Sovember 1968
DIURETIC 2-AMIXO-4-ARYLA~lINO-6-MERCAPTO-S-TRIAZIXES
cryst,allized from a suitable solvent or distilled. The hydrochloride salts were prepared by dissolving the base in EtOH or Et20 and adding ethanolic HCI. 1,2-Dihydro-3H-imidaz0[1,5-a] indol-%-ones(Table IV). Procedure C. Reaction of the 2-(Aminomethyl)indole with N,N’Carbonyldiimidazole.-A solution or suspension of 0.02 mole of the dry 2-(aminomethyl)indole in 40 ml of dry T H F or C6H6 was cooled and a solution of 3.87 g (0.022 mole) of 92y0 K,K’carbonyldiimidazole in 40 ml of T H F was added. The mixture was allowed to st,and at, room temperature for 18-20 hr and then heated on the steam bath for 1-4 hr. The solvent was distilled iising a rotat,ing evaporator and the residue was warmed v,-ith abont, SO ml of HzO. The product was filtered off and washed with H,O (if solid) or extracted into C6&. The C6R6 layer was washed wit,h HzO and concentrated. Cyclization was usiially incomplete, and further piirification wm obt~ainedby crystallization of the base or salt from a suitable solvent or by partition chromatography. The salts were obtained by dissolving the base in Et20 or EtOH and adding ethanolic HC1 or excess maleic acid. Procedure D. By Aminoalkylation of the 1,2-Dihydro-3Himidazo [ 1 &a] indol-3-one.-A solution or suspension of 0.01 mole of the 1,2-dihydro-3H-imidazo[ 1,5-a]indol-3-one in 30 ml of diglyme was added dropwise to a suspension of 0.011 mole of .50Yc NaH (in mineral oil) in 20 ml of diglyme. The mixture was stirred for 30-60 min and a solrition of 0.012 mole of the dialkylaminoethyl chloride in 20 nil of diglyme was added. T h e reaction mixtiire was heated at, refliix t,emperature for 5 hr, filtered while hot, and cwnc~entrRted. The residiie was dissolved in diliite FICl
1167
and extracted with C6Hs to remove nonbasic impurities. The aqneous layer was t’reated with excess 5 S NaOH and extracted with C6Hs. The C6H6 layer was washed (H,O), dried (MgSO,), and concentrated. The residue was converted to the hydrochloride salt and recrystallized from a suitable solvent. Procedure E. 7-Chloro-2-piperidinomethyl-l,2-dihydro-3Himidazo[1,5-a]indol-3-one Hydrochloride.-A mixtiire of 1.03 g (0.00S mole) of 7-chloro-1,2-dihydro-3H-imidazo[l,5-a]indol-3one, 0.50 ml (0.005 mole) of piperidine, 0.40 ml (0.005 mole) of 37y0 HCHO, and 40 ml of EtOH was heated on the steam bath for 2 hr. Some insoluble material was filtered off and the mother liqiior was roncentrated. The residual oil was dissolved in 5 ml of EtOII, and 1.5 ml of 3 .Y ethanolic HCI was added. The precipitate was filtered off and recrystallized from MeOH.
Acknowledgment.-We TI ish t o thank JIr. L. Braricone and associates for the microanalyses, JIr. C. Pidacks and staff for the partition chromatography, and A h . W. Fulmor and associates for the infrared and nmr spectra. I n particular, we gratefully acknowledge the assistance given by JIr. G. 0. JIorton in his interpretation of the nmr spectra. We also thank Dr. P. J. Kohlbrenner and co-workers for preparation of some of the 2-indolecarboxylic acids used as intermediates and Dr. A. C. Osterberg. Dr. E. Greenblntt, and associates for the pharmacological testing rcsults.
Synthesis anti Diuretic Activity of 2-Amino-4-arylamino-6-mercapto-s-triazines anti Related Derivatives 11. H.
