Preparation of new 5-aroylamino substituted 3-nicotinoyl/isonicotinoyl-1,3,4-thiadiazol-2(3H)-ones with anti-inflammatory activity

Article abstract of DOI:10.1016/S0014-827X(98)00073-1

A series of 1,3,4-thiadiazol-2(3H)-ones (2a-j) with a nicotinoyl/isonicotinoyl group in position 3 and an aroylamino substituent in position 5 of the ring was prepared and evaluated for antipyretic and anti-inflammatory activities. All the title compounds

Full text of DOI:10.1016/S0014-827X(98)00073-1

Il Farmaco 53 (1998) 586±589
Preparation of new 5-aroylamino substituted 3-nicotinoyl/isonicotinoyl-
1,3,4-thiadiazol-2(3H)-ones with anti-in¯ammatory activity
a,
a
Silvia Schenone , Olga Bruno , Angelo Ranise , Francesco Bondavalli , Walter Filippelli ,
a
a
b
*
Giuseppe Falconeb, Brunella Piuccib, Salvatore Sorrentinob
a
Á
Dipartimento di Scienze Farmaceutiche dell'Universita, Viale Benedetto XV 3, I-16132 Genoa, Italy
Á Á
Istituto di Farmacologia e Tossicologia, Facolta di Medicina e Chirurgia, II Universita degli Studi, Via S. Andrea delle Dame 8, I-80138 Naples, Italy
b
Received 2 July 1998; accepted 8 September 1998
Abstract
A series of 1,3,4-thiadiazol-2(3H)-ones (2a±j) with a nicotinoyl/isonicotinoyl group in position 3 and an aroylamino substituent in position
5 of the ring was prepared and evaluated for antipyretic and anti-in¯ammatory activities. All the title compounds and in particular 2e, 2i and
2j exhibited anti-in¯ammatory activity and were devoid of antipyretic properties. q 1998 Elsevier Science S.A. All rights reserved.
Keywords: 1,3,4-Thiadiazol-2(3H)-ones; Substituted thiadiazolones; Anti-in¯ammatory agents
1. Introduction
As acyl substituents, we selected at the beginning the
nicotinoyl and isonicotinoyl moieties and an aroylamino
function with some para-substituent groups having different
electronic and lipophilic properties to verify their possible
in¯uence on the above-mentioned activities.
Within the framework of a research programme on anti-
in¯ammatory agents, we focused our attention on ®ve-
membered heterocyclic structures with three heteroatoms,
at present on the thiadiazole ring.
Such a ring system has been studied previously for its
many and interesting pharmacological properties but only
recently as a potential source of antiphlogistic and antipla-
telet agents, either as a simple monocycle [1±7] or as a
member of heteropolycyclic systems [8±13]. In particular
we have been concerned about monocyclic 1,3,4-thiadia-
zoles having a carbonyl group in position 2 and heteroaroyl
and amidic substituents in positions 3 and 5, respectively, of
the ring:
2. Chemistry
The synthesis of the title compounds was accomplished
as illustrated in Scheme 1 and Table 1, by reacting nicoti-
noyl/isonicotinoyl hydrazide with the relevant acylisothio-
cyanates to give the corresponding acylthiosemicarbazides
(1a±j). Subsequent cyclization with phosgene, in the
presence of sodium acetate, led to the expected 1,3,4-thia-
diazol-2(3H)-ones (2a±j) in good to excellent yields
(Scheme 1). The intermediate isonicotinoyl thiosemicarba-
zides (1f±j) were prepared in the past as potential antituber-
cular agents [14,15], but their physical and spectral data
were not available.
The thiadiazole instead of triazole structure was
con®rmed by 13C NMR spectroscopy, which showed only
three typical amide carbonyl resonances in the range of
160±170 ppm and no thiocarbonyl signal beyond 170 ppm
(for example see the 13C NMR spectrum of 2g).
Our aim was to verify whether such thiadiazolones, so far
not investigated and resembling the well known pyrazo-
lones analogues, were actually endowed with antipyretic
and anti-in¯ammatory activities.
Yields, m.p., IR and NMR spectral data are given in
Tables 2 and 3.
* Corresponding author.
0014-827X/98/$ - see front matter q 1998 Elsevier Science S.A. All rights reserved.
