20% solution
of NH4Cl (70 ml), the aqueous layer was separated and extracted with ether (100 ml). The ethereal
solutions where combined and the bases were extracted into 10% hydrochloric acid (150 ml). The
acid aqueous layers were made alkaline with 20% NaOH and the bases were extracted with ether
(200 ml). After processing of the extract, the residue was either dissolved in benzene and the solution
filtered through a layer of Al203 (50 g), or was crystallized from a mixture of benzene and light pe-
troleum. Bases obtained were transformed by neutralization with suitable acids to the corresponding
salts.
N′-[1-(2-Thienyl)-1-cyclohexyl]-N,N-diethylethylenediamine (VIIa): Grignard reagent, prepared
from 2-bromothiophene, reacted with the amino nitrile Va (6.7 g, 0.03 mol) and gave 4.5 g (53%) of
oily VIIe which was transformed to the dihydrochloride monohydrate, m.p. 175 – 178 °C (ethanol–ether).
1H NMR spectrum: 1.22 t, 6 H (CH3); 7.15 dd, 1 H, J(4,5) = 5.0, J(3,4) = 3.0 (H-4 of thienyl); 7.50 d,
1 H, J(3,4) = 3.0 (H-3 of thienyl); 7.70 d, 1 H, J(4,5) = 5.0 (H-5 of thienyl). For C16H32Cl2N2OS
(371.4) calculated: 51.74% C, 8.69% H, 19.09% Cl, 7.54 % N, 8.63% S; found: 51.92% C, 8.20% H,
19.48% Cl, 7.51% N, 8.77% S.
N-[1-(5-Bromo-2-thienyl)-1-cyclohexyl]-N-benzylmethylamine (VIIb): Grignard reagent, prepared
from 2,5-dibromothiophene was treated with the amino nitrile Vb (13.7 g, 0.06 mol) and gave 12.25 g
(56%) of VIIb. 13C NMR spectrum (CDCl3): 2 × 22.26 t (C-3 and C-5); 25.99 t (C-4); 33.76 q (CH3);
2 × 36.00 t (C-2 and C-6); 54.45 t (NCH2); 60.73 s (C-1); 109.73 s (C-5 of thienyl); 124.52 d (C-3
of thienyl); 126.53 d (C-4 of benzyl); 2 × 128.18 d (C-2 and C-6 of benzyl); 2 × 128.33 d (C-3 and
C-5 of benzyl); 129.00 d (C-4 of thienyl); 140.95 s (C-1 of benzyl); 148.94 s (C-2 of thienyl).
Neutralization with oxalic acid afforded the hydrogen oxalate, m.p. 188 – 189 °C (aqueous ethanol).
1H NMR spectrum: 1.20 – 2.20 m, 10 H (5 × CH2 of cyclohexyl); 2.08 s, 3 H (N−CH3); 3.50 s, 2 H
(N−CH2); 7.00 d, 1 H, J(3,4) = 5.0, (H-3 of thienyl); 7.21 d, 1 H J(3,4 = 5.0 (H-4 of thienyl); 7.32 s,
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5 H (C6H5CH2). Mass spectrum, m/z (%): 363 (9), 320 (5), 272 (4), 243 (60), 175 (46), 120 (22), 97
(19), 91 (100), 81 (32), 45 (42). For C20H24BrNO4S (454.4) calculated: 52.86% C, 5.32% H, 17.59%
Br, 3.08% N, 7.06% S; found: 52.71% C, 5.50% H, 17.38% Br, 3.14% N, 6.95% S.
N-[1-(2-Thienyl)-1-cyclohexyl]-N-(2-phenylethyl)methylamine (VIIc): Reaction of the Grignard re-
agent, prepared from 2-bromothiophene, with amino nitrile Vc (14.55 g, 0.06 mol) afforded 13.7 g
(76%) of oily VIIc which was neutralized with maleic acid and gave the hydrogen maleate mono-
hydrate, m.p. 117 – 119 °C (ethanol–ether). 13C NMR spectrum: 2 × 22.48 t (C-3 and C-5); 24.20 t
(C-4); 31.37 t (CH2 of benzyl); 2 × 33.09 t (C-2 and C-6); 34.14 q (CH3); 51.39 t (NCH2); 68.05 s
(C-1); 126.76 d (C-3 of thienyl); 127.80 d (C-4 of phenethyl); 2 × 128.55 d (C-2 and C-6 of phenethyl);
2 × 128.85 t (C-3 and C-5 of phenethyl); 130.34 d (C-4 of thienyl); 2 × 135.35 d (CH=CH of maleate);
2 × 137.37 s (C-2 of thienyl and C-1 of phenethyl); 2 × 167.24 s (2 × C=O of maleate). For
C23H31NO5S (433.6) calculated: 63.72% C, 7.21% H, 3.23% N, 7.40% S; found: 63.92% C, 6.91% H,
3.45% N, 7.62% S.
