ANTIHISTAMINE SUBSTANCES. TRICYCLIC ANALOGUES OF N-(4,4-DIPHENYL-3-BUTENE-1-YL)NIPECOTIC ACID AND SOME RELATED COMPOUNDS

Article abstract of DOI:10.1135/cccc19940667

Alkylation of ethyl nipecotate with bromides VII - X gave amino esters Ib - Vb.Alkylation of ethyl piperazine-2-carboxylate with 4-bromo-1,1-diphenyl-1-butene afforded compound Vb.Final products Ia - Va were obtained by acid hydrolysis of corresponding esters Ib - Vb.Some of the compounds showed significant antihistamine and antiulcer activities.

Full text of DOI:10.1135/cccc19940667

Antihistamine Substances
667
ANTIHISTAMINE SUBSTANCES. TRICYCLIC ANALOGUES
OF N-(4,4-DIPHENYL-3-BUTENE-1-YL)NIPECOTIC ACID
AND SOME RELATED COMPOUNDS
a
a
b
a
Karel SINDELAR , Alexandra SILHANKOVA , Jiri URBAN , Jan METYS ,
a
a
Martin VALCHAR and Zdenek POLIVKA
a Research Institute for Pharmacy and Biochemistry,
130 00 Prague 3, The Czech Republic
b The J. Heyrovsky Institute of Physical Chemistry,
Academy of Sciences of the Czech Republic, 182 23 Prague 8, The Czech Republic
Received July 15, 1993
Accepted September 30, 1993
Alkylation of ethyl nipecotate with bromides VII – X gave amino esters Ib – Vb. Alkylation of ethyl
piperazine-2-carboxylate with 4-bromo-1,1-diphenyl-1-butene afforded compound Vb. Final product
Ia – Va were obtained by acid hydrolysis of corresponding esters Ib – Vb. Some of the compounds
showed significant antihistamine and antiulcer activities.
Derivatives of dibenzo[b,e] thiepin, thieno[2,3-c]-2-benzothiepin and related tricyclic
4
systems with aminoalkyl side chains proved important antihistamine activities1 –
.
Introduction of a hydrophilic substituent (especially carboxyl) into their molecules de-
creased usually their unwanted sedative effects5, due to suppression of their penetration
through the blood-brain barrier. In connection with a research after new antihistaminic
substances, compounds Ia – Va were prepared fulfilling the mentioned conditions. With
regard to the fact that all of these compounds are structurally related to compounds
SK&F 89976 (VI), a GABA uptake inhibitor6, anticonvulsant action was also expected
for the new products.
The synthesis of the carboxylic acids Ia – IVa started by alkylations of ethyl nipeco-
tate with bromides VII (ref.7), VIII (ref.8), IX and X in acetone in the presence of potas-
sium carbonate. The obtained amino esters Ib – IVb were hydrolyzed with dilute
hydrochloric acid which resulted in the final products. The bromo compounds IX and X
were prepared by Grignard reactions of cyclopropylmagnesium bromide with the corre-
sponding tricyclic ketones and by the following reaction of the tertiary alcohols ob-
tained with 48% hydrobromic acid in the acetic acid.
Alkylation of ethyl piperazine-2-carboxylate9 with 4-bromo-1,1-diphenyl-1-butene10
under similar conditions resulted in the mixture of amino esters Vb and XII which was
separated by chromatography on silica gel. A similar alkylation in tetrahydrofuran in
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Sindelar, Silhankova, Urban, Metys, Valchar, Polivka:
the presence of triethylamine afforded Vb as the single product. Its hydrolysis with
dilute hydrochloric acid gave the amino acid Va.
For the purpose of pharmacological evaluation, amino acids Ia – Va were used in the
form of water-soluble salts (hydrochlorides, hydrogen oxalates) and these were tested
by methods of biochemical and behavioural pharmacology.
