Journal of Medicinal Chemistry, 1971, Vol. 14, No.1
NEW COMPOUNDS
83
TABLE I1
n S NCORi R ~R,X No.
Ri
Ra
R8
MP, Ce
194-196" 3-Pyc H H Me Et 170-172" 2 3-Py 183- 184a 3 3-Py Et Et H n-Pr 134-136" 4 3-Py H C&(CHz)6 159-1 615 5 3-Py H C6H5 99-100 6 3-Py H 4-ClCaHr 192-193" 7 3-Py H 4-CHsOCsHd 130-134" 8 3-Py 68-69 H C6H5 9 CH4CHz)a 64-65 10 (CH3)zCHCHz H CeH5 11 CH3(CHz)io H C6H5 55-56 a As picrate. Elemental analyses were performed by A. Bernhardt, West Germany. of the theoretical values. All compounds were analyzed for C, H, N, S. Py = pyridyl. 1
thiaxolidines in Table I were unstable and too toxic for pharmacological test. None of the thiazolidines described in Table I1 showed significant activity in mice kept on a hyperlipidic diet in comparison with choline. Experimental Section
All melting points were obtained in open capillary tubes and are uncorrected. General Procedure for Compounds in Table 1.-The 3-dimethylaminoacetylthiazolidines were prepared according to the literature% and were converted into quaternary salts by treating their ethereal soln with an equimolar amount of Me1 for 12 hr a t room temp. The ppt was washed with EtzO, dried in vacuo, and immediately analyzed for I-. General Procedure for Compounds in Table 11.-The thiazolidines used for acylation were known products; they were synthesized according to described methods."rb The nicotinyl derivatives were prepared by adding nicotinyl chloride. HC1 (0.02 mole) portionwise to a soln of the appropriate thiazolidine (0.02 mole) and EtrN (0.04 mol) in CHpClp (100 ml). After 20 hr a t room temp the s o h was concentrated in vacuo to dryness and washed (HpO); the residue was dissolved in EtOH and purified by dilution (HzO) and the sepd oil was crystd as the picrate in the usual way (EtOH). For the preparation of the other acyl derivatives, EtZO, and KPCOIwere used instead of CH&lp and EtaN, respectively.
Acknowledgment.-We thank Mr. A. Cleric0 for helpful assistance in synthetic work. (2) (a) R. Tondeur, R. Sion and E . Deray, Bull S O C .Chim. Fr., 2493 (1964). (b) E. D.Bergmann and A. Kaluazyner, Reel. Trau. Chim. Pays-Bas, 1 8 , 289 (1959).
Some Amides of 2-Hydroxy(or Alkoxy-) 3-methoxybenzoic Acid E. COSTAKIS A N D G. TSATSAS* Laboratory of Pharmaceutical Chemistry, University of Athens, Athens 144, Greece Received July 6 , 1970
The fact that amides of vanillic acid and their derivatives show various biological activities, notably analeptic, 1-3 antibacterial, and a n t i f ~ n g a lprompted ,~ us to
* T o whom correspondence should be addressed. (1) K. Kratzl and E. Kvasnicka, Monatsh. Chem., 88, 18 (1952). (2) K. Kratzl, K. H. Ginzel, E. Kvaanicka and M . Qelbock-Hochsteher, PTOC.Int. Conpr. Biochem., Bnd, 1961, 437 (1953).
Crystn solvent
Formulab
EtOH CisHisNsOsSa EtOH CieHi9N508Sa EtOH CigHziNEOeSa EtOH CieHi9N50sS5 EtOH CZ~HZ~N~O~S' EtOH Ci jHirNzOS EtOH CziHi&lNsOsS",d EtOH C2zHi9Ns09Sa Ligroin CirHisNOS Ligroin CirHisNOS EtOH-Hz0 CziHs3NOS The analytical results were within k 0 . 4 7 , C1 anal. also.
perform the synthesis and pharmacological evaluation of the title amides. The standard methods of synthesis are given in the Experimental Section. All of the amides listed in Table I were tested for antibacterial and antifungal action^,^ and some of them were examined for CNS activity in for antiinflammatory activity in rats and guinea p i g ~ , ~ -and l~ analeptic activity in mice and rats.13-15 None of the compounds in these tests showed anything worthy of note. Experimental Section16
Amides were purified by recrystn or distn under reduced pressure. The 2-alkoxy- (methoxy-, ethoxy-, or isopropoxy-) 3-methoxy benzoic acids and their corresponding chlorides were prepared as reported previ0usly.~7 2-Acetoxy-3-methoxybenzoyl chloride was obtained in 88% yield, by treating the corresponding acid with SOCL. Low yields (25-30%) were encountered when 2hydroxy-3-methoxybenzoyl chloride was prepared by refluxing ovanillic acid with excess SOClz in C&B for 1.5 hr.ls Amides of 2-Alkoxy-3-methoxybenzoicAcid.-A soln of the 2-alkoxy-3-methoxybenzoyl chloride (0.05 mole) in 20 ml of anhyd Et20 was added dropwise with vigorous stirring to a soln of the amine (0.05 mole) in 40 ml of 1 N NaOH. Stirring was continued 30 min after completion of the addition. The mixture was extd with EtzO. The combined exts were dried (NazS04)and evapd (see Table I). 2-Hydroxy-3-methoxybenzamides.