synthesis of potential anthelminticsir.amu.ac.in/2480/1/t 2395.pdf · either by hydrolysis of...

SYNTHESIS OF POTENTIAL ANTHELMINTICS

( SUMMARY )

A THESIS SUBMITTED FOR THE DEGREE OF

Doctor of Philosophy IN

Chenrvstrij TO

THE ALIGARH MUSLIM UNIVERSITY, ALIGARH

SYED ABUZAR M. Phil.

DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE

LUCKNOW-226001 JUNE, 1982


( SUMMARY )



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( SUMMARY )



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S U M M A R Y

1

The survey of world-wide incidence of various

helminth infestat ions in man which appeared time to time

reveals that despite several measures taken to eradicate

helminth infections i t s growing trend has not been

checked . Although helminth infections are not generally-

f a t a l , they contribute to the major public health problems 2 3

in tropical and subtropical regions of the world ' and

may also lead to several c l in ica l complications causing

even death of the patient in absence of immediate medical

care. The high prevalence of helminth infections i s

part ly due to the poor sanitary habi ts and lack of

prophylaxis followed by masses, abundance of proper natural

conditions for the developments of helminth juveniles and

part ly due to the lack of suitable drugs available for the

treatment of different forms of helminthiasis. The present

thesis i s an effort to develop ideal chemotherapeutic

agents for the treatment of infections due to hookworms and

cestodes, the two major helminth diseases of t ropics .

The efforts to substi tute c lass ical anthelmintics by

more effective and safer drugs was unsuccessful t i l l 1961

when Merck came out with the discovery of thiabendazole ,

a new class of anthelmintic possessing broad spectrum of

ac t iv i ty against a variety of nematode parasi tes in man

and domestic animals. This led to the discovery of a series

2

of potent benzimidazole anthelmintics of which mebendazole

and fenbendazole showed high promise in curing nematode

and cestode infesta t ions and also established benzimidazole

heterocycle as a useful pharmacophore for building molecules

with broad spectrum of an t iparas i t ic ac t iv i ty .

The f i r s t chapter of the thesis presents a review

dealing,with 1he recent developments in the treatment of

hookworm and cestode infections. The second chapter

comprises of the synthesis and biological ac t iv i ty of -the

different classes of the compounds based on the powerful

anthelmintic ac t iv i ty associated with benzimidazoles , d i -

aiyl sulfides and sulfones and bitoscanate . This study

has been carried out with a view to develop be t t e r

anthelmintics as also to delineate minimal s t ructural

requirements for optimal anthelmintic ac t iv i ty in the

molecular frame-work exhibited by the ilead» molecules.

Synthesis of 5(6)-N-heteroarylbenzimidazolos and

benzthiazoles

Several 5(6)-(l-benzimidazolyl)benzimidazoles and

6-(l-benzimidazolyl)benzthiazoles (6) have been prepared

s t a r t ing with ihe condensation of 5(6)-aminobenzimidazoles

( la) and 6-aminobenztliiazoles (lb) with 2,4-dinitrochloro-

benzene or 2-nitrobenzoylchloride to give 5(6)-{2>4«

dinitrophenyl)aminobenzimidazoles and benzthiazoles (2)

3

and 6-( 2 - n i t r o b e n z o y l ) a m i n o b e n z t h i a z o l e (3 ) r e s p e c t i v e l y .

Reduct ion of 2 and J w i t h Raney-n icke l and H2 o r h y d r a z i n e -

hyd ra t e and Raney-n icke l gave the co r r e spond ing amines ( 4 and

£) which were c y c l i z e d w i th d i f f e r e n t c y c l i z i n g agen t s to

8 9 give the t i t l e p r o d u c t s (6 and 7) ' .

O 2N,

l b \ _ _ / G 0 C 1

2, R^NOg, X=WH,S

4, R ^ H g , X*NH,S

1 . Reduct i m v 2 . C y c l i z a t i o n

2 , R=NO 2

£, R=NH2,NCS RJ > - N

5, CSC1-R=NH2

N > ^ N

H. ,cr^ s^x-^-7

6 , R=H,GH5, X=S,NH

R ^ H , CH3, SH, NHOO OE t

R2=NHC0CH,,NHC0H,NCS, / NCOOEt

NH-C sNHOOOEt

S y n t h e s i s of 2 , 2 i - d i s u b s t i t u t e d - 5 , 5 » - d i b e n z i m i d a z o l y l d e r i v a t i v e s

Based on the powerful a n t h e l m i n t i c a c t i v i t y a s s o c i a t e d

w i t h benz imidazo le s , s e v e r a l 2 , 2 » - d i s u b s t i t u t e d - 5 , 5 « -

d i b e n z i m i d a z o l y l d e r i v a t i v e s (11) have been prepared i n

o r d e r to s tudy the r o l e of b t n z i m i d a z o l e moiety a s a

4

c a r r i e r molecule. The key intermediates in the synthesis

of above compounds were 3,3»—dinitro (or diamino)-4,4'-

diamino (or dinitro)diphenyl derivatives (9) obtained

e i ther by hydrolysis of 4,4 '-diacetamido-3,3 ,-dinitro

diphenyl derivatives (8a) or by amination of 4,4 ' -dichloro-

3,3 '-dinitrodiphenyl derivatives (8b) or by direct'

reaction of 5-chloro~2-nitroacetanilide with sodium sulfide.

Reduction of 8 with hydrazine-hydrate and Raney-nickel,

Raney-nickel and H2 or ferrous sulphate—ammonia gave the

corresponding 3,3«,4,4'-tetra-aminodiphenyl derivatives

(10). Reaction of 10 with 1,3-dicarbalkoxy-S-methyliso-

thioureas, acetic acid or formic acid yielded the t i t l e

compounds 11.

? Red. K2N- NH,

2 , R = 3-NH2 o r 3-N02

R = 4-NH2 o r 4-N02

RJ

HC1 or NH-

R1

-<TX> 8 a , R = 3-N02 , R = 4-NHAc

b , R1 = 3-N09 , R = 4-01 1 1 , R = NHCOOR , H, CH,

R = OH-f t CpH[-

X = S,S02 ,G0,CH2 ,0

i—\ S(CH2)2S, COW NCO

5

Synthesis of 2,5-diarylbt ,nzimidazoles and t h e i r cycl ic

analogs

Synthesis of 2, 5-diarylbenzimidazoles was

undertaken based on the a c t i v i t y of several 2 -ary lbenz i -

midazoles . 4-Amino-3-nitrobiphenyl (12) , on reac t ion

with n i t robenzoyl chlor ides ,gave •fc-(aroyl)amino-3-

ni t rob ipheny l s (l/3a) which were reduced with hydrazine-

hydrate and Raney-nickel to y i e ld the corresponding

amines 13b. Gyclization of l^b with acid gave 2 , 5 -

diarylbenzimidazoles (14a) . Reaction of 2-(4-amino-

phenyl)-5(6)-phenylbenzimidazole (14a, R= 4-NH2) with

a lky l chloroformates and thiophosgene yielded 2-( 4-

carbalkoxyaminophenyl and 4- isothiocyanatophenyl) -5(6)-

phenylbenzimidazoles (14b) . Similar react ion of 14a

(R = 2-NH2) with a lky l chloroformates and potassium e thy l

xanthate yie lded the cyc l ic products 15, while the

reac t ion of 13b with thiophosgene yie lded l -( 2-amino,

2- isothiocyanato and 4- isothiocyanatobenzoyl)-2-

meroapto-5-phenylbenzimidazoles ( l 6 a - c ) . 4-Amino-3-

n i t rob iphonyl (12) was a lso used to prepare e thy l

5(6)-phenylbenzimidazolc-2-carbamate (17) by reduction

followed by oyc l i sa t ion of the r e s u l t i n g amine wi th

1,3-dicarbethnxy-S-methyl isothiourea .

6

Ph

1 . Red.

2 . Cyc l .

12

0 H H

Ph'

16a , R = 2-NH2

b , R = 2-NCS

c , R = 4-NCS

HCOOEt

Ij5a, R = 2 $ 4-N02

b , R = 2 & 4-NH2

i1^

l \ >

14a, R = H, 2-NH2,4-NH2

b , R = 4-NHC00CH3,

l 4 a | 4-NHC00Et,4-NCS

iS, x = s,o

2 - S u b s t i t u t e d - 5 ( 6 ) - ( 4 - s u b s t i t u t e d phenoxy, phenylthio

and sulfono)benzimidazoles

5-(4-Acetamidophenoxy and pheny l th io ) -2 -n i t roan i l i ne s

(18)were used to prepare several benzimidazoles of the

"tyP*3 £k» Reduction of 18 with hydrazine-hydrate and

Raney-nickel and subsequent cyc l iza t ion with formic acid ,

a c e t i c acid and 1,3-dicarbalkoxy-S-methylisothioureas gave

7

the corresponding 2 , 5 ( 6 ) - d i s u b s t i t u t e d benzimidazolcs (19) .

Oxidation of 19 (X=S) with KMn04-CH,C00H gave the sulfones

19 (X=S02). Acid hydro lys i s of 19 with 10# HGl gave the

corresponding amines (2_0) which were t r ea ted with

thiophosgene to give 2 - subs t i t u t ed -5 (6 ) - (4 - i so th iocyana to -

phenoxy, phenylthio and sulfono)benzimidazoles (21 ) .

^ N v s ^ x " N r : ^ \ ^ ' N H 2 l .Red.

Ac]

18, X = 0,S 19, R = H, CH5, H

NHCOOR11

'R

RK GH3, C2H5

x = o,s,so2

SON

1* csci2 ^ \ ^ - x N ^ "

N

2 1 , R = H,0H,,_ ~~ NHCOOR1

IT ^R H

HgN

R = CH r, CpHj-

X =: 0 , S , S 0 2

20, R = H, CH3, NHC00RJ

,1 R = CH^, C2Hc

X = 0, S, S02

S y n t h e s i s of 5 (6 ) - th iophcnoxymethy l and phonoxymethyl

bonzimidazole-2-carbamates

The h igher homologue (2£) of fenbendazole was

synthesized s t a r t i n g from 4-chloro-3-ni t robenzyl bromide

(22) by the sequence of reac t ions described below. This

has helped in eva lua t ing the e f f ec t of in t roduct ion of one

8

methylene un i t a t 5 (6 ) -pos i t ion of benzimidazole on

b io log i ca l a c t i v i t y of fenbendazole.

22

1. PhXNa B r H 2 C s ^ \ . N 0 2 2 . UH3

3 . Red. 4 . C y c l .

'-^NHCOOR t

2 2 , X = 0 , S, R = CH3 ,C2H5

H

AcHN-

Synthesis of 1,2 and 1 ,3 -d i subs t i tu t ed alkanes and

1, 4 -d i subs t i t u t ed p iperaz ines

In order to study the change in b io log ica l a c t i v i t y

of 4 ,4 , -d i i so th iocyana tod iphenyl su l f ide and sulfone by

inc reas ing the d i s tance between two a ry l functions by

in t roduc t ion of 2 or 3 CH2 u n i t s , synthes is of 1 ,3- and

1 ,2 -d i subs t i tu t ed alkanes (27) was undertaken. 4-Acetami-

dothiophonol (24) , on react ion with 1,2-dibromocthane and

1,3-dibromopropane, y ie lded 1,2 and l , 3 - d i - ( 4-acetamido-

phonylthio)alkanes (2£) . Oxidation of 2_5 with KMnO4~OH,COOH

gavo the corresponding sulfones 2£ (X=S02) which were

hydrolysed in presence of acid to give -the desired amines

26. Reaction of 2_6 with thiophosgenc yie lded the t i t l e

compounds 27.

^ V SH ^ ^ V X ( C H2 ) n X > ^ > , + Br(CH2)nBr

R"*SX ^ / N i 2£, R=NHAc, X=S,S02,n=2,3

26, R=NH2, X=S,S02, n=2,3

27, R=NCS, X=S,S02, n=2,3

9

The synthesis of compounds of the type *i0 obtained

by replacement of th io and sulfono l inkage of 4 , 4 ' -

d i isothiocyanatodiphenyl sul f ide and sulfone by piperazine

moiety, a more ac t ive pharmacophore for antinematode

a c t i v i t y , was also ca r r i ed out . The synthes is s t a r t s with

the reac t ion of e i t h e r anhydrous piperazine or 4 - n i t r o -

phenylpiperazine (28) with 4-ni t robenzoyl chloride to

give l , 4 ~ d i s u b s t i t u t e d piperazines (29) . Reduction of 2_9_

gave the corresponding diamines which were converted to

i so th iocyana tes (j50) by t r e a t i n g with thiophosgene.

R-N N - H ~ > R-N BT-CO ~V 7~N02

28, R=H, 4-ni t rophenyl 29_, B=4-nitrophenyl

R=4-nitrobenzoyl 1 . Red.

V 2 . CSC12

R—N N-CCW' NViJGS \ / \=J

£0, R=4~isothiocyanatophenyl

R=4-i so th io cyan a to ben zoyl

Synthesis of s u b s t i t u t e d thiocarboxamides, carboxamides

and th ioureas

Several subs t i t u t ed thiocarboxamides,and carboxamides

have been prepared as s t r u c t u r a l analog of b i t o scana t e .

Reaction of d i f fe ren t piporazines and a n i l i n e s with

10

va r ious phenyl isothiocyanates gave the thiocarboxamides

( J l ) which were reduced to the corresponding amines (3,2).

Conversion of ^2 in to i so th iocyanates by react ing with

thiophosgene resu l t ed in an unusual desulphurizat ion of

thiocarboxamides to give carboxamides (33, X=0).

Thiocarboxamides (23 , X=S) carrying "the isothiocyanato

function were conveniently prepared by react ion of one

mole of p iperaz ines with p_-phenylenediisothiocyanate

( b i t o s c a n a t e ) . Several th ioureas were a lso prepared

e i t h e r by reac t ion of 2-aminobenzimidazole'or 4-aminoaceta-

n i l i d e on subs t i t u t ed phenyl isothiocyanates

•NCS

H - N N-R \ / )n r~\

-NHC - N N - R 2

\ /

SCN

/ V 2 H-N N-R

3 1 , R =3-N02 , 4-N02 , 4-NHAc

Red. 31(R1=4-N02)

/ / V S - N H - C - IT

/ •R <—HpN

CSClo

13, X = 0,S

M/

s I! / \ 2

NHC- N N—R

2i

r

The unusual desulphur izat ion of thiocarboxamides

and th ioureas with thiophosgene was studied by converting

a number of thiocarboxamides, th ioureas and thiamide to

t h e i r corresponding oxygen analogs with the help of

11

th iophosgene and p o s s i b l e mechanism f o r d e s u l p h u r i z a t i o n

v v , ,12 has been proposed

S

RNH-C-R1 csci, S r 0 r S

RN=:C* Gl

o r

m

R-

? = 0'

:t s 01"

L RJ

0 11 1 H20

I RN=C-R

Gl

B i o l o g i c a l A c t i v i t y ;

Most of the compounds have been e v a l u a t e d fo r

t h e i r a n t h e l m i n t i c a c t i v i t y a g a i n s t N ippos t rongy lus

b.Iiasili,Qnsis i n r a t s , Nematosp i ro ides dubius i n mice ,

Ancylostoma ceylanicum i n hamste r s and Hymenolepis nana

i n r a t s and mice . A l a r g e number of 2 , 5 - d i s u b s t i t u t o d

bcnz imidazo le d e r i v a t i v e s showed promis ing antihookworm

and a n t i c e s t o d e a c t i v i t y which i s r e p o r t e d in the t h e s i s *

The b e s t compounds of t h i s s tudy were found to be 2 , 2 * -

d i c a r b o m e t h o x y a m i n o - 5 , 5 ' - d i b e n z i m i d a z o l y l oxide ( 1 1 ,

X=0,R=NHC00CH5) and s u l p h i d e ( 1 1 , X=S, R=NHC00CH„) which

e x h i b i t e d 100$ removal of A, oej[lmii_cam a t a s ing le o r a l

dose of 12 .5 -25 mg/kg i n hamste r whi le 100$ of the

H.nana worms were e x p e l l e d by 2,2<-dicarbomethoxyamino~

5 , 5 ' - d i b e n z i m i d a z o l y l s u l f i d e ( 1 1 , X=S, R=NHC00GH3) and

12

methyl 5(6)-( 4-isothiocyanatophenylt i i io)benzimidazole-2-

carbamate (21 , X=S, R=NHCOQCH,) a t s ingle o ra l doses

of 70 and 30 mg/kg respec t ive ly from r a t s . Compound 11

(X=0, R=NH0OOCH5) was 100$ ef fec t ive in causing complete

e rad ica t ion of H.nana from r a t s at a single o ra l dose

of 250 mg/kg. The r e s u l t s of the in v i t r o ant imicrobial

a c t i v i t y of some of the compounds are also reported in

the t h e s i s *

13

R JL LJLJLiL JL&JLJi

P.A.J . J a n s sen , P r o g . Drug R e s . , 18 , 191 (1974) .

Mg-di_cine_._in the Tro p i c s , E d i t e d by A.¥.Woodruff,

Chu rch i l l L i v i n g s t o n e , London, 1974, p .143 and 157.

T rop ica l M e d i c i n e . 5 th E d . , E d i t e d by G.W.Hunter,

J .C .Swar t zwe lde r and D.F .Clyde , V.B.Saunders Co.

P h i l a d e l p h i a , 1976, p .451-592 and 593.

S.Sharma and E . S . C h a r l e s , P^qg J t_pju^_Re>s i , 2%,

( i n p r e s s ) .

S.Sharma and S.Abuzar, P r o g . Drug R e s . , ( i n p r e s s ) .

J . C . K a t i y a r , A.B.Sen and B .K .Bha t t acha rya , N a t u r e ,

214, 708 (1967 ) .

M.R.Samuel, p r o g . Drug R e s . . 1% 96 (1975 ) .

S.Abuzar, S.Sharma and R . N . I y e r , I n d i a n J._ Chem.,

19B, 599 ( 1 9 8 0 ) .

S.Abuzar and S.Sharma, ^ ^ N _ a t u r f o r s c h . , 36b, 108

( 1 9 8 1 ) .

S.Abuzar and S.Sharma, Arch^Xharm. ( i n p r e s s ) .

S.Abuzar and S.Sharma, I n d i a n J . Chem., 20B,

230 (1981) .

S.Abuzar, S.Sharma and R . N . I y e r , IndianJN uJ3hem. ,

19B, 211 ( 1 9 8 0 ) .




Chemistrq TO


BY




* TO * v *

* MY PARENTS *

Telex : 0 5 3 5 - 2 8 6 Telegram : CENDRUG Phone • 32411-18 PABX OTTT «ff5^5, it*Z 5FFT =7° 1 7 3

S5^r*=T\3R 226001 ( ^ ro r )

CENTRAL DRUG RESEARCH INSTITUTE Chattar Manzi l , Post Box No. 173

UJCKNOW—226001 (INDIA)

June 8,1982

CJRJOIJ3AIE

This i s to c e r t i f y tha t the work embodied in

t h i s thes i s has been ca r r i ed out by Mr.Syed Abuzar

under our supervis ion. He has f u l f i l l e d the requirements

for the degree of Doctor of philosophy of the Aligarh

Muslim Univers i ty regarding -the nature and period of

i n v e s t i g a t i o n a l work. The work included in t h i s

t h e s i s has not been submitted for any other degree and,

unless otherwise s t a t e d , i s a l l o r i g i n a l .

(M. i iyas) Reader

Department of Chemistry, A.M.U., Aligarh.

-~^ . . - H N A A A ^

(S. Sharma) S c i e n t i s t

Medicinal Chemistry Division, C.D.R.I . , Lucknow

ACKHOWIBDGBMBM

I t i s a g r e a t p l e a s u r e fo r me to e x p r e s s my humble

g r a t e f u l n e s s t o my mentor , Dr. Satyavan Sharma, S c i e n t i s t ,

M e d i c i n a l Chemistry D i v i s i o n , Gen t r a l Drug Research

I n s t i t u t e , Lucknow, f o r sugges t ing the problems, s k i l f u l

gu idance , con t inued i n s p i r a t i o n and u n t i r i n g h e l p dur ing

the course of p r e s e n t s t u d i e s .

I am h i g h l y g r a t e f u l t o D r . M . I l y a s , Reader ,

Department of Chemis t ry , A.M.U. A l i g a r h , f o r h i s keen

i n t e r e s t and i n v a l u a b l e h e l p .

My s i n c e r e thanks a r e a l s o due to D r . R . N . I y e r ,

E m e r i t u s S c i e n t i s t , Med ic ina l Chemistry D i v i s i o n , CDRI,

Lucknow f o r h i s many h e l p f u l d i s c u s s i o n s .

I am indeed i n d e b t e d to Dr .N i tya Anand, FNA, D i r e c t o r

and D r . S . P . P o p l i , S c i e n t i s t I n c h a r g e , Med ic ina l Chemistry

D i v i s i o n , CDRI, f o r p r o v i d i n g l a b o r a t o r y f a c i l i t i e s , to

Dr .A.B.Sen aid h i s a s s o c i a t e s f o r p r o v i d i n g b i o l o g i c a l

s c r e e n i n g r e s u l t s ; to the s t a f f of RSIC f o r p r o v i d i n g

s p e c t r o s c o p i c and a n a l y t i c a l d a t a and t o the Counci l of

S c i e n t i f i c and I n d u s t r i a l Resea rch , New Delhi fo r the

award of F e l l o w s h i p .

My d e l i g h t f u l thanks are die to a l l my c o l l e a g u e s

i n Med ic ina l Chemistry D i v i s i o n , e s p e c i a l l y D r s . E . S .Char les ,

J .S ingh , Mess. V.K.Agarwal, R.K.Jain, S.Gupta, A. G.

Jhingran aid Miss R.Rastogi for t h e i r co-operation and

cheerful companionship.

F i n a l l y , I wish to extend my g ra te fu l thanks to

my b ro the r Syed Akhtar, for h i s i n s p i r a t i o n and constant

encouragement.

June 1982. (Syed Abuzar) Med.Chem.Div.

C O N T E N T S

g.ajg ! £ •

LIST OP ABBREVIATIONS

PREFACE

CHAPTER I REGENT DEVELOPMENTS IN THE

TREATMENT OF HOOKWORM AND

CESTODE INFECTIONS

CHAPTER I I SYNTHESIS OF POTENTIAL NEMATO-

DICIDAL AND CESTODICTDAL AGENTS

1. Introduction . . . . . .

2 . B a s i s of work . . . . . .

3. Chemistry . . . . . . . . .

3.1 Synthesis of 2-suostituted 5(6)-N-heteroarylbenzimidazoles . . .

i

i i i

1. The hookworm i n f e c t i o n s . .

1.1 Chemotherapy of hookworms . .

1.11 Older drugs . . . . .

1.12 New candidate antihookworm agents . . . . . . .«

1.13 Recent antihookworm agents mt

2. The cestode in fec t ions

2 .1 Chemotherapy of oestodes .

2.11 Older drugs . . . .«

2.12 New ant ices tode drags

2.2 The hydatid disease

2.21 Treatment of hydatid i n f e c t i o n s . . . •

3 . Conclus ion . . . . . . . ,

4. Re fe rences . . . , . « , ,

2

3

3

5

13

15

17

17

18

32

33

35

36

55

57

66

66

3.2 S y n t h e s i s of 2 ~ s u b s t i t u t e d 6-N-h e t e r o a r y l b e n z t h i a z o l e s . , . 68

3 .3 S y n t h e s i s of 2 , 2 » - d i s u b s t i t u t e d -5 , 5 ' -d iben z imidazo ly l d e r i v a t i v e s . . . • • • 70

3 . 4 Syn thes i s of 2 , 5 ( 6 ) - d i a i y l -benz imidazo le s and t h e i r c y c l i c ana logs . . . . . . 83

3.5 S y n t h e s i s of 2 - s u b s t i t u t e d 5 ( 6 ) -( 4 - s u b s t i t u t e d phenoxy, p h e n y l -t h i o and sul fono)ber iz in i i -d a z o l e s . . . . . . • • • 87

3.6 S y n t h e s i s of a l k y l 5 ( 6 ) - t h i o -phenoxy and phonoxymethyl-benz imidazo le -2 -ca rbama te s . . . 95

3 .7 S y n t h e s i s of 1 , 2 - d i s u b s t i t u t e d e thanes and 1 , 3 - d i s u b s t i t u t e d propanes . . . . . . . . . 96

3.8 Syn thes i s of s u b s t i t u t e d t h i o -carboxamides , carboxamides and t h i o u r e a s . . . . . . 98

3.9 S y n t h e s i s of 1 , 4 - d i s u b s t i t u t e d p i p e r a z i n e s . . . . . . 104

4. Exper imen ta l . . . . . . 107

5 . B i o l o g i c a l a c t i v i t y . . . . . . 215

5 . 1 Anthe lmin t i c t e s t i n g . . . 215

5 .11 Antihookworm t e s t i n g . . . 215

5 .12 C e s t o d i c i d a l t e s t i n g . . . 219

5.2 A n t i m i c r o b i a l a c t i v i t y . . . 221

5 . 2 1 A n t i b a c t e r i a l a s s a y . . . . . . 221

5.22 Ant i funga l a s say . . . . . . 223

5.23 R e s u l t s . . . . . . . . . 224

6 . R e f e r e n c e s . . . . . . . . . 226

SUMMARY

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PREFACE

The success i n s u c c e s s f u l e r a d i c a t i o n of

h e l m i n t h i a s i s depends on the p rope r use of a broad-spect rum

a n t h e l m i n t i c drug and s t r i c t p r o p h y l a c t i c r e g u l a t i o n s

fo l lowed by the p a t i e n t s . Both t he se r equ i r emen t s have

been met to a g r e a t e x t e n t i n s e v e r a l advanced c o u n t r i e s

of the wor ld l e a d i n g to complete e l i m i n a t i o n of the

s e v e r a l forms of h e l m i n t h i a s i s from the p o p u l a t i o n .

However such a s i t u a t i o n does n o t p r e v a i l i n d i f f e r e n t

p a r t s of the t h i r d world and even some advanced n a t i o n s .

The h a b i t and h a b i t a t , poor s a n i t a t i o n , low l i v i n g

s t a n d a r d s and o c c u p a t i o n a l needs a r e the main c r i t e r i o n s

f o r Hie profound i n c r e a s e i n he lmin th i n f e s t a t i o n s a l l

ove r tiae world which has been p a r t i a l l y man i f e s t ed due to

l a c k of a s u i t a b l e d rug . This has a l s o he lped i n g i v i n g

r i s e to m u l t i p l e i n f e c t i o n which, many a t imes poses

s e r i o u s c l i n i c a l c o m p l i c a t i o n s and i s d i f f i c u l t to c u r e .

Recent su rveys have i n d i c a t e d the h igh p reva lence of

i n t e s t i n a l h e l m i n t h i a s i s of which i n f e s t a t i o n s due to

hookworms and c e s t o d e s a r e p a r t i c u l a r l y i m p o r t a n t .

I n the a g r i c u l t u r e - b a s e d c o u n t r i e s l i k e I n d i a ,

the hookworm i n f e c t i o n s have a g r e a t b e a r i n g wi th the

h e a l t h , g e n e r a l w e l l - b e i n g and soc io-economic development

of the r u r a l masses because of the b l o o d - s u c k i n g n a t u r e of

i v .

the p a r a s i t e s . Cestodes are equal ly important i n t e s t i n a l

helminths because of the p o t e n t i a l danger of producing

c y s t i c e r c o s i s by them. Thus there i s a great deal of

concern over evolving an anthelmint ic which would not only

e l iminate the roundworms but also simultaneously remove

tapeworms, i f p resen t , from the g a s t r o i n t e s t i n a l t r a c t of

the man. The present work i s mainly d i r ec t ed towards the

synthes is of p o t e n t i a l anthelmint ic agents showing ac t iv i ty

aga ins t hookworms and ces todes .

The f i r s t chapter of the t h e s i s deals with the

present s t a tu s of the disease caused by hookworms and

cestodes and the var ious c lasses of compounds discovered to

t r e a t these i n f ec t ions in man and animals. The second

chapter covers the syn thes i s of var ious subs t i t u t ed -5 (6 ) -N-

heteroarylbenzimidazolesand benz th iazo les . In addit ion a

s e r i e s of 2 ,2«-d i subs t i tu ted-5 ,5 ' -d ibenz imidazo les and

2 , 5 - d i s u b s t i t u t e d benzimidazolos have been synthesized as

the s t r u c t u r a l congeners of benzimidazole an the lmin t ics . A

number of 1,2- and 1 ,3 -d i subs t i tu t ed alkanes and 1,4-

d i s u b s t i t u t e d p iperaz ines have also been prepared. A se r ies

of thiocarboxamides, carboxamides and th ioureas have been

synthesized and the mechanism of thiophosgene induced

desulphur isa t ion of those compounds i s s tudied.

The compounds, thus synthesized, have been evaluated

v .

for the i r antihookworm act iv i ty against Nippostrongylus

b r a s i l i ensign in r a t s , Nemajiosja roi de s dub jus in mice and

.Ancylostoma ce lani cam^ in hamsters, anticestode act ivi ty

against Hymenolepis nana in mice and r a t s and in yi tro

antimicrobial act ivi ty against different s t ra ins of

bacter ia and fungi $ a l l these screening resul ts are

reported in the present -thesis,

RECENT DEVELOPMENTS IN THE TREATMENT OF HOOKWORMS

AND CESTODE INFECTIONS

1

The g a s t r o i n t e s t i n a l t r a c t of man i s the most

common seat of p r ed i l ec t i on for severa l i n fec t ive diseases

apparently because of the abundance of idea l condit ions for

surv iva l and r e p l i c a t i o n of the p a r a s i t e s . The i n t e s t i n a l

helminth in fec t ions cons t i t u t e one of "the most widely

prevalent disease of man af fec t ing nearly 2500 mi l l ion

people around the world . A number of helminths p a r a s i t i z i n g

the g a s t r o i n t e s t i n a l t r a c t are asymptomatic and rare ly

cause much t rouble to the host while a few bear great

public heal th s igni f icance and also hamper the soc io

economic development by i n h i b i t i n g the production of milk,

meat, wool and l e a t h e r in several t h i r d world and

developing countr ies of the world. The hookworms and ihe

cestodes are two important helminth p a r a s i t e s which

have recent ly a t t r a c t e d the c lose r a t t e n t i o n of medicinal

chemists , p a r a s i t o l o g i s t s and c l i n i c i a n s because of t h e i r

world-wide prevalence, g r ea t e r pathogenic s ignif icance and

concomitant det r imenta l e f fec ts on human body funct ions .

Among the measures avai lable today fo r t r e a t i n g

i n t e s t i n a l he lmin th i a s i s , the che mo the rapeu t ic approach

seems to be qui te r a t i ona l and deserve de t a i l ed work ou t .

During the l a s t two decades severa l newer c l a s ses of compounds

2

have been s y n t h e s i z e d which have p rov ided d e f i n i t e advantage

over 1he c l a s s i c a l antihookworm and a n t i c e s t o d e d rugs . The

p re sen t review i s mainly concerned i n p r o v i d i n g a p r e c i s e

account of the r ecen t developments i n the chemotherapy of

hookworm and ces todc i n f e c t i o n s i n man and domest ic a n i m a l s .

A d e t a i l e d account of the c l a s s i c a l a n t h e l m i n t i c s used to

t r e a t v a r i o u s forms of i n t e s t i n a l h e l m i n t h i a s i s i s 2—8 a v a i l a b l e .

1 • The Hookworm I n f e c t i o n s ,

The hookworm i n f e c t i o n s , c h i e f l y p r e v a l e n t i n the

r u r a l p o p u l a t i o n of a g r i c u l t u r e based r e g i o n s of t h e under

developed wor ld , i s a c q u i r e d by walking ba re foot i n damp

s o i l contaminated wi th i n f e c t i v e l a r v a e . The hookworm

l a r v a e p e n e t r a t e the s k i n and migra te to l u n g s and f i n a l l y

to i n t e s t i n e where t hey deve lop i n t o a d u l t worms and l i v e

on the d i r e c t b lood feed of the h o s t . The d i s e a s e i s

d i s t r i b u t e d widely i n the t r o p i c a l and s u b - t r o p i c a l r eg ions

of the worldj however i t i s endemic i n I n d i a , China, J apan ,

C e n t r a l .America, Mexico, Panama, West I n d i e s , Venezuela ,

Pe ru , A r g e n t i n a , Paraguay and v a r i o u s p a r t s of Nor thern

and E a s t e r n Af r i ca . I t i s e s t i m a t e d 9^ t h a t more than

700-800 m i l l i o n people around the world a r e the v i c t i m s of

hookworm d i s e a s e , i n I n d i a the i n f e c t i o n i s common i n

farmers working i n r i c e , banana , maize and po t a to f i e l d s

and a f f e c t s n e a r l y 205 m i l l i o n people i n Assam, Bengal ,

3

Bihar , Orissa , Kerala, Madras, U t t a r Pradesh and o1ii<er

pa r t s of the country.

The hookworms are endoparas i t ic nematodes found

a t tached to the mucosa of the i n t e s t i n a l wa l l . The common

hookworms which i n f e c t man are An cylo stoma duo den ale ,

An colostoma oeylanicum and Ne cator amerioanus. The domestic

animals are also in fec ted by var ious hookworms l i ke

Ancylostoma caninum (dogs), Ancylostoma b raz i l i en se ( c a t s ) ,

Bunostomum trigonocephalum ( c a t t l e ) and (xiaigeria

pachyscel is (sheep and g o a t s ) .

The main c l i n i c a l manifes ta t ions of t h i s disease are

marked hypochromic microcytic anaemia leading to general

weakness, fat igue and lack of physical and mental growth

and reduced produc t iv i ty of the hos t . In add i t ion , the

pa t i en t may also experience abdominal pain, cons t ipa t ion ,

anorexia and g iddiness .

1 • 1 .Qhemptherapy of hookworms

1.11 Older drugs

The c l a s s i c a l drags which hove been used to t r e a t

var ious human and animal hookworm i n f e s t a t i o n s were drawn

chief ly from halogenated hydrocarbons ( te t rachloroe thylene 12 and mantomidc (1) e t c . ) and subs t i t u t ed phenols ( 2 , 4 , 5 -

t r ich lorophenol (2) , 4-cyano-2-iodo-6-nitrophonol (3)

e t c . ) ; however t h e i r c l i n i c a l use was l imi ted due to t h e i r

4

low a c t i v i t y mad narrow margin of safety and, therefore ,

have been replaced slowly by more act ive drugs. Another

group of compounds showing a wide range of pharmacological

and a n t i p a r a s i t i c a c t i v i t y are the quarternary ammonium

s a l t s of which bephenium hydroxynaphthoate (4) was developed 15 by Wellcome l a b o r a t o r i e s as human antihookworm drug •

Bephenium hydroxynaphthoate has been recommended at a dose

of 5 g (=2.5 g of base) per adult showing 28-90$ clearance

of N.amcricanus and 80-100$ clearance of A.duodenale

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and produces severa l side e f f e c t s . Following the discovery

of bephenium, a la rge number of i t s s t r u c t u r a l analogs were

synthesized but none surpassed -the potency of the parent 21-28

drag The most ac t ive congeners of bephenium were

5

thenium (5) , d i p h e z y l (6) and s t y i y l p y r i d i n i u m (7)

but none proved i t s u s e f u l n e s s i n t r e a t i n g c l i n i c a l

hookworm i n f e c t i o n s and were conf ined i n c o n t r o l l i n g canine

and f e l i n e hookworm d i s e a s e s .

R X*

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A few cyanine dyes have a l s o been used i n the t r ea tmen t

of hookworm i n f e s t a t i o n s i n man and an imals i the most

impor t an t be ing d i t h i a z a n i n e (8) which i s g iven t o p a t i e n t s

having N.aaerica^ujB and A.duodonale i n f e c t i o n s wi th

v a r i a b l e a c t i v i t y ^1J .

H 3 C H 2 C \ -N + N /CH2CH3

CH = CH -CH=CH - C H ^ 8

1,12 New cand ida te antihookworm a g e n t s

Be^zj.midazole_s

The f i r s t t r u e l y modern a n t h e l m i n t i c was th iabendazo le

(2) d i s cove red i n 1961 by Merck . The drug shows high

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a c t i v i t y a g a i n s t human hookworms a t a dose of 25-100 mg/kg

given i n a s i n g l e or m u l t i p l e doses^ ~ 5 4 . Thiabendazole i s

one of the most a c t i v e d rugs f o r t r e a t i n g creeping e r u p t i o n

caused by the l a r v a e of A . b r a z i l i e n s e i n man. At a dose of

50 mg/kg given o r a l l y 5 ^ ' 5 o r a p p l i e d l o c a l l y ' , i t

e f f e c t i v e l y cu re s the l e s i o n s .

The d i s cove ry of t h i a b e n d a z o l e s t i m u l a t e d a world-wide

r e s e a r c h r e s u l t i n g i n the e v o l u t i o n of a s e r i e s of powerful

a n t h e l m i n t i c s 10-18 (Tabic 1 ) . The most p o t e n t members of

t h i s s e r i e s a re mebendazole (12) and fenbendazole ( 1 4 ) .

Mebendazole p o s s e s s e s h igh a c t i v i t y a g a i n s t a number of

s p e c i e s of nematode and ce s tode p a r a s i t e s i n d i f f e r e n t

h o s t s . The drug causes complete c l e a r a n c e of Nippos t rongy lus

39 40 b r a s i l j e n s i s i n m i c e - ^ , A. ceylanicum i n hamste r s and

41 A.caninum i n dogs and has been recommended as an i d e a l

42 a n t h e l m i n t i c f o r smal l an ima l s ' . Mebendazole i s equa l l y

e f f e c t i v e i n e l i m i n a t i n g N.amer icanus and A.duodenale

i n f e c t i o n s i n a d u l t and c h i l d p a t i e n t s a t a dose of 100 mg/ 43—41;

a d u l t given twice a day fo r 3 days ^ J. The c h i l d r e n

a c c o r d i n g l y r e c e i v e lower dosages .

Fenbendazole (14) e x h i b i t s p o t e n t a c t i v i t y a g a i n s t

d i f f e r e n t s p e c i e s of l ung worms and i n t e s t i n a l nematodes. 46 I t g ive s high cure r a t e s a g a i n s t A.caninum i n dogs and

Haemonchus c o n t o r t u s i n sheep and goa t s ' a t a dose of

50 and 5 mg/kg r e spec t ive ly . When given a t a dose of 100 49

mg/kg i t a lso el iminated N.amoricanus i n man .

The other 'bcndazolo' anthelmint ics have also been

used successful ly to t r e a t hookworms in fec t ions i n c a t t l e , 50 sheep, g o a t s , poultry and pets with good success-' . Some

of them, l i k e flubendazole ( 1 7 ) 5 1 and ciclobendazole (18) 5

have shown promising r e s u l t s i n t r ea t i ng human hookworm

d i seases ,

The majority of benzimidazole an the lmint ics were

e a r l i e r shown to exer t t h e i r a c t i v i t y by i n h i b i t i n g the

fumarate-reductase enzyme a c t i v i t y of the pa ra s i t e s which

plays cruc ia l r o l e in worms anaerobic cyc le . The i n h i b i t i o n

of t h i s s tep in Iho metabolism would cut-off the energy

supply of the worm leading to i t s p a r a l y s i s . Later the

a c t i v i t y of var ious benzimidazole anthelmint ics (9-18) has

been a t t r i b u t e d to t h e i r a b i l i t y to bind with mammalian

tubul in and t o i n h i b i t the assembly of micro tubule s-5 .

