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Synthesis and pharmacological evaluation of newer substituted 2-oxo/thiobarbiturinylbenzoxa/thiazepine derivatives as potent anticonvulsant agents.

MirdulaTyagi* and Archana

Medicinal chenmistry Lab, Department of Chemistry, Meerut College, Meerut-250004 (U.P.) India.

DOI : http://dx.doi.org/10.13005/ojc/310113

ABSTRACT:

A new series of 4-(2'-Oxo/thiobarbiturinyl)-2-(substitutedphenyl)-3-[(substitutedaminomethylene)]-2,3-dihydro-1,5-benzothiazepines (5a-5l) and 4-(2'-oxo/thiobarbiturinyl)-2-(substituted-phenyl)-3-(substitute daminomethylene)]-2,3-dihydro-1, 5- benzoxazepines (6a-6l) were synthesized. All the newly synthesized compounds were screened in vivo, for their acute toxicity and anticonvulsant activity in MES and PTZ models and were compared with standard drugs phenytoin sodium and sodium valporate. Out of the compounds studied, the most active compound of this series was 5 h, showed activity (90%) more potent than the standard drug.

KEYWORDS:

series; thiobarbiturinyl; substitutedphenyl)-3-[(substitutedaminomethylene)

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Tyagi M, Archana. Synthesis and pharmacological evaluation of newer substituted 2-oxo/thiobarbiturinylbenzoxa/thiazepine derivatives as potent anticonvulsant agents. Orient J Chem 2015;31(1).


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Tyagi M, Archana. Synthesis and pharmacological evaluation of newer substituted 2-oxo/thiobarbiturinylbenzoxa/thiazepine derivatives as potent anticonvulsant agents. Orient J Chem 2015;31(1). Available from: http://www.orientjchem.org/?p=7532


Introduction

The barbiturates comprise an important and valuable class of central nervous system depressants. Barbituric acid (2,4,6–trioxohexahydrophrimidine) derivative, phenobarbital and mephobarbital are used for clinical treatment of epilepsy. Further substitution pattern at 5th position of barbituric acid3-8 by different alkyl, aryl or heteroaryl moieties plays a pivotal role in modulation of anticonvulsant activity. Moreover, compounds containing a fused seven, membered heterocyclic ring i.e. bengzothiazepine/ benzoxazepine nucleus make up a broad class that attracted attention in the past few years owing to its wide range of biological activities especially anticonvulsant and CNS depressant activities 9-14. However, these compounds have not been in clinical use as they possess either less activity or more side effects.

Incorporating these moieties in 5th position of 2-oxo/thiobarbituric acid nucleus might be thought to yield more potent anticonvulsant compounds as substituted moieties are themselves anticonvulsant and substituting at 5th position further results in protecting against convulsions. Thus, the substitution by these moieties may be synergistic. The present project is therefore, aimed at synthesizing such compounds.

Chemistry

The synthetic routes of compounds are outlined in scheme 1. 5-Acetyl-2-oxo/thiobarbituric acid 1a-1b were synthesized by the reaction of 2-oxo/thiobarbituric acid and acetyl chloride. Compounds 1a-1b on reaction with different aromatic aldehydes yielded 1-(2′-oxo/thiobarbiturinyl)-3-chalcones i.e. compounds 2a-2f which on cyclization with 2-thio/aminophenol in presence of glacial acetic acid yielded compounds 3a-3f and 4a-4f respectively. compounds 3a-3f and 4a-4f further undergoes Mannichreaction with different substituted anilines to afford compounds 5a-5l and 6a-6l.

Scheme 1 Scheme 1 
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Results and Discussion

Anticonvulsant activity and acute toxicity of these new substituted 2-oxo/thiobarbiturinylenzoxa/thiazepine derivatives 2a-2f, 3a-3f, 4a-4f, 5a-5l and 6a-6l are represented in Table-1.

Table1: Anticonvulsant activity and toxicity data of compounds 1a-6l (Scheme 1) Table1: Anticonvulsant activity and toxicity data of compounds 1a-6l (Scheme 1) 

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Anticonvulsant activity (maximum electroshock induced seizures and pentylenetetrazol induced seizure pattern test)

The characteristic feature of the compounds of this series is the incorporation of two heterocyclic moieties, that is 2-oxo/thiobarbituric acid and benzoxazepine/benzothiazepine into a single molecular framework with the aim to develop more potent anticonvulsant agents with minimum or no side effects.

Scheme 1B Scheme 1B 

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5-Acetyl-2-oxo/thiobarbituric acids 1a-1b showed 10-20% anticonvulsant activity at a dose of 50 mg/kg i.p. in maximal electroshock and pentylenetetrazole induced seizures, respectively. Screening of step-2 compounds 1-(2′-oxo/thiobarbiturinyl)-3-arylidenylchalcones 2a-2f revealed that these compounds showed somewhat increase in anticonvulsant activity in both the models (ranging from 20 to 50% and 10 to 50% in MES and PTZ models,  respectively) in comparison to step-1 compounds when tested at same dose.

Compounds 4-(2′-oxo/thiobarbiturinyl)-2-substitutedphenyl)-2,3,-dihydro-1,5-benzothiazepines 3a-3f showed high percentage protection ranging from 40 to 80% and 30 to 80% in MES and PTZ models, respectively. The most active compound among 3a-3f is compound 3d. This compound was found to be equipotent (80% protection) to phenytoin sodium (standard drug for MES model) and sodium valproate (standard drug for PTZ model) and hence due to its potent nature it was studied in detail at three graded doses (17.5, 25 and 50 mg/kg i.p.) for its anticonvulsant activity and was found to possess 20, 40, 80% and 20, 30, 80% protection of seizures in MES and PTZ models, respectively. It was also observed that compound 3c (having 3-methoxyphenyl group) showed least activity 40% while compound 3d (having 2-chlorophenyl group) exhibited maximum response 80% in comparison to other substituted compounds.Further compounds having thiobarbituric acid possess more potent activity than the compounds having oxobarbituricacid ring.

Further, the next step compounds(5a-5l) was characterized by presence of different arylaminomethylene substitutions at the third position of benzothiazepine ring.They exhibited potent anticonvulsant activity ranging from 60 to 90% and 50 to 90% inbothmodels, that is MES and PTZ respectively.Out of the twelve compounds 5a-5l the most active compound is 5h. (having 4-methoxyphenyl aminomethylen substitution at third position of benzothiazepine ring and 2-chlorophenyl substitution at second position of benzodiazepine ring) was found to be most potent compound of this series exhibiting 90% inhibition in both MES and PTZ models. This compound was found to be more potent (90% protection) to phenytoin sodium (standard drug for MES model) and sodium valproate (standard drug for PTZ model). This compound was studied in details at three graded doses(17.5, 25 and 50mg/kg i.p.) for its anticonvulsant activity and was found to possess 20, 50, 90% and 20, 40, 90% protection of seizures in MES and PTZ models, respectively. On the other hand compounds 4a-4f possessed benzoxazepine ring with 2-oxo/thiobarbituric acid, substituted by different moieties at second position exhibited aniconvulsnat activity ranging from 40 to 70% and 30 to 60% in both MES and PTZ models respectively. So the compounds 4a-4f showed a decrease in anticonvulsant activity in comparison to compounds 3a-3f i.e. benzothiazepine compounds.Further the compounds of next step i.e. 6a-6l were characterized by different arylaminomethylene substitutions at the third position of benzoxazepine ring. All the twelve compounds 6a-6l of this step exhibited anticonvulsant activity ranging from 50 to 70% and 40 to 60% protection of seizures in MES and PTZ models, respectively.

