Indian Journal of Chemistry Vol. 428, July 2003, pp. 1723-1728

Synthesis of some new benzothialoxazepinyl indoles as an antipsychotic agents :!:

Kiran Baja/, V K Srivastava, S Lata, Ramesh Chandra* & Ashok Kumar*

Medicinal Chemistry Division, Department of Pharmacology L.L.R.M. Medical College, Meerut

&

§ Department of Polymer Sciences & Chemical Technology c.C.S. University , Meerut

Received 31 October 2001; accepted (revised) 5 November 2002

Some new 3-(2'-substitutedaryl -2',3'-dihydro-1 ',5'-benzothiaJoxazepin-4'-yl)indoles 3a-h, 3-(2'-substitutedary 1-3'­subst itutedary laminomethy lene-2' ,3'-dihydro- 1 ',5' -benzothiaJoxazepi n-4' -y I)indoles 4a-p and 3-(2' -subst itutedary 1-3'­substitutedarylazo-2 ',3'- dihydro-I ',5'- benzothiaJoxazepin-4'-y l)indoles Sa-p have been sy nthesized and evaluated for antip­sychotic activity. 3-[2'-( 4"-N,N-dimethylphenyl)-3' -arylaminomethylene-2' ,3 '-dihydro-1 ,5-benzothiazepin-4'-y ll indole 4i showes most promising antipsychotic activity. The structures of all the compounds were determined by IR, IH NMR and mass spectrometry .

Indoles possess a wide range of therapeutic activities such as anticonvulsant', antidepressant2

, anti-inflam­mator/, CYS4 and antipsychotic5 activities. Further­more, a wide spectrum of biological activities includ­ing antidepressant6

.7

, sedativeS, tranquilizing9 and psychotropics"o activities have been reported in dif­ferent benzothiaJoxazepine derivatives. With a view to achieve better psychotropic activity, we have pre­pared some new derivatives of benzothiaJoxazepinyl­indoles.

3-Acetylindole 1 on reaction with different aro­matic aldehydes yielded chalcones 2a-d. The struc­tures of all the compounds were derived from elemen­tal analysis and spectral (IR, 'H NMR, Mass) data. The appearance of a signal at 8 9.70 (s, IH,NH of in­dole exchangeable with D20), 8.60(d,J=12.SHz, IH , =CH-Ar) and 6.60 (d,J=12.SHz, 1 H, -COCH=) con­firms the structure.

On the other hand, the reaction of chalcones 2a-d with 2-aminobenzene thiol/phenol in the presence of a few drops of glacial acetic acid in ethanol gave the respective 3-(2'-substitutedaryl-2',3'-dihydro-l " 5'­benzothiaJoxazepin-4'-yl)indoles 3a-h. On the basis of analytical and spectral data, appearance of C-S-C band at 745 cm- ' , C-O-C at 1030 cm- ' and C=N at 1460 cm- ' in the IR spectrum clearly indicated the presence of thiazepine as well as oxazepine ring . On

.'

t Part of Ph. D thesis. t The paper has been presented in 6th National Conference on Slructrure based Drug Design held at Vadodara.

the other hand, the di sappearance of peak at 8 8.60 (d, 1 H, = CH-Ar) and the appearance at 8 6.45 (t, J= 8.30 Hz, Cr H of thiazepine ring) and 8 6.48 (t, J= 8.50 Hz, CrH of oxazepine ring) further confirmed the struc­ture. Compounds 3a-h underwent Mannich reaction with different aromatic anilines in presence of for­maldehyde and yielded 3-(2'-subsitutedaryl-3'-substi­tutedaryl-aminomethylene-2' ,3'-dihydro-l ',S'- benzo­thia/oxazepine-4'-yl )indoles 4a-p. The structure of the compounds 4a-p were confirmed by lR, 'H NMR and mass spectra. Compounds 3a-h reacted with dia­zonium salts of different aromatic anilines and yielded the corresponding arylazo compounds Sa-p (Scheme I). The formation of Sa-p were confirmed by the appearance of N=N band at 1420 cm-' in the IR spectrum.