Compounds Ia – Va showed only low affinity to the GABA-ergic receptors. In the
test of inhibition of binding of 10 nM [3H]muscimol in the rat brain (the tested com-
pounds were used in the concentration of 100 nM), the inhibition amounted to 80 – 90% of
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the original binding. The inhibition of re-uptake of GABA in the rat brain (1 nM
[3H]GABA was as the ligand; the tested compounds were used in the concentration of
1 000 nM) amounted to 60 – 80%. Up to oral doses of 100 mg/kg, the tested compounds
did not show anticonvulsant activity in mice (test with electroshock and penetrazole
seizures were used). Compound IIIa in the oral dose of 10 mg/kg showed a weak pro-
tective action in the test of anticonvulsant activity against bicuculine convulsions in
mice; the other compounds up to dose of 50 mg/kg proved inactive. The acute oral
toxicity of all tested compounds in mice (approximate ID50 values) amounted to
500 – 1 000 mg/kg.
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Sindelar, Silhankova, Urban, Metys, Valchar, Polivka:
Some of the compounds showed significant antihistamine and antiulcer activities.
Histamine aerosol test in guinea pigs (per cent of protection after the dose of 1 mg/kg):
Ia, 50; IIa, 37.5; IIIa, 25; IVa, 66 (in the dose of 0.1 mg/kg protection still by 33%).
Test of gastric ulcers induced by indomethacin in rats (oral ED50 given): Ia, 16.0; IIa,
49.3; IIIa, 30.3; IVa, 33.8.
EXPERIMENTAL
The melting points of analytical samples were determined with the Mettler FP-5 or in the Kofler
block and they are not corrected; the analytical samples were dried in vacuo of about 40 Pa at a room
temperature or at a suitably elevated temperature. UV spectra (in methanol, λmax in nm (log ε)) were
recorded with the Unicam SP 8000 spectrophotometer; IR spectra (wavenumbers in cm−1) with Uni-
cam SP 2000 or Perkin–Elmer 298 spectrophotometers, NMR spectra (in CD3SOCD3 unless stated
otherwise) on a Tesla BS 567A (1H at 100 MHz, 13C at 25.14 MHz) or on a Varian XL-200 (1H at
200.057 MHz, 13C at 50.309 MHz), chemical shifts are given in ppm (δ-scale), coupling constants (J)
in Hz. The mass spectra (m/z, %) were measured on a Varian MAT-44S (GC-MS) spectrometer. The
homogeneity of the products and composition of the mixtures were checked by thin-layer chromato-
graphy (TLC) on silica gel (Silufol UV254). Preparative chromatographic separations were carried out
on columns of silica gel (Fluka 60). The extracts were dried with Na2SO4 or K2CO3 and solvents
were evaporated under reduced pressure on a rotary evaporator.
9-(3-Bromopropylidene)thioxanthene (IX)
Grignard reagent was prepared from cyclopropyl bromide (16.0 g, 0.13 mol) and Mg dust (3.3 g,
0.136 mol) in tetrahydrofuran (100 ml). After refluxing for 30 min, the mixture was cooled to room
temperature and was treated over 10 min with a suspension of thioxanthone (19.0 g, 0.09 mol) in
70 ml tetrahydrofuran. It was refluxed for 5 h, after cooling decomposed with 20% aqueous NH4Cl
(added dropwise) and diluted with ether (100 ml). The organic layer was separated and evaporated.
The residue (26.6 g) was dissolved in acetic acid (120 ml), the solution was treated with 48%
aqueous HBr (60 ml, 0.53 mol), and the mixture was stirred for 3 h at room temperature. It was
diluted with water, extracted with benzene, the extract was evaporated and the residue was chromato-
graphed on silica gel (100 g). Elution with a mixture of benzene–light petroleum 1 : 2 gave 11.9 g
(42%) of IX, m.p. 62.5 – 64.5 °C. Reference11, mentioning this compound, did describe neither the
method of preparation, nor characterization of the product. UV spectrum (heptane): 230 (4.50), 267
(4.16), 323 (3.58). IR spectrum (KBr): 742, 771 (ArH); 1 580, 3 000, 3 048 (Ar); 1 628 (C=C).