-To a cooled s o h of 2acetoxy-3-methoxybenzoyl chloride (0.05 mole) in 50 ml of dry CsHg was added dropwise with stirring a soln of amine (0.05 mole) and Et3N (0.05 mole) in 30 ml of dry C6H6. Stirring was (3) B. Botta, L. Canonica, and E. Pavanati, Atti. Sac. Lamb. Sci. Med. Biol., 9, 22 (1954). (4) I. A. Pearl and D. L. Beyer, J . Amer. Chem. Sac., 16, 2627 (1953). (5) G. Coppi, A. Maselli, and C . Ciani-Bonardi, Farmaco Ed. Sci., 30, 203 (1965). (6) F. M. Berger, J. Pharmacol. E z p . Ther., 98, 470 (1948). (7) J. R. Boissier, Actual. Pharmacol., 12, 7 (1959). (8) C. Bianchi, Arch. Int. Pharmacodyn. Ther., i l l , 227 (1957). (9) C. Bianchi and J. Franceschini, Brit. J. Pharmacol., 9,280 (1954). (10) L. 0.Randall and J. T. Selitto, Arch. I n t . Pharmacodyn. Ther., ill, 409 (1957). (11) J. Reinhart and E. de Beer in "Biological Standardization," J. Burn, D. Finney, and L. Goodwin, Ed., 2nd ed, Oxford University Press, London, 1950, p 316. (12) E. Adami and E. Maraezi, Arch. Int. Pharmacodyn. Ther., 10'7, 322 (1956). (13) P. Siegmund and M. Wolf, Arch. Exp. Pathol. Pharmakol., 216, 323 (1952). (14) G. Chen and B. Bohner, J. Pharmacol. Exp. Ther., 181, 179 (1961). (15) R. Rushton and H. Steinberg, Nature (London), 191, 1017 (1963). (16) Melting points and boiling points are not corrected. (17) G. Tsatsas and E. Costakis, J . Med. Chem., 11, 870 (1969). (18) M. A. ELF. Ibrahim, H. A. El-Mangouri, aud Y. M. Abou-Zeid, Congr. Sei. Farm. Conf. Comun., d l s t , 1961,468 (1962).
84
Journal of IMedicinal Chemistry, 1971, Vol. 14, AYo.1
NEW COMPOUNDS
TABLE I AMIDESO F 2-HYDROXY- (OR ALKOXY-)
3-METHOXYBENZOIC A C I D
O=CR
&OR,
OCH, Alp or bp, (mm) "C
Yield,c
4
93-94 206-208 (35) 175-178 (10) 183-183 (18)
78 66 71 70
5
178-180 (10)
64
S O
1 2 3
6
'lo
87-88
EtOII
71
EtOH
76
EtOH EtOH
7 8 9 10 11
71- 72 121-122 174-176 (11) 184-186 (13) 178-180 (14)
6s
12
204-206 (11)
89
13
Recrystnd solvent
83 72 83
90
89 -90
-l i
EtOH
14 15 16 17 18
70-80 1.57 1% 168-170 (16) 172-174 (10) 175-177 (IO)
61
19
213-215 (14)
84
20
203-203
21 22 23
.i8-59 b3-86 127-128
60 64 68
E-PI3 E-PE E-EtOH
120-121
70
E-EtOH
108- 109
69
E-EtOH
24
H
25 All compds were analyzed for C, H, X.
* Also nip 56-57".
continued 50 min after completion of the addition at room temp. Et3N.HC1 was removed by filtration and the filtrate was evapd t o dryness. To the dry residue was added 3 g of Na~C03in 50 ml of H2O (if necessary a few ml of EtOH was added) and the mixture wab refluxed for 2 hr. After cooling, the s o h was made strongly alkaline with l0T0 KOH, the mixture was washed with CHC13, acidified, and extd with CHCl3 and the solvent was evaporated t o dryness. Yields and physical constants are given in Table I.
Purified compds.
87 60 64
(lay
EtOH EtOH
82
E, ether, €'E, petroleum ether 185-45')
tions among isomers. Now we wish t o report the preparation and testing for rat hepatocarcinogenic action of the four isomeric p-dimethylaminophenylazodibenzothiophenes (Table I). TABLE I S , A V - V - D ~ ~ ~ ~ ~ ~ ~ - p - X Yield,
s
0
Z '
Mp,
oc
1
Carcinogenic Activity of Dibenzothiophene Analogs of p-Dimethylaminoazobenzene ELLISV. BROW&* A N D RUSSELL ISBRANDT Department of Chemistry, University of Kentucky, Lexington, Kentucky 40606 Received July 1 1 , 1970
Our previous worki has shown that replacement of the unsubstituted ring of p-dimethylaminoazobenzene (DAB) with heterocyclic rings lead to a number of very active carcinogens and shows some interesting varia* To whom correspondence should be addressed. (1) E . V. Brown and W.M. Fisher, J . M e d . Chem., 111, 1113 (1969)
38.6 170-176 2 57.2 184-187 3 20.6 219-220 4 43.5 163-164 a All compounds (C20H17NsS) were analyzed for C, H, and and the results were within 3 ~ 0 . 4 %of the theoretical value.
N
Experimental Section2
All of the azo compounds were prepared by coupling PhNbIez with the appropriate aminodibenzothiophenes. A typical procedure is given below. 1- and 2-aminodibenzothiophene were prepared by the procedures developed by Gilman and coworkers*-6 (2) All melting points were determined on a Fisher-Johns apparatus and are corrected. The C , H analyses were performed in this department on an I; and M Model 185 analyzer by M r . Daryl Sharp. (3) H. Gilman and J. F . Nobis, J . Amer. Chem. Soc., H, 274 (1949). (4) H. Gilman and A. L . Jacoby, J . Org. Chem., 3, 108 (1938). (5) H. Gilman and G . R . Welder, J . Smer. Chem. Soc., 78, 2906 (1954).