PII S0014-827X(98)00073-1

S. Schenone et al. / Il Farmaco 53 (1998) 586±589
587
night at room temperature, the solvent was evaporated under
reduced pressure and the residue treated with water (50 ml).
The white solids obtained were ®ltered and crystallized
from THF/dry ethanol (1:1) (Table 2).
4.3. General procedure for 1,3,4-thiadiazol-2(3H)-ones
(2a±j)
To a suspension of each acylthiosemicarbazide 1a±j (20
mmol) and anhydrous sodium acetate (4.1 g, 50 mmol) in
anhydrous THF (60 ml), a phosgene solution (20% in
toluene, 12 ml, , 22 mmol) was added dropwise with
stirring and cooling with water.
Scheme 1.
Table 1
The reaction mixture was stirred overnight at room
temperature, the solvent was evaporated under reduced
pressure and the residue treated with water (50 ml).
The resulting white solids were ®ltered and crystallized
from N,N-dimethylformamide (DMF) (Table 3).
Compounds
Ar
Compounds
1,2
1,2
4.4. Pharmacology
a
b
c
C6H
f
5
The following pharmacological activities were evaluated
by standard procedures [16]:
C6H4-pCH3
C6H4-pOCH3
C6H4-pCl
2-Furyl
g
h
i
d
e
1. antipyretic activity by yeast-induced pyrexia in albino
rats (5 rats/group);
j
2. anti-in¯ammatory activity, evaluated by carrageenan-
induced paw edema in rats (Table 4).
3. Pharmacology
For the most active compounds 2e, 2i, 2j, the respective
ED50 values were determined by administration of three
dosages (25, 50, 100 mg/kg).
Compounds 2a±j were evaluated for antipyretic and anti-
in¯ammatory activities.
5. Results and conclusions
4. Experimental
All the compounds tested 2a±j were devoid of antipyretic
activity, unlike the pyrazolone analogues, but were
endowed with anti-in¯ammatory properties (Table 4).
The most active derivatives were 2e, with an ED50 of
44.97 (22.90±88.33) mg/kg and 2i and 2j with an ED50 of
51.29 (44.37±59.29) and 16.98 (8.86±32.53) mg/kg, respec-
tively, 4 h after the treatment.
It was interesting to remark that the best results were
obtained in the isonicotinoyl set (2i and 2j) and that the
furoyl substituent showed superior in¯uence over the
benzoyl groups in both series (2e and 2i).
In conclusion, we found that the present 1,3,4-thiadiazol-
2(3H)-ones are in general effective as antiphlogistic but not
as antipyretic agents. As far as the acylamino substitution at
the 5-position of the ring is concerned, no clear structure±
activity relationship was derivable from para-substitution
into the phenyl ring, the unique elicitable remark being
that the electron-withdrawing Cl group was more effective
than other electron-releasing groups, but only in the isoni-
cotinoyl series.
4.1. Chemistry
Melting points were determined with a BuÈchi 530 ap-
paratus. IR spectra were measured in KBr with a Perkin±
Elmer 398 spectrophotometer. 1H NMR spectra were
recorded in (CD3)2SO solution on a Hitachi Perkin±Elmer
R-600 (60 MHz) instrument, 13C NMR spectra were
measured with a Varian Gemini 200 (50.30 MHz) spectro-
meter in (CD3)2SO solution, chemical shifts are reported as
d (ppm) relative to TMS as internal standard; J in Hz.
Analyses for C, H, N were within ^ 0.3% of the theoretical
values.
4.2. General procedure for acylthiosemicarbazides (1a±j)
To a suspension of nicotinoyl or isonicotinoyl hydrazide
(2.74 g, 20 mmol) in anhydrous tetrahydrofuran (THF) (40
ml), a solution of the relevant acylisothiocyanate (21 mmol)
in anhydrous THF (10 ml) was added dropwise with stirring
at room temperature. The reaction mixture was stirred over-

588
S. Schenone et al. / Il Farmaco 53 (1999) 586±589
Table 2
Yields, physical and spectroscopic data of compounds 1a±j
Compound
M.p.
