Synthesis and Antidepressant Activity of Some New Coumarin Derivatives

The coumarin-3-cinnamoyl derivatives 2a-d were prepared via ClaisenSchmidt condensation of 3-acetylcoumarin 1 with different aromatic aldehydes. Cycloaddition reaction of 2b,e with guanidine and thiourea yielded the corresponding aminopyrmimidine 3a,b and thioxypyrimidine derivatives 4a,b, respectively. Compounds 4a,b were condensed with chloroacetic acid or 3bromopropionic acid to yield coumarin 3-thiazolo-pyrimidine 5a,b and thiazinopyrimidine 6a,b derivatives, respectively. Compounds 4a,b were condensed with chloroacetic acid and aromatic aldehyde to yield the aryl methylene derivatives 7a,b which could be prepared directly by condensation of compounds 5a,b with aromatic aldehydes. Compounds 2a-e were condensed with malononitrile or ethyl cyano acetate in presence of ammonium acetate to yield cyanopyridine 8a,b and cyanopyridone 9ad derivatives, respectively, which were prepared by condensation of 3acetylcoumarin 1, malononitrile or ethylcyanoacetate and aromatic aldehydes in presence of ammonium acetate. Condensation of compounds 2a,b,e with o-phenylenediamine in refluxing ethanol led to the formation of 10a-c as intermediate, followed by cleavage by thermolysis to benzimidazole derivative 11 along with compounds 12a-c as mixture, which were obtained directly by fusion of a,&unsaturated ketones 2 with ophenylene diamine at 200-220°C, while compound 11 could be prepared in pure form by fusion of 1 with o-phenylene diamine at the same temperature. The pharmacological screening showed that many of these obtained 196 Nehad A. Abdel-Latif compounds have good antidepressant activity comparable to TranylcypromineB as reference drugs.

Based on the previous findings, it is of interest to synthesize some new coumarin-3-derivatives starting with 3-acetylcoumarin and incorporating to biologically active moieties such as pyrimidine, cyanopyridine and cyanopyridone.

Experimental
All melting points are uncorrected and were taken on Electro-thermal IA 9000 series digital melting point apparatus.Analytical data were obtained from the microanalytical unit, National Research Centre, Cairo, Egypt.The I R spectra (KBr) were recorded on a Pye Unicam SP-1000 spectrophotometer.The 'H-NMR spectra (6, ppm) were recorded at 270 MHz on Varian EM-360 Spectrometer using TMS as an internal standard.The Central Services Laboratory, National Research Centre.
The mass spectra were performed using VG 2AB-3F spectrometer (70eV).All reactions were followed by TLC (silica gel, aluminum sheets 60 F254, Merck).The physical and analytical data of the synthesized compounds are given in Table 1.

General procedure
To a solution of compounds 2b,e (2 mmol), sodium hydroxide (0.2g in 1 ml water) in ethanol (30 ml), guanidine hydrochloride (0.2g, 2 mmol) was added.The reaction mixture was refluxed for 5-7 hr, allowed to cool, then poured onto cold water, the solid formed was collected by filtration and crystallized from the proper solvent to give compounds 3a,b, respectively.

General procedure
To a mixture of 2b,e (2 mmol), sodium hydroxide (0.29 in I ml water) in ethanol (30 ml), thiourea (0.15g, 2 mmol) was added.The reaction mixture was heated under reflux for 3-5 hr, allowed to cool.The solid formed was filtered off and crystallized from the proper solvent to give the corresponding thioxopyrimidine derivatives 4a,b.

Preparation of compounds 5a,b and 6a,b:
General procedure A mixture of compounds 4a,b (2 mmol), chloroacetic acid or bromopropionic acid (2 mmol) in a mixture of glacial acetic acid (30 ml) and acetic anhydride (10 ml) in the presence of anhydrous sodium acetate (39) was refluxed for 6-7 hr.The reaction mixture was cooled and poured onto cold water with stirring, the solid formed was filtered off and crystallized from the proper solvent to give the corresponding 5a,b and 6a,b, respectively.

Method 6:
A mixture of compound 5a,b (2 mmol), the appropriate aldehydes (2 mmol), acetic acid (30 ml) and acetic acid anhydride (10 ml) was refluxed for 2-3 hr., allowed to cool, then poured onto water the solid formed was collected by filtration and crystallized from the proper solvent to yield the title compounds 7a,b.
The obtained products from method B were identified by m.p., mixed m.p.'s and TLC by comparison with authentic samples, but method (A) gives better yield than method (B).

