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Synthesis of Some Substituted Carbamodithioic Acid Esters and Their Anticholinergic Properties.

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859
Carbamodithioic Acid Esters
Synthesis of Some Substituted Carbamodithioic Acid Esters and Their
Anticholinergic Properties
Cihat Safak, Hakki Erdogan, and Mevliit Ertan
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Hacettepe, Ankara-Turkey
Riimeysa Sunal
Department of Pharmacology, Faculty of Pharmacy, University of Hacettepe, Ankara-Turkey
Received March 3, 1988
Eight new dithiocarbamateshave been prepared by the reaction of S-chloro-3-methyl-6-(2-bromopropionyl)-2-benzoxazolinoneand substituted
potassium dithiocarbamate derivatives. Their structures have been elucidated by uv-, IR-, and NMR-spectra and by elemantaryanalysis. The tithave been assayed for their antispasmodic activity On guile
neapig ileum, they possess spezific anticholinergic properties.
Esters of N-substituted and N,N-disubstituted carbamodithioic acid derivatives have various pharmacological activities such as antibacterial, antifungal, antiviral, herbicide, and tuberculostatic propertie~l-~).
These activities are more pronounced in N-monosubstituted dithiocarbamoic esters
than in N,N-disubstituted carbamodithioic acid derivatives due to the lability of the hydrogen attached to the N.
Fencarbamide I,(N,N-diphenylthiocarbamoic acid S-2-(di-ethylamino)ethyl ester) is an anticholinergic drug@.
Substituierte Ester der Dithiocarbamoylsaure und ihre anticholinergen
Eigenschaften
8 n e w Ester von Dithiocarbamaten wurden aus 5-chlor-3-methyl-6-(2brompropionyl)-2-benzo~azolinonund Kalium-dithiocarbamaten hergestellt. Die Struktur der hergestellten SubstanZen wurde durch UV-, IR-,
und NMR Spektren, so wie durch Elementaranalvsen bestimmt. ihre anticholinergen Aktivitaten am Meerschweinchen Ileim getestet. Alle Derivative besitzen spezifische anticholinerge Eigenschaften.
R
Compound
R
c ZHC ,
1
N-
/
cz Hs
2
3
In this paper, we aimed to determine the contribution of
the benzoxazolone ring and that of the substituents on the Natom of the dithiocarbamate to the anticholinergic activity.
We synthesized eight new compounds (formula given below)
and determined their anticholinergic activities on guinea-pig
ileum.
To synthesize compounds 1-8 N,N-disubstituted dithiocarbamate potassium derivatives, prepared by the reaction
of aliphatic or heterocyclic amines (a) with CS2 and KOH,
were heated with 5-chloro-3-methyl-6-(2-bromopropionyl)2-benzoxazolinone (b) in methanol (Scheme 1).
6
7
n
0
N8
5-Chloro-3-methyl-6-(2-bromopropionyl)-2-benzoxazoliu
none used in this reaction was prepared by heating 5-chloro-3-methyl-2-benzoxazolinone
and 2-bromopropionic acid made, because the stability of this center of chirality a to C=O
in polyphosphoric acid’! Although all compounds have an is expected to be rather low. Diastereomers of 3 and4 were not
asymmetric center, separations of optical antipodes were not observed (‘H-NMR).
Arch. Pharrn. (Weinheim) 321,859-861 (1988)
0 VCH Verlagsgesellschqft mbH, 0-6940 Weinheim, 1988 036S4233l88l1212-08S9$02.S0l0
R-YH
R
+ CS,
KOH
Safak, Erdoian, Ertan, and Sunal
D
R-y-C-SK
R
a
Scheme -1
N-CH,
1-8
All spectral data are in accordance with the assumed structures. The
UV spectra show two main intensive absorption bands (log E > 4) at 282
and 225 nm. For IR- and ‘H-NMR-data see Table 3. In mass spectra, molecular ion peaks were not seen in all compounds except 4 (M’. = 413).
The base peaks of 1,2,6,7 and 8 are at m/z 210/212. This fregmentation
is due to a-cleavage besides the -C=O-moiety of the side chain. In the methyl substituted piperidine derivatives (3,4, and 5) the base peak is m/z =
142 formed by a-cleavage of the S=C-S-increment.
In addition, since all compounds have one chlorine atom typical isotope
peaks are seen in their spectra.
The compounds synthesized were assayed for their antispasmodic activity. They were not effective against BaCl, induced contractions and although they antagonized histamine, the results obtained were not statistically significant.
