Thiazole and benzothiazole derivatives of cytisine

Article abstract of DOI:10.1007/s10600-006-0182-7

Several new derivatives were prepared by reacting N-1(5-R-thiazol-2-yl)-2- chloroacetamides and N-1(6-R-benzothiazol-2-yl)chloroacetamides with cytisine.

Full text of DOI:10.1007/s10600-006-0182-7

Chemistry of Natural Compounds, Vol. 42, No. 4, 2006
THIAZOLE AND BENZOTHIAZOLE DERIVATIVES OF CYTISINE
V. A. Saprykina, V. I. Vinogradova, R. F. Ambartsumova,
T. F. Ibragimov, and Kh. M. Shakhidoyatov
UDC 547.79+547.95
N
R
N
R
Several newderivatives were prepared by reacting -1(5- -thiazol-2-yl)-2-chloroacetamides and -1(6- -
benzothiazol-2-yl)chloroacetamides with cytisine.
Key words: cytisine, alkylation, thiazole, benzothiazole.
The thiazole ring is known to be a part of vitamin B , cocarboxylase, and the cyclic system of penicillin [1].
1
Compounds containing the benzothiazole moiety are also of special interest because they have an even broader spectrum of
biological activity. Thus, they possess antibacterial [2], antiulcer [3], antitumor [4, 5], anti-inflammatory [6], antiallergic [7],
and antiarrhythmic [8] activities.
Thus, adding the aforementioned moieties to the natural alkaloid cytisine (1) gives hope that new biologically active
compounds can be prepared.
In continuation of research on the chemical modification of 1 [9], we prepared its new synthetic derivatives containing
thiazole and benzothiazole moieties.
For this, cytisine was amidoalkylated with -1(5- -thiazol-2-yl)-2-chloroacetamides (2a-c) togive -1[5- -thiazol-2-
N
R
N
R
yl]aminocarbonylmethyl cytisine derivatives (3a-c) in yields of 63-87%.
H
N CH CONH
2
S
R
NH
N
+
N
N
N
−
HCl
ClCH CONH
S
R
2
H
O
2a - c
3a - c
O
1
R = H, CH3, C2H5
Reaction of 1 with -1(6- -benzothiazol-2-yl)chloroacetamides (4a-d) proceeded analogously to 2a-c. The yields of
N
R
products (5a-d) were slightly higher (79-95%).
CH CONH
2
S
R
N
N
+
1
N
N
−HCl
ClCH CONH
S
R
2
4a - d
5a - d
O
R = H, CH3, OCH3, Cl
The results showed that the presence of electron-donating substituents in the 5-position of the thiazole ring and the
6-position of benzothiazole compounds increased the yields of3b, 3c, and 5b-d.
The structures of 3a-c and 5a-d were confirmed by IR and PMR spectra.
The IR spectra of 3a-c and 5a-d contained characteristic absorption bands for theα-pyridone ring at 1645-1662, 1520-
-1
-1
1555, and 796-808 cm . The amide carbonyl (N–CH –CO–NH) absorption appeared at 1556-1583 cm . The NH group was
2
-1
characterized by absorption at 3247-3289 cm .
According to preliminary data, some of the synthesized compounds exhibit bactericidal activity.
S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan,
Tashkent, fax (99871) 120 64 75, e-mail: tim_icps@yahoo.com. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp.
379-380, July-August, 2006. Original article submitted May 5, 2006.
0009-3130/06/4204-0470 ©2006 Springer Science+Business Media, Inc.
470