(8C)
Yield
(%)
IR
(cm21
1H NMR
d (ppm)
Analyses
(C,H,N)
)
1a
189±190
83
85
90
90
85
3235 (NH)
1665, 1655
(CyO)
7.40±7.70 and 7.90±8.50 (2m, 7H, 5H Ar 1 2H Py), 8.70±8.90 and 9.10±
9.30 (2m, 2H, Py), 11.40, 11.57 and 12.90 (3s, 3H, 3NH, disappear with
D2O)
C14H12N4O2S
C15Hl4N4O2S
C15Hl4N4O3S
C14H11N4O2SC1
C12H10N4O3S
1b
1c
1d
1e
185±186
3270
1670, 1650
2.43 (s, 3H, CH3), 7.35 and 7.97 (2d, J ˆ 7:8, 4H, C6H4), 7.50±7.70, 8.20±
8.50, 8.70±8.90 and 9.10±9.30 (4m, 4H, Py), 10.7±11.2 (m, 3H, 3NH,
disappear with D2O)
280 (dec.)
270 (dec.)
192 (dec.)
3285
1676, 1661
3.90 (s, 3H, OCH3), 7.02 and 8.10 (2d, J ˆ 9:6, 4H, C6H4), 7.35±7.70,
8.25±8.50, 8.70±8.90, 9.10±9.30 (4m, 4H, Py), 12.24 and 12.5±12.8 (2m,
3H, 3NH, disappear with D2O)
3215
7.53 and 8.11 (2d, J ˆ 9:0, 4H, C6H4), 7.35±7.70, 7.95±8.50, 8.70±8.90
and 9.10±9.30 (4m, 4H, Py), 11.2, 11.6 and 12.6 (3m, 3H, 3NH, disappear
with D2O)
1697, 1675
3130
6.60±6.80 (m, 1H, H-4 Fur), 7.30±8.10 (m, 3H, 2H Fur 1 1H Py), 8.20±
8.60, 8.60±9.00 and 9.10±9.40 (3m, 3H, Py), 11.0±11.6 (m, 3H, 3NH,
disappear with D2O)
1676, 1655
1f
1g
1h
1i
200±202
187±188
75
75
73
93
65
3210
7.30±7.80 (m, 2H, Ar), 7.80±8.30 (m, 5H, 3H Ar 1 2H Py), 8.70±8.90 (m,
2H, Py), 11.40, 11.60 and 12.60 (3m, 3H, 3NH, disappear with D2O)
2.42 (s, 3H, CH3), 7.33 (d, J ˆ 8:0, 2H, Ar), 7.70±8.15 (m, 4H, 2H Ar 1
2H Py), 8.65±8.95 (m, 2H, Py), 11.20 (s, 3H, 3NH, disappear with D2O)
3.84 (s, 3H, OCH3), 7.01 and 8.08 (2d, J ˆ 9:0, 4H, C6H4), 7.88 and 8.78
(2d, J ˆ 6:0, 4H, Py), 11.40 (s, 3H, 3NH, disappear with D2O)
7.54 and 8.11 (2d, J ˆ 8:0,4H, C6H4), 7.92 and 8.83 (2d, J ˆ 6:0, 4H, Py),
11.3, 11.7 and 12.7 (3m, 3H, 3NH, disappear with D2O)
6.60±7.00 (m, 1H, H-4 Fur), 7.70±8.30 (m, 4 H, 2H Py 1 2H Fur), 8.86
(d, J ˆ 6.0, 2H, Py), 10.8±12.3 (br s, 3H, NH, disappear with D2O)
C14Hl2N4O2S
C15Hl4N4O2S
C15Hl4N4O3S
C14H11N4O2SCl
C12H10N4O3S
1690, 1670
3255
1675, 1660
3260
259±260
(dec.)
1675, 1660
3290
280 (dec.)
1676, 1660
3185
1j
184±185
1685, 1675
Table 3
Yields, physical and spectroscopic data of compound 2a±j
Compound
M.p.
(8C)
Yield
(%)
IR
(cm21) (CyO)
1H NMR
d (ppm)
Analyses
(C,H,N)
2a
2b
234±235
86
90
1712, 1697,
1678
7.40±7.80 and 8.00±8.50 (2m, 7H, 5H Ar 1 2H Py), 8.70±9.20 (m, 2H,
Py), 12.2±13.2 (br m, 1H, NH, disappears with D2O)
C15H10N4O3S
C16Hl2N4O3S
232 (dec.)
