228 Lakhan and Singh Arch. Pharm.

17 E. J. Corey and B. W. Erickson, J. Org. Chem. 36, 3553 (1971). 18 R. Zamboni and J. Rokach, Tetrahedron Lett. 1983, 999. 19 Proton and carbon magnetic resonance, infrared and mass spectral data were obtained for each

20 We would like to thank Dr. P. Borgear for kindly providing us with a sample of native LTB, (to

[Ph 8791

stable synthetic intermediate and were in full accord with the assigned structures.

Prof. W. Konig for comparisons).

Arch. Pharm. (Weinheim) 318, 228-238 (1985)

Syntheses of Some New 4(3H)-Quinazolinones as Potential CNS Active Agents

Ram Lakhan* and Om Prakash Singh

Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India Eingegangen am 15. November 1983

More than fifty 2-(N-substituted aminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones 2 4 have been prepared. Some of them were tested for CNS activities on mice and found to be either depressants or stimulants.

Syothese einiger neuec 4(3H)-Cbinezolinone d s poteatielle ZNS-aktive Substanzen

Mehr als funfzig 2-(N-substituierte Aminoethylthio)-3-aryl-6-iod-4(3H)-chinazolinone 26 wurden synthetisiert. Einige von ihnen wurden an Mausen gepriift auf ihre das ZNS stimulierende oder dampfende Wirkung.

4(3H)-Quinazolinones with wide spectrum of biological activities are known. Several of its derivatives are potent antihypertensive’), antifibrillatory, choleretic, antiphlogistic’), amoebicidal’), antifunga14) and bactericidal’) agents. They have also been successfully tested as CNS depressants6), muscle relaxants’) and antiinflammatory agents’). Methaqualone, 2-methyl-3-o-tolyl-4(3H)-quinazo- linone, is used clinically as an anti~onvulsant~) with considerable success. 6-Bromo-3-phenyl-2-(~,N-diethylcarbamoylmethylthio)-4(3H)-quinazolinone and 6-bromo-3-m-

chlorophenyl-2-(N,N-ethylphenylcarbamoylmethylthio)-4(3H)-quin~o~none are found to be active against P. gallinaceurn in chicks at 4 quinine equivalent dosage”). Herbicidal and plant growth regulating”), antifertility’*), pe~ticidal’~), antit~bercular’~) and antileukemic activities”) are also reported with this ring system.

Several 2-(N,N-disubstituted aminoethylthio)-3-aryl-4(3H)-quinazolinones and thiones were prepared by Tregubenko et al.’@ and evaluated as radioprotective agents. 2-Fluoromethyl- 3-aryl-4(3H)-quinazolinones are reported to be more potent CNS depressant and less toxic than methaqualone”).

03656233/851030?-0228 S 02.5010

8 VCH Verlagrge$&chaft mbH, Weinhcim 1985

318185 Quinazolinones as Potential CNS Active Agenu 229

Keeping in view the various activities of 4-(3H)-quinazolinones, it was considered of interest to synthesize some 4(3H)-quinazolinones incorporating substituted aminoethyl moiety. This report describes experiments directed towards the synthesis of 2- (~-aminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones 2, 2-(B-diethylaminoethylthio)- 3-aryl-6-iodo-4(3H)-quinazolinones 3, 2-(~-N-isopropylaminoethylthio)-3-aryl-6-iodo- 4(3H)-quinazolinones 4, 2-(~-piperidinoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones 5 and 2-(~-N-phenyl-N-methylaminoethylthio)-3-aryl-6-iodo-4(3H)-quin~olinones 6.

.- 4 0 0 ri

.- 4 0 0 E:

4 .- d \o d

4 .- 0 0 h(

.- 4 0 0 E:

4 .- d \o d

+ -+

+ t

.- a v) \o

a ;;r r-l M r-l a ri

230 Lakhan and Singh Arch. Pharm.

The various compounds were prepared according to scheme 1. Substituted arylisothio- cyanates were refluxed with 5-iodoanthranilic acid in absol. ethanol for 6 h. Excess ethanol was removed. The solid obtained was washed with 5 % sodium hydrogen carbonate solution followed by aqueous ethanol. It was dissolved in sodium hydroxide solution and reprecipitated by the addition of dil. hydrochloric acid. Recrystallisation from chloroben- zene/ethanol (2: 1) gave 1. 2-(N-Substituted or N,N-disubstituted aminoethy1thio)- 3-aryl-6-iodo-4-(3H)-quinazolinones 2-6 were prepared by stirring 10 % alcoholic alkaline solution of 1 with p-N-substituted or p-N,N-disubstituted aminoethyl bromide hydrobro- mides. The product was washed with water, a little ethanol and recrystallised from a suitable solvent to obtain 2-6. The structures of 1 to 6 were confirmed by elementary analyses, IR and NMR spectra.