Mebendazole i s known to d i s rup t cytoplasmic microtubules 54 resu l t ing i n degeneration of Ascari_s suum i n t e s t i n a l co l l s .

More recent ly i t has been shown tha t mebendazole and

fenbendazole bind ( i n h i b i t i o n constants 1.9 x 10 and

6.5 x 10" respec t ive ly) with embroyonic tubul in of A.suum

which has been ca r r i ed out by i n h i b i t i o n s tudios with %

10

R. r ^ • N

'N H

N W, NHCOOGH, H

2 , R = H, Thiabendazole

10 , R = NHCOOPI^,

n

Cambendazole

,55,56

1 1 , R = Bu-, parbendazole

12, R = OOph, Mebendazole 1^, R = OPr, Oxibendazole 14, R = SPh, Fenbendazole 15, R = SOph, Oxfendazole 16, R = Spr, Albendazole 17, R = C0C6H4F(£),

Flubendazole 18, R = CO-<3 ,Ciclobendazole

Thus the anthelmint ic ac t ion of co lch ic in

benzimidazole an the lmint ics may be due to t h e i r d i f f e r e n t i a l

binding a f f i n i t i e s between nematode and mammalian tubul in

(the i n h i b i t i o n constant of mebendazole and fenbendazole

for bovine bra in tubul in i s 250-400 times h i ^ i e r than for

A.^uum embryonic t u b u l i n ) .

imidazol ines

In a follow up study of the p o t e n t i a l i t y of

imidazolines i n pa ra s i t e chemotherapy, Janssen Pharmaceutica

came out with a new broad spectrum anthe lmint ic , te t ramisolo

(i£L) • Tetramisole i s a raccmic mixture of R- and S-, 2 , 3 , 5 ,

6-tetrahydro-6-phonylimidaze [2 ,1 -b] th iazo le which have 58 been resolved and i i ieir absolute conformation es tab l i shed .

The anthelmint ic a c t i v i t y of totramisole i s due to i t s

11

S(-) - i somer cal led levamisole 5 . levamisole possesses high.

a c t i v i t y aga ins t d i f fe ren t g a s t r o i n t e s t i n a l nematodes of

sheep, dogs, swine, fowl, c a t t l e , horses and man. At a dose

of 2.5 mg/kg given o r a l l y i t e l imina tes var ious round worms 59 60 including hookworms in man and shows fewer side ef fec ts '

Levamisole i s a potent i n h i b i t o r of fumarate-reductase i n

va r ious nematodes and shows immunostimulant p roper t i es in CO

man aid animals . The R( + )-isomer, su rpr i s ing ly has

an t idepressant a c t i v i t y .

Pyrimi dines

Tetrahydropyrimidines are another c lass of

compounds wi th potent anthelmint ic a c t i v i t y which has been

s tudied ex tens ive ly a t P f i ze r l a b o r a t o r i e s . The most ac t ive C.-T

member of t h i s s e r i e s i s pyrante l (20) . Pyrante l pamoate

has been found to give 75-9l/° cure r a t e s aga ins t N.americanus

and A»duodenalc i n man at a dose of 10-100 mg/kg depending

upon the nature and i n t e n s i t y of the i n f e c t i o n s . I t i s

equal ly e f fec t ive aga ins t var ious i n t e s t i n a l helminths of

sheep, goats , dogs, c a t t l e , horse , swine and fowl.

12

The s t r u c t u r a l m o d i f i c a t i o n s of p y r a n t e l have l e d to

the s y n t h e s i s of a l a r g e number of i t s mo lecu la r congeners

of which morante l (21) 5 and oxan te l (22) 6 have shown

h igh promise i n cu r ing d i f f e r e n t nematode i n f e c t i o n s i n

man and animal s.

20, R = H, P y r a n t e l

2 1 , R = GH5, Morante l

22, Oxantel

I s o t h i o cyan a t e s

.Among the s e v e r a l a r y l i s o t h i o c y a n a t e s p o s s e s s i n g

h igh nema tod i c ida l a c t i v i t y , phenyl i s o t h i o c y a n a t e (£3) a n ( i

1 , 4 - p h e n y l e n e d i i s o t h i o c y a n a t e (24 , b i t o s c a n a t e , developed

by Hoechs t ) show high antihookworm a c t i v i t y i n man. 2J3 has

been demons t ra ted to cure human hookworm i n f e c t i o n s a t a gq

dose of 300 mg/kg given i n t h r e e d iv ided doses . C l i n i c a l

s t u d i e s c a r r i e d out wi th b i t o s c a n a t e have shown t h a t the

drug g ives 47-96$ and 25-96$ cure r a t e s a g a i n s t A.duodenalo

and N^amcricanus i n f e c t i o n s r e s p e c t i v e l y at a dose of

3 x 100 mg f o r a d u l t s and 2 x 100 mg fo r c h i l d r e n given a t 70—72 12 h r i n t e r v a l s . The s i d e e f f e c t s of b i t o s c a n a t e a re

n a u s e a , v o m i t i n g , headache , abdominal pa in aid weakness which

13

are generally mild and t ransient ,

•NCS

S2» R = H

24, R = NCS, B i t o s c a n a t e

Recen t ly Ciba l a b o r a t o r i e s have i n t r o d u c e d 4 - i s o -

t h i o c y a n a t o - 4 ' - n i t r o d i p h e n y l a m i n e (25., amoscanate) f o r

73 t r e a t m e n t of hookworm and o t h e r nematode i n f e c t i o n s i n man

Three doses of t h i s compound a t 100, 125 o r 250 mg a t 8 o r

12 h r i n t e r v a l s were found to cause complete removal of

£m duodonale and N, am e r i c anus i n man . The oxygen analogs

of amoscanate i s n i t r o s c a n a t e (2§_) which e l i m i n a t e s hookworms

77 from c a t s and dogs .

0 ^ — / ^ — X —P \ - N C S

25_, X = NH, Amoscanate

26_, X = 0 , N i t r o s c a n a t e

1•13 Recent antihookworm a g e n t s

F e b a n t c l (27) and amidan te l (28) a rc the two new

a n t h e l m i n t i c developed by Baye r . Feban t c l shows h igh a c t i v i t y

a g a i n s t d i f f e r e n t s p e c i e s of nematodes and cos todes i n mice,

r a t s , dogs, sheep and c a t t l e . At a dose of 1-5 mg/kg i t

e l i m i n a t e d A.coninum, ^ £ i n a _ r i a s tenqceph&la , Nomatospiroides

14

du.bi.as_, H. con t o r t u s and B. t r igonocephalum from v a r i o u s

animals ' . Amidantel a l s o c l e a r s N ippos t rongy lus muri_s,

N .dubius and A. caninum a t a dose of 250 x 3 , 250 x 4 and WW • • • M l •». • » ' * " • — » •—• • I I . •> I I I . * III > •fcJI '

25 mg/kg r e s p e c t i v e l y '

S^t\Ysl$HCOGE2OOH3 H>_c

^ - " " ^ N H - G ^ C=:NC00GH5(CIH5)2N l

NHC00CH,

NHC0CH20CH,

27, Feb ante 1 28 , Amidantel

A s e r i e s of ave rmec t ins (v2S), produced by Str^pto^m^cos

a v e r m i t i l i s _ . have been developed a t Merck l a b o r a t o r i e s Op

which show h igh o r d e r of a n t i p a r a s i t i c a c t i v i t y

Avermectin B-, and B~ p o s s e s s marked a c t i v i t y a g a i n s t

^ • c j ^ ^ u m a n ( i A«^S2i . i i£SS£ i n dogs a t an o r a l dose of

0 .003-0 .005 mg/kg . L a t e r i t was demonstra ted 12iat

compounds of t h i s c l a s s a re h i g h l y e f f e c t i v e a g a i n s t v a r i o u s

g a s t r o i n t e s t i n a l he lmin ths of shoep and c a t t l e a t an o r a l

dose of 0 .05-3 m g / k g 8 4 .

29 , Avermectin

http://du.bi.as_

15

2» Ihe^ Cestpdei infections

The cestode infections are generally considered

as the helminth diseases of minor importance as compared

to nematode and trematode infect ions. This i s probably

because the cestodes produce lesser pathogenic manifest

ations and are prevalent in smaller section of the

population. The comparative rate of incidence of various

helminth diseases would indicate that nearly 2500 million

people are infected with in tes t ina l nematodes while 200 6 8S million subjects harbour schistosomiasis ' . In contrary,

about 100 million people arc the victims of in tes t ina l

cestodes a l l over the wor ld 1 ' 8 o » 8 7 .

Although the incidence of cestode infections i s

not as high as other helminth infes ta t ions , they have a

d i s t inc t influence on the human and animal health, and

are generally di f f icul t to eradicate. In addition, the

risk of acquiring cysticercosis and hydatid disease poses

potent ial danger of producing several serious and grave

c l in ica l manifestations for which an ideal remedy i s yet

to be discovered.

The cestodes, infecting man, possess a world-wide

d is t r ibut ion; however, they are chiefly prevalent in the

tropical and subtropical regions. The endemic areas of

this infection are I ran, Iraq, I s r ae l , Jordan, Lebanon,

16

Saudi Arabia, Syr ia , Turkey, Pak is tan , Ind i a , Tibet , Korea,

Japan, U.S.S.R. , d i f fe ren t pa r t s of Africa, Mexico, B raz i l ,

Peru and Chi le . The cestode in fec t ions have also been

repor ted from some pa r t s of Europe, Aus t ra l ia and

America.

Like hookworms, the cestodes are also endoparas i t i c ,

hermaphrodite tape l i k e helminths l i v ing in the alimentary

canal of the v e r t e b r a t e s . The main cestodes infec t ing man a r e J^g-Giii 8§g±*&$£. (*>eef tapeworm), T.solium (pork t ape

worm), Diphyllobothrium latum ( f i sh tapeworm) and

Hymenqlepjs nana (dwarf tapeworm). The important cestodes

i n fec t ing animals are Dipylidium caninum and D.mansoni

( ca t s and dogs), Monie_zia e.xpjnsa (sheep) , jP«£igiî2£59iS

(dogs, fj>xes), T.hydatigena (d?gs) , T.â^niôjrmi^s ( ca t s ) 321(1 R a i l l i g t i n a ces,tincillus ( fowls) .

The l i f e cycle of cestodes normally requi res one

in termedia te host such as c a t t l e , pigs and f i shes . Man

acquires t h i s i n f ec t i on by ea t ing poorly cooked infec ted

beef, pork or f ish} the cys t i c e r c i present i n the f lesh

emerge out and a t t ach themselves to i n t e s t i n a l wall where

they grow, a t t a i n matur i ty and l i v e for several years with

the hos t . The cestode in fec t ions are general ly asymptomatic;

however the pa t ien t may suffer from nausea, d iar rhea ,

hunger pa ins , weakness, malaise , weight l o s s and anaemia.

17

The c y s t i c e r c i may migrate in any par t of the body and cause

severa l oomplications. The, cysts may cause bl indness and

nervous disorders i f migrate in eye and bra in respec t ive ly ,

2 • 1 Chemotherapy of Costodes

2.11 Older drugs

A number of p lan t products such as Aspidium

pie o re gin ( e x t r a c t of male fern , Dryopteris mas) ,

a recol ine (£0) , pumpkin seeds ^~^ have been used since

long for t r e a t i n g human c e s t o d i a s i s . Several t i n compounds

have bean shown to possess high a c t i v i t y against d i f ferent 92 cestode p a r a s i t e s in man and animals^ . A few der iva t ives

of aor id ines such as quinaorine (31) and ac ran i l

(2^) were used e a r l i e r to cure cestode in fec t ions in

man. In general these drugs showed severa l toxic e f fec t s

i n h o s t s , required in tens ive medical care of the pa t i en t s

and a lso did not cause complete e l iminat ion of the

i n f e c t i o n . Due to these shortcomings b e t t e r chemothera-

peu t ic agents wore discovered which slowly replaced older

drugs i n the c l i n i c a l treatment of c e s t o d i a s i s . 9H3

NH-CH-(CH 2 ) 5 NEt 2

COOCH.

2P.

OCH,

^r^y-

NHCHg-CH-GHgNEtg OCH,

C l / ^ / ^ i J

18

2.12 New _Anjfc^ejstode^J)rugs

This i s an old an t imicrob ia l , germicidal and

fungicidal agent which has been found to el iminate

T.pisif i^Si .s and D.caninum from dogs and cats a t a dose of

200 mg/kg^ and Monj._e.zia sp. from sheep a t a dose of

150 m g / k g 1 0 1 ' 1 0 2 .

The drug has been extensively used since 1959 to 103-105 t r e a t T . s a d n a t a i n f ec t ion in man J . The usual

recommended adul t dose of dichlorophene i s 60-100 mg/kg not

exceeding 5 g in. a day; the chi ldren receive accordingly

smaller doses . The' cure r a t e s were between 50-86$.

Dichlorophene i s usual ly safe at the rapeu t i c doses and does

not produce any side ef fec ts* however some a l l e r g i c

reac t ions may be not iced . At higher doses the drug may

produce nausea, vomiting, d iar rhea , co l i c and jaundice and

may requi re spec ia l care to p a t i e n t s with hear t and l i v e r

di seases .

or bi 33., Di chlo rophene

http://Monj._e.zia

IS

M t h i o n o l (34)

This was i n i t i a l l y used as an a n t i m i c r o b i a l and

t o p i c a l a n t i s e p t i c agent bu t l a t e r found to e x h i b i t a c t i v i t y

a g a i n s t a wide range of nes tode p a r a s i t e s i n men and

a n i m a l s . I t caused 70-85$ removal of T.hxda^tjLgena, T .ov i s_

and M.mul t i ceps a t a dose of 150 mg/kg whi le a l l the

D.can_inu.m worms fr.im dogs were e l i m i n a t e d a t a dose of

150-200 mg/kg and no s i d e e f f e c t s were observed excep t 107 o c c a s s i o n a l d i a r r h e a and s o f t e n i n g of f aeces . The drug

showed 100% e f f i c a c y a g a i n s t M^ni^ezia and Jnonlp^cje^phala

s p e c i e s i n sheep a t a dose of 100 mg/kg ' .

B i t h i o n o l has a l s o been used s u c c e s s f u l l y to

t r e a t T^s^a^riata and D.latum i n f e c t i o n s i n man ^. A

dose of 40-60 mg/kg, given once o r i n two d i v i d e d dose s ,

was s u f f i c i e n t to cure p a t i e n t s i n f e c t e d w i th T . s ^ g i n a t a or

D. la tum; however sco lex was removed only i n 37 .5-50$ of the

c a s e s . The common s i d e e f f e c t s of t h i s d rug a re nausea , 112 v o m i t i n g , a n o r e x i a , g e n e r a l f a t i g u e and e p i g a s t r i c pain

High c u r e r a t e s i n human c c s t o d i a s i s have a l s o been ob ta ined

when the p a t i e n t s were g iven a combination of 0 . 5 - 1 g of

b i t h i o n o l w i t h 1-2 g of n i c l o s a m i d e 1 1 4 ' 1 1 5 .

01

01 CI

34 , B i t h i o n o l

20

Halogenated salicylanjLlj-.'fes

Niclosamide (Yomesan, 35_) i s the f i r s t member of "1 ~Lf> 117

t h i s c l a s s i^iich was introduced in I960 by Bayer * and

since then i t became the primary drug to t r e a t d i f fe ren t

forms of tapeworm in fec t ions in man and animals. In the

prel iminary experiments ca r r i ed out on animals, i t showed

high cure r a t e s a g a i n s t T.h^datlggna., jyumulticeps and

D.caninum i n dogs a t a dose of 50 or 100-300 mg/kg ' .

At lower dosages (110-200 mg/kg) a l s o , given in capsules or

in food, i t el iminated a l l T^jsifjsrmi^s and D.caninum 120

in fec t ions from dogs . Later i t was demonstrated t h a t niclosamide can cause complete e rad ica t ion of T.hydatigena in

121 dogs a t a dose as low as 32 or 62 mg/kg . The drug i s

also highly ef fec t ive aga ins t D.caninum (250 mgAg) and

H.taeniaeformis (750 mg dose or 100-200 mg/kg) in c a t s 1 2 2 ' 1 2 5 .

Sheep in fec ted with M. ex pans a and M.benedeni were

completely freed of tapeworms when t rea ted with niclosamide

a t a dose of 75 mg/kg and no tox ic e f fec t was

observed 4 " . I t was also highly ef fec t ive against

^ i i l i £ . t i S a i n chickens a t a dose of 20-25 mg/kg 1 27» 1 2 8 .

20

Halogenated< s a l i c y l a n i l i des

Niclosamide (Yomesan, 35.) i s the f i r s t member of

t h i s c l a s s th ich was introduced in i960 by Bayer ' and

since then i t became the primary drug to t r e a t d i f fe ren t

forms of tapeworm in fec t ions in man and animals. In the

preliminary experiments ca r r i ed out on animals, i t showed

high cure r a t e s a g a i n s t T,h^dat±£^aa.f M.multiceps and -1 -1 o "l-i n

D.caninum in dogs a t a dose of 50 or 100-300 mg/kg ' v.

At lower dosages (110-200 mg/kg) a l s o , given in capsules or

in food, i t e l iminated a l l T.pisiformis and D.caninum 120 in fec t ions from dogs . La ter i t was demonstrated t h a t

niclosamide can cause complete e rad ica t ion of T.hydatigena in 121 dogs a t a dose as low as 32 or 62 mg/kg . The drug i s

also highly ef fec t ive aga in s t D.caninum (250 mg/kg) 9 and

H.taeniaeformis (750 mg dose or 100-200 mg/kg) in c a t s 1 2 2 ' 1 2 5 .

Sheep in fec ted with M.expansa and M.benedeni were

completely freed of tapeworms when t r ea t ed with niclosamide

a t a dose of 75 mg/kg and no t ox i c e f fec t was

observed . i t was also highly ef fec t ive agains t

^ i JLl ie j t ina in chickens a t a doso of 20-25 mg/kg 1 2 7 » 1 2 8 .

21

In clinical practice niclosamide has shown

excellent results in treating practically all human

tapeworm infections1 9~-L^. Patients suffering with D.lalum

and H.nana infections were given 2-4 chcwable tablets

(each containing 1 g of niclosamide) after breakfast when

all the cases were cured with minor side effects . I t

cured Diphy 11 oboth rium infection in several patients when

given 1 g/adult followed by 1 g/adult after two hours and 139

then a saline purge after 3-4 hours .

Treatment of H.nana infection in adult and child

patients can be carried out at different dose schedules.

When niclosamide was given at a dose of 1 g per adult daily

for 6-13 days, the drag gave 74-75$ cure rates against 140 141 H.nana ' . Better results were obtained against the

above infection by giving the patients 60 mg/kg of the drug

followed by 15 mg/kg for 6-7 days1 4 2 '1 4 5 . Children infected

with H.nana were given 0.5 g of niclosamide daily for 6 days

or a single dose of 100-130 mg/kg of the drug when high 140-14-4

cure rates were achieved J--*-

Niclosamide has also been found to possess high

activity against I.solium and T.saginata in man. A dose of

2-3.5 g/adult given in single or divided doses with or

without a saline purge, has been found to cure 85-97$ of

patients infected with T.solium and T. sagLnata1^8'1^9 >l42 > l 4 5 ~ 1 4

Niclosamide is practically devoid of any

22

c o n t r a - i n d i c a t i o n and may be used s a f e l y du r ing pregnancy

a l s o -* . The drug p o s s e s s e s low t o x i c i t y which i s p robably

due t o i t s poor a b s o r p t i o n through the i n t e s t i n a l w a l l .

Based on t h e h igh a c t i v i t y e x h i b i t e d by

n i c l o s a m i d e , Hoechst l a b o r a t o r i e s i n t r o d u c e d 4 ' -bromo-Y-

r e s o r c y l a n i l i d e ( T e r e n o l , ^S_) as an u s e f u l v e t e r i n a r y

c e s t o d i c i d a l agent ^ 1 ' 1 ^ 2 . At a dose of 10-25 mg/kg,

151 t e r e n o l e l i m i n a t e d H.d^minuta from r a t s . I t was e q u a l l y

e f f e c t i v e a g a i n s t Mpniezia i n c a t t l e and g o a t s a t a dose

of 0.5 ml of suspens ion (65 mg of t e r e n o l ) / k g body weight . l ^ ^ - l ^

when 100?» c l e a r a n c e of the tapeworms were observed .

Oxyclozanide (!37) i s a po lyha logena ted ana log of

n i c l o s a m i d e developed by 101 l a b o r a t o r i e s •* . The drug

removed 13 day old H . d i j a n u t a from r a t s a t a dose of 4 mg/kg,

I t i s a we l l t o l e r a t e d compound which d e s t r o y e d the 7 day

o ld H . d i m i m t a i n mice a t the s i m i l a r dose given i n above 1^7

exper iment J ,

01

^ k ^ OH HO 01

C l ^ ^ j / ^ ^ C0-NH " ~ \

v01

23

Merk Sharpe and Dhome developed a diiodo analog

of niclosamide, rafoxamide (38) which showed cestodicidal

activity in rodents infected with H»nana and H.<y :muta' 158

During the search of more potent congeners of

niclosamide, a large number of substituted salicylanilides

have been prepared at this laboratory many of which exhibit

cestodicidal activity superior to -that of parent

drag7' 5 9 ~ . Thus, a series of 5-chloro-3'-nitro-4'-

substituted salicylanilides were found to possess high

anticestode activity b 0 ~ 1 6 5 . t h e ^es^ compound of the

s e r i e s was 5 - c h l o r o - 3 « - n i t r o - 4 ' - c y c l o h e x y l a m i n o s a l i c y l a n i l i d c

(39) which e l i m i n a t e d a l l the worms of H.nana i n mice a t a

dose of 30-50 mg/kg 1 . S i m i l a r l y 2 » - c h l o r o - 4 , 4 « - d i n i t r o s a -

l i c y l a n i l i d e (40) and 4 « , 5 - d i c h l o r o - 3 ' - n i t r o s a l i c y l a n i l i d e

(41) c l e a r e d 100$ of H.nana i n f e c t i o n i n mice a t a s i n g l e

o r a l dose of 250 mg/kg'

-OH

C0-N

16 2

19

24

OH R 1 R 2

^ ^ ^ OONH —(f \ nram ....

40, R = R1 = 4-N02 , R = 2-C1

41, R = 5-C1, R1 = 4-C1, R2 = 3-N02

A s e r i e s of subs t i tu ted-3 ,5 -d ib romosa l i cy lan i l ides

have been prepared many of which caused 100$ e rad ica t ion

of H.nana from r a t s and mice a t a dose of 10-250 mg/kg1 , 5 .

The best member of t h i s s e r i e s was 3 ,5-dibromo-2 ' -chloro-

4»- i so th iooyana tosa l i cy lan i l ide (42) with marked

anthelmint ic a c t i v i t y and would be discussed l a t e r .

NOS

i s o t h i o cy an ate s

Bitoscanate (42.) i s fee f i r s t member of t h i s

c l a s s T*Iioh was developed by Hoeohst l a b o r a t o r i e s in 1960>s

to t r e a t hookworm and cestode in fec t ions in man and

animals y . At a dose of 6 mg/kg i t showed high a c t i v i t y 170 aga ins t T.jgisi_formls_ in dogs . I t a lso eliminated

99.2-100$ of the H.nana woxtns from mice when given a t a

dose of 50-170 m g / k g 1 7 1 ' 1 7 2 .

25

Clin ica l s tud ies with b i toscana te showed 1iiat the

drug was e f fec t ive in el iminat ing .H.nana from chi ldren

(5-9 years old) a t a dose of 200 mg/kg given in two divided

doses a t 12 hours i n t e r v a l . The cure rate was 67$. The

older ch i ldren and a d u l t pa t i en t s needed 300 mg/kg ( in three

doses of 100 mg, 12 hours apar t ) to y i e l d 95$ cures agains t 17"5

H.nana i n f ec t i on .

SON—(/ \ — NCS

i2

A s e r i e s of subs t i t u t ed diphenyl su l f ides ,

d i s u l f i d e s , su l fox ides , suIfones, e t h e r s , methanes, ketones

and ethylenes carrying an isothiooyanato group in one or

both the phenyl r ings have been synthesized of which 4 , 4 ' -

d i isothiocyanatodiphenyl sulfono (44) and i t s corresponding I V 4- 1 VV

su l f ide (4£) showed the highest a c t i v i t y l^~J-i'% Compound

44 was highly e f f ec t i ve in removing >90$ H.nana worms from

mice and r a t s a t a dose of 10 and 100 mg/kg respec t ive ly , i t s

maximum to l e ra t ed dose in mice was found to be > 2.7 g/ 17 4 175 kg ' . Fur ther s tud ies on -this compound indica ted

tha t i t was also ef fec t ive agains t Taenia spec ies , D._canlnum

and R a i l l i e t i n a species at an o ra l dose of 50-100 mg/kg .

4 ,4 ' -Di iso th iocyanatodiphenyl su l f ide (4£) exhibi ted marked

a c t i v i t y agains t H.nana i n mice and r a t s a t a dose of

2G

/ 174-177 50 mg/kgj i t s maximum t o l e r a t e d dose was 2.7 g/kg

SON NCS

44, X = S02

45., X = S

Based on the powerful ces tod io ida l a c t i v i t y of

niclosamide and 44, a s e r i e s of lialogenated i so th iocyana to-

s a l i c y l a n i l i d e s were synthesized possessing potent a c t i v i t y

against H.nana in r a t s »lo4,lfo5^ Tû ês t compound of

th i s c l a s s was 3 ,5-d ibromo-2«-chl . i ro-4 ' - i so th iocyanatosa l i -

cy lan i l ide (42) which displayed high order of a c t i v i t y

against a number of nematodes and cestodos in d i f ferent

h o s t s . At a dose of 100 mg/kg, i t caused 100$ e l iminat ion

°f H.nana i n mice and r a t s and H.diminuta in Mastomys.

natal^n^sis, and also provided 100$ cure ra tes except fo r

H.nana i n mice where the cure r a t e was 82$. In t h i s t e s t

the drug was found to be b e t t e r than niclosamide but

i n f e r i o r to praz iquante l .

In an expanded study _42 was evaluated aga ins t a

number of nematode and cestode p a r a s i t e s . I t removed 100$ o f H»njin.a_ from mice and r a t s , Railj.ie^tina species from fowls S0Ci^L 5§££iS. species from c a t s a t a dose of 25-70 mg/kg. I t

was equal ly e f fec t ive aga ins t ^^yjôstama ceylanicurn in

hamsters, SyjQhaoia obvpjLata in mice, As par i di a g a l l i in fo

27

Tq_xascaris s p e c i e s , Toxocara s p e c i e s , AjiS5J_lostoma

tubagfo_rmis_ and Qnathosjoma S£in^gj3jmm * n c a ^ s an<^

A.ce^ar i icum and T.canis i n dogs a t a dose r ang ing from

25-50 mg/kg given fo r 1-3 d a y s 1 6 7 .

Some of the i s o t h i o c y a n a t o n a p h t h a n i l i d e s have

a l s o been found to p o s s e s s h igh o r d e r of a c t i v i t y a g a i n s t

d i f f e r e n t ce s todes ' 1 8 0 . The most p o t e n t member of t h i s

c l a s s was ^ which r e s u l t e d i n 100$ e l i m i n a t i o n of H.nana

i n r a t s a t an o r a l dose of 7 .5 mg/kg . I t a l s o showed

h igh a c t i v i t y a g a i n s t H . d i M n u t a i n r a t s and Taenia

s p e c i e s i n dogs . A s i n g l e o r a l dose of 5 g/kg of t h i s

compound was w e l l t o l e r a t e d by r a t s . I t was equa l l y safe

when given to mice , Mastomys and dogs .

OH

CO-NH—>

46

The oxygen ana log of amoscanate ( 4 7 , N i t r o s c a n a t e ,

GrS-23654) has been found to p o s s e s s high anti tapeworm

a c t i v i t y i n dogs . At a dose of 1 g /kg or 250 mg/kg x 2 ,

i t e l i m i n a t e d a l l Ejghinococcus g ranu losus wh i l e a dose of

6 4 mg/kg of the drug was s u f f i c i e n t to remove T.hy_datige_nji

from dogs . I n a n o t h e r experiment a g a i n s t B.g^anulojsus

i n dogs , n i t r o s c a n a t e was given as 25$ suspens ion a t a dose

of 100,200 and 400 mg/kg d i v i d e d i n 1-3 d o s e s , when t h r e e

28

doses of 400 mg/kg removed 92.6$ of "the tapeworms. The -l o p

lower doses were l e s s ac t ive ,

) 2 N \ /— 0 — \ \ - N G S

47

Subs titu. te d^ Ami di ne s

In 196 5, Wellcome l abo ra to r i e s reported the

an the lmint ic a c t i v i t y of a s e r i e s of subs t i t u t ed naphtha-

midines of which N,N~dibutyl-4-n-hexyloxy-l-naphthamidine

(48, Bunamidine) was found to exhib i t the most potent

t a e n i c i d a l a c t i v i t y . Since "then bunamidine has be on

used extens ively to t r e a t var ious costodo in fec t ions in

dogs, c a t s , sheep and pou l t ry . Although "this drug i s too

toxic for humans, i t may bo successful ly used to prevent

man from hydatid disease by e l iminat ing Echinococcus

r e se rvo i r s from c a t s and dogs.

At a dose of 15-40 mg/kg, bunamidine hydrochloride

caused 90-100$ clearance of Dijiylidium from cats and

dogs ~ . Treatment of sheep infec ted with M.oxp_ans_a

needed 12.5 mg/kg of the drug for l i g h t e r in fec t ions while

a dose of 25-50 mg/kg of i t was required for e l iminat ing T O O

heavier in fec t ions . Bunamidine was also highly ef fec t ive

i n e l imina t ing majority of T.pis i formis , H.taenjaefprmis

29

and M.malji_ce£S from cats and dogs at a dose of 25-50 mg

(base)/kg. The drug showed differential response against "1 Q / ] Og

American and English strains of T. pi si for mis ~ . The

efficacy of various salts of bunamidine has been demonstrated

against R.cesticillus t R . t e t r a g p n a and R . e c h i n o b o t h r i d a 18Q i n ch ickens .

^ B u £ HN=C-N „

^ B u S

46 °G6H13

Benzimidazoles

Mebendazole (12) was g iven to 31 p a t i e n t s i n f e c t e d

w i t h T.solium and T . s a g i n a t a a t a dose of 100 mg twice d a i l y

f o r 2 days o r a t 200 mg twice d a i l y f o r 4 days when 20,

7 2 . 7 , and 90$ cure r a t e s were ob t a ined ^ . I n ano ther

c l i n i c a l t r i a l s c a r r i e d out i n Costa R i c a , 37 p a t i e n t s with

T.sol ium and 4 p a t i e n t s w i th T . s a g i n a t a i n f e c t i o n s were

t r e a t e d by mebendazole a t a do so of 100-300 mg given twice

d a i l y f o r 2-6 d a y s . This t r e a t m e n t removed long cha ins of

p r o g l o t t i d s from s e v e r a l p a t i e n t s 24-48 hours a f t e r drug

a d m i n i s t r a t i o n and only fewer s i d e e f f e c t s were n o t i c e d ^ .

Mebendazole was e q u a l l y e f f e c t i v e i n removing

tapeworms from p e t s . At a dose of 1 g given d a i l y fo r 14

days , i t k i l l e d both mature and immature c y s t i c e r c i of

30

of T.^si/o_rinis_ in r a b b i t s 1 9 . I t has boon used to t r e a t

Uînâriâ sôji^coghaLa, T.îs iformis and D.tcaninum. in fec t ions 193 i n dogs a t a dose of 100 mg given twice for 5 days . The

cysts of T.hydatigena and T.ovis in sheep were k i l l e d by

mebendazole when given a t a dose of 50 mg/kg given for 14 1Q4 consecutive days y .

Fenbendazole (14) has been found ef fec t ive in

e l iminat ing H.djjminuta from r a t s and M.expansa from sheep

and c a t t l e at a dose of 10-25 m g / k g 1 9 5 ' 1 9 6 and o ther

tapeworms from domestic animals 9 ' 9 9 .

Oxfendazole ( l£) has been used to t r e a t dogs

in fec ted with Bchinococcus £ranulosuj and T.hydatigena and

sheep--carrying Moniezia a t a dose of 4.5-20 mg/kg when the 200—20? animals were cured considerably .

Albendazole (16) shows high a c t i v i t y i n removing

Moniezia from sheep a t a dose of 10 mg/kg 0 5 » 2 0 4 and

T.saginata from calves at a dose of 45-50 mg/kg 2 0 5 , . I t

also caused complete e rad ica t ion of na tu ra l i n fec t ions of

M.oxpansa and M.benedeni from sheep at a dose of 10-20 20R

mg/kg and was highly ef fec t ive agains t Mesocestoides cor t i 206 m dogs .

Squibb l a b o r a t o r i e s have developed two in jec tab le

benzimidazoles, [5- [ (cyc lopropylmethyl )su l f inyl ] - lH-

benzimidazol-2-yl]carbamic acid methyl e s t e r (49_) and

31

[ 5 - [ ( 2 - m e t h y l p T O p y l ) s u l f i n y l ] - l H - b e n z i m i d a z o l - 2 - y l ] c a r b a m i c

acid methy l e s t e r (£0) to t r e a t nematode and ces tode

i n f e c t i o n s . A s i n g l e s , c . i n j e c t i o n of 49 given a t a dose

of 5 mg/kg removed 100$ of Monie^zia from n a t u r a l l y i n f o c t e d

sheep . I t was e q u a l l y e f f e c t i v e a g a i n s t Moniezia s p . a t an 207 o r a l dose of 2.5 mg/kg .

R'

0 t s- u

49,

50,

H

R

R .

- N

^SJHCOOCH, 3

= A ^ = - ^

P r a z i q u a n t e l

A l a r g e number of p y r a z i n o - i s o q u i n o l i n e s (£1) have

been s y n t h e s i z e d j o i n t l y by Merck and Bayer l a b o r a t o r i e s

•which show h igh a c t i v i t y a g a i n s t H.nana i n mice a t a minimum

i n h i b i t o r y c o n c e n t r a t i o n s of 25-50 mg/kg ~ . From t h i s

se r i e s , 2 - c y c l o h e x y l c a r b o n y 1 - 1 , 2 , 3 , 6 , 7 , l i b - h e x a h y d ro-4H-

p y r a z i n o [ 2 , l - a ] i s o q u i n o l i n - 4 - o n e (5_2^ EMBAY 8440, B i l t r i c i d e , 21 2 21 4-P r a z i q u a n t e l ) emerged as the most p o t e n t a n t h e l m i n t i c ~ .

P r a z i q u a n t e l p o s s e s s e s h igh a c t i v i t y a g a i n s t -fee blood f lukes

Schis tosoma haematobium, S. japonicum, S.mansoni and

S . jn t e r ca l a tu rn -)~ and ces tode p a r a s i t e s i n man and 21 R 21Q

animals ' y . Recen t l y the p h y s i c a l , chemical and

b i o l o g i c a l p r o p e r t i e s of p r a z i q u a n t e l has been pub l i shed .

At a dose of 2 .5 mg/kg, p r a z i q u a n t e l e l i m i n a t e d a l l

32

T.hydat igona from dogs aid Hydat igera, t ae rdaeformis , from

c a t s 2 2 1 . However, a dose of 1 mgAg o f t h e d r u S w a s

s u f f i c i e n t to remove a l l t h e worms of T . p i s i f o r m i s and 222

$• j j g g g j - a 0 f o r m i s f r o m d ° S s a n d c a t s r e s p e c t i v e l y

Hamsters i n f e c t e d w i t h D.latum showed h igh response when 223

t r e a t e d wi th p r a z i q u a n t e l u s i n g a t a dose of 50 mg/kg

Z

5J: BT

2 •2 ^®JiE.4s$i^L2i2SSSS.

The h y d a t i d d i s e a s e , p r e v a l e n t wherever man i s

c l o s e l y a s s o c i a t e d wi th d o g s , sheep and c a t s , i s one of the

most s e r i o u s and f a t a l i n f e c t i o n caused by c e s t o d e s . The

d i s e a s e i s a c q u i r e d by i n g e s t i o n of eggs of Etchingcoccus

^ r j n u l o s u s end E . m u l t i l o c u l a r i s . The d e f i n i t e h o s t s fo r

these c e s t o d e s are the canine animals such as dogs , wolves ,

f o x e s , j a c k a l s and c a t s who harbour the a d u l t s worms i n

t h e i r small i n t e s t i n e s . The i n t e r m e d i a t e h o s t s a r e man,

sheep , c a t t l e , dogs and camels .

33

The h y d a t i d d i s e a s e s g e n e r a l l y do n o t sh-»w any

symptom a t the e a r l y s t a g e , however v a r i o u s c l i n i c a l

m a n i f e s t a t i o n s such as nausea , vague abdominal p a i n ,

b u l g i n g of the r i g h t hypochondium o r e p i g a s t r i u m duo t o

h e p a t i c enlargement and r e c u r r e n t p y r e x i a a s s o c i a t e d with

coughing paroxysms may occur which depend upon t h e s i z e ,

type and s i t e of the c y s t s . Sometimes the cys t may

r u p t u r e due to some r e a s o n s which may g i v e r i s e to anaphy

l a c t i c shock wi th vasomotor c o l l a p s e , oedema, u t r i c a r i a

and r e s p i r a t o r y d i s c o m f o r t .

2 . 2 1 £r££L%l££Lj2^

Arcco l ino hydrobromidc (30) has been used s ince

l ong to t r e a t dogs i n f e c t e d w i th Bchi no coccus . At a

dose of 4 m g / k g , a re co l ino HBr o r HC1 g ives 95-98$ p oA ? pc;

e f f i c a c y a g a i n s t E.^ranj^osus^ i n dogs ' .

B i t h i o n o l (^54) and i t s co r re spond ing s u l f o x i d e have

boon recommended for t r e a t i n g dogs c a r r y i n g B . m u l t i l o c u l a r i s

i n f e c t i o n and g ive h igh cure r a t e s a t 150 and 200 mg/kg 226 r e s p e c t i v e l y

Nic losamide (£5_) shows v a r i a b l e a c t i v i t y a g a i n s t 227 2?ft

E . g r a n u l o s u s ' , however a t a s i n g l e o r a l dose of

50 and 100 mg/kg i t removed 50$ and 98-100$ of these 22Q

tapeworms from dogs .

34

Bunamidine (48) i s the most ex tens ive ly used drug

aga ins t B.g_ramlosus_ i n dogs aid sheep and i s general ly

employed as i t s hydrochloride or hydroxynaphiiioate. The

drag i s general ly given in two doses a t 24 or 48 hours

i n t e r v a l s 30-232^ Bumamidine hydrochloride removed 90-94$

°f I* .a.fiVlA.?„^P-,ls. wo:c&s from several dogs a t a s ing le dose of

50 mg/kg •55, 5 4 , while at a dose of 25 mg/kg, 50 mg/kg or

25 rng/kg given twice a t 48 hour i n t e r v a l s resu l ted in 98.8 ,

85.9, and 98.5$ reduction of E.granulosus respec t ive ly in 23S 12 dogs ^ . i n some count r ies dogs and sheep with p o t e n t i a l

exposure of E.granulosus i n f ec t i ons were t r e a t e d biweekly

(with 100 mg/kg) or monthly (with 25 rag/kg) by bunamidine

for a long period r e s u l t i n g i n sharp f a l l i n hydatid i n f e c t

i o n s . No tox ic symptoms developed oven 1iie animals were

t r e a t e d fo r severa l years * ' ^ . Bunamidine hydrochloride

i s a l so e f fec t ive aga ins t E.mul. ti. 1JDCiilar±s i n dogs a t a

dose of 40 mg/kg 2 2 6 .