1709, 1698
1676
2.41 (s, 3H, CH3), 7.34 and 8.04 (2d, J ˆ 8:0, 4H, C6H4), 7.50±7.70, 8.10±
8.40, 8.70±8.90 and 9.00±9.20 (4m, 4H, Py), 12.50 (s, 1H, NH, disappears
with D2O)
2c
226±227
241±242
90
84
1710, 1696,
1670
3.89 (s, 3H, OCH3), 7.10 and 8.12 (2d, J ˆ 9:0, 4H, C6H4), 7.50±7.80,
8.25±8.45, 8.70±8.90, 9.00±9.20 (4m, 4H, Py), NH not detectable
7.55 and 8.13 (2d, J ˆ 9:0, 4H, C6H4), 7.40±7.80, 8.10±8.40, 8.70±8.90
and 9.00±9.20 (4m, 4H, Py), 12.4±12.9 (br m, 1H, NH, disappears with
D2O)
C16Hl2N4O4S
2d
1702, 1685
C15H9N4O3SCl
2e
2f
224 (dec.)
250 (dec.)
237 (dec.)
224 (dec.)
238 (dec.)
235 (dec.)
65
90
90
55
91
45
1740, 1720
1680
1745, 1660
6.70±6.90 (m, 1H, H-4 Fur), 7.40±7.70 and 8.00±8.50 (2m, 4H, 2H Fur, 1
2H Py), 8.70±8.90 and 9.00±9.20 (2m, 2H, Py), NH not detectable
7.20±7.90 and 8.00±8.40 (2m, 7H, 5H Ar 1 2H Py), 8.70±9.00 (m, 2H,
Py), 12.5±12.9 (m, 1H, NH, disappears with D2O)
C13H8N4O4S
C15H10N4O3S
C16Hl2N4O3S
C16Hl2N4O4S
C15H9N4O3SCl
C13H8N4O4S
2ga
2h
2i
1740, 1660
1740, 1656
1742, 1662
1740, 1655
2.40 (s, 3H, CH3), 7.39 and 8.00 (2d, J ˆ 8:4, 4H, C6H4), 7.77 and 8.82
(2d, J ˆ 6:0, 4H, Py), 12.4±12.8 (br s, 1H, disappears with D2O)
3.87 (s, 3H, OCH3), 7.11 and 8.12 (2d, J ˆ 9:0, 4H, C6H4), 7.77 and 8.83
(2d, J ˆ 6:0, 4H, Py), 12.0±13.0 (br s, 1H, NH, disappears with D2O)
7.58 and 8.13 (2d, J ˆ 8:0, 4H, C6H4), 7.75 and 8.85 (2d, J ˆ 6:0, 4H, Py),
12.3±12.9 (br s, 1H, NH, disappears with D2O)
2j
6.70±6.90 (m, 1H, H-4 Fur), 7.70±7.90 (m, 1H, H-3 Fur), 8.00±8.20 (m,
1H, H-5 Fur), 8.37 and 9.18 (2d, J ˆ 5:5g, 4H, Py), NH not detectable
a
13C NMR, d: 164.00, 166.42, 168.20 (3 CyO).

S. Schenone et al. / Il Farmaco 53 (1998) 586±589
589
Table 4
Anti-in¯ammatory activity by carrageenan-induced rat paw edema testa of compounds 2a±j
Compound
Dose
(mg/kg p.o.)