R' = R2 = €1; 3 R' = R2 = Et; 4 R' = H, RZ = CIl(CI13)2: 5 R'R' = (CH,),; 6 R' = C,H,, R2 = CH3

The compounds 2k, 3g, 3i, 3k, 4b, 4i, Sk, and 6i were tested for CNS activity on mice. The compounds were administered intraperitoneally to a group of mice in three different dosages. The results are recorded in table 1. None of the tested compounds exhibited analgesic and max. electro-seizure properties at 200 mg/kg i.p. dosage. From the results it is evident that the compounds 4b, 4i and 4k are CNS stimulants while 2k, 3g, 3i, 3k and 6i are CNS depressants. All of them are well tolerated up to loo0 mg/kg i.p. dose level.

The authors wish to thank the Director, CDRI, Lucknow, for pharmacological screening, Professor R. C. Aggarwal, Head of the department of Chemistry for providing necessary facilities and the CSIk, New Delhi for awarding a Junior Research Fellowship to one of them (OPS).

Experimental Psrt M.P.: in open capillary on Gallenkamp apparatus, uncorr. IR specrra: Perkin-Elmer 257 and 720 spectrophotometers. NMR spectra: Varian AdOD spectrometer at 60 MHZ at US0, TMS as int.

31818s Quinarolinones as Potential CNS Active Aeents 23 1

E , g s 0

42 3-u; 0 0 o w N W m 3

v! P-

v! P-

v! W

'? W

v)

0, z d

% 5 V

W W N

0 W

F

f

m

rs

-

stand. Elementary analyses: Coleman Analyser. Purity of compounds checked by TLC using silica gel G (E. Merck).

5-Iodoanthranilic acid was prepared by known method'". N-Substituted and N, N-disubstituted fl-aminoethyl bromide hydrobromides were obtained from the corresponding @-amin~ethanols'~) by reaction with 48 % hydrobromic acid by literature method"."). The following intermediates were prepared:

@-Brornoethylamine hydrobromide, m.p. 17G172" @-Diethylaminoethyl bromide hydrobromide, m.p. 21S212" (lit.") m.p. 208"). @-Isopropylaminoethy1 bromide hydrobromide, m.p. 12S131". @-Piperidinoethyl bromide hydrobromide, m.p. 238". @-N-Phenyl-N-methylaminoethyl bromide hydrobromide, m.p. 259".

m.p. 174O).

272 Lakhan and Sinnh Arch. Pharm.

6-lodo-2-thio-3-(4'-methyl-3'-chlorophenyl)-4(3H)-quinazotinone (lk) Equimolar quantities of 5-iodoanthranilic acid (6.6 g) and 4-methyl-3-chlorophenylisothiocyanate (4.55 g) were refluxed in 25 ml absol. ethanol on a water bath for 6 h. On cooling, the solid product was washed with 5 % sodium hydrogen carbonate solution followed by a little aqueous ethanol, dissolved in sodium hydroxide solution and reprecipitated by the addition of dil. hydrochloric acid. It was crystallised from chlorobenzene/ethanol (2 : 1).

Following the above procedure 6-iodo-2-thio-3-(2'-methyl-3'-chloro)phenyl-, 3-(2'-methyl-5'- ch1oro)phenyl- and 3-(4'-methoxy-3'-chloro)phenyl-4(3H)-quinazolinones were prepared. Their yields, m.p., analytical data and characteristic IR peaks are recorded in table 2. 6-Iodo- 2-thio-3-phenyl-, m-tolyl-, p-tolyl-, m-chlorophenyl-, p-chlorophenyl-, p-bromophenyl-, p-meth- oxyphenyl- and p-ethoxyphenyl-4(3H)-quinazolinones ( la to lh) were prepared according to Bhargava et aLZ'.

2-@ Diethylaminoethylthio)-3-(4'-chlorophenyl)-6-iodo-4(3H)-quinazolinone (3e)

4.0 g 6-Iodo-2-thio-3-(4'-chlorophenyl)-4(3H)-quinazolinone was dissolved in just sufficient 10 % ethanol. sodium hydroxide solution and treated with 2.76 g p-diethylaminoethyl bromide hydrobromide in 10 ml absol. ethanol. The mixture was stirred and allowed to stand for 40 min. The product was washed several times with water followed by a little ethanol. It was crystallised from ethanol to form white fibrous crystals. NMR (TFA): S (ppm) = 1.41 (1, J = 7 Hz, 6H, N(CH2C&)2),

3.16-3.96(m,8H,-C&-C&N<CH2 ),7.&7.9for aromaticprotons (m,6H),8.33(d, J = 2Hz, cE2

1H) for C-5 aromatic proton of the quinazolinone ring.