EXPERIMENTAL
IR spectra were obtained on a Perkin—Elmer Model 2000 Fourier—IR spectrometer. PMR spectra were recorded on
a Tesla BS-567A instrument at working frequency 100 MHz in C D N with HMDS internal standard. The purity of products
5
5
was monitored by TLC on Silufol UV-254 plates (Czech Rep.) using CHCl :CH OH (10:1) and development by Dragendorff's
3
3
reagent.
Compounds 2a-c [10] and 4a-d [11, 12] were synthesized by reaction of chloroacetylchloride with the appropriate
heterocyclic amines in benzene.
Synthesis of 3a-c and 5a-d (general method). Alkaloid 1 and chloroacetamides 2a-c and 4a-d were condensed by
boiling in absolute benzene for 4 h at a 2:1 ratio of reagents, respectively.
Products 3a-c and 5a-d were white crystalline compounds that crystallized well from appropriate organic solvents.
Elemental analyses of the prepared compounds agreed with those calculated.
N-1(Thiazol-2-yl)aminocarbonylmethylenecytisine (3a). Yield 63%, R 0.63, mp 190-191°C (hexane),
f
C H N O S.
16 18
4 2
-1
IR spectrum (KBr, ν cm ): 3149, 3094, 2930, 1695, 1645, 1556, 1434, 1422, 1275, 800.
PMR spectrum (100 MHz, Py-d , δ, ppm, J/Hz): 1.43 (2H, br.s, H-8), 2.05 (1H, m, H-9), 2.55-2.93 (5H, m, H-7, H-11,
5
H-13), 3.28 (2H, s, N–CH –CO), 3.80 (1H, dd, J = 15.7, 6.4, H -10), 4.16 (1H, d, J = 15.7, H -10), 5.78 (1H, br.d, J = 7, H-5),
2
ax
eq
6.45 (1H, br.d, J = 9, H-3), 6.93 (1H, d, J = 6, H-4′), 7.05 (1H, dd, J = 9, 7, H-4), 7.43 (1H, d, J = 6, H-5′).
N-1(5′-Methylthiazol-2-yl)aminocarbonylmethylenecytisine (3b). Yield 87%,
R 0.68, mp 208-209°C
f
(benzene:petroleum ether, 2:1, C H N O S.
17 20
4 2
-1
IR spectrum (KBr, ν cm ): 3276, 3094, 2936, 1694, 1662, 1583, 1551, 1520, 1440, 1424, 1296, 802.
PMR spectrum (100 MHz, Py-d , δ, ppm, J/Hz): 1.45 (2H, m, H-8), 2.10 (1H, m, H-9), 2.50-2.77 (5H, m, H-7, H-11,
5
H-13), 3.85 (1H, dd, J = 15.7, 6.4, H -10), 4.01 (1H, d, J = 15.7, H -10), 5.76 (1H, dd, J = 1.2, 7, H-5), 6.40 (1H, dd, J = 1.2,
ax
eq
9, H-3), 7.10 (1H, s, H-4′), 7.09 (1H, dd, J = 7, 9, H-4).
N-1(5′-Ethylthiazol-2-yl)aminocarbonylmethylenecytisine (3c). Yield 81%, R 0.66, mp 111-112°C (EtOH:H O,
f
2
1:1), C H N O S.
18 22
4 2
-1
IR spectrum (KBr, ν cm ): 3153, 2932, 1675, 1651, 1568, 1553, 1455, 1344, 1258, 801.
PMR spectrum (100 MHz, DMSO-d , δ, ppm, J/Hz): 1.15 (3H, t, CH ), 1.43 (2H, m, H-8), 2.45-2.95 (5H, m, H-7,
6
3
H-11, H-13), 3.17 (2H, CH ), 3.30 (2H, s, N–CH –CO), 3.73 (2H, H-10), 6.02 (1H, d, J = 7, H-5), 6.15 (1H, d, J = 9, H-3), 7.05
2
2
(1H, s, H-4′), 7.27 (1H, dd, J = 7, 9, H-4).
N-1(Benzothiazol-2-yl)aminocarbonylmethylenecytisine (5a). Yield 79%, R 0.81, mp 125-127°C (benzene:ether,
f
1:1), C H N O S.
20 20
4 2
-1
IR spectrum (KBr, ν cm ): 3122, 3034, 2938, 1703, 1651, 1601, 1568, 1548, 1536, 1442, 1265, 796.
PMR spectrum (100 MHz, Py-d , δ, ppm, J/Hz): 1.45 (2H, m, H-8), 2.08 (1H, m, H-9), 2.63-2.80 (5H, m, H-7, H-11,
5
H-13), 3.30 (2H, s, N–CH –CO), 3.83 (1H, dd, J = 15.7, 6.4, H -10), 4.18 (1H, d, J = 15.7, H -10), 5.77 (1H, dd, J = 1.8, 7,
2
ax
eq
H-5), 6.48 (1H, dd, J = 1.8, 9, H-3), 7.07-7.45 (5H, Ar, H-4).
N-1(6′-Methylbenzothiazol-2-yl)aminocarbonylmethylenecytisine (5b). Yield 93%, R 0.77, mp 122-123°C
f
(benzene:hexane, 1:1), C H N O S.
21 22
4 2
-1
IR spectrum (KBr, ν cm ): 3289, 3034, 2937, 1703, 1652, 1607, 1568, 1542, 1462, 1262, 796.
PMR spectrum (100 MHz, Py-d , δ, ppm, J/Hz): 1.45 (2H, m, H-8), 2.05 (1H, m, H-9), 2.18 (3H, CH ), 2.63-2.88 (5H,
5
3
m, H-7, H-11, H-13), 3.31 (2H, s, N–CH –CO), 3.82 (1H, dd, J = 15.7, 6.4, H -10), 4.18 (1H, d, J = 15.7, H -10), 5.75 (1H,
2
ax
eq
*
*
br.d, J = 7, H-5), 6.44 (1H, br.d, J = 9, H-3), 7.00 (1H, d, J = 8, H-4′), 7.12 (1H, m, H-4), 7.20 (1H, s, H-7 ), 7.75 (1H, d,
J = 8, H-5′).
N-1(6′-Methoxybenzothiazol-2-yl)aminocarbonylmethylenecytisine (5c). Yield 95%, R 0.84, mp 109-110°C
f
(benzene:hexane, 1:1), C H N O S.
21 22
4 3
-1
IR spectrum (KBr, ν cm ): 2939, 1698, 1651, 1606, 1568, 1548, 1471, 1437, 1260, 798.
PMR spectrum (100 MHz, Py-d , δ, ppm, J/Hz): 1.45 (2H, m, H-8), 2.05 (1H, m, H-9), 2.50-2.88 (5H, m, H-7, H-11,
5
H-13), 3.33 (2H, s, N–CH –CO), 3.58 (3H, s, OCH ), 3.90 (1H, dd, J = 15.7, 6.4, H -10), 4.10 (1H, d, J = 15.7, H -10), 5.78
2
3
ax
eq
*
(1H, dd, J = 1.8, 6.8, H-5), 6.46 (1H, dd, J = 1.8, 9, H-3), 7.03 (1H, dd, J = 6.8, 9, H-4), 7.22 (1H, s, H-7′), 6.95-7.18 (1H,
H-5′), 7.75 (1H, d, J = 7.5, H-4′).
*
471