Bunamidine hydroxynaphthoate, a t a single o ra l

dose of 100 mg/kg c leared 97$ of E.granulosus in fec t ion

from 12 of 15 dogs 2 5 8 .

Mebendazole (12) i s another recent drug which has

been f^und to exhibi t high a c t i v i t y aga ins t B.gra^lp_sus_ at

a s ing le or mul t ip le dose of 1.25-160 mg/kg causing

s ign i f i can t reduct ion of p a r a s i t e s i n d i f fe ren t animals ^ ~ .

35

Mebendazole, given i n t rape r i tone a l l y a t 75-150 mg/kg d a i l y 241

f o r 3 days , was 95-100$ e f f e c t i v e a g a i n s t B . m u l t i l o c u l a r i s

P r a z i q u a n t e l (£2) i s i h e l a t e s t drug i n t r o d u c e d

to t r e a t h y d a t i d d i s e a s e s i n dogs, c a t s and sheep wi th h igh 242 243 s u c c e s s . I t i s 100$ e f f e c t i v e a g a i n s t B . g r a n u l o s u s f

244 / and E . m u l t i l o c u l a r i s a t a dose of 5 mg/kg.

5» Oonelusion

I t i s ev iden t from the p r e s e n t survey t h a t a number

of b road-spec t rum a n t h e l m i n t i c s have been developed

r e p l a c i n g old t r a d i t i o n a l d rugs which can bo used s u c c e s s

f u l l y to o r a d i c a t o v a r i o u s g a s t r o i n t e s t i n a l he lmin ths from

both man and domest ic a n i m a l s . However, keeping i n view

the h igh r a t e of i n c i d e n c e of i n t e s t i n a l h e l m i n t h i a s i s

d i s e a s e , r i s k of r e i n f e c t i o n and lack of l o n g - e f f e c t i v e

d r u g s , the s ea rch f o r newer chemotherapeut ic agen t s s t i l l

c o n t i n u e s . There i s ample scope to develop l o n g e r - a c t i n g

drugs e f f e c t i v e on immature , mature and c y s t i c forms of the

worms. Syn thes i s of l a r g e number of compounds based on

emper i ca l aid s emi -emper i ca l approach and e v a l u a t i o n of t h e i r

a n t h e l m i n t i c e f f i c a c y and d e t a i l e d SAR of p o t e n t drug s e r i e s

would h e l p i n e n l i g h t e n i n g newer avenues .

36

P . A . J . J a n s s e n , PE£^,._^ru^_Res. , 1 8 , 191 (1974) .

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by R . J . S c h n i t z e r and E.Hawking, Academic p r e s s ,

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pergamon p r e s s , Oxford, 1972 p . 1 4 5 .

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37

1 3 . D.Huggins, Ana±s.JEac,_ n a c . Sande pub 1 . Med.. Trop_._ L_iab . ,

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38

T.A.Mi l l e r , fe^^JTet^ j t e s . , 27, 54 ( 1 9 6 6 ) .

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97_, 371 (1975) .

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1799 (1978) .

51

200. T . P . K i s t n e r , D.Wyse, R . A . S c h i l t z , E.Averkin and

A.Cary, V e t ^ _ p a r a s i t . , 5 , 195 ( 1 9 7 9 ) .

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and A . J . H i g g i n s , Verb.^ Rejo., 104, 338 (1979) .

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R . C . P a r i s h , B x n e r i e n t i a , ^ 2 , 702 (1976) .

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121 (1978) .

206. S.Lloyd, E . J . L . S o u l s b y and V . J . T h e o d o r i d e s ,

E x p e r i e n t i a . £ 4 , 732 (1978) .

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1574 (1978) .

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129275 (1975) .

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P.Andrews, Gez^jOffen. , 2331713 (1975) ;

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2362539 (1975) ; C h e m ^ J b s t r . , 84, 5007 (1976) .

52

2 1 1 . J . S e u b e r t , R .Poh lkc , H.Thomas and P.Andrews,

Ger. Off o n . , 2441261 (1976) ; C h j n u ^ b s t r . , 85 ,

5687 (1976) .

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S£?Bj~M^tr.'» .§£> 142999 (1976 ) .

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1036 (1977) .

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87, 95211c ( 1 9 7 7 ) .

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Arzne im-Forsch . , 2 1 ( I ) , 5 42 (1981) .

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Wschr . , 89, 255 (1976) .

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115 (1977) .

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19, 212 (1975) .

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No.10, 81 (1974 ) .

53

226. T.Sakamoto, M.Or ihara , T . S a r a s h i n a , Y. l sh imoto and

H.Kamiya, Jap_, ._J ._£arasi t ,^ , 20, 120 (1971) .

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B u l l . J / H O . 22» 67 (1968) .

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] i § A e ^ £ a r j j a n » i > 46° ( 1 9 7 5 ) .

235. F .L .Andersen , R.M.Loveless a i d L .A. Jensen ,

A£i . J^_I i i i ._§^s« » 3£ , 673 (1975) .

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Vet , pa r a s i t . , 2 , 299 (1976) .

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ggts,»-Vpt^, , So i . t 19 , 299 (1975 ) .

http://Vejt._B.ec

A . I . K r o t o v , L.V.Rusak, S.A. T re t ' y akov and

A. I .Chernyaeva , c i t e d i n H e ^ . _ A b s t r . , 49, 4614

(1980) .

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Acta .Paras i J A i j _lugpj lav ica t 7 , 75 (1976) .

N.Gtlra lp , Y . T i g i n , T.Oguz, R . T i n a r and A.BurgA,

J?S\. J igAj^^ev . , No. 2 , 129 (1976 ) .

M.A. Gemmell, P .D.Johns tone and G-. Qudemans,

Res. Yet. S c i . . 2£ , 121 (1977) .

C h a £ t e r ^ l _

SYNTHESES OP POTENTIAL NEMATODICIDAL AND

CESTODICIDAL AGENTS

55

1 . INTRODUCTION;

I n 1947, when S t o l l p r e s e n t e d a world-wide

survey of v a r i o u s he lmin th i n f e s t a t i o n s i n man, i t was

found t h a t ihe number of s u b j e c t s s u f f e r i n g from d i f f e r e n t

i n t e s t i n a l h e l m i n t h s was n e a r l y 2000 m i l l i o n * . This may

be a t t r i b u t e d p robab ly due to l a c k of s u i t a b l e drugs and

i n a d e q u a t e knowledge of v a r i o u s a s p e c t s of the d i s e a s e

a t t h a t t i m e . Since t h e n , more than t h r e e decades have

passed b u t t h e number of c a s e s wi th i n t e s t i n a l nematode

and ces tode i n f e c t i o n s does n o t seem to have d e c l i n e d

d e s p i t e s e v e r a l measures taken to e l i m i n a t e h e l m i n t h i a s i s

from masses . I t i s e s t i m a t e d t h a t more than 2500 m i l l i o n

people s u f f e r from d i f f e r e n t forms of i n t e s t i n a l nematode 2 "3

i n f e c t i o n s *J w h i l e more than 870 m i l l i o n people ca r ry

the ce s tode p a r a s i t e s ' .

Although the poor s a n i t a r y h a b i t s , l ack of p rophy lax i s

and p reva l ence of p r o p e r n a t u r a l c o n d i t i o n s f o r development

of he lmin th j u v e n i l e s a r e ihe main c r i t e r i o n s f o r the

overwhelming i n c r e a s e i n t h e i n c i d e n c e of i n t e s t i n a l

h e l m i n t h i a s i s , t h e n o n - a v a i l a b i l i t y of an i d e a l a n t h e l m i n t i c

to masses i s a l s o an impor t an t f a c t o r . An i d e a l an the lmin t i c

Values i n d i c a t e sum of the p a t i e n t s i n f e c t e d wi th d i f f e r e n t nematode and ces tode p a r a s i t e s .

56

for i n t e s t i na l helminthiasis should be safe aid have

broader spectrum of ac t iv i ty which could be used effectively

to eradicate both nematodes and cestodes, i f co-existing,

from the gas t rointes t inal t r ac t . Such type of an

anthelmintic would certainly play a v i t a l role in the

treatment of such diseases because of the high concurrence

of multiple helminth infections in several tropical and

sub-tropical regions of the world.

Since l a s t f if teen years, a good progress has been

made in the chemotherapy of in tes t ina l helminthiasis. In

addition, a more detailed study has been carried out

directed towards the biochemistry of the helminth parasi tes ,

host-parasi te relat ionships and mode of action of several

known anthelmintics. This has greatly helped in providing

be t t e r treatment of t h i s disease in humans. The evolution

of powerful anthelmintics derived from benzimidazoles,

arylisothiocyanates and imidazolines has successfully

eliminated several bottle-necks (such as toxici ty and

selective action of c lass ical drugs) in the chemotherapy

of man and domestic animals-7. However, the final answer

to the problem has not yet been achieved. I t i s in th is

context that the pursuit to find be t t e r chemotherapeutic

agents for the treatment of in tes t ina l helminthiasis s t i l l

continues.

57

2» BASIS OF WORK;

One of the most remarkable achievements i n the

modern chemotherapy of h e l m i n t h i a s i s has been the

r e c o g n i t i o n of benz imidazo le nuc leus as a u s e f u l pharma

cophore fo r the s y n t h e s i s of p o t e n t ant inematode d rags .

This has r e s u l t e d i n the d i scove ry of a s e r i e s of

benz imidazo le a n t h e l m i n t i c s p o s s e s s i n g powerful a c t i v i t y

a g a i n s t d i f f e r e n t he lmin th p a r a s i t e s i n man arid an ima l s . n

2-phenylbenz imidazo le ( 1 , phenz ido le ) i s the f i r s t

member of t h i s s e r i e s which has been used to t r e a t animal

h e l m i n t h i a s i s i n e a r l y 60»s i n combinat ion wi th pheno th-

i a z i n e . S u b s t i t u t i o n of the phenyl r e s idue i n phenzidole

by a 4 - t h i a z o l y l moiety gave t h i a b e n d a z o l e (2) which

proved t o be a h i g h l y s u c c e s s f u l drug i n the t r ea tment

of hookworm i n f e c t i o n s , c r eep ing e r u p t i o n and a lso showed

an t i i n f l ammato ry a c t i v i t y . The d i s cove ry of t h i s b road

spectrum a n t h e l m i n t i c s t i m u l a t e d r e s e a r c h i n the

benz imidazole a n t h e l m i n t i c s i n v a r i o u s l a b o r a t o r i e s of

the wor ld . The e f f o r t s r e s u l t e d i n the s y n t h e s i s of

cambendazole (j5), a n o t h e r congener of t h i a b e n d a z o l e , with

po ten t a n t h e l m i n t i c a c t i o n , c a r r y i n g a 4 - t h i a z o l y l and

i -p ropoxycarbonylamino func t ion a t 2 and 5 - p o s i t i o n s

r e s p e c t i v e l y of benz imidazo le r i n g .

58

The s u b s t i t u t i o n of a ry l and h e t e r o a i y l group by a

carbalkoxyamino function a t 2-pos i t ion of benzimidazole

proved to be highly f r u i t f u l as severa l compounds (4-11)

were shown to possess high cure r a t e s against var ious o

human and animal helminth in fec t ions . The most ac t ive

compounds of t h i s s e r i e s are mebendazole (j>) and

fenbendazole (7) which showed great promise in chemother

apy of human and animal i n t e s t i n a l nematodes. Some of a ry l i so th iocyana tes such as phenyl i so th io-

cyanate ( l 2 j " and 1,4-phenylenediisothiocyanate ( r j , 10 b i toscana te ) are highly e f fec t ive in e l iminat ing

hookworm i n f e s t a t i o n s from d i f f e r en t hosts including

humans.

Several d i a r y l su l f ides and sulfones have also been

shown to exhib i t high ces tod ic ida l a c t i v i t y from t h i s

l abo ra to ry . The most ac t ive compounds of t h i s s e r i e s

are 1, 4-di isothiocyanatodiphenyl . sulf ide (14) and

sulfone ( I S ) 1 1 .

Although severa l drags have emerged possessing high

a c t i v i t y against d i f f e ren t human and animal helminth

p a r a s i t e s , none can be an idea l as most of them e i t h e r

possess low the rapeu t i c ind ices or i f safe do not el iminate

a l l the g a s t r o i n t e s t i n a l nematodes and cestodes since

mixed helminth i n f ec t ion i s a common and concurrent

59

I! 7 N H

( p h e n z i d o l e )

§..

7,

io»

1 1 ,

R

R

R

R

R

R

R

R

H

h R

3, R

H (Thiabendazo le )

NHCOOpr^,(Cambendazole)

JL H 3

= Bu£,(parbenda»ole)

= Coph (Mebendazole)

= Opr, ( Oxibendazole)

= Sph (Fenbendazole)

= SOph (Oxfendazole)

= SPr (Albendazole)

= COC6H4P(£)(Plubendazole)

- ° ° -<r j (G ic lobendazo le )

1 6 , R = D i f f e r e n t

s u b s t i t u e n t s

R = N-acy l and N - a r o y l group

1 7 , R = CF,, R1 = H 5 R

18» R = H, RX= S u b s t i t u t e d

phenyl 1£ , R = H, R1 = N02

20, HOE-33258 OH

1 2 -R-TT

H 2 1 , X = S,S0 2

60

problem in severa l developing count r ies of the world.

Hence, the need to develop new compounds possessing a l l

the requirements of an i d e a l drug can not be overlooked.

Keeping in view, the v e r s a t a l i i y of benzimidazole

nucleus in bu i ld ing molecules with wide-spectrum of

b i o l o g i c a l a c t i v i t y , i t was considered r a t iona l to

synthesize va r ious N-heteroarylbenzimidazoles and AC

b e n z t h i a z o l e s of the type I , I I wi th an aim to enhance the

I , R = CH5, H

X = NH, S

RX= CH3, H, NHCOOBt, SH

R2= NOS, FHCOOH3, NHCOH

b i o l o g i c a l p r o f i l e of benz imidazo le s as a l s o to nap out

the minimal s t r u c t u r a l r equ i rements f o r op t imal a c t i v i t y .

The s y n t h e s i s of I and I I was a l so suppor ted by the f a c t

t h a t s e v e r a l 5 ( 6 ) - a c y l , a roy lamino , 5 - s u b s t i t u t e d phenyl 12—17 and 2 - t r i f l u o r o m e t h y l b e n z i m i d a z o l e s (16.-12.) show

All the p r o t o t y p e molecu les have been denoted i n Roman numbers whi le -fee de f a c t o compounds s y n t h e s i z e d are given i n Arab ic numbers. "~

61

marked anthelmint ic a c t i v i t y (Scheme 1-3).

The powerful anthelmint ic a c t i v i t y exhibi ted by

seve ra l alkyl 5 (6 ) - subs t i t u t ed benzimidazole-2-carbamates

(4-12.) , some of which even used to t r e a t human helmin

t h i a s i s , i s thought to be due to an appropriate

subs t i t uen t a t 5 (6 ) -pos i t ion and carbamate moiety a t

2-pos i t ion of benzimidazole r i n g . Maintaining these

minimal s t r u c t u r a l requirements i t was considered of

i n t e r e s t to synthesize a s e r i e s of di-benzimidazole s of

the type I I I with d i f fe ren t subs t i t uen t s a t 2 , 2 ' - p o s i t i o n s ,

This work was ca r r i ed out to study the role of benzimi

dazole ring as a c a r r i e r molecule in y i e ld ing high

b i o l o g i c a l a c t i v i t y and also to e s t a b l i s h the s t r u c t u r e -

a c t i v i t y r e l a t i o n s h i p in 2 ,5 -d i subs t i t u t ed benzimidazoles

(Scheme 4-11).

H I I I , R = H, CH , NHCOOCH,, NHCOOEt

X = S, S02 , 00, CH2, 0,

n -SCH9CH~S-, CON NCO

c * \ / Although, a la rge number of 2-arylbenzimidazoles

V ftp

such as phenzidole , thiabendazole , cambendazole , T O

H0E-33258 (20) have been shown to exh ib i t powerful

anthelmint ic ac t ion in human and animals, a de ta i l ed study Discussed in Sec .3 .

62

directed towards exploring the "biological potential of o

v a r i o u s 2 - a r y l b e n z i m i d a z o l e s i s s t i l l l a c k i n g . Hence,

i t was proposed to s y n t h e s i z e a s e r i e s of 5 (6 ) -pheny l -2 -

s u b s t i t u t e d a r y l b e n z i m i d a z o l e s and t h e i r c y c l i c ana logs

of t h e t y p e IV, V (Scheme 1 2 ) .

IV, R = 2-tfH2, 4-NH2, 4-NCS

4-NHC00Et, 4-NHC000H5

V, X = 0,S

11 The demons t ra t ion of high c e s t o d i c i d a l a c t i v i t y of

4 , 4 ' - d i i s o t h i o c y a n a t o d i p h e n y l s u l f i d e (14) and 4 , 4 ' - d i i s o -

11 t h i o c y a n a t o d i p h e n y l su l fone (15„) has e s t a b l i s h e d a

d e f i n i t e r o l e of s u l f i d e and sul fone l i n k a g e i n he lminth

chemotherapy. This f a c t was f u r t h e r suppor ted by

i n t r o d u c t i o n of fenbendazole (7) as a broad spectrum

a n t h e l m i n t i c and 2 - a r y l t h i o and su l fono benz imidazo les

(21) r e p o r t e d by e a r l i e r workers i n t h i s l a b o r a t o r y wi th 19 h igh c e s t o d i c i d a l a c t i v i t y . These o b s e r v a t i o n s l e d us

to s y n t h e s i z e v a r i o u s s u b s t i t u t e d d i a r y l s u l f i d e s and

s u l f o n e s and t h e i r r e l a t e d compounds of the type VI

where one of the a r y l s of 14 and 15_ has been r e p l a c e d

by more v e r s a t i l e benz imidazole pharmacophore and to

63

evaluate the i r "biological ac t iv i t i e s (Scheme 13 and 14).

RxXXxCCK H

V I , R = H, 0H 3 , JtfHCOOCH,, NHCOOEt X = S, S0 2 , 0

&K NHAC, NH2, NCS

S y n t h e s i s of h i g h e r homolog of fenbendazole (7) and

i t s oxygen ana log was a l so under taken i n o r d e r to e v a l u a t e

the change i n i t s b i o l o g i c a l a c t i v i t y by i n t r o d u c t i o n of a

CHp u n i t a t 5 - p o s i t i o n of benz imidazo le r i n g (VII )

(Scheme 1 5 ) .

X CH^^Y^^-N^ JJ

&' ~LXX V I I , R = CH^, C2H5, X = 0,

N ^NHCOOR H

The h igh c e s t o d i c i d a l a c t i v i t y of 14 and 15_ prompted

u s f o r a f u r t h e r probe i n "this d i r e c t i o n . Henco, few

more d i i s o t h i o c y a n a t o d i a r y l s u l f i d e s and s u l f o n e s of the

type VIII were p r e p a r e d and e v a l u a t e d f o r t h e i r c e s t o d i c i d a l

a c t i v i t y where t h e d i s t a n c e between two a r y l t h i o and

su l fono f u n c t i o n s i s i n c r e a s e d by i n t r o d u c t i o n of two o r

t h r e e CH2 u n i t s . Some o i l i e r a c t i v e pharmacophores such

64

as 1, 4-dicarbonylpiperazine and 1-carbonylpiperazine

have also been introduced between two phenyl r ings

(VIII) and the change in a c t i v i t y was s tudied (Scheme

I 6 , t o $ . 2 0 ) .

VI I I , R = NHAe, KH2, N02, NCS

X = S(CH2)nS, S02(CH2)nS02 , n = 2,3

/—\ / \ CON N , CON NCO

\ / \ — /

Despite 1,4-phenylenediisothiocyanate (1£, b i toscana te )

has been used to t r e a t various hookworm in fec t ions ,

i t has some ser ious s ide e f fec t s and i s a lso tox ic to

animals . Hence i t s c l i n i c a l a c c e p t i b i l i t y i s s t i l l

doubtful and conf l i c t ing views have been reported

This led us to carry out some s t r u c t u r a l changes in

the parent molecule by in t roduc t ion of e i t h e r piperazine

or benzimidazole res idues , which are accepted pharma

cophores in antinematode drugs, on e i t h e r side of

i so th iocyanato funct ion . This i s in conjunction with

the fac t s 1iiat s ome of the a ry l th iou reas and ureas 21 22 show marked an the lmint ic a c t i v i t y ' . Thus, the

compounds of the types IX-XI were synthesized and

screened for t h e i r antihookworm a c t i v i t y (Scheme 17

and 18 ) .

65

*f R X

N \ N N ~ R

H \ /

^

IX, R2 = CH,, 0H2Ph, Ph , COOEt

R1 = 3-N02 , 4-N02 , 4-NH2,

4-NCS

R = H, CI

X = S, 0

¥yVR

X, Rx = N0 2 , NH2, NCS

R =* H, 01

X = Sf 0

•NHCOCH,

H

XI , R = H, CI

During the r e a c t i o n of t h iooa rboxamides , th ioamide

and t h i o u r e a s wi th t h i o p h o s g e n e , the unusua l d e s u l p h u r i z -

a t i o n of these compounds was observed which was s t u d i e d in

d e t a i l by c o n v e r t i n g a number of th iooarboxamides ,

th ioamide and t h i o u r e a s i n t o t h e i r co r respond ing

carboxamides , amide and u r e a s . The mechanism of

d e s u l p h u r i z a t i o n has a l s o been d i s c u s s e d (Scheme 1 9 ) .

66

3 . GHMISmY:

3 .1 Synthesis of 2 - subs t i tu ted 5(6)-N-heteroarylben-

zimidazoles

Benzimidazole (£2) and 2-methylbenzimidazole (2/3),

obtained by reac t ion of (3-phenylenediamine with formic and 23 a c e t i c acids , were n i t r a t e d using HNO -HpSCK mixture to

give 5(6 )-nitrobenzimidazoic (24) and 2-methy 1-5(6 ) - n i t r o -O A

benzimidazole (,25) . Ca ta ly t i c hydrogenation of 2A and 2_5

using Raney-nickel i n a paar hydrogcnator afforded the

respect ive 5(6)-aminobenzimidazoles (26_ and 27) , which

were condensed with 2,4-dini t rochlorobenzene in e thanol i n

presence of t r io thylamino to y i e ld 5 ( 6 ) - ( 2 , 4 - d i n i t r o -

phenyl)aminobenzimidazole (28) and 2-methy1-5(6)-( 2 ,4 -

dinitrophenyl)aminobenzimidazole (29) r e spec t ive ly .

Hydrogenation of 28 and 29 in presence of Raney-nickel

c a t a l y s t gave the corresponding 5(6)-(2,4-diaminophonyl)

aminobenzimidazoles (^0 and .31). Be t te r y i e lds of £0 and

^1 were obtained by reducing 28 and 2£ with hydrazinc-

hydrate and Raney-nickel in eth.anol-THF mixture. Cyclization

of £0 snd- 51 with formic and a c e t i c acids r e su l t ed in

formation of 2 - s u b s t i t u t e d - 5 ( 6 ) - ( 2 , 5 - d i s u b s t i t u t e d - l -

benzimidazolyl)benzimidazoles (32-35) (Scheme 1 ) .

6?

— ^ ^ M HNO. —rf i

R' H

22, R = H

22, R = GH3

H 2 S0 4 ' ^ H

24, R = H

2£, R = CH

NO,

Ra-Ni, H2

^NAA:

2 2 , R = H, RJ = ^

2 4 , R = CH3, R1 = H

2 5 , R = R1 = CH3

Scheme 1

68

3.2 Synthesis of 2 - subs t i tu t ed 6-H-heteroaryl

benzthiazoles Of.

N i t r a t i o n of benzthiazole and 2-methylbenzthia-27 zole ' -with M O T - H 2 S O mixture gave 6-n i t robenz th iazole

(56) and 2-methyl-6-ni t robenzthiazole (2,7) r e spec t ive ly .

Reduction of 2§. with SaClp-HCl gave 6-aminobenzthiazole

(58) . However 6-amino-2-methylbenzthiazole (39) could 27 not be prepared by l i t e r a t u r e method but i t was obtained

in good y i e ld by reduct ion of 21 with hydrazine-hydrate and

Raney-nickel. Reaction of 38. sxxd 59 with 2, 4-dinitr-~>nhloro-

benzene in ethanol in presence of t r ie thylamine gave good

y i e ld s of 6-(2 ,4-dini t rophenyl)aminobenzthiazole (40) and

2-methyl-6-(2,4-dini t rophenyl)aminobenzthiazole (41) ,

which were reduced smoothly using freshly washed Raney-nickel

and hydrazine-hydrate in ethanol-THF mixture to y ie ld the

corresponding 2 - s u b s t i t u t e d - 6 - ( 2 , 4-diaminophenyl)aminoben-

z th iazo les (42 and 45 j . Treatment of 42 and 43_ with

thiophosgene in acetone afforded 2-subs t i tu ted-6- ( 2 -

mercapto-5- isothiocyanato- l -benzimidazolyl )benzthiazolcs

(44 and 45.). The cyc l i za t ion of 42 and 45_ was car r ied out

by t r e a t i n g with formic and ace t ic acids to y i e ld d i r e c t l y

2 - s u b s t i t u t o d - 6 - ( 2 , 5 - d i subs t i t u tod- l -b en zimidazolyl b e n z t h

i azo l e s (47-50). A s i m i l a r c y c l i z a t i on of J£ with 1,5-

dicarbothoxy-S-methylisothiourea in e thanol gave 2-mothyl-6-

[2-carbcthoxyamino-5-(N,N«-dicarbGthoxyguanidino)-l-

benzimidazolyl]benzthiazole (46) i n poor y i e ld (Scheme 2) .

69

R^^S NC-2

1 6 , R

21 . R

5a» R

= H, R1 = N 0 2 3 . g - 1 9

= CH,, R1 = N0 2

= H, R1 = NH2

= CH5, R1 = NH2

•* H I

4 0 , R = H

4 1 , R = CH,

\K

N 2 H 4 . H 2 0 / R a - N i

NH,

46 , R = GOOG2H5 47 , R = R = H

4 8 , R = H, R1 = CH, — 9

4g, R = CH3, R1 = H

5 0 , R = R1 = CH3

Scheme 2

70

Reaction of 3^ w i _ t h 2-ni t robenzoylchlor ide in presence

of t r i e thy lamine afforded 2-methyl-r 6'—( 2-nitrobenzoyl)amino-

benzthiazole (5.1) which was reduced using Raney-niokel and

hydrogen in a paar hydrogenator to give 2-methyl-6-( 2-

aminobenzoyl)aminobenzthiazole (£2) . Reaction of 52 with

thiophosgene in a c e t i c acid-HCl-chloroform mixture afforded

the i so th iocyanate 5J> in poor y i e ld which was converted

thermally i n t o 2-me thyl -6- ( 2- thioxo-4-oxo-3-quinazol inyl)

benzthiazole (,54). The l a t t e r was a lso prepared by react ion

of 5_2 with one mole of thiophosgene (Scheme 3 ) .

3.3 Synthesis of 2 ,2 ' - subs t i t u t ed -5 ,5 ' - d ibenz imidazo ly l

de r iva t ives

m-Chloroacetanil ide (5£) , obtained by acc ty la t ion

of m-chloro an i l ine using AoOH-AcpO, was n i t r a t e d v with

ace t i c a c i d - n i t r i c acid mixture to give 5-ch loro-2-n i t roace-

t a n i l i d e (_5_6). Reaction of £6 with sodium sulf ide in

e thanol yielded the deacotylated su l f ide 3 ,3 ' -d iamine-4 , 4 ' -

d in i t rod iphenyl su l f ide (5_7). I t ' s s t r uc tu r e was confirmed

by NMR of i t s ace ty l de r iva t ive 3,3«-diacetamido-4,4»-

d in i t rod iphenyl su l f ide (£8) obtained by ace ty la t ion of £7

with AcOH-Ac20 mixture . Reduction of 5J7 with ferrous

sulphate-ammonia in acetone gave 3 ,3 ' ,4 ,4 ' - t e t raaminod ipheny l

su l f ide (_5_9). Since t h i s amine (_59) was highly suscept ible

to a e r i a l oxidat ion i t was immediately t r ea ted with formic

71

H2N-

acoci

N0 2

> S ^ ^ C H .

39

0

N H

N=C=S

N

S-" ^CH,CSClo

53

0

• N

H

N

S ^ C H

'NO, 51

R a - N i , H2

V

0 N

S ^ ^CH,

11

CSC1,

0

N

I T ^ S H

N

jj

54

and ace t i c acids a t t h e i r refluxing temperatures to afford

the corresponding dibenzimidazoles (6.0-6J.). Reaction of

£9, with 1,3 -d i carb alkoxy-S-me thy l i so th ioureas in ethanol

gave 2,2»-dicarbalkoxyamino-5,5 '-dibenzimidazolyl su l f ides

(62 and 6J5) (Scheme 4 ) .

4 ,4 ' -Dichlorodiphenyl sulfone (_64) was n i t r a t e d with

HN05-H2S04 to afford 4 ,4>-d ich lo ro -3 ,3 ' -d in i t rod ipheny l

sulfone (6_5_) which was t rea ted with ammonia in DMSO to 31 give 4 , 4 ' - d i a m i n o - 3 , 3 ' - d i n i t r o d i phenyl sulfone (66)^ .

The pos i t i ona l isomer of 6_6, 3 ,3 , -d i amino-4 ,4>-d in i t ro -

diphenyl sulfone (67) was obtained in poor yie ld by d i r e c t

oxidat ion of 5.7 us ing KMnO in 80$ aqueous ace t ic acid.

Reduction of 66_ or 67 with hydrazine-hydrate and Raney-

n i cke l in ethanol-THF mixture gave 3 ,3 ' , 4 ,4<- t e t r a - amino-

diphenyl sulfone (6_8) which was allowed to react with

formic and ace t ic ac ids to afford the 5 ,5 ' -dibenzimidazolyl

sulfone (6J?) and 2 ,2 ' -d imethyl -5 ,5 ' -dibenzimidazolyl

sulfone (70) r e spec t ive ly . Cyclizat ion of 68 with 1 ,3-

dicarbalkoxy-S-methylisothioureas in refluxing ethanol

gave 2,21-dicarbalkoxyamino-5>5'-dibenzimidazolyl sulfones

(71 and 12) (Scheme 5 ) .

4-Acetamidobenzoic ac id (7£) , obtained by reduction

and subsequent ace ty l a t i on of 4-ni t robenzoic acid, was

n i t r a t e d using fuming n i t r i c acid to give 4-ace tanido-3-•z p

ni t robonzoic acid ( 7 4 r . The hydrolysis of 74 in

73

AcHN-

§ 5 . a = ii

£ 6 , R = N02

Na2S

56 ^

RHN

0 ^

'NHR

-NO,

5L R = H

58 , R = GOCH,

R ^ N

N

A, * N"^R

52 [FeS04-NH5

V

//NCOOR CH,S-C

D NNHCOOR

ROOCBN^^N

H HCOOR

Scheme 4

74

64

NaNO,

Cl H 2 S 0 4 ' ( P ^ 2

65

V

NH,/BMSO 5

R'

2 N2H4 .H20

< Ra-Ni

Cycl izat ion

Nl/

7 2 , R = NHC0U0oHc

Ct R

RJ

6 6 , R = N 0 2 , R1 = NH2

a 6 7 , R = NH2 , RJ

/K

KMnO 4

NO,

Schemes

75

c o n c e n t r a t e d HC1 y i e l d e d 4 - a m i n o - 3 - n i t r o b e n z o i c ac id

(15.) > which was reduced wi th Raney-n icke l and H2 i n a 33 p a a r hydrogena tor to g ive 3 ,4 -d iaminobenzoic a c i d (76)

Reac t ion of 1 ,3 -d ica rba lkoxy-S-me thy l i so t h i o u r e a s wi th 76

a f fo rded the c o r r e s p o n d i n g 2-carba lkoxyaminobenzimidazole-

5 ( 6 ) - c a r b o x y l i c a c i d s (77 and 7 8 ) .

Attempts to p repa re 2 , 2 » - d i c a r b a l k o x y a m i n o - 5 , 5 ' -

d i b e n z i m i d a z o l y l ke tone (81 and 82) by F r i e d e l - C r a f t s

a r o y l a t i o n of a l k y l benz imidazo l e -2 -ca rbama te s (72, and

33a ,§0) > ob t a ined by c y c l i z a t i o n of o-phenylenediamine wi th

1 , 3 - d i c a r b a l k o x y - S - m e t h y l i s o t h i o u r e a s , w i t h 77 and 78 d id

n o t work because of t h e i r poor s o l u b i l i t y i n d i f f e r e n t

o r g a n i c s o l v e n t s . ( Scheme 6 ) ,

In an a l t e r n a t i v e approach to p repare 81 and 82,

4 , 4 ' - d i c h l c r o b e n z o p h e n o n e ( 8 3 ) , p repa red from 4 - c h l o r o -

b e n z o y l c h l o r i d e and chlorobenzene i n CS? i n presence of 3 4

A1C1, , was n i t r a t e d u s i n g E^SO^-HNO- to y i e l d 3 , 3 ' -35 d i n i t r o - 4 , 4 ' -d i ch lo robenzophenone (84) . Amination of

84 in DMSO a t 140°C w i t h ammonia gas a f fo rded the 36 co r r e spond ing 4, 4 ' - d i a m i n o - 3 , 3 ' - d in i t robenzophenone (8J>)

which was c a t a l y t i c a l l y hydrogenated u s i n g Raney-n icke l to 37 give 3 , 3 ' , 4 , 4 ' - t e t r a - a m i n o b e n z o p h e n o n e (86) . Reac t ion

of 86_ wi th 1 ,3 -d ica rba lkoxy-S-me thy l i s o t h i o u r e a s i n

r e f l u x i n g e t h a n o l y i e l d e d t h e t i t l e compounds (81 and 82)

i n good y i e l d s . The Wolf f -Kishner r e d u c t i o n of 85_ u s i n g

76

r ^ \ / C 0 2 H

AcHN' 1 . HNO

22

OoH 2 Ra-Ui HO^^^Y*^ —^

H.

ROOCHN ATO S.

H

7 9 , R = OH-

§ 0 , R = C2H5

= COCH,

V

7 7 , R = CH3

7 8 , R = CQHJ-

76

ROOCHN

8 1 , R = CH,

8 2 , R = C5HC

Scheme 6

77

hydrazine-hydrate and potassium hydroxide in s t e e l "bomb

a t 170°C d i r e c t l y y ie lded the 3 ,3 ' ,4 ,4" - t e t ra -aminod ipheny l -

methane (87 ) 5 7 which was cycl ized with 1,3-aicarbalkoxy-S-

methyl isothioureas in ethanol to give 2 ,2 ' -d ica rba lkoxy-

amino-5,5 ,-dibenzimidazolylmethanes (go and 21) • Treatment

of 86 and 87 with formic and g l a c i a l a c e t i c ac ids afforded

the corresponding 5 ,5 ' -d ibenzimidazolyl ketones (88 and

82) and methanes (9,2 and 22.) (Scheme 7 ) .

Acetylat ion of 4-acetamidophenol (£4) using pyr id ine-38 ace t ic anhydride gave 4-acetoxyaoetani l ide (25.) » w n i c t l

was n i t r a t e d using fuming n i t r i c acid to give 4-acetoxy-2-

n i t r o a o e t a n i l i d u (2§.) • Select ive hydrolysis of 2§. with

aqueous KOH gave 3-nitro-4-acetamidophenol (22) which

when t r ea t ed with 5 -ch lo ro -2 -n i t roan i l i ne (28) and 5-chloro-

2 - n i t r o a c c t a n i l i d e (£6_) could not y i e ld 22 a n d 1 Q 0 under

d i f f e ren t experimental condi t ions . In another attempt,

4-acetamidophcnol (24) was t r ea ted with 5 -ch loro-2-n i t ro -

aco tan i l ido (5__6) to give 5-( 4-acetamidophenoxy ) - 2 - n i t r o -

ace t an i l i de (101). N i t r a t i o n of 101 under d i f fe ren t

experimental condi t ions also did not y i e ld the required

in termediate 100 which could have led to the formation of

the compounds of the type m (X=0). (Scheme 8 ) .

4 ,4 ' -Din i t rod ipheny l e the r (102) 5 9 , prepared from

4-ni t rophenol and l -chloro-4-ni t robenzene in. presence of

KOH in dry DMF, was reduced with hydrezlne-hydrate and ^

78

NO,

- >

C l " ^ ^

Ra-M

H2N H,

C y c l i z a t i o n

V

8 1 , R

82, R

88 , R

2 0 , R

a2., a

= NHCOOCH •z> X = CO

NHCOOG2H5, X = CO

H, X = CO

C H , , X = CO

NHCOOCH,, X = CH2

NHCOOC2H5, X = CH2

H, X = CH2

0x1-7, X = OHp

814

NH,

M/

Wolff-Kishner Redn

Scheme 7

79

^ V ° R

AcHN'

'NO,

2i» R = H

25., R = COCH,

9 4

A c H i r ^ /

•NHAc

*N0o

1 0 1

° 2 N V ^ : : V 0C0CH3

AcHN'

96

*

^ N - ^ ^ v ^ 0 1 1

A c H N ' ^ ^

97

NO,

0

- >

AcHN

NHR

CI~(JHTO2 |

^ v ^ 0 ^ ^ ^ 5,6, R=C0CH,

^A N0 o

9 9 , R = H

1 0 0 , R=C0CH, ^

i i i I

I I I (X = 0)

Scheme 8

80

Raney-nickel to give 4, 4'-diaminodiphenyl e the r (1031) .

Acetylat ion of lOJ, with acet ic anhydride gave 4 , 4 r -

diacetamidodiphenyl e t h e r (10£) which was n i t r a t e d using

a c e t i c a c i d - n i t r i c ac id mixture to y i e ld 4 ,4 f -diaoetamido-

3 ,3 ' -d in i t rod ipheny l e the r (105.) in good y i e l d . Hydrolysis o f i9.5_ by 50/» HC1 or 10$ aqueous KOH gave 4,4«-diamino-3,

3 ' -d in i t rod ipheny l e the r (106) which was conveniently

reduced with f reshly washed Raney-nickel and hydrazine-

hydrate to afford 3 ,3 ' , 4 , 4 ' - t e t r a - aminod ipheny l e the r (107).

Treatment of 107 with 1,3-dicarbalkoxy-S-methylisothioureas

yie lded the t i t l e compounds 2 ,2 t -d icarbalkoxyamino-5 ,5 ' -

dibenzimidazolyl oxides (110 and 111) . Fur ther react ion of

86_ with 98$ formic and g l a c i a l a ce t i c ac ids yielded the

corresponding dibenzimidazoles (108 and log) (Scheme 9 ) .

