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Abstract
Azapyrimidine (1,2,4-triazine) ring is the backbone for several pharmacologically active compounds mostly as antimicrobial and anticancer drugs. A brief survey is given on the reported synthetic procedures and the biological importance of 1,2,4-triazine derivatives.
In the present study, 3-substituted-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazin-6(1H)-ones 3a-c were synthesized starting with 2-substituted-4-(arylmethylene)-5(4H)-oxazolones 1a-c. The later were prepared by reacting 5-oxazolones derivatives with hydrazine hydrate, ring opening took place and gave -acylaminoacryloylhydrazides 2a-c which were cyclized by heating in sodium hydroxide 4% for 5 minutes to give 3a-c as reported.
3a-c were used as starting compounds for the synthesis of new interesting heterocyclic systems. Thus, compounds 3a-c were converted into Mannich bases 4a-c and their bis-Mannich bases 5a-c upon treatment with formaldehyde solution and morpholine in methanol.
Heating of 3a-c with DMFDMA gave the corresponding dimethylenamines 6a-c, while longer reaction time led to further methylation with the formation of 1-methyl derivatives 7a-c.
On the other hand, Thiation of 3a-c with phosphorus pentasulfide in dry pyridine gave the corresponding 1,2,4-triazine-6(1H)-thiones 8a-c.
Moreover, thienotriazines 9a-c were prepared by thiation of compounds 5a-c & 6a-c using phosphorus pentasulfide in dry pyridine or by heating 8a-c with DMFDMA.
In addition, chlorination of 3a,b with phosphorus oxychloride gave the 6-chloro derivatives 10a,b. Heating of 10a & 10b in ethanol with hydrazine hydrate gave the corresponding 6-hydrazino-1,2,4-triazines 11a,b.
The latter compounds 11a,b underwent condensation with formic acid to give triazolotriazines 12a,b. Furthermore, compounds 11a,b were reacted with carbon disulfide and pyruvic acid to give 3-thioxo-triazolotriazines 13a,b and triazinotriazine 14b respectively.
On the other hand, reaction of the 6-chloroderivatives 10a,b with different primary and secondary amines gave 6-substitutedamino derivatives 15a-d.
Moreover, alkylation of compounds 8a-c with ethyl bromoacetate, chloroacetamide and different alkyl halides afforded 6-alkylthio-1,2,4-triazines 16a-c, 17a-c and 18a-f respectively.
The present study involves the synthesis of the following new compounds:
1) 1-(Morpholinomethyl)-3-phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazin-6 (1H)-one (4a).
2) 1-(Morpholinomethyl)-3-(4-chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazin-6 (1H)-one (4b).
3) 1-(Morpholinomethyl)-3-(4-methoxyphenyl)-5-(3,4,5-trimethoxy-
benzyl) -1,2,4-triazin-6 (1H)-one (4c).
4) 5-[2-Morpholino-1-(3,4,5-trimethoxyphenyl)ethyl]-1-(morpholino-methyl)-3-phenyl-1,2,4-triazin-6(1H)-one (5a).
5) 5-[2-Morpholino-1-(3,4,5-trimethoxyphenyl)ethyl]-1-(morpholino-methyl)-3-(4-chlorophenyl)-1,2,4-triazin-6(1H)-one (5b).
6) 5-[2-Morpholino-1-(3,4,5-trimethoxyphenyl)ethyl]-1-(morpholino-methyl)-3-(4-methoxyphenyl)-1,2,4-triazin-6(1H)-one (5c).
7) 5-[2-Dimethylamino-1-(3,4,5-trimethoxyphenyl) vinyl]-3-phenyl-1,2,4-triazin-6(1H)-one (6a).
8) 5-[2-Dimethylamino-1-(3,4,5-trimethoxyphenyl) vinyl]-3-(4-chloro-phenyl)-1,2,4-triazin-6(1H)-one (6b).
9) 5-[2-Dimethylamino-1-(3,4,5-trimethoxyphenyl) vinyl]-3-(4-methoxy-phenyl)-1,2,4-triazin-6(1H)-one (6c).
10) 5-[2-Dimethylamino-1-(3,4,5-trimethoxyphenyl)vinyl]-3-phenyl-1-methyl-1,2,4-triazin-6(1H)-one (7a).