SHAH,
C.
v. DELIWALA,~
Department of Chemotherapy, Haffkine Institute, Parel, Bombay-id, India 4ND
u.I products devoid of sulfur mere obtained. Such failures (10) W H. Miller,
R. 0. Rohlin,
J r , and E B 4stnood. J A m Chem
Soe , 6 7 , 2201 (1945). (11) RI Israel, H. K . Protopapa, H K. Schlein, and E J. Modest, J . M e d . Chem., 7 , 792 (1964). (12) I. B Douglas8 and T. B. Johnson, J . A m . Chem. S o c , 6 0 , 1486
(1938).
(13) R.0. RoLlin, Jr., and J. K.Clapp. ibid., 72, 4890 (1950). (14) 0. Clauder and G . Bulcsu, J l o u y . K e m . Folyoirat, 57, 68 (1951); Chem. Abstr., 46, 4023 (1952). (15) C. M. Kagawa and C. G . Van .-\rman, J . Pharmncol. E s p t : . T / ~ < w p , 124, 318 (19.58).
lli0
NH,CNS
+
HCI
\ HCOOH
p C H a > p-CL Furthermore, the Iriring the experiment each group of four animals w:is hoii;;ccl in an improved metal)olism cage described by Modi, el ~ l . 1 ~ One groiip was iisetl its initrented control arid received uriilly t,he vehicle only c~~iisibting of 0.5 nil of 2f;k st,nrcli ~oliitiiiii. .inother grtriip 1.oc~ivet1hytlrcic~hloioi.hiazidef2.5 nig 'kg 1 :i-
reference standard suspended in the vehicle. The other groups received the various test compounds in the same vehicle. Since the dose-response curve is found t,o be parabolic, the dose selected for each of t,he test, conipourids was the optimal responsive dose as deterniiiied in previous experimeiits by the method of Rlodi, et a1.18 The urine was collected for 24 hr, its volume was measured, and the concentrations of N a + and K + (by Eel flame photometer) and C1- (by tit,ration) were determined. The resiilts are calculated as the mean of four test groups and expressed as t,he percentage of those in the control groups aitd are given in the tables. Intermediates.-o-Chlorophenylbig~~anide,~~m-chlorophenyl~n-fliioropheiiylbigriaiibigiranide,*" p-chlorophe~iylbig~iaiiide,'~ ide,*' o-tolylbiguanide,20 and ni-tolylbigiianidez0 were prepared by the condensation of the requisite arylamines with dicyandiamide using aqiieoris medium. Phenylbiguanidezz and ometho~yphenylbiguanide~~ were prepared by using pyridine as solverit** while p-tolylbiguanide*O was prepared by fusion of t,he mixture of p-toluidine hydrochloride and dicyandiamide. 2-Amino-4-arylarnino-s-triazines were obtained from the arylbiguanide hydrochlorides by refluxing with formic acid. l 4 2-Amino-4-aniIino-6-mercapto-s-triazine(I).-To a mixture of phenylbiguanide (88.5 g, 0.5 mole) and alcoholic KOH (26.4 g of 8.5%, 0.4 mole, in 500 ml), 40 ml of CS2 was added. The orangecolored reaction mixtiire was stirred mechanically and refliixed for 14 hr with additional amounts of CS? (10 ml) at, intervals of 4 hr. During the entire coiirse of the react,ion, evolution of H?S was detected by lead acetate paper. The reaction mixtnre was then cooled in ice-wat,er and the solid was collected by filtration (product A). The filtrate on neutralization with HCl afforded the desired alkali-soluble compound 1 which was purified by redissolving in alkali arid neutralizing to p H 6.5 with HCl; crystallized from 80% EtOH, yield 13.95 g, (12.7%), mp 267268' dec (lit.8 263-265' dec), hydrochloride mp 195-200" der, picrate mp 216-217" der (lit.