1H NMR spectrum (100 MHz, CDCl3): 3.02 q, 2 H (H-2′, J = 7.0); 3.48 t, 2 H (H-3′, J = 7.0); 5.91 t,
1 H (H-1′, J = 7.0); 7.20 – 7.70 m, 8 H (ArH). For C16H13BrS (317.3) calculated: 60.57% C, 4.13% H,
25.19% Br, 10.11% S; found: 60.63% C, 4.23% H, 25.06% Br, 10.12% S.
(E)-4-(3-Bromopropylidene)-4,9-dihydrothieno[2,3-c]-2-benzothiepin (X)
Grignard reagent was prepared from cyclopropyl bromide (17.0 g, 0.14 mol) and Mg dust (3.4 g,
0.14 mol) in tetrahydrofuran (100 ml). After 30 min refluxing, the mixture was cooled to room tem-
perature and treated dropwise over 15 min with a solution of thieno[2,3-c]-2-benzothiepin-4(9H)-one1
(21.0 g, 0.09 mol) in tetrahydrofuran (40 ml). The mixture was refluxed for 90 min, after cooling
decomposed with 20% aqueous NH4Cl (100 ml, added dropwise) and diluted with ether (100 ml).
The organic layer was separated, dried, evaporated, the residue was dissolved in small amount of
benzene and the solution was filtered through silica gel. Processing of the filtrate gave 20.6 g (93%)
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of oily XI. 1H NMR spectrum (100 MHz, CDCl3): 0.40 – 0.95 m, 4 H (CH2 of cyclopropoane);
1.80 m, 1 H (CH of cyclopropane); 2.12 bs, 1 H (OH); 4.45 and 4.65 AB system, 2 H (2 × H-9,
J = 13.0); 7.02 d, 1 H (H-2, J = 5.8); 7.28 m, 3 H (H-6, H-7, H-8); 7.35 d, 1 H (H-3, J = 5.8); 7.65 m,
1 H (H-5).
A solution of alcohol XI (18.9 g, 69 mmol) in acetic acid (100 ml) was treated at 5 – 15 °C with
48% aqueous HBr (50 ml, 0.44 mol), the mixture was stirred for 5 h at room temperature, diluted
with water, extracted with benzene, the extract was evaporated and the residue was chromatographed
on silica gel (80 g). Elution with a mixture of benzene–light petroleum (1 : 3) gave 14.8 g (64%) of
X, m.p. 94 – 97 °C (cyclohexane). This product is contamined by a small quantity of the Z-isomer
(E : Z = 9 : 1). UV spectrum (heptane): 230 (4.29), 276 (3.77), 313 (3.65). IR spectrum (CS2): 690,
709, 761, 787 (ArH); 842, 861, 872 (H in thiophene). 1H NMR spectrum (signals of E-isomer,
100 MHz, CDCl3): 2.94 q, 2 H (2 × H-2′), 3.50 t, 2 H (2 × H-3′); 6.01 t, 1 H (H-1′); 6.80 – 7.50 m,
6 H (ArH). For C15H13BrS2 (337.3) calculated: 53.41% C, 3.88% H, 23.69% Br, 19.01% S; found:
53.55% C, 3.95% H, 23.33% Br, 18.65% S.
General Procedure for the Preparation of Amino Acids Ia – IVa
A mixture of respective bromopropylidene compounds (15 mmol), ethyl nipecotate (2.7 g, 17 mmol),
K2CO3(2.9 g, 21 mmol) and acetone (100 ml) was stirred and refluxed for 16 h. The mixture was
filtered, the filtrate was evaporated, the residue distributed between 5% NaHCO3 and benzene and
the organic layer was evaporated. The residue (the crude ester) was dissolved in 10% aqueous hydro-
chloric acid (100 ml, 0.29 mol) and the solution refluxed for 16 h. After cooling, the clear solution
was separated from semisolid crude product by decantation, the product was dissolved in acetone, the
solution was filtered with active carbon and the filtrate was evaporated. The residue, representing the
hydrochloride of the product, was purified by crystallization from a mixture of ethanol and ether. In
some cases, the crude hydrochloride was decomposed with aqueous ammonia, the base was isolated
by extraction with ether and transformed to the hydrogen oxalate by treatment with oxalic acid in
acetone.
