1,3,5-Triazine-6-thiones as Antithyroidal Agents 963

l-Aryl-2-amino/hydrazino-4-phenyl-1,6-dihydro-l,3,5- triazine-6- thione and Related Thiocar bamides/Thiosemicarbazides as Antithyroidal Agents R. Prasad and P.K. Srivastava*

Department of Chemistry, Banaras Hindu University, Varanasi, India 221005

Received September 29, 1992; in revised form December 15, 1992.

Different I -aryl-2-benzylmercapto-4-phenyl- 1,6-dihydro- 1,3,5-triazine-6- thiones have been synthesized by known methods. These triazines on treat- ment with ammonia/hydrazine hydrate afforded the corresponding 1 -aryl- 2-amino/hydrazino-4-phenyl- 1,6-dihydro- 1,3,5-triazine-6-thiones which on treatment with arylisothiocyanates afforded the related thiocarb- amides/thiosemicarbazides. Some of these compounds show appreciable antithyroidal activity.

1-Aryl-2-amino/hydrazino-4-phenyl-1,6-dihydro-1,3,5-triazin-6-thion und verwandte Thiocarbamide/Thiosemicarbazide als Thyreostatika

Verschiedene l-Aryl-2-benzylmercapto-4-phenyl-1,6-dihydro-l,3,5-tri- azin-6-thione wurden nach bekannten Methoden hergestellt. Bei deren Umsetzung mit AmmoniakkIydrazinhydrat entstehen die Titelverbindun- gen, die mit Arylisothiocyanaten die entspr. Thiocarbamide bzw. Thiose- micarbazide liefern. - Einige dieser Verhindungen sind bemerkenswert thyreostatisch wirksam.

The antithyroidal'-4) activity of some disubstituted thiocarbamides/thio- semicarbazides led us to search for new members of this series containing a triazinyl moiety.

This communication deals with l-aryl-2-amino/hydrazi- no-4-phenyl- 1,6-dihydro- 1,3,5-triazine-6-thiones 2,3 and the corresponding N-aryl-N' -( 1 -aryl-4-phenyl-6-thioxo- 1,6- dihydro- 1,3,5-triazin-2-yl)-thiocarbarnides/thiosemicarb- azides 4,5. The precursor 1 -aryl-2-benzylmercapto-4-phe- nyl-1,6-dihydro- 1,3,5-triazine-6-thione (1) was prepared according to The amino/hydrazino triazines 2,3 were obtained in excellent yields when equimolar quantities of triazines and saturated alcoholic ammonia/hydrazine hydrate were refluxedhtirred for 9- 10 h. The amino/hydra- zino triazines 2,3 when treated with arylisothiocyanates afforded the related thiocarbamides/thiosemicarbazides 45 .

Experimental Part

Mps: Open capillary, uncorrected.- IR spectra: Perkin-Elmer model 720 spectrophotometer in KBr.- 'H-NMR spectra: JEOL FX 90Q Fourier trans- form spectrometer, TMS as internal standard.

2-Amino-1 -(4-hrornophenyl)-4-phenyl-l,h-dihydro-I ,3,S-triazine-h-thione ( 2 4

A solution of l a (9.32 g, 20 mmol) in absol. ethanol saturated with ammonia (70 ml) was refluxed for 6 h with stirring. Alcoholic ammonia was added in fraction (10 ml) time to time to keep the reaction mixture ammoniacal. It was then cooled, the precipitate was filtered and washed with petroleum ether and benzene to remove benzylmercaptan. The amino derivative was crystallized from ethanol, yield 4.3 g (60%), m.p. 254°C.- IR (KBr): 3310, 3150 (y N-H): 1640 (C=N); 1150 cm-' (C=S).- 'H-NMR ([DGIDMSO): 6 (ppm) = 7.12-7.94 (m, 9H, aromat.), 2.50 (s, 2H. NH2).- CISHIIBrN4S Calcd. C 50.1 H 3.06 N 15.6 Found C 50.3 H 3.21 N 15.5.

By a similar procedure 2-amino-1 -(4-methoxyphenyl)-4-phenyl-l,6-dihy- dro-l,3,5-triazine-6-thione (2b) was prepared: yield 4.0 g (65%), m.p. 234°C.- IR (KBr): 3300,3100 (y NH); 1625 (C=N); 1100 cm-' (C=S).- 'H- NMR ([D6]DMSO): 6 (ppm) = 7.10-7.80 (m, 9H aromat.): 4.30 (s, 3H, OCH,); 2.80 (s, 2H, NH2).- CI6Hl4N40S Calcd. C 61.9 H 4.52 N 18.1 Found C 62.1 H 4.25 N 18.3.