ALD 50 Studies

The toxicity study of these compounds indicate their good safety margin.

Conclusion

While considering all the newly synthesized compounds of this series together, we may conclude that:

  1. 2-Thiobarbituric acid, containing compounds were found to possess potent anticonvulsant activity in comparison to 2-oxobarbituric acid, containing compounds.
  2. Presence of benzothiazepine moiety has shown better anticonvulsant activity than the compounds having benzoxazepine moiety.
  3. Compounds having benzothiazepine moiety with thiobarbituric acid showed better anticonvulsant activity than the compounds having benzoxazepine moiety with oxobarbituric acid.
  4. 2-Chlorophenyl substitution at second position of benzothiazepines ring showed more potent activity than other substituted benzothiazepines.
  5. Presence of electronegative atom (chlorine) plays a pivotal role to increase the anticonvulsant activity. Regarding acute toxicity studies it may be concluded  that all the compounds showed high value of ALD 50 thus indicating a good safety margin.

Experimental

Chemistry

Melting points were determined in open capillaries with the help of thermonic melting point apparatus  and are uncorrected. 1R spectra (KBr) are recorded on Backmann Acculab-10-spectrophotometer. 1H NMR spectra were recorded by Bruker WM 400 FT instrument using CDCl3 as solvent and tetramethylsilane (TMS) as internal reference standard. All chemical shift (d)are in ppm. The purities of the compounds were checked by thin layer chromatography (TLC) on silicagel-G plates of 0.5mm thickness. The elemental analysis of the compounds were performed on HeracusCarlo Erba 1108 analyser.

5-Acetyl-2-oxobarbituric acid 1a

Acetyl chloride (50 ml) was added to 2-oxobarbituric acid (20 g) drop by drop with stirring at 0-50C The reaction mixture was further stirred for 10 h using a magnetic stirrer and kept overnight. The excess of acetyl chloride was distilled off with the help of a distillation assembly and the residue thus obtained was washed with petroleum ether 40-600C, a number of times and then poured onto ice. The solid thus obtained was filtered with the help of a filteration pump and recrystallised from methanol/water to give compounds 1a (75%), mp 180°C; 1R (KBr) 3100 (NH), 1750, 1720, 1700, 1690, (C=O) cm-1; 1HNMR (CDCl3) of 9.25 (ss, 2H, 2NHCO), 5.79 (s, 1H, CHCOCH3), 2.47 (s, 3H, COCH3) (ppm); MS : M+ 170.  Anal. calcd. for C6H6N2O4; C, 42.35; H,3.52; N, 16.47. Found :  C, 42.33; H, 3.50; N, 16.51.

5-Acetyl-2-thiobarbituric acid (1b)

77%,m.p. 250°C (methanol/water); 1R (KBr) 3140 (NH), 1133 (C=S) cm-1;1H NMR (CDCl3) d 9.28 (ss, 2H, 2NHCO), 5.71 (s,1H, CHCOCH3), 2. 50 (s, 3H,COCH3) (ppm); MS : M+ 178. Anal. calcd. for C6H6N2O3S ; C, 38.70; H, 3.22; N,15.05. Found :C, 38.71; H, 3.20; N, 15.07.

1-(21-Oxobarbiturinyl)-3-(2-chlorophenyl) chalcone (2a)

A mixture of 5-acetyl-2-barbituric acid (0.01 mole) and 2-chloroaldehyde (0.01 mole) in absolute methanol (50ml) in presence of 2% NaOH were refluxed for 12h. The resulting mixture was concentrated, cooled and poured onto ice. The solid thus obtained was filtered, washed with petroleum ether (40-60°C) and recrystallised from methanol/water to give compound 2a (90%), mp 240°C; IR (KBr) 3320 (NH), 1620 (CH=CH), 1730, 1720, 1715, 1680 (amidic (C=O),1580 (CC of aromatic ring), 710 (C-Cl) cm-1; 1H NMR (CDCl3) d 5.80 (m, 1H, CHCO), 6.65 (d, 1H, -COCH=), 7.80-7.27 (m, 4H,Ar-H), 8.30 (d, 1H, = CH-Ar), 9.30 (ss, 2H, 2NHCO) (ppm); MS : M+292.5. Anal. calcd for C13H9N2O4Cl; C,53.33; H,3.07; N,9.57. Found C,53.30;  H, 3.02; N, 9.59.

1-(2′-Oxobarbituriyl)-3-(p-hydroxyphenyl)-chalcone (2b)

85%, mp 250ºC (DMF); 1R (KBr) 3320 (NH), 1620 (CH=CH), 1690, 1710, 1715 (amidic C=O), 1530 (CC) of aromatic ring cm-1; 1H NMR (CDCl3) d 9.10 (3, 1H, Ar-OH) 5.80 (m, 1H, CHCO), 6.65 (d, 1H,- COCH=), 7.10 -8.10 (m, 4H, Ar-H), 8.48 (d,1H, =CH-Ar), 9.25 (ss, 2H, 2NHCO) (ppm); MS : M+ 258. Anal.Calcd.for C13H10N2O5 ;  C, 60.46; H, 3.93 ; N, 10.85. Found : C. 60.40 ; H, 3.85; N, 10.88

1-(2′-Oxobarbiturinyl) -3-(m-methoxyphenyl)-chalcone (2c)

80%, mp 280ºC (methanol/water) ; IR (KBr) 3345 (NH), 1600 (CH=CH), 1680, 1700, 1710 (amidic C=O), 1550 (CC) of aromatic ring cm-1 ; 1H NMR (CDCl3) d 3.47 (s, 3H, Ar-OCH3), 5.75 (m, 1H, CHCO), 6.69 (d, 1 H, -COCH=), 7.50-8.45 (m, 4H, Ar- H), 8.30 (d, 1H, = CH-Ar), 9.28 (ss, 2H, 2NHCO) (ppm) ; MS : M+ 288. Anal.Calcd.for C14H12N2O5 ;  C, 58.33 ; H, 4.16 ; N, 9.72. Found : C, 58.32; H, 4.15 ; N, 9.76.

1-(21-Thiobarbiturinyl) -3- (o-chlorophenyl) chalcone (2d)

86%, mp 275°C (ethanol/water); IR (KBr) 3343 (NH), 1610 (CH=CH), 1690, 1715 (amidic (C=O), 730 (C-Cl), 1510 (CC) of aromatic ring, 1031 (C=S) cm-1; 1H NMR (CDCl3) d 5.83 (m 1H, CHCO), 6.73 (d. 1H,-COCH=), 7.15-8.00 (m, 4H, Ar-H), 8.45 (d, 1H, = CH-Ar), 9.29 (ss, 2H, 2NHCO) (ppm); MS: M+ 308.5. Anal.Calcd.for C13H9N2O3ClS; C, 50.56; H, 2.91 ; N, 9.07; Found : C, 50.50; H, 2.95; N, 9.01.

