2 - chloro phenothiazine was prepared by the method of knoevenagal (loc. cit); (1914). 2-Chloro-10-chloroacetyl phenothiazine (1): To a solution of

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1 103

2 104 SCHEME II SOME NEW SUBSTITUTED BENZYLIDENE AMINOTHIAZOL / OXAZOL PHENOTHIAZINES; SUBSTITUTED AZETIDINYL THIAZOL/ OXAZOL PHENOTHIAZINES HAVE BEEN SYNTHESIZED AS SHOWN IN SCHEME-II, INVOLVES THE PREPARATIONOF - 2-Chloro-10-chloroacetyl phenothiazine (1). 2-Chloro-10- (2-aminothiazol-4-yl)-phenothiazine (2). 2-Chloro-10- (2-aminooxazol-4-yl)-phenothiazine (2'). 2-Chloro-10- [2-(substituted benzylidene)-aminothiazol-4-yl]- phenothiazines (3a-3g). 2-Chloro-10-[2-(substituted benzylidene)-aminooxazol-4-yl]- phenothiazines (3a'-3g'). 2-Chloro-10-[2-{3'-chloro-2'-oxo-4'-(substituted phenyl)-1'-azetidinyl}- thiazol-4-yl]-phenothiazines (4a - 4g). 2-Chloro-10-[2-{3'-chloro-2'-oxo-4'-(substituted phenyl)-1'- azetidinyl}- oxazol-4-yl]-phenothiazines (4a'-4g').

3 chloro phenothiazine was prepared by the method of knoevenagal (loc. cit); (1914). 2-Chloro-10-chloroacetyl phenothiazine (1): To a solution of 2-chlorophenothiazine in benzene (dry, 100 ml), chloroacetyl chloride (0.02 mole) was added drop by drop for about 1 hour with constant stirring. Then the mixture was stirred vigrously for one hour and after that refluxed for an hour. When the mixture was cooled, poured it onto ice and kept it at room temperature in a desiccator for about one week. The resulting mixture was filtered and recrystalised from methanol. Compound 1 : M.P. 189ºC; Yield 86%. Recrystallised Solvent : Methanol, Molecular formula C 14 H 9 Cl 2 ONS, Elemental Analysis : Calculated % C : 54.19, H : 2.90, N : 4.51, Found % C : 54.20, H : 2.89, N : IR (KBr) max in cm -1 : 660 (C Cl), 755 (C C), 680 (C S C), 1140 (C S), 1265 (C N), 1540 (C=C of aromatic ring), 1090 (C O C), 1720 (C=O), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 3.45 (s, 2H, CH 2 Cl), (m,7h,ar H). MS: [M] + m/z Chloro-10- (2-aminothiazol-4-yl)-phenothiazine (2): A mixture of 2-chloro-10-chloroacetyl phenothiazine (1) (0.01 mole), methanol (50 ml) and thiourea (0.01 mole) was refluxed for about 6-8 hours and after refluxing allowed to stand it overnight. The solid thus separated, was filtered and washed with NaHCO 3 solution (2%) and then with water. After washing, dried and recrystallised from methanol. Compound 2 : M.P. 167ºC; Yield 80%, Recrystallised Solvent : Methanol, Molecular formula C 15 H 10 S 2 N 3 Cl, Elemental Analysis : Calculated % C : 54.29, H : 3.01, N : 12.66, Found % C : 54.36, H : 3.02, N : IR (KBr) max in cm -1 : 665 (C Cl), 685 (C S C), 750 (C C) 1135 (C S), 1260 (C N), 1540 (C=C of aromatic ring), 1625 (C=N), 3040 (aromatic C H), 3320 (NH 2 ). 1 H NMR (CDCl 3 ) in ppm: 6.30 (s, 2H, NH 2 exchangeable with D 2 O), (m, 8H, Ar H). MS: [M] + m/z 331.