Following this procedure other 2-(~-diethylaminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones, 2-(~-piperidinoethylthio)-3-aryl-6-iodo-4(3H)-quin~otinones, 2-(~-aminoethylthio)-3-aryl-6-iodo- 4(3H)-quinazolinones, 2-(~-N-isopropylaminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones and 2- (~-N-phenyl-N-methylaminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones were prepared. Their yields, m.p., analytical data and characteristic IR peaks are reported in tables 3 to 7.

Table 3: 2-(~-Aminoerhylrhio)-3-aryI-6-iodo-4(3H)-quinazolinones * 2

No. Substituents Yield M.P. Molecular Formula** Calc. Found Characteristic IR peaks 2 x Y % OC N (cm-1)

H H 65 298 C16H141N30S 9.9 10.0 3260m, 3200w, 1730s, 1650s, 1500m, 750s.

3-CH3 H 60 287 C17H161N30S 9.6 9.7 3160w, 3080w, 1710s, 1660m, 1620m, 1530s.

4-CH3 H 70 296 C ~ ~ H ~ ~ ~ N J O S 9.6 9.5 3250w, 3200w, 1660s, 1515s.

3-CI H 70 280 Cl6H13C11N30S 9.2 9.3 3250m, 3220m, 1720m, 1665s, 1610m, 1520s.

4-CI H 75 290 C16H13ClIN30S 9.2 9.5 3 2 4 0 ~ , 3 1 9 5 ~ , 1 7 2 0 ~ , 1670s, 1610w, 1530w.

31818s Quinazolinones as Potential CNS Active Agents 233

Forts. Table 3 ~ -~

No. Substituents Yield M.P. Molecular Formula** Calc. Found Characteristic IR peaks 2 x Y % OC N (cm-1)

f 4-Br €I 80 291 C ~ ~ H ~ ~ B T I N ~ O S

g 4-Me0 H 75 287 C17H161N302S

h 4-Et0 H 70 270 ClsHleIN302S

i 2-Me 3-C1 75 292 C17H15ClIN30S

j 2-Me 5x1 70 306 C17H15ClIN30S

k 4-Me 3-CI 80 305 C ~ ~ H ~ S C I I N ~ O S

I 4-Me0 3-C1 85 274 C17H15CUN302S

8.4 8.1 3250w, 3200w, 1720s, 1665s, 1610m, 1520m.

9.2 9.3 3280m, 3200w, 1715w, 1685s, 1610s, 1510s.

9,O 8.8 3260w, 3200w, 1720s, 1670s, 1610w, 1520s.

8.9 8.9 3260m, 3220m, 1740s, 1660s, 1620m, 1 5 0 5 ~ .

8.9 8.9 3300w, 322Ow, 1700s, 1675s, 1620s, 1520s.

8.9 9.0 3260m, 3220w, 1670s, 1620m, 1525s.

8.6 8.6 3260w, 3220w, 1725m, 1665s, 1615m, 1510m.

* Compounds Za, 2d and Zh crystallised from ethanol, 2e from chlorobenzene/ethanol (1 : l ) , 2f from benzene/ethanol (1 : l), Zg from benzenelethanol (2 : 1) while the remaining were crystallised from benzenelethanol (3 : 1).

* * Analyses for C, H and S were found within 2 0.4 % of the calculated values.

Tabl

e 4

2-(~

-Die

ihyl

amin

oe~h

yl~h

io)-

3-ar

y16-

iodo

-4(3

H)-

qu~a

zoli

non~

' 3

No.

Subs

titue

nts

Yie

ld

M.P

. M

olec

ular

C

alc.

Fo

und

Cal

c.

Foun

d C

hara

cter

istic

IR p

eaks

3

x

Y

%

OC

Form

ula*

* C

H

(cm

-1)

a b

C d e f g h i j k I

H H

3CH

3 H

KH

3

H

3-CI

H

4-C1

H

4-Br

H

4-M

e0

H

4-E

t0

H

2-M

e 3C

1

2-M

e 5-

CI

4-M

e 3-

CI

4-M

e0

3x1

75

310

60

298

65

295

75

262

70

137

70

292

70

305

70

275

60

25 9

75

298

80

299

60

176

50.1

50

.2

4.6

51.1

50

.9

4.9

51.1

51

.3

4.9

46.7

46

.7

4.1

46.7

47

.1

4.1

43.0

43

.3

3.8

49.5

49

.5

4.7

50.5

50

.5

5.0

47.8

48

.0

4.4

47.8

47

.6

4.4

41.8

47

.8

4.4

46.4

46

.5

4.2

4.6

5.1

4.8

4.3

4.5

3.6

4.8

4.9

4.2

4.5

4.3

4.3

1720

s. 1

640s

, 160

0w.