1-(2′-Thiobarbiturinyl)-3-(p-hydroxyphenyl) chalcone (2e)

82%, mp 205°C (DMF); IR (KBr) 3345 (NH), 1620 (CH=CH), 1705, 1715 (amidic C=O), 1500 (CC) of aromaticring, 1060 (C=S) cm-1 ;1H NMR (CDCl3) d 9.15 (s, 1H. Ar-OH),, 5.65 (m, 1H, CHCO), 6.80 (d, 1H, -COCH=), 7.00-8. 15 (m, 4H, Ar-H), 8.40 (d, 1H, = CH-Ar), 9.26 (ss, 2H, 2NHCO) (ppm); MS: M+ 290. Anal.Calcd.for C13H10N2O4S ; C,53.79; H,3.44; N,9.65; Found : C,53.81; H,3.47; N,9.68.

1-(2′-Thiobarbiturinyl)-3-(m-methoxyphenyl) chalcone (2f)

80%, mp 220°C (benzene/petroleum ether); IR (KBr) 3330 (NH), 1630 (CH =CH), 1685, 1690 (amidic C =O), 1560 (CC) of aromatic ring, 1030 (C=S) cm-1 ; 1H NMR (CDCl3) d 3.43 (s, 3H, Ar-OCH3), 5.60 (m, 1HCHCO), 6.75 (d, 1H, -COCH=), 7.30-8.60 (m, 4H, Ar-H), 8.30 (d, 1H, = CH-Ar), 9.20 (ss, 2H, 2NHCO) (ppm) ; MS : M+ 304. Anal.Calcd.for C14H12N2O4S ;  C, 53.79 ; H, 3.44; N, 9.65. Found : C,. 53.81; H, 3.47; N, 9.68.

4-(21-Oxobarbiturinyl)-2-(o-chlorophenyl)-2, 3 – dihydro-1, 5-benzothiazepines (3a)

The methanolic solution (50mL) of 1-(21- oxobarbiturinyl)- 3- (m-chlorophenyl)- chalcone (2a) (0.01 mol) was added 2-aminothiophenol (0.01 mol) with few drops of glacial acetic acid and refluxed for 3-5 h. After refluxing solvent was distilled off under reduced pressure and the solid thus obtained was recrystallized from ethanol to give 3a (85%), mp 148°C; IR (KBr) 3345 (NH), 1690, 1710, 1715 (amidic C = O), 1629 (C=C), 1460 (C=N), 690 (C-Cl), 671 (C-S-C) cm-1; 1H NMR (CDCl3) δ 9.25 (ss, 2H,) 2NHCO), 3.60  (t, 1H, -CH), 7.65 (d, 2H, C3-H of thiazepine ring), 7.70-6.65 (m, 8H, Ar-H), 6.49 (t, 1H, C2-H of thiazepine ring) (ppm);  MS : M+ 399.5 .Anal. Calcd.for C19H14N3O3SCl ;  C, 57.07; H, 3.50; N, 10.51. Found : C, 57.10; H, 3.48; N, 10.55.

4 – (21-Oxobarbiturinyl) – 2- (p-hydroxyphenyl) -2,3 – dihydro – 1,5 -benzothiazepines (3b)

78%, mp 158°C (Ethanol); IR (KBr) 3320 (NH), 1700, 1710, 1715 (amidic C=O), 3438 (OH), 1638 (C=C), 1469 (C=N), 680 (C-S-C) cm-1 ; ‑1H NMR (CDCl3) δ 9.23 (ss, 2H, 2NHCO), 3.91 (t,1H, -CH), 9.11(s, 1H, Ar-OH), 7.68 (d, 2H, C3-H of thiazepine ring). 7.72-6.69 (m, 8H,  Ar-H), 6.48 (t, 1H, C­2-H of thiazepine ring) (ppm). MS : M+ 381. Anal.Calcd for C19H15N3O4S; C, 59.8; H, 3.93; N, 11.02.Found : C,59.02; H,3.95; N, 11.05.

4-(21-Oxobarbiturinyl) – 2 – (m – methoxyphenyl) – 2,3 – dihydro – 1,5 – benzothiazepines (3c)

78%, mp 146°C (methanol) ; IR (KBr) 3343 (NH), 1690, 1700, 1725 (amidic C=O), 1625 (C=C), 1462 (C=N), 1225 (OCH3), 675 (C-S-C) cm-1 ; 1H NMR (CDCl3) δ 9.21 (ss, 2H, 2NHCO), 3.62 (t, 1H,-CH), 7.75-6.71 (m, 8H, Ar-H), 7.65 (d, 2H, C3H of thiazepine ring), 6.45 (t, 1H, C2-H of thiazepine ring), 3.42 (s, 3H, OCH3) (ppm) ; MS : M+ 411. Anal.Calcd.for C20H17N3O5S; C, 58.39 ; H, 4.13 ; N, 10.21. Found : C, 58.35; H, 4.15; N, 10.25.

4 – (21-Thiobarbiturinyl) – 2 – (o-chlorophenyl) – 2, 3- dihydro – 1,5 -benzothiazepine (3d)

80%, mp 155°C (ethanol); IR (KBr) 3330 (NH), 1700,  1710 (amidic C=O), 1050 (C=S), 1625 (C=C), 1455 (C=N), 680 (C-Cl)          cm-1; 1H NMR (CDCl3) 9.30 (ss, 2H, 2 NHCO), 3.57 (t, 1H,-CH), 7.71-6.74 (m, 8H, Ar-H), 7.68 (d, 2H, C3-H of thiazepine ring), 6.40 (t, 1H, C­2-H of thiazepine ring) (ppm); MS : M+ 415.5 Anal Calcd. for C19H14N3O2S2Cl; C, 54.87; H, 3.36 ; N, 10.10. Found : C, 54.82 ; H, 3.31; N, 10.13.

4 – (21-Thiobarbiturinyl) – 2 – (p-hydroxyphenyl) – 2,3 – dihydro – 1,5 -benzothiazepine (3e)

78%, mp 170°C (ethanol); IR (KBr) 3415(NH), 1690,  1705 (amidic C=O), 1060 (C=S), 3440 (OH), 1640 (C=C), 1470 (C=N), 688 (C-S-C) cm-1 ; 1H NMR CCDCl3) δ  9.20 (ss, 2H, 2NHCO), 3.62 (t, 1H,-CH), 7.70-6.65 (m, 8H, Ar-H), 9.15 (s, 1H, Ar-OH) 7.63  (d, 2H, C3-H of thiazepine ring), 6.42 (t, 1H, C­2-H of thiazepine ring) (ppm); MS : M+ 397. Anal.Calcd.for C19H15N3O3.S2; C,57.43; H,3.77; N, 10.57. Found : C,57.40; H,3.79; N, 10.60.