N-[1-(2-Thienyl)-1-cyclohexyl]-N-(3-phenylpropyl)methylamine (VIId): Reaction of the Grignard
reagent, prepared from 2-bromothiophene, was reacted with the amino nitrile Vd (15.4 g, 0.06 mol)
and gave 15.4 g (82%) of oily VIId which was transformed to the hydrogen oxalate, m.p. 127 – 129 °C
(acetone–ethanol–ether). 13C NMR spectrum: 2 × 22.48 t (C-3 and C-5); 24.20 t (C-4); 27.04 t (C−CH2−C
of 3-phenylpropyl); 32.42 t (Ph-CH2); 2 × 33.24 t (C-2 and C-6); 33.76 q (N−CH3); 49.60 t (N−CH2);
66.78 s (C-1); 125.94 d (C-3 of thienyl); 127.58 d (C-4 of phenyl); 128.07 d (C-5 of thienyl); 4 × 128.33 d
(C-2, C-3, C-5 and C-6 of phenyl); 129.60 d (C-4 of thienyl); 138.04 s (C-1 of phenyl); 141.03 s
(C-2 of thienyl); 2 × 164.41 s (2 × COOH of oxalate). Mass spectrum, m/z (%): 313 (M+, C20H27NS,
0.4), 270 (0.5), 242 (0.7), 165 (8), 97 (13), 44 (100). For C22H29NO4S (403.5) calculated: 65.48% C,
7.24% H, 3.47% N, 7.95% S; found: 65.29% C, 7.32% H, 3.77% N, 8.25% S.
N-[1-(2-Thienyl)-1-cyclohexyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]methylamine (VIIe): Reaction of
2-thienylmagnesium bromide with the amino nitrile Ve (18.15 g, 0.06 mol) gave 13.0 g (60%) of
VIIe, m.p. 90 – 91 °C (benzene–light petroleum). IR spectrum (Nujol): 713, 801, 817 854 (Ar-H); 1 028,
1 145, 1 231, 1 266 (ArOR); 1 515, 1 591, 1 606, 3 005, 3 065, 3 093 (Ar); 2 798, 2 815 (CH3). 13C NMR
spectrum (CDCl3): 2 × 22.33 t (C-3 and C-5); 25.99 t (C-4); 34.28 q (N−CH3); 35.78 t (Ar-CH2);
2 × 36.45 t (C-2 and C-6); 52.66 t (N−CH2); 2 × 55.87 q (OCH3); 60.58 s (C-1); 111.30 d (C-5 of
C6H3), 112.48 d (C-2 of C6H3); 120.78 d (C-6 of C6H3); 122.95 d (C-5 of thienyl); 124.14 d (C-3 of
thienyl); 126.01 d (C-4 of thienyl); 133.78 s (C-1 of C6H3); 147.08 s and 147.30 s (C-3 and C-4 of
C6H3); 148.79 s (C-2 of thienyl). For C21H29NO2S (359.5) calculated: 70.15% C, 8.13% H, 3.90% N,
8.92% S; found: 70.27% C, 8.24% H, 4.08% N, 8.94% S.
Hydrogen oxalate, m.p. 136 – 137 °C (ethanol–ether). Mass spectrum, m/z (%): 359 (M+,
1
C21H29NO2S, 0.2), 278 (0.3), 208 (18), 165 (100), 97 (66), 44 (48). H NMR spectrum: 1.00 – 2.20 m,
10 H (5 × CH2 of cyclohexyl); 2.68 s, 3 H (N−CH3); 3.72 s and 3.74 s, 2 × 3 H (2 × OCH3); 3.80 bs,
4 H (Ar−CH2CH2N); 6.70 – 7.40 m, 5 H (C6H3, H-3 and H-4 of thienyl); 7.68 d, 1 H, J(4,5) = 5.0
(H-5 of thienyl). For C23H31NO6S (449.6) calculated: 61.45% C, 6.95% H, 3.12% N, 7.13% S;
found: 61.09% C, 6.83% H, 2.84% N, 6.96% S.