4 106 2-Chloro-10- (2-aminooxazol-4-yl)-phenothiazine (2'): A mixture of 2-chloro-10-chloroacetyl phenothiazine (1) (0.01 mole), ethanol (50 ml) and urea (0.01 mole) was refluxed for 6-8 hours and after refluxing allowed it to stand overnight. The separated solid was filtered and washed with 2% solution of NaHCO 3 and then with water, dried and recrystallised from ethanol/water. Compound 2' : M.P. 225ºC; Yield 72%, Recrystallised Solvent : Ethanol / Water, Molecular formula C 15 H 10 N 3 SOCl, Elemental Analysis : Calculated % C : 57.05, H : 3.16, N : 13.31, Found % C : 56.94, H : 3.15, N : IR (KBr) max in cm -1 : 660(C Cl), 755 (C C), 1065 (C O C), 695 (C S C), 1145 (C S), 1265 (C N), 1535 (C=C of aromatic ring), 1615 (C=N), 3045 (aromatic C H), 3320 (NH 2 ). 1 H NMR (CDCl 3 ) in ppm: 6.30 (s, 2H, NH 2 exchangeable with D 2 O), (m, 8H, Ar H). MS: [M] + m/z Chloro-10-[2-(2, 6-dichlorobenzylidene)-aminothiazol-4-yl]- phenothiazine (3a) To a solution of 2-chloro-10-(2-aminothiazol-4-yl)-phenothiazine (2) (0.01 mole) and 2,6-dichloro benzaldehyde (0.01 mole) in ethanol (50 ml) and few drops of glacial acetic acid were added. The mixture was heated under reflux for hours. The solvent was distilled off and the residue was washed with pet. ether, and recrystallised from ethanol/water. Compound 3a : M.P. 198 o C; Yield 48%. Recrystallised Solvent : Ethanol/ Water, Molecular formula C 22 H 12 N 3 Cl 3 S 2. Elemental Analysis : Calculated % C : 54.04, H : 2.46, N : 8.59, Found % C : 54.13, H : 2.45, N : IR (KBr) max in cm -1 : 665(C Cl), 685 (C S C), 755 (C C), 1140 (C S), 1260 (C N), 1535 (C=C of aromatic ring), 1560 (C=N), 3060 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 11H, Ar H), 8.3 (s, 1H, N=CH Ar). MS: [M] + m/z 488.

5 107 2-Chloro-10-[2-(2, 6-dibromobenzylidene)-aminothiazol-4-yl]- phenothiazine (3b) Compound 3b : M.P. 193 o C; Yield 42%. Recrystallised Solvent : Benzene, Molecular formula C 22 H 12 N 3 SO 2 Cl 2. Elemental Analysis : Calculated % C : 45.71, H : 2.07, N : 7.27, Found % C : 45.76, H : 2.06, N : IR (KBr) max in cm -1 : 660 (C Cl), 680 (C S C), 745 (C C), 1150 (C S), 1250 (C N), 1540 (C=C of aromatic ring), 1575 (C=N), 3065 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 11H, Ar H), 8.25 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2, 6-diiodobenzylidene)-aminothiazol-4-yl]-phenothiazine (3c) Compound 3c : M.P. 182 o C; Yield 43%. Recrystallised Solvent : Ethanol, Molecular formula C 22 H 12 N 3 S 2 I 2 Cl. Elemental Analysis : Calculated % C : 39.31, H : 1.78, N : 6.25, Found % C : 39.26, H : 1.79, N : IR (KBr) max in cm -1 : 655(C Cl), 1135 (C I), 685 (C S C), 750 (C C), 1135 (C S), 1240 (C N), 1550 (C=C of aromatic ring), 1565 (C=N), 3055 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 11H, Ar H), 8.20 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2, chlorobenzylidene)-aminothiazol-4-yl]-phenothiazine (3d) Compound 3d : M.P. 184 o C; Yield 47%. Recrystallised Solvent : Methanol/ Water, Molecular formula C 22 H 13 N 3 S 2 Cl 2. Elemental Analysis : Calculated % C : 58.14, H : 2.86, N : 9.25, Found % C : 58.02, H : 2.85, N : IR (KBr) max in cm -1 : 550 (C-Br), 660 (C Cl), 690 (C S C), 755 (C C), 1150 (C S), 1245 (C N), 1555 (C=C of aromatic ring), 1580 (C=N), 3060 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 12H, Ar H), 8.35 (s, 1H, N=CH Ar). MS: [M] + m/z 454.

6 108 2-Chloro-10-[2-(2, bromobenzylidene)-aminothiazol-4-yl]-phenothiazine (3e) Compound 3e : M.P. 179 o C; Yield 49%. Recrystallised Solvent : Acetone, Molecular formula C 22 H 13 N 3 S 2 BrCl. Elemental Analysis : Calculated % C : 52.95, H : 2.60, N : 8.42, Found % C : 53.02, H : 2.61, N : IR (KBr) max in cm -1 : 555 (C-Br), 650 (C Cl), 695 (C S C), 760 (C C), 1155 (C S), 1250 (C N), 1540 (C=C of aromatic ring), 1585 (C=N), 3050 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 12H, Ar H), 8.30 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2, iodobenzylidene)-aminothiazol-4-yl]-phenothiazine (3f) Compound 3f : M.P. 176 o C; Yield 45%. Recrystallised Solvent : Benzene / Hexane, Molecular formula C 22 H 13 N 3 S 2 ICl. Elemental Analysis : Calculated % C : 48.39, H : 2.38, N : 7.69, Found % C : 48.49, H : 2.39, N : IR (KBr) max in cm -1 : 645 (C Cl), 580 (C-I), 690 (C S C), 765 (C C), 1145 (C S), 1240 (C N), 1560 (C=C of aromatic ring), 1590 (C=N), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 12H, Ar H), 8.25 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(4, N, N dimethyl aminobenzylidene)-aminothiazol-4-yl]- phenothiazine (3g) Compound 3g : M.P. 187 o C; Yield 44%. Recrystallised Solvent : Methanol, Molecular formula C 24 H 19 N 4 S 2 Cl. Elemental Analysis : Calculated % C : 62.27, H : 4.10, N : 12.10, Found % C : 62.19, H : 4.11, N : IR (KBr) max in cm -1 : 655(C Cl), 700 (C S C), 765 (C C), 685 (C S C) 1140 (C S), 1245 (C N), 1555 (C=C of aromatic ring), 1585 (C=N), 3030 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 2.15 [s, 6H (CH 3 ) 2 N-Ar], (m, 12H, Ar H), 8.35 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2,6-dichlorobenzylidene)-aminooxazol-4-yl]-phenothiazine (3a') To a solution of 2-chloro-10- (2-amino oxazol-4-yl)-phenothiazine (2') (0.01 mole) and 2, 6-dichloro benzaldehyde (0.01 mole) in ethanol (50mL) and