1725

s,16

65s,

162

0s,

1525

m.

1725

s, 1

670s

, 162

0w,

1525

m.

1725

m, 1

680s

, 162

Om

, 16

0Om

, 157

0m, 1

530m

.

1730

m, 1

700s

, 168

0s,

162O

w, 1

500s

. 17

25m

, 167

0s, 1

6151

~1,

15 20

s. 17

25m

, 167

5s, 1

620s

, 15

20s.

1725

s, 1

680s

. 161

5w,

1600

w, 1

520s

. 17

35s,

166

0s, 1

625w

, 15

00m

. 17

10s,

160

Ow

, 157

5m,

1500

s.

173O

s, 16

80s,

162

0w,

1500

m.

1720

m, 1

685s

,161

0w,

1545

s, 1

505s

. -

* ** S

atis

fact

ory

anal

yses

for N

and

S w

ere

also

foun

d.

Com

poun

dsh,

3e a

nd 3b

crys

talli

sed f

rom

etha

nol, 3d a

nd %

from

ben

zene

/eth

anol

(1 :

l), 3g

and 31

from

ben

zene

/eth

anol

(2

: 1)

w

hile

oth

ers

wer

e cr

ysta

llise

d fr

om b

enze

ne/e

than

ol (

3 :

1).

318/8S Ouinazolinones as Potential CNS Active Anents 235

Tables: 2-($-N-lsopropylaminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones* 4

No. Substituents Yield M.P. Molecular Formula** Calc. Foundcharacteristic IR peaks 4 x Y % OC N (cm-1)

a

b

C

d

e

f

g

h

i

j

k

I

H H

3-CH3 H

4-CH3 H

3-CI H

4C1 H

4-Br H

4MeO H

4-EtO H

2-Me 3-CI

2-Me 5-C1

4-Me 3-C1

4-Me0 3-CI

65

65

60

60

70

60

75

60

60

60

65

60

321

317

3 14

287

307

307

290

309

303

291

299

27 3

9.0 9.3

8.8 8.7

8.8 8.9

8.4 8.4

8.4 8.3

7.7 7.6

8.5 8.5

8.3 8.4

8.2 8.2

8.2 8.3

8.2 8.4

7.9 8.2

3260m,1725s, 1650s, 1615m, 1515111.

3265s, 1730s, 1665s, 1605m,1510m.

3275m, 1720s, 1660s, 1600w, 1 5 1 0 ~ .

3260m, 1725m,1655s, 1605m,1590w, 1510m.

3200w, 1705s, 1660111, 1610s, 1590w, 1520s.

3250m,1725m, 1650s, 1590s, 1540s.

3300m,1730w, 1690s, 1610s, 1515s.

3250w, 1725111, 1665s, 1605m,1505m.

3260m, 1720111, 1680s, 1610m, 1510m.

3275m,1725m,1670s, 1605m,15lOm.

3265m, 1725m,1680s, 1620m, 1520m.

3300m, 1735m,1670s, 1620s, 1510s.

* Compound 40 crystallised from chlorobenzene/ethanol ( 2 : l ) , 4e and 4b from ethanol, 4d and 4f from bemene/ethanol (1 : l) , 4g from benzene/ethanol (2 : 1) while the remaining were crystallised from benzene/ethanol (3 : 1).

* * Satisfactory analyses for C, H and S were also obtained.

236 Lakhan and Singh Arch. Pharm. ~~

Table 6: 2 4 - Piperidinoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones’ 5 ~

No. Substituents Yield M.P. Molecular Calc. FoundCalc. Foundcharacteristic 5 x Y 7% OC Formula** C H IR peaks (cm-1)

a H H

b 3-CH3 H

c 4-CH3 H

d 3-CI H

e 4-CI H

f 4-Br H

g 4-Me0 H

h 4-Et0 H

i 2-CH3 3-C1

j 2-CH3 5-CI

k 4-CH3 3-CI

I 4-Me0 3-CI

60

70

60

75

65

60

70

60

60

65

75

60

289

125

320

265

174

293

285

275

296

302

179

276

51.3 51.8 4.5 4.4

52.1 52.4 4.8 4.6

52.1 52.2 4.8 4.9

48.0 48.2 4.0 3.8

48.0 47.7 4.0 4.2

45.0 44.7 3.8 3.9

50.7 51.1 4.6 4.3

51.6 51.9 4.9 4.7

48.9 49.4 4.3 4.1

48.9 48.8 4.3 4.4

48.9 48.9 4.3 4.3

47.5 47.9 4.1 4.2

1720s, 1645 , 151ow.