1-[1-(5-Bromo-2-thienyl)-1-cyclohexyl]piperidine (VIIf). Reaction of the Grignard reagent, pre-
pared from 2,5-dibromothiophene, with 1-(1-piperidinyl)cyclohexane-1-carbonitrile17 (Vf, 19.4 g, 0.06 mol)
afforded a mixture of bases (12.4 g) whose crystallization from cyclohexane gave first the by-product,
identified as 2,5-bis[1-(1-piperidinyl)-1-cyclohexyl]thiophene (X) (0.75 g, 6%). IR spectrum (Nujol):
791 (ArH); 1 588, 3 068, 3 085 (Ar); 2 665, 2 735, 2 780, 2 795 (NCH2). 1H NMR spectrum
(CDCl3): 1.10 – 2.20 m, 32 H (10 × CH2 of cyclohexyl and 4 × H-3, 4 × H-4, 4 × H-5 of piperidyl);
2.34 bm, 8 H (4 × H-2, 4 × H-6 of piperidyl); 6.66 s, 2 H (H-3 and H-4 of thienyl). 13C NMR spectrum
(CDCl3): 4 × 22.41 t (2 × C-3, 2 × C-5 of cyclohexyl); 2 × 25.26 t (2 × C-4 of piperidyl); 2 × 26.37 t
(2 × C-4 of cyclohexyl); 4 × 27.34 t (2 × C-3, 2 × C-5 of piperidyl); 4 × 36.08 t, (2 × C-2, 2 × C-6
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of cyclohexyl); 4 × 46.68 t (2 × C-2, 2 × C-6 of piperidyl); 2 × 60.20 s (2 × C-1 of cyclohexyl);
2 × 122.58 d (C-3, C-4 of thienyl); 2 × 144.61 s (C-2, C-5 of thienyl). Mass spectrum, m/z (%): 414
(M+, C26H42N2S, 3), 310 (43), 247 (14), 245 (34), 177 (10), 166 (71), 165 (100), 97 (32), 84 (25), 81
(22), 55 (11), 41 (17). For C26H42N2S (414.7) calculated: 75.30% C, 10.21% H, 6.76% N, 7.73% S;
found: 75.35% C, 10.19% H, 6.53% N, 7.98% S.
Neutralization of X with HCl in ether gave the dihydrochloride sesquihydrate, m.p. 202 – 204 °C
(ethanol–ether). For C26H4444Cl22NS + 1.5 H2O (514.7) calculated: 60.68% C, 9.20% H, 13.78% Cl,
5.44% N; found: 60.76% C, 8.96% H, 13.46% Cl, 5.17% N, 6.18% S.
Evaporation of the mother liquor after isolation of X and crystallization of the residue from ethanol
afforded 9.6 g (49%) of VIIf, m.p. 50 – 52 °C. 1H NMR spectrum (CDCl3): 1.20 – 2.00 m, 16 H
(5 × CH2 of cyclohexyl and 2 × H-3, 2 × H-4, 2 × H-5 of piperidyl); 2.30 bt, 4 H (2 × H-2, 2 × H-6
of piperidyl); 6.55 d, 1 H, J(3,4) = 5.0 (H-3 of thienyl); 6.94 d, 1 H, J(3,4) = 5.0 (H-4 of thienyl).
13C NMR spectrum (CDCl3): 2 × 22.11 t (C-3, C-5 of cyclohexyl); 24.87 t (C-4 of piperidyl); 25.99 t
(C-4 of cyclohexyl); 2 × 27.04 t (C-3, C-5 of piperidyl); 2 × 35.80 t (C-2, C-6 of cyclohexyl); 2 × 46.31 t
(C-2, C-6 of piperidyl); 60.58 s (C-1 of cyclohexyl); 109.28 s (C-5 of thienyl); 124.29 d (C-3 of
thienyl); 128.92 d (C-4 of thienyl); 148.94 s (C-2 of thienyl). Mass spectrum, m/z (%): 329 (M+,
C15H22BrNS, 23), 327 (24), 286 (28), 284 (31), 245 (100), 244 (45), 243 (98), 242 (30), 203 (13),
201 (12), 177 (83), 175 (73), 166 (13), 165 (19), 164 (17), 163 (18), 122 (21), 108 (10), 97 (17), 86
(17), 84 (17), 81 (62), 55 (42), 41 (63). Hydrogen maleate, m.p. 134 – 135.5 °C (ether). For
C19H26BrNO4S (444.4) calculated: 51.35% C, 5.90% H, 17.98% Br, 3.15% N, 7.22% S; found:
51.06% C, 5.92% H, 17.90% Br, 3.39% N, 7.30% S.