Experimental Section

All the melting points were taken in open capillar­ies and are uncorrected. Purity of the products was routinely checked by TLC using the solvent system benzene-methanol in different proportions on Silica gel G plates. IR spectra were recorded in KBr on a Perkin-Elmer 3100 FfIR spectrophotometer, 'H NMR spectra on Brucker DRX-300 FfNMR and mass spec­tra on Jeol D-300.

3-Substituted benzylidene acetylindoles 2a-d. To an ethanolic solution of 3-acetylindole (0.01 mole) were added different aromatic aldehydes (0.01 mole) and 2% NaOH solution (2mL) and the mixture was refluxed for 10-12 hr. The resultant reaction mixture

1724 INDIAN J. CHEM., SEC B, JUL Y 2003

~~) R" ~::::N ON~N{):)

Q~ R 5a-p

HCHO 4-6 hr

H I

~ ~Nn ~

~ }NHCH~:JO 4a-p Q.

R

R

2a H W

diC~):)

X

2b

2c

2d

3a

3b

3c

3d

3e

4-0 CH3

4-N(CH3)2

3-0CH3,4-0H

H

4-0CH3

4-N(CH3)2

3-0CH3,4-0H

H

s

s

s s

3a·h

exNH

, ~I ~

XH

I~ R

4/Se

1 G""" AoOH

4/Sf

(Few drops) 4/S9

3-4 hr 4/Sh

H

R

4- OCH3

4-0CH3

4-0CH3

4-0CH3

R' I R"

H

2-CI

3-CI

2-0CH3

X

S

S

0

0

3f 4-0CH3

39 4-N(CH3)2

3h 3-0CH3,4-0H

o o

o o ~ ~I

2a-d OCH==CH -0 R

R R' I R" X

H H S 4/Sa

ROCHO r' %N,OH R R'I R" X

10-12 hr 4/Si 4-N(CH3)2 H S

4/Sj 4-N(CH3)2 3,(;1 S

H 0 I 4/Sk 4-N(CH3)2 H

4/Sb H 2-CI S

4/Sc H 3-CI 0

4/Sd 0 ~ 4/51 . 4-N(CH3)2 2-CI 0

~I 4/5m 3-0CH3-4-OH 3-CI S

COCH3 H 2-0CH3 4/So 3-0CH3-4-OH 2-0CH3 S

1 4/50 3-0CH3-4-OH H 0

4/Sp 3-0CH3-4-OH 3-CI 0

Scheme I

was concentrated to half of its volume and poured onto crushed ice. The solution was then mixed with benzene and separated by separating funnel. The ben­zene from the organic layer was di stilled off and the residue thus obtained was washed with water several times and finally recrystallised from appropriate sol­vents. Physical and analytical data of compound 2a-d are given in Table I. Compound 2a: IR (KBr) : 3370

(NH), 1650 (CO), 1620 (C=C) em-I; IH NMR (CDCh): 86.68-7.00 (m, 10H, Ar-H), 9.70 (s, 1H, NH of indole exchangeable with D20), 6.60 (d, J=12.50 Hz, lH ,-COCH=), 8.60 (d, J= 12.50 Hz, lH, = CH-Ar) ; MS: rnIz (%):247(8.4), M+,

3-(2' -substitutedaryl-2',3' -dihydro-l ' ,5' -benzo­thia/oxazepun-4'-yl) indoles 3a-h. To an ethanolic solution of chalcones 2a-d (0.01 mole) were added