7 109 few drops of glacial acetic acid were added. The mixture was refluxed for about hours. Now the reaction mixture was cooled, filtered and the residue was washed with NaHCO 3 solution (2%) and then with water, dried and recrystallised from ethanol. Compound 3a' : M.P. 188 o C; Yield 47%, Recrystallised Solvent : Methanol, Molecular formula C 22 H 12 N 3 Cl 3 OS, Elemental Analysis : Calculated % C : 55.87, H : 2.53, N : 8.88, Found % C : 55.95, H : 2.52, N : IR (KBr) max in cm -1 : 670 (C Cl), 750 (C C), 1070 (C O C), 1145 (C S), 1265 (C N), 1530 (C=C of aromatic ring), 1565 (C=N), 3040 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 11H, Ar H), 8.2 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2,6-dibromobenzylidene)-aminooxazol-4-yl]- phenothiazine (3b') Compound 3b' : M.P. 183 o C; Yield 49%, Recrystallised Solvent : Ethanol/ Water, Molecular formula C 22 H 12 N 3 Br 2 SClO, Elemental Analysis : Calculated % C : 47.01, H : 2.13, N : 7.47, Found % C : 47.09, H : 2.12, N : IR (KBr) max in cm -1 : 560 (C Br), 660 (C Cl), 760 (C C), 1065 (C O C), 690 (C S C), 1150 (C S), 1250 (C N), 1535 (C=C of aromatic ring), 1560 (C=N), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 11H, Ar H), 8.25 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2,6-diiodobenzylidene)-aminooxazol-4-yl]-phenothiazine (3c') Compound 3c' : M.P. 178 o C; Yield 45%, Recrystallised Solvent : Methanol, Molecular formula C 22 H 12 N 3 I 2 SClO, Elemental Analysis : Calculated % C : 40.27, H : 1.83, N : 6.40, Found % C : 40.18, H : 1.84, N : IR (KBr) max in cm -1 : 665 (C Cl), 590 (C-I), 755 (C C), 1060 (C O C), 695 (C S C), 1140 (C S), 1255 (C N), 1540 (C=C of aromatic ring), 1570 (C=N), 3030 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 11H, Ar H), 8.35 (s, 1H, N=CH Ar). MS: [M] + m/z 655.

8 110 2-Chloro-10-[2-(2-chlorobenzylidene)-aminooxazol-4-yl]-phenothiazine (3d') Compound 3d' : M.P. 181 o C; Yield 52%, Recrystallised Solvent : Acetone, Molecular formula C 22 H 13 N 3 Cl 2 SO, Elemental Analysis : Calculated % C : 60.27, H : 2.96, N : 9.58, Found % C : 60.12, H : 2.95, N : IR (KBr) max in cm -1 : 650 (C Cl), 745 (C C), 1070 (C O C), 705 (C S C), 1155 (C S), 1240 (C N), 1535 (C=C of aromatic ring), 1570 (C=N), 3055 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 12H, Ar H), 8.30 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2-bromobenzylidene)-aminooxazol-4-yl]-phenothiazine (3e') Compound 3e' : M.P. 175 o C; Yield 51%, Recrystallised Solvent : Acetic Acid, Molecular formula C 22 H 13 N 3 BrSClO, Elemental Analysis : Calculated % C : 54.71, H : 2.69, N : 8.70, Found % C : 54.68, H : 2.70, N : IR (KBr) max in cm -1 : 555 (C Br), 650 (C Cl), 765 (C C), 1075 (C O C), 710 (C S C), 1160 (C S), 1230 (C N), 1545 (C=C of aromatic ring), 1580 (C=N), 3060 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 12H, Ar H), 8.20 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(2-iodobenzylidene)-aminooxazol-4-yl]-phenothiazine (3f') Compound 3f' : M.P. 172 o C; Yield 48%, Recrystallised Solvent : Ethanol, Molecular formula C 22 H 13 N 3 ISClO, Elemental Analysis : Calculated % C : 49.85, H : 2.45, N : 7.93, Found % C : 49.93, H : 2.46, N : IR (KBr) max in cm -1 : 660 (C Cl), 595 (C I), 760 (C C), 1080 (C O C), 690 (C S C), 1145 (C S), 1230 (C N), 1540 (C=C of aromatic ring), 1585 (C=N), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: (m, 12H, Ar H), 8.25 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-(4-N,N-dimethyl aminobenzylidene)-aminooxazol-4-yl]- phenothiazine (3g') Compound 3g' : M.P. 185 o C; Yield 54%, Recrystallised Solvent : Benzene / Pet. Ether, Molecular formula C 24 H 19 N 4 SClO, Elemental Analysis : Calculated