Preparation of cyanoaminopyridine 8a-e and cyanopyridone 9a-e derivatives:
Method A: A mixture of Za,e (2 mmol), malononitrile or ethyl cyanoacetate (2 mmol) and ammonium acetate (0.39, 4 mmol) in absolute ethanol (30 ml) was refluxed for 3-5 hr.After cooling, the formed product was collected by filtration, washed with ethanol, dried and crystallized from the proper solvent to give the corresponding cyanoaminopyridines 8a-e and cyanopyridones 9a-e, respectively.
The obtained products from methods B and C were identified by its m.p.; mixed m.p. and Rf values on TLC by comparison with authentic samples from method A.

Reaction of chalcones 2a,b,e with o-phenylenediamine: Method A: In butanol (Formation of diazipene derivatives)
A mixture of compound 2a,b,e (1 mmol) and o-phenylenediamine (0.1 19, 1 mmol) in absolute butanol (30 ml) was heated under reflux for 10-12 hr.The solvent was evaporated under reduced pressure till dryness, the oily product was triturated with petroleum ether (40-60°C) and the separated solid was filtered off, washed with petroleum ether (40-60°C), dried and crystallized from the proper solvent to give the corresponding benzodiazipine derivatives IOa-c.

Method B: By fusion
Equimolecular amounts of 2a,b,e (1 mmol) and o-phenylenediamine (0.I I g, 1 mmol) were fused together in an oil bath at 200-220°C for 4-6 hr.After cooling, the obtained solid was crushed and extracted with hot dioxane, evaporated under reduced pressure and the residue was solidified with methanol, the obtained solid was filtered off, and crystallized from ethanol to give 11.The filtrate was evaporated under reduced pressure, the obtained residue was solidified with n-hexane to give compounds 12a-c.

Thermolysis of benzodiazipine derivatives IOa-c:
Benzodiazipine derivatives IOa-c (0.5 mmol) were heated in an oil bath at 200-220°C for 4-6 hr.After cooling, the dark mass was crushed and extracted with hot dioxane then evaporated under reduced pressure, the residue was solidified with methanol, the obtained solid was filtered off and crystallized from ethanol to give 11 in 35-40% yield.The filtrate was evaporated under reduced pressure, the obtained residue was solidified with n-hexane to give 12a-c.The obtained products were identified by m.p. and Rf values in comparison with authentic samples from the above method (method B).Frequently, these clonic seizures are preceded by akyphotic curvature of the spine but this sign does not constitute a positive response.In addition to the vehicle control group a series of five positive control animals receiving TranylcypromineB at 5 mgl kg i. p. with a 0.5 hours pretreatment time are subjected to the test in order to check the effectiveness of the tryptamine HCI solution which is relatively unstable.

Reaction of 3-acetyl coumarin
A 100% response is expected fresh tryptamine HCI solution should be prepared hourly as needed [37,38].The normalized percent potentiation is calculated as follows: % animals potent in drug group-% animals potent in vehicle 100 X I -% animals potent in vehicle group A dose-response was obtained in the same manner at the peak time of drug effect expect that a group size of 10 animals is used and four different doses are tested in addition to the vehicle and the TranylcypromineB groups.
All the tested compounds showed potent antidepressant activities via MA01 mechanism than TranylcypromineB.Compounds 6a, 7b and 9b showed 12.8, 12.1 5, 12.06 more activities than that of TranylcypromineB respectively, these compounds exhibit good therapeutic windows & high safety margins.
Formation of 10 was believed to take place with the addition of the diamine ethylenic double bond of 2, followed by interamolecular condensation of the amino group with the carbonyl function, affording 10 as final products (Scheme 3).However, compound 11 could be prepared in pure form by fusion of 3-acetyl coumarin 1 with o-phenylenediamine at the same conditions.
Route A I with o-phenylene diamine.Formation of compound I I A mixture of Sacetyl coumarin 1 (0.19g, 1 mmol) and o-phenylene diamine (0.1 I g , 1 mmol) was fused in an oil bath at 200-220°C for 6 hrs.The obtained residue was solidified with methanol.The obtained solid was collected by filtration and crystallized from the proper solvent to give benzimidazole derivative I I, in 60% yield.The product was identified by its m.p. and Rf value in comparison with authentic sample.

Table 1 :
Physical and analytical data of newly synthesized Monoamino seizures in rats caused by an intravenous infusion of tryptamine HCI.This procedure can be used to elucidate the in vivo MA0 inhibiting properties of compounds.Procedure:Group of 5 male Webster rats weighing 150-2009 are used test compounds, standard or vehicle controls are administered intraperitoneally 0.5, 1, 2 and 4 hours prior testing.At the time of testing 5mglkg tryptamine HCI Freshly dissolved in saline are injected intravenously.Immediately after tryptamine HCI administration, the animals are observed individually for three minutes for the appearance of clonic pedaling movements of the forepaws, which is considered a positive response.