/

BAJAJ et at.: SYNTHESIS OF BENZOTHIAJOXAZEPINYL INDOLES

Compd m.p. Yield Recrystal-(0C) (%) Iisation

solvent

2a 195 72 AJG

2b 200 65 BIG

2c 192 68 FiG

2d 214 55 A

3a 201 65 B

3b 210 45 AJG

3c 212 60 FiG

3d 222 42 A

3e 240 68 B

3f 230 50 FiG

3g 224 55 AJG

3h 228 45 BIG

4a 218 60 AJG

4b 216 55 CIH

4c 238 62 A

4d 234 65 E/G

4e 226 68 C

4f 221 58 BIG

4g 232 58 C

4h 239 50 F

4i 236 65 BIG

4j 214 60 B

4k 223 45 D

41 225 40 D

Table I - Physical , analytical and biological data of compounds 2-5

Mol. Found % Gross CNS Catalepsl Formula (Calcd) behaviourd scored (M.wt)

C17H I3NO (247)

C18H1SN02 (277)

C1.)f18N20 (290)

C H N

82.62 5.3 I 5.70 (82.59 5.26 5.67)

77.94 5.44 5.01 (77.98 5.42 5.05)

78.66 6.25 9.68 (78.62 6.21 9.66)

No effect

do

do

C18H1SN03 (293)

73.76 5.08 4.74 do (73.72 5.12 4.78)

C23H 18"'2S (354)

77.93 5.11 7.95 Depressant (77.97 5.08 7.91)

C24H:roN2S0 75.04 5.17 7.25 do (384) (75.00 5.21 7.29)

C2sH23N3S 75.53 5.82 10.6 I do (397) (75 .57 5.79 10.58)

C24H:roN2S02 72.04 4.98 6.96 Depressant (400) (72.00 5.00 7.00)

C23H I8N20 81.62 5.35 8.24 do (338) (81.66 5.33 8.28)

C24H:roN20 2 (368)

C25H23N30 (381)

C24H:roN20 3 (384)

C~25N3S (459)

C~2~3SCI (493.5)

C~2~3OCI (477.5)

78.30 5.47 7.57 (78.2t; 5.43 7.6 I)

78.78 6.06 11 .06 (78.74 6.04 11.02)

75.04 5.25 7.25 (75 .00 5.21 7.29)

78.47 5.48 9.19 (78.43 5.45 9.15)

72.91 4.70 8.47 (72.95 4.86 8.51)

75.43 5.06 8.75 (75.39 5.03 8.80)

C31H27N302 78.69 5.75 8.92 (473) (78.65 5.71 8.88)

C31 H27N3SO 76.1 1 5.56 8.55 (489) (76.07 5.52 8.59)

C31Hu,N3SOCI 71 .02 4.95 8.06 (523.5) (71 .06 4.97 8.02)

. C31Hu,N302CI 73.34 5.16 8.32 (507.5) (73.30 5.12 8.28)

do

do

do

Depressant

do

do

do

do

do

do

C32H~303 76.37 5.80 8.38 Depressant (503) (76.34 5.77 8.35)

C32H~4S 76.45 5.94 11.20 do (502) (76.49 5.98 l1.I6)

C32H~4SCI 71.6 I 5.43 10.48 do (536.5) (71.58 5.41 10.44)

C32H~40 79.05 6.20 11 .55 do (486) (79.0 I 6. 17 11.52)

73.74 5.62 10.80 (73.78 5.57 10.76)

Depressant

1.4

1.8

1.8

1.8

1.2

1.6

1.6

1.8

1.6

1.4

1.2

1.8

1.6

1.2

1.6

1.6

1.4

1.4

Pento­barbitone f

induced sleeping time

in minutes

22

22

39

33

37

20

39

31

64

61

63

61

57

60

59

56

82

65

64

62

1725

Amphetamineg

induced SB (Mean score)

2.6

2.7

2.2

2.8

3.8

3.4

2.6

3.6

1.4

1.6

2.0

2.4

2.0

2.0

2.8

2.6

0.0

0.0

1.2

1.4

-Contd

1726 INDIAN J. CHEM., SEC B, JULY 2003

Table I - Physical, analytical and biological data of compounds 2-5- Contd

Compd m.p. Yield Recrys- Mol. Found % Gross CNS Catalepsy" Pento- Amphetamine£ (DC) (%) tallisation Formula (Calcd) behaviourd scored barbitone f induced SB

solvent (M.wt) induced (Mean score) sleeping time

C H N in minutes

41 225 40 D C32H29N40CI 73 .74 5.62 10.80 Depressant 1.4 62 1.4 (520.5) (73.78 5.57 10.76)