Edema volume (ml ^ SE)b at the following times (h) after treatment (in parentheses percent inhibition
activity)
0
1
2
3
4
Control
±
1.5 ^ 0.1
1.4 ^ 0.1
1.6 ^ 0.1
1.6 ^ 0.1
1.5 ^ 0.1
1.4 ^ 0.1
1.5 ^ 0.1
1.4 ^ 0.1
1.5 ^ 0.1
1.5 ^ 0.1
1.5 ^ 0.1
1.4 ^ 0.1
1.6 ^ 0.1
1.5 ^ 0.1
1.6 ^ 0.1
1.4 ^ 0.1
1.6 ^ 0.1
1.3 ^ 0.1
1.8 ^ 0.1
1.9 ^ 0.1
2.1 ^ 0.1
2.2 ^ 0.1
Indomethacin
5
1.6 ^ 0.1 (30)
1.8 ^ 0.1 (40)
1.9 ^ 0.1 (10)
1.7 ^ 0.1 (35)
1.6 ^ 0.1 (30)
1.7 ^ 0.1 (35)
1.6 ^ 0.1 (30)
1.7 ^ 0.1 (35)
1.8 ^ 0.1 (0)
1.7 ^ 0.1 (35)
1.6 ^ 0.1 (30)
1.9 ^ 0.1 (5)
1.7 ^ 0.1 (35)
1.8 ^ 0.1 (40)
1.6 ^ 0.1 (30)
1.8 ^ 0.1 (40)
1.5 ^ 0.1 (25)
1.6 ^ 0.1 (46)
1.9 ^ 0.1 (30)
1.9 ^ 0.1 (30)
1.8 ^ 0.1 (23)
1.7 ^ 0.1 (19)
1.8 ^ 0.1 (23)
1.6 ^ 0.1 (46)
1.7 ^ 0.1 (50)
1.8 ^ 0.1 (23)
1.8 ^ 0.1 (23)
1.7 ^ 0.1 (21)
2.0 ^ 0.1 (23)
1.7 ^ 0.1 (50)
1.8 ^ 0.1 (54)
1.7 ^ 0.1 (19)
1.8 ^ 0.1 (54)
1.5 ^ 0.1 (42)
1.6 ^ 0.1 (65)
2.0 ^ 0.1 (37)
2.0 ^ 0.1 (37)
1.8 ^ 0.1 (50)
1.7 ^ 0.1 (47)
1.9 ^ 0.1 (35)
1.7 ^ 0.1 (47)
1.7 ^ 0.1 (67)
1.9 ^ 0.1 (35)
1.8 ^ 0.1 (50)
1.8 ^ 0.1 (30)
2.1 ^ 0.1 (22)
1.8 ^ 0.1 (50)
1.8 ^ 0.1 (70)
1.7 ^ 0.1 (47)
1.9 ^ 0.1 (55)
1.5 ^ 0.1 (62)
1.6 ^ 0.1 (69)
2.1 ^ 0.1 (32)
2.0 ^ 0.1 (45)
1.9 ^ 0.1 (43)
1.8 ^ 0.1 (39)
1.9 ^ 0.1 (43)
1.8 ^ 0.1 (54)
1.8 ^ 0.1 (56)
1.9 ^ 0.1 (43)
1.9 ^ 0.1 (43)
1.8 ^ 0.1 (39)
2.2 ^ 0.1 (19)
1.8 ^ 0.1 (56)
1.8 ^ 0.1 (74)
1.7 ^ 0.1 (54)
1.9 ^ 0.1 (60)
1.5 ^ 0.1 (67)
2a
2b
2c
2d
2e
50
50
50
50
25
50
100
50
50
50
25
50
100
25
50
100
2f
2g
2h
2i
2j
a Each compound was tested on a group of ®ve albino rats (180±250 g). Compounds were given by gastric probe 30 min before carrageenan (0.1 ml of 1%
solution).
b SE was always smaller than ^ 0.1 ml and so rounded up to this value.
[8] F. Russo, M. Santagati, A. Santagati, A. Caruso, S. Trombatore, M.
Á
Amico-Roxas, Nuovi sistemi policiclici azotati. Sintesi e proprieta
Acknowledgements
farmacologiche di derivati benzofuro-e-tienotiadiazolopirimidinici,
Il Farmaco Ed. Sc. 38 (1983) 762±774.
We thank MURST (Co®nanziamento Nazionale) for
®nancial aid and Messrs A. Panaro, C. Rossi and F. Tuber-
oni for analytical support.
[9] G. Mazzone, F. Bonina, A.M. Panico, G. Puglisi, G. Marchetta, M.
Amico-Roxas, A. Caruso, G. Blandino, Sintesi e valutazione biolo-
gica preliminare di imidazo[2,1-b]-1,3,4-tiadiazoli-2,6-diarilsosti-
tuiti, Il Farmaco Ed. Sc. 39 (1984) 585±598.
[10] G. Mazzone, G. Puglisi, A.M. Panico, R. Pignatello, A. Corsaro, A.