1-[3-(10,11-Dihydrodibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidine-3-carboxylic acid (Ia).
The bromopropylidene derivative7 VII (4.7 g, 15 mmol) afforded by reaction with ethyl nipecotate
(2.7 g, 17 mmol) and hydrolysis 1.9 g (28%) Ia hydrogen oxalate, m.p. 125 – 135 °C (ethyl acetate–
1
ether). H NMR spectrum (200 MHz): 1.46 m, 1 H (H-5a″); 1.78 – 1.96 m, 3 H (H-5e″, 2 × H-4″);
2.82 m, 5 H (2 × H-2′, H-3″, H-2a″, H-6a″); 3.11 m, 4 H (2 × H-10, 2 × H-11); 3.20 – 3.49 m, 4 H
(2 × H-1′, H-2e″, H-6e″); 5.90 t, 1 H (H-3′, J = 7.1); 6.98 – 7.50 m, 8 H (ArH); 9.12 bs, 3 H
(3 × COOH). 13C NMR: 21.7 t (C-5″), 24.2 t (C-2′), 25.4 t (C-4″), 34.1 t and 34.8 t (C-10, C-11),
38.5 d (C-3″), 51.2 t (C-6″), 55.8 t (C-1′), 61.1 t (C-2″), 122.8 d (C-3′), 125.4 d, 126.3 d, 126.9 d,
127.2 d, 127.4 d, 127.8 d, 128.7 d, 130.4 d (Ar), 134.1 s (C-5), 137.0 s, 137.6 s (C-9a, C-11a), 140.9 s,
141.3 s (C-4a, C-5a), 164.3 s (COOH in oxalate), 171.4 s (COO− in oxalate), 173.1 s (COOH). For
C26H29NO6 (451.5) calculated: 69.16% C, 6.47% H, 3.10% N; found: 68.60% C, 6.82% H, 3.00% N.
1-[3-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)propyl]piperidine-3-carboxylic acid (IIa). The
bromopropylidene derivative8 VIII (5.0 g, 15 mmol) gave by reaction with ethyl nipecotate (2.7 g,
17 mmol) and the following hydrolysis 2.2 g (34%) of IIa hydrochloride hemihydrate, m.p.
163.5 – 165.5 °C. IR spectrum (Nujol): 768 (ArH); 876, 1 204, 1 721 (COOH); 1 588, 3 050 (Ar);
2 530, 2 615, 2 670 (NH+); 3 420 (OH). 1H NMR spectrum (200 MHz): 1.41 m, 1 H (H-5a″);
1.74 – 1.92 m, 3 H (H-5e″, 2 × H-4″); 2.35 m, 2 H (H-2a″, H-6a″); 2.75 – 3.18 m, 7 H (H-2e″,
H-6e″, H-3″, 2 × H-2′, 2 × H-1′); 3.68 d, 1 H and 4.76 d, 1 H (2 × H-6, J = 13.8); 5.90 t, 1 H (H-3′,
J = 7.2); 6.93 – 7.40 m, 8 H (ArH); 11.2 bs, 1 H (COOH). 13C NMR spectrum: 21.8 t (C-5″), 23.9 t
(C-2′), 25.1 t (C-4″), 32.2 t (C-6), 38.5 d (C-3″), 51.2 t (C-6″), 55.5 t (C-1′), 60.9 t (C-2″), 125.1 d
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Sindelar, Silhankova, Urban, Metys, Valchar, Polivka:
(C-3′), 2 × 127.1 d, 127.7 d, 127.8 d, 128.2 d, 128.4 d, 128.7 d, 131.0 d (Ar); 133.8 s (C-11), 136.4 s
and 136.6 s (C-4a, C-6a), 138.8 s (C-11a), 143.0 s (C-10a), 173.0 s (COOH). For C23H26ClNO2S +
0.5 H2O (425.0) calculated: 65.00% C, 6.40% H, 8.34% Cl, 3.30% N, 7.54% S; found: 65.14% C,
6.61% H, 8.42% Cl, 3.83% N, 7.31% S.