I -(4-Bromopheiiyl)-2-hydrazino-4-phenyl-1 ,h -dihydro-1,3,5-triazine-h- thione (3a)

A solution of l a (9.32 g, 20 mmol) in benzene (300 ml) and hydrazine hydrate (1.0 g, 20 mmol) was stirred at room temp. for 8 h, filtered and washed with excess of petroleum ether to remove benzylmercaptan, The hydrazino compound was crystallized from ethanol/DMF (4:1), yield 5.0 g (68%). m.p. 176°C.- IR (KBr): 3450, 3310, 3170 (y NH NH,); 1640 (C=N): 1090 cm-' (C=S).- 'H-NMR ([D,]DMSO): 6 (ppm) = 9.85-10.20 (b, lH, NH); 7.20-8.30 (m, 9H aromat.); 2.80 (s, 2H, NH2).- C15H12BrN5S Calcd.C48.1H3.21N18.7FoundC48.0H3.29N18.5.

By a similar procedure 1 -(4-methoxyphenyl)-2-hydrazino-4-phenyl-l,6- dihydro-1,3,S-triazine-h-thione (3b) synthesized, yield 5.6 g (86%), m.p. 17OOC.- IR (KBr): 3410,3330,3110 (y NH NH,); 1630 (C=N); 1100 cm-' (C=S).- 'H-NMR ([D,]DMSO): 6 (ppm) = 9.60-9.95 (b, lH, NH); 7.20- 7.90 (m, 9H aromat.): 3.70 ( s , 3H, OCH,); 2.50 (s, lH, NH2).- C16H15N50S (* +) Calcd. C 59.1 H 4.62 N 21.5 Found C 59.3 H 4.38 N 21.7.

1 -(4-Methoxyphenyl)-3-[1-(4-bromophenyl)-4-phenyl-6-thioxo-l,6-dihy- dro-l,3,5-triazine-2 -yl] thiocarbamide (4a)

A solution of 2a (1.88 g, 5 mmol) and 4-methoxyphenyl isothiocyanate (0.99 g, 6 mmol) in benzene was refluxed for 1.5 h. The desired thiocarba- mide was separated as an insoluble mass as the reaction progressed. The precipitate was crystallized from ethanol, yield 2.0 g (78%), m.p. 237°C.- IR (KBr): 3340, 3270 (y N-H); 1615 (C=N); 1090 cm-' (C=S); 1530 cm" (thioureido linkage).- 'H-NMR ([D6]DMSO): 6 (ppm) = 2.65 (s, 2H, NH), 4.53 (s, 3H, OCH& 7.12-8.35 (m, 13 H aromat.).- C23H18BrNSOS2 Calcd. C 52.7 H 3.44N 13.4FoundC 52.4 H 3.67 N 13.9.

Similarly other compounds of this type were synthesized (Table 1).

Arch. Pharm. (Weinheim) 326,963-966 (1993) 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 19930365-6233/93/1212-0963 $5.00 + .25/0

964 Prasad and Srivastava

Table 1: I -Aryl-3-[ 1 -aryl-4-phenyl-6-thioxo- 1.6-dihydro- 1,3,5-triazin-2-y1] thiocarbamide+’

Compound Ar Number

R M o l e c u l a r m.p. Yie ld f ormu 1 a (‘C) (%.I

4-BKC ’4 6’ 4

4-prC6H4

4-BrC6H4

4-BrC6H4

4-BrC6H4

4-BrC6H4

4-CH30C6H4

4-CH30C6H4

4-CH30C6H4

4-CH33C6H4

4-CH 30C 6H4

4-CH30C6!i4

4-CH 30C6H4

6 5 2-CH3C6H4

4-CH3C6H4

2-ClC6H4

4-C1C6H4

‘6’5

C H

2-CH3C6H4

4-CH3<z6H4

4-CH 3.X H 4

2-C 1 C 6H4

4-C1C6H4

C H BrN50S2

222116BrN5S2

C23H18BrN5S2

C H 9rN5S2

,2 2H 5BrC 1 N 5S

C22H15BrC1N5S2

C23H19N5’S2

C24H21N50S2

C24H21N50S2

C24H21N532S2 C23H18C1N 0s

C23918C1N 0s

2 3 18

2 3 18

5 2

5 2

-

2 3 7

2 4 1

2 2 8

250

2 0 0

2 0 7

2 3 6

2 0 4

199

170

2 1 0

2 2 2

70

0 8

81

85

69

7 7

85

88

89

85

7 5

7 7

+) All compounds gave elemental analysis (C, H, N) within k 0.30 of calculated values.