Caruso, M.G. Leone, M. Amico-Roxas, Synthesis and biological
activity of acetamides, arylureas and 2-alkoxyphenyl-6-phenyl-
1,3,4-oxa(thia) diazolo-[3,2-a]-S-triazin-5,7-diones derived from 2-
amino-5-alkoxyphenyl-1,3,4-oxa(thia)diazole, II Farmaco Ed. Sc.
42 (1987) 963±972.
References
[1] T.D. Connor, C.R. Kostlan, M.D. Mullican, D.L. Flynn, G.P. Shrum,
P.C. Unangst, Preparation of (3,5-ditertiary-butyl-4-hydroxy-phenyl)
thiadiazoles, -oxadiazoles and -triazoles as antiin¯ammatory agents,
Eur. Patent Appl. EP 371438 (1990).
[11] F. Russo, S. Guccione, N.A. Santagati, A. Caruso, M.G. Leone, A.
Felice, G. Attaguile, M. Amico-Roxas, New heterocyclic ring system
[2] J.B. Bantich, D.N. Hardern, R.A. Appleton, J. Dixon, D.J. Wilkinson,
Preparation of anti-in¯ammatory 4-(heterocyclylamino)phenol deri-
vatives, PCT Int. Appl. WO90 14338 (1990).
V
± Synthesis and pharmacological activity of 6H-1,3,4-
thiadiazolo[30,20:1,2]-5-oxopyrimido[5,4-b]indole derivatives and of
1-phenyl-6H-1,2,4-triazolo[10,50:1,2]-5-oxopyrimido[5,4-b]indole, Il
Farmaco Ed. Sc. 43 (1988) 409±420.
[3] D.H. Boschelli, D.T. Connor, C.R. Kostlan, J.B. Kramer, M.D. Mulli-
can, J.C. Sircar, Preparation of (3,5-di-ter-butyl-4-hydroxyphenyl-
thio)-1,3,4-thiadiazoles, oxadiazoles, and analogs as antiin¯amma-
tory agents, Eur. Patent Appl. EP 449211 (1991).
[12] M. Bhalla, V.K. Svristava, T.N. Bhalla, K. Shanker, Synthesis of
1,3,4-thiadiazolo[3,2-a]-S-triazine-5,7-dithione derivatives and their
pharmacological evaluation, Boll. Chim. Farm. 133 (1994) 521±
526.
[4] D.H. Boschelli, D.T. Connor, Preparation of 3-(2-anilinophenyl)-
1,2,4-oxadiazoles and -thiadiazoles as antiin¯ammatories, US Patent
5114958 (1992).
[13] M. Santagati, M. Modica, A. Santagati, F. Russo, A. Caruso, V.
Cutuli, E. Dipietro, M. Amico-Roxas, Synthesis and pharmacological
properties of benzothiazoles, 1,3,4-oxadiazoles and 1,3,4-thiadiazoles
derivatives, Pharmazie 49 (1994) 880±884.
[5] U. Misra, A. Hitkari, A.K. Saxena, S. Gurtur, K. Shanker, Biologi-
cally active indolylmethyl-1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 4H-
1,3,4-triazoles and 1,2,4-triazines, Eur. J. Med. Chem. 31 (1996) 629±
634.
[14] Y.T. Chen, T.I. Chang, Acylthiosemicarbazides and related
compounds, Hua Hsuch Pao 30 (1994) 10±16 (Chem. Abstr. 61
(1994) 3064h).
[6] G. Linz, F. Himmelsbach, H. Pieper, V. Austel, B. Guth, J. Weisem-
berger, Five membered heterocycles [thiazoles, imidazoles, thiadia-
zolones], pharmaceutical agents containing them, their use as aggre-
gation inhibitors and methods for their production, PCT Int. Appl.
W097 15567 (1997).
[15] M. Lipp, F. Dallaker, G. Koenem, 1-Isonicotinoyl-4-acylthiosemicar-
bazides, Chem. Ber. 91 (1958) 1660±1664.
[16] C.A. Winter, G.W. Nuss, Pyrogenic effects of bacterial lipopolysac-
carides as an assay of antipyretic drugs in rats, Toxicol. Appl. Phar-
macol. 5 (1963) 247±256.
[7] C.K. Lau, Diphenyl-1,2,3-thiadiazoles as anti-in¯ammatory agents
and preparation thereof, US Patent 5677318 (1997).