9 111 % C : 64.50, H : 4.25, N : 12.54, Found % C : 64.61, H : 4.24, N : IR (KBr) max in cm -1 : 645 (C Cl), 755 (C C), 1085 (C O C), 700 (C S C), 1150 (C S), 1240 (C N), 1555 (C=C of aromatic ring), 1590 (C=N), 3030 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 2.20 [s, 6H (CH 3 ) 2 N-Ar], (m, 12H, Ar H), 8.30 (s, 1H, N=CH Ar). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2,6-dichlorophenyl)-1'-azetidinyl}- thiazol-4-yl]-phenothiazine (4a): In the solution of compound 3a i.e. 2-chloro-10[2-(2, 6-dichloro benzylidene)-aminothiazol-4-yl]-phenothiazine (0.01 mole) and chloroacetyl chloride (0.02 mole) in benzene (dry 50 ml), triethylamine (3-4 drops) was added dropwise with constant stirring for one hour. The reaction mixture was more stirred by magnetic stirrer for about 4 hours and refluxed for 8 hours. The reaction mixture was cooled and then poured into ice cold water. After filtration recrystallised from ethanol/water. Compound 4a : M.P. 237 o C; Yield 32%. Recrystallised Solvent : Ethanol/ Water, Molecular formula C 24 H 13 N 3 S 2 Cl 4 O. Elemental Analysis : Calculated % C : 50.97, H : 2.30, N : 7.43, Found % C : 51.11, H : 2.31, N : IR (KBr) max in cm -1 : 665(C Cl), 680 (C S C), 760 (C C), 1150 (C S), 1260 (C N), 1530 (C=C of aromatic ring), 1555 (C=N), 1710 (C=O), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.65 (d, 1H, N CH), 6.40 (d,1h,ch Cl), (m, 11H, Ar H). MS:[M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2,6-dibromophenyl)-1'-azetidinyl}- thiazol-4-yl]-phenothiazine (4b): Compound 4b : M.P. 232 o C; Yield 27%. Recrystallised Solvent : Benzene / Pet. Ether, Molecular formula C 24 H 13 N 3 S 2 Br 2 Cl 2 O. Elemental Analysis : Calculated % C : 44.03, H : 1.98, N : 6.42, Found % C : 44.12, H : 1.99, N : IR (KBr) max in cm -1 : 660 (C Br), 650(C Cl), 685 (C S C), 765 (C C), 1160 (C S), 1250 (C N), 1540 (C=C of aromatic ring), 1560 (C=N), 1725 (C=O), 3030 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.60 (d,1h,n CH), 6.45 (d,1h,ch Cl), (m, 11H, Ar H). MS:[M] + m/z 654.

10 112 2-Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2,6-diiodophenyl)-1'-azetidinyl}- thiazol-4-yl]-phenothiazine (4c): Compound 4c : M.P. 223 o C; Yield 28%. Recrystallised Solvent : Ethanol, Molecular formula C 24 H 13 N 3 S 2 I 2 Cl 2 O. Elemental Analysis : Calculated % C : 38.50, H : 1.73, N : 5.61, Found % C : 38.39, H : 1.72, N : IR (KBr) max in cm -1 : 645 (C Cl), 595 (C I), 690 (C S C), 760 (C C), 1165 (C S), 1245 (C N), 1530 (C=C of aromatic ring), 1565 (C=N), 1720 (C=O), 3035 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.50 (d,1h,n CH), 6.40 (d,1h,ch Cl), (m, 11H, Ar H). MS:[M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2-chlorophenyl)-1'-azetidinyl}-thiazol- 4-yl]-phenothiazine (4d): Compound 4d : M.P. 230 o C; Yield 25%. Recrystallised Solvent : Ascetic Acid, Molecular formula C 24 H 14 N 3 S 2 Cl 3 O. Elemental Analysis : Calculated % C : , H : 2.64, N : 7.91, Found % C : 54.42, H : 2.63, N : IR (KBr) max in cm -1 : 655(C Cl), 680 (C S C), 770 (C C), 1155 (C S), 1240 (C N), 1545 (C=C of aromatic ring), 1570 (C=N), 1730 (C=O), 3040 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.55 (d,1h,n CH), 6.50 (d,1h,ch Cl), (m, 12H, Ar H). MS:[M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2-bromophenyl)-1'-azetidinyl}- thiazol-4-yl]-phenothiazine (4e): Compound 4e : M.P. 221; Yield 32%. Recrystallised Solvent : methanol / Water, Molecular formula C 24 H 14 N 3 S 2 BrCl 2 O. Elemental Analysis : Calculated % C : 50.08, H : 2.43, N : 7.30, Found % C : 50.13, H : 2.42, N : IR (KBr) max in cm -1 : 600 (C Br), 660 (C Cl), 690 (C S C), 750 (C C), 1170 (C S), 1250 (C N), 1535 (C=C of aromatic ring), 1585 (C=N), 1710 (C=O), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.65 d,1h,n CH), 6.45 (d,1h,ch Cl), (m, 12H, Ar H). MS:[M] + m/z 575.