1-[3-(2-Thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-3-yl]piperidine (IX): Reaction of the Grignard
reagent, prepared from 2-bromothiophene with the amino nitrile VIa (12.55 g, 0.06 mol) gave 12.6 g
(79%) of oily IX which was transformed to the hydrochloride, m.p. 203 – 205 °C (ethanol). Mass
spectrum, m/z (%): 267 (M+, C14H21NS2, 12), 220 (6), 206 (100), 192 (29), 183 (14), 149 (16), 123
(16), 110 (25), 99 (13), 97 (19), 84 (41), 55 (10), 45 (14). For C14H22ClNS2 (303.9) calculated: 55.3% C,
7.3% H, 11.6% Cl, 4.6% N, 21.1% S; found: 55.2% C, 7.2% H, 11.7% Cl, 4.4% N, 20.8% S.
2-{4-[3-(2-Thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-3-yl]-1-piperazinyl}ethanol (VIIIa): Grignard
reagent, prepared from 2-bromothiophene was reacted with the amino nitrile VIb (7.7 g, 0.03 mol)
and gave 5.0 g (53%) of VIIIa, m.p. 115.5 – 116.5 °C (benzene–cyclohexane). IR spectrum (Nujol):
719, 822, 840 (Ar-H); 1 051, 3 170 (OH); 2 700, 2 775 (NCH2); 3 060 (Ar). 13C NMR spectrum
(CDCl3): 29.90 t (C-5); 28.38 t (C-6); 35.70 t (C-4); 36.30 t (C-2); 2 × 45.12 t (C-3 and C-5 of
piperazinyl); 57.74 t (NCH2); 58.49 s (C-3); 59.23 t (CH2OH); 123.70 d (C-5 of thienyl); 125.12 d
(C-3 of thienyl); 126.24 d (C-4 of thienyl); 145.43 s (C-2 of thienyl). For C15H24N2OS2 (312.5) cal-
culated: 57.65% C, 7.74% H, 8.96% N, 20.52% S; found: 57.88% C, 7.72% H, 8.81% N, 20.40% S.
Hydrogen oxalate, m.p. 181 – 183 °C (aqueous ethanol–ether). For C17H26N2O5S2 (402.5) calculated:
50.72% C, 6.51% H, 6.96% N, 15.93% S; found: 50.62% C, 6.51% H, 7.08% N, 15.88% S.
2-{4-[3-(2-Thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-3-yl]-1-piperazinyl}ethyl Acetate (VIIIb)
A solution of VIIIa (2.0 g, 6.4 mmol) in pyridine (10 ml) was treated with acetic anhydride (2.9 g, 29 mmol)
and the mixture was stirred for 7 h at room temperature. It was then diluted with water and extracted
with ether. Processing of the extract gave 1.13 g (51%) of oily VIIIb which was transformed to the
bis(hydrogen maleate), m.p. 144 – 145 °C (acetone). IR spectrum (KBr): 702, 862 (Ar); 1 225, 3 378,
3 480 (COOH); 1 484, 2 942 (CH2, CH3); 1 362, 1 384, 1 572 (COO−); 1 738 (ester); 2 707 – 2 611
(NH+). For C25H34N2O10S2 (586.7) calculated: 51.18% C, 5.84% H, 4.78% N, 10.93% S; found:
51.24% C, 6.09% H, 4.88% N, 10.88% S.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Substituted 1-(2-Thienyl)cyclohexylamines
901
1-[3-(2-Thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-3-yl]-4-(2-benzyloxyethyl)piperazine (VIIIc)
A solution of VIIIa (3.12 g, 10 mmol) in N,N-dimethylformamide (50 ml) was stirred and treated at
60 °C with an oily suspension of NaH (0.50 g, 16.6 mmol). The mixture was stirred for 30 min,
treated with benzyl chloride (1.6 g, 12.6 mmol) and stirred at 60 °C for further 3 h. After dilution
with water it was extracted with ether. Processing of the extract gave a mixture which was separated
by chromatography on Al2O3 (100 g). Elution with benzene afforded 1.8 g (45%) of VIIIc which was
transformed to the bis(hydrogen maleate), m.p. 142 – 145 °C (acetone–ether). For C30H38N2O9S2
(634.8) calculated: 56.76% C, 6.03% H, 4.41% N, 10.10% S; found: 56.48% C, 6.09% H, 4.15% N,
10.18% S. Continued chromatography using elution with chloroform recovered 1.0 g (32%) of the
starting VIIIa, m.p. 115.5 – 116.5 °C (benzene–cyclohexane).