* 206-207' dec). Product A was purified by dissolving in dilute HC1 and reprecipitating with NaOH. It, was crystallized from met,hyl Cellosolve to get l-phenyl-2-thioammeline, yield 19.38 g (17.6%), mp 290" dec. 1-Phenyl-2-thioammeline (63)was also prepared by the method of Welcher and coworkers,6 mp 286-288" dec (lit.8 286-288' dec). Both of these were found identical in all respects including ir spectra. All of the 2-amino-4-arylamino-6-mercapto-s-triazines arid the 1-aryl-2-thioammelines were similarly obtained and are recorded in Tables I and 11, respectively. 1-p-Chlorophenyl-2-thioammeline (66)was also obtained from p-rhl~rophenyldicyandiamide~~ according to Welcher's method6 for S-pheriylthioammeline, mp 283-285', yield 43.57,. Anal. (18) K. N. Modi, h l . N. Vartak, X. i'i. Shah, K . Lotlikar, a n d U. K. Sheth, Arch. Intern. Pharmacodyn., 144, 51 (1963). (19) F. H. S. Curd a n d F. L. Rose, J . Chem. Soc., 362 (1946). (20) H. King and I. SI. Tonkin, zbzd., 1063 (1946). (21) S. L. Shapiro, V. .4.Parrino, E. R o g o n , and L. Freedman, J . A m . Chem. Soc., 81, 3795 (1959). ( 2 2 ) B. R. Jacobs a n d Z. E . Jolles (to IC1 Ltd.), British Patent 587,907 (1947); Chem. Abstr., 42, 214i (1948). ( 2 3 ) hP. Furukawa, 3 '. Seto, and S. Toyoshima, Chem. Pharm. Bvil. (Tokyo), 9 , 9 1 4 (1961); Chem. Abstr., 67, 166172 (1962). (24) F. H. S. Curd and F. L. Rose, .I. Chem. Soc., 729 (1946).
(CgHSClN&3) X. It, was soliible in very diliite HCl hiit insoliible in cold dilute XaOH. 2-Amino-4-anilino-6-allylmercapto-s-triazine (4).-To a filtered ( 1.1 g, 0.003 solution of 2-amino-4-anilino-6-niercapt~o-s-triazine mole) in 25 nil of 0.5 A' NaOH was added allyl bromide (0.67 g, 0.0055 mole) and the resulting mixture was stirred for 10 min. After 1 hr the solid that separated was collected by filtration, washed (H?O), and dried. All the S-alkyl derivatives were obtained as described above. 2-Amino-4-anilino-6-hydroxy-s-triazineHydrochloride (2).2-Amino-4-anilino-6-mercapto-s-trinzitie ( 1.1 g, 0.003 mole) was dissolved in 13 ml of aqiieoiis 0.7 .V SaOH. To this, HpOy ( 5 nil of 13c/;) was added dropwise with continuous stirring. The temperature was not, allowed to exceed 4:". After 30 min the reaction mixture was neutralized with HC1 and the solid was filtered, washed (HtO), and crystallized (EtOH-HCI) to give fine needles of 2, dried at 150" in oucuo. All of the 2-amino-4-arylamino-6-hydroxy-s-triazineswere prepared by following this method. Action of Raney Nickel on 2-Amino-4-anilino-6-mercapto-striazine.-2-Amino-4-anilino-6-mercapto-s- triazine (0.53 g, 0.0023 mole) was finely powdered and suspended in satiirated NaHC03 (50 ml). Raney nickel ( R 6 , 4.5 g) was added t,o i t . The mixture was refluxed for 4 hr and filtered hot. The filtrate after neiitralization with €IC1 was evaporated to dryness. The residue ITas treated with EtOH and filtered. The filtrate on evaporation gave 163 mg ( 3 7 . 5 5 ) of 2-amino-4-anilino-s-triazine, rnp 229-231'. I t was recrystallized from EtOH, mp 233-234'. The mixture melting point with the compoiind prepared by treating phenylbiguanide wit,h formic acid was tiot depressed. dnal. (CpHJF,) ?;. Action of Raney Nickel on l-Phenyl-2-thioammeline.-lPhenyl-2-thioammeline (300 mg) was suspended in 50 ml of EtOH containing about 2.8 g of Raney Ni (Wc). The reaction mixt'nre was refluxed for 3 hr when an almost clear solution was obtained. It was then cooled to room temperature and filtered, atid the filtrate was evaporated to dryness. The residue was crystallized (EtOH); one obtains 2-amino-l-atiiliiio-s-triazine, 142 mg (32.65
