| Abstract: |
Certain novel 2,3-dihydroquinazolin-4(1H)-ones bearing either chalcone , pyrazole or thiazole moieties have been synthesized with a survey of their analgesic and anti-inflammatory activities.
In addition, novel 3,4-dihydro-1H-benzo[e][1,2,4]triazepin-5(2H)-ones have been synthesized with a survey of their C.N.S. activities.
The starting material in this investigation was anthranilic acid (I) which was utilized to obtain N-alkyl isatoic anhydride (IIIa,b) via its reaction with either dimethylsulphate or ethyl iodide in aqueous sodium carbonate solution to give the alkylated product II a,b which were then cyclized under the effect of ethylchloroformate.
To abtain the target 2,3-dihydroquinazolin-4(1H)-ones, the following routes were followed:
1- Refluxing N-alkyl isatoic anhydride (IIIa,b) with p- amino acetophenone in glacial acetic acid for 4 hours afforded the intermediate N-(4-acetylphenyl)-2-(alkylamino)benzamides (IVa,b).
2- Cyclization of intermediates IVa,b was achieved using formalin in ethanol containing catalytic amount of acetic acid to form the 2,3-dihydroquinazolin-4(1H)-one derivatives Va,b.
3- Condensation of Va,b with aromatic aldehyde was conducted in methanol in the presence of sodium hydroxide to yield the desired chalcones VIa-h.
4- Cyclization of chalcones VIa-d was performed using either hydrazine hydrate or phenyl hydrazine to afford the novel 4,5-dihydro-1H-pyrazol-3-yl VIIa-d or their N-phenyl analogs VIIe-h .
5- Condensation of compound Va with thiosemicarbazide was achieved in ethanol containing catalytic amount of acetic acid to obtain the novel hydrazinecarbothioamide VIII intermediate.
6- The hydrazinecarbothioamide intermediate VIII was cyclized using phenacyl bromides in refluxing ethanol with further addition of anhydrous sodium acetate to afford the novel thiazole containing compounds IXa,b.
On the other side, the target 3,4-dihydro-1H-benzo[e][1,2,4] triazepin-5(2H)-ones were obtained adapting the following steps:
1- Reacting N-methyl isatoic anhydride (IIIa) with phenylhydrazine in ethanol containing catalytic amount of acetic acid afforded the key intermediate 2-(methylamino)-N'-phenylbenzohydrazide(X).
2- Cyclization of the playmaker intermediate X with formalin was conducted in ethanol in the presence of drops of acetic acid to give the six-membered 2,3-dihydroquinazolin-4(1H)-one XI upon refluxing while the seven-membered 3,4-dihydro-1H-benzo[e][1,2,4] triazepin-5(2H)-ones XII was formed by stirring the reactants together at room temperature.
3- Condensation of intermediate X with aromatic aldehyde in refluxing acetic acid for 6 hours gave only the seven membered 3,4-dihydro-1H-benzo[e][1,2,4] triazepin-5(2H)-ones compounds XIIIa-h.
4- Moreover, the intermediate X was cyclized under the effect of carbon disulfide in potassium hydroxide ethanolic solution to afford the novel 2-thioxo 3,4-dihydro-1H-benzo[e][1,2,4] triazepin-5(2H)-one compound (XIV).
5- Reacting N-methyl isatoic anhydride (IIIa) with either nicotinic or isonicotinic acid hydrazides gave the amide intermediates XV or XVI.
6- Cyclization of the former amide intermediates XV and XVI with formalin in ethanol containing catalytic of acetic acid formed the six membered 2,3-dihydroquinazolin-4(1H)-one XVII and the seven membered 3,4-dihydro-1H-benzo[e][1,2,4] triazepin-5(2H)-ones XVIII respectively.
The present investigation involved the synthesis of the following known intermediates:
1) N-Methyl anthranilic acid (IIa).
2) N-Ethyl anthranilic acid (IIb).
3) N- Methyl isatoic anhydride(IIIa).
4) N- Ethyl isatoic anhydride(IIIb).
5) N-(4-acetylphenyl)-2-(methylamino)benzamide(IVa).
6) 3-(4-Acetylphenyl)-1-methyl-2,3-dihydroquinazolin-4(1H)-one(Va).
7) 2-(Methylamino)-N'-phenylbenzohydrazide(X).
8) N'-[2-(Methylamino)benzoyl]nicotinohydrazide(XV).
The following newly synthesized intermediates were also prepared:
1) N-(4-Acetylphenyl)-2-(ethylamino)benzamide(IVb).
2) 3-(4-Acetylphenyl)-1-ethyl-2,3-dihydroquinazolin-4(1H)-one(Vb).
3) 2-{1-[4-(1-Methyl-4-oxo-1,2-dihydroquinazolin-3(4H)-
yl)phenyl]ethylidene}hydrazinecarbothioamide(VIII).
4) N'-[2-(Methylamino)benzoyl]isonicotinohydrazide(XVI).
Also, one reported final compound was synthesized:
1) 1-Methyl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one(XI).
The present study comprised the synthesis of the following new target final compounds:
1) 3-{4-[3-(4-Methoxyphenyl)acryloyl]phenyl}-1-methy-2,3-
dihydroquinazolin-4(1H)-one(VIa).
2) 3-{4-[3-(4-Nitrophenyl)acryloyl]phenyl}-1-methyl-2,3-
dihydroquinazolin-4(1H)-one(VIb).
3) 3-{4-[3-(4-Chlorophenyl)acryloyl]phenyl}-1-methyl-2,3-
dihydroquinazolin-4(1H)-one(VIc).
4) 3-[4-(3-Phenylacryloyl)phenyl]-1-methyl-2,3-dihydroquinazolin-
4(1H)-one(VId).