Arch. Pharm. (Weinheim) 326,963-966 (1993)

1,3,5-Triazine-6-thiones as Antithyroidal Agents 965

Table 2: 1 -Aryl-4-[ 1 -aryl4-phenyl-6-thioxo- 1,6-dihydro- 1,3,5-triazin-2-yl] thiosemicarbazide+) ~~

Compound A r R Molecular m.p. Y ie ld Number formula ( " C ) ( % )

4-BrC6H4

.Q-BrC6H4

4-BrC6H4

4-BrC6H4

4-BrC6H4

4-BrC6R4

4-CH30C6H4

4-CH30C6H4

4-CH30C6H4

4-CH30C6H4

4-CH30C6H4

4-CH30C6H4

4-CH30C6H4

C6H 5 2-CH3C6H4

4-CH 3C6H4

2-C1C6H4

4-C1CgH4

'gH5 2-CH C H 3 6 4 4-CH3C6H4

2-C1C6H4

4-ClC6H4

4-CH30C6H4

C H BrN60S2

C22H17BrN6S2 C H BrN6SZ

2 3 1 9

23 1 9

23 1 9

22 1 6

C H BrN6S2

C H BrC1N6S2

C22H16BrC1N6S2

C23H20N60S2

C24H22N63S2

C24H22N60S2

C23H19C1N60S2

C23H19C1N63S2

C24H22N602S2

220

208

190

181

205

160

215

195

240

190-91

155

175

78

84

63

70

69

74

71

66

57

62

65

60

~ ~~ ~~ ~ ~ ~ ~~ ~~ ~

+) All compounds gave elemental analysis (C, H, N) within + 0.30 of calculated values

Table 3: Pharmacological screening results of 1 -aryl-3-[ 1 -aryl-4-phenyl-6-thioxo- 1,6-dihydro-l,3,5-triazin-2-yl] thiocarbamides.

Compound Number

~~

Thyroid r a d i o a c t i v i t y dpm f s t d . error Approximate Inorganic 1311 e s t i m a t e d a c t i v i t y

i n r a t s 1311 up take PB 1311

(Thiourac i l= l .OO)

B 1 an k 98076f 6 2 87698f40 9637f03 - T h i o u r a c i l 23549228 16123f14 7106211 1 .oo

P 4a 19250i28 12135f21 6051f10 1.22

?2 22994f18 14954f12 7949209 1.02

% 18351214 10175f22 8038f24 1.28

- 4b 26892219 17986228 7694+13 0.87

22 20812f35 13015i15 68 99 i 0 3 1.13

- 4f 16882* 14 10073216 6649i12 1.39

22 4h

4 i

- -

244872 25 16943f13 7109f15

22018215 15189t14 6279i07

21113+22 13912225 7058f18

0.96

1.06

1.11

19431f18 12154f17 6182212 1 . 2 1 ii 4k 24487225 16943t13 7109i.15 0.96

41 19250f28 12135i21 6051f10 1.22

- -

I-~4-Merhoxyphenyl)-4-jl-(4-hromophenyl)-4-phenyl-6-thioxo-~,6-dihy- 8.56-8.73 (b, 2H, NH); 9.93 (s , IH, NH).- C23H,9BrN60S2 (539.4), Calcd. C51.2H3.52N 15.6FoundC51.1 H3.36N 15.4. dro-l,3,5-triazin-2-yl]-thiosemicarbazide (Sa)

Similarly other thiosemicarbazides were synthesized (Table 2). A solution of 3a (1.87 g, 5 mmol) and 4-methoxyphenyl isothiocyanate