4m 230 50 BIG C)I H26N3S02C1 68.99 4.85 7.80 do 1.4 62 1.4 (539.5) (68.95 4.82 7.78)

4n 235 62 D C.12H29N3SO) 71.82 5.46 7.81 do 1.6 59 .8 (535) (71.78 5.42 7.85)

40 254 58 AlG C3IH27 N)0 3 76.10 5.48 8.63 do 1.2 66 2.0 (489) (76.07 5.52 8.59)

4p 249 60 B C) I H26N30 )C1 71.02 4.93 8.06 do 69 1.6 (523.5) (71.06 4.97 8.02)

5a 260 50 D C29H22N4S 75.94 4.76 12.25 do 1.6 42 1.8 (458) (75.98 4.80 12.23)

5b 252 45 BIG C29H21N4SCI 70.70 4.30 11.34 do 1.4 37 1.6 (492.5) (70.66 4.26 11.37)

5c 255 52 E C29H21N40Cl 73.07 4.44 11.79 do 35 2.8 (476.5) (73.03 4.41 11.75)

5d 265 50 D C30H24 N40 2 76.30 5.12 11.82 do 1.2 37 2.9 (472) (76.27 5.08 11 .86)

5e 270 45 BIG C30H24N4S0 73 .80 4.88 11.44 do 1.8 47 2.6 (488) (73.77 4.92 11.48)

Sf 268 42 DIG C30H23 N4S0CI 68.86 4.44 10.68 do 1.6 41 2.6 (522.5) (68.90 4.40 10.72)

5g 259 48 A/G C30H23N402CI 71.12 4.58 11.10 do 1.2 34 2.8 (506.5) (7 1.08 4.54 11.06)

5h 278 40 C C31H26N40 3 74.14 5.22 11.20 do 1.4 38 3.0 (502) (74.10 5.18 11.16)

5i 272 40 E/G C3I H27NsS 74.29 5.43 13.93 Depressant 1.6 51 1.8 (50 1 ) (74.25 5.39 13.97)

5j 264 45 B C31H26NsSCI 69.43 4.82 13.03 do 1.8 50 2.0 (535.5) (69.47 4.86 13.07)

5k 275 50 D C) IHn NsO 76.74 5.61 14.47 do 1.6 48 2.2 (485) (76.70 5.57 14.43)

51 277 52 D C31 H26NsOCI 71.58 5.04 13.44 do 1.4 44 2.6 (5 19.5) (71.61 5.00 13.47)

5m 254 52 B C)oH2)N4S02C1 66.81 4.23 10.36 do 1.4 49 2.4 (538.5) (66.85 4.27 10.40)

5n 258 55 C C) IH26N4S03 69.58 4.87 10.77 do 1.2 50 2.0 (520) (69.66 4.92 10.49)

50 263 48 DIG C30H24N403 73 .73 4.52 11 .54 do 39 2.2 (488) (73.77 4.92 11.48)

5p 267 40 E/G C30H23 N40)CI 68.95 4.44 10.68 do 1.2 40 2.0 (522.5) (68.90 4.40 10.72)

a Recrystallisation solvents; A=CH)OH , B=C2HsOH, C=C6H6, D=AcOH, E=DM~, F=CHCI3, G=H20 and H= Pet. ether. b Biological ac tiv ity of all the compounds were tested at a dose of 40 mg/kg i.p. c AL Dso of all the newly sy nthesized compounds are >1000 mg/kg whereas compound 4 i has ALD50 > 1600 mg/kg in mice. d Term depressant implies (a) inhibition in locomotor activity (b) inhibition in exploratory movements, (c) increase in immobility time (d) loss of righting reflex. e Score of cataleptic behavi our at 60 with reference to propylene glycol treated group of rats; Haloperidal (0.5 ml, i.p.) induced group scored 2.2 with reference to control group. f Increase in pentobarbitone induced sleeping time in minutes after the test drug treatment; Clorpromazine (standard drug, 4mgikg; i.m.) showed 57 minutes increase in sleeping time. g Protection against Amphetamine (4mg/kg, i.p.) induced stereotyped behaviour (SB) h All the compounds showed stati stically significant biological results .