11) 5-[2-Dimethylamino-1-(3,4,5-trimethoxyphenyl)vinyl]-3-(4-chloro-phenyl)-1-methyl-1,2,4-triazin-6(1H)-one (7b).
12) 5-[2-Dimethylamino-1-(3,4,5-trimethoxyphenyl)vinyl]-3-(4-methoxy-phenyl)-1-methyl-1,2,4-triazin-6(1H)-one (7c).
13) 3-Phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6(1H)-thione (8a).
14) 3-(4-Chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6(1H)-thione (8b).
15) 3-(4-Methoxyphenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6(1H)-thione (8c).
16) 3-Phenyl-5-(3,4,5-trimethoxyphenyl) thieno [3,2-e] [1,2,4] triazine (9a).
17) 3-(4-Chlorophenyl)-5-(3,4,5-trimethoxyphenyl) thieno [3,2-e] [1,2,4] triazine (9b).
18) 3-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl) thieno [3,2-e] [1,2,4] triazine (9c).
19) 6-Chloro-3-phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (10a).
20) 6-Chloro-3-(4-chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (10b).
21) 6-Hydrazino-3-phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (11a).
22) 6-Hydrazino-3-(4-chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (11b).
23) 6-Phenyl-8-(3,4,5-trimethoxybenzyl)-[1,2,4-triazolo][3,4-f][1,2,4]-triazine (12a).
24) 6-(4-Chlorophenyl)-8-(3,4,5-trimethoxybenzyl)-[1,2,4-triazolo]-
[3,4-f][1,2,4]-triazine (12b).
25) 6-Phenyl-8-(3,4,5-trimethoxybenzyl)[1,2,4-triazolo][3,4-f][1,2,4]-triazine-3(2H)-thione (13a).
26) 6-(4-Chlorophenyl)-8-(3,4,5-trimethoxybenzyl)[1,2,4-triazolo]-
[3,4-f][1,2,4]-triazine-3(2H)-thione (13b).
27) 7-(4-Chlorophenyl)-3-methyl-9-(3,4,5-trimethoxybenzyl)-4H-[1,2,4]- triazino[3,4-f] [1,2,4] triazin-4-one (14b).
28)N-(4-Chlorophenyl)-3-Phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6-amine (15a).
29) N-(4-Chlorophenyl)-3-(4-chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6-amine (15b).
30)3-(4-Chlorophenyl)-N-(4-methylphenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6-amine (15c).
31)N,N-Dimethylamine-3-Phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazines-6-amine (15d).
32) 6-(Ethoxycarbonylmethylthio)-3-phenyl-5-(3,4,5-trimethoxybenzyl) -1,2,4-triazine (16a).
33) 6-(Ethoxycarbonylmethylthio)-3-(4-chlorophenyl)-5-(3,4,5-trimethoxy-benzyl) -1,2,4-triazine (16b).
34) 6-(Ethoxycarbonylmethylthio)-3-(4-methoxyphenyl)-5-(3,4,5-trime-thoxybenzyl) -1,2,4-triazine (16c).
35) 3-Phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6-thioacetamide (17a).
36) 3-(4-Chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6-thio-acetamide (17b).
37) 3-(4-Methoxyphenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine-6-thio-acetamide (17c).
38) 6-Methylthio-3-phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (18a).
39) 6-Ethylthio-3-phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (18b).
40) 6-Methylthio-3-(4-chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (18c).
41) 6-Ethylthio-3-(4-chlorophenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (18d).
42) 6-Benzylthio-3-phenyl-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (18e).
43) 6-Benzylthio-3-(4-methoxyphenyl)-5-(3,4,5-trimethoxybenzyl)-1,2,4-triazine (18f).
Identification of the new compounds was substantiated by elemental analyses as well as IR, 1HNMR & Mass spectroscopy.
The cytotoxic activity and preliminary antimicrobial screening of some representative examples of the above new compounds were performed and the results showed that compounds 9b and 10b were the most active ones against breast carcinoma cell line (MCF7) while compound 14b was the most active one against colon carcinoma cell line (HCT 116).
The antimicrobial activity of twenty selected compounds revealed that most of them exhibited high antimicrobial activity.