Reaction of 1 ,2 -e thaned i th io l with _5_6_ in presence

of KOH did not afford the desired compound 113 which would

have y ie lded l ,2-d i - (3-amino-4~ni t rophenyl th io)e thane (112)

on deace ty la t ion . The l a t t e r compound was prepared

conveniently by t r e a t i n g 98 with 1 ,2 -e thanedi th io l which

was reduced with 10$ Pd/C in la rge excess of ethanol under

high pressure of Hp in a paar hydro gen at or to give very

poor y i e l d of the te t ra-amine 114. Treatment of 114 with

1,3-dicarbalkoxy-S-methylisothioureas in refluxing ethanol

gave l ,2-di- (2-carbalkoxyaminobenzimidazolyl-5(6)- thio)ethanes

( i i l -an* 116.) (Scheme 1 0 ) .

81

0

AcHW

0 ^

AcM

OH CI

NO, 0

0.

102

Si/

R a - N i , H2

0

1 0 4

(CH3CO)20

<

•NHAc

0

HNOy' ftCOtt

•NO,

\ ^ ^ N H A

HVOJI ^ V ' V

H 2 r ^ ^

i25.

O y c l . H 2 N

< -H2N

106

0

107

NH000CH,

NHOOOC2H5

"'T~"~

1TH.

Scheme - 9

R H L K ^ ^ V 1 CI + H^-CH2-0H2-SH

£ 6 , R = COCH,

9 8 , R = H

WW-

0

V S - C H 2 - C H 2 - S > s v X ^ s ^ N H R

1 1 2 , R = H

1 1 ^ , R = COCH^

112 \^

P d - C , H2

H2IS<^Vvi /S"* CH2""CH2 " S Y ^ / ^

\ANH„ n2r^x 114

ROOCHN

S- CHp-GH. - S v . ^ V , - 1 S T

1 1 5 , R = CH^

1 1 6 , R = C2H

H NHCOOR

Scheme 10

83

4-Chloro-3-nitrobenzoyl chlor ide (117), obtained by

treatment of 4-chloro-3-ni t robenzoic acid -with S0C12» was

reacted with anhydrous piperazine to get l , 4 - d i - ( 4 - c h l o r o -

3-ni t robenzoyl)p iperaz ine (119). Treatment of llg, with

ammonia in DMSO gave very poor y i e ld of the diamine 121

which was prepared in b e t t e r y i e lds by t r e a t i n g anhydrous

piperazine with 4-acetamido-3-nitrobenzoyl chloride (11§)

in dry benzene to get l ,4 -d i - (4-ace tamido-3-n i t robenzoyl )

piperazine (120). The se lec t ive .hydrolysis of 120 with

aqueous KOH in ethanol a t room temperature gave 1 ,4-di -

(4-amino-3-ni t robenzoyl)piperazine (121) . Reduction of

121 using Raney-nickel and hydrogen in THF or ethanol a t

3.5 kg/cm pressure in a Paar hydrogenator afforded 1,4-di-

(3>4-diaminobenzoyl)piperazine (l£2,) which reacted with

1,3-dicarbalkoxy-S-methyl isothioureas in ethanol to yield

the corresponding 1,4-di-(2-oarbalkoxyaminobenzimidazolyl-

5(6) -carbonyl )p iperaz ines (123 and 124) (Scheme 11) .

3.4 Synthesis of 2 ,5(6)-diarylbenzimidazoles and

t h e i r cyc l ic analogs

4-Jimino-3-nitrobiphenyl (l£5_) , obtained by

subsequent n i t r a t i o n , reduct ion, ace ty l a t ion , n i t r a t i o n

and hydrolysis of b iphenyl , was reduced with hydrazine-

hydrate and Raney-nickel in ethanol-THF mixture to give

3,4-diaminobiphenyl (126_)41. Treatment of 126 with 1 ,3-

dicarbethoxy-S-methyl isothiourea afforded e thyl 5(6)-phenyl-

T R-

1 1 7 , R = 01

1 1 8 , R = NHAc

HN NH \ /

N-CO

XT <

CH*S-C \

0 0 - N N -CO.

\ J

NOOOR

NHCOOR

1221 R = NH000CH,

1 2 4 , R = NHCOOOoH,-

Scheme 1 1

85

benzimidazole-2-carbamate (127). When 12£ was t r ea t ed with

d i f fe ren t benzoyl ch lo r ides in re fluxing dry benzene the

corresponding 4 —(aroyl)amino-3-nitrobiphenyls (128-13.0)

were obtained. Reduction of 128-130 with hydrazine-hydrate

and Raney-nickel gave 3-amino— 4 — (aroyl)aminobiphenyls

(131-133) which were subjected to acid catalysed cyc l iza t ion

in ethanol to give the corresponding 2-subs t i tu tod 42 bcnzimidazolcs (134-136) . Treatment of 136 with thiophos-

gene in acetone y ie lded 2-(4- isothiocyanatophenyl)~5(§)-

phenylbenzimidazole hydrochloride (13_9). S imi lar ly ,

reac t ion of 13J> with e thy l and methyl chloroformates

afforded 2-( 4-carbalkoxyaminophenyl)-5(6)-phenylbenzimidazolos

(iiQ. a n d 141). Treatment of 13£ with a lky l chloro formates

or potassium e thy l xanthate yie lded the cycl ic products

9-phenylbonzimidazo[l ,2-c]quinazolin-6-one and 6-thione

(111 ^ ^ 138). When 135 was allowed to reac t with methyl

and e thy l chloroformate in acetone i t y ie lded a mixture of

137 and 114. The s t ruc tu re of 137 and 13_8 was confirmed by

t h e i r mass and ^C-NMR spec t ra . 137 and 138 had t h e i r M

a t m/z 311 and 327 which corresponds to the cyc l i c products, 13 The •'C-NMR spectrum of 1^7 in DMSO-dg showed the chemical

s h i f t of C-9 a t 135.31 6 which was in agreement with the

ca lcu la ted value (136. I 6) i f s t ruc tu re 137 i s taken in to

account. Had -the cyc l i za t i on occurred through the o the r

n i t rogun to y i e ld i t s pos i t i ona l isomer 10-phenylbenzimidazo

88

[ l , 2 - c ]qu inazo l in -6 -one , the ca lcu la ted value for C-10 would

have been a t 6 150.0. The ca lcu la t ion i s based on the

e f fec t of var ious groups present in 5-phenylbenzimidazole

fused with a quinazolin-nucleus ' . The s t ruc tu re of 137 13

was fur ther supported by the fac t t h a t C-NMR of 5 (6 )-phenyl-

benzimidazole and 2-(2-aminophenyl)-5(6)-phenylbenzimidazole

(i!5.) showed the absorpt ion for 5(6)-carbon a t 6 133.14 and

132.98 r e spec t ive ly .

Treatment of 13J5 with two moles of thiophosgene in

presence of t r i o thy laminc' y ie lded l - ( 4- isothiocyanatobenzoyl)-

2-mercapto~5-phenylbenzimidazole (14!5)« When 13_£ was allowed

to r eac t with two moles of thiophosgene under s imi l a r

experimental condi t ions , i t yielded only 144 out of three

poss ible products 142, 144 and 14^. The s t ruc tu re was

supported by i t s IR and mass spec t ra . The IR spec t ra of

144 and 145, had sharp bands a t 1640 and 1635 cm"" correspond

ing to C=N absorption of the benzimidazole r i n g . The high

carbonyl absorption a t 1680 and 1710 cm in 144 and 1J£

a lso supported the formation of these compounds ^ thus

excluding the p o s s i b i l i t y of the presence of 146 in the

i s o l a t e d product. The mass spec t ra of both the compounds

had M a t m/z 387 and c lea r ly ind ica ted the l o s s of a t h io l

group (32) from the (M+-l6l) a t m/z 194 in 144 and from

molecular ion a t m/z 355 in 145 which i s not possible in

uncyclized products ,

87

The react ion of 132 with one mole of thiophosgene

r e su l t ed in the formation of only l -(2-aminobenzoyl)-2-

mercapto-5-phenylbenzimidazole (143_) along -with the small

amount of corresponding isothiooyanate 144. The s t ruc tu re

of 14^ w a s confirmed by i t s mass (M+ a t m/z 345), and IR

absorpt ion (1690 cm"1 for NC0N-C6H4-2-NH2)45. Furthermore,

i s o l a t i o n of 144 from the reac t ion mixture can only be

accounted by formation of 143 as intermediate (Scheme 12) .

3.5 Synthesis of 2 - subs t i tu ted 5 (6 ) - (4 - subs t i t u t edph-

enoxy, phenylthio and sulfono)benzimidazoles

Reaction of 4-acetamidothiophenol with 5-chloro-

2 -n i t r oace t an i l i de (^6) and 5 -ch lo ro -2-n i t roan i l ine (98) in

presence of KOH in n-propanol gave excel lent y i e ld s of

5- (4-ace tamidophenyl th io) -2-ni t roani l ine (147) and 5-( 4-

ace tamidophenyl th io) -2-n i t roaoetani l ide (148) r espec t ive ly .

A l t e rna t ive ly , 147 was also prepared by se lec t ive hydrolysis

of 148 with aqueous KOH. Reduction of 147 with hydrazinc-

hydrato and Ranoy-nickol in THF-othanol mixture afforded

4-( 4-acetamidophenylthio)-o-phenylenodiamine (149) which

was condensed with l ,3-dicarbalkoxy-S-methyl isothiouroas- . in

ref luxing ethanol to afford a lkyl 5(6 )-( 4-ace t ami do phenyl

thio )benzimidazole-2-carbamates (150 and 1£1) in good y i e l d s .

142. w a s also t r e a t e d with formic and g l a c i a l ace t i c acids

to givo -the corresponding benzimidazole (152) and 2-mothyl-

benzimidazole (153_). Select ive hydrolysis of amido function

88

r ^ N / N H ;

' < ^ 125

NH 2 .NH 2 .H 2 0

Ra-Ni

f i ^ M I H ,

^X 126

^ ^

G0G1

1 2 8 , R = H

1 2 ^ , R = 2 -N0 2

1 5 0 , R = 4 -N0 2

NCOOC2H5

CH,S-C

\l/ NHCOOCgHc

^ \ -

" ^ ^

— N

N - ^NHCOOG 2 H 5

127

N 2 H 4 . H 2 0 / E a - N i ^ ^ ^

H f| 4-R

0 Ho

l ^ l , R = H

I 5 2 , R = 2-NH2

1 2 5 , R = 4-NH2

H • >

^ ^

1 2 4 , R

Ul> R

1 3 6 , R

-R

X^1

H

2-NH;

4-ITH.

Scheme 12 ( C o n t d . )

83

145 , * = 2-NH2

144, R = 2-NCS

145., R = 4-NCS

Scheme 12

90

i n 15_0 and 151 w i t h 10f* HC1 a f fo rded the a l k y l 5 ( 6 ) - ( 4 -46

aminophenyl th io)benz imidazo le -2- -carbamates (15.4 and 15.5J

A s i m i l a r h y d r o l y s i s of 15.2 and 15? u s i n g c o n c e n t r a t e d HG1

y i e l d e d the c o r r e s p o n d i n g amines (15_6_ and 15_7). However,

when 150 and 15,1 were r e f l u x e d i n 50$ HC1 fo r a l o n g e r

p e r i o d , complete h y d r o l y s i s of t h e compounds took p lace

g i v i n g r i s e to 2-amino-5(6 )-( 4 -aminophenyl th io)benz imidazole

(JL58).

Oxidation of 15_Q.-15J> was ca r r i ed out us ing 80$

aqueous ace t ic acid and KMnO. a t room temperature to yie ld

t h e i r corresponding sulfones (15_9-16_,2) of which 15_§. and

16_0 were s e l ec t i ve ly hydrolysed with 10$ HC1 to y ie ld

a lky l 5(6)-(4-aminophenylsulfono)benzimidazole-2-carbamates

(1§.2. s^-d- 1§.4) • S imi lar ly , l6l_ and 16_2 were hydrolysed

with 50/o HC1 to give 5(6 )-(4-aminophenylsulfono)benzimidazole

(16_6_) and 2-methyl-5(6 )-( 4-aminophenylsulfono)benziinidazole

(167) while hydrolysis of 159 or 160 in 50$ HG1 yielded

2-amino-5(6 )-( 4-aminophenylsulfono)benzimidazole (16J5).

The amines 15jt, 15_5_, 16J5 and 164 were allowed to react with

thiophosgene in presence of t r iothylamine in large volume

of acetone (duo to t h e i r poor s o l u b i l i t y in acetone) to

afford t h e i r corresponding i so th iocyana tes I68,_l6g, 1T2 311(1 112 r e spec t ive ly . Treatment of thiophosgene with

i£I.> i5£>» 166 and 167 in acetone and t r i e thylamine also

yie lded -the- des i red i so th iocyana tes 170, 171, 174 and 175

(Scheme 13) .

NHR

N0 2 AcHN'

•NHR

£ 6 , R = OOCH,

2§> R = H

1 4 7 , R = H

1 4 8 , R = GOOH3

147

^nr AcHN^^^X N - ^ N H A c M ' ^ X '

H COOR 141 150 , R = CH3

1 5 1 , R = 02H5

ir

RC02H

1£4, R = NHCOOCH,

1§5 , R = UHCOOC2H5

156, R = H

i52. * = CH3

I 5 8 , R = NH2

AcHN-^s.

1£2, R = H

±52. R = CH3

Scheme 1? (Contd . )

92

iKXX H

1^2, R = NHOOOCH,

1 6 0 , R = NHCOOC-IL-• — — c. p

1 6 1 , R = H

1 6 2 , R = CH,

NHCOOC2H5

iaa-isi KMnO.

15.Q-15I

162., R = NHOOOOH5

1 6 4 , R

1 6 £ , R = NH2

1 6 6 , R = H

1 6 7 , R = CH,

CSC1,

CSC12

1,54-157 SON

1 6 8 , R

1 6 2 , H

1 7 0 , R

171» R

1 7 2 , R

1 1 2 » R

1741 R

iZ5.. R

u NHCOOCH^,

NHOOOC2H5

H, X = 3

CEU, X =

NHCOOCH-,

NHCOOC2H5

— a

H

X = S

, X = S

s

x = so2

, x = so2

H, X = SO2

CH5, X = S0 2

Schj2m£jL2

93

Reaction of 4-acetami do phenol (94) and 5-chloro-2-

n i t r o a n i l i n e (98) in presence of KOH in dry DMF yielded

5-(4-acetamidophenoxy)-2-ni t roani l ine (176) in 44°/° y i e l d .

176, was reduced with hydrazine-hydrate and Raney-nickel in

THF-ethanol mixture t o give 4-( 4-acetamidophenoxy )-o-

phenylenediamine (177) which was not i s o l a t e d and was

used as such in fu r the r r e a c t i o n s . Reaction of 177 with

1,3-dicarbalkoxy-S-methyl isothioureas in refluxing ethanol

gave a lky l 5(6)-(4-acetamidophenoxy)benzimidazole-2-

carbamates (178 and 179) which were hydrolysed s e l ec t i ve ly

with 10$ HG1 to give the corresponding amines (180 and 181).

Reaction of 177 with formic and g l a c i a l ace t i c ac ids

y ie lded 5(6)-(4-acetamidophenoxy)benzimidazole (182) and

2-methyl-5(6)-(4-acetamidophenoxy)benzimidazole (183)

respec t ive ly which were i s o l a t e d as t h e i r hydrochlor ides .

Hydrolysis of 182 and 18^ in concentrated HC1 afforded

the corresponding amines 184 and 18Jj as t h e i r hydrochlorides

which wore bas i f i ed with aqueous ammonia to givo the free

bases . Thj aminos 180, 181, 184, 185 were t r e a t e d with

thiophosgene in acetone in presence of two moles of

t r ie thylaminc to give t h e i r corresponding 5 ( 6 ) - ( 4 - i s o t h i o -

cyanatophenoxy)benzimidazolcs (186-189) (Scheme 14) .

94

AcHN' • ^ / ^ ^ N 0 o AcHPT^^ \ ^ S j O ?

9 4 98 176

<r HCOOR AcHN-

N 2 H 4 . H 2 0 / R a - N i

•NH^

1 7 8 , R = CH^

122, R * C 2 H 5

177

RC02H

V

N^TTHCOOR Ac H

O s / \

1 8 1 , R = C2H5

V

- N

H 1 8 2 , R = H

1 8 J , R = G H3

SCN-H H

NHCOOC2H5

186 , R = NHCOOCH-

1 8 7 , R

1 8 8 , R = H

1 8 9 , R = CH,

1 8 4 , R = H

1 8 5 , R = CH^

Scheme 1 4

95

3.6 Synthesis of 5(6)-thiophenoxy and phenoxymethyl

benzimidazole-2-carbamates

4-Chloro-3-nitrobenzaldehyde (190.) , prepared

by n i t r a t i o n of 4-chlorobenzaldehyde in KN0,-H2SO4» was

reduced with sodium borohydride in methanol t o give 4-

chloro-3-n i t robenzyl alcohol (191) • Treatment of 191

with ammonia in s t e e l bomb at 150°C gave the corresponding

amino compound 192 which could not be converted to i t s

bromide or chlor ide by action of PBr„ or th ionyl chlor ide ,

However, when 191 was t r ea ted with PBr, in dry benzene i t

gave 4-chloro-3-ni t robonzyl bromide (194) in good y ie ld

which was t r ea t ed with phenol and thiophenol in presence

of K2C0.v in acetone to give 2-nitro-4-(phenoxy) and 2-

nitro -4-( thiophenoxy)methylchlorobcnzenes (19£ and lffi?).

When 194 was allowed to reac t with one mole of thiophenol

in ethanol in presence of KOH i t y ie lded a mixture of 196

and 2~thiophenoxy-5-thiophenoxymethylnitrobenzene (197) in

poor y i e l d s . However, b e t t e r y ie ld of 1£7 was obtained

when two moles of thiophenol was reacted with one mole o f iS 4 . in e thanol ic potassium hydroxide. Reaction of 19,5

with aqueous ammonia solut ion in THF a t 150°C in a s t e e l

bomb gave 2-nitro-4-phenoxymethylanil ine (198) . Similarly

12,6. was t r ea t ed with aqueous ammonia in THF a t 150°C in

s t e e l bomb to y i e l d the amine 199 which could not be

i s o l a t e d . However, 199 was obtained when ethanol was

96

taken as solvent in place of THF in the above reac t ion .

Attempts to reduce l^g with hydrazine-hydrate and Raney-

n i c k e l , Raney-nickel and H2 or FeS04-NH5 were unsuccessful

as i t always gave a complex mixture of the products . In

cont rary , 199 was reduced smoothly with FeSO^-NH* in

acetone to give the required diamine jOO i n good y i e ld

which was t r ea ted with 1,3-dicarbalkoxy-S-methylisothiou-

reas in re fluxing ethanol to afford a lky l 5(6 )-thiophenoxy-

methylbenzimidazole-2-carbamates (201 and 2Q2)"1" (Scheme 15),

3.7 Synthesis of 1 ,2 -d i subs t i tu t ed ethanes and 1,3-

d i s u b s t i t u t e d propanes

Reaction of 4-acctamidothiophenol with 1,2-

dibromoethane and 1,3-dibromopropane in presence of KOH

yie lded l , 2 - d i - ( 4-acetamidophenylthio)ethane (203_) and

l ,3-<ii-(4-acetamidophenylthio)propane (204) which were

oxidized with KMnO. in 80$ aqueous a c e t i c acid to give

the corresponding sulfones (20J? and 206J. Hydrolysis of

203_, 2p_5_ and 206 with concentrated HC1 gave respect ive

l ,2-di - (4-aminophenyl th io) and l ,2-di - (4-aminophenyl-

sulfono)ethanes (2CT7 and 208) and 1,3-di-( 4-aminophenyl-

sulfono)propane (20§) r e spec t ive ly . Treatment of 207-209

with thiophosgene in 50$ aqueous ace t ic acid or 10$ HOI

During the course of our i nves t iga t ion Haugwitz e t a l . 9

reported the synthesis and b io log i ca l a c t i v i t y of" compound 201 with no da ta .

97

O g K ^ x . C H O NaBH 0

CH^OH ->

2 N\ r ^r \ /GH 2 0H

i22

°XJ GH2Br

PBr,

PBr,

^ o r SOGl2

1 9 1 , R = NH;

i2£ f R = Cl

1^4 G-X H

125,, x = o, R

126., X = S, R

127 , X = S, R

Cl

Cl

S C6H5

^ > r

A,

191

NH,

H2OH

192

U- -NHCOOR H

200

Scheme 15

98

afforded the corresponding l , 2 - d i - ( 4- iso th iocyanato-

phenylthio) and 1 ,2-di- (4- isothiocyanatophenylsulfono)

ethanes (210, and 211.) and l , 3 - d i - ( 4-isothiooyanatophenyl-

sulfono)propane (212) . N i t r a t i o n of 20£ and 20_6_ under

d i f f e r en t experimental condit ions f a i l ed to y ie ld the

required d in i t ro compound _21/3 and hence, dibenzimidazoles

of tiae type H I (X=S02-(CH2)n-302 , n = 2,3) could not be

prepared ( Scheme 16 ) .

3.8 Synthesis of s u b s t i t u t e d thiocarboxamides,

carboxamides and th ioureas

Subs t i tu ted phenyl isothiocyanates (219-223)

were prepared by treatment of the corresponding an i l i ne s

(2i i^218) with thiophosgene in acetone or 10fo HC1.

Reaction of 4 - subs t i tu ted piperazines with 219-222

y ie lded the corresponding subs t i t u t ed phenyl -4-subs t i tu ted-

1-piperazinylthiocarboxamides (2_27-.23_8) in good y i e l d s .

Attempts to reduce 227-23_8 by Ranoy-nickel and H2,

hydrazine-hydrate and Raney-nickel, sodium d i t h i o n i t e

2n-CH,C0GH or S&-HC1 were unsuccessful . However, " . '*.

227-252 were successful ly reduced with FoS04-NH, using

largo volume of aqueous ammonia (as they are poorly

soluble even in hot aqueous ammonia). The reac t ions of

amines (2J5£-244), obtained by F G S 0 4 - N H , reduct ion, with

one mole of thiophosgono in acetone led to an unusual

desulphurizat ion of thiocarboxamides to t he i r corresponding

99

AcHN

+ B r ( C H 2 ) n B r -

n = 2 , 3 AcHN

S-(CH2)£&Y^

222.1 n = 2

2 0 4 , n = 3

NHAc

AcHN'

Q q

2 0 5 , n = 2

2 0 6 , n = 3

KMnO 4 H1

• X - ( C H 2 ^

2 0 7 .

2 0 8 ,

2 0 9 .

X

X

X

=

=

=

S, n

so2,

so2,

=

n

n

2

=

=

2

3

X HNO.

*

0 II ?,

°2NV!fV?f(CH2 ^ V ^ V ^ 2

AcHN"

21J5, n = 2 , 3

NHAc SGN

CSC1,

V

X - ( O H 2 ) - X Y ^

2 1 0 , X = S, n = 2

2 1 1 , X = S 0 2 , ii = 2

2 1 2 , X = S 0 2 , n = 3

Scheme 16

100

carboxamides along with formation of i so th iocyanates

which were i s o l a t e d in poor y i e l d s . A s imi l a r react ion o f ^22""^i§ with two moles of thiophosgene yielded the

4~iso th iocyanatophenyl -4-subs t i tu ted- l -p iperaz inylcarbox-

amides (£4£-£5J)) in good y i e ld and no corresponding th io

analogs could be i s o l a t e d . The 4~isothiocyanatophenyl-4~

subs t i tu ted-1-piperaz inyl th iocarboxamides {22jr226.) were

prepared by reac t ion of one mole of 4 - subs t i tu ted

p iperaz ines on 1,4-phenylenediisothiocyanate (2_2J3) in

acetone under high d i l u t i o n a t room temperature and the

product pur i f ied by c r y s t a l l i z a t i o n or by column

chromatography (Scheme 17) .

Reaction of 2-aminobenzimidazole (j2£l) with

4-ni t rophenyl isothiocyanate (219) and 2 -ch lo ro -4 -n i t ro -

phenylisothiocyanate (220) in ref luxing e thy l ace ta te

gave N-( 4-n i t rophenyl) -N ' - (2-benzimidazoly l ) th iourea

(252) and N-(2-chloro-4-ni t rophenyl)-N»-(2-benzimidazolyl)

th iourea (25J>)« The FeS04-NH, reduction of £52 gave the

required N-(4-aminophenyl)-N'~(2-benzimidazolyl)thiourea

(25.4) which was t r ea t ed with two moles of thiophosgene to

y i e l d N-(4- isothiocyanatophenyl)-N'-(2-benzimidazolyl)urea

(2^5) . Similar reac t ion of 4-ominoacetanilide with

221°; and 2_20 gave the N-( 4-acetamidophenyl)-N t -( 4 - n i t r o -

phcnyl) thiourea (,256.) and N-( 4-acetamidophenyl)-N >-( 2-

ch loro-4-n i t rophenyl ) th iourea (2_57) respec t ive ly

(Scheme 18) .

101

csci2

2 1 4 , R = H, R = 4 -N0 2

21£ , R = C I , R 1 = 4-NO,

216,, R = H, R1 = 3-N0 2

2 1 7 , R - H, R1 = 4-NKG(

2 1 8 , R = H, R1 = 4-NH2

^

m HR

V

H

2 2 7 - 2 3 8

N NR

227-232

V

CSC1,

SON YTR f /-A ^ ^ A v N ^ N NR2

\ / H

2 2 4 , R = H, R = CH5

22£ , R = H, R2 = CH2Ph

226 , R = H, R2=COOC2R"5

k A N ^ { NR2 A N H

2CSC12

• >

J C I K ^ Y ' R °

^ > ^ l i ^ N A H

NR

222-244 24^-250

Scheme 17

102

,R R 1 - !

^ N ,

2 1 9 , R = HjR 1 = 4 -N0 2

2 2 0 , R = 0 1 , R 3 ^ 4-N0 2

- N

H

25i

NHCOCH.

V

H

1 25_2, R = H, Rx = N0 2

25_£, R = 0 1 , R1 = N 0 2

25 2 PeS0 4 -NH 5

V

25i» R = H

25_7, R = Cl

HOOCH,

^ > ,

H

25_4 H

N - 0 0 - N - ^ V—

H H W /

CSC1,

NCS < r

255

*NH,

Scsheme 18

103

Keeping in view the a b i l i t y of thiophosgene to

desulphurize th ioureas and thiocarboxamides, the reaction

was extended to thioamide a l so , and i t s conversion to

corresponding amide was demonstrated. Thus, a number of

t h i o u r e a s , thiocarboxamides (2J>8-26_4) and thioamide (2J5J5),

when reacted with thiophosgene in acetone a t room

temperature gave the corresponding ureas and carboxamidos

(267-27^) and amide (.274). The th ioureas and the

thiocarboxamides (2_§j3-2_64) were prepared by reac t ion of

phenyl and a lkyl i so th iocyana tes with corresponding amines.

The products obtained a f te r thiophosgene treatment were

compared (mixed m.p . , Co-I ft and Co-TLC) with the ureas and

carboxamides prepared d i r e c t l y from phenyl or a lkyl

i sooyanates with amines and acetamide obtained by react ion

of a c e t i c anhydride with benzylamine (26j7-g74).

A probable mechanism of desulphurizat ion involves

the i n i t i a l a t t ack of sulphur of t h iou reas , thiocarboxamides

or thioamide (258-26^) a t thiophosgene r e su l t i ng in the

formation of an ac t iva ted complex which on synchronous

l o s s of carbon d i su l f ide affords "the chloro intermediate

(26§.)» A l t e rna t ive ly , 266 may a lso be obtained by

nuc leoph i l i c react ion of the chloride inn on the ac t iva ted

complex. Simultaneous react ion of water with 26j5 y ie lds

the corresponding oxygen analogs (2j6j[-274). The

intormediacy of 266 was fu r the r supported by converting i t

104

i n t o corresponding subs t i t u t ed anidine (,275) by action

of N-methylpiperazine in dry acetone (Scheme 19) .

3.9 Synthesis of 1, 4 -d i subs t i tu ted piperazines

Reaction of anhydrous piperazine with 1-chloro-

4-nitrobenzene in presence of KpCO- in acetone in s t e e l

bomb a t 150° C gave l - (4 -n i t ropheny l )p ipe raz ine (2J6J and

no l , 4 -d i - (4 -n i t r opheny l )p ipe raz ine (27_7) could be i s o l a t e d .

When 276 was allowed to react with 4-nitrobenzoyl chloride

in dry benzene in presence of t r i e thy lamine , i t y ie lded

l - ( 4-ni t robenzoyl) -4-( 4-ni t rophenyl)piperazine (£78) which

was reduced with FcSO^-NEU to give the corresponding

diamine (279). Treatment of 279 with thiophosgene in

acetone in presence of t r iethylamine gave l - ( 4 - i s o t h i o -

cyanatobenzoyl)-4-( 4-i so thiooyanatophenyl) piperazine (280).

S imi lar ly , anhydrous piperazine reacted with two moles of

4-nitrobenzoyl ch lor ide to y ie ld 1 ,4-di - (4-ni t robenzoyl)

piperazine (281). Reduction of 281 with Raney-nickel and

H2 in a Paar hydrogenator afforded 1,4-di-(4-aminobenzoyl)

piperazine (282). The synthes is of l , 4 - d i - ( 4-isothiocyanato

benzoyl)piperazine (2§2) was achieved by react ion of 282

with thiophosgene in 10$ HC1-CHC1, mixture (Scheme 20) .

105

s 11 1

R - NH - G - K-

CSC1,

-HC1 - >

2^8, R = Ph, R = NHCH^h

2^9, R = Ph, R1 = NHC6H4Cl(m)

260, R

261 , R

Ph, R = NH06Hi;L

262, R

26^ , R

26 4, R

265, R

Ph, R = NBt2

Ph, R1 = N

Ph, R1 N N-CH,

V-/ 3

E t , R1 = N / \>

W CH 2 Ph , R 1 = OH,

r R - N =

R - N =

I?1

R1 " 0 1

o r

3 - C = S l - ^ l C * C I

E 1

i

-cs.

fl 1 R - NH - C - Rx

267-274

*£ -HC1

CI i i

R - N = C - R

266

260 /""A

HN NCH,

ph - N = C - NH -\~y N a N I OH,

106

ci—\_VNO2

CO

I • N N

\ CO

V \Y_ NO.

^ ^ •NO,

CO

• ^

281

1 . R e d u c t i o n 2 . CSC12

^ R

'N1

2 8 2 , R = NH2

2 8 5 , R = NCS

C 6 H ^ 0 2 ( 4 )

276

0 -4 V - V N - C O - ^ V N O ,

278

R e d u c t i o n

H ^ —<f V - N N-CO

m CSCTo

-0~ra:

SON

280

Scheme 20

107

4. BXPEMMMTAL;

The s t r u c t u r e s of a l l the compounds were

r o u t i n e l y checked by IR recorded on p e r k i n - E l m e r 157 and

177 i n f r a c o r d s p e c t r o p h o t o m e t e r s . The NMH s p e c t r a were

o b t a i n e d on Var ian A60-D and BM-360L (60 MHz) o r R-32

(90 MHz) s p e c t r o m e t e r s u s i n g TMS as i n t e r n a l r e f e r e n c e .

Mass s p e c t r a were t a k e n on J e o l JMS-D300 ( ~ 7 0 ev)

i n s t r u m e n t . The p u r i t y of a l l the compounds was checked

on s i l i c a - gel G-p l a t e s and s p o t s were l o c a t e d by I 2

v a p o u r s , KMnO. (2$) spray or Dragendorff«s r e a g e n t sp r ay .

Mel t ing p o i n t s were taken i n s u l p h u r i c ac id ba th and are

u n c o r r e c t e d .

Benzimidazole (22) and 2-methylbenzimidazole (23_)

These compounds were p repared by t r e a t i n g

o-phenylene diamine ( 1 5 . 5 g, 0.125 mol) w i t h formic acid

and g l a c i a l a c e t i c a c i d r e s p e c t i v e l y .

22, y i e l d 12 g ( 8 1 . 6 $ ) , m . p . l 7 1 ° ( l i t . 2 3 m.p .171-2°)

2£, y i e l d 9.9 g ( 6 0 $ ) , m . p . l 7 6 ° ( l i t . 2 3 m . p . l 7 6 ° )

2 - M e t h y l - 5 ( 6 ) - n i t r o b e n z i m i d a z o l e ( 25)

Gone, n i t r i c ac id ( 1 3 . 3 ml , d=1.4) was added dropwise

t o i c e - c o o l e d mix tu re of 23 (11 g, 0 .83 mol) i n H2S0

(10 ml , d=1.84) du r ing 30 m i n u t e s . The r e a c t i o n mix ture

was poured on crushed i c e and produc t i s o l a t e d , y i e l d

108

12.5 g ( 8 5 / 0 , m.p.217° ( l i t . 2 4 m . p . 2 1 9 ° ) .

S i m i l a r l y 5 ( 6 ) - n i t r o b e n z i m i d a z o l e (24) was prepared o 24

by n i t r a t i o n of 22 i n 90$ y i e l d , m.p .20 l72 ( l i t . m.p .

2 0 5 ° ) .

5(6 )-Aminobenzimidazole (26_)

A mix tu re of 24 (10 g, 0 .061 mol) and Raney-n icke l (about 1.5 g) i n e t i i ano l (200 ml) was shaken with, hydrogen

2 a t 3 .5 kg/cm i n a p a a r hydrogena to r f o r 12 h r . The

c a t a l y s t was f i l t e r e d o u t , s o l v e n t removed from f i l t r a t e

and the product was p u r i f i e d as i t s h y d r o c h l o r i d e , y i e l d

4.9 g ( 6 0 $ ) , m.p.288° ( l i t . 2 5 m . p . 2 9 0 ° ) .

Us ing -fete above method 27 was o b t a i n e d as i t s

h y d r o c h l o r i d e by r e d u c t i o n of 2£, y i e l d 62$ , m.p.298°

( l i t . 2 5 m . p . 2 9 8 - 9 ° ) .

5«( 6 ) - ( 2 ,4 -Din i t ropheny l ) aminobenz imidazo le (28)

A mix tu re of 26 ( 4 g, 0 .03 n o l ) , l - c h l o r o - 2 , 4 -

d i n i t r o b e n z e n e ( 6 . 1 g, 0 .03 n o l ) and t r i e t h y l a m i n e ( 4 . 4 ml,

0 .03 mol) i n 95$ e t h a n o l (50 ml) was r e f luxed f o r 14 h r .

The r e a c t i o n mix tu re was cooled and the s e p a r a t e d s o l i d

f i l t e r e d , washed s u c c e s s i v e l y wi th cold e t h a n o l (3x10 ml ) ,

w a t e r (15 ml) and d r i e d , y i e l d 6 .27 g ( 7 0 $ ) , m .p .141° .

IR(KBr) cm"*1 • 1330, 1580 ( N 0 2 ) , 1610 (Arom).

MR(DMS0-d6)6 : 6 . 8 8 - 7 . 6 (n , 4H, Ar-H), 8.05 (dd , 1H,

Ar~S> £ t o N0 2 , J=2 4 9Hz), 8 . 1 ( s , 1H,

109

N=CH-N), 8.75 (d , 1H, Ar-H, o to both

N0 2 , J=3Hz).

Ana lys i s fo r : C ^ H g N ^ (299)

Calcd . : C, 52.17? H, 3 . 0 1 ; N, 23.40

Found j C, 52 .50 ; H, 3 .35j N, 23 .61$ .

S i m i l a r l y 29_ was p repa red by r e a c t i o n of 27, wi th

l - c h l o r o - 2 , 4 - d i n i t r o b e n z e n e i n e t h a n o l , y i e l d 70$,

m.p . > 3 0 0 ° .

IR(KBr) e n " 1 : 1325, 1530 ( N 0 2 ) , 1615 (Arom).

NMR(CDC13 + • 2 .55 ( s , 3H, C-CH^), 6 . 9 - 8 . 1 (m, 5H,

DMS0-d6) 6 Ar-H) , 8.9 (d , 1H, Ar-H, o- to bo th

N0 2 , J=2 .5Hz) .

Ana lys i s f o r : C l 4 H 1 1 N 5 0 4 (313)

Calcd. : C, 53 .67 ; H, 3 . 5 1 ; N, 22.36

Found t C, 54 .12 ; H, 3 . 8 5 ; N» 22 .10$ .

5( 6* ) - (2 ,4 -Diaminopheny l )aminobenz imidazo le (30)

A s o l u t i o n of 28 ( 5 . 0 g, 0.016 mol) and Raney-

n i c k e l ( ^ - " 0 . 5 g) i n 95$ e t h a n o l (100 ml) was shaken wi th

hydrogen under 2 .5 kg/cm p r e s s u r e i n a p a a r hydrogena to r

f o r 24 h r . The c a t a l y s t was f i l t e r e d and so lven t was

removed i n v a c u o . The amine was p u r i f i e d by a c i d - b a s e

t r e a t m e n t , y i e l d 2 .5 g ( 6 2 $ ) , m . p . 1 1 5 ° .

IR(KBr) cm' 1

Ana lys i s f o r

Calcd.

Found

3200-3400 (NH,NH2).

C13H13N5 ( 2 3 9 )

C, 6 5 . 2 7 ; H, 5 . 4 4 ; ff, 29.29

0, 6 5 . 6 4 ; H, 5 .12 ; N, 29 .68$.

no Under s i m i l a r r e a c t i o n cond i t i on compound 31 was

p r e p a r e d by r e d u c t i o n of 29 wi th Raney-n icke l and H2 ,

y i e l d 70°/, m.p . > 3 0 0 ° .

1 iR(KBr) cm

Ana lys i s f o r

Calnd.

Found

3200-3300(NH,NH2).

G14H15N5 ( 2 5 3 )

C, 6 6 . 4 0 ; H, 5.91? N, 27.66

C, 6 6 . 6 8 ; H, 6 . 2 2 ; N, 27 .34$ .

5 ( 6 ) - ( 5 - P o r m a m i d o - l - b e n z i m i d a z o l y l ) b e n z i m i d a z o l e (^2)

A s o l u t i o n of 30 ( 1 . 0 g, 0 .0041 mol) was r e f luxed

i n 9df> formic a c i d (15 ml) f o r 8 h r . The r e a c t i o n mixture

was coo led and n e u t r a l i z e d w i th d i l u t e sodium hydroxide

s o l u t i o n . The s o l i d , l i ius o b t a i n e d , was f i l t e r e d ,

washed wi th w a t e r , d r i e d and p u r i f i e d over s i l i c a ge l

column us ing e t h y l a c e t a t e - b e n z e n e ( 9 : 1 ) mix ture as

e l u a n t , y i e l d 0 .74 g ( 6 5 # ) , m.p . > 3 0 0 ° .

IR(KBr) cm"1

Mass a t m/z

A n a l y s i s f o r

Oalcd.

Found

; 1660 (CO).

: 277 (M+)

i C 1 5 H n N 5 0 (277)

i C, 6 4 . 9 8 ; H, 3 .97 ; N, 25.27

i C, 6 5 . 3 5 ; H, 4 . 2 1 ; N, 25.56/c

Us ing -the s i m i l a r method _3j£ was p repared in 62$ y i e l d

by t r e a t i n g 3.1 wi th formic a c i d .