11 113 2-Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2-iodophenyl)-1'-azetidinyl}-thiazol-4- yl]-phenothiazine (4f): Compound 4f : M.P. 212; Yield 34%. Recrystallised Solvent : Ethanol/ Water, Molecular formula C 24 H 14 N 3 S 2 ICl 2 O. Elemental Analysis : Calculated % C : 46.30, H : 2.25, N : 6.75, Found % C : 46.21, H : 2.26, N : IR (KBr) max in cm -1 : 650 (C Cl), 590 (C I), 680 (C S C), 760 (C C), 1160 (C S), 1240 (C N), 1530 (C=C of aromatic ring), 1590 (C=N), 1725 (C=O), 3050 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.70 (d,1h,n CH), 6.50 (d,1h,ch Cl), (m, 12H, Ar H). MS:[M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(4-N,N-dimethyl aminophenyl)-1'- azetidinyl}-thiazol-4-yl]-phenothiazine (4g): Compound 4g : M.P. 228; Yield 29%. Recrystallised Solvent : Acetone, Molecular formula C 26 H 20 N 4 S 2 Cl 2 O. Elemental Analysis : Calculated % C : 57.88, H : 3.71, N : 10.38, Found % C : 57.76, H : 3.70, N : IR (KBr) max in cm -1 : 655(C Cl), 685 (C S C), 765 (C C), 1165 (C S), 1250 (C N), 1525 (C=C of aromatic ring), 1600 (C=N), 1730 (C=O), 3040 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 2.30 [s, 6H (CH 3 ) 2 N-Ar], 4.70 (d,1h,n CH), 6.40 (d,1h,ch Cl), (m, 12H, Ar H). MS:[M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2, 6-dichlorophenyl)-1'-azetidinyl}- oxazol-4-yl]-phenothiazine (4a') : In the solution of compound 3a' i.e. 2-chloro-10-[2-(2,6-dichloro benzylidene)-aminooxazol-4-yl]-phenothiazine (0.01 mole) and chloroacetyl chloride (0.02 mole) in benzene (dry 50 ml), triethyl amine (3-4 drops) was added dropwise with constant stirring for one hour. The reaction mixture was more stirred by magnetic stirrer for about 4-5 hours and refluxed for 8 hours, cooled and then poured into ice cold water. The solid thus obtained was filtered and recrystallised from ethanol. Compound 4a' : M.P. 231 o C; Yield 34%. Recrystallised Solvent : Ethanol, Molecular formula C 24 H 13 N 3 SCl 4 O 2. Elemental Analysis : Calculated % C : 52.45, H : 2.36, N : 7.65, Found % C : 52.53, H : 2.37, N : IR (KBr) max

12 114 in cm -1 : 670 (C Cl), 760 (C C), 1070 (C O C), 700 (C S C) 1160 (C S), 1260 (C N), 1530 (C=C of aromatic ring), 1585 (C=N), 1710 (C=O), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.65 (d,1h,n CH), 6.40 (d,1h,ch Cl), (m, 11H, Ar H). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2, 6-dibromophenyl)-1'-azetidinyl}- oxazol-4-yl]-phenothiazine (4b') : Compound 4b' : M.P. 226 o C; Yield 31%. Recrystallised Solvent : Methanol / Water, Molecular formula C 24 H 13 N 3 SBr 2 Cl 2 O 2. Elemental Analysis : Calculated % C : 45.14, H : 2.03, N : 6.58, Found % C : 45.21, H : 2.02, N : IR (KBr) max in cm -1 : 550 (C Br), 660 (C Cl), 765 (C C), 1065 (C O C), 705 (C S C), 1165 (C S), 1250 (C N), 1545 (C=C of aromatic ring), 1590 (C=N), 1720 (C=O), 3035 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.60 (d,1h,n CH), 6.35 (d,1h,ch Cl), (m, 11H, Ar H). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2, 6-diiodophenyl)-1'-azetidinyl}- oxazol-4-yl]-phenothiazine (4c') : Compound 4c' : M.P. 220 o C; Yield 35%. Recrystallised Solvent : Acetic Acid, Molecular formula C 24 H 13 N 3 SI 2 Cl 2 O 2. Elemental Analysis : Calculated % C : 39.34, H : 1.77, N : 5.73, Found % C : 39.27, H : 1.76, N : IR (KBr) max in cm -1 : 650 (C Cl), 590 (C-I), 750 (C C), 1060 (C O C), 710 (C S C), 1145 (C S), 1245 (C N), 1535 (C=C of aromatic ring), 1600 (C=N), 1705 (C=O), 3050 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.50 (d,1h,n CH), 6.50 (d,1h,ch Cl), (m, 11H, Ar H). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2-chlorophenyl)-1'-azetidinyl}- oxazol-4-yl]-phenothiazine (4d') : Compound 4d' : M.P. 229 o C; Yield 38%. Recrystallised Solvent : Methanol, Molecular formula C 24 H 14 N 3 SCl 3 O 2. Elemental Analysis : Calculated % C : 55.97, H : 2.72, N : 8.16, Found % C : 56.04, H : 2.71, N : IR (KBr) max in cm -1 : 655 (C Cl), 760 (C C), 1070 (C O C), 715 (C S C), 1150 (C S), 1240 (C N), 1535 (C=C of aromatic ring), 1610 (C=N), 1715 (C=O), 3045