5-[1-(1-Piperidinyl)-1-cyclohexyl]thiophene-2-carboxylic Acid (XI)
A stirred solution of VIIf (9.0 g, 27.4 mmol) in ether (80 ml) was treated dropwise at (−50) – (−60) °C
over 2 min with 15% solution of butyllithium in hexane (25 ml, 40 mmol). The mixture was stirred
for 2 min and poured into a suspension of solid CO2 (ca 50 g) in ether (50 ml). After evaporation of
the excessive CO2, the mixture was washed with water and the undissolved solid XI was filtered and
crystallized from 40% acetic acid; yield 2.2 g (27%), m.p. 175.5 – 178.5 °C. IR spectrum (Nujol):
1 700, 3 260, 3 360 (COOH); 1 530, 1 595 (Ar); 2 250 (NH+). Mass spectrum, m/z (%): 293 (M+,
C16H23NO2S, 18), 250 (48), 236 (11), 208 (302), 163 (32), 141 (57), 135 (24), 97 (16), 84 (100), 56
(18). For C16H23NO2S (293.4) calculated: 65.46% C, 7.90% H, 4.77% N, 10.93% S; found: 65.46% C,
7.77% H, 4.50% N, 11.18% S.
Evaporation of the ethereal solution gave a mixture (4.1 g) which was separated by chromato-
graphy on silica gel (280 g). Elution with chloroform gave first the starting VIIf (1.25 g, 14%, m.p.
50 – 52 °C) and further a halogen-free product which was identified as 1-[1-(2-thienyl)-1-cyclo-
hexyl]piperidine (IV) (1.26 g, 18%) which was transformed to the hydrochloride melting at 245 – 247 °C
(ethanol–ether). Literature18 gave for the hydrochloride the m.p. of 230 – 235 °C. IR spectrum
(Nujol): 703, 810, 846 (ArH); 2 380, 2 440, 2 580 (NH+); 3 055 (Ar). 13C NMR spectrum: 21.81 t
(C-4 of piperidyl); 2 × 22.48 t (C-3 and C-5 of cyclohexyl); 2 × 22.71 t (C-3 and C-5 of piperidyl);
23.98 t (C-4 of cyclohexyl); 2 × 32.12 t (C-2 and C-6 of cyclohexyl); 2 × 46.68 t (C-2 and C-6 of
piperidyl); 68.42 s (C-1 of cyclohexyl); 127.88 d (C-3 of thienyl); 129.07 d (C-5 of thienyl); 130.94 d
(C-4 of thienyl); 135.95 s (C-2 of thienyl). Mass spectrum, m/z (%): 249 (M+, C15H23NS, 12), 206
(21), 165 (41), 164 (21), 97 (100), 84 (34). For C15H24ClNS (285.9) calculated: 63.02% C, 8.46% H,
12.40% Cl, 4.90% N, 11.21% S; found: 62.80% C, 8.19% H, 12.56% Cl, 5.04% N, 10.96% S.
The authors thank the following colleagues at the Research Institute for Pharmacy and Biochemistry
for co-operation: Dr M. Cech, Mrs R. Svatosova and Mrs A. Svatonova (elemental analyses), Dr J.
Taimr (NMR spectra), Dr M. Ryska (mass spectra), Dr E. Svatek and Mrs R. Hanusova (IR spectra), Dr
R. Lapka, Mrs B. Moserova, Dr J. Sedlackova, and Mrs J. Brychnacova (pharmacology). This work was
supported by the Grant No. Z 001/42-540 of the Ministry of Health and by the Grant No. 307/93 of the
Grant Agency of the Czech Republic.
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