Journal of Medicinal Chemistry, 1971, Vol. 14, No. 1 53
NOTES 1 N aq K H C 0 3 was added 17 g (0.16 mole) of ethyl chloroformate with vigorous stirring. When COZ evolution subsided the organic phase was washed with HzO, dried ( M g s o ~ )and , evapd to an oil. Vacuum distillation provided 14.5 g of pure 31: bp 107110' (0.1 mm); ir (film) 5.8p-; nmr 6 5.2 (s, 2 H): 5(6H)-PhenanthridinecarboxylicAcid, Ethyl Ester (34).-A solution of 9.1 (50 mmoles) of 5,6-dihydrophenanthridine(prepared according to the method of Wooten and McKee5) was (5) W. C. Wooten and R . L. McKee, J . Amer. Chem. S o c . , 11, 2946 (1949).
treated with ethyl chloroformate as in the preceding experimental procedure. Pure 34 was obtained as a colorless liquid: bp 158-159' (10 p ) ; ir (film) 5.8 p ; nmr 6 4.8 (s, 2 H ) .
Acknowledgment.-We wish to express our appreciation for the valuable chemical technical assistance contributed by J l r . Hans Wiedermann, and the valuable pharmacological technical assistance contributed by n h . Charles W. Scott.
Notes TABLE I
Synthesis and Activity of Some 1,2,4-Triazolylthiazolidones A. ANDOLSEK,B. STANOVNIK, M . TISLER,* Department of Chemistry
hI.
LIK.4R.
AND
P.
SCHAUER
Institute of Microbiology, University of Ljubljana, Ljubljana, Yugoslavia Received J u n e 29, 1970
Thiazolidine derivatives exhibit sedative,' anesthetic, a n t i c o n v ~ l s a n t , ~antituberc~lous,~a m e b i ~ i d a l , ~and fungicidal6 activity. Previous publications from this l a b o r a t ~ r y ~ -have ' ~ shown that some derivatives of 5carboxymethylthiazolidine - 2,4 - dione inhibit viral growth. I n continuing these investigations some new thiazolidine derivatives have been synthesized. 1,2,4-Triazolylthioureas (1) (Table l), obtained by condensing 4amino-l,2,4(4H)-triazole with several isothiocyanates, were cyclized with maleic anhydride t o the corresponding thiazolidin-4-ones (2) (Table 11). The 1,2,4-triazolylthioureaswere also condensed with 1,2-dibromoethane to afford the corresponding thiazolidines (3). It can be envisaged that the reaction could take place to give two different monocyclic products, ie., 3a or 3b, or even a bicyclic product. To ascertain the structure of the products, some of these were hydrolyzed with HC1 a t 200". The expected primary cleavage products would be 4a and PhNHB+C1- from 3a, or
Reaction time, lir
R P - C Z H ~ O C ~ H A0.5 P-ClCsHc 0.5 n-CaHg 2.0 2,6->fe&& 6.0 2,4-hfezC& 1.0 o-CHsOCsHa 1.0 p-CHsOCsHa 0.5 a All compds had analyses of the theoretical values. NO.
1 2 3 4 5 6 7
H,NN
Mp, ' C
Formula"
38 CiiH13N50S 70 CsH5ClNbS 6 C7HiaN5S 8 CllH13N5S 57 CiiHlsN5S 26 CioHiiNsOS 45 CioHilNsOS and S within 0.4%
RNHCSNHN 1
3
0
2
3b
* To whom correspondence should be addressed. (1) W.J. Doran and H. A . Shoule, J. Ore. Chem., 3, 193 (1939). (2) A. R.Surrey, J. Amer. Chem. SOC., 71,3354 (1949). (3) H. D . Troutman and L. M . Long, ibid., IO, 3436 (1948). (4) N. P. Buu-Hoi, N. D. Xuong, and F. Binon, J . Chem. Soc., 716 (1956). (5) A. R. Surrey and R. A . Cutler, J . Amer. Chem. Soc., 16, 578 (1954). (6) J. Kinugawa and H . Nagase, Yakugaku Zasshi, 86, 101 (1966). (7) M.TiSler, Vestn. Slou. Kem. Drust., 4,91 (1957). (8) A. KrbavCif, M. Plut, A . Pollak, M. TiSler, M. Likar, and P. Schreau, J. Med. Chem., 9,430 (1966). (9) M.Tidler, Ezperientia, 14, 261 (1956). (10) P . Schauer, M . Likar, M . TiSler, A. KrhavEi:, and A. Pollak, Pathol. ~ i c r o b i o z . as, , 382 (1965). (11) P. Schauer, A. KrbavEif, M. TiSler, and M. Likar, Ezperientia, aa, 304 (1966). (12) P. Schauer, M. Likar, M . TiSler, and A . Krbavci:, Pathol. Microbiol., 99,506 (1966).