BAJAJ et aL.: SYNTHESIS OF BENZOTHINOXAZEPINYL INDOLES 1727

2-amino benzenethioUphenol (0.01 mole) with a few drops of glacial acetic acid and refluxed for 3-4 hr. The solvent was distilled under reduced pressure and the residual solid thus obtained was recrystallised with appropriate solvents. The physical and analytical data of compounds 3a-h are given in Table I. Com­pound 3a: IR (KBr): 3370 (NH), 1460 (C=N), 745 (C­S-C) cm· l

; IH NMR (CDCh): 8 6.70-7.20 (m, 14H, Ar-H), 6.45 (t, J=8.30 Hz, I H, CrH of thiazepin ring), 7.70 (d, J=8.54Hz, 2H, Cr H2 of thiazepine ring), 9.70 (s, IH, NH of indole exchangeable with 0 20 ); MS:

mJz (%):354(4.5), M+ and other important ions are given in Scheme II . Compound 3e: iR (KBr) 3372 (NH), 1460 (C=N), 1030 (C-O-C) cm-I; IH NMR (CDCh): 86.70-7.21 (m, 14H, Ar-H), 6.48 (t, J=8.30 Hz, IH, C2-H of oxazepine ring) , 7.70 (d, J=8.54 Hz, 2H, Cr H2 of oxazepine ring) , 9.70 (s, 1 H, NH of in­dole exchangeable with 0 20); MS: mJz (%):338(5 .2), M+.

(m/z 354, r.i.4 .5%)

A

~

3-(2' -substituted aryl-3' -substituted arylamino­methylene-2',3' -dihydro-l' ,5' -benwthia/oxazepin-4'­yl)indoles 4a-p. Different aromatic ani lines

~I +~fj(~ vN~lt

~ ,...N 9" l· ~s~ )8 (m/z 249, r.i. 12%)

S (m'=m/z 223.83) (m/z 277, r.j. 8%)

B 1----~:o l '

-N

(m/z 249, r.j. 12%)

H I

(m'=m/z 153.35)

(m/z 233, r.j. 5%)

I-H

-C:Hs

(m/z 154, r.i. 100%)

(m/z 105, r.i. 10%)

(m/z 107, r.i. 25%)

(m/z 128, r.j. 10%) (m/z 115, r.i. 10%)

H

DL..-_-CD-CH~H~' + o<~:(f (m/z 142, r.j . 2%)

lCH:CH

-H

I t

~ (m/z 115, r.i. 10%)

(m/z 107, r.i. 25%)

Scheme II

(m/z 212, r.j. 15%)

H !-C.H. I It

<:0 (m/z 136, r.j. 75%)

! - CH

~H~ s~

(m/z 123, r.j. 5%)