N-1(6′-Chlorobenzothiazol-2-yl)aminocarbonylmethylenecytisine (5d). Yield 89%, R 0.76, mp 244-245°C
f
(benzene), C H N O SCl.
20 19
4 2
-1
IR spectrum (KBr, ν cm ): 3311, 2943, 1651, 1598, 1568, 1549, 1538, 1444, 1421, 1262, 808.
PMR spectrum (100 MHz, Py-d , δ, ppm, J/Hz): 1.48 (2H, m, H-8), 2.08 (1H, m, H-9), 2.48-2.90 (5H, m, H-7, H-11,
5
H-13), 3.33 (2H, s, N–CH –CO), 3.91 (1H, dd, J = 15.7, 6.4, H -10), 4.10 (1H, d, J = 15.7, H -10), 5.77 (1H, br.d, J = 6.8,
2
ax
eq
H-5), 6.43 (1H, br.d, J = 8.8, H-3), 7.00-7.15 (1H, H-4), 7.27 (1H, dd, J = 8, 1.6, H-5′), 7.65 (d, J = 8, H-4′), 7.86 (1H, d,
J = 1.2, H-7′).
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
M. D. Mashkovskii, Medicinal Preparations, Vol. 2 [in Russian], Izd. Med. Lit., Tashkent (1998).
P. D. Cook, A. M. Kawasaki, and P. P. Kung, PCT Int. Appl. WO 9805332; Chem. Abstr., 128, 167445 (1998).
T. Machinami, K. Yasufuku, and M. Shibahara, Jpn. Pat. No. 02167268; Chem. Abstr., 113, 191360 (1990).
A. F. J. Flini and R. C. Schnur, Eur. Pat. No. 343893; Chem. Abstr., 112, 178956 (1990).
R. C. Schnur, R. J. Gallaschun, D. H. Singleton, et al., J. Med. Chem., 34, 1975 (1991).
S. Hibi, J. Okamoto, K. Tagami, et al., J. Med. Chem., 37, 3062 (1994).
A. F. Kreft III, J. H. Musser, and D. M. Kubrak, Brit. Pat. No. 2202223; Chem. Abstr., 110, 135096 (1989).
L. Desantis Jr., PCT Int. Appl. WO 9323082; Chem. Abstr., 120, 144163 (1994).
V. A. Saprykina, V. I. Vinogradova, R. F. Ambartsumova, T. F. Ibragimov, A. Sultankulov, and
Kh. M. Shakhidoyatov, Khim. Prir. Soedin., 479 (2004).
10.
G. Vasiliu and L. Gerther, Rev. Univ., "C. I. Parhon" si politen Bucuresti, Ser. Stut Nat., 4, No. 8, 97 (1955);
Chem. Abstr., 52, 1994g (1958).
11.
12.
E. Costakis, P. Canonne, and G. Tsatsas, Can. J. Chem., 47, No. 23, 4483 (1969).
P. N. Bhargava and P. Ram, Bull. Chem. Soc. Jpn., 38, 339 (1965).
472