1-[3-(Thioxannnthene-9-ylidene)propyl]piperidine-3-carboxylic acid (IIIa). Reaction of IX (4.8 g,
15 mmol) with ethyl nipecotate (2.7 g, 17 mmol) and the following hydrolysis resulted in 2.9 g
(42%) of IIIa hydrogen oxalate, m.p. 155 – 160 °C (acetone–ether). 1H NMR spectrum (200 MHz):
1.49 m, 1 H (H-5a″); 1.82 – 1.97 m, 3 H (H-5e″, 2 × H-4″); 2.86 m, 5 H (H-2a″, H-6a″, 2 × H-2′,
H-3″); 3.23 – 3.54 m, 4 H (H-2e″, H-6e″, 2 × H-1′); 5.90 t, 1 H (H-3′, J = 7.0); 7.31 – 7.54 m, 8 H
(ArH); 8.80 bs, 3 H (3 × COOH). 13C NMR spectrum: 21.8 t (C-5″, 24.3 t (C-2′), 25.2 t (C-4″),
38.8 d (C-3″), 51.4 t (C-6″), 55.5 t (C-1′), 60.8 t (C-2″), 125.9 d and 126.1 d (C-3′, Ar), 126.8 d,
126.9 d, 127.3 d, 2 × 127.5 d, 128.0 d, 128.9 d (Ar), 130.9 s (C-9), 132.5 s and 132.8 s (C-4a,
C-10a), 136.6 s and 137.6 s (C-9a, C-8a), 164.6 s (COOH in oxalate), 171.6 s (COO− in oxalate),
173.3 s (COOH). For C24H25NO6S (455.5) calculated: 63.28% C, 5.53% H, 3.08% N, 7.04% S;
found: 63.55% C, 6.09% H, 3.18% N, 7.18% S.
In this case, the intermediate crystalline ester IIIb, i.e. ethyl 1-[3-(thioxanthene-9-ylidene)propyl]-
piperidine-3-carboxylate, was isolated as hydrochloride, m.p. 161 – 164 °C (benzene). IR spectrum
(Nujol): 740, 770 (ArH), 1 221, 1 309, 1 736 (COOR); 1 581, 1 666, 3 043 (Ar); 2 523, 2 608
(NH+). 1H NMR spectrum (100 MHz): 1 22 t, 3 H (CH3, J = 7.0); 1.60 – 3.60 m, 13 H (CH and
CH2); 4.13 q, 2 H (OCH2, J = 7.0); 5.94 t, 1 H (H-3′, J = 7.0); 7.30 – 7.60 m, 8 H (ArH). For
C24H28ClNO2S (430.0) calculated: 67.04% C, 6.56% H, 3.26% N, 8.25% Cl, 7.46% S; found:
67.09% C, 6.71% H, 3.31% N, 8.50% Cl, 7.25% S.
