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

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 5^th position of barbituric acid^3-8 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 5^th 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 5^th 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  Click here to View scheme 1

 

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)  Click here to View table

 

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  Click here to View scheme

 

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 (C…C 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 (C…C) 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 (C…C) 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 (C…C) 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 (C…C) 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 (C…C) 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 C₁₉H₁₅N₃O_3.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 : M⁺  554 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 : M⁺  550.5 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 : M⁺  536.5 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 : M⁺  532 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 : M⁺  550.5. 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 : M⁺  546. 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 : M⁺  522. 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 : M⁺  518.5 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 : M⁺  504.5. 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 : M⁺  500. 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 : M⁺  518.5 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 : M⁺  514. 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 : M⁺  538.  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 : M⁺  534.5.  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 : M⁺  520.5  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.

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