4 – (21-Thiobarbiturinyl) – 2 – (m-methoxyphenyl) – 2,3 – dihydro – 1,5 -benzothiazepine (3f)

75%, mp 164°C (methanol); IR (KBr) 3410 (NH), 1700,  1710 (amidic C=O), 1055 (C=S), 1629 (C=O), 1460 (C=N), 1230 (OCH3), 680 (C-S-C) cm-1 ; 1H NMR CDCl3) δ9.23 (ss, 2H, 2NHCO), 3.59 (t, 1H,-CH), 7.71-6.68 (m, 8H, Ar-H), 7.60 (d, 2H, C3-H of thiazepine ring), 6.48 (t, 1H, C­2-H of thiazepine ring) (ppm); MS : M+427. Anal.Calcd.for C20H17N3O4S2; C,56.20 ; H,3.98; N,9.83. Found : C,56.22 ; H, 3.94; N,9.80.

4 – (21-Oxobarbiturinyl) – 2 – (o-chlorophenyl) – 2,3 – dihydro – 1,5 -benzoxazepines (4a)

The methanolic solution (50mL) of 1-(21-oxobarbiturinyl)-3-(m-chlorophenyl)-chalcone (2a) (0.01 mol) was added 2-aminophenol (0.01mol) with few drops of glacial acetic acid and refluxed for 3-5h. After refluxing solvent was distilled off under reduced pressure and the solid thus obtained was recrystallized from ethanol to give 4a (85%), mp 150°C ; IR (KBr) 3340 (NH), 1680, 1700, 1710 (amidic C=O), 1633 (C=C), 1470 (C=N), 660 (C-Cl), 1075 (C-O-C) cm-1 ; 1H NMR (CDCl3) δ 9.26 (ss, 2H, 2NHCO), 3.91 (t, 1H,-CH), 7.72 (d, 2H, C3-H of oxazepine ring), 6.52 (t, 1H, C2-H of oxazepine ring), 7.72-6.74 (m, 8H, Ar-H) (ppm) ; MS : M+383.5.. Anal.Calcd.for C19H14N3O4Cl; C,59.45; H,3.65 ; N, 10.95. Found : C,59.48; H,3.62; N,10.91.

4 – (21-Oxobarbiturinyl) – 2 – (p-hydroxyphenyl) – 2,3 – dihydro – 1,5 -benzoxazepines (4b)

76%, mp 160°C (ethanol) ; IR (KBr) 3347 (NH), 1690, 1710, 1715 (amidic C=O), 3444 (OH), 1624 (C=C), 1474 (C=N), 685 (C-O-C) cm-1 ; 1H NMR (CDCl3) δ 9.30 (ss, 2H, 2NHCO), 3.85 (t, 1H,-CH), 7.70 (d, 2H, C3-H of oxazepine ring), 6.50 (t, 1H, C2-H of oxazepine ring), 7.70-6.74 (m, 8H, Ar-H) 9.10 (s, 1H, Ar-OH) (ppm) ; MS : M+ 365.. Anal.Calcd. for C19H15N3O5; C,62.46; H,4.10; N,11.50. Found : C,62.41; H,4.13; N,11.48.

4 – (21-Oxobarbiturinyl) – 2 – (m-methoxy phenyl) – 2,3 – dihydro – 1,5 -benzoxazepines (4c)

80%, mp 156°C (benzene) ; IR (KBr) 3330 (NH), 1700, 1710, 1715 (amidic C=O), 1628 (C=C), 1465 (C=N), 1230 (OCH3), 1070(C-O-C) cm-1 ; 1H NMR (CDCl3) δ 9.28 (ss, 2H, 2NHCO), 3.57 (t, 1H,-CH), 7.64.6.68 (m, 8H, Ar-H) 7.68 (d, 2H, C3 –H of oxazepinering), 6.48 (t, 1H, C2-H of oxazepine ring), 3.48 (s, 3H,  OCH3) (ppm) ; MS : M+ 395. Anal.Calcd.for C20H17N3O6; C, 60.75; H,4.30; N,10.63. Found : C,60.72; H,4.33; N,10.67.

4 – (21-Thiobarbiturinyl) – 2 – (o-chlorophenyl) – 2,3 – dihydro – 1,5 – benzoxazepine (4d)

85%, mp 166°C (ethanol); IR (KBr) 3320 (NH), 1690,  1720 (amidic C=O), 1070(C=S), 1633(C=C), 1470 (C=N), 660 (C-Cl) 1075 (C-O-C) cm-1 ; 1H NMR (CDCl3) δ 9.26 (ss, 2H, 2NHCO), 3.59 (t, 1H,-CH), 7.72-6.62 (m, 8H, Ar-H), 7.70 (d, 2H, C3-H of oxazepine ring), 6.52 (t, 1H, C­2-H of oxazepine ring) (ppm); MS : M+ 332. Anal.Calcd. for C19H14N3O3SCl; C, 68.67 H,4.21; N, 12.65. Found : C,68.64 ; H,4.24; N,12.67.

4 – (21-Thiobarbiturinyl) – 2 – (p-hydroxyphenyl) – 2,3 – dihydro – 1,5 -benzoxazepine (4e)

80%, mp 173°C (ethanol); IR (KBr) 3345 (NH), 1700,  1715 (amidic C=O), 1080 (C=S), 3438 (OH), 1628 (C=C), 1465 (C=N),  1072 (C-O-C) cm-1 ; 1H NMR (CDCl3) δ 9.23 (ss, 2H, 2NHCO), 3.62 (t, 1H,-CH), 7.72 (d, 2H, C3-H of oxazepine ring), 6.50 (t, 1H, C­2-H of oxazepine ring), 9.15 (s, 1H, Ar-OH), 7.70-6.74 (m, 8H, Ar-H), (ppm); MS : M+ 381. Anal Calcd.for C19H15N3O4S; C, 73.75;  H,3.93; N, 11.02 Found : C,73.70 ; H,3.95 ; N,11.08.

4 – (21-Thiobarbiturinyl) – 2 – (m-methoxyphenyl) – 2,3 – dihydro – 1,5  – benzoxazepine (4f)

75%, mp 178°C (benzene); IR (KBr) 3347 (NH), 1690,  1720 (amidic C=O), 1060 (C=S), 1630 (C=C), 1470 (C=N), 1233 (OCH3), 1080 (C-O-C) cm-1 ; 1H NMR (CDCl3) δ 9.33 (ss, 2H, 2NHCO), 3.65 (t, 1H,-CH), 6.48 (t, 1H, C2-H of oxazepine ring), 7.68 (d, 2H, C3-H of oxazepine ring), 3.48 (ss, 3H, OCH3),  7.65-6.71 (m, 8H, Ar-H), (ppm); MS : M+ 395. Anal.Calcd.for C20H17N3O4S; C,60.75;  H,4.30; N, 10.63. Found : C,60.78; H,4.26 ; N,10.65.

4 – (21-Oxobarbiturinyl) – 2 – (o-chlorophenyl) – 3 [(p-chlorophenylaminomethylene)] -2,3 – dihydro – 1,5 – benzothiazepines (5a)

62%, mp 185°C; IR (KBr) 3320 (NH), 1690, 1710, 1715 (amidic C=O), 1625 (C=C), 1465 (C=N), 715 (C-Cl), 678 (C-S-C) cm-1 ; 1H NMR (CDCl3) δ 9.25 (ss, 2H, 2NHCO), 3.60 (t, 1H,-CH), 7.62 -6.74 (m, 12H, Ar-H) 3.70 (d, 1H, C3-H of thiazepine ring), 6.45 (t, 1H, C2-H of thiazepine ring), 3.04 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H, NHCH2CH=) (ppm) ; MS : M+ 467.. Anal.Calcd. for C26H19N4O3SCl2; C,66.80; H,4.06; N,11.99. Found : C,66.84;  H,4.10; N,11.94.