13 115 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.50 (d,1h,n CH), 6.45 (d,1h,ch Cl), (m, 12H, Ar H). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2-bromophenyl)-1'-azetidinyl}- oxazol-4-yl]-phenothiazine (4e') : Compound 4e' : M.P. 218 o C; Yield 36%. Recrystallised Solvent : Benzene, Molecular formula C 24 H 14 N 3 SBrCl 2 O 2. Elemental Analysis : Calculated % C : 51.52, H : 2.50, N : 7.51, Found % C : 51.42, H : 2.51, N : IR (KBr) max in cm -1 : 555 (C-Br), 645 (C Cl), 770 (C C), 1050 (C O C), 700 (C S C), 1140 (C S), 1230 (C N), 1530 (C=C of aromatic ring), 1590 (C=N), 1720 (C=O), 3030 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.55 (d,1h,n CH), 6.40 (d,1h,ch Cl), (m, 12H, Ar H). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(2-iodophenyl)-1'-azetidinyl}- oxazol- 4-yl]-phenothiazine (4f') : Compound 4f' : M.P. 210 o C; Yield 32%. Recrystallised Solvent : Ethanol/ Water, Molecular formula C 24 H 14 N 3 SICl 2 O 2. Elemental Analysis : Calculated % C : 47.52, H : 2.31, N : 6.93, Found % C : 47.48, H : 2.30, N : IR (KBr) max in cm -1 : 660 (C Cl), 600 (C I), 765 (C C), 1070 (C O C), 705 (C S C), 1160 (C S), 1250 (C N), 1550 (C=C of aromatic ring), 1580 (C=N), 1725 (C=O), 3045 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 4.65 (d,1h,n CH), 6.40 (d,1h,ch Cl), (m, 12H, Ar H). MS: [M] + m/z Chloro-10-[2-{3'-chloro-2'-oxo-4'-(4-N,N-dimethyl aminophenyl)-1'- azetidinyl}- oxazol-4-yl]-phenothiazine (4g') : Compound 4g' : M.P. 224 o C; Yield 31%. Recrystallised Solvent : Acetone, Molecular formula C 26 H 20 N 4 SCl 2 O 2. Elemental Analysis : Calculated % C : 59.65, H : 3.82, N : 10.70, Found % C : 59.61, H : 3.83, N : IR (KBr) max in cm -1 : 665 (C Cl), 760 (C C), 1080 (C O C), 710 (C S C), 1155 (C S), 1230 (C N), 1560 (C=C of aromatic ring), 1570 (C=N), 1720 (C=O), 3055 (aromatic C H). 1 H NMR (CDCl 3 ) in ppm: 2.25 [s, 6H (CH 3 ) 2 N-Ar], 4.60 (d,1h,n CH), 6.55 (d,1h,ch Cl), (m, 12H, Ar H). MS: [M] + m/z 523.

14 116 Mass spectral study of: 2-chloro-10-[2-{3'-chloro-2'-oxo-4'-(2,6-dichlorophenyl)-1'-azetidinyl}-oxazol-4-yl]-phenothiazine (4a') Mass spectral fragmentation of compound 4a' is illustrated in Scheme- II'. The percent relative intensities of all the peaks are given in table-1. On electron impact, compound 4a' gave molecular ion peak [M] + at m/z 549, which was not a base peak. The cleavage of C-N bond of oxazolyl phenothiazine ring resulted into two ions [a] + at m/z 232 and [b] + at m/z 316, and out of these [a] + was the base peak. In route I, ion [a] + on losing sulphur radical formed ion [c] + at m/z 200 and on losing CHS radical formed ion [d] + at m/z 187. Same kind of fragmentation pattern has been reported by Sadhanani et al (1973) and Morosawa et al (1982). In route II, there were two modes of fragmentation observed in the decomposition of ion [b] +. In mode 1 (imine fragment) COCHCl moiety was lost and ion [e] + at m/z 240 has been formed and in mode 2 (iso-cyanate fragment), isocyanate moiety remained attached with [b] + and yielded ion [f] + at m/z 109. This type of fragmentation has also been reported by Auriel et al (1989). In mode 1 ion [e] + on losing C 6 H 3 Cl 2 (2,6-dichlorophenyl)moiety converted into ion [h] + at m/z 94, which on elimination of H radical yielded ion [i] + at m/z 93. Ion [i] + further eliminated two cyanide radicals and gave ion [j] + at m/z 41. On the another side ion [e] + converted into ion [g] + at m/z 239 after removing a proton, which on ejection of dichlorophenyl moiety yielded ion [i] + at m/z 93. This ion eliminated to cyanide radicals and converted into ion [j] + at m/z 41. In mode 2 ion [f] + on releasing iso-cyanate radical gave ion [k] + at m/z 67, which on losing a cyanide radical yielded the ion [j] + at m/z 41.