I l l

5( g ) - ( 5 - A c e t a m i d o - 2 - m e 1 i i y l - l - b e n z i m i d a z o l y l ) b e n z i m i -

dazole (33)

A s o l u t i o n of 29. (1» 2 S» 0.005 mol) in g l a c i a l

a c e t i c a c i d (15 ml) was r e f l u x e d f o r 8 h r . The r e a c t i o n

mix tu re was cooled and n e u t r a l i z e d w i t h d i l u t e NaOH

s o l u t i o n . The s o l i d , itius s e p a r a t e d , was f i l t e r e d ,

washed wi th w a t e r , d r i e d a id p u r i f i e d over s i l i c a gel

column u s i n g e t h y l a c e t a t e a s e l u a n t , y i e l d 1.0 g (66 / ; ) ,

m.p . ^300 .

1680 (CO).

2 .02 ( s , 3H, 000H 5 ) , 2.42 ( s , 3H, C-CH^),

6 . 9 - 8 . 0 (m, 6H, Ar-H) ,

305 (M+)

IR(KBr) cm

NMR(TPA) 6

- 1

Mass a t m/z

Ana lys i s for

Calcd.

Found

G17H15F5° ( 3 0 5 )

C, 6 6 . 8 8 ; H, 4 . 9 1 | N, 22.95

C, 6 6 . 7 3 ; H, 5 . 2 5 ; N, 23.21):.

S imi l a r p rocedure was employed for the p r e p a r a t i o n

o: f 25. fey r e a c t i o n of 3_1 wi th g l a c i a l a c e t i c a c i d .

6 - N i t r o b e n z t h i a z o l e (j>6)

This compound was p repared by the n i t r a t i o n of

b e n z t h i a z o l e ( 13 .5 g, 0 . 1 mol) i n HN0_ (10 .7 ml, d=1.5)

and H 2 S0 4 (21 .5 ml , d=1.84) a t 1 0 ° , y i e l d 9.0 g ( 5 0 / 0 ,

m.p .173° ( l i t . 2 6 m . p . 1 7 4 ° ) .

S i m i l a r l y ^7 was ob ta ined by n i t r a t i o n of 2 -methy l -

112

b e n z t h i a z o l e , y i e l d 80£, m . p . l 6 4 - 5 ° ( l i t . m .p . l65 ) .

6 -Aminobenzth iazole (^8)

This was p repa red by r e d u c t i o n of ^S_ ( 5 . 0 g, 0.027

mol) in m e t h a i o l (50 ml) u s ing Sn012 ( 2 5 g) i n concen t r a t ed

HC1 (50 m l ) , y i e l d 3.6 g ( 8 6 . 5 / 0 , m.p .83° ( l i t . , m.p .

8 4 - 5 ° ) .

6 -Amino-2-methylbenz th iazo le (29)

A s o l u t i o n of h y d r a z i n e - h y d r a t e (20 .6 g, 0.4*) mol)

i n e thanol (30 ml) was added dropwise t o r e f l u x i n g mixture

of 27 ( 1 0 . 0 g, 0.05 mol) and Raney-n icke l ( /—'l g) i n

ethanol (50 m l ) . Re f lux ing was con t inued f o r 30 minutes

and t h e r e a c t i o n m i x t u r e f i l t e r e d i n h o t . The so lven t was

removed in_ vacuo and the r e s u l t i n g s o l i d was c r y s t a l l i z e d

from e t h a n o l , y i e l d 7 .0 g ( 8 3 # ) , m.p.119-121° ( l i t . 2 7

m.p.122 ) .

IR(KBr) cm"1 : 3200, 3300 (NH2) .

NMR(0DGL5) 6 J 2 .92 ( s , 3H, C-CH^), 7.95 (d , 1H, Ar-H,

m to NH2, J=9Hz), 8.28 (dd, 1H, Ar-H,

£ to - S - , J=3 4 9Hz), 8.7 (d , 1H, Ar-H,

o to - S - , J=3Hz)

A n a l y s i s f o r : C ^ N ^ S (194)

Calcd . : C, 49 .48 ; H, 3.09

Found : C, 49 .12; H, 2 . 7 4 $ .

113

$ - ( 2 , 4 - D i n i t r o p h e n y l ) a m i n o b e n z t h i a z o l e (40)

A s o l u t i o n of 38 ( 2 . 5 g, 0.016 m o l ) , l - c h l o r o - 2 , 4 -

d i n i t r o b e n z e n e (3 .36 g, 0.016 mol) and t r i e t h y l a m i n e ( 1 . 5

g, 0.016 mol) i n e t h a n o l (40 ml) was r e f luxed f o r 15 h r .

The r e a c t i o n mixture was cooled and t h e s e p a r a t e d pure

p roduc t was f i l t e r e d , washed wi th e t h a n o l (3x20 ml) and

d r i e d , y i e l d 4.02 g ( 8 0 . 5 / 0 , m .p .201° .

iR(KBr) cm"1

Mass a t m/z

NMR(DMSO-dg) 6

Analysis for

Calcd.

Found

: 1315, 1580 (N02), 1605 (Arom), 3230 (NH),

j 316 (M+)

; 7.08 (d, 1H, Ar-H, m to N02, J=9Hz),

7.48 (dd, 1H, Ar-H, p. to -S-, J=1.5 *

8.5Hz), 8.06 (d, 1H, Ar-H, o to -S-,

J=1.5Hz), 8.11 (d, 1H, Ar-H, m to -S-,

J=6Hz), 8.16 (dd, 1H, Ar-H, £ to N02,

J=2.0 * 6.5Hz), 8.8 (d, 1H, Ar-H, o to

N02, J=2.5Hz), 9.3 (s, 1H, S-CH=N).

°13H8N4°4S ( 5 l 6 >

C, 49 .46; H, 2.80

C, 49 .72; H, 2.52/fc.

S i m i l a r l y compound j£L was p repared by r e a c t i o n of

22 w i t h l - c h l o r o - 2 , 4 - d i n i t r o b e n z e n e i n r e f l u x i n g e t h a n o l ,

y i e l d 85.5$£, m . p . l 8 l ° .

iR(KBr) cm"1 : 1335 , 1585 ( N 0 2 ) , 1620 (Arom), 3280 (NH)

NMR(lMS0-d6) 6 s 2 .8 ( s , 3H, C-CH^), 7.16 (d , 1H, Ar-H,

m to N02 , J=9Hz), 7 . 4 (dd, 1H, Ar-H,

114

JD to - S - , J = 2 . 5 4 9Hz), 7 .88 (m, 2H,

Ar-H, o ^ m to - S - ) , 8.15 (dd, 1H,

Ar-H, p. to N0 2 , J=3 & 9Hz), 9.0 (d , 1H,

Ar-H, o to N0 2 , J=2.7Hz)

A n a l y s i s f o r : C1 4H1 0N404S (330)

Calcd. j C, 50 .90 ; H, 3 .03 •

Pound : G, 50 .80 ; H, 3 . 3 6 $ .

6 - ( 2 , 4-Di amino phenyl )aminob en z t h i a z o l e (42)

To a warm mix tu re of 40 ( 2 , 5 g, 0 ,008 mol) and

Raney -n i cke l ( 0 . 3 g) i n THF (15 ml) and e t h a n o l (15 ml)

was added dropwise a s o l u t i o n of h y d r a z i n e - h y d r a t e

(6 .6 g, 0.0133 mol) i n e t h a n o l (15 ml ) . When "foe yellow

co lour of the s o l u t i o n d i s a p p e a r e d , the c a t a l y s t was

f i l t e r e d off and p roduc t ob ta ined on removal of s o l v e n t ,

was c r y s t a l l i s e d from e t h a n o l , y i e l d 1.56 g ( 7 8 $ ) , m.p .

1 2 0 ° .

iR(KBr) cm"1 : 3150-3300 (NH2).

Compound 43_ was a l s o ob ta ined by r e d u c t i o n of 41

w i t h h y d r a z i n e - h y d r a t e and Raney-n icke l i n 75$. y i e l d

m.p.146 .

IR(KBr) cm"1 , 3200-3350 (NH2).

6 - ( 2 - T h i o x o - 5 - i s o t h i o c y a n a t o - l - b e n z i m i d a z o l y l ) b e n z t h i

a z o l e (44)

Thiophosgene ( 0 . 4 8 ml, 0.0062 mol) i n acetone

(50 ml) was added dropwise to a s t i r r e d s o l u t i o n of 42_

115

( 0 . 8 g, 0.0031 mol) i n ace tone (100 m l ) . S t i r r i n g was

con t inued for 4 h r and then r e a c t i o n mix tu re r e f l uxed f o r

2 h r . The s e p a r a t e d s o l i d was f i l t e r e d and the mother

l i q u o r was c o n c e n t r a t e d t o ge t a f u r t h e r crop of p roduc t .

The combined s o l i d p roduc t was c r y s t a l l i z e d from a c e t o n e ,

y i e l d 0,55 g ( 5 4 $ ) , m .p .245 -46° .

iR(KBr) cm*1 j 2040 (NOS).

A n a l y s i s f o r j c i 5 H 8 N 4 S 3 ^ 5 4 0 ^

Oalcd. j G, 52.94j H, 2.35

Found 1 C, 52 .62 ; H, 2. 72#.

In s i m i l a r manner compound 45_ was p repa red from J 3

and thiophosgene in a c e t o n e ,

2 -Methy l -6 - [2 -ca rbe thoxyamino- ' 5 -(N , N ' - d i c a r b e t h o x y -

guanid ino ) - l - b e n z i m i d a z o l y l ] b e n z t h i a z o l e (_4^)

A s o l u t i o n of 1 , 3 - d i c a r b e t h o x y - S - m e t h y l i s o t h i o u r e a

( 0 . 8 7 g, 0.0036 mol) i n e t h a n o l (30 ml) was added t o the

s o l u t i o n of 43. ( 0 . 5 g, 0.0018 mol) i n e t h a n o l (10 ml) and

the r e a c t i o n mixture r e f l u x e d for 15 h r . The so lven t was

removed i n vacuo and t h e r e s u l t i n g s o l i d p u r i f i e d on a

s i l i c a gel column u s i n g 10$ e t h y l a c e t a t e i n benzene as

e l u a n t , y i e l d 0.42 g ( 4 2 # ) , m .p .98 -100° .

IR(KBr) cm"1 j 1720 (C=0).

NMR(TFA) 6 • 0 . 7 5 - 1 . 1 0 [m, 9H, (CH2GH3)5] , 2.66

( s , 3H, S-C-CH3), 3 . 8 - 4 . 1 [m, 6H

(CH 2CH 3 ) 3 ] , 6 . 8 - 7 . 5 (m, 6 H , Ar-H)

Analysis for C25H27N7°6S (546)

Calcd. j C, 54.07; H, 4.88

Pound • C, 54. 41; H, 4.76$.

6-[5-Formamido--l--benzimidazolyl]benzthiazole (47)

A so lu t ion of 42 (0.6 g, 0.0023 mol) in 98$ formic

acid (30 ml) was re fluxed for 8 h r . The react ion mixture

was cooled and neu t r a l i z ed with 30$ aqueous ammonia. The

separated so l id was f i l t e r e d off, dr ied and subjected t o

charcoal t reatment , i t was fu r the r pur i f ied on a s i l i c a gel

column using 15$ e thyl aceta te in benzene as e luan t , y ie ld

0.38 g (55/0 , m.p.235-36°.

IR(KBr) cm"1 : 1650 (CO), 3250 (NH).

Mass a t m/z : 294 (M+)

Analysis f o r : C15H10N40S (294)

Calcd. : C, 61.22; H, 3.40

Found : C, 60.86; H, 3.16$.

Compound 49_ was prepared s imi la r ly from _4j5 in

re f luxing 98$ formic ac id .

6-(5-Acetamido-2-methyl-l-benzimidazolyl)benzthiazole (48)

A solu t ion of 42 (0.6 g, 0.0023 mol) in g l ac i a l

a c e t i c acid (20 ml) was refluxed fo r 8 hr . The product was

worked-up as above and pur i f ied on a s i l i c a gel column

using benzene as e luant , y ie ld 0.46 g (6 2$), m.p.241°.

IR(jfflr) cm"1 j 16 75 (CO), 3250 (NH).

117

NMR(DMSO-d6) 6 : 1.95 ( s , 3H, COOH^), 2.32 ( s , 3H, C-CR^),

6 .9 ( d , 1H, Ar-H, m to UHAG » Ja9Hz) ,

7 .2 (d , 1H, Ar-H, m to - S - , J=9Hz),

7 .52 (dd, 1H, Ar-H, £ to - S - , J = 3 & 9Hz),

7 . 84 (d , 1H, Ar-H, o t o - S - , J=2 .5Hz) ,

8 .22 (dd, 2H, Ar-H, o to NHAc, J=3 & 9Hz),

9 .38 ( s , 1H, N=GH-S)

Ana lys i s f o r : C1 7H1 4N40S (322)

Calcd. j G, 63.35? H, 4 .34

Found j C, 63.72} H, 4 .42$ .

S i m i l a r l y jjO was p repared from 43 and g l a c i a l a c e t i c

a c i d .

2-Methyl -6- ( 2 - n i t r o b e n z o y l )aminobenz th iazo le (5JJ

A s o l u t i o n of 2 - n i t r o b e n z o y l c h l o r i d e (1 .12 g,

0.0061 mol) i n dry benzene (25 ml) was added dropwise to a

s t i r r e d s o l u t i o n of 3g_ ( l . O g, 0.0061 mol) i n dry benzene

(30 ml) and t r i e t h y l a m i n e ( 0 , 6 l g, 0.0061 mol) a t room

t e m p e r a t u r e . S t i r r i n g was con t inued f o r 8 h r . The

s e p a r a t e d s o l i d was f i l t e r e d and washed wi th wate r (2x10 ml)

to remove t r i e t h y l a m i n e h y d r o c h l o r i d e . The produc t was

d r i e d and c r y s t a l l i z e d from e t h a n o l , y i e l d 1.3 g ( 7 2 $ ) ,

m . p . l 9 8 ° .

iR(KBr) cm"1 j 1340, 1520 (N0 £ ) , 1640 ( 0 0 ) , 3400 (Ml),

NMR(lMS0-d6) 6 t 2 .75 ( s , 3H, CHj), 7 . 6 - 8 . 2 5 (m, 6 H ,

Ar-H), 8.5 (d , 1H, Ar-H, -S-CLCH-, J=2Hz),

118

A n a l y s i s fo r

Oalcd.

Pound

: c1 5 H l : L N 5 0 3 5 (513)

: C, 57 .89 ; H, 3 .53

j C, 5 8 . 2 1 ; H, 3 .18$ .

2-Methyl-6-( 2-aminobenzoyl ) aminobenz th iazo le (5.2)

A mixture of 51 ( 1 . 0 g, 0.0032 mol) and Raney-nicke l 2

( ^ 0 .2 g) i n e t h a n o l (50 ml) was hydrogenated a t 2.5 kg/cm

p r e s s u r e i n a P a a r hydrogena to r fo r 6 h r . The produc t was

worked-up as u s u a l and c r y s t a l l i z e d from e t h a n o l , y i e l d

0.72 g ( 7 9 * ) , m . p . 1 7 0 0 .

- 1 iR(KBr) cm"

Mass a t m/z

ITOR(EM30-d6) 6


Calcd.

Found

: 1620 (CO), 3270, 3340 (NH2).

s 283 (M+)

: 2.76 ( s , 3H, C-CH^), 6 .31 ( b s , 2H, NH2) ,

6 . 5 - 7 . 8 (m, 6H, Ar-H), 8.5 (d , 1H,

S-C=CH, J=2Hz)

C15H15R5OS (283)

C, 63.60} H, 4.52

C, 6 3 . 4 8 ; H, 4.32?*.

2-Methyl -6- ( 2 - i s o t h i o c y a n a t o b e n z o y l ) a m i n o b e n z t h i a z o l e (5J5 )

A s o l u t i o n of th iophosgene ( 0 . 0 5 4 ml , 0.0007 mol)

i n chloroform (10 ml) was added dropwise to a s t i r r e d

s o l u t i o n of 5_2 ( 0 . 2 g, 0.0007 mol) i n g l a c i a l ace t ic , acid

( 4 m l ) and 10?o HC1 (5 ml) a t room t e m p e r a t u r e . S t i r r i n g

was con t inued f o r 1 h r . The chloroform l a y e r was washed

wi th wa te r , d r i e d (Na2S0 ) and c o n c e n t r a t e d t o ge t a s o l i d

119

which was washed w i t h p e t . e t h e r , y i e l d 0 .08 g (38/0 >

m.p.185 .

iR(KBr) cm -1 : 1660 (00), 2090 (NCS).

2 - M e t h y l - 6 - ( 2 - t h i o x o - 4 - o x o - 3 - q u i n a z o l i n y l ) b e n z t h i a z o l e (<54)

A s o l u t i o n of th iophosgene ( 0 . 1 3 ml, 0.0015 mol) in

acetone (20 ml) was added dropwise to a s t i r r e d s o l u t i o n

o f 51 (°»5 g, 0.0018 mol) i n acetone (50 ml) a t room

t e m p e r a t u r e . S t i r r i n g was con t inued fo r 6 h r and the

s o l i d s e p a r a t e d was f i l t e r e d and c r y s t a l l i z e d from e t h a n o l ,

y i e l d 0.35 g (63 f / ) , m.p . >300° .

IR(KBr) cm"1

Mass a t m/z


Oalcd.

Found

1680 ( 0 0 ) , 3400 (NH).

325 (M+)

C16H11N2 0 S2 ( 3 2 5 )

0, 58 .00 ; H, 3 .32

0, 5 8 . 3 5 ; H, 3 .56^ .

5 - G h l o r o - 2 - n i t r o a c e t a n i l i d e (5JS.)

m - C h l o r o a c e t a n i l i d e _55 (64 .0 g, 0 .38 mol) was

n i t r a t e d by c o n c e n t r a t e d M O , (27 .5 ml , d=1.5) i n a c e t i c

a c i d - a c e t i c anhydr ide m i x t u r e , y i e l d 44 g (58.6$-), m.p .

117-18° ( l i t . 2 9 m . p . 1 1 7 - 1 8 ° ) .

3 » 3 ' - D i a m i n o - 4 , 4 t - d i n i t r :di phenyl s u l f i d e (57j

A s o l u t i o n of sodium s u l f i d e (5 .6 g, 0 .024 mol) i n

50'/ aqueous e t h a n o l (20 ml) was added dropwise to a s t i r r e d

s o l u t i o n of 56 ( 1 0 . 0 g, 0.046 mol) i n e t h a n o l (60 ml) and

120

the r e a c t i o n mix ture was r e f l u x e d for 12 h r on a wa te r

b a t h . The s o l i d which came out on c o o l i n g the r e a c t i o n

m i x t u r e was f i l t e r e d , washed wi th 50$ aqueous e t h a n o l ,

d r i e d and p u r i f i e d by column chromatography u s i n g s i l i c a

gel and b e n z e n e - e t h y l a c e t a t e ( 2 : 1 ) as e l u a n t , y i e l d 3.6 g

( 3 8 . 5 * 0 , m . p . l 9 5 ° .

iR(KBr) cm"1 : 1300, 1550 (N0 2 ) , 1600 (Arom), 3280,

3400 (NH2).

: 306 (M+)

• 6 .37 (dd, 2H, Ar-H, £ to NH2, J=2 .5 &

8Hz) , 6 .87 ( d , 2H, Ar-H, 0 to NH2,

J=3Hs) , 7.2 ( s , 4K, 2xNH2), 7.82 (d ,

2H, Ar-H, 0 to N0 2 , J=9Hz)

C12H10N4°4S ( 5 0 6 )

0, 47 .05 ; H, 3 .26 ; N, 18 .30

C, 47 .50; H, 3 . 4 8 ; N, 1 7 . 9 5 $ .

Mass a t m/z

CD a , + 3 DMSO-dg ) 6

NMR(CDC1, +


Calcd.

F j u n d

3 , 3 ' -D iace t amido-4 , 4 ' - d i n i t r o d i p h e n y l s u l f i d e (58)

A mix tu re of 5.7 ( l . O g, 0.0032 mol) i n a c e t i c

anhydr ide (2 ml) and g l a c i a l a c e t i c acid (10 ml) was

r e f l u x e d fo r 4 h r . The r e a c t i o n mix tu re was c o o l e d , the

s e p a r a t e d s o l i d was f i l t e r e d , washed s u c c e s s i v e l y with

10^ NaHCO, s o l u t i o n and w a t e r . Another c rop was ob ta ined

on d i l u t i o n of f i l t r a t e w i th w a t e r . The combined produc t

was re c r y s t a l l i s e d from a c e t o n e , y i e l d 1.0 g ( 8 0 $ ) ,

m.p.175 .

121

iR(KBr) cm"1 : 1320, 1580 (iST02), 1600 (Arom), 1700

(CO), 3300 (NH).

NMR(0DC13 + : 2 .1 ( s , 6H, 2xCOCH3), 7.05 (dd , 2H,

BMS0-a6) 6 A r _ g > £ t 0 mACf J = 2 u 9Ez)t 7 # 9 2 ( d >

2H, Ar-H, o to N02 , J=9Hz), 8.14 (d,

2H, Ar-H, o to NHAc, J=3Hz)

Analysis for : C^gE^^OgS (390)

Calod. : C, 49.23; H, 3.59

Found : C, 49.50; H, 3.86$.

3 ,3 ' ,4 ,4 ' -Te t ra -aminodiphenyl sulf ide (59)

A hot so lu t ion of 5J (1 .4 g, 0.0032 mol) in acetone

(20 ml) and aqueous ammonja (25 ml) was mixed with hot

so lu t ion of FeSO (7.0 g) in water (20 ml) and aqueous

ammonia so lu t ion (30 ml) and the reac t ion mixture heated

on water bath fo r 30 minutes. Then product was ext rac ted

with ethyl ace ta te (5x20 ml) , combined e x t r a c t s dried

(NapSO.) and solvent removed in vacuo to get crude product,

y i e l d 0.6 g (75$) , This was used as such in fur ther s t eps .

5,5 ,-DibeJ.izimidazolyl sulphide (60)

A solut ion of 59 (0.6 g, 0.0023 mol) in 98/c formic

acid was refiuxed fo r 5 hr on water ba th . The react ion

mixture was cooled, neu t r a l i z ed with aqueous ammonia

s o l u t i o n , ex t rac ted with methylene chlor ide (2x30 ml) ,

dried (Na2S0.) and solvent removed in. vacup_. The residual

s o l i d was fu r the r pu r i f i ed by charcoal t rea tment , y i e ld

122

0.45 g ( 7 0 / 0 , m . p . 2 6 0 - 2 ° .

iR(EBr) cm"1

Mass a t m/z

Ana lys i s f o r

Calcd.

Found

1605 (Arom), 3350 (NH).

266 (M+)

<aAi?4 s ( 2 6 6 )

C, 6 3 . 1 5 ; H, 3.75

t C, 6 3 . 5 0 ; H, 4 .10K

S i m i l a r l y 6 l was p repared by t r e a t i n g 59 "with

re f l u x i n g a c e t i c a c i d ,

2 , 2 ' - D i c a r b o m e t h o x y a m i n o - 5 , 5 ' - d i b e n z i m i d a z o l y l

s u l p h i d e (62)

A s o l u t i o n of 5J} (0 .5 g, 0.002 mol) and 1 , 3 - d i c a r b o -

methoxy-S-methyl i so t h i o u r e a (0 .85 g, 0,0042 mol) i n

e t h a n o l (50 ml) was r e f l u x e d o v e r n i g h t . The r e a c t i o n

m i x t u r e was coo led . The s e p a r a t e d s o l i d was f i l t e r e d ,

washed wi th e t h a n o l (3x20 ml), wate r (3x20 ml) and d r i e d ,

The p roduc t was then c r y s t a l l i z e d from a c e t i c a c i d - w a t e r ,

y i e l d 0 .53 g ( 6 # ) , m.p . > 280° .

- 1 iR(KBr) cm

NMR(TFA) 6


Calcd.

Found

: 16 00 (Arom), 1710 (GO), 2700-

2800 (C-H), 3300 (NH).

1 3.6 ( s , 6H, 2x0CH3), 7 . 1 - 7 . 2 (m, 6 H ,

Ar-g)

C18H16N6°4S ( 4 l 2 > C, 52.42} H, 3 .88 ; N, 20.38

C, 52 .80 ; H, 3 .52 ; N, 20.72'^.

123

Similarly 6_3_ was prepared by react ion of £9 with

1,3-di carbethoxy-S-methylisothiourea in refluxing e thanol .

4 ,4 ' -D ich lo ro -3 ,3 ' -d in i t rod ipheny l sulfone (6_5)

This was obtained by n i t r a t i o n of 4 , 4 ' - d i c h l o r o d i -

phenyl sulfone 64 (6 .0 g, 0.021 mol) using H2SOVIET0-

mixture a t 60°. The product i s o l a t e d by pouring i t into

water , y i e ld 6.7 g (86$), m.p.201° ( l i t . 5 0 m.p.201-202°).

4,4 '-Diamino-3,3 ' - d i n i t r o d i phenyl sulfone (66J

.Ammonia gas was passed in a so lu t ion of 6_5 (5.0 g,

0.013 mol) in DM SO a t 140° for 5 h r . The react ion mixture

cooled and d i lu t ed with water . The separated so l id was

f i l t e r e d , washed with water and dr ied , y i e ld 3.52 g (80/0,

m.p.286° ( l i t . 5 1 m.p.287°) .

3,3 '-Diamino-4, 4 ' -d in i t rod ipheny l sulfone (67)

To a hot so lu t ion of 3 ,3 ' -d i amino-4 ,4» -d in i t rod i -

phenyl sulf ide 5_7 (0.5 g, 0.0016 mol) in 80^ aqueous ace t ic

acid (250 ml) was added KMn04 (0 .5 g) in small por t ions

during 30 minutes with constant s t i r r i n g . S t i r r ing was

continued for 5 hr a t room temperature and excess KMnO.

was decomposed with H202 so lu t ion i n cold. Then the

reac t ion mixture was d i lu t ed with water (250 ml ) . The

separated solid was f i l t e r e d , washed with water (3x20 ml)

and d r i ed , y ie ld 0.2 g (36.36/O, m.p. 276-8°.

124

iR(KBr) cm"1 : 1150 ( S 0 2 ) , 1320, 1560 (N0 2) f 1620

(Arom), 3300, 3400 (NH2).

Mass a t m/z ; 338 (M+)

NMR(MS0-d6) 6 j 6 .9 (dd, 2H, Ar-H, £ to NH2, J = 2 . 5 6

9Hz), 7.65 (d , 2H, Ar-H, o to NH2,

J=2 .5Hz) , 8.16 ( d , 2H, Ar-H, o to N0 2 ,

J=9Hz).

Ana lys i s f o r : C ^ ^ ^ O g S (338)

Calcd. : C, 42 .60 ; H, 2 . 9 5 ; N, 16.56

Found • G, 43 .04; H, 3 .16 ; N, 16.28'/-.

3 , 3 ' , 4 , 4 < - T e t r a - a m i n o d i p h e n y l s u l f o n e (68)

To a warm s o l u t i o n of 66_ ( 5 . 0 g, 0.015 mol) i n THF-

e t h a n o l ( 1 : 1 , 200 ml) and Raney-n icke l ( ~ 1 . 5 g ) , was

added dropwise a s o l u t i o n of h y d r a z i n e - h y d r a t e (5 .75 ml,

0.12 mol) i n e t h a n o l ( 25 ml) d u r i n g 30 m i n u t e s . Af ter

a d d i t i o n was comple te , the r e a c t i o n mix ture was re f luxed

f o r 3 h r on a w a t e r b a t h . The c a t a l y s t was f i l t e r e d and

the p roduc t was worked up a s u s u a l and p u r i f i e d by a c i d -

base t r e a t m e n t , y i e l d 2.9 g (72/ i ) , m .p .148 -52° .

IR(KBr) cm"1 • 1125 ( S 0 2 ) , 1620 (Arom), 3200-3350

(NH2) .

5 , 5 ' - D i b e n z i m i d a z o l y l sulphone (69)

A s o l u t i o n of 6_8 ( l . O g, O.OO36 mol) i n 98^- formic

a c i d (20 ml) was heated fo r 5 h r on a wa te r b a t h . The

125

r e a c t i o n mixture was c o o l e d , n e u t r a l i z e d wi th 30'/ aqueous

ammonia s o l u t i o n . The s e p a r a t e d s o l i d was f i l t e r e d ,

washed wi th wate r (3x20 m l ) , d r i e d and p u r i f i e d over a

s i l i c a gel column u s i n g e t h y l a c e t a t e as e l u a n t , y i e l d

0.76 g ( 7 1 $ ) , m.p . >300° .

iR(KBr) cm"1 : 1145 ( S 0 2 ) , 1620 (Arom), 3400 (NH).

Mass a t m/z j 298 (M+)

NMR(DM30-d6) 6 : 7 .65 ( b s , 6H, Ar-H), 8.2 ( s , 2H,

2xN=CH-N).

S i m i l a r l y 70 was p repa red from 68 and a c e t i c a c i d .

2 ,2 <-Dicarbome thoxy amino-5,5 ' - d i b e n z i m i d a z o l y l sulphone (71)

A s o l u t i o n of 68 ( l . O g, 0.0036 mol) and 1 , 3 - d i -

ca rbome thoxy-S-me thy l i so th iou rea ( 1 . 5 g, 0.0072 mol) i n

e t h a n o l (30 ml) was re f luxed f o r 15 h r . The r e a c t i o n

mix tu re was worked-up as u sua l and re c r y s t a l l i z e d from

a c e t i c a c i d - w a t e r , y i e l d 0.98 g ( 6 1 . 8 $ ) , m.p . > 280° .

iR(KBr) cm"1 ; 1715 (CO), 2700-2900 (C-H), 3350 (NH).

NHR(TtfA) 6 J 3.6 ( b s , 6 H , 2 X O C H 3 ) , 7 . 5 - 7 . 8 (m, 6H,

Ar-H)

Ana lys i s fo r : C 1 8 H l 6 N 6 0 6 S (444)

Calcd. : 0, 48 .64 ; H, 3 .60 ; N, 18 .91

Found ; C, 48.28j H, 4 .06 ; N, 1 9 . 3 2 $ .

S i m i l a r l y compound 72 was p repared from 68 and 1 , 3 -

d i c a r b e t h o x y - S - m e t h y l i s o l i i i o u r c a i n r e f l u x i n g e t h a n o l .

126

4-Acetamido-3-nitrobenzoic acid (74)

This compound was prepared "by nitration of

4-acetamidobenzoic acid 22 (50 g, °»27 mol) with HNO ,

(200 ml, d=1.5), yield 52 g (87/0, m.p.220° ( l i t . ^

m.p.22l .

4-Amino-3-nitrobenzoic acid (75)

Hydrolysis of 74 (10.0 g, 0.044 mol) in concentrated

HC1 (30 ml) gave the required product, yield 6.15 g (76$),

m.p.282-83° ( l i t . 3 2 m.p.284°).

3,4-Diaminobenzoic acid (7§.)

Catalytic hydrogenation of 75_ (l.O g, 0.0054 mol)

using Raney-nickel (about 200 mg) in ethanol and H2 at o

3 kg/cm pressure in a Paar hydrogenator gave the product

by usual work-up, yield 0.6 g (72.3$), m.p.215-16°

( l i t . 3 5 m.p.215-18°).

2-Garbethoxyaminobenzimidazole-5(6)-carboxylic acid (78)

A mixture of 7§_ (l.O g, 0.0065 mol) and 1,3-dicarbe-

thoxy-S-methylisothiourea (1.53 g, O.OO65 mol) in ethanol

(30 ml) was refluxed for 12 hr. The product was worked-up

as usual and recrystallised from acetic acid-water, yield

1.0 g (62.5/0, n.p. >280°.

IR(KBr) cm"1 ; 1595 (Arom), 1700 (CO), 2800-2900

(G-H), 3350 (MH).

127


C a l c d .

Found

NMR(TFA) 6 : 1 . 0 ( t , 3H, CH2CH5, J = 7 H z ) , 4 . 0 8 ( q ,

2H, CK2CH3, J = 7 H z ) , 7 . 2 - 8 . 0 5 (m, 3H,

C 1 1 H 1 1 N 3 0 4 ( 2 4 9 )

C, 5 3 . 0 1 ; H, 4 . 4 1

0 , 5 3 . 4 2 ; H, 4 . 6 8 $ .

S i m i l a r l y compound 77 was p r e p a r e d from 75 and 1 , 3 -

d i c a r b o m e t h o x y - S - m e t h y l i s o t h i o u r e a i n r e f l u x i n g e t h a n o l ,

y i e l d ( 5 6 # ) , m . p . 3 0 0 ° .

i R ( K B r ) cm"1 : 1600 (Arom) , 1720 (GO), 2600-2700

( C - H ) , 3350 (NH).

3 . 5 2 ( s , 3H, 0 0 H 3 ) , 7 . 2 - 8 . 2 (m, 3H, A r - H ) . NMR(TFA) 6


C a l c d .

Found

C 1 0 H 9 N 3 ° 4

C, 5 1 . 0 6 ; H, 3 . 8 2

0 , 5 0 . 6 0 ; H, 4 . 1 2 $ .

4 , 4 ' -D i c h l ^ rob en zo phen one ( 83)

4 - C h l o r o b e n z o y l c h l o r i d e ( 6 . 0 g , 0 . 0 0 3 4 mol ) was

t r e a t e d w i t h c h l o r o b e n z e n e ( 3 . 8 g , 0 . 0 3 3 mol ) i n p r e s e n c e

o f A101 3 ( 1 0 . 0 g) i n d r y CS2 ( 5 0 m l ) , y i e l d 4 .6 g ( 5 4 . 8 $ ) ,

m . p . 1 4 5 ° ( l i t . 5 4 m . p . 1 4 4 - 4 6 ° ) .

4 , 4 ' - D i c h l o r o - 3 , 3 ' - d i n i t r o b e n z o p h e n o n e ( 8 4 )

T h i s compound was p r e p a r e d by n i t r a t i o n of £T3 ( 6 . 0 g,

0 . 0 2 3 mol ) i n H 2 S 0 4 ( 2 4 m l , d = 1 . 8 4 ) and HN03 ( 2 4 m l , d = 1 . 4 2 )

a t 60 . The p r o d u c t was worked up i n u s u a l manne r and

128

c r y s t a l l i z e d from e t h a n o l , y i e l d 6 .75 g ( 8 2 . 8 / 0 , m.p .

144-5° ( l i t . 3 5 m . p . 1 4 6 . 5 ° ) .

4 , 4 ' - D i a m i n o - 3 , 3 ' - d i n i t r o b e n z o p h e n o n e (85)

NH, gas was bubbled to a s o l u t i o n of 84 ( l . l g, 3

0.0032 mol) i n DMSO (20 ml) a t 140° f o r 4 h r . The product

was i s o l a t e d on d i l u t i o n wi th w a t e r , y i e l d 0.9 g ( 9 2 . 7 $ ) ,

m.p .121 ( l i t . m.p .121 ) .

iR(KBr) cm"1 : 1320, 1530 (N0 2 ) , 1600 (Arom), 1625 ,

(CO), 3380, 3500 (NH2) .

NMR(DMS0-d6) 6 J 7.05 (d , 2H, Ar-H, o to NH2, J=9Hz),

7 .7 (dd, 2H, Ar-H, £ to N0 2 , J=2 & 9Hz),

8.26 (d , 2H, Ar-H, o to N0 2 , J=2Hz).

3 , 3 ' , 4, 4 ' -Tet ra-aminobenzophenone (86_)

A mix ture of 85_ ( 3 . 0 2 g, 0 .01 mol) and Raney-nickel

(about 0.5 g) i n e t h a n o l (100 ml) was shaken wi th H2 a t 2

3 .5 kg/cm i n a P a a r hydrogena to r fo r 16 h r and produc t

worked-up i n usua l manner, y i e l d 2.0 g ( 8 2 . 6 $ ) , m.p.217°

( l i t . 3 7 m . p . 2 1 7 ° ) .

iR(KBr) cm"1 j 1625 (CO), 3320-3380 (NH2).

NMR(DMSO-dg) 6 : 6.46 ( d , 2H, Ar-H, J=9Hz), 6 .75 (dd ,

2H, Ar-H, J=2 *. 9Hz), 6 .9 (d , 2H, Ar-H,

J=2Hz) .

129

2 , 2 ' - D i c a r b o m e t h o x y a m i n o - 5 , 5 , - d i b e n z i m i d a z o l y l ketone (81_)

A s o l u t i o n of 86 (0 .5 g, 0.002 mol) and 1 , 3 -

d i c a r b o m e t h o x y - S - m e t h y l i s o t h i o u r e a (0 .86 g, 0 .0041 mol)

i n e t h a n o l (20 ml) was r e f l u x e d fo r 12 h r . The produc t was

i s o l a t e d in u sua l manner and r e c r y s t a l l i s e d from a c e t i c

c i d - w a t e r , y i e l d 0.55 g ( 6 5 . 5 * ) , m.p . > 2 8 0 ° . a

- 1 iR(KBr) cm

NMR(TFA) 6


Cal cd.

Found

: 1590 (Arom), 1630, 1705 (CO), 2700-2900

(C-H), 3300 (NH).

: 3.62 ( s , 6H, 2 X O C H 3 ) , 7 . 4 - 7 . 8 5 (m, 6H,

Ar-H)

s °19H16N6°5 ( 4 0 8 )

: 0, 55 .88 ; H, 3.92

: C, 56 .30 ; H, 3 . 6 5 * .

S i m i l a r l y 82 was p repa red from 86_ and 1 ,3 -d ica rbe thoxy-

S - m e t h y l i s o t h i o u r e a i n e t h a n o l .

5 , 5 ' - D i b e n z i m i d a z o l y l ke tone (88)

A s o l u t i o n of 86 ( 0 . 5 g, 0.002 mol) i n 98* formic

ac id (15 ml) was heated for 3 h r on a wa te r b a t h . The

r e a c t i o n mixture was coo led , n e u t r a l i z e d w i t h aqueous

ammonia s o l u t i o n . The s o l i d thus s e p a r a t e d was f i l t e r e d ,

washed wi th w a t e r , d r i e d , y i e l d 0 , 4 g ( 7 4 * ) , m .p . 280° .

IR(KBr) cm"1 j 1620 (Axon), 1645 (CO).

Mass a t n / z : 262 (M+)

NMR(33MSO-d6) 6 : 7 . 5 - 8 . 5 (m, 8H, Ar-H 4 N = C M ) .

130

A n a l y s i s f o r • C ^ R ^ ^ O (262)

Calcd. 5 C, 6 8 . 7 0 ; H, 3.81

Found : 0 , 6 8 . 3 2 ; H, 4 .12$ .

S i m i l a r l y 89 was p repared from 86 and g l a c i a l

a c e t i c a c i d .

3 , 3 ' , 4 , 4 » - T e t r a ~ a m i n o d i p h e n y l methane (87)

A mix tu re of 8£ ( 3 . 0 g , 0.01 m o l ) , 99$ h y d r a z i n e -

h y d r a t e (3 ml , 0 .08 mol) and KOH (3 g) was hea ted i n s t e e l

bomb a t 170° fo r 24 h r . The r e a c t i o n mix tu re was cooled ,

the s e p a r a t e d pure s o l i d ( 1 . 2 g) was f i l t e r e d , washed wi th

w a t e r and d r i e d . The f i l t r a t e was e x t r a c t e d wi th e t h y l

a c e t a t e (3x20 m l ) , washed wi th wa te r (3x20 m l ) , d r i e d

(NapS04) and s o l v e n t removed in vacuo . The product

c r y s t a l l i s e d from e t h a n o l , y i e l d 1.45 g ( 6 4 $ ) , m.p.136

( l i t . 5 7 m . p . l 3 7 ° ) .

iR(KBr) cm"1 : 1600 (Arom), 3300-3500 (NH2).