1725m, 1655s, 1610w, 1530m.

1720s, 1670s, 1600w, 1510m.

1730m, 1690m, 1660s, 1610w. 1510s.

1735m,1675s, 1620w, 1570m, 1540s.

1720m, 1670s, 1610w, 1560w, 151ow.

1720s, 1660s, 1605s, 1505s.

1730s, 1655s, 1620m, 1515s.

1690s, 1600w, 1570m, 1540m.

1725m, 1690s, 1600s, 1505s.

1730w, 1660s, 1615m, 1570w, 1515m.

1725w, 1660s, 1605s, 1515m.

* Compound SP crystallised from chlorobenzene/ethano1(2 : l), 5e and 5b from ethanol, Sd and Sf from benzeneiethanol(1 : l), Sg and 51 from benzeneiethanol ( 2 : 1) while the rest were crystallised from benzeneiethanol (3 : 1).

* * Satisfactory analyses for N and S were also found.

* * * NMR(CDC1,): G(ppm) = 1.55 (m,6H)for3’,4‘and5’methyleneprotonsofthepiperidincring, 2.3S2.83 (m, 6H) for 2’ and 6’ methylene protons of the piperidine ring and methylene group adjacent to the piperidine nitrogen, 3.16-3.43 (m, 2H) for methylene group attached to the sulphur, 7.08-8.10 for aromatic protons (m, 6H), 8.48 (d, J = 7 Hz, 1H) for C-5 aromatic proton of the quinazolinone ring.

318/85 Quinazolinones as Potential CNS Active Agents 237

Table 7: 2-(P-N-Phenyl- N-methy1aminoethy1thio)-3-aryl-6-iodo-4(3H)-quinazo1inones8 6

No. Substituents 6 x y

a H H

b 3-CH3 H

c 4-CH3 H

d 3-Cl H

e 4-Cl H

f 4-Br H

g 4-Me0 H

h 4-Et0 H

i 2CH3 3-c1

j 2-CH3 5-Cl

k 4-CH3 3CI

I 4-Me0 3CI

Yield M.P. Molecular Calc. FoundCalc. FoundCharacteristic % OC Formula** C H IR peaks (cm-1)

70 313 C23H201N30S 53.8 53.4 3.9 3.5 1720m, 165Ss, 1 6 1 5 ~ . 1515m.

70 295 C24HzzIN30S 54.7 55.0 4.2 4.0 1730m, 1710s, 1670s, 1615m, 1535s.

60 301 C24H22IN30S 54.7 54.2 4.2 4.4 1715~, 1665~, 1610m, 1520s.

75 284 CZ3Hl9CIIN30S 50.4 50.0 3.5 3.9 1730m, 1670s, 1615m, 1595w, 1520s.

65 300 CZ3Hl9CIIN30S 50.4 50.8 3.5 3.5 1715s, 1670m, 1620m, 1600w, 1540s, 1500m.

65 239 Cz3H19BrIN30S 46.6 47.0 3.2 3.0 1730s, 1675s. 1620w, 1605m, 1500s.

60 303 C ~ ~ H Z Z I N ~ O ~ S 53.0 52.9 4.1 4.3 1 7 2 0 ~ , 1685~, 1610s, 1515s.

60 283 CZ5Hz4IN3O2S 53.9 54.0 4.3 4.3 1730m, 1665s, 1630m, 1620m, 15 20s.

65 220 C24H21ClIN30S 51.3 50.9 3.7 4.0 1720~, 1670~, 1615m, 1520s.

70 309 C24H21CUN30S 51.3 51.3 3.7 3.8 1 7 2 0 ~ , 1690~, 1670s, 1610s, 1520s.

75 303 C24H21CIIN30S 51.3 51.5 3.7 3.6 1 7 3 0 ~ , 1665~, 1615m, 1520s.

60 278 C24H21CllN302S 49.9 50.1 3.6 3.7 1720m, 1665s, 1615m, 152Om, 1505s.

* Compounds 6a, 6e and 6b crystallised from ethanol, 6d and Ufrom benzene/ethanol (1 : 1). 6g and 61 from benzene/ethanol (2 : 1) while the remaining were crystallised from benzene/ethanol (3 :

* * Satisfactory analyses for N and S were also obtained. 1).

238 Lakhan and Singh Arch. Pharm.

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