1728 INDIAN 1. CHEM., SEC B,1UL Y 2003

(0.001 mole) and formaldehyde (0.001 mole) were added to the methanolic solution of compound 3a-h (0.001 mole) and refluxed for 4-6 hr. The resultant mixture was concentrated, cooled and poured onto ice. The separated solid was filtered and recrystallised from appropriate solvents. Physical and analytical data of compounds 4a-p are given in Table I. Com­pound 4i: IR (KEr); 3373, 3050 (NH), 1462 (C=N), 748 (C-S-C) cm-'; 'H NMR (COCl) : 8 6.72 - 7.25 (m, 18H, Ar-H), 9.73 (s, IH, NH of indole exchange­able with 0 20), 6.48 (d,J =8.34 Hz, 1 H, C2-H of thi­azepine ring), 7.71 (m, IH, Cr H of thiazepine ring), 1.65 (hump, 2H, NHCH2 CH), 3.08 (hump, 1 H, CH2NH) ,1.35(ss, 6H,N(CH)h); MS: mlz (%):502(4.3), M+ . Compound 4k: IR (KEr): 3372, 3060, (NH), 1611 (C=N), 103 I (C-O-C) cm-' ; 'H NMR (COCl) : 8 6.72 - 7.25 (m, I8H, Ar- H ), 9.73 (s, IH, NH of in­dole exchangeable with 0 20), 6.48 (d,J=8.3 Hz, IH, Cz-H of oxazepine ring), 7.71 (m, IH, C) -H of oxazepine ring), 1.63 (hump, 2H, NHCH2CH), 3.08 (hump, IH, CH2NH), 1.35 (ss, 6H, N(CH)2); MS: mlz (%):486(5.4), M+.

3-(2' -substituted aryl-3' -substituted arylazo-2' ,3' -dihydro-l' ,5 ' -benzothia /oxazepin-4' -yl)indo­les 5a-p. The aryldiazonium salt solution of different ani lines (0.002 mole) was added dropwise with stir­ring to the ethanolic sol ution of compound 3a-h (0.002 mole) containing sodium acetate at 0-5°C. The reaction mixture was kept at room temperature for 2 hr and then poured onto ice-cold water. The solid thus obtained was washed with water, filtered and recrys­tallised with appropriate solvent. The characterstic physical and analytical data of compounds 5a-p are given in Table I. Compound Sa: IR (KBr): 3370 (NH), 1599 (C=N), 1420 (N=N), 1507 (CN), 748 (C­SoC) cm-'; 'H NMR (CDCI) : 8 6.70-7.20 (m, 19H, Ar-H), 9.72 (s, I H, NH of indole exchangeable with 0 20), 6.50 (d,J=8.30 Hz, IH, Cz-H of thiazepine ring) , 7.72 (d, 1=8.50 Hz, IH, Cr H of thiazepine ring); MS: mlz (%):458(3.9), M+. Compound 5c: IR(KEr): 3372 (NH), 1595 (C=N), 1420 (N=N), 1510 (CN), 1031 (C-O-C) cm-'; 'H NMR (COCh): 86.70-7.25 (m, 18 H, Ar-H), 9.73 (s, IH, NH of indole ex­changeable with 0 20), 6.52 (d,J=8.30, C2 -H of oxazepine ring), 7.71 (d,J=8 .50 Hz, IH, C)-H of oxazepine ring); MS: mlz (%):476(3.2), M+.

Biological evaluation All the newly synthesized compounds were

screened for their antipsychotic activities VIZ.

induction of catalepsy", hypnotic activity'2, am­phetamine antagonism I I and antidepressant I3

·'4.15 ac­tivity. Compounds were administered intraperitonealy (i.p.) to albli no rats (n = 5/compound) and tested at a dose of 40 mg /kg. Acute toxicity studies of all newly synthesized compounds have been done by the method of Smith l6

. The results are shown in the Table I.

In the drug interaction studies, chalcones 2a-d did not show any biological activity, whereas all other compounds showed statistically significant antipsy­chotic activities. Compound 4i (40 mg/kg, i.p.) was found to be more potent. It antagonized the sterotyped behaviour induced by arnphetanirnne (4 mg/kg, i.p.) and increased the length of s.\eeping time (82 minutes) in comparison with reference drug chlorpromazine (4 mg/kg, i.m.) which increased the sleeping length to 56 minutes. This compound showed promising scoring of catalepsy and also gave very promising responses to­wards antidepressant activities viz. locomotor activity, exploratory behaviour and despair behaviour with ref­erence to the propylene glycol treated control group.

Acknowledgement The authors are thankful to CDR!, Lucknow for

providing the spectral data of the compounds.

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