NMR(CDC15 + : 3.56 ( s , 2H, CH2), 6 .24 -6 .42 (m, 6 H ,

6 ' Ar-H) .

2 ,2 ' -D ica rbomethoxyamino-5 ,5 ' -d ibenz imidazo ly lme thane (90)

A s o l u t i o n of 87 ( 0 , 8 g, 0.0035 mol) and 1 , 3 -

d ioa rbome thoxy -S -me thy l i so th iou rea (1 .45 g, 0.0070 mol)

i n e t h a n o l (30 ml) was r e f luxed f o r 15 h r . The p roduc t was

i s o l a t e d i n u s u a l manner and re c r y s t a l l i s e d from a c e t i c

a c i d - w a t e r , y i e l d 0.86 g ( 6 2 . 7 $ ) , m .p . > 3 0 0 ° .

131

iR(KBr) cm"1

NMR(TFA) 6

Ana lys i s f o r

Calcd.

Found

: 1710 (CO), 2600-2950 (C-H)

3300 (tfH).

: 3.6 ( s , 6H, 2 X O C H 3 ) , 3.86 ( s , 2H,

- C H 2 - ) , 6 . 9 6 - 7 . 1 5 (m, 6H, Ar-H)

J ^ A ^ e ^ (594)

t 0, 57 .86 ; H, 4.56

j 0, 5 8 . 2 2 ; H, 4 .34$ .

In s i m i l a r manner °J. was p r epa red by t r e a t i n g 87

wi th - l " ,3 -d ica rbe th .oxy-S-methy l i so th iourea i n r e f l u x i n g

e than o l .

5 ,5 1 -Dibenz imidazo ly lmethane (£2)

87 ( 0 . 4 g, 0 .0017 mol) was heated in 98$ formic

ac id for 2 h r on w a t e r b a t h . The p roduc t was worked-up

as u s u a l and f i n a l l y c r y s t a l l i z e d from w a t e r , y i e l d 0.30 g

( 7 0 $ ) , m . p . 1 2 0 - 2 ° .

iR(KBr) cm - 1 : 1600 (Arom), 3100-3350 (NH).

i 4 .1 ( s , 2H, Cg 2 ) , 6 . 9 - 7 . 6 (m, 6H,

Ar-H), 8.12 ( s , 2H, 2xN=CM)

t 0 1 5 H l 2 N 4 (248)

j C, 7 2 . 5 8 ; H, 4 .83

: 0, 72 .42 ; H, 5 . 12$ .

Using t h e above method, S3, was p repa red by r e f l u x i n g 87

i n g l a c i a l a c e t i c a c i d .

i^MR(DMS0-d6) 6


Calcd.

Found

132

4-Acetoxyacetanil ide (95.)

This compound was prepared by ace ty la t ion of

4-acetamidophenol 94 (15 g, 0.1 mol) by ace t i c anhydride

in g l a c i a l a ce t i c ac id using l i t e r a t u r e method, y ie ld

15.44 g (8C#), m.p.148-52° ( l i t . 3 8 m.p.151-4°) .

4-Acetoxy-2-ni t roace tani l ide (96)

N i t r a t i on of 95 (10.0 g, 0.051 mol) in HNO (10 ml,

d=1.5) was done under cooling and s t i r r i n g . The reac t ion

mixture was poured on ice and product f i l t e r e d , dried and

r e c r y s t a l l i z e d from 50$ aqueous e thano l , y ie ld 7.8 g

(64/0 , m.p.142-4° ( l i t . 3 8 m.p.145-46 0) .

4-Acetamido-3-nitrophenol (97)

To a hot suspension of 96 (1.0 g, 0.00 42 mol) in

e thanol (10 ml) was added 10$ aqueous solut ion of KOH

(O.25 g) and mixture heated for 15 minutes on water ba th .

Solvent removed and Hie residue ac id i f i ed with d i l u t e HC1.

The c r y s t a l s separated on cooling, were f i l t e r e d , washed

and d r ied , y i e ld 0.70 g (85.3/°), m.p.2l8° ( l i t . 3 8

m.p.218-20°) .

5-( 4-Acetamidophenoxy)-2-nitroacetanil ide (101)

A solu t ion of potassium-4-acetamidophenoxide

(0.5 g, 0.0031 mol) and 5 -ch lo ro-2-n i t roace tan i l ide (5.6.)

(O.67 g, 0.0031 mol) in dry DMF (30 ml) was re fluxed for

133

2 4 h r . The r e a c t i o n mix tu re was c o o l e d , d i l u t e d w i th

w a t e r (100 ml) and e x t r a c t e d w i t h e t h y l a c e t a t e (3x25 m l ) .

The combined e x t r a c t was d r i ed (Na 2 S0 4 ) , so lvent removed

i&. YJQ®i£. 8Xi^i '^ie r e s i d u e c r y s t a l l i s e d from e t h a n o l , y i e l d

0 .48 g (48j t) , m . p . 1 7 8 0 .

- 1 iR(KBr) cm

iTMR(DMSO-d6) 6


Calcd.

Found

: 1320, 1520 ( N 0 2 ) , 1600 (Arom), 1660,

1700 (CO), 3250 (NH).

: 2.06 ( s , 6H, 2xC0CH3), 6 . 8 (dd, 1H,

Ar-H, £ t o WHAc, J = 2 . 5 & 9Hz), 7.06 (d ,

2H, Ar-H, m to NHAc, J=9Hz), 7 .42 (d ,

1H, Ar-H, 0 to NHAc (m t o N 0 2 ) , J=2Hz),

7 .68 (d , 2H, Ar-H, o to NHAc, J=9Hz),

8 .0 ( d , 1H, Ar-H, o to N0 2 , J=9Hz),

1 0 . 0 ( s , 1H, NHCO)

: G16H15N3°5 ( 5 2 9 >

: C, 5 8 . 0 5 ; H, 4.55

: C, 58 .42 ; H, 4 . 3 5 ^ .

4 , 4 i - D i n i t r o d i p h e n y l e t h e r (102)

A mix tu re of potass ium 4 -n i t rophenox ide (20 .0 g,

0 .113 mol) and l - c h l o r o - 4 - n i t r o b e n z e n e ( 1 7 . 8 g, 0,113 mol)

was r e f luxed in dry DMF (50 ml) f o r 40 h r and worked-up

m.p. as u s u a l , y i e l d 1 2 . 5 g (42.6J&), m.p .142° ( l i t . 5 9

1 4 2 - 3 ° ) .

134

4 ,4 ' -D iaminod ipheny l e t l i e r (10J5)

This was o b t a i n e d by r e d a c t i o n of 102 (10.0 g,

0 .038 mol) by hydrazine^iydra te and Raney-n icke l by the

method as d e s c r i b e d f o r 3_9_, y i e l d 5.5 g ( 7 2 . 3 $ ) , m.p .

185-6° ( l i t . 3 9 m . p . 1 8 6 - 7 0 ) .

4 , 4 ' - D i a c e t a m i d o d i p h e n y l e t h e r (104)

A c e t y l a t i o n of 10J5 (2 .0 g, 0 .01 mol) by a c e t i c

anhydr ide i n an usua l manner gave 2 .2 g of the p roduc t ,

y i e l d 77 .4$ , m . p . 2 2 2 ° .

- 1 iR(KBr) cm

NMR(DMSO-dg) 6

Ana lys i s f o r

Calcd.

Found

: 1660 (CO), 3280 (NH).

; 2 .0 ( s , 6H, 2 X C O C H 5 ) , 6.8 ( d , 4H, Ar-H,

m to NHAc, J=9Hz), 7.45 (d , 4H, Ar-H,

o to M A c , J=9Hz), 9.76 ( s , 2H, 2xNHC0)

: C j L g H ^ N ^ (284)

: C, 67 .60 j H, 5.63

: C, 67.25? H, 5 .46$ .

4 , 4 ' - D i a c e t a m i d o - 3 , 3 1 - d i n i t r o d i p h e n y l e t h e r (^05.)

To an i c e cooled (10°) s o l u t i o n of 104 (5 .0 g,

0 .017 mol) i n g l a c i a l a c e t i c a c i d (30 ml) was added

dropwise fuming HN0, ( 6 . 2 4 ml, d=1.5) d u r i n g 20-30

minu te s wi th s t i r r i n g . The s t i r r i n g was con t inued for

2 h r du r ing coo l ing and then t h e mix tu re poured on crushed

i c e . The s o l i d s e p a r a t e d was f i l t e r e d , washed wi th wate r

(3x30 m l ) , d r i e d and re c r y s t a l l i z e d from e t h a n o l , y i e l d

135

5 . 4 g ( 8 2 . 1 $ ) , m . p . 2 l 2 ° .

IR(KBr) cm""1 : 1320, 1500 (N0 2 ) , 1670 (GO), 3240 (NH).

NMR(CDOL5) 6 : 2 .2 ( s , 6H, 2xC0CH5), 7 .18 (dd, 2H,

Ar-H, £ to N0 2 , J=3 4 9Hz), 7.65 (d ,

2H, Ar-H, o to N0 2 , J=3Hz), 8.65 (d ,

2H, Ar-H, m to N0 2 , J=9Hz)

A n a l y s i s f o r : C ^ g R ^ ^ (374)

Oalcd. j C, 5 1 . 3 3 | H, 3 .74 ; N, 14 .97

Found : C, 51 .56 ; H, 3 .28 ; N, 15 .32 /c

4 ,4»-Diamino-3 ,3 ' - d i n i t r o d i p h e n y l e t h e r (106_)

105 ( 4 . 0 g, 0.0106 mol) was r e f l u x e d in 50$ HC1

(50 ml) f o r 5 h r . The r e a c t i o n mix tu re was cooled ,

n e u t r a l i z e d w i t h aqueous ammonia and the s e p a r a t e d s o l i d

was f i l t e r e d , washed with w a t e r (3x20 ml) and d r i e d . The

p roduc t was r e c r y s t a l l i z e d f n a e t h a a o l , y i e l d 2 .8 g

(9054), m . p . 1 7 6 0 .

iR(KBr) cm"1 • 1320, 1510 (N0 2 ) , 1600 (Arom), 3360,

3500 (NH2).

NMR(0DC15) 6 : 5.85 (hump, 4H, 2xNg2) , 6 .65 (d , 2H,

Ar-H, 0 to NH2, J=9Hz) , 7.0 (dd, 2H,

Ar-H, jo t 0 N 02» J = 5 * 9Hz), 7.51 (d , 2H,

Ar-H, o to N0 2 , J=3Hz) .

Ana lys i s f o r j C i2H10N4°5 ^ 2 9 ° )

Oalcd. : C, 49 .65 ; H, 3 .44 ; N, 19 .31

Found : C, 49 .26; H, 3 .82 ; N, 1 9 . 6 8 $ .

136

3 , 3 ' , 4 , 4 ' - T e t r a - a m i n o d i p h e n y l e t h e r (107)

To a warn s o l u t i o n of 106 ( 1 . 0 g, 0 .0034 mol) i n

ethanol-THF ( 1 : 1 , 30 ml) and Raney-n icke l ( r ^ 0 . 2 g) was

added dropwise h y d r a z i n e - h y d r a t e ( 1 . 3 7 g, 0.0272 mol) in

e t h a n o l (10 m l ) . Af t e r t he a d d i t i o n was comple te , the

r e a c t i o n mix tu re was h e a t e d t i l l i t was c o l o u r l e s s . The

c a t a l y s t was f i l t e r e d off , washed w i th e t h a n o l and

s o l v e n t removed to ge t o i l y p r o d u c t , y i e l d 0.6 g (76/0).

This was no t p u r i f i e d and used as such for nex t s t e p .

2 ,2» -Dica rbomethoxyamino-5 ,5 ' -d ibenz imidazo ly l oxide (110)

A mix tu re of 107 (0 .6 g, 0.0026 mol) and 1 , 3 -

d ica rbomcthoxy-S-methy l i so t h i o u r e a ( 1 . 7 4 g, 0.0052 iml )

i n e t h a n o l (30 ml) was re f luxed for 12-15 h r . The

p roduc t was worked-up as u s u a l and r e c r y s t a l l i z e d from

DMSO, y i e l d O.63 g ( 6 2 £ ) , m.p . > 3 0 0 ° .

- 1 iR(KBr) cm

NMR(TFA) 6


Calcd.

Pound

: 1600 (Arom), 1710 (CO), 2700-

2900 (C-H), 3350 (NH).

: 3.58 (s, SH, 2xOOH5), 6.7-7.2 (m, 6H,

Ar-H)

'• °lA6N605 (396)

: 0, 52.02; H, 4.04,

: G, 51.68; H, 4.44$.

137

I n s i m i l a r manner compound 111 was p repa red from 107

and 1 , 3 - d i c a r b e t h o x y - S - m e t h y l i s o t h i o u r e a i n e t h a n o l while

108 and 109_ were o b t a i n e d by r e f l u x i n g 107 i n formic and

a c e t i c a c i d s r e s p e c t i v e l y .

l , 2 - D i ~ ( 3 - a m i n o - 4 - n i t r o p h e n y l t h i o ) e t h a n e (112)

A s o l u t i o n of e t h a n e d i t h i o l (1 .96 ml , 0.017 mol)

and KOH ( 1 . 9 4 g, 0 .034 mol) i n e t h a n o l (20 ml) was s t i r r e d

a t room tempera ture f o r 30 m i n u t e s . To t h i s s t i r r e d

s o l u t i o n , was added a s o l u t i o n of 5 - c h l o r o - 2 - n i t r o a n i l i n e

98 ( 6 . 0 g, 0 .034 mol) i n e t h a n o l (25 m l ) . The r e a c t i o n

mix tu re was r e f luxed f o r 2 h r on a wa te r b a t h . The

s e p a r a t e d s o l i d was f i l t e r e d a f t e r c o o l i n g the r e a c t i o n

m i x t u r e , washed w i th e thanol (3x20 ml) and w a t e r (3x20 ml)

and d r i e d , y i e l d 3.0 g ( 4 6 . 5 $ ) , m.p .265-6° ( d ) .

IR(KBr) cm"1 : 1320, 1560 (N0 2 ) , 1620 (Arom), 3350,

3475 (NH2).

NMR(DM30-d6) 6 ' : 3 .28 ( s , 4H, S - (CH 2 ) 2 -S ) , 6.45 (dd, 2H,

Ar-H, 2 t o NH2» J = 5 * 9 H z )> 6 ' 8 4 (d» 2H» A r ~ S , o to NH2, J=3Hz), 7 .34 ( s , 4H,

2xNH2 exchangeable i n D 2 0) , 7.79 ( d ,

2H, Ar-H, o to N0 2 , J=9Hz) .

1 , 2 - D i - ( 3 , 4 -d i aminopheny l th io )e thane (114)

A suspens ion of 112 ( l . O g, 0.0027 mol) and 10$

Pd/C ( ~> 200 mg) i n e t h a n o l (200 ml) was shaken i n p a a r p

hydrogena to r a t 3 .5 kg/cm p r e s s u r e f o r 10 h r . The c a t a l y s t

138

was f i l t e r e d and washed with ethanol (2x10 ml) . Solvent

was removed from f i l t r a t e in vacuo to get crude

te t ra-amine which was c r y s t a l l i s e d from ethanol , y i e ld

0.2 g (24$), m.p. 115°.

-1 iR(KBr) cm

Mass a t m/z

: 1605 (Arom), 3200, 3300 (NH2)

j 306 (M+).

l ,2-Di-(2-carbomethoxyaminobenzimidazolyl-5(6 ) - th io )

ethane (115)

A so lu t ion of 114 (0 .4 g, 0.0013 mol) and 1 ,3 -

dicarbomethoxy-S-methylisothiourea (0 .54 g, 0.0026 mol)

i n e thanol (25 ml) was refluxed for 15 h r . The compound

was i s o l a t e d as usua l , y i e ld 0.35 g (57 .3 /0 , m.p. > 280°#

- 1 iR(KBr) cm

NMR(IFA) 6

Analysis for

Oalcd.

Found

1600 (Arom), V715 (CO), 2700-

2900 (C-H), 3340 (NH).

2.72 ( s , 4H, S-(0H2)2-S), 3.58 ( s , 6H,

2X0CH3), 7.08-7.22 (m, 6H, Ar-H)

C20H20%°4S2 ^ 4 7 2 ) C, 50.84; H, 4.23

C, 51.22; H, 4.64$.

Similar ly Il6_ was prepared from 114 and 1 ,3 -

dicarbethoxy-S-methyl isothiourea in ref luxing e thanol .

139

4 - C h l o r o - 3 - n i t r o b e n z o y l c h l o r i d e (117) and 4-acetamido-

3 - n i t r o b e n z o y l c h l o r i d e (118)

[These were p r epa red by r e f l u x i n g 4 - c h l o r o - 3 ~

n i t r o b e n z o i c ac id and 4 - a c e t a m i d o - 3 - n i t r o b e n z o i c acid wi th

t h i o n y l c h l o r i d e i n dry benzene i n 70 and 72$ y i e l d s . The

a c i d c h l o r i dee were used as su ch i n n e x t s t e p .

l , 4 - D i - ( 4 - c h l o r o - 3 - n i t r o b e n z o y l ) p i p e r a z i n e (119)

A s o l u t i o n of anhydrous p i p e r a z i n o ( 0 . 5 g> 0.0058

mol) i n dry benzene (20 ml)was added dropwiso to a

s t i r r e d s o l u t i o n of 4 - c h l o r o - 3 - n i t r o b e n z o y l c h l o r i d e 117

(2 .56 g, 0.0116 mol) i n dry benzene (100 m l ) . S t i r r i n g

was con t inued f o r 5 h r a t room t e m p e r a t u r e . The sepa ra t ed

s o l i d was f i l t e r e d , washed wi th benzene (3x10 m l ) , w a t e r

(5x10 ml) and d r i e d , y i e l d 2 .2 g ( 8 3 . 6 $ ) , m .p .224° .

iR(KBr) cm*"1 • 1340, 1535 (N0 2 ) , 16 40 (NCO), 2670,

2920 (C-H).

3 .47 ( s , 8H, 4xN-0H2), 7 . 6 - 7 . 8 (m, 4H,

Ar-H, m h .£ to N 0 2 ) , 8.0 (d , 2H,

Ar-H, o to N0 2 , J=3Hz)

C 1 8 H 1 # 4 ° 6 C 1 2 < 4 " )

C, 47 .68 ; H, 3.09

C, 47 .56; H, 3 .15$ .

NMR(BMSO-dg) 6

Ana lys i s f o r

Oalcd.

Found

S i m i l a r l y 120 was p repared from 4 -ace t amido -3 -

n i t r o benzoyl c h l o r i d e (118) and anhydrous p ipe raz ino in

dry benzene , y i e l d 88 . l / 0 , m .p .250° .

140

iR(KBr) cm' - 1 : 1360, 1540 ( N 0 2 ) , 1650 (NCO), 1670

(NH00), 2700, 2950 (C-H), 3300 (NH)

: 2 .02 ( s , 6H, 2xCOCH5), 3.6 ( s , 8H,

N - ( C H 2 ) 4 ) , 7 . 2 - 8 . 2 5 (m, 6H, Ar-H)

i G22^2^6°8 ( 4 9 8 )

: C, 5 3 . 0 1 ; H, 4 .41

; 0, 5 2 . 6 5 ; H, 4.

NMR(TPA) 6


Calcd,

Pound

1 , 4 - D i - ( 4 - a m i n o - 3 - n i t r o b e n z o y l ) p i p e r a z i n e (121)

To a s t i r r e d suspens ion of 120 (4 .6 g, 0 .0092 mol) i n

e t h a n o l (100 ml) was added dropwise a t room tempera tu re a

10% aqueous s o l u t i o n of KOH i n smal l f r a c t i o n s t i l l a l l

t h e compound went i n t o the s o l u t i o n . S t i r r i n g con t inued f o r

5 h r a t room t empera tu re , the s e p a r a t e d s o l i d was f i l t e r e d ,

washed w i th e t h a n o l (3x20 m l ) , wa t e r (3x20 m l ) , d r i e d and

c r y s t a l l i s e d from DMSO-water, y i e l d 2 . 4 g ( 6 2 . 8 $ ) ,

m.p .280° ( d ) .

- 1 iR(JEBr) cm

NMR(DMS0-d6) 6


Calcd.

Pound

1350, 1520 (N02), 1600 (Arom), 1640

(-NC0).

3.55 (s, 8H, N-(CH2)4), 6.98 (d, 2H,

Ar-H, m to N02, J=8Hz), 7.42 (dd, 2H,

Ar-H, p_ to W02, J=2 * 9Hz), 7.5-7.7 (bs,

4H, 2xNH2), 7.95 (d, 2H, Ar-H, o to N02,

J=2Hz)

C, 52.17; H, 4.34

C, 52.53; H, 4.68#.

141

l , 4 - M - ( 3 , 4 - d i amine-benzoyl) p i pe raz ine (122)

A suspens ion of 121 ( 1 . 0 g, 0 .0024 mol) i n e t h a n o l -

THF ( l j l , 200 ml) and Raney-n icke l ( ^ 0 . 3 g) was shaken

on a P a a r hydrogena to r a t 3 .5 kg/cm p r e s s u r e for 12 h r .

The c a t a l y s t was f i l t e r e d off and washed wi th ho t

alcohol-THF (3x25 m l ) . The f i l t r a t e was c o n c e n t r a t e d and

the r e s i d u e c r y s t a l l i z e d from e t h a n o l , y i e l d 0.45 g ( 5 3 ^ ) ,

m.p .266-7 .

iR(KBr) cm"1 ; 1590 (Arom), 1620 (CO), 3180, 3240 (NH2).

Mass a t m/z : 354 (M+).

1 , 4-Di-( 2-carbomethoxy aminobenzimidazoly l -5(6 ) -

c a r b o n y l ) p i p e r a z i n e (123)

A s o l u t i o n of 122 ( 0 . 3 g, 0 .008 mol) and 1 , 3 -

d i c a r b o m e t h o x y - S - m e t h y l i s o t h i o u r e a (0 .35 g, 0.0017 mol)

i n e t h a n o l (25 ml) was r e f l uxed for 15 h r . The r e a c t i o n

m i x t u r e was coolod , the s o l i d t hus s e p a r a t e d was f i l t e r e d ,

washed w i th wa te r (3x10 ml), e t h a n o l (3x10 ml) and

d r i e d , y i e l d 0 .18 g ( 4 1 ^ ) , m.p . > 2 8 0 ° .

iR(KBr) cm"1 j 1 |20 (CO), 2750-2950 (C-H),

3460 (NH).

NMR(TFA) 6 s 3.35 (hump, 8H, 2 J - (Cg 2 ) 4 ) , 3.6 ( s , 6H,

2xOCH3), 7 . 0 - 7 . 5 (m, 6 H , Ar-H)

Ana lys i s fo r • C2 4H2 4pQ06 (520)

Calcd. - C, 55.38$ H, 4 . 6 l j N, 21 .53

Found : C, 5 4 . 9 5 ; H, 4 .88 ; N, 21 .32$ .

142

I n s i m i l a r manner 124 was p repa red from 101 and

1 , 3 - d i c a r b e t h o x y - S - m e t h y l i s o t h i o u r e a .

4-Amino- 3 - n i t r obi phenyl (125)

4 -Ace tamido-3 -n i t rob ipheny l (25 .6 g, 0 .1 mol) was

suspended i n b o i l i n g e t h a n o l (100 ml) and potass ium

hydroxide ( 1 2 . 8 g) i n w a t e r (12 ml) was added. The r e a c t i o n

mix tu re was hea t ed on w a t e r ba th for 25 minu tes and cooled .

C r y s t a l s s e p a r a t e d a f t e r 10 minu tes which were f i l t e r e d and

p u r i f i e d by washing w i th 30$ aqueous e t h a n o l , y i e l d 18 .5 g

( 8 6 . 4 $ ) , m . p . l 6 8 ° ( l i t . 4 0 m . p . 1 6 7 - 9 ° ) .

3 ,4-Diaminobiphenyl (126)

This was p repa red by r e d u c t i o n of 125_ u s i n g h y d r a z i n e -

h y d r a t e and Raney-n icke l and w^rked-up as u s u a l , y i e l d 65$,

m . p . l 0 3 ° ( l i t . 4 1 m . p . l 0 2 ° - 1 0 3 ° ) .

E t h y l 5(6 ) -phenyrDenzimidazole-2-carbamate (1,27)

A mix ture of 126_ ( l . O g, 0 .0054 mol) and 1 , 3 -

d i c a r b e t h o x y - S - m e t h y l i s o t h i o u r e a (1 .26 g, 0.006 mol) i n

e t h a n o l (50 ml) was re f luxed for 12 h r . The r e a c t i o n

mix tu re was cooled and produc t i s o l a t e d as u s u a l and

c r y s t a l l i z e d from a c e t i c a c i d - w a t e r , y i e l d 0 .9 g ( 6 0 $ ) ,

m . p . 2 2 0 ° .

IR(KBr) cm""1 ; 1700 (CO), 2700-2900 (C-H),

3400 (FH).

143

NMR(Ti'A) 6 : 1.0 ( t , 3H, CHgCH^, J=8Hz), 4.0 ( q,

2H, CH2 0H5, J=8Hz) , 6 . 8 - 7 . 3 (m, 8H,

A n a l y s i s f o r : C ^ H ^ N ^ (281)

Oalcd. : C, 68.37? H, 5.33

Found : C, 68.56$ H, 5.66/i .

4 - ( B e n z o y l ) a m i n o - 3 - n i t r o b i p h e n y l (128)

A s o l u t i o n of benzoyl c h l o r i d e (0 .77 g, 0.0055 mol)

i n dry benzene (20 ml) was added dropwise to a r e f l u x i n g

s o l u t i o n of 125_ ( 1 . 0 g, 0.0046 mol) i n dry benzene (30 ml)

and r e f l u x i n g con t inued fo r 12 h r . The r e a c t i o n mix tu re

was cooled and s u c c e s s i v e l y washed w i t h w a t e r (3x20 ml)

and 10$ NaHCO, s o l u t i o n (3x20 m l ) . The o rgan i c l a y e r

was d r i e d (Na2S0 ) and so lven t removed in vacuo to ge t

a s o l i d mass which was c r y s t a l l i z e d from benzene , y i e l d

1.2 g (81$ ) , m . p . 1 4 0 0 .

iR(KBr) cm*"1 : 1320, 1580 (N0 2 ) , 1680 (CO).

NMR(DMS0-d6) 6 : 7 . 25 -7 .95 (m, 12H, Ar-H), 8.18 (d , 1H,

Ar-H, o to N0 2 , J=2Hz)

Ana lys i s f o r • C L ^ I ^ ^ O - ^ 5 1 8 )

Calcd. • 0, 7 1 . 6 9 , H, 4.46

Pound j 0, 72.00j H, 4.42/c.

S i m i l a r l y , compounds 129 and 130 were p repared

by t r e a t i n g 12J5 w i t h co r respond ing ac id c h l o r i d e s i n dry

benzene .

Analys i s f o r

Calcd .

Found

144

1 2 ^ , y i e l d 75$, in .p .151° .

iR(KBr) cm"1 : 1320, 1520 (N0 2 ) , 1685 (CO).

NMR(DMS0-d6) 6 : 7 . 3 2 - 8 . 0 (m, 11H, Ar-H), 8.12 (d , H i ,

PhC=CH-C-N02, J=2Hz)

A n a l y s i s for : C ^ H - ^ N ^ (363)

Oalcd. : C, 62.90} H, 3.57

Found : 0, 6 3 . 3 2 ; H, 3 .83$ .

1^0, y i e l d 76$, m . p . 2 4 4 ° .

iR(KBr) cm"1 : 1340, 1520 (N0 2 ) , 1680 (CO)

G19H13N3°5 ( 5 6 5 )

C, 62.90} H, 3.57

C, 6 2 . 7 8 ; H, 3 .68$ .

3-Amino- 4? - (benzoy l )aminob ipheny l ( l ^ l )

To a warm m i x t u r e of 128 ( 1 . 0 g, 0.0031 n o l ) and

Raney-n icke l (/-*^0.2 g) i n ethanol-THF ( 2 : 1 , 50 m l ) , a

s o l u t i o n of h y d r a z i n e - h y d r a t e ( 1 .25 g, 0.0248 mol) i n

e t h a n o l (20 ml) was added dropwise and r e f l u x i n g

con t inued for 1 h r . Ca t a ly s t was f i l t e r e d off and mother

l i q u o r was c o n c e n t r a t e d to get a s o l i d which was

c r y s t a l l i z e d from e t h a n o l , y i e l d O.65 g ( 7 2 $ ) , m.p .

198 -200° .

iR(KBr) cm"1 j 16 35 (CO), 3200-3400 (NH,NH2).

Ana lys i s for j C igR" l6N20 (288)

Calcd. s C, 79.13} H, 5.55

Found : C, 79.43} H, 5 .28$ .

145

In s i m i l a r manner 13„2 and 125 were p repared by

reducing 12_9_ and 130 w i t h h y d r a z i n e - h y d r a t e and Raney-

n i c k e l i n ethanol-THF m i x t u r e .

1 2 2 , y i e l d 64$, m . p , 1 8 8 ° .

iR(KBr) cm' 1


Calcd.

Found

1 3 3 , y i e l d 61

iR(KBr) cm - 1


Calcd*

Found

m

1620 (CO), 3200-3300 (NH,NH2)

G19H17N3° ( 3 0 3 )

C, 75 .24 ; H, 5.61

C, 75 .62 ; H, 5 . '

p . 2 2 8 ° .

1625 (CO), 3200-3300 (NH,NH2)

C 19 H 17 N 3 0 ( 3 ° 5 )

C, 75 .24 ; H, 5 . 6 l

C, 7 5 . 3 8 ; H, 5 . 46$ .

2 ,5 (6 ) -D ipheny lbenz imidazo l e (l3_4)

A s o l u t i o n of l ^ l ( 1 . 0 g, 0 .0034 mol) i n e t h a n o l

(10 ml) and c o n c e n t r a t e d h y d r o c h l o r i c ac id (20 ml) was

r e f l u x e d f o r 8 h r . The r e a c t i o n mix tu re was coo led , the

s e p a r a t e d s o l i d was f i l t e r e d and b a s i f i e d wi th aqueous

ammonia s o l u t i o n . The aqueous l a y e r was e x t r a c t e d w i th

e t h y l a c e t a t e (2x30 m l ) , d r i e d (NagSO.) and s o l v e n t

removed i n vacuo t o g e t pure p r o d u c t , y i e l d 0 .58 g ( 6 2 $ ) ,

m .p .196 0 ( l i t . 4 2 m . p . 1 9 7 - 8 ° ) .

iR(KBr) cm - 1 : 1620 (Arom).

143

Mass a t m/z

Ana lys i s for

Calcd.

Found

: 270 (M+)

: C 1 9 H 1 ^ 2

: C, 84 .10 ; H, 5 .18

: C, 8 3 . 6 8 ; H, 5 .53$ .

Compounds 1J5_ and 1J56_ were p repared s i m i l a r l y from

132 and 1 3 3 .

i21f y i e l d 63$, m . p . 2 1 5 ° .

iR(KBr) cm~x

Mass a t m/z

Ana lys i s f o r

Oalod.

Found

1^6, y i e l d 58$, m

iR(KBr) cm - 1

Mass a t m/z


Calcd.

Found

IS05 (Arom), 3150-3420 (NH,NH2).

285 (M+)

C19H15N3 ( 2 8 5 )

C, 8 0 . 0 0 ; H, 5.26

C, 80 .32 ; H, 5 .48$ .

p . 2 2 7 - 8 ° .

1600 (Arom), 3200-3400 (NH,NH2)«

285 (M+)

C i g H 1 5 N 3 (285)

C, 80 .00 ; H, 5.26

C, 80 .24 ; H, 5 .12K

2 - ( 4 - l s o t h i o c y a n a t o p h e n y l ) - 5 ( 6 ) - p h e n y l b e n z i m i d a z o l e -

h y d r o c h l o r i d e (139)

A s o l u t i o n of th iophosgene ( 0 . 2 7 ml , 0.0035 mol)

i n dry ace tone (10 ml) was added dropwise to a s t i r r e d

s o l u t i o n of l ? 5 ( 1 . 0 g, 0.0035 mol) i n dry acetone

147

(35 ml) a t room t e m p e r a t u r e . The s t i r r i n g was con t inued

for 8 h r , the s e p a r a t e d h y d r o c h l o r i d e was f i l t e r e d , washed

w i th e t h y l a c e t a t e (3x10 ml) and d r i e d , y i e l d 0 .78 g

( 6 5 # ) , m . p . 2 9 5 - 8 ° .

IR(KBr) cm"1 • 1605 (Arom), 1630 (C=F), 2050 (NCS),

2600-2900 ( s a l t ) ,

Ana lys i s f o r s C^H^N^S.HCl (363 .5 )

Calcd. i C, 66 .24 j H, 3.85

Found : C, 6 6 . 3 8 ; H, 3 .62$ .

2-( 4-Carbomethoxyaminophenyl)-5(6 ) -phenylb enzimi dazo l e( 141)

Methyl ch lo roformate ( 0 . 4 g, 0.0042 mol) was added

to a s o l u t i o n of 1 3 6 ( 1 . 0 g, 0.0035 mol) i n p y r i d i n e (20 ml)

and the r e a c t i o n mix tu re hea t ed a t 100° fo r 1 h r . The

r e a c t i o n mixture was cooled and d i l u t e d wi th w a t e r (100 ml)

The s e p a r a t e d s o l i d was f i l t e r e d , washed wi th w a t e r ,

d r i e d and c r y s t a l l i z e d from e t h a n o l , y i e l d 1.0 g ( 8 5 $ ) ,

m.p .210 .

iR(KBr) cm"1 : 1600 (Arom), 1710 (CO), 3320 (NH).

NMR(TFA) 6 : 3.5 ( s , 3H, OCH^), 6 . 8 - 7 . 6 (m, 12H,

Ar-H)

Ana lys i s f o r • C 2 l H 1 7 N,0 2 (343)

Calcd. : C, 73 .46 ; H, 4.95

Found : C, 73 .72 ; H, 5 .22$ .

S i m i l a r l y 140 was p repared from 136_ and e t h y l

ch lo ro fo rmate , y i e l d 80^, m.p .255° .

148

iR(KBr) cm' - 1

NMR(niSO-dg) 6

A n a l y s i s for

Galcd.

Found

: 1600 (Arom), 1700 (CO), 3300-3400 (NH).

: 1.2 ( t , 3H, CH2CH5, J=7Hz), 4 . 1 (q ,

2H, CH20H3, J=7Hz) , 7 . 2 - 8 . 3 (m, 12H,

Ar-H)

C22H19F3°2 ( 3 5 7 )

0, 73 .94 ; H, 5 .32

C, 74 .35 ; H, 5.12f».

9-Phenylbenzimidazo ' [ 1 , 2 - c ] q u i n a z o l i n - 6 - o n e (137)

A mixture of 1/35 ( 1 . 0 g, 0.0035 mol) and e t h y l

ch lo roformate ( 0 . 3 8 g, 0.0035 mol) i n p y r i d i n e (20 ml)

was r e f l u x e d f o r 2 h r . The r e a c t i o n mix ture was cooled

and d i l u t e d wi th w a t e r . The s e p a r a t e d s o l i d was f i l t e r e d ,

washed thoroughly w i t h w a t e r , d r i e d and c r y s t a l l i z e d from

DMSO, y i e l d 0.83 g ( 7 5 $ ) , m .p .296° .

iR(KBr) cm"1 : 1620 (C=N), 1710 (CO)

Mass a t m/z : 311 (M+)

A n a l y s i s f o r j C20H13N3° ^ 5 1 1 ^

Calcd . : C, 77 .17 ; H, 4 .14

Found j C, 77 .38 ; H, 4 .53$ .

Under i d e n t i c a l r e a c t i o n c o n d i t i o n , 9 - p h e n y l h e n z i -

m i d a z o [ l , 2 - c ] q u i n o z o l i n e - 6 - t h i o n e (1^8) was p repa red by

r e a c t i o n of i;3J? w i t h potass ium e t h y l x a n t h a t e i n p y r i d i n e ,

y i e l d 72$, m . p . 2 5 5 - 6 ° .

-1 iR(KBr) cm" : 1160 (C=S), 1630 <c~N)v

143

Mass a t m/z : 327 (M+)

A n a l y s i s fo r : C^H-^N^S (327)

Calcd. j C, 73 .39 ; H, 3.91

Found ! C, 73 .52 ; H, 4 . 2 6 $ .

l - (2 -Aminobenzoy l ) -2 -mercap to -5 -phenyrbenz imidazo le (143_)

Thiophosgene (0.1-3 ml , 0.0016 mol) i n ace tone

(20 ml) was added dropwise to a s t i r r e d s o l u t i o n of 132

( 0 . 5 g, 0.0016 mol) i n dry ace tone (30 ml) and t r i e t h y 1 -

amine (0 .32 ml, 0 .0032 mol) dropwise a t room t e m p e r a t u r e .

The s t i r r i n g was con t inued f o r 5 h r and t h e s o l i d

s e p a r a t e d was f i l t e r e d , washed w i th ace tone (3x10 m l ) ,

d r i e d and c r y s t a l l i z e d from DMSO-wator, y i e l d 0 .24 g

( 4 5 / 0 , m .p .275° .

iR(KBr) cm"1 : 1690 (CO), 3200-3400 (NH2) .

Mass a t m/z • 345 (M+)

A n a l y s i s f o r ; C^H-^N^OS (345)

Calcd. : C, 69 .56 ; H, 4 .34

Found : C, 70 .04 ; H, 4 .15$ .

15$ of 144 was a l s o ob ta ined from mother l i q u o r .

l - ( 4 - l s o t h i o c y a n a t o b e n z o y l ) - 2 - m e r o a p t o - 5 - p h e n y l b e n z i -

midazole (145)

To a s t i r r e d s o l u t i o n of 13J3 ( 0 . 5 g, 0.0016 mol) i n

dry ace tone (30 ml) and t r i e thy lamine (0 .6 5 ml, O.OO65

m o l ) , a s o l u t i o n of th iophosgene (0 .25 ml , 0.0032 mol) i n

150

dry ace tone (30 ml) was added dropwise a t room, t e m p e r a t u r e .

S t i r r i n g was con t inued f o r 10 h r . Solvent was removed

i n vacuo and the r e s i d u e c r y s t a l l i z e d from benzene , y i e l d

0 .41 g ( 6 5 / 0 , m . p . l 9 5 ° .

IR(KBr) cm"1

Mass a t m/z

Ana lys i s f o r

Calcd,

Found

S 1680 ( 0 0 ) , 2060 (N3S).

: 387 (M+) , base peak 162 .

; C 2 l H 1 3 N 5 0S 2 (387)

: C, 6 5 . 1 1 ; H, 3.35

: 0, 6 5 . 3 8 ; H, 3 .25$ .

S i m i l a r l y 144 was p repa red from 13.2 and two moles

of th iophosgene and p u r i f i e d by column chromatography

u s i n g s i l i c a gel column and e t h y l a c e t a t e - b e n z e n e (ls'-fc)

as e l u a n t , y i e l d 50$, m .p .255 -56 0 .