15 117

16 118

17 119 Table 1: Mass fragmentation data of compound 2-chloro-10-[2-{3'-chloro- 2'-oxo-4'-(2,6-dichlorophenyl)-1'-azetidinyl}-oxazol-4-yl]-phenothiazine (4a'): Selected Ions Molecular Formula m/z % Relative intensity (r.i.) [M] + C 24 H 13 N 3 SCl [a] + C 12 H 7 NSCl [b] + C 12 H 6 N 2 O 2 Cl [c] + C 12 H 7 NCl [d] + C 11 H 6 NCl [e] + C 10 H 5 N 2 OCl [f] + C 4 HN 2 O [g] + C 10 H 4 N 2 OCl [h] + C 4 H 2 N 2 O [i] + C 4 HN 2 O [j] + C 2 HO [k] + C 3 HNO 67 65

18 120 RESULT AND DISCUSSION: 1. Antinflammatory activity against carrageenan induced oedema: The result of antiinflammatory activity of all these compounds has been shown in tables (2,3,4,5). The antiinflammatory activity of the compounds (3a-3g), i.e. 2-chloro- 10-[2- (substituted benzylidene)-aminothiazol-4-yl]-phenothiazines varying from to 27.03% (Table-2). It is clear that when the compound was substituted with 2, 6-dichlorophenyl (compound 3a, 27.03%) showed more potent anti-inflammatory activity than the compound which was substituted with 2, 6-dibromophenyl (compound 3b, 16.22%) and with 2, 6-diiodophenyl group (compound 3c, 13.52%). The compounds 3d and 3e, substituted by 2- chloro and 2-bromophenyl groups respectively were less active (24.33%, 21.63%) than compound 3a but more active than 3b. However the compound 3f, which was substituted by 2-iodophenyl group was found to be less active (10.82%) than its disubstituted compound (3c). And compound 3g which was substituted by N,N-dimethyl aminophenyl exhibited promising antiinflammatory activity (18.92%). It is interestingly enough, the anti-inflammatory activity of 2-chloro-10- [2-{3'-chloro-2'-oxo-4'-(substitutedphenyl) 1'- azetidinyl} thiazol-4-yl] phenothiazines (4a-4g) is more (ranging between to 29.55%) (Table-4) than that of their parent compounds (3a-3g). Moreover, corresponding oxazoles, i.e. 2-chloro-10-[2- (substitutedbenzylidene) aminooxazol-4-yl] phenothiazines (3a'-3g') showed a decrease in activity ( %, Table-3) as compared to their corresponding thiazoles (3a-3g). The cyclised compounds (4a'-4g'), i.e. 2-chloro-10-[2-{3'-chloro-2'-oxo- 4'- (substitutedphenyl) 1'-azetidinyl} oxazol-4-yl] phenothiazines, very clearly showed an increase in anti-inflammatory activity ( %, Table-5) at a dose of 50 mg/kg p.o. The compound which was substituted by 2, 6-

19 121 dichlorophenyl group (4a') was more active (48.56%) than the reference drug phenyl butazone (38.8%) at 50 mg/kg p.o. Considering the potentiality of compound 4a', it was tested at three graded doses, i.e. 25, 50 and 100mg/kg p.o. This compound showed better activity (35.93%, 48.56%, 71.42%) at all the three tested doses (25, 50 and 100 mg/kg p.o. respectively) as compared to reference drug phenyl butazone (15.2%, 38.8%, 65.4%). Fig-4 shows the bar diagram of anti-inflammatory activity of compound 4a, 4a' and reference drug phenyl butazone. 2. Analgesic activity: All these compounds were also screened for their analgesic activity at 50 mg/kg p.o. From the results it is clear that the compound 4a' which exhibited better anti-inflammatory activity and was associated with less analgesic activity (32.67%) than reference drug, while compound 4a found to possess most potent analgesic activity (39.68%) as compared to reference drug phenyl butazone. Fig-5 shows the bar diagram of analgesic activity of compound 4a,4a' and reference drug phenyl butazone. 3. Ulcerogenic activity: Considering the potentiality of compound 4a', it was studied for ulcerogenic liability. Graded dose of compound 4a' and phenyl butazone were injected intraperitoneally in albino rats and incidence of gastric ulceration was determined. The result clearly shows that the ulcerogenic activity of compound 4a' and phenyl butazone was dose dependent. However, the active compound (4a') had much less ulcerogenic liability (UD 50 of compound 4a'=124.6 mg/kg i.p. and UD 50 of phenylbutazone = 66.6mg/kg i.p.). 4. Acute toxicity: All the compounds showed ALD 50 > 800mg/kg. p.o. However the active compound 4a' showed ALD 50 >1000mg/kg. p.o.