1-[3-(4,9-Dihydrothieno[2,3-c]-2-benzothiepin-4-ylidene)propyl]piperidine-3-carboxylic acid
(IVa). The bromopropylidene compound X (5.1 g, 15 mmol) was reacted with ethyl nipecotate (2.7 g,
17 mmol) and the crude product gave by hydrolysis and further processing 3.0 g (41%) of IVa hy-
1
drogen oxalate hemihydrate, m.p. 95 – 105 °C (acetone–ether). H NMR spectrum (200 MHz): 1.47 –
1.96 m, 4 H (2 × H-4″, 2 × H-5″); 2.41 m, 2 H (H-2a″, H-6a″); 2.80 m, 3 H (H-3″, 2 × H-2′);
3.16 m, 4 H (H-2e″, H-6e″, 2 × H-1′); 3.93 d, 1 H and 4.58 d, 1 H (2 × H-9, J = 13.2); 6.00 t, 1 H
(H-3′, J = 6.5); 7.05 d, 1 H (H-3, J = 5.4); 7.15 – 7.38 m, 5 H (ArH), 9.25 bs, 3 H (3 × COOH).
13C NMR spectrum: 21.7 t (C-5″), 24.2 t (C-2′), 25.0 t (C-4″), 34.2 t (C-9), 38.6 d (C-3″), 51.6 t
(C-6″), 55.3 t (C-1′), 60.8 t (C-2″), 122.1 d (C-3′), 2 × 127.6 d, 127.8 d, 128.1 d, 128.7 d, 129.0 d
(Ar), 134.1 s (C-4), 135.9 s (C-3a), 137.2 s and 137.6 s (C-8a, C-10a), 143.6 s (C-4a), 164.6 s
(COOH in oxalate), 172.0 s (COO− in oxalate), 173.4 s (COOH). For C23H25NO6S2 + 0.5 H2O
(484.6) calculated: 57.00% C, 5.41% H, 2.89% N; found: 57.12% C, 5.75% H, 2.72% N.
Ethyl 1-(4,4-Diphenyl-3-butene-1-yl)piperazine-3-carboxylate (Vb)
A) A mixture of ethyl piperazine-2-carboxylate9 (3.0 g, 18.9 mmol), 4-bromo-1,1-diphenylbutene10
(5.6 g, 18.9 mmol), triethylamine (1.9 g, 18.9 mmol) and tetrahydrofuran (45 ml) was refluxed for
24 h. The precipitated triethylamine hydrobromide was filtered off, the filtrate was evaporated, the
residue was dissolved in ether and the solution neutralized with HCl in ether; yield 5.5 g (63%)
of Vb dihydrochloride hydrate, m.p. 167 – 169 °C. IR spectrum: 703, 744 (ArH); 1 261, 1 290,
1 308, 1 329, 1 743 (COOR); 1 490, 1 542, 3 010 (Ar); 1 630 (C=C); 2 400, 2 540, 2 635 (NH+);
3 440 (NH). Mass spectrum: 364 (M+, C23H28N2O2, 0.05), 291 (1.6), 171 (100), 128 (10), 98 (17),
1
97 (21), 91 (8), 56 (10), 44 (12). H NMR spectrum (200 MHz): 1.24 t, 3 H (CH3, J = 6.8); 2.53 m,
2 H (H-2a, H-5a); 3.38 – 3.58 m, 7 H (H-2e, H-5e, H-6a, 2 × H-1′, 2 × H-2′); 3.84 d, 1 H
(H-6e, J = 10.8); 4.25 q, 2 H (OCH2, J = 6.8); 4.81 d, 1 H (H-3, J = 7.2); 6.17 t, 1 H (H-3′, J = 6.2);
7.17 – 7.44 m, 10 H (ArH); 10.40 bs, 1 H (NH+). 13C NMR spectrum: 14.0 q (CH3), 24.3 t (C-2′),
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38.2 t (C-6), 47.0 t (C-5), 48.5 t (C-2), 52.0 d (C-3), 55.1 t (C-1′), 63.0 t (OCH2), 123.8 d (C-3′),
127.2 d (2 Ar), 127.6 d and 127.7 d (C-4 of Ph), 128.5 d, 128.8 d, 129.5 d (2 Ar), 139.0 s (C-4′),
141.7 s and 143.7 s (C-1 of Ph), 164.8 s (CO). For C23H30Cl2N2O2 + H2O (455.4) calculated: 60.65% C,
7.08% H, 15.57% Cl, 6.15% N; found: 60.23% C, 6.73% H, 15.69% Cl, 6.02% N.