(0.99 g, 6 mmol) in benzene was refluxed for 45 min, washed with petrole- um ether to remove the excess of isothiocyanate and crystallized from eth- anol, yield 2.1 g (78%), m.p. 220°C.- IR (KBr): 3420, 3280, 3100 (YN-H); 1645 (C=N), 1520 (thioureido linkage); 1100 cm-l (C=S).- 'H-NMR ([D,IDMSO): 6 (ppm) = 3.75 (s, 3H, OCH,); 7.00-7.45 (m, 13 H arornat.);

Pharmacological screening7)

Male Holfzman rats (100-125 g) were maintained on low iodide diet for 3 days, then divided into groups consisting of four rats. The animals in each group received injections (ip.) of 1 rnl of either a blank (0.9% NaCI),

Arch. Pharm. (Weinheim) 326,963-966 (1993)

966 Prasad and Srivastava

Table 4: Pharmacological screening results of 1 -aryl-4-[ 1 -aryl-4-phenyl-6-thioxo- I ,6-dihydro- 1,3,5-triazin-2-yl] thiosemicarbazide

Compound Number

Thyroid r a d i o a c t i v i t y dpm 2 s t d . error Approximate 13'1 u p t a k e PB Inorganic 1311 e s t i m a t e d a c t i v i t y

i n ra t s ( T h i o u r a c i l = 1.00)

C o n t r o l 8670210 7289t11 1295211 - T h i o u r a c i l 4660216 4032-+12 618221 1.00

2% 41 l o + 10 3371227 645222 1.13

2 5097246 4259215 698242 0.91

4735218 3905t21 705231 0.98

sa 4405238 3752t27 608222 1.05

4110t10 3371227 645222 1.13

5f 4209220 3139+11 894219 1-10

4753218 3905t21 705231 0.98

5895t19 5054i12 709209 0.79

2 4804234 4053218 718220 0.97

2s

22

22 2

2 4579211 3764218 703225 1.01

P

- 5k 4381t05 3501t32 735211 1.06

51 3941222 3025t09 819220 1.18 -

thiouracil, or one of the test compounds. 1 h later t pCi of Na l3'I (carrier free) was injected intraperitoneally. 3 h after the injection of I3'1, the ani- mals were sacrificed and the thyroids were removed. The whole lobes were placed in ground glass homogenizing tubes and counted in a Nuclear Chicago well scintillation counter to determine total thyroid uptake. The whole lobes were then homogenized in 1 ml of 0.05 M barbital buffer (pH 8.6) containing 1.0 x thiouracil. 1 ml of cold 20% trichloroacetic acid (TCA) was added and the homogenate was centrifuged. The precipitate was washed twice with 1 ml of cold 10% TCA. The original supernatant and the two washes were combined and the radioactivity was determined. 13'1 in this fraction indicated the concentration of inorganic I3'I or TCA- soluble I3lI. The washed precipitate was counted in the homogenizing tube. The radioactivity in this fraction indicated the PB I3'I (protein-bound iodine) or the TCA precipitable I3'I. The counts were all corrected for counting efficiency and are expressed as disintegration per min.

All compounds were dissolved in saline for injection. Thiouracil was dissolved with heating to 50°C. All compounds were assayed at concentra- tion equimolar to 0.5 mg of thiouracil (3.9 p mole) and the biological effect was noted. Tables 3 and 4 summarize the observations made with

compound 4a to 41 and 5a to 51. It is obvious from tables 3 and 4 that com- pounds 4a, 4e, 4f, 4j, 41, 5e, 5f, 51 have appreciable antithyroid activity. The presence of chloro and anisyl groupings appear to enhance the antithy- roid efficacy.

References

P.K. Srivastava, R. Chandra, M.B. Gupta, Current Science 1982, 51 ,

P.K. Srivastava, J.S. Upadhyaya, M.P. Shanna, J . Phurnz. Sri. 1979, 41, 191-193. J.S. Upadhyaya, P.K. Srivastava, J . ind. Chem. Sor. 1982, 59, 808; Chem. Ahstr. 1982,97, 182262~. P.V. Smith, R.L. Frank, Org. Synth. 1948,28, 89-91. R. Chandra, P.K. Srivastava, J . Chem. Eng. Dutu 1983,28, 278-279. J. Goerdeler, T. Neuffer, Tetruhedron Lett. 1967,2791-2793. R.W. Rawson, D.A. McGinty, J . Phurrnacol. Exptl. Therap. 1948, 93, 940.

[Phl14]

692-695.

Arch. Pharm. (Weinheim) 326, 963-966 (1993)