Yield, %
164 176 134 168-170 182-184 152-154 172-174 for C,H,N,
1 4a
4b
4-amino-1,2,4-triazole .HCl and 4b from 3b. From the hydrolysates of 3a (R = CeHj) PhNHS+Cl- and an unidentified product were isolated. Similarly, when 2phenylimino-3-phenylthiazolidine, as a model compound, was hydrolyzed under the same conditions, 3phenylthiazolidin-2-one and PhNH3+C1- were identi-
54 Journal of Medicinal Chemistry, 1971, Vol. 14, Yo. 1
NO.
R
Reaction time, hr
1 p-C2HjOCfiH4 2 P-ClCsHa 3 2,4-hIe2C6H3 4 O-CH3OC6H4 a See Table I, footnote a.
15 10 17 10
hed as degradation products. These results favor structure 3a arid such hydrolytic cleavages are lino\vn to have synthetic importance for the synthesis of thiazolidinediones. l 3 The antiviral activity n-as tested with Herpes simplex 31 the virus as described earlier.'d At 3.10-3-j.10-4 test compounds were found t o be either toxic or inactive (2, R = C8Hj;arid 3, R = p-C2HjOC6H4).
colorless compd, mp 196", which by riiiiip and ir bpectra n a s identified with an authentic specimeii of PhSH,+Cl-. IIydrolysi3 of 2-phenyliniino-3-phetiylthiax~liditie1*wab doiie in essentially the same manlier and upon evaporating the reartioii mixture m vacuo the known 3-pheiiylthiazolidiri-2-one'8 way isolated
Experimental Section16
cis-l-[(2-Piperidinocyclohexyl)carbonyl]-
I-( 1,2,4-Triazolyl-4)-3-phenylthiourea (1, R = CfiH5).-A mixture of 4-amiri~1,2,4(4H)-tria~olel~ (8.4 g, 0.1 mole), phenyl isothiocyariate (13.5 g, 0.1 mole), and EtOH (30 ml) was heated on a water bath for 15 niin. The product which sepd upon cooling was collected, washed Tyith IStOI-I, and recrystd from the same solvent: yield 15.0 g (68';); nip 175" (lit." mp 105"). A T K L(CsHsS&j, ~. C, II, S . By the same procedure other substituted triaxolylthioureas were obtained (Table I). In a11 cases EtOH was used as solveiit for recrystii. If the product did not sep or if only :L little of the product Pepd, the solvent wah evapd in vacuo to dryiiess and the residue was then purified by crystn. 2- [( 1,2,4-Triazolyl-4)imino] -3-phenyl- 5 carboxymethylthiazolidin-4-one (2, R = C6Hj).--4 mixtiire of 1 ( R = CsTT;; 4.35 g, 0.02 mole), finely powdered maleic anhydride (1.96 g, 0.02 mole), aiihyd C6I16 (50 xd),and aiihyd 3Ie&O (30 nil) was heated under reflux oii a water bath for 24 hr. Some SleaCO was added mid the mixture heated t u boiling to give an almost clear s o h . Upon filtration the filtrate wna evnpd t o dryness in vacuo and the residue recrystd from lIe2CO t o give 0.45 g (ic:;j of the pure compound, mp 2.51-233'. d n d . (C13HllNj03d), C, I%,?;, s. 111 practically the srtme way other 3-substituted derivatives (2) were prepd (Table IIj. A11 c ~ m p d swere purified by recmrystii from KtOH. 2-Phenylimino-3-( 1,2,4-triazol-4-yl)thiazolidine(3, R = C6Hjj. -To a soln of 1 ( R = C6H5; 2.19 g. 0.01 mole) in D31F (10 ml) niihgd K?CO, (1.39 g, 0.01 mole) :uid I,.'-dibromoethane (1.88 g, 0.01 mole) were added and the rectctioii misture was stirred at rooni temp for 13 hr. The product wah filtered oft' axid refrom EtOII: yield 0.6 g (24c;); nip 190-192". A n a l . ,NjS), C, 11, Ii. The ,>ame compound could be obtained iii 49(; yield if iiivtead of KrCOi 20 1111 of I.)lIF WRH used alI ogether. lii a n niialogoui way the following :3-(1,2,4-triazol-4-yl)thiszolidiries vere synthesized and cryitd from Et'OH. 