4 – (21-Oxobarbiturinyl) – 2 – (o-chlorophenyl) – 3 – [(p-methoxyphenylaminomethylene)] – 2,3-dihydro-1,5-benzothiazepines (5b).

70%, mp 172°C (ethanol) ; IR (KBr) 3342 (NH), 1710, 1715, 1720 (amidic C=O), 1630 (C=C), 1462 (C=N), 720 (C-Cl), 671, (C-S-C), 1229 (OCH3) cm-1 ; 1H NMR (CDCl3) δ 9.26 (ss, 2H, 2NHCO), 3.62 (t, 1H,-CH), 7.66 -6.64 (m, 12H, Ar-H) 3.72 (d, 1H, C3-H of thiazepine ring), 7.66-6.64 (m,12H, Ar-H), 3.72 (d, 1H, C3-H of thiazepine ring), 6.43 (t, 1H, C2-H of thiazepine ring), 3.06 (hump, 1H, CH2NH exchangeable with D2O), 1.65 (t, 2H, NHCH2CH=), 3.45 (s.3H, OCH3) (ppm) ; MS : M+ 534.5. Anal.Calcd.for C27H23N4O4SCl; C,60.61; H,4.30; N,10.47. Found : C,60.65;  H,4.32; N,10.42.

4 – (21-Oxobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3 – dihydro – 1,5-benzothiazepines (5c)

68%, mp 167°C (methanol) ; IR (KBr) 3345 (NH), 1700, 1715, 1725 (amidic C=O), 1638 (C=C), 1465 (C=N), 710 (C-Cl), 678 (C-S-C), 3457 (OH) cm-1 ; 1H NMR (CDCl3) δ9.23 (ss, 2H, 2NHCO), 3.68 (t, 1H,-CH),7.64-6.60 (m, 12H, Ar-H), 3.70 (d, 1H, C3-H of thiazepine ring), 6.58 (t, 1H, C2-H of thiazepine ring), 3.12 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H, NHCH2CH=) 9.15 (s, 1H, Ar-OH) (ppm) ; MS : M+ 456.5 Anal. Calcd.for C26H21N4O4SCl; C,68.34; H,4.60; N,12.26. Found : C,68.30;  H,4.62; N,12.22.

4 – (21-Oxobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-methoxyphenylaminomethylene)] – 2,3 – dihydro – 1,5 – benzothiazepines (5d)

54%, mp 184°C (DMF/Water) ; IR (KBr) 3330 (NH), 3460  (OH), 1680, 1700, 1715 (amidic C=O), 1645 (C=C), 1480 (C=N), 682 (C-S-C), cm-1 ; 1H NMR (CDCl3) δ 7.64-6.62 (m, 12H, Ar-H), 9.27 (ss, 2H, 2NHCO), 3.57 (t, 1H. CH-), 3.75, (d, 1H, C3-H of thiazepine ring), 6.41 (t, 1H, C2-H of thiazepine ring), 3.44 (s, 3H, OCH3), (,1H, Ar-OH), 3.10 (hump, 1H, CH2NH exchangeable with D2O), 1.60 (t, 2H, NHCH2CH=) (ppm) ; MS : M+ 516 Anal. Calcd.for C27H24N4O5S; C,62.79; H,4.65 ; N,10.85. Found : C,62.76;  H,4.63; N,10.88.

4 – (21-Oxobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3-dihydro-1,5-benzothiazepines (5e)

52%, mp 173°C (benzene); IR (KBr) 3360 (NH), 1670, 1700, 1720 (amidic C=O), 1650 (C=C), 1465 (C=N), 710 (C-Cl), 688 (C-S-C), cm-1 ; 1H NMR (CDCl3) δ 9.30 (ss, 2H, 2NHCO), 3.55 (t, 1H, CH-), 7.65-6.78 (m, 12H, Ar-H) 3.72 (d, 1H, C3-H of thiazepine ring), 6.55 (t, 1H, C2-H of thiazepine ring), 3.35 (s, 3H, OCH3), 3.10 (hump, 1H, CH2NH exchangeable with D2O), 1.68 (t, 2H, NHCH2CH=) (ppm) ; MS : M+ 534.5 Anal. Calcd.for C27H23N4O4SCl; C,60.61; H,4.30; N,10.47. Found : C,60.63;  H,4.28; N,10.43.

4 – (21-Oxobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3 – dihydro – 1,5 – benzothiazepines (5f)

67%, mp 168°C (DMF/Water); IR (KBr) 3347 (NH), 1700, 1710, 1720 (amidic C=O), 3432 (OH), 1618 (C=C), 1458 (C=N), 1221 (OCH3), 665 (C-S-C), cm-1 ; 1H NMR (CDCl3) δ 9.29 (ss, 2H, 2NHCO), 3.59  (t, 1H, CH-), 7.68-6.80 (m, 12H, Ar-H) 3.70 (d, 1H, C3-H of thiazepine ring), 6.40 (t, 1H, C2-H of thiazepine ring), 6.40 (t, 1H, C2-H of thiazepine ring), 3.41 (s, 6H, 2xOCH3). 3.00 (hump, 1H, CH2NH exchangeable with D2O), 1.59 (t, 2H, NHCH2CH=) (ppm) ; MS : M+ 530 Anal. Calcd.for C28H26N4O5S; C,63.39 ; H,4.90 ; N, 10.56. Found : C,63.41;  H,4.88 ; N, 10.58.

4 – (21-Thiobarbiturinyl) – 2 – (o-chlorophenyl) – 3- [(p-chlorophenylaminomethylene)]- 2,3 – dihydro – 1,5 – benzothiazepines (5g)

53%, mp 177°C (ethanol); IR (KBr) 3328 (NH), 1680, 1710, (amidic C=O), 1620 (C=C), 1440 (C=C), 720 (C=Cl), 690 (C-S-C), 1130 (C=S) cm-1 ; 1H NMR (CDCl3) δ  9.27 (ss, 2H, 2NHCO), 3.65 (t, 1H, CH-), 7.65- 6.74 (m, 12H, Ar-H) 3.72 (d, 1H, C3-H of thiazepine ring), 6.55 (t, 1H, C2-H of thiazepine ring), 3.10 (hump, 1H, CH2NH exchangeable with D2O), 1.65 (t, 2H, NHCH2CH=) (ppm) ; MS : M554 Anal. Calcd.for C26H19N4O2S2Cl2; C,56.31 ; H,3.42; N,10.10. Found : C,56.33;  H,3.45; N,10.14.