However, the compounds antagonized acetylcholine induced
contractions, indicating a specific anticholinergic activity
with 2,4,7 and 8 (Table 1). The compounds containing a tertiary N within a ring (2-8) showed pronounced anticholinergic activities when compared to 1. Our results are in accordance with those obtained from the literature?
Table 1: Inhibition of maximum contractions
As can be seen from the results (Table 1) the compounds
synthesized have specific anticholinergic activities in guineapig ileum.
Experimental Part
Chemistry
Material and Methods
Diethylamine, piperidine, 2methyIpiperidine, 3-methylpiperidine, 4-methylpiperidine, 3,5-dimethylpiperidine, 2,6-dimethylpiperidine, morpholine and 5-chloro-2-benzoxazolinonewere purchased from Merck and Aldrich.
Potassium salts of substituted dithiocarbamic acids and 5-chloro-3-methyl-6-(2-bromopropionyl)-2-benzoxazolinone~~
were prepared as reported.
Melting points: Thomas Hoover Cappilary Melting Point Apparatus. UV spectra Hitachi 220s Spectrophotometer, methanol.-1R Spectra: Perkin-Elmer 457 IR Grating Spectrophotometer, KBr pellets. - ‘H-NMR
spectra: Bruker 200 MHz, CDCI,, tetramethylsilane as intern standard. Mass spectra were recorded on Bruker EI-CMS-47 at 70 eV. - Elemental
analysis: Fachbereich Pharmazie, Mainz/West Germany.
% Inhibition
Compound
(10 - 7 ~ )
Acetylcholine
(0.64 rglml)
Histamine
(0.1 Pglrnl)
**
*
**
**
~~
10 0.5
7 0.4
3 k 0.3
37 f 0.3
20 0.2
53 0.3
No inhibition
No inhibition
38 0.2
*76 0.2
53 f 0.3
*66 0.5
**58 f 0.5
**64 5 0.3
*73 50.5
*86 k 0.4
5-Chloro-3-methyl-6-/2-(N,N-disubstitutedthiocarbamoylthiolgropionyll-2-benzoxazolinones (1-8)
Equimolar amounts of 5-chloro-3-methyl-6-(2-bromopropionyl)-2-benzoxazolinone and the corresponding potassium dithiocarbamate derivative
were refluxed in methanol for 2 h. Then, the solution was evaporated
i. vac. to dryness. The precipitates formed were washed with water and
crystallized from the appropriate solvent given in Table 2. Some physical
and spectral properties of the compounds are given in Tables 2 and 3.
* p < 0.01, ** p < 0.05
Table 2: Empiric formula, molecular weight, melting point and %yield.’
Compound
Empiric formula
M.w.
m.p. (“C)
Crystal. solv.
7% Yield
386.9
398.9
412.9
412.9
412.9
426.9
426.9
400.9
109
139
126
129
141
170
103
114
isopropanol
isopropanol
methanol
methanol
methanol
isopropanol
methanol
methanol
89
84
78
82
so
82
76
79
* The literature quotations at the compound numbers indicate the paper where the pertinent dithiocarbamate is described.
Arch. Pharm. (Weinheim) 321,859-861 (1988)
86 I
Carbamodithioic Acid Esters
Table 3: Spectral and Elemental Analysis of the Compounds
‘H-NMR (CDC13)*
(PPm)
1
1.16 (t, 6H, (CH~ -CHZ)~ N),
1.49 (d, 3H, CH3-CH-),
3.34 (s, 3H, -N-CH3),
3.45 (q,4H, (CH3-CH2)2N3
5.61 (q, lH, CHJ-CH-),
7.53 (s, lH, benzoxaz. H-7),
7.81 (s, lH, benzoxaz. H-4)
3.46 (m,10H, piperidine)
1.19 (d, 3H, -CH?),
3.41 (m, 9H, piperidhe)
MASS
m/z (70 eV)
1765 (CO, Lactam),
1705 (CO, Keton),
1255 (CS)
212; 210 (100 %);
126; 116; 88; 72;
57; 43
1750 (CO, Lactam),
1685 (CO, Keton),
1230 (CS)
1765 (CO, Lactam),
1690 (CO, Keton),
1220 (CS)
212; 210 (100 %);
126; 78; 57
4
0.86 (d, 3H, -CH+,
3.46 (m, 9H, piperidhe)
1750 (CO, Lactam),
1690 (CO, Keton),
1255 (CS)
5
0.87 (d, 3H, -CH$,
3.46 (m, 9H, piperidine)
1755 (CO, Lactam),
1685 (CO, Keton),
1215 (CS)
0.87 (d, 6H, 2 X CH?),
3.47 (m,8H, piperidme)
1760 (CO, Lactam),
1685 (CO, Keton),
1220 (CS)
1765 (CO, Lactam),
1685 (CO, Keton),
1225 (CS)
1.27 (d, 6H, 2 X CH$,
3.45 (m, 8H, piperidme)
8
3.63 (t, 4H, -CHz-N-CHz-),
4.10 (t, 4H, -CHz-O-CHz)
1755 (CO, Lactam),
1680 (CO, Ketone),
1220 (CS)
212; 210; 174;
144; 142 (100 %);
126; 98; 83; 72;
56; 55
413 (MI; 379;
212; 210; 144;
142 (100 %); 126;
98; 83; 72; 56; 55
379; 212; 210;
144; 142 (100 %);
126; 98; 83; 72;
56; 55
212; 210 (100 %);
182; 156; 112; 78;
72; 69; 57; 56; 55; 43
212; 210; 188;
187; 126; 112;
98; 87; 70; 56;
55 (100 %); 43
367; 212; 210
(100 %); 130; 126;
97; 86; 84; 72; 71
Analysis
Calc. Found.