5) 3-{4-[3-(4-Methoxyphenyl)acryloyl]phenyl}-1-ethyl-2,3-
dihydroquinazolin-4(1H)-one(VIe).
6) 3-{4-[3-(4-Nitrophenyl)acryloyl]phenyl}-1-ethyl-2,3-
dihydroquinazolin -4(1H)-one(VIf).
7) 3-{4-[3-(4-Chlorophenyl)acryloyl]phenyl}-1-ethyl-2,3-
dihydroquinazolin-4(1H)-one(VIg).
8) 3-[4-(3-Phenylacryloyl)phenyl]-1-ethyl-2,3-dihydroquinazolin-4(1H)-
one(VIh).
9) 3-{4-[5-(4-Methoxyphenyl) -4,5-dihydro-1H-pyrazol-3-yl]phenyl}- 1-
methyl-2,3-dihydroquinazolin-4(1H)-one(VIIa).
10) 3-{4-[5-(4-Nitrophenyl) -4,5-dihydro-1H-pyrazol-3-yl]phenyl}-1-
methyl-2,3-dihydroquinazolin-4(1H)-one(VIIb).
11) 3-{4-[5-(4-Chlorophenyl) -4,5-dihydro-1H-pyrazol-3-yl]phenyl}-1-
methyl-2,3-dihydroquinazolin-4(1H)-one(VIIc).
12) 3-{4-[5-Phenyl -4,5-dihydro-1H-pyrazol-3-yl]phenyl}-1-methyl-2,3-
dihydroquinazolin-4(1H)-one(VIId).
13) 3-{4-[5-(4-Methoxyphenyl)-1-phenyl -4,5-dihydro-1H-pyrazol-3-
yl]phenyl}-1-methyl-2,3-dihydroquinazolin-4(1H)-one(VIIe).
14) 3-{4-[5-(4-Nitrophenyl)-1-phenyl -4,5-dihydro-1H-pyrazol-3-
yl]phenyl}-1-methyl-2,3-dihydroquinazolin-4(1H)-one(VIIf).
15) 3-{4-[5-(4-Chlorophenyl)-1-phenyl -4,5-dihydro-1H-pyrazol-3-
yl]phenyl}-1-methyl-2,3-dihydroquinazolin-4(1H)-one(VIIg).
16) 3-{4-[5-Phenyl-1-phenyl -4,5-dihydro-1H-pyrazol-3-yl]phenyl}-1-
methyl-2,3-dihydroquinazolin-4(1H)-one(VIIh).
17) 3-{4-[1-(2-(4-((4-Chlorophenyl)thiazol-2-yl)hydrazono)ethyl]phenyl}
-1-methyl-2,3-dihydroquinazolin-4(1H)-one(IXa).
18)3-{4-[1-(2-(4-(Phenylthiazol-2-yl)hydrazono)ethyl]phenyl}-1-methyl-
2,3-dihydroquinazolin-4(1H)-one(IXb).
19) 1-Methyl-3-phenyl-3,4-dihydro-1H-benzo[e][1,2,4]triazepine-5(2H)-
one(XII).
20) 2- Phenyl-1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e][1,2,4]
triazepine-5(2H)-one(XIIIa).
21) 2-(4-Chlorophenyl)1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e]
[1,2,4] triazepine-5(2H)-one(XIIIb).
22) 2-(4-Methoxy phenyl)1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e]
[1,2,4]triazepine-5(2H)-one(XIIIc).
23) 2-(4-Nitrophenyl)1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e]
[1,2,4]triazepine-5(2H)-one(XIIId).
24) 2-(4-Hydroxyphenyl)1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e]
[1,2,4]triazepine-5(2H)-one(XIIIe).
25) 2-(2-Nitrophenyl)1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e]
[1,2,4]triazepine-5(2H)-one(XIIIf).
26) 2-(4-Bromophenyl)1-methyl-3-phenyl-3,4-dihydro-1H-benzo[e]
[1,2,4]triazepine-5(2H)-one(XIIIg).
27) 2-(3,4,5-Trimethoxyphenyl)1-methyl-3-phenyl-3,4-dihydro-1H-
benzo[e][1,2,4]triazepine-5(2H)-one(XIIIh).
28) 1-Methyl-3-phenyl-2-thioxo-3,4-dihydro-1H-benzo[e][1,2,4]
triazepin-5(2H)-one(XIV).
29) N-(1-Methyl-4-oxo-1,2-dihydroquinazolin-3(4H)-yl) nicotinamide
(XVII).
30) 3-Isonicotinoyl-1-methyl-3,4-dihydro-1H-benzo[e][1,2,4]triazepin-
5(2H)-one(XVIII).
Finally, The analgesic and anti-inflammatory activities for the selected new compounds (Va, VIa, VIb, VIc, VId, VIIa, VIIb, VIIe, VIIf )were studied. The study showed that the chalcones bearing 4-chlorophenyl group VIc or 4-nitrophenyl group VIb were the most active ones as analgesic. Both chalcone VIc and N-phenyl pyrazole bearing 4-methoxy phenyl group VIIe showed a higher anti-inflammatory activity than celecoxib but still lower than that of diclofenac sodium. Moreover, the chalcone VIc has nearly the same ulcerogenic index as that of the selective COX-2 inhibitor celecoxib.
Moreover, evaluation of the C.N.S. activities for benzotriazepine derivatives(XII,XIIIa-h,XIV,XVIII) revealed that the benzotriazepine derivatives with no subtituent at 2-position (XII, XVIII) and that containing sulfur group at 2-position (XIV) showed the same antipsychotic activity as the reference drug clozapine but unfortunately having nearly the same side effects.
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