4 – (21-Thiobarbiturinyl) – 2 – (o-chlorophenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3 – dihydro – 1,5 – benzothiazepines (5h)

44%, mp 183°C (ethanol); IR (KBr) 3347 (NH), 1700, 1710, (amidic C=O), 1628(C=C), 1490 (C=N), 730 (C=Cl), 675 (C-S-C), 1235 (OCH3) 1127 (C=S) cm-1 ; 1H NMR (CDCl3)  δ 9.30 (ss, 2H, 2NHCO), 3.68 (t, 1H, CH-), 7.68- 6.64 (m, 12H, Ar-H) 3.70 (d, 1H, C3-H of thiazepine ring), 6.58 (t, 1H, C2-H of thiazepine ring), 3.08 (hump, 1H, CH2NH exchangeable with D2O), 1.70 (t, 2H, NHCH2CH=), 3.52 (s, 3H, OCH3), ppm) ; MS : M550.5 Anal. Calcd.for C27H23N4O3S2Cl; C,58.85 ; H,4.17 ; N,10.17. Found : C, 58.82 ;  H, 4.19 ; N,10.20.

4 – (21-Thiobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3- [(p-chlorophenylaminomethylene)]- 2,3-dihydro-1,5-benzothiazepines (5i)

55%, mp 163°C (methanol); IR (KBr) 3348 (NH), 1690, 1700, (amidic C=O), 1133 (C=S), 1648 (C=C), 1478 (C=N), 760 (C-Cl), 680  (C-S-C), 3460 (OH) cm-1 ; 1H NMR (CDCl3) δ 9.26 (ss, 2H, 2NHCO), 3.75 (t, 1H, CH), 7.65-6.74 (m, 12H, Ar-H), 3.70  (d, 1H, C3-H of thiazepine ring), 6.65 (t, 1H, C2-H of thiazepine ring), 3.15 (hump, 1H, CH2NH exchangeable with D2O), 1.68 (t, 2H, NHCH2CH=),  9.10 (s, 1H, Ar-OH) (ppm) ; MS : M536.5 Anal. Calcd.for C26H21N4O3S2Cl; C, 58.15 ; H,3.91 ; N,10.43. Found : C,58.11;  H,3.94; N, 10.45.

4 – (21-Thiobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3-dihydro-1,5-benzothiazepines (5j)

68%, mp 185°C (DMF/Water); IR (KBr) 3328 (NH), 3465 (OH), 1680, 1700 (amidic C=O), 1650 (C=C), 1470 (C=N), 1128 (C=S), 680 (C-S-C), cm-1 ; 1H NMR (CDCl3) δ 7.60-6.75 (m, 2H, Ar-H), 9.30 (ss, 2H, 2NHCO), 3.52 (t, 1H, CH-), 3.75 (d, 1H, C3-H of thiazepine ring), 6.45 (t, 1H, C2-H of thiazepine ring), 3.48 (S, 3H, OCH3)  9.11 (s, 1H, Ar – OH), 3.13 (hump, 1H, CH2NH exchangeable with D2O), 1.65 (t, 2H, NHCH2CH=), (ppm) ; MS : M532 Anal. Calcd.for C27H24N4O4S2; C,60.90 ; H, 4.51 ; N,10.52 . Found : C,60.92 ;  H,4.48 ; N,10.54.

4 – (21-Thiobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3 – dihydro -1,5-benzothiazepines (5k)

60%, mp 162°C (benzene); IR (KBr) 3350 (NH), 1700, 1720 (amidic C=O), 1145 (C=S), 1653 (C=C), 1470 (C=N), 730 (C-Cl), 690  (C-S-C), cm-1 ; 1H NMR (CDCl3) δ 9.36  (ss, 2H, 2NHCO), 3.48 (t, 1H, CH-), 7.68-6.60 (m, 12 H, Ar-H), 3.70  (d, 1H, C3-H of thiazepine ring), 3.38 (s, 3H, OCH3) 3.08  (hump, 1H, CH2NH exchangeable with D2O), 1.64 (t, 2H, NHCH2CH=) (ppm) ; MS : M550.5. Anal.Calcd.for C27H23N4O3S2Cl; C, 58.85; H,4.17; N,10.17. Found : C,58.88;  H, 4.12; N,10.14.

4 – (21-Thiobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3-dihydro-1,5-benzothiazepines (5l)

70%, mp 182°C (DMF/Water); IR (KBr) 3350 (NH), 1710, 1715 (amidic C=O), 1150 (C=S), 3435 (OH), 1620 (C=C), 1470 (C=N), 1220 (OCH3), 670  (C-S-C), cm-1 ; 1H NMR (CDCl3) δ 9.23  (ss, 2H, 2NHCO), 3.63 (t, 1H, CH-), 7.62-6.60 (m, 12H, Ar-H), 3.71 (d, 1H, C3-H of thiazepine ring), 6.43 (t, 1H, C2-H of thiazepine ring), 3.44 (s, 6H, 2xOCH3), 3.04  (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H, NHCH2CH=) (ppm) ; MS : M546. Anal.Calcd.for C28H26N4O4S2; C,61.53 ; H,4.76; N,10.25. Found : C,61.55 ;  H,4.79; N,10.21.

4 – (21-Oxobarbiturinyl) – 2 – (o-chlorophenyl) – 3 – [(p-Chlorophenylaminomethylene)]- 2,3 – dihydro – 1,5 – benzoxazepines (6a)

65%, mp 189°C (ethanol); IR (KBr) 3343 (NH), 1690, 1710, 1720 (amidic C=O), 1630 (C=C), 1469 (C=N), 1040 (C-O-C), 715 (C=Cl), cm-1 ; 1H NMR (CDCl3) δ 9.29  (ss, 2H, 2NHCO), 3.58 (t, 1H, -CH), 7.60-6.68(m, 12H, Ar-H), 3.72 (d, 1H, C3-H of thiazepine ring), 6.50 (t, 1H, C2-H of thiazepine ring), 3.08 (hump, 1H, CH2NH exchangeable with D2O), 1.65 (t, 2H, NHCH2CH=) (ppm) ; MS : M522. Anal.Calcd.for C26H19N4O4Cl2; C,59.77 ; H, 3.63 ; N,10.72 . Found : C,59.74  ;  H, 3.65 ; N,10.70.

4 – (21-Oxobarbiturinyl) – 2 – (o-chlorophenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3-dihydro-1,5-benzoxazepines (6b)

55%, mp 195°C (benzene); IR (KBr) 3350 (NH), 1700, 1710, 1715 (amidic C=O), 1637 (C-C), 1469 (C=N), 715 (C-Cl), 1035 (C-O-C), 1221 (OCH3) cm-1 ; 1H NMR (CDCl3) δ  9.24 (ss, 2H, 2NHCO), 3.60 (t, 1H, -CH), 7.65-6.74  (m, 12H, Ar-H), 3.70 (d, 1H, C3-H of oxazepine ring), 6.59 (t, 1H, C2-H of oxazepine ring), 3.12 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H, NHCH2CH=), 3.39 (s. 3H, OCH3) (ppm) ; MS : M518.5 Anal. Calcd. for C27H23N4O5Cl; C, 62.48  ; H,4.43; N,10.80. Found : C,62.46;  H,4.47; N,10.78.