c
49.7
4.9
7.2
49.4
4.7
7.1
C 51.2
H 4.8
N 8.9
C 52.3
H 5.1
N 8.6
51.0
4.8
8.7
52.5
5.2
8.5
C 52.3
H 5.1
N 8.6
52.2
5.2
8.5
C 52.3
H 5.1
N 8.6
5.2
5.3
8.6
H
N
c
53.4
5.4
8.3
c 53.4
H 5.1
N 8.3
53.4
5.6
8.3
53.5
5.2
8.2
C 58.0
H 4.2
N 8.9
57.8
4.3
8.8
H
N
* For compounds 2-8only the protons at the amine portion are quoted, because those ofthe propionyl benzoxazole group are moreor less constant.
Pharmacology
References
Cole-Parmer Organ Bath 61300, Ugo Bade Recorder “Gemini” 7070,
Ugo Basile Isometric Transducer 7003. - Local bread, male guinea-pigs
were used (250-300 g). Guinea-pig ileum assay was performed according
to Magnus method. Tyrode solution was composed of NaCl(8 g/l), KCI
(0.2 g/l), MgCI, (0.1 g/l), CaCI, (0.2 g/l), NaH,PO, (0.05 g/l), NaHCO,
(1 g/l), glucose (1 g/l). The bath solution was aerated with a mixture of
95 % CO, and 5 % 0,, maintained at 37 O C .
Maximum contractions were obtained by 0.64 g/ml acetylcholine, 0.1 g/
ml histamine and 200 g/ml BaC1,. The compounds tested were used as antagonists at 10-7 M concentration. The antagonists were allowed to equilibrate for 15 min.
During bioassay any change in colour or precipitation was not observed.
However, additional studies were not carried out for determination of decomposition.
Student t test was used for statistical analysis.
1 V. T. Zsolnai, Arzneim. Forsch. 21, 121 (1971).
2 U. Goksoyr, Acta Chem. Scand. 1341 (1964).
3 D. Martin, A. E. Martini, and A. Rieche, Ger. (East) 35, 129 (CI.
C07c5),Feb. 11,1965,Appl. July27,1962;C.A.63,9869e(1965).
4 D. R. Baker, Eur. Pat. Appl. Ep, 174.680 (CI. C07C 1155);C.A. 104,
202324k (1986).
5 J. John and M. W. H. D’Amico, Brit. Pat. 769,222, March, 6, 1957;
C. A. 51, 757911 (1957).
6 W. Wirth, R. Gosswald, KLH. Risse, and U. Horlein, Arch. Int. Pharmacodyn. 151, 515 (1964).
7 H. Erdogan, Turkish Pharmacol. and Clin. Res. 3, 12 (1985).
8 A.M. Cliffordand J. G.Lichty, J. Am. Chem.Soc.54,1163 (1932).
9 M. L. G. Davendra, J. Indian Chem. SOC.42,413 (1965).
10 W. Marckwald, Ber. Dtsch. Chem. Ges. 29, 46 (1986).
11 T. P. Forest and S. Ray, J. Chem. SOC.D 22, 1537 (1970).
12 H. Ripperger, Tetrahedron 25, 725 (1969).
13 W. Marckwald, Ber. Dtsch. Chem. Ges. 32. 5230 (1899).
14 J. D’Amico and M. W. Harman, Brit. Pat. 769.222, March, 6, 1957;
C. A. 51, 12424c (1957).
[Ph 4841
Arch. Pharm. (Weinheim) 321,859-861 (1988)
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