- 1 iR(KBr) cm

Mass a t m/z

Ana lys i s fo r

Calcd .

Found

1710 (CO), 2080 (NCS)

387 (M+) , base peak 329

G21H13N30 S2 ( 3 8 7 )

C, 6 5 . l l ; H, 3.35

C, 6 5 . 2 3 ; H, 3 . 5 0 $ .

5 - ( 4 - A c e t a m i d o p h e n y l t h i o ) - 2 - n i t r o a o e t a n i l i d e (148)

To a s o l u t i o n of 4-ace tamidoth iophen cfl. ( 5 . 0 g,

0 .03 mol) i n n - p r o p a n o l (30 m l ) , 10$ aqueous s o l u t i o n of

KOH (1 .66 g, 0 .03 mol) was added a t room tempera ture and

s t i r r i n g was con t inued for 30 m i n u t e s . To t h i s was added

a s o l u t i o n of 5 - c h l o r o - 2 - n i t r o a c e t a n i l i d e 5_6_ (6 .42 g,

0 .03 mol) i n n - p r o p a n o l (20 m l ) . The r e a c t i o n mix tu re

http://65.ll

151

was refiuxed for 5 h r , cooled and the c r y s t a l l i z e d so l id

f i l t e r e d , washed successively with n-propanol (2x10 ml)

and water (3x10 ml) and dr ied, y ie ld 7.8 g (75.5#) ,

m.p.196 .

iR(KBr) cm"1 : 1300, 1570 (N02), 1600 (Arom), 1660,

1705 (CO), 3280 (NH).

x*MR(BMS0-d6) 6 j 2.02 ( s , 3H, C0CH3), 2.08 [ s , 3H,

COCH, o to N02 ) , 6.86 (dd, 1H, Ar-H,

p. to NHAc, J=3 4 9Hz), 7.4-7.95 (m, 6H,

Ar-H), 10.2 (hump, 1H, NHOO).

Analysis for • C. ,-H, cN,0.S (345)

Calcd. : C, 55.65; H, 4.34

Found : 0, 55.95; H, 4.10$.

Similar ly 147 was prepared from 4-acetamidothiophenol

and 5- tahloro-2-ni t roani l ine (98) in n-propanol .

147 was also prepared by s e l e c t i v e hydrolysis of

148 described below.

5-(4-Acetamidophenyl thio)-2-ni t roani l ine (147)

To a suspension of 148 (10.0 g, 0.029 mol) in

b o i l i n g ethanol (50 ml) was added a so lu t ion of KOH (2.0 g)

in water (10 ml) . The react ion mixture was heated for

5 minutes on a water bath and l e f t a t room temperature.

The product c r y s t a l l i z e d a f t e r co i l i ng which was f i l t e r e d ,

washed with 50$ aqueous ethanol and dr ied , y ie ld 6.2 g

152

( 7 0 . 8 £ ) , m.p .176-7

iR(KBr) cm

MR(MSO-d 6 ) 6

Ana lys i s f o r

Calcd.

Found

~ 1 : 1300, 1560 (N0 2 ) , 1600 (Arom), 1650

(GO), 3260, 3340, 3470 (NH,NH2).

2 . 1 ( s , 3H, 00CH5), 6 .25 (dd , 1H, Ar-H,

£ to NH2, J=2&9Hz), 6.55 (d , 1H, Ar-H,

o to NH2, J=2Hz) , 7.45 (d , 2H, Ar-H, m

t o NHAc, J=9Hz), 7 .78 ( d , 2H, Ar-H, o

to NHAc, J=9Hz), 7 .84 (d , 1H, Ar-H,

0 t o N0 2 , J=9Hz), 1 0 . 2 (hump, 1H,NHC0)

C 14 H 13 N 3°3 S ( 3 0 3 )

C, 55 .44 ; H, 4.29 J N, 13.86

C, 55 .12 ; H, 4 . 6 5 ; N, 14 .24$ .

5 - (4 -Acc tamidopheny l th io ) -o -pheny lcned iamine (149)

To a warm mix tu re of 147, (6 .06 g, 0.02 mol) and

Raney-n icke l ( ^^ 0 .8 g) i n ethanol-THF ( 1 : 1 , 50 m l ) , was

added dropwise h y d r a z i n e - h y d r a t e i n e t h a n o l ( 8 . 0 g, 0.16

mol) w i t h o c c a s s i o n a l s h a k i n g . When s o l u t i o n he came

c o l o u r l e s s the c a t a l y s t was f i l t e r e d off , washed wi th

e t h a n o l (3x10 ml) and t h e f i l t r a t e was evapora ted i n vacuo

t o g e t crude d iamine , y i e l d 3 .8 g (78.156). This p roduc t

was a s such used i n n e x t s t e p .

E thy l 5 ( 6 ) - ( 4 - a c e t a m i d o p h e n y l t h i o ) b e n z i m i d a z o l e - 2 -

carbamate (151)

A mixture of 149 (9 .0 g, 0.033 mol) and 1 , 3 - d i c a r b -

e t h o x y - S - m e t h y l i s o t h i o u r e a ( 7 . 7 g, 0 .0034 mol) i n e t h a n o l

153

(150 ml) was r e f l u x e d fo r 16 h r . The r e a c t i o n mix ture was

coo led and the s e p a r a t e d s o l i d was f i l t e r e d , washed wi th

e t h a n o l , d r i e d and r e c r y s t a l l i z e d from a c e t i c a c i d - w a t e r ,

y i e l d 8.69 g ( 7 0 . 4 $ ) , m . p . 2 3 5 - 6 ° .

iR(KBr) cm"1 s I65O (C0C23) , 2-700 (NHGOO), 2700-2800

(G-H), 3400 (NH).

NMR(Ti\A.) 6 : 0 .98 ( t , 3H, CHgCH^, J^8Hz) , 2 .0 ( s ,

3H,COCH5), 3 .98 (q , 2H, CHgCHy J=8Hz),

6 . 8 - 7 . 1 (m, 7H, Ar~H)

A n a l y s i s f o r : C18H18£T405S (370)

Calcd. : C, 58 .37 ; H, 4 .86 ; N, 15 .15

Found : C, 58 .68 ; H, 4 .44 ; N, 1 5 . 4 6 $ .

Us ing s i m i l a r expe r imen ta l c o n d i t i o n 15Q was a l so

p r epa red from 149_ and 1 , 3-dicarbomethoxy-S-me t h y l i s o t h i o u r e a

i n r e f l u x i n g e t h a n o l .

5 ( 6 ) - ( 4 -Ace tamidopheny l th io ) -2 -methy lbenz imidazo le (15J5)

A s o l u t i o n of 149 ( 7 . 5 g, 0 .027 mol) i n g l a c i a l

a c e t i c a c i d (40 ml) was r e f l u x e d o v e r n i g h t . The r e a c t i o n

mix tu re was cooled and the c r y s t a l l i z e d s a l t of the

p roduc t was f i l t e r e d , washed wi th benzene and t r e a t e d

wi th aqueous ammonia to give f ree base ( 3 . 7 g ) . Another

crop of pure p roduc t ( 2 . 8 g) was o b t a i n e d from the mother

l i q u o r on n e u t r a l i z a t i o n w i th 30$ aqueous ammonia s o l u t i o n ,

t o t a l y i e l d 6 .5 g ( 7 9 . 7 $ ) , m.p.258-6 0 ° .

154

IR(KBr ) cm""1 ; 1680 (GO), 3250 (NH).

NMR(TtfA) 6 ; 2 . 0 8 ( s , 3H, COCH^), 2 . 4 9 ( s , 3H,

C-CH 3 ) , 6 . 9 - 7 . 2 5 (m, 7H, Ar-H)

A n a l y s i s f o r : O ^ H - ^ O S ( 2 9 7 )

C a l c d . : 0 , 6 4 . 6 4 ; H, 5 . 0 5

Pound : C, 6 4 . 2 6 ; H, 5 . 4 4 $ .

Compound 15_2 was p r e p a r e d s i m i l a r l y from 149 and

f o r m i c a c i d .

5 ( 6 ) - ( 4 - A o e t a m i d o p h e n y l s u l f o n o ) - 2 - m e t h y l b e n z i m i d a z o l e (162)

KMnO. ( 4 . 0 g) was a d d e d t o a s t i r r e d s o l u t i o n of

i S 5 ( 4 , ° S, 0 . 0 1 3 mo l ) i n 80$ a q u e o u s a c e t i c a c i d (250 ml )

d u r i n g 30 m i n u t e s a t room t e m p e r a t u r e . S t i r r i n g was

c o n t i n u e d f o r f u r t h e r 5 h r and t h e n e x c e s s of KMnO. was

decomposed by c a r e f u l a d d i t i o n of 30$ H20p s o l u t i o n

d u r i n g c o o l i n g . When the r e a c t i o n m i x t u r e became c o l o u r l e s s ,

i t was d i l u t e d w i t h l a r g e amount of w a t e r . The s o l i d

s e p a r a t e d a f t e r 30 m i n u t e s was f i l t e r e d , washed w i t h

w a t e r and d r i e d t o g e t p u r e compound, y i e l d 3 . 4 g ( 7 7 . 2 $ ) ,

m . p . > 2 8 0 ° .

i R ( K B r ) cm"1 • 1155 ( S 0 2 ) , 1690 (CO) , 3200-3400 (NH),

NMR(DMSO-dg) 6 : 2 . 0 3 ( s , 3H, C0CH5) , 2 . 4 8 ( s , 3H, C-CH^),

7 . 5 - 7 . 9 (m, 7H, Ar-H)

A n a l y s i s f o r s C, ,-H, r-N,0,S ( 3 2 9 ) l o 15 3 3

C a l c d . : C, 5 8 . 3 5 } H, 4 .55

Found : C, 58 .72? H, 4 . 9 2 $

155

S i m i l a r l y compounds 159-161 were p r epa red by

o x i d a t i o n of 15,0-152. r e s p e c t i v e l y .

5 ( 6 ) - ( 4-Aminophenylsulfono)~2-methylbenzimidazole (167)

A s o l u t i o n of 16_2 ( 1 . 0 g, 0.003 mol) i n c o n c e n t r a t e d

HG1 (20 ml) was r e f l u x e d fo r 12 h r . The r e a c t i o n mixture

was coo led , and the s e p a r a t e d h y d r o c h l o r i d e f i l t e r e d ,

washed with benzene (3x10 m l ) , d r i e d and n e u t r a l i z e d wi th

30$ aqueous ammonia s o l u t i o n to get a pure f ree b a s e , y i e l d

0.65 g (74 .750 , m . p . l 3 0 ° .

IR(KBr) cm"1 j 1140 ( S 0 2 ) , 3100-3400 (NH,NH2).

NMR(DMSO-dg) 6 • 2 .48 ( s , 3H, C-CH^), 5.96 ( s , 2H, NH2),

6 . 53 (d , 2H, Ar-H, o to NH2, J=9Hz),

7 . 3 5 - 7 . 9 5 (m, 5H, Ar-H)

A n a l y s i s f o r j C14H13N3°2S ^ 2 8 7 ^

Calcd. • C, 58.53? H, 4.52

Found ; C, 58.22} H, 4 .12$ .

S i m i l a r l y 15.6, 15_J7 and 166 were ob ta ined by h y d r o l y s i s

o f 152 , 152 a11*1 L6A w i t h c o n c e n t r a t e d HC1.

E t h y l 5 ( 6 ) - ( 4 - a m i n o p h e n y l s u l f o n o ) b e n z i m i d a z o l e - 2 -

carbamate (164)

A s o l u t i o n of 160 ( 1 . 0 g, 0.0025 mol) i n 10$ HOI

(50 ml) was hea t ed on wa te r ba th fo r 30 m i n u t e s . The

r e a c t i o n mix tu re was cooled in i c e and n e u t r a l i z e d w i th 30$

aqueous ammonia s o l u t i o n . The s e p a r a t e d s o l i d was f i l t e r e d ,

156

washed wi th wa te r and d r i e d . I t was p u r i f i e d by a c i d - b a s e

t r e a t m e n t , y i e l d 0.76 g ( 8 5 . 3 $ ) , m .p .250° .

iR(KBr) cm""1 ; 1140 ( S 0 2 ) , 1715 (NHC00), 2750-2950 (C-H),

3100-3350 (NH,NH2).

MR(TPA) 6 l 0 .98 ( t , 3H, CH2CH3, J=7Hz), 4.0 (q , 2H,

CH2-CH5, J=?Hz) , 7 . 1 - 8 . 9 (m, 7H, Ar-H)

A n a l y s i s f o r j G l 6 H l 6 N 4 0 4 S (J60)

Caicd. : C, 5 3 . 3 3 ; H, 4 .44

Found s C, 53 .74 ; H, 4 .82$ .

S i m i l a r l y 154, 15_5_ and 16_3 were p repa red from 1,50,

15.1 and 15J1 r e s p e c t i v e l y i n 10$ HC1.

When 150 , 1 5 1 , 15J3 and 160 were re f luxed in

c o n c e n t r a t e d HC1 fo r 24-30 hr complete h y d r o l y s i s took

p l a c e g iv ing r i s e to compounds 15J3 and l6jj r e s p e c t i v e l y .

5 ( 6 ) - ( 4 - l s o t h i o c y a n a t o p h e n y l s u l f o n o ) - 2 - m e t h y l b e n z i m i -

dazo le (175_)

Thiophosgene ( 0 . 1 4 ml , 0.0018 mol) i n acetone (15 ml)

was added dropwise to a s t i r r e d s o l u t i o n of 167 ( 0 . 5 gt

0.0017 mol) i n ace tone (120 ml) a t room t e m p e r a t u r e . The

s t i r r i n g was c o n t i n u e d fo r 6 h r . The so lven t was removed

iS. y.3;Cuo and the s o l i d ob t a ined was washed wi th water (3x10

ml) and hexane (3x10 ml) to ge t 175 , y i e l d 0 .38 g ( 6 6 . 6 $ ) ,

m . p . 2 2 0 - 2 2 ° .

iR(KBr) cm"1 : 1150 (SO,,), 2050 (NCS).

157

KMR(TPA) 6 : 2 . 5 6 ( s , 3H, C-CH^), 6 . 9 - 8 . 1 (m, 7H,

Ar-H)

A n a l y s i s f o r : C^H^N-jOgSg ( 3 2 9 )

C a l o d . j C, 5 4 . 7 1 ; H, 3 . 3 4

Found j C, 5 4 .84} H, 3.08°/°.

S i m i l a r l y compounds 1 6 8 - 1 7 4 were p r e p a r e d from

1 5 4 , 1 5 1 , 15_2» 15.8, V$2, 1 6 4 and l6_6 i n l a r g e amount of

a c e t o n e due to t h e i r p o o r s o l u b i l i t y .

5 - ( 4 - A c e t a m i d o p h e n o x y ) - 2 - n i t r o a n i l i n e ( 1 7 6 )

A s o l u t i o n of p o t a s s i u m 4 - a c e t a m i d o p h e n o x i d e 94

( 1 5 . 0 g , 0 . 0 7 9 mol ) and 5 - c h l o r o - 2 - n i t r o a n i l i n e 98 ( 1 3 . 7 g,

0 . 0 0 7 9 mol ) i n dry DMP ( 5 0 ml) was r e f l u x e d f o r 24 h r . The

r e a c t i o n m i x t u r e was c o o l e d , d i l u t e d w i t h w a t e r (250 ml)

and e x t r a c t e d w i t h e t h y l a c e t a t e (3x50 m l ) . The combined

e x t r a c t s were d r i e d (NaoSO.) and s o l v e n t was removed

i n v a c u o . The r e s i d u e was c r y s t a l l i z e d from a q u e o u s

e t h a n o l to g e t 8 . 2 g p r o d u c t . The f i l t r a t e was chroma t o -

g r a p h e d o v e r s i l i c a g e l column u s i n g b e n z e n e and 20$ e t h y l

a c e t a t e - b e n z e n e a s e l u a n t t o g e t 1 . 8 g more p r o d u c t and

s t a r t i n g m a t e r i a l , t o t a l y i e l d 1 0 . 0 g ( 4 4 $ ) , m . p . 2 l 8 ° .

IR (KBr ) cm"1 ; 1 3 6 0 , 1510 ( N 0 2 ) , 1620 ( A r o m ) , l 6 8 0 (CO),

3 3 3 0 , 345 0 (NH,NH 2) .

NMR(CDCEL5 + t 2 . 0 3 ( s , 3H, COCH ) , 6.02-6.2 (m, 211,

DMS0-d6) 6 Ar^f o and £ t o N H 2 ) , 6 .86 ( d , 2H,

158

^ r -H , m t 0 NHAo, J=9Hz), 7.07 ( s , 2H,

NH2), 7.52 (d , 2H, Ar-H, o to NHAc,

J=9Hz), 7.85 (d, 1H, Ar-H, o to N02,

J=9Hz), 9.59 ( s , 1H, NH)

Analysis for : ^^L^^O^ (287)

Caicd. t C, 58.53; H, 4.52

Found • G, 58.21; H, 4.62$.

4-( 4-Acetamidophenoxy)-o-phenylenediamine (177)

To a warm so lu t ion of 176 (10.0 g, 0.034 mol) in

ethanol-THF ( 1 : 1 , 100 ml) and Raney-nickel (1.5 g) was

added dropwise with s t i r r i n g a so lu t ion of hydrazine-

hydrate (14 g, 0.28 mol) in ethanol (20 ml) . The s t i r r i n g

and heat ing was continued for few minutes and the product

i s o l a t e d as u sua l , y i e ld 6.8 g (76$) . This was not

pur i f i ed and used in fu r the r r e a c t i o n s .

Methyl 5(6)-(4-acetamidophenoxy)benzimidazole-2-

carbamate (178)

A mixture of 177 (2.0 g, 0.0076 mol) and 1 ,3 -

dicarbomethoxy-S-methylisothiourea (1.68 g, 0.008 mol) in

e thanol (50 ml) was refluxed for 15 h r . The react ion

mixture was worked-up in usual manner and the product

r e c r y s t a l l i s e d from ace t i c acid-water , y i e ld 2.2 g (83.3$),

m.p. > 2 8 0 ° .

159

- l I R ( K B r ) cm

NMR(TFA) 6


C a l c d .

Found

: 1600 ( A r o m . ) , 1670 , 1710 (CO),

2 7 0 0 - 2 8 0 0 ( 0 - H ) , 3310 (NH).

i 2 . 0 7 ( s , 311, C0CH3) , 3 . 5 7 ( s , 3H,

0CH 5 ) , 6 . 6 - 7 . 2 (m, 7H, Ar-H)

J C 1 7 H 1 6 N 4 ° 4 ( 5 4 0 )

j C, 6 0 . 0 0 ; H, 4 . 7 0

: 0 , 6 0 . 4 2 ; H, 4 . 2 5 $ .

I n s i m i l a r m a n n e r compound 17ft was p r e p a r e d from 177

and 1 , 3 - d i c a r b e t h o x y - S - B i e t h y l i s o t h i o u r e a i n r e f l u x i n g

e t h a n o l .

M e t h y l 5 ( 6 ) - ( 4 - a m i n o p h e n o x y ) b e n z i m i d a z o l e - 2 - c a r b a m a t e (180)

A s o l u t i o n of 17_8 ( 0 . 5 g , 0 . 0 0 1 4 mol ) i n 1 0 $ HC1

(50 m l ) was h e a t e d on w a t e r b a t h f o r 30 m i n u t e s . The

r e a c t i o n m i x t u r e was c o o l e d , n e u t r a l i z e d w i t h aqueous

ammonia s o l u t i o n . The s o l i d t h u s s e p a r a t e d was f i l t e r e d ,

washed w i t h w a t e r (3x10 ml ) and d r i e d , y i e l d 0 .36 g

( 8 3 . 7 ? 0 , m . p . 2 8 5 ° .

i R ( K B r ) cm"1 ; 1600 (Arom), 1720 (CO), 26 5 0 -

2800 ( C - H ) , 3250 -3320 (NH,NH2)

NMR(TFA) 6 : 3 . 5 8 ( s , 3H, OCH^), 6 . 7 - 7 . 2 (m, 7H,

Ar-H)

A n a l y s i s f o r : C - ^ H ^ ^ O , ( 2 9 8 )

C a l c d . : C, 6 0 . 4 0 ; H, 4 . 6 9

Found ; C, 6 0 . 7 2 ; H, 4 . 2 4 $ .

160

I n s i m i l a r way 181 was p repa red by h y d r o l y s i n g 179

i n 10$ HC1 f o r 30 m i n u t e s .

5 (6) - (4 -Ace tamidophenoxy)benz imidazo le (182)

A s o l u t i o n of 177 ( 1 . 0 g, 0.0038 mol) i n 98/° formic

acid was hea ted for 2 h r on a wa te r b a t h . The r e a c t i o n

mix tu re was cooled and n e u t r a l i z e d wi th aqueous ammonia

s o l u t i o n . The s e p a r a t e d s o l i d was f i l t e r e d , washed w i th

w a t e r , d r i e d and p u r i f i e d by a c i d base t r e a t m e n t ,

y i e l d 0.55 g (63.1%), m . p . 8 0 - 2 ° .

IR(KBr) cm""1

NMR(DMSO-dg) 6


Galea .

Found

: 16 40 (CO), 3100-3200 (NH).

: 2.02 ( s , 3H, OOCH^), 6 . 7 6 - 7 . 6 (m, 7H,

Ar-H), 8.13 ( s , 1H, N = C M )

C15H13N3°2 ( 2 6 7 )

C, 6 7 . 4 1 ; Z, 4.86

0, 6 7 . 1 5 ; H, 5 .28$ .

Compound 183 was p repa red s i m i l a r l y from 177 and

g l a c i a l a c e t i c a c i d .

5(6 ) - ( 4-Aminophenoxy )benzimidaz )le d i hydro c h l o r i d e (184)

i § 2 (0 .5 g, 0.0018 mol) i n c o n c e n t r a t e d HOI (20 ml)

was r e f l u x e d f o r 4 h r . The r e a c t i o n mix tu re was cooled

and the s e p a r a t e d h y d r o c h l o r i d e was f i l t e r e d , washed

w i t h dry e t h e r and d r i e d , y i e l d 0 . 4 g ( 7 1 . 4 $ ) ,

m . p . 2 4 0 - 2 ° .

lei

iR(KBr) cni"1(HCl): 1600 (Arom), 2500-2850 ( sa l t ) .

NMR(D20)(HC1) 6 : 7.15-7.9 (m, 7H, Ar-H), 9.22 (s, 1H,

N=CH-N)

Analysis for : C-^H-^Cl^O (298)

Calcd. j C, 52.34; H, 4.36

Found : G, 52.68* H, 4.86/0.

Similarly 185, was prepared by hydrolysis of 183

in concentrated HC1.

Methyl 5(6)-(4-isothiocyanatophenoxy)benzimidazole-2-

carbamate (186)

A solution of thiophosgene (0.13 ml, 0. 0016 mol)

in acetone (20 ml) was added dropwise to a stirred

solution of 180 (0.5 g, 0.0016 mol) in acetone (100 ml)

at room temperature. Stirring was continued for 5 br at

same temperature and then the solvent removed in vacuo.

The product was precipitated while washing with water.

The solid thus obtained, was purified by f i l t rat ion

through si l ica gel column using chloroform as eluant,

yield 0.46 g (80.7/0, m.p.220°.

iR(KBr) cm"1 : 1720 ( 0 0 ) , 2100 (NCS), 3380 (NH).

NMR(TFA) 6 ; 3.6 ( s , 3H, OCH,), 6 . 6 - 7 . 3 (m, 7H, Ar-H)

162

Analysis fo r

Calod,

Found

G16H12N4°3S ( 3 4 0 )

C, 56.47} H, 3.52

C, 56.82; H, 3.12#.

Similar ly 187-189 were prepared by t r e a t i n g

thiophosgene with t h e i r respec t ive amines 181, 184 and

4-Chloro-3-nitrobenzaldehyde (19_0)

4-Chlorobenzaldehyde (50 g, 0.35 mol) was added

gradual ly to a s t i r r e d mixture of KNO, (27.5 g) i n H2S04

(300 ml) a t 15-20°. The mixture was heated a t 70° for

30 minutes. 'The reac t ion mixture was cooled and poured

on i c e . The so l id , thus obtained, was f i l t e r e d , washed

with water, dried and r e c r y s t a l l i z e d from ohloroform-

hexane, y ie ld 26.4 g (40$), m.p.64° ( l i t . m.p .64.5-65°) .

4-0hloro-3-ni t r>benzyl alcohol (191)

Sodium borohydride (2.24 g) was added in small

po r t ions to an ice cooled, s t i r r e d so lu t ion of 190 (24.0 g,

0.128 mol) in methanol (100 ml) . The react ion mixture

was s t i r r e d for 3 h r and solvent removed in vacuo. The

residue was taken in benzene (100 ml) and washed with

water (5x20 ml) , dr ied (Na2S04) and concentrated. The

r e s u l t i n g so l id was r e c r y s t a l l i z e d from chloroform-hexane,

y i e ld 14.0 g (57 .8$) , m.p.64° ( l i t . 4 8 m.p.64-65°) .

163

4-Amino-3-n. i t robenzyl a l c o h o l (192)

A mix tu re of 1£1 ( 1 . 0 g, 0.0053 m o l ) , e t h a n o l (10 ml)

and aqueous ammonia (20 ml , d=0.88) was hea t ed in s t e e l

bomb a t 140-50° f o r 20 h r . The r e a c t i o n mix tu re was cooled,

s o l v e n t removed i n vacuo and e x t r a c t e d w i th e t h y l a c e t a t e

(3x20 m l ) . The combined e x t r a c t s were d r i e d (Na 2 S0 4 ) ,

c o n c e n t r a t e d and the crude p roduc t was p u r i f i e d by column

chromatography u s i n g s i l i c a gel column and chloroform as

e l u a n t , y i e l d 0 .58 g ( 6 5 . 1 $ ) , m . p . l 0 8 ° .

IR(KBr) cm"1 : 1340, 1520 (U0 2 ) f 3320, 3450

(NH2 ,0H).

Mass a t m/z : 168 ( M + )

NMR(MSO-dg) 6 % 4 .32 ( s , 2H, CH20H), 6 .9 (d , 1H, Ar-H,

o to NH2, J=9Hz) , 7 . 2 - 7 . 3 2 (m, 3H, Ar-H

and NH2) , 7.82 (d , 1H, Ar-H, o to N0 2 ,

J=2Hz)

Ana lys i s f o r : CyHgNgO- (168)

Oalcd. : C, 50.0? H, 4 .76 ; N, 16.66

Pound : C, 49.52} H,4 .95 j N, 1 6 . 2 4 $ .

4 - C h l o r o - 3 - n i t r o b e n z y l bromide (194)

To a s t i r r e d and cooled s o l u t i o n of lffl (25 .0 g,

0.13 mol) in dry benzene (350 ml) was added dropwise PBr^

( 1 4 . 4 ml) i n dry benzene (80 m l ) . S t i r r i n g was cont inued

for 4-5 h r a t room t e m p e r a t u r e . The r e a c t i o n mixture was

http://4-Amino-3-n.it

164

poured in 500 ml cold water . The benzene l a y e r was

separa ted , washed with water , dried (Na2S0 ) and

concentrated to get an o i l , which was pur i f ied using s i l i c a

gel column and hexane as e luan t , y i e ld 30 g (89$).

iR(neat ) cm""1 : 1350, 1540 (1T02).

MR(CD013) 6 : 4.35 ( s , 2H, CH2Br), 7.38 ( s , 2H,

Ar-H, m and £ to N0 2) , 7.75 (d, 1H,

Ar-H, o to N02, J=2Hz)

Analysis fo r j C^BrClNOg (250.5)

Calcd. : C, 33 .53 | H, 1.99

Found j 0, 33.14; H, 2.41$.

2-Nitro-4-phenoxymethylohlorobenzene (lft5)

A mixture of 1^4 (10.0 g, 0.039 mol) , phenol (3 .8 g,

0.04 mol) and K2C0, (6 .5 g) in dry acetone (200 ml) was

re fluxed with constant s t i r r i n g for 16 hr . The react ion

mixture was cooled, solvent was removed in vacuo and the

residue taken in benzene. The so lu t ion was washed

success ively with water , 10$ NaOH so lu t ion and water,

d r ied (Na2S0.) and concentrated to get an o i l which was

chromatographed over s i l i c a gel column in hexane, yiold

8.8 g (83 .

IR(neat) cm"1 : 1360, 1540 (N02) , 1605 (Arom)

165

NMR(CDC15) 6 J 4.96 ( s , 2H, OCH2), 6 . 7 5 - 7 . 4 5 (m, 7H,

Ar-H, OCgHc- and m and jo to N 0 2 ) , 7 .8

(d , 1H, Ar-H, o to N0 2 , J=2Hz)

Ana lys i s for • 0 - ^ - ^ 0 , 0 1 (263 .5)

Calod. j C, 59 .20 ; H, 3 .79

Found : C, 58 .78 ; H, 3 .38# .

S i m i l a r l y , 1S»6_ was p repared from 194 and t h i o p h e n o l ,

as an o i l , y i e l d 85$.

i R ( n e a t ) cm"1 : 1340, 1540 (N0 2 ) .

Mass a t m/z : 279 and 281 (M+)

NMR(CCa4) 6 J 3 .94 ( s , 2H, S-CH2), 7.12 ( s , 5H,

S C 6 % ) » 7.25 ( s , 2Hf Ar-H, m and jo to

N 0 2 ) , 7 .52 ( d , 1H, Ar-H, o to N02

J=2Hz)

A n a l y s i s f o r • C13H10C3Jro2S (279 .5 )

Calod. : C, 5 5 . 8 1 ; H, 3.57

Found : C, 56.25} H, 3 . 2 2 ^ .

2 -Thiophenoxy-5- th iophenoxymethyln i t robenzene (197)

Reac t ion of 194 wi th 2 moles of t h i o p h e n o l i n

p resence of KOEt i n re f l u x i n g e t h a n o l y i e l d e d the produc t

which was p u r i f i e d by column chromatography u s i n g s i l i c a

gel column and hexane as e l u a n t , y i e l d 68$, m . p . 8 6 - 7 ° .

iR(KBr) cm"1 : 1340, 1520 (N0 2 ) .

Mass a t m/z : 353 (M+)

NMR(CDCl-) 6 : 3 .92 ( s , 2H, S-GH2), 6 .62 (d , 1H, Ar-H,

m to N0 2 , J=9Hz) , 7 .13 ( s , 6H, Ar-H,

CH2SG6H5 and £ to N 0 2 ) , 7.36 ( s , 5H,

SC6H5), 7.95 (d , 1H, Ar-H, o to

N 0 2 , J=2 .5 Hz)

A n a l y s i s for ; C1 9H1 5N02S2 (353)

Calcd. j C, 6 4 . 5 8 ; H, 4 .24 ; N, 3.96

Found : C, 6 4 .42 ; H, 4 .54 ; N, 4 .42$ ,

2 - N i t r o - 4 - p h e n o x y m e t h y l a n i l i n e (198)

A mix ture of 19,5 ( 1 . 0 g, 0.0037 m o l ) , aqueous

ammonia s o l u t i o n (20 ml, d=0.88) and e t h a n o l (20 ml)

was hea t ed i n s t e e l bomb for 20 h r a t 150 . The so lven t

was removed i n vacuo and r e s i d u e e x t r a c t e d w i th e t h y l

a c e t a t e (3x30 m l ) . The combined e x t r a c t s were d r i e d

(NapSO ) and c o n c e n t r a t e d . The p roduc t was p u r i f i e d on

s i l i c a ge l column u s i n g hexane-benzene (1*1) a s e l u a n t ,

y i e l d 0.35 g ( 3 8 $ ) , m . p . 1 1 2 0 .

iR(KBr) cm"1 : 1340, 1560 (N0 2 ) , 3310,

3450 (NH2).

Mass a t m/z : 244 (M+)

NMR(DMS0-d6) 6 I 4 .89 ( a , 2H, 0CH2) , 6 . 84 -7 .37 (m, 9H,

Ar-H & NH2) , 7 .97 (d , 1H, Ar-H, o t o

N 0 2 , J=2.5Hz)

Ana lys i s f o r : C1 5H l 2N20_ (244)

Calcd. : C, 6 3 . 9 3 ; H, 4 . 9 1 ; N, 11 .67

Found : C, 6 4 .35 ; H, 5 .26; N, 1 1 . 4 2 $ .

167

S i n i l a r l y 199 was p repa red from 19JZ and NH* i n THF-

aqueous ammonia in s t e e l bomb a t 150 .

Y ie ld ( 3 7 . 7 / 0 , m . p . 8 4 - 5 ° .

iR(KBr) cm"1 : 1340, 1560 (N0 2 ) , 3340,

3480 (NH2) .

Mass a t m/z $ 260 (M+)

NMR(DMS0-d6) 6 : 4.06 ( s , 2H, S-CH2), 6 .87 (d , 1H, Ar-H,

o to NH2, J=9Hz), 7 . 1 - 7 . 4 (m, 8H, Ar-H

i NH2) , 7 .81 (d , 1H, Ar-H, o to N0 2 ,

J = 2 . 5 H z ) .

A n a l y s i s f o r : 0 1 5 H 1 2 N 2 0 2 S (260)

Calcd. : C, 6 3 . 9 2 ; H, 4 . 9 1 ; N, 11 .47

Found j C, 6 4 . 1 2 ; H, 5 .28 ; N, 1 1 . 2 0 $ .

4-Thiophenoxymothyl-o-phenylonediamine (200)

A ho t s o l u t i o n of FeSO ( 4 . 0 g) i n aqueous ammonia

(25 ml) was added to a ho t s n l u t i o n of 19.9 (0 .5 g, 0.002

mol) i n acetone (20 ml) and aqueous ammonia s o l u t i o n (25 m l ) .

The r e a c t i o n mix tu re was hea ted f o r 30 minutes on wa te r

ba th and the p roduc t worked-up as u s u a l , y i e l d 0.35 g

( 7 9 . 5 $ ) . This p roduc t was used as such i n f u r t h e r s t e p s .

Methyl 5 (6 ) - th iophenoxymethy lbenz imidazo le -2 -ca rbamate (201)

A mix tu re of 200 (0 .35 g, 0.0015 mol) and 1 , 3 -

d i c a r b o m e t h o x y - S - m e t h y l i s o t h i o u r e a ( 0 . 5 g, 0.002 mol) i n

ethan.>l (25 ml) was r e f l u x e d for 15 h r . Usual work-up of

168

t h e r e a c t i o n mix tu re gave the p roduc t which was

r e c r y s t a l l i z e d from e t h a n o l o r a c e t i c a c i d - w a t e r , y i e l d

0 . 4 g ( 8 5 $ ) , m . p . 2 0 0 ° .

iR(KBr) cm"1 : 1600 (Arom). 1710 (GO), 3300 (WH).

Mass a t m/z : 313 (M+)

NMR(TFA) 6 : 3 .54 ( s , 3H, 0CH3), 3 .71 ( s , 2H, S0H2),

6 . 73 ( s , 5H, Ar-H, S-C6H5), 6 .95 (d ,

3H, Ar-H benzimidazole}

Ana lys i s f o r : C ^ H - j c N ^ S (313)

Calcd. : 0, 61 .34 ; H, 4 . 7 9 ; N, 13 .41

Found • C, 6 1 . 5 2 ; H, 4 .58 ; N, 13 .28$

S i m i l a r l y , compound 202_ was p repa red from 200 and

1 , 3 - d i c a r b e t h o x y - S - m e t h y l i s o t h i o u r e a , y i e l d 75$, m.p. 250 ,

IR(KBr) cm"1 : 1600 (Arom), 1700 (CO), 2700-2900

(C-H), 3300 (NH).

Mass a t m/z : 327 (M+)

A n a l y s i s fo r : O ^ H - ^ ^ S (327)

Calcd. • C, 6 2 . 3 8 ; H, 5 .19 ; N, 1 2 . 8 4

Found j C, 6 2 . 8 0 ; H, 5 .56 ; N, 1 3 . 1 2 $ .

l , 2 - D i - ( 4 - a c e t a m i d o p h e n y l t h i o ) e t h a n e (203)

A mix tu re of 4 -ace tamido th iopheno l (94 5.0 g,

0 .03 mol) and K0H ( 1 . 6 7 g, 0 .03 mol) i n e t h a n o l (50 ml) was

s t i r r e d a t room tempera tu re for 30 m i n u t e s . To t h i s

169

s o l u t i o n , was a d d e d , a s o l u t i o n of d i b r o m o e t h a n e ( 1 . 3 ml»

0 . 0 1 4 mol ) i n e t h a n o l (10 ml ) d r o p w i s e w i t h s t i r r i n g .

S t i r r i n g was c o n t i n u e d and r e a c t i o n m i x t u r e h e a t e d f o r 30

m i n u t e s . The s e p a r a t e d s o l i d was f i l t e r e d o f f , washed w i t h

e t h a n o l (3x10 m l ) , w a t e r (3x10 ml ) and d r i e d , y i e l d 4 . 5 g

( 8 4 . 8 $ ) , m . p . 2 6 8 ° .

- 1 i R ( K B r ) cm'

FMR(DMS0-d6) 6


C a l c d .

Pound

1600 (Arom) , 1670 (CO) , 3300 (NH).

2 . 0 2 ( s , 6H, 2XC0CH,), 2 . 9 8 ( s , 4H,

S ( C H 2 ) 2 S ) , 7 . 1 5 ( d , 4H, Ar-H, o t o S,

J = 9 H z ) , 7 . 5 0 ( d , 4H, Ar-H, o t o NHAc,

J = 9 H z ) , 1 0 . 0 ( s , 2H,2xUH,D20 e x c h a n g e a b l e )

C 1 8 H 2 0 N 2 ° 2 S 2 ( 3 6 0 )

0 , 6 0 . 0 0 ; H, 5 . 5 5 ; N, 7 . 7 7

C, 6 0 . 3 8 ; H, 5 . 8 8 ; N , 8 . 1 2 $ .

S i m i l a r l y 2!04 was p r e p a r e d from 9_4 and 1 , 3 - d i b r o m o -

p r o p a n e i n p r e s e n c e of K0H i n e t h a n o l and p u r i f i e d by

f i l t r a t i o n t h r o u g h s i l i c a g e l column u s i n g benzene a s

e l u a n t , y i e l d 8 0 ^ , m . p . 1 2 0 - 2 1 ° .

1 i R ( K B r ) cm

CDC1, ' 3 DMS0-d6) 6

NMR(CDC13 +

: 1600 (Arom) , 1660 ( 0 0 ) , 3300 (NH).

i 1 .77 ( t , 2H, C-CH 2 -0 , J = 6 H z ) , 2 . 0 2 ( s ,

6H, 2xCOCg5) , 2 . 8 7 ( t , 4H, S ( C H 2 ) 2 ,

J = 6 H z ) , 7 . 1 3 ( d , 4H, Ar-H, m t o ¥HAc,

J = 9 H z ) , 7 . 4 2 ( d , 4H, Ar-H, o t o NHAo,

J = 9 H z ) , 9 . 4 ( s , 2H, 2xNgQ0)

170

Ana lys i s fo r : OjoHg^OgSg (374)

Calnd. { C, 6 9 . 6 2 ; H, 5.88

Found : C, 70 .04 . H , 6 . 2 8 ^ .

l , 2 - D i - ( 4 -ace t amidopheny l su l fono)e thane (205_)

To a suspens ion of 203_ ( 5 . 0 g, 0 .013 mol) i n a c e t i c

a c i d - w a t e r ( 8 : 2 , 250 m l ) , KMn04 (10 g) was added i n t h r e e

p o r t i o n s a t 30 minu tes i n t e r v a l w i t h s t i r r i n g a t room

t e m p e r a t u r e . The s t i r r i n g was con t inued for 4 h r . The

r e a c t i o n mix tu re was coo led , t h e excess KMnO, was decomposed

u s i n g H202 s o l u t i o n . I t was d i l u t e d w i t h wa te r (500 m l ) .