4 – (21-Oxobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3-dihydro-1,5-benzoxazepines (6c)

61%, mp 200°C (methanol); IR (KBr) 3353 (NH), 1700, 1712, 1717 (amidic C=O), 1634 (C=C), 1470 (C=N), 720 (C-Cl), 1045 (C-O-C), 3468 (OH) cm-1 ; 1H NMR (CDCl3) δ 9.30 (ss, 2H, 2NHCO), 3.57 (t, 1H, -CH), 7.78 – 6.60 (m,12J. Ar-H), 3.75 (d, 1H, C3-H of oxazepine ring), 6.61 (t, 1H, C2-H of oxazepine ring), 3.16  (hump, 1H, CH2NH exchangeable with D2O), 1.70 (t, 2H, NHCH2CH=), 9.15  (s, 1H, OH- Ar), (ppm) ; MS : M504.5. Anal.Calcd.for C26H21N4O5Cl; C, 61.84 ; H,4.16 ; N,11.10. Found : C,61.80;  H, 4.18 ; N,11.13.

4 – (21-Oxobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3-dihydro-1,5-benzoxazepines (6d)

48%, mp 207°C (methanol); IR (KBr) 3347 (NH), 3458 (OH), 1690, 1700, 1710  (amidic C=O), 1630 (C=C), 1490 (C=N), 1035 (C-O-C), cm-1 ; 1H NMR (CDCl3) δ 7.80-6.85  (m, 12H, Ar-H), 9.35 (ss,  2H, 2NHCO), 3.60 (t, 1H, CH-), 3.75 (d, 1H, C3-H of oxazepine ring), 6.61 (t, 1H, C2-H of oxazepine ring), 3.31  (s, 3H, OCH3), 9.10  (s, 1H, Ar-OH), 3.12 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H, NHCH2CH=) (ppm) ; MS : M500. Anal.Calcd.for C27H24N4O6; C,62.4; H, 4.8; N, 11.2. Found : C, 62.8;  H,4.4 ; N, 11.4.

4 – (21-Oxobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3-dihydro-1,5-benzoxazepines (6e)

58%, mp 192°C (DMF/Water); IR (KBr) 3350 (NH), 1670, 1700, 1720 (amidic C=O), 1647 (C=C), 1460 (C=N), 715 (C-Cl), 1025  (C-O-C), cm-1 ; 1H NMR (CDCl3) δ 9.36 (ss, 2H, 2NHCO),3.50. (t, 1H, CH-) 7.85-6.70 (m, 12H, Ar-H) 3.77 (d, 1H, C3-H of oxazepine ring), 6.40 (t, 1H, C2-H of oxazepine ring), 3.02 (hump, 1H, CH2NH exchangeable with D2O), 1.60 (t, 2H, NHCH2CH=) (ppm) ; MS : M518.5 Anal. Calcd.for C27H23N4O5Cl; C,62.48; H, 4.43 ; N, 10.80. Found : C, 62.44 ;  H,4.45 ; N,10.77.

4 – (21-Oxobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3-dihydro-1,5-benzoxazepines (6f)

61%, mp 198°C (ethanol); IR (KBr) 3350 (NH), 1700, 1710, 1720 (amidic C=O), 3434 (OH), 1618 (C=C), 1458 (C=N), 1221 (OCH3), 1030 (C-O-C), cm-1 ; 1H NMR (CDCl3) δ 9.40 (ss, 2H, 2NHCO), 3.56 (t, 1H, CH-), 7.80-6.74 (m, 12H, Ar-H). 3.70 (d, 1H, C3-H of oxazepine ring), 6.40 (t, 1H, C2-H of oxazepine ring), 3.41 (s, 6H, 2xOCH3), 3.00 (hump, 1H, CH2NH exchangeable with D2O), 1.59  (t, 2H, NHCH2CH=) (ppm) ; MS : M514. Anal.Calcd.for C28H26N4O6; C, 65.36 ; H, 5.05 ; N,10.89.  Found : C,65.33;  H,5.07 ; N,10.84.

4 – (21-Thiobarbiturinyl) – 2 – (o-chlorophenyl) – 3 – [(p- chlorophenylaminomethylene)]- 2,3-dihydro-1,5-benzoxazepines (6g)

52%, mp 200°C (ethanol); IR (KBr) 3329 (NH), 1690,, 1710 (amidic C=O), 1630 (C-O-C), 1140 (C=S), cm-1 ; 1H NMR (CDCl3) δ 9.36 (ss, 2H, 2NHCO), 3.62 (t, 1H, CH-), 7.70-6.68 (m, 12H, Ar-H) 3.75 (d, 1H, C3-H of thiazepine ring), 6.45 (t, 1H, C2-H of thiazepine ring), 3.05 (hump, 1H, CH2NH exchangeable with D2O), 1.58 (t, 2H, NHCH2CH=) (ppm) ; MS : M538.  Anal.Calcd.for C26H19N4O3SCl2;  C, 57.99; H,3.53 ; N,10.40.  Found : C,57.97;  H,3.56 ; N, 10.38.

4 – (21-Thiobarbiturinyl) – 2 – (o-chlorophenyl) – 3 – [(p-methoxyphenylaminomethylene)]- 2,3-dihydrobenzoxazepines (6h)

69%, mp 171°C (benzene); IR (KBr) 3345 (NH), 1700, 1710 (amidic C=O), 1625 (C=C), 1440 (C=N), 760 (C-Cl), 1028 (C-O-C), 1148 (C=S), 1230 (OCH3) cm-1 ; 1H NMR (CDCl3) δ 9.30 (ss, 2H, 2NHCO), 3.68 (t, 1H, CH-) 7.88-6.78 (m, 12H, Ar-H) 3.72  (d, 1H, C3-H of oxazepine ring), 6.59 (t, 1H, C2-H of oxazepine ring), 3.12 (hump, 1H, CH2NH exchangeable with D2O), 1.62 (t, 2H, NHCH2CH=), 3.39  (s, 3H, OCH3) (ppm) ; MS : M534.5.  Anal.Calcd.for C27H23N4O4SCl;  C,60.61 ; H,4.30 ; N, 10.47.  Found : C, 60.63;  H,4.34 ; N, 10.41.

4 – (21-Thiobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-chlorophenylaminomethylene)]- 2,3-dihydro-1,5- benzoxazepines (6i)

48%, mp 175°C (methanol); IR (KBr) 3347 (NH), 1700, 1715, (amidic C=O), 1630 (C=C), 1460 (C=N), 730 (C-Cl), 1030 (C-O-C), 1145 (C=S), 3455 (OH) cm-1 ; 1H NMR (CDCl3) δ 9.28 (ss, 2H, 2NHCO), 3.60 (t, 1H, CH-), 7.85-6.80 (m, 12H, Ar-H), 3.77 (d, 1H, C3-H of oxazepine ring), 6.62 (t, 1H, C2-H of oxazepine ring), 3.15 (hump, 1H, CH2NH exchangeable with D2O), 1.58 (t, 2H, NHCH2CH=), 9.20 (s, 1H, Ar- OH) (ppm) ; MS : M520.5  Anal. Calcd. for C26H21N4O4SCl;  C,59.94; H,4.03 ; N,10.75.  Found : C,59.90 ;  H, 4.05 ; N,10.71.