B) A mixture of ethyl piperazine-2-carboxylate9 (0.50 g, 3.16 mmol), 4-bromo-1,1-diphenyl-
butene10 (0.91 g, 3.16 mmol), K2CO3 (0.87 g, 6.3 mmol), KI (12 mg, 0.07 mmol) and acetone
(10 ml) was refluxed for 24 h, filtered, the filtrate was evaporated, and the residue was chromato-
graphed on silica gel (20 g). Elution with chloroform and then chloroform–ethanol (20 : 1) recovered
first 0.14 g of the starting 4-bromo-1,1-diphenylbutene and then gave 0.17 g (19%) of ethyl 1,4-bis-
1
(4,4-diphenyl-3-butene-1-yl)piperazine-2-carboxylate (XII), oil. H NMR spectrum (100 MHz): 1.22 t,
6 H (2 × CH3, J = 7.2); 2.0 – 3.3 m, 15 H (aliphatic CH and CH2); 4.14 q, 4 H (2 × OCH2, J = 7.2);
6.04 t, 2 H (CH=); 7.1 – 7.5 m, 20 H (ArH). Dihydrochloride hemihydrate, m.p. 124 – 126 °C (ethyl
acetate–ethanol). Mass spectrum: 570 (M+, C39H42N2O2, 0.1), 497 (2), 377 (100), 303 (6), 129 (26),
115 (18), 111 (17), 97 (17), 91 (40). For C39H44Cl2N2O2 + 0.5 H2O calculated: 71.76% C, 6.95% H,
10.86% Cl, 4.29% N; found: 71.48% C, 6.79% H, 10.83% Cl, 4.25% N.
Conclusion of the chromatography by elution with chloroform–ethanol (20 : 1) gave finally 0.48 g
(42%) of Vb identical with the product prepared by method A.
1-(4,4-Diphenyl-3-butene-1-yl)piperazine-3-carboxylic Acid (Va)
A solution of Vb (4.4 g, 12 mmol) in 6 M HCl (180 ml) was refluxed for 14 h. After cooling, the
precipitate was filtered, dissolved in water, the solution was filtered with active carbon while hot, the
filtrate was evaporated and the residue crystallized from 5% hydrochloric acid; 3.2 g (62%) of Va
dihydrochloride hydrate, m.p. 158 – 162 °C. 1H NMR spectrum (200 MHz): 2.42 m, 2 H (H-2a,
H-5a); 3.30 – 3.52 m, 7 H (H-2e, H-5e, H-6a, H-2′, H-1′); 3.77 d, 1 H (H-6e, J = 11.3); 4.57 d, 1 H
(H-3, J = 9.8); 6.10 t, 1 H (H-3′, J = 5.7); 7.16 –7.44 m, 10 H (ArH); 10.1 super bs, 1 H (COOH).
13C NMR spectrum: 24.3 t (C-2′), 38.2 t (C-6), 47.0 t (C-5), 48.8 t (C-2), 52.4 d (C-3), 55.1 t (C-1′),
123.9 d (C-3′), 127.2 d, 128.4 d, 128.8 d, 129.5 d (2 × C-2 and C-3 of Ph), 127.55 d and 127.65 d
(C-4 of Ph), 139.0 s (C-4′), 141.7 s and 143.6 s (2 × C-1 of Ph), 166.2 s (CO).
The authors thank the following colleagues at the Research Institute for Pharmacy and Biochemistry
in Prague for co-operation: Mr M. Cech, Mrs R. Svatosova and Mrs A. Svatonova (elemental analyses),
Dr E. Svatek and Mrs A. Hradkova (IR spectra), Dr N. Dlohozkova and Mrs J. Ezrova (biochemical
pharmacology), Dr H. Frycova, Mrs Z. Paduanova and Mrs L. Horakova (animal pharmacology).
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