20 122 Conclusion: 1. Benzylidene amino oxazoles (3a'-3g') are less active than the corresponding thiazoles (3a-3g). 2. Azetidinones (4a-4g and 4a'-4g') are more active than their parent compounds. 3. Compound which was substituted by 2,6-dichloro phenyl (4a') is found to be most active.

21 123 Table-2: Biological data of-2-chloro-10-[2-(substituted benzylidene)- aminothiazol-4-yl]-phenothiazines (3a-3g). Comp. R Mean increase in paw vol + SE Antiinflammatory activity % Analgesic activity % Control 0.37 ± ALD 50 3a 2,6-Cl 2 C 6 H ± ** > 800 3b 2,6-Br 2 C 6 H ± ** > 800 3c 2,6-I 2 C 6 H ± ** > 800 3d 2-ClC 6 H ± ** > 800 3e 2-BrC 6 H ± ** > 800 3f 2-IC 6 H ± ** > 800 3g 4-N(CH 3 ) 2 C 6 H ± ** >800 ** Tested at dose of 50 mg/kg p.o.

22 124 Table-3: Biological data of-2-chloro-10-[2-(substituted benzylidene)-amino oxazol-4-yl]-phenothiazines (3a'-3g'). Comp. R Mean increase in paw vol + SE Antiinflammatory activity % Analgesic activity % Control ± ALD 50 3a' 2,6-Cl 2 C 6 H ± ** >800 3b' 2,6-Br 2 C 6 H ± ** >800 3c' 2,6-I 2 C 6 H ± ** 7.89 > 800 3d' 2-ClC 6 H ± ** >800 3e' 2-BrC 6 H ± ** >800 3f ' 2-IC 6 H ± ** >800 3g' 4-N(CH 3 ) 2 C 6 H ± ** >800 ** Tested at a dose of 50 mg/kg p.o.

23 125 Table-4: Biological data of-2-chloro-10- [2-{3'-chloro-2'-oxo-4'-(substituted phenyl)-1'-azetidinyl}-thiazol-4-yl]-phenothiazines (4a-4g). Comp. R Mean increase in paw vol + SE Antiinflammatory activity % Analgesic activity % Control ± ALD ± * a 2,6-Cl 2 C 6 H ± ** > ± *** b 2,6-Br 2 C 6 H ± ** > 800 4c 2,6-I 2 C 6 H ± ** > 800 4d 2-ClC 6 H ± ** > 800 4e 2-BrC 6 H ± ** > 800 4f 2-IC 6 H ± ** > 800 4g 4-N(CH 3 ) 2 C 6 H ± ** > 800 * Tested at a dose of 25 mg/kg p.o. ** Tested at a dose of 50 mg/kg p.o. *** Tested at a dose of 100 mg/kg p.o.

24 126 Table-5: Biological data of-2-chloro-10-[2-{3'-chloro-2'-oxo-4'-(substituted phenyl)-1'-azetidinyl}-oxazol-4-yl]-phenothiazines (4a'-4g') Comp. R Mean increase in paw vol + SE Antiinflammatory activity % Ulcerogenic activity (UD 50 ) mg/kg. i.p. Analgesic activity % Control ± ALD ± * a' 2,6-Cl 2 C 6 H ± ** > ± *** b' 2,6-Br 2 C 6 H ± ** > 800 4c' 2,6-I 2 C 6 H ± ** > 800 4d' 2-ClC 6 H ± ** > 800 4e' 2-BrC 6 H ± ** > 800 4f ' 2-IC 6 H ± ** > 800 4g' 4-N(CH 3 ) 2 C 6 H ± ** >800 Phenyl butazone * 38.8** 65.4*** > 800 * Tested at a dose of 25 mg/ kg p.o. ** Tested at a dose of 50 mg/kg p.o. *** Tested at a dose of 100 mg /kg p.o.

25 127 % Anti-Inflammatory Activity Doses (mg/kg p.o.) Compound 4a Compound 4a' Phenylbutazone Fig. - 4 : Bar Diagram of Anti-inflammatory Activity of Compound 4a, 4a' & Phenyl butazone % Anti-Inflammatory Activity Doses (mg/kg p.o.) Compound 4a Compound 4a' Phenylbutazone Fig. - 5 : Bar Diagram of Analgesic Activity of Compound 4a, 4a' & Phenyl butazone

26 128