4 – (21-Thiobarbiturinyl) – 2 – (p-hydroxyphenyl) – 3 – [(p-methoxyphenylaminomethylene] – 2,3- dihydro-1,5- benzoxazepines (6j)

65% ,mp 166C0 (methanal); IR(KBr) 3337 (NH), 3460 (OH), 1680, 1700 (midic C=O), 1640 (C=C), 1455 (C=N), 1150 (C=S), 1040(C-O-C) Cm1; 1H NMR (CDCl3), 7.80-6.68(m, 12H,Ar-H), 9.32 (ss,2H 2NHO), 3.59 (t,1H,CH-), 3.75 (d,1H, C3-H of oxazepine ring), 3.45 (s,3H,OCH3), 9.15 (s, 1H, Ar-OH) 3.02 (hump,) 1H, CH2NH exchangeable with D2O), 1.60 (t,2H NHCH2CH=), 6.40 (t,1H, C2-H of oxazepine ring) (ppm); MS:+ M 516, Anal. calcd. fer C27H24N4O5S; C,62.79; H,4.65; N,10.85. Found: C, 62.74; H,4.62; N,10.87.

4 – (21-Thiobarbiturinyl) – 2 – (m-methoxyphenyl) – 3 – [(p-chlorophenylaminomethylne)]  – 2,3 – dihydro- 1-5 – benzoxazepines (6K)

50%, mp 1740C (DMF/Water); IR (KBr) 3345 (NH), 1710, 1715 (amidic C=O), 1133 (C=S), 1615 (C=C), 1455 (C=N), 720 (C-Cl), 1040 (C-O-C) cm-1; 1H NMR (CDCl3) δ 9.33 (ss, 2H, 2NHCO), 3.58 (t,1H, CH-), 7.90-6.85 (m,12H,Ar-H), 3.73 (d,1H, C3-H of  oxazepine ring,), 6.65 (t,1H C2 –H of oxazepine ring), 3.34 (s,3H, OCH3), 3.20 (hump, 1H CH2NH exchangeable with D2O), 1.60 (t, 2H, NH CH2CH=) (ppm;) MS; M+ 534.5.Anal Calcd.for C27H23 N4O4SCl;  C, 60.61; H, 4.30; N,1O.47. Found: C, 60.63; H, 4.27; N, 10.49.

4-(21-Thiobarbiturinyl)-2- (m-methoxyphenyl)-3[(p-methoxyphenylaminomethylene)] -2,3-dihydro-1,5-benzoxazepines (6l)

45%, mp 2100C (ethanol);IR (KBr) 3348 (NH), 1700, 1710 (amidic C=O), 1127 (C=S), 1620 (C=C), 1452 (C=N), t210 (OCH3), 1048 (C-O-C) cm-1; 1H NMR (CDCl3) δ 9.38 (ss,2H, 2NHCO), 3.60 (t,1H,CH-), 7.88-6.74 (m,12H,Ar-H), 3.77 (d,1H,C3-H of oxazepine ring), 6.60 (t,1H, C2-H of oxazepine ring), 3.40 (S,6H, 2×OCH3), 3.28 (hump,1H, CH2NH exchangealele with D2O), 1.62 (t,2H, NHCH2CH=) (ppm); MS: M+ 530 Anal. Calcd.for C28H26 N4O5S; C, 63.39; H,4.90; N,1056. Found: C, 63.37; H, 4.43; N, 10.58.

Pharmacological Evaluation

Anticonvulsant Activity

Maximum Electroshock Seizure (MES) Test

This  test was performed according to the method of Tomen et.al15. The group of ten rats was treated with test drugs (50mg/kg i.p.) phenytoin sodium (30mg/kg i.p.). After 1h, they were subjected to the shock of 150 mA by convulsiometer through ear electrodes for 0.2s and the presence or absence of extensor response was noted. Animals in which extensor response was abolished were taken as protected rats.

Pentylenetetrazole (PTZ) induced seizures test. This test was performed by following the method of Fischer16. The rats were injected with pentylenetetrazol in dose of 70 mg/kg subcutaneously in scruff of neck. After 2-4 min of PTZ injection animals developed sequence of excitement, myoclonic jerks, clonic seizures, one or more maximum tonic seizures. Animals exhibiting these seizures patterns were selected standard drug used in this model was sodium valproate (80 mg/kg i.p) and was injected 60 min prior to PTZ challenge.

Approximate lethal dose (ALD50)

Approximate 50% lethal dose (ALD50) of the compounds were determined in albino mice. The mice of either sex 20-25g were used. The test compounds were injected intraperitoneally at different dose levels in groups of 10 animals. After 24 h of drug administration, percent mortality in each group was abserved from the data obtained. ALD50 was calculated by the method of Smith17.

Acknowledgements

The authors are thankful to Central Drug Research Institute (CDR1), Lucknow, India for elemental and spectral analysis. One of us (Dr. Mirdula Tyagi) is thankful to University Grants Comission (UGC) New Delhi, for the award of PDF.

References

  1. Goodman and Gilman’s The Pharmacological Basis of Therapeutics ; McGraw-Hill : New York, 1996; p 471.
  2. Goodman and Gilman’s The Pharmacological Basis of Therapeutics ; McGraw-Hill : New York, 1996; p 472.
  3. Siddiqui N.A. &Ahsan W., Arch PharmaChem, Like Sci, 2009, 342, 173.
  4. Goel B., Sharma S., Bajaj K., Bansal E., Singh T., Malik N., Lata S., Tygai C., Panwar H., Agarwal A. & Kumar A., Indian J. Pharma. Sci, 2005, 67 194.
  5. Archana, Srivastav V.K. & Kumar A., Bioorganic and Med. Chem. (2004) 1257.
  6. Archana, Rani P., Bajaj K., Srivastava V.K., Chandra R. & Kumar A., Arzneim. Forsch / Drug Res. 53 (2003) 301.
  7. Sarma G.V. S.P., Rao J.V. & Suresh B., Chem. Abstr, 133 (2000) 120291 g.
  8. Osman A. N., Kandel M.M. & Ahmed M., Indian . J. Chem. ,1996., 35 B 1073.
  9. Garg N., Chandra T., Archana, Jain B.A. & Kumar A., Eur. J. Med. Chem., 2010 .,45 1529.
  10. Zhong T.P., Guan L.P., Li-Mingzhao, Hu-Pi-Pio& Shan Zuan, Eur, J. Med. Chem. 2008 ., 43 1216.
  11. Bajaj K., Archana& Kumar A., Eur. J. Med. Chem. 2004.,39 ,369.
  12.  Bajaj K., Srivastave V.K. & Kumar A., Indian. J. Chem. 2003., 42 B 1149.
  13.  Youssef, K.M. & Said M.M., Egypt. J. Pharm. Sci. 1996., 37 ,45.
  14. Sarro G.D., Chimmirri A., Sarro A.D., Gittu R., Grasso S. &Zappala M., Eur. J. Med. Chem. 1995., 30, 925.
  15. Toman  J.E.P. Swingarel E.A. &Goudman L.S., Neuro J. Physiol (1946) 231.
  16. Fisher R.S. Brain Res. Rev. ; 1989., 14 .,245.
  17. Smith Q.E., J. Pharmacol. Exp. Ther. 1950, 100408.