'L-(p-Chloropheiiylimiiio) (3, I1 = 4 ) was obtained in yield, nip 223-225'. Anal. (CjlHl C, H, S , S. L'-(p-I':thosypheiiyliniiiio) (3, I< = jOCJ3a) was obtniiied in g r ; yield, mp 198-200". A n a l . ~ C 1 3 1 ~ 1 2 ~C, 2 0H, s ) 9, , S. Z i p - AIethoxyphenylimino) H = p-CH,OCsH*) n-as obtained in 6 5 yield, mp 231- 3". .Inn!. (C1,Hl,S5OS), C, 13, N. Hydrolysis of 2-PhenyIimino-3( 1,2,4-triazol-4-yl)thiazolidine. -Conipd 3 ( R = CGH2;0.5 g ) U-RS heated with 10 ml of HCl (,1:2) n t 200' in a sealed tube for 1 hr. After evapti in V ~ C L L O t,o dryness the residue x a sublimed ~ in ca-cuo and afforded N
-
(13) XI. .lspelund, A c t a d c i i d . Abornais, M a t h . P h y s . , 24, 1 (1964). (14) P. Schauer and AI. Likar, Pathol. X i c w b i o l . , 28, 371 (1965). (15) Melting points were determined on a Iiofler heating microscope and are corrected. (16) C. I'. 11, .Wen and A. 13ell "Organic Syntheses," Collect. Tol, 3, Kiley, S e w York, S. T.,1955, 9 9 6 . ( 1 7 ) If.S. Solanki and J, P. Trivedi, J . I n d i a n Chem. Soc., 42, 817 (1Y65).
(18)
\V.TTill, Ber., 1 6 , 344
(1882)
piperidine and Related Compounds. Oral Hypoglycemic Agents
Screening for :mtidi:ibetic ageiits revealed that C ~ A 1-[ (2-pipericliiiocycloliexyl)carboriyl]piperidi~ie hydrochloride (7a, Table I), pobse5scd good hypoglycemic activity iii the glucose-primed, fasted, intact rut. This compound is :L reprcseiitative of a class of compounds not previously msocinted \\-it11 hypoglycemic activity As :Lresult, :I study aimed :kt obtniiiing insight into the various strueturd features riecessuq for hypoglycemic activity in thi\ claw of compounds \t as made. Chemistry-Compounds 1-17 I\ ere prqinred according to the 5ynthctic sequence outlined in Scheme I. The desired qyrithctic intermediatcs (I) \\ere obt:iiricd by refluxing a mixture of equiv amouiit.; of thc appropriate mixture of E t arid M e 2-oxocycloa1kaiioiiecal.boxylate and iecoridary aniiiic for 1'i.T, hr-14 da Treatment of these keto amide3 I\ ith primarq- or seeondnry amines i i i benzene, :iccording to thc niethod of Stork and co\vorlm-s,l afforded t h e eiiarriiries 11 hich 'r\ ere hydrogcnated (PtOJ to afford compounds 11. Compounds 18 arid 19 were prepared according to the sequence outlined in Scheme 11. Treatment of 1-(1cyclohexeii-1-yl) piperidiiie ivith phen\rl arid cyclohexyl isocyanate, according t o the method of Hunig and cou-orkers,* :iff orded the enamine intermediates which were cntiilytically reduced to compounds I1 (NR3R-I = piperidino). Biological Testing.-Glucose-primed, fasted (1s-24 hr), Upjohn Sprague-Dav ley, pathogen-free, male rat:, were the test aiiimalz. The test compound IT as administered orally :tt various dosages in 0.5 nil of sterile vehicle (6 rats group). Immediately follon iiig admin-
* T o whom correspondence should be addressed. (1) G . Stork, .I, Brizzolara, H. Landesman, J. Szmusskovicz, and R . Terrell, J . Amer. Chem. Soe., 86, 207 (1963). (2) S. Hunig, K . Hubner, and E. Benzing, Chem. Reu., 96, 926 (1962).