The s e p a r a t e d pure s o l i d was f i l t e r e d , washed wi th w a t e r

s e v e r a l t imes and d r i e d , y i e l d 4.2 g ( 7 1 . 1 8 $ ) , m.p.282 .

iR(KBr) cm - 1 : 1160 ( S 0 2 ) , 1600 (Arom), 1680 (CO),

3300 (NH).

NMR(DMS0-d6) 6 : 2 .03 ( s , 6H, 2 X C O C H 5 ) , 3 .4 ( s , 4H,

S0 2 (CH 2 ) 2 S0 2 ) , 7 .67 ( s , 8H, Ar-H). ,

A n a l y s i s f o r : C 1 8 H 2 0 N 2 0 6 S 2 (424)

Oalcd. • C, 50 .46 ; H, 4 .67 ; N, 6 . 5 4

Found ; 0, 5 0 . 8 6 ; H, 4.25} N, 6 .80$ .

S i m i l a r l y 206 was p repa red by o x i d i z i n g 204 w i th

EMnO in 80^ aqueous a c e t i c a c i d .

Yie ld 6 4 . 5 $ , m . p . 2 3 8 ° .

iR(KBr) cm - 1 • 1140 ( S 0 2 ) , 1590 (Arom), 1690 (CO),

3250 (NH).

171

Mass a t m/z

NMR(CD£U + DMSO-d6) 6


C a l c d .

Found

J 438 (M+)

j 1 . 7 - 1 . 9 (m, 2H, C-GH 2) , 2 . 1 ( s , 6H,

2xG0CH 3) , 3 . 1 4 ( t , 4H, 2xS0 2CH 2 , J = 6 H z ) ,

7 . 55 ( d , 4H, Ar-H, m t o NHAc, J = 9 H z ) ,

7 . 7 8 ( d , 411, Ar -H , o t o NHAc, J = 9 H z ) ,

1 0 . 0 5 ( s , 2H, 2XBH00)

C 19 H 22 W 2°6 S 2 ( 4 3 8 )

0 , 5 2 . 0 5 ; H, 5 . 0 2

C, 5 2 . 4 3 } H, 5 . 3 6 $ .

l , 2 - D i - ( 4 - a m i n o p h e n y l t h i o ) e t h a n e ( 2 0 7 )

A s o l u t i o n of 203 ( 0 . 5 g , 0 0013 mol) i n c o n c e n t r a t e d

HC1 (25 ml ) was r e f l u x e d o v e r n i g h t . The r e a c t i o n m i x t u r e

was c o o l e d , n e u t r a l i z e d w i t h a q u e o u s ammonia s o l u t i o n .

The s e p a r a t e d amine was f i l t e r e d , w a s h e d w i t h w a t e r and

d r i e d , y i e l d 0 . 2 5 g ( 6 5 . 7 / 0 , m . p . 1 0 0 0 .

- 1 iR (KBr ) cm"

CDCl^ -

DMSO-dg) 6

tfMR(CDd5 +


Ga2. c d .

Pound

• 1600 (Arom) , 3320-3430 (NH 2 ) .

2 . 7 ( s , 4H, S ( C H 2 ) 2 S ) , 4 . 5 5 ( b s , 4H,

2xNH 2 ) , 6 . 4 2 ( d , 4H, Ar-H, 0 t o NH2 ,

J = 9 H z ) , 6 . 9 4 ( d , 4H, Ar-H, m t o NH2 ,

J = 9 H z ) .

C 1 4 H 1 6 N 2 S 2 ^ 2 7 6 )

C, 6 0 . 4 3 ; H, 5 . 7 5 ; N, 1 0 . 7 1

C, 6 0 . 8 2 ; H, 5 . 3 2 ; N, 1 0 . 3 8 # .

S i m i l a r l y 208 and 209 were p r e p a r e d from 205 and 206

172

by r e f l u x i n g i t w i th c o n c e n t r a t e d HC1.

208, y i e l d 72$, m.p . > 3 0 0 ° .

IR(KBr) cm"1 : 1160 ( S 0 2 ) , 5380, 3480 (NH2) .

MR(DMS0-d6) 6 l 3 .21 ( s , 4H, S0 2 (CH 2 ) 2 S0 2 ) , 6 .15 ( s , 4H,

2xNH2), 6.56 (d , 411, Ar-H, o to NH2,

J=9Hz) , 7.36 (d , 4H, Ar-H, m to NE2,

J=9Hz)

Ana lys i s f o r : C 1 4 H l 6 N 2 0 4 S 2 (340)

Calcd . : C, 4 9 . 4 1 ; H, 4 .70 ; N, 8 .23

Pound : C, 49 .80 ; H, 5 .20; N, 8 .58$ .

203- (2HC1), y i e l d 70$, m .p .255° .

iR(KBr) cm"1 j 1150 ( S 0 2 ) , 2550-2820 ( S a l t ) .

NMR(TFA) 6 : 1 . 7 - 2 . 2 (m, 2H, C-0H 2 -0) , 2 . 9 - 3 . 4 (m,

4H, 2xS02CH2), 7 . 3 - 7 . 9 (m, 8H, Ar-H)

1 , 2 - D i r ( 4 - i s o t h i o c y a n a t o p h e n y l t h i o ) e t h a n e (210)

Thiophosgene (0 .22 ml , 0 .0028 mol) was added to a

s t i r r e d s o l u t i o n of 207 d i h y d r o c h l o r i d e ( 0 . 5 g, 0 .0014 mol)

i n 50$ aqueous a c e t i c a c i d . The s t i r r i n g was cont inued

f o r 3 h r at room t e m p e r a t u r e . The s e p a r a t e d s o l i d

was f i l t e r e d , washed w i t h wa te r and d r i e d , y i e l d 0 .28 g

( 5 5 $ ) , m.p . 280° .

173

IR(KBr) cm 1

Mass a t m/z


Galcd.

Pound

2100 (NCS).

360 (M+)

G 1 6 H 1 2 N 2 S 4 (360)

C, 5 3 . 3 3 ; H, 3.33

C, 53.68} H, 3 .22$ .

S i m i l a r l y 211 and 212 were p r epa red from 208 and

J209 and th iophosgene i n 50$ aqueous a c e t i c ac id and 10$

H01 r e s p e c t i v e l y .

211 , y i e l d 62$ , m .p . > 2 8 0 ° »

iR(EBr) cm ^

Mass a t m/z


Calcd.

Pound

: 1140 ( S 0 2 ) , 1580 (Arom), 2100 (NCS)

: 424 (M+)

j C1 6H1 2W204S4 (424)

: 0, 45.28? H, 3.77

: 0, 45 .58 ; H, 3 .56$ .

212, y i e l d 55$, m . p . 1 7 8 - 8 0 ° .

iR(KBr) cm""1 : 1140 ( S 0 2 ) , 1590 (Arom), 2100 (NCS),

Mass a t m/z : 438 (M+)

A n a l y s i s f o r • C 1 7 H 1 4 N 2 0 4 S 4 (438)

Calcd. : C, 46 .57 ; H, 3.19

Found : C, 4 6 . 6 8 ; H, 3 .48$ .

General Method f o r p r e p a r i n g a r y l i s o t h i o e y a n a t e s

(219-221)

Var ious a r y l i s o t h i o e y a n a t e s (219-223) were prepared

by the method as d e s c r i b e d for 2 - c h l o r o - 4 - n i t r o p h e n y l

174

i s o t h i o c y a n a t e (220) from t h e i r r e s p e c t i v e l y amines

(214 -218 ) .

Thiophosgene ( 8 . 9 ml , 0.116 mol) i n ace tone (50 ml)

was added dropwise to a s t i r r e d s o l u t i o n of 23.^ (20 g,

0 .1158 mol) i n ace tone (250 ml) du r ing 30 minutes a t room

t e m p e r a t u r e . The s t i r r i n g was con t inued fo r 3-4 h r ,

s o l v e n t was removed i n vacu_o and the r e s u l t i n g s o l i d was

c r y s t a l l i z e d from hexane , y i e l d 20.5 g ( 8 5 . 6 $ ) , m .p .102-4 ,

IR(KBr) cm"1 : 1340, 1530 (N0 2 ) , 2040 (NCS).

iTCHKCDOU) 6 : 7.25 (d , 1H, Ar-H, m to N0 2 , J=8 .5Hz) ,

8.02 (dd, 1H, Ar-H, p. to c h l o r o , J=3 4

8 .5Hz) , 8.17 ( d , 1H, Ar-H, o to ch lo ro ,

J=3Hz).

Ana lys i s for : O^ClNgOgS (214 .5 )

Calcd. : C, 39 .42 ; H, 1.74

Found i C, 39 .10 ; H, 1 .40$ .

N - ( 4 - I s o t h i o c y a n a t o p h e n y l ) - l - f f l e t h y l - 4 - p i p e r a z i n y l t h i o -

carboxamide (224)

A s o l u t i o n of N - m e t h y l p i p e r a z i n e (0 .57 ml,

0.0052 mol) i n a c e t o n e (100 ml) was added dropwise to a

s t i r r e d s o l u t i o n of 22J5 ( 1 . 0 g, 0.0052 mol) i n ace tone

(300 ml) d u r i n g 1 h r . S t i r r i n g was con t inued for 4 hr a t

room t e m p e r a t u r e . The so lven t was removed from the

r e a c t i o n mix ture and the s o l i d t h u s ob t a ined was

17S

r e c r y s t a l l i z e d from c h l o r o f o r m , y i e l d 1 .2 g ( 7 9 . 8 $ ) ,

m . p . 1 9 0 - 3 .

i R ( K B r ) cm

NMR(DMSO-dg) 6


C a l c d .

Found

; 2070 (NCS), 2 8 0 0 , 2900 ( C - H ) , 3150 (NH).

: 2 . 3 1 ( s , 3H, N-C£5), 2 . 5 1 ( t , 4H,

N ( G H 2 ) 2 , J = 5 H z ) , 3 . 5 5 - 3 . 7 5 (hump, 1H,

NH) , 3 . 9 7 ( t , 4H, CSN(CH 2 ) 2 , J = 5 H z ) , 7 . 1 2 -

7 . 3 * (m, 4H, Ar-H)

0 1 3 H l 6 N 4 S 2 ( 2 9 2 )

C, 5 3 . 4 2 ; H, 5 . 4 7

C, 5 3 . 7 6 ; H, 5 . 2 8 $ .

S i m i l a r l y compounds 225 and 226 were p r e p a r e d by

r e a c t i o n of j223> w i t h c o r r e s p o n d i n g p i p e r a z i n e s .

N - ( 4 - N i t r o p h e n y l ) - l - m e t h y 1 - 4 - p i p e r a z i n y l t h i o c a r b o x a m i d e

( 2 2 7 )

A s o l u t i o n of N - m e t h y l p i p e r a z i n e (5 m l , 0 . 0 4 5 mol )

i n b e n z e n e (20 m l ) was added d r o p w i s e to a s t i r r e d s o l u t i o n

o f 21.9 ( 8 . 0 g , 0 . 0 4 4 mol ) i n b e n z e n e (50 ml) a t room

t e m p e r a t u r e . S t i r r i n g was c o n t i n u e d f o r 3 h r , t he p r o d u c t

i s o l a t e d a s above and c r y s t a l l i z e d from c h l o r o f o r m - h e x a n e ,

y i e l d 1 0 . 2 g ( 8 1 . 6 % ) , m . p . 1 0 0 - 1 0 2 ° .

- 1 i R ( K B r ) cm

NMR(CDC1, + 3

: 1 3 2 5 , 1540 ( N 0 2 ) , 2800 , 2900 ( C - H ) ,

3150 (NH).

: 2 . 3 3 ( s , 3H, N-CH^) , 2 . 5 0 ( t , 4H,

DMS0-d6) 6 N ( C H 2 ) 2 , J = 5 H z ) , 2 . 7 - 2 . 9 3 (hump, 1H, NH),

176


Calcd.

Found

4 .00 ( t , 411, CSN(CH2)2, J=5Hz), 8.00

( d , 2H, Ar-H, m to N0 2 , J=9Hz) , 8.10

(d , 2H, Ar-H, o to N0 2 , J=9Hz).

°12H16N4°2S ^ 2 8 0 ^

C, 51 .42 ; H, 5 .71

C, 51 .14 ; H, 5.3655.

In s i m i l a r manner compounds 228-255 were p repared by

t r e a t i n g 219-221 w i t h the co r r e spond ing p i p e r a z i n e s .

N - ( 4 - A c e t y l a m i n o p h e n y l ) - l - m e t h y l - 4 - p i p e r a z i n y l t h i o -

carboxamide (23_6_)

A s o l u t i o n of F - m e t h y l p i p e r a z i n e ( 0 . 5 7 ml, 0.0052

mol) i n ace tone (50 ml) was added dropwise to a s t i r r e d

s o l u t i o n of 222 ( 1 . 0 g, 0.0052 mol) and the r e a c t i o n

mix tu re was r e f luxed for 5 h r . The s e p a r a t e d s o l i d was

f i l t e r e d and r e c r y s t a l l i z e d from a c e t o n e , y i e l d 1.1 g

( 7 2 . 5 3 0 , m . p . 2 1 2 0 .

- 1 iR(KBr) cm

MR(CDC15 +

DMS0-d6) 6

1670 (CO), 2700-2800 (0 -H) , 3200 (NH).

2.02 ( s , 3H, 00Cg 3 ) , 2 .23 ( s , 3H, N-CH^),

2 . 3 4 - 2 . 5 (m, 4H, 0H 3-N(CH 2) 2) , 3.83

( t , 4H, C3!T(CH2)2, J=5 .5Hz) , 7.03 (d ,

2H, Ar-H, o to NHAc, J=9Hz), 7.40 (d , 2H,

Ar-H, m to NHAc, J=9Hz), 9.25 ( s , 2H,

2xNH)

177

A n a l y s i s f o r : C l 4H2 0N40S (292)

Calcd. s C, 54 .10 ; H, 6 . 8 1 ; N, 1 5 . 4 1

Found : C, 53 .68 ; H, 6 . 4 2 ; N, 1 5 . 8 2 $ .

Compounds 2^7 and 23_8 were p r epa red s i m i l a r l y from

222 and the co r r e spond ing p i p e r a z i n e s .

N-( 4 - A m i n o - 2 - c h l o r o p h e n y l ) - l - m e t h y l - 4 - p i p e r a z i n y l t h i o -

carboxamide (239)

A hot s o l u t i o n of PeSO (28 g) i n ammonia (100 ml ,

d=0.88) and wa te r (100 ml) was added to a ho t s o l u t i o n of

230 ( 4 . 0 g, 0 .0127 mol) i n aqueous ammonia (250 ml, d=0.88)

The r e a c t i o n mix tu re was hea t ed on w a t e r ba th for 30

minu te s and worked-up i n u sua l manner. The r e s u l t i n g

s o l i d was re c r y s t a l l i z e d from e t h y l a c e t a t e , y i e l d 2.45 g

( 7 3 $ ) , m . p . 1 8 0 - 5 ° .

iR(KBr) cm"1 : 2780, 2900 (C-H), 3150, 3250 (NH2).

NMR(CDC15 + ; 2 .27 ( s , 3H, N-CH*), 2 .42 ( t , 4H,

DMS0-d6) 6 CH3-N(CH2)2 , J=5 .5Hz) , 3 .94 ( t , 4H,

CSW(0H2)2, J=5 .5Hz) , 6 .52 (dd , 1H,

Ar-H, ^ t o o h l o r o , J=2 .5 h 8Hz), 6 .7

( d , 1H, Ar-H, o to c h l o r o , J=2 .5Hz) ,

7 .0 (d , 1H, Ar-H, m t o c h l o r o , J=8Hz)

A n a l y s i s f o r j C^gH^Cll^S (284 .5 )

Calcd. i C, 5 0 . 6 1 ; H, 5 .97 ; N, 1 9 . 6 8

Found t C, 5 0 . 2 5 ; H, 6 . 3 5 ; N, 20 .10$ .

178

S i m i l a r l y compounds 240-244 were p repared by

r e d u c t i o n of t h e co r r e spond ing n i t r o compounds,

1ST—( 4-1 s o t h i o c y a n a t o p h e n y l ) - l - p h e n y 1 - 4 - p i p e r a z i n y l

carboxamide (2j?0)

A s o l u t i o n of th iophosgene ( 0 . 5 0 ml , 0 ,0064 mol)

i n a c e t o n e (50 ml) was added dropwise t o a s t i r r e d

s o l u t i o n of 244 ( 1 . 0 g, 0.0032 mol) i n ace tone (100 ml)

du r ing 30 minutes and the r e a c t i o n m i x t u r e s t i r r e d a t

room tempera ture f o r 3 h r . Solvent was removed in vacuo

and the r e s i d u a l s o l i d was c r y s t a l l i z e d from chloroform-

p e t . e t h e r , y i o l d 0 .71 g ( 6 5 $ ) , m . p . 1 8 2 - 4 ° .

iR(KBr) cm"1 j 1635 (CO), 2050 (NCS), 2700, 2800 (C-H),

3250 (NH).

NMH(CDC15 + : 3 .2 ( t , 4H, ArN(CH2)2 , J=5Hz), 3 .74

DMS0-d6) 6 ( t > ^ C0N(CH2)2, J=5Hz), 6 . 8 - 7 . 6 (m,

9H, Ar-H), 8.55 ( s , 1H, NH)

A n a l y s i s fo r j C^gE^gE^OS (338)

Calcd. : C, 63.90* H, 5.32

Found : C, 64.25$ H, 5 .76$ .

Compounds 245-249_ were p repared s i m i l a r l y from t h e i r

r e s p e c t i v e aminos 239-243 and t h i o p h o s g e n e .

U - ( 2 - B o n z i m i d a z o l y l ) - N ' - ( 4 - n i t r o p h e n y l ) t h i o u r e a (252)

A mix tu re of 2-aminobonzimidazolc (j25_l,. 1.0 g,

0.0075 mol) and 219 (1 .35 g, 0.0075 mol) i n o t h y l - a c e t a t u

179

(30 ml) was re f luxed for 4 h r on a wa te r b a t h . The

r e a c t i o n mixture was l e f t overn igh t a t room tempera tu re

and the c r y s t a l l i z e d yel low n e e d l e s were f i l t e r e d , washed

w i th co ld e t h y l a c e t a t e (2x10 ml) and d r i e d , y i e l d 1.78 g

( 7 6 / 0 , m. p . 243-4° .

iR(KBr) cm - 1 ; 1315, 1540 (N0 2 ) , 3250 (NH).

-Analysis f o r • C - ^ H ^ N ^ S (313)

Calcd . : C, 53 .60 ; H, 3 .51

Found : 0, 55 .26 ; H, 3 .91$ .

S i m i l a r l y compound 253> was p repa red by r e a c t i o n of

2-aminobenzimidazole (251) and 22_0,yield 75 .5$ , m . p . 2 l 8 ° .

- 1 iR(KBr) cm


Calcd.

Pound

1305, 1560 (N0 2 ) , 3250 (NH).

G 14 H 10 C 1 N 5°2 S ( 3 4 7 ' 5 )

C, 48 .34 ; H, 2 .88

C, 48 .72; H, 3 .20$ .

N- (2 -Benz imidazo ly l ) -Ni - ( 4 -aminopheny l ) th iou rea (25_4)

A hot s o l u t i o n of PeS0 4 ( 7 . 0 g) i n aqueous ammonia

(50 ml , d=0.88) and wa te r (50 ml) was added to a hot

s o l u t i o n of 2jp_2 ( l . O g, 0.0032 mol) i n ammonia (100 ml ,

d = 0 . 8 8 ) . The r e a c t i o n mix tu re was h e a t e d on wate r ba th

for 30 minutes and worked-up as u s u a l , y i e l d 0.55 g (62$) ,

m.p.86 .

iR(KBr) cm - 1 : 3200, 3350 (NHo).

180

Analysis for

Calcd.

Found

J C14H13N5S (283)

: 0, 59.36; H, 4.59

j C, 59.62; H, 4.81$.

N-(2-Benzimidazolyl)-N'-(4-isothiocyanatophenyl)ure8.H01>(225.)

A solu t ion of thiophosgene (0.27 ml, 0.0035 mol) in

acetone (20 ml) was added dropwise t o a s t i r r e d solut ion

of 254 (0.5 g, 0.0017 mol) i n acetone (50 ml) a t room

temperature and the product i s o l a t e d as usual as i t s

hydrochlor ide , y ie ld 0 .4 g (65$), m.p.256-59 .

- 1 iR(KBr) cm

Analysis for

Calcd.

F ound

16 25 (CO), 2040 (1TCS), 3350 UH).

c15Hl2cnjsr5os (345.5)

C, 52.09} H, 3.47

C, 51.75; H, 3.22$.

N-( 2-Chloro~4-nitrophenyl)-N t-(4-acetylaminophenyl)

th iourea (2J57)

A solut ion of 4-aminoacetanil ide (0 .7 g, 0.0046 mol)

in acetone (20 ml) was added dropwise to a ref luxing

so lu t ion of 220 ( l .O g, 0.0046 mol) in acetone (30 ml).

Refluxing was continued for 4 hr on a water bath . The

solvent was removed in vacuo and the res idual sol id

c r y s t a l l i z e d from acetone, y i e ld 1.1 g (65$), m.p.2180 .

iR(KBr) cm -1 : 1330, 1500 (N02), 1655 (CO), 3220 (NH).

: 2.05 (s, 3H, C0CH3), 7.42 (d, 2H, Ar-H,

EMSO-dg) 6 £ t0 N H A G > J = 9 H 2 ) > 7 # 6 2 (d) 2H, Ar-H,

NMR(CDC1, +

181

M a i y s i s f o r

C a l c d .

Found

o t o NHAc, J = 9 H z ) , ' 8 * 0 5 - 8 . 3 5 (m, -45.* Ar-H'

o and m t o c h l o r o ) , 8 . 7 ( d d , 1H, Ar-H,

2 t o c h l o r o , J = 3 i 9Hz)

C 1 5 H 1 5 C 1 N 4 0 5 S ( 3 6 4 . 5 )

C, 4 9 . 3 0 ; H, 3 . 5 9

C, 4 8 . 9 2 ; H, 3 .92/».

S i m i l a r l y 256 was p r e p a r e d from 219 and 4 -aminoace

t a n i l i d e i n 78$ y i e l d , m . p . l 0 5 ° .

-1 i R ( K B r ) cm

CDG13

DMSO-dg) 6

NMR(CDG15 +

1 3 0 0 , 1500 ( N B 2 ) , 1655 ( 0 0 ) , 3200 (NH).

2 . 1 ( s , 3H, C0CH5) , 7 . 35 ( d , 2H, Ar-H,

o t o NHAc, J = 9 H z ) , 7 . 5 8 ( d , 2H, Ar-H,

m t o NHAc, J = 9 H z ) , 7 .86 ( d , 2H, Ar-H,

m t o N 0 2 , J = 9 H z ) , 8 . 1 2 ( d , 2H, Ar-H,

o t o N 0 2 , J=9Hz)

C 1 5 H 1 # 4 ° 3 S ( 3 3 0 )

C, 5 4 . 5 4 ; H, 4 . 2 4

C, 5 4 . 2 5 ; H, 4 . 5 8 $ .

The t h i o u r e a s ( 25 8 -26_0 ) 5 0 " " 5 2 , t h i o c a r b ox amide ( 2 6 4 ) 5 5

and t h i o a m i d e ( 2 6 5 ) ^ were p r e p a r e d by l i t e r a t u r e me thods

i n good y i e l d s .

N - P h e n y l d i e t h y l a m i n o t h i o c a r b o x a m i d e ( 2 6 l )

To a s t i r r e d s o l u t i o n of p h e n y l i s o t h i o c y a n a t e

( 1 . 3 5 g, 0 . 0 1 mol ) i n benzene ( 2 0 ml) was added d r o p w i s e

a s o l u t i o n of d i e t h y l a m i n e ( 0 . 7 3 g, 0 . 0 1 mol ) a t room


C a l c d .

Pound

182

t e m p e r a t u r e . S t i r r i n g was c o n t i n u e d f o r 3 h r a t same

t e m p e r a t u r e and t h e n h e a t e d on w a t e r h a t h f o r 10 m i n u t e s .

The s o l v e n t was removed i n v a c u o t o g e t v i s c o u s o i l , y i e l d

1 . 8 g ( 8 9 / 0 .

- 1 i R ( n e a t ) cm

NMR(CDC13) 6


C a l c d .

Found

1 3 4 0 , 1530 ( N 0 2 ) .

1 . 0 8 ( t , 3H, CH2CH5, J = 8 H z ) , 3 . 5 2 ( q ,

2H, CH20H5 , J = 8 H z ) , 7 . 1 ( s , 5H, Ar-H)

C 1 1 H 1 6 N 2 S ^ 2 0 8 )

0, 6 5 . 0 0 ; H, 7 . 6 9

C, 6 4 . 6 8 ; H, 7 . 2 8 $ .

S i m i l a r l y 26_2 and 26_3_ were p r e p a r e d by a c t i o n of

p i p e r l d i n e and N - m e t h y l p i p e r a z i n e on p h e n y l i s o t h i o o y a n a t e

i n b e n z e n e .

The G e n e r a l method of d e s u l p h u r i z a t i o n i s i l l u s t r a t e d by

p r e p a r a t i o n of 26 7 from 2_5_8 and t h i o p h o s g e n e

A s o l u t i o n of 2_5_8 ( l . 2 l g , 0 . 0 0 5 mol) i n a c e t o n e

(40 m l ) was added d r o p w i s e d u r i n g 30 m i n u t e s t o a s t i r r e d

s o l u t i o n of t h i o p h o s g e n e ( 0 . 4 4 m l , 0 . 0 0 5 mol) i n a c e t o n e

(15 m l ) a t room t e m p e r a t u r e . The r e a c t i o n m i x t u r e was

s t i r r e d f o r 2 h r and s o l v e n t removed . The r e s i d u e

c r y s t a l l i z e d from b e n z e n e , y i e l d 0 .85 g ( 7 5 / 0 , m . p . l 6 6 - 6 7 C

( l i t . 5 5 m . p . 1 6 7 - 8 ° ) .

S i m i l a r l y o t h e r u r e a s and c a r b o x a m i d e s (25J3-264)

and amide 265 were p r e p a r e d from t h e i r r e s p e c t i v e t h i o

a n a l o g s ( m . p . , y i e l d g i v e n ) .

183

268 (185° , l i t . 5 6 m . p . l 8 4 ° , 75#) , 269 (190° , l i t . 5 7 m.p .

192° , QOfo), 270 ( 8 5 ° , 7 6 / 0 , 271 (152° , 75#) , 272 (16 7-69° ,

85#) , 2J2 (116° , l i t . 5 8 m .p .118 -19° , 80#) and amide 274

( 6 0 ° , l i t . 5 9 m . p . 6 1 ° , 7 5 ^ ) .

A l l the u r e a s and carboxamides (267-^71) were

p r e p a r e d by r e a c t i o n of the co r r e spond ing i s o c y a n a t e s and

amines . The amide 274 was o b t a i n e d by a c t i o n of a c e t i c

anhydr ide on benzy lamine ,

1 - M e t h y l - 4 - [ ( N - p h e n y l - N ' - c y c l o h e x y l ) amidlno ] p i p e r a z i n e

To a s t i r r e d s o l u t i o n of 271 ( 1 . 0 g, 0.0042 mol)

and t r i e t h y l a m i n e (0 .86 g, 0.0084 mol) i n dry acetone

(25 ml) was added dropwise a s o l u t i o n of th iophosgene

(O.36 ml , 0.0042 mol) when a d d i t i o n was complete , N-methyl-

p i p e r a z i n e (0 .42 g, 0.0042 mol) i n dry ace tone (10 ml)

was added dropwise w i t h c o n s t a n t s t i r r i n g . S t i r r i n g was

con t inued for 2 h r a t room tempera ture and so lven t

removed i n vacuo . The p roduc t was chromatographed over

s i l i c a gel column u s i n g benzene as e l u a n t , y i e l d 0.26 g

( 2 0 . 3 # ) , m .p .240° .

iR(KBr) cm""1 : 1630 (C=N), 2680, 2740, 2950 (0 -H) ,

3320 (UH).

Ana lys i s f o r : 0±QE2^4 (300)

Calcd. : 0, 72 .00 ; H, 9.30

Found : C, 72 ,40 ; H, 8 . 95$ .

184

N - ( 4 - N i t r o p h e n y l ) p i p e r a z i n e (276 )

A m i x t u r e of a n h y d r o u s p i p e r a z i n e ( 5 . 0 g , 0 . 0 5 8

m o l ) , 4 - c h l o r o n i t r o b e n z e n e ( 1 8 . 3 g, 0 .116 mol ) and

p o t a s s i u m c a r b o n a t e ( 8 . 1 g, 0 . 0 5 8 mol ) i n d ry a c e t o n e

(100 ml) was h e a t e d i n s t e e l bomb f o r 15 h r a t 1 2 0 - 3 0 .

The r e a c t i o n m i x t u r e was c o o l e d , p o t a s s i u m c a r b o n a t e

f i l t e r e d o u t and s o l v e n t was removed i n v a c u o . The c r u d e

p r o d u c t was ch roma to g r a p h e d o v e r s i l i c a g e l column u s i n g

e t h y l a c e t a t e and 1 0 $ m e t h a n o l i n e t h y l a c e t a t e a s e l u a n t .

The u n r e a c t o d 4 - c h l o r o n i t r o b e n z e n e (5 g) was r e c o v e r e d ,

y i e l d 6 . 5 g ( 5 4 . 1 ^ ) , m . p . l 2 5 ° .

i R ( K B r ) cm - 1

Mass a t m/z

CDCl-, + 3

EMSO-dg) 5

NMR(CDC15 +


C a l c d .

Found

j 1 3 0 0 , 1580 ( N 0 2 ) , 2800 , 2900 ( C - H ) ,

3300 (NH).

: 207 (M+)

: 1 . 7 ( b s , 1H, NH), 2 . 9 ( t , 4H, M ( C H 2 ) 2 ,

J = 6 H z ) , 3 . 2 7 ( t , 4H, A r - N ( C H 2 ) 2 ,

J = 6 H z ) , 6 . 6 4 ( d , 2H, Ar-H, m t o N 0 2 ,

J = 9 H z ) , 7 . 9 3 ( d , 2H, Ar -H, o t o N 0 2 ,

J=9Hz)

C 10 H 13 N 3°2 ( 2 0 7 )

C, 57.97; H, 6.28

C, 58.42; H, 6.68/*.

l - (4 -Ni t robenzoyl ) -4 - (4 -n i t rophenyl )p iperaz ine (278)

To a so lu t ion of 2J6_ (0.5 g, 0.0024 mol) in dry

185

b e n z e n e (30 ml ) was a d d e d d r o p w i s e a t room t e m p e r a t u r e

a s o l u t i o n of 4 - n i t r o b e n z o y l c h l o r i d e ( 0 . 5 g, 0 .0026 mol )

i n d ry b e n z e n e (20 ml ) w i t h c o n s t a n t s t i r r i n g . S t i r r i n g

was c o n t i n u e d f o r 2 h r a t room t e m p e r a t u r e and t h e n

r e a c t i o n m i x t u r e was r e f l u x e d f o r 3 h r . I t was t h e n

c o o l e d and washed s u c c e s s i v e l y w i t h 5$ NaHCO, s o l u t i o n

(3x20 m l ) , w a t e r (3x20 ml ) and d r i e d (Na 2 S0 ) . The

s o l v e n t was removed i n vacuo, and t h e r e s i d u e c r y s t a l l i z e d

from e t h a n o l , y i e l d 0 .6 g , ( 7 0 $ ) , m . p . 1 7 4 - 5 ° .

i R ( K B r ) cm"1 : 1 3 2 0 , 1520 ( N 0 2 ) , 1600 (Arom) , 1635

(CO).

3 . 5 ( b s , 4H, A r S ( C H 2 ) 2 ) , 3 .65 ( b s , 4H,

ArC0N(CH 2 ) 2 ) , 6 . 8 2 ( d , 2H, Ar-H, 0 t o

N ( C H 2 ) 2 , J = 9 H z ) , 7 .6 ( d , 2H, Ar-H, 0

t o NCO, J = 9 H z ) , 8 . 0 ( d , 2H, Ar-H, 0 t o

N 0 2 , J = 8 . 5 H z ) , 8 . 2 ( d , 2H, Ar-H, m t o

NCO, J=9Hz)

C 17 H 16 N 4°5 ( 3 5 6 )

C, 5 7 . 3 0 } H, 4 .38

C, 5 7 . 7 5 ; H, 4 . 6 6 $ .

l - ( 4 - A m i n o b e n z o y l ) - 4 - ( 4 - a m i n o p h e n y l ) p i p e r a z i n e ( 2 7 9 )

NMR(CDC1 +

DMS0-d6) 6


C a l c d .

Found

To a h o t s o l u t i o n of 278 ( 0 . 5 g , 0 . 0 0 1 4 mo l ) i n

a c e t o n e (30 ml ) and a q u e o u s ammonia s o l u t i o n (30 ml) was

added a h o t s o l u t i o n of f e r r o u s s u l f a t e ( 4 g) i n w a t e r

188

(20 ml) and aqueous ammonia s o l u t i o n (30 ml, d=0 .88 ) .

The r e a c t i o n mix tu re was hea t ed a t w a t e r ba th f o r 30

minu t e s and r e a c t i o n worked-up as u s u a l . The produc t was

re c r y s t a l l i z e d from "benzene, y i e l d 0 .2 g ( 5 0 $ ) , m.p .126-7 .

iR(ZBr) cm' - 1

Mass a t m/z

CDC1, + 3 DMS0-d6) 6

NMR(CDC1, +

Analys i s fo r

Calcd.

Found

: 1585 (Arom), 1620 (NCO), 3300, 3400

(NH2) .

: 296 (M+)

: 2.92 ( t , 4H, Artf(CH2)2 , J=6Hz), 3.65

( t , 4H* ArCOW(CH2)2, J=6Hz), 6 . 4 - 6 . 7 2

(m, 6H, Ar-H), 7 . 14 (d , 2H, Ar-H, o

t o NCO, J=9Hz)

: 0 1 7H 2 0N 40 (296)

: C, 6 8 . 9 1 ; H, 6.75

: 0, 6 9 . 3 8 ; H, 6 . 4 5 $ .

l - ( 4 - I s o t h i o c y a n a t o b e n z o y l ) - 4 - ( 4 - i s o t h i o c y a n a t o p h e n y l )

p i p e r a z i n e (280)

Thiophosgene ( 0 . 2 5 ml, 0.0032 mol) i n acetone

(20 ml) was added dropwise to a s t i r r e d , s o l u t i o n of 279)

( 0 , 5 g , 0.0016 mol) i n ace tone (20 ml) a t room t e m p e r a t u r e .

The s t i r r i n g was con t inued f o r 4 h r . The s e p a r a t e d

h y d r o c h l o r i d e was f i l t e r e d , washed wi th ace tone (3x10 ml)

and d r i e d . F r e e base was obtained by t r ea tmen t wi th

t r i e t h y l a m i n e , y i e l d 0.42 g ( 6 5 . 6 0 ) , m . p . l 2 5 ° .

iR(KBr) cm - 1 : 1635 (CO), 2100 (NCS).

NMR(DMSO-d6) 5 : 3 . 1 5 - 3 . 3 0 (m, 4H, N ( G g 2 ) 2 ) , 3 . 45 -3 .62

(m, 4H, 00N(CH2)2) , 6 . 8 6 - 7 . 8 (m, 8H,

Ar-H) .

i C i g H l 6 F 4 0 S 2 (380)

: C, 60.00? H, 4 .21

: C, 60.32? H, 4 .10$ .

.Analysis for

Calcd.

Found

r , 4 - D i - ( 4 - n i t r o b e n z o y l ) p i p e r a z i n e (281.)

To a s t i r r e d s o l u t i o n of 4-ni t ro"benzoyl c h l o r i d e

( 4 . 5 g, 0.0242 mol) and t r i e t h y l a m i n e (2 .35 g, 0.0232

mol) i n dry benzene (50 m l ) , was added dropwise a

s o l u t i o n of anhydrous p i p e r a z i n e ( 1 . 0 g, 0.012 mol) i n

dry benzene a t room t empera tu re du r ing 30 m i n u t e s .

S t i r r i n g was con t inued f o r 5 h r a t room tempera ture and

the s o l i d s e p a r a t e d was f i l t e r e d , washed wi th 5$ NaHCO

s o l u t i o n (5x20 ml) and w a t e r (3x20 ml) and d r i e d , y i e l d

4 .0 g ( 8 9 . 4 $ ) , m.p . > 3 0 0 ° .

iR(KBr) cm""1

Mass a t m/z


Calcd.

Found

j 1350, 1510 (N0 2 ) , 1630 (CO), 2650,

2720, 2900 (C-H).

384 (M+)

C, 56.25} M, 4.16

C, 56.62} H, 3 .84$ .

188

1, 4~Di-( 4-aminoDenzoyl)piperazine (282)

A suspension of 281 (1.0 g, 0.0026 mol) and Raney-

nickol ( /^ 0.2 g) in ethsnol-THF mixture ( 1 : 1 , 100 ml) 2

was hydrogenatod in a Paar hydrogenator at 3.5 kg/cm

of hydrogen for 6 h r and the product worked-up as usual

which was re c r y s t a l l i s e d from e thanol , y ie ld 0.58 g (69/0),

m.p.250 .

iR(KBr) cm"1 : 1590 (Arom), 1620 (CO), 3300, 3420 (NH2).

Mass at m/z i- 324 (M+)

NMR(DMSO-dg) 6 1 3.52 [s, 8H, N(CH2)4], 5.5 (s, 4H,

2xNH2), 6.52 (d, 4H, Ar-H, o to NH2,

J=9Hz), 7.2 (d, 4H, Ar-H, m to NH2,

J=9Hz)

Analysis for : C l 6H 2 cp 40 2 (324)

Calcd. : C, 66.66 j H, 6.17

Found : C, 67.12j H, 5.92#.

1 , 4-Di-( 4-Isothiocyanato"benzoyl)piperazine (283)

A solu t ion of thiophosgene (0 .24 ml, 0.0031 mol) in

chloroform (30 ml) was added dropwise to a s t i r r e d

so lu t ion of 282 (0 .5 g, 0.0015 mol) in 10jt aqueous

hydrochlor ic acid (30 ml) a t room temperature during 30

minutes. S t i r r i n g was continued for 4 hr a t room

temperature and the chloroform l a y e r was separated from

aqueous l aye r . I t was washed with water (3x10 ml) , dried

189

(Na2SO ) and t h e s o l v e n t removed i n vacuo* The r e s i d u a l

s o l i d was t r i t u r a t e d w i t h hexane to g e t a pure p r o d u c t ,

3 ' ie ld 0.36 g ( 5 7 . 1 * ) , m .p .220° .

IR(KBr) cm"1 : 1625 ( 0 0 ) , 2100 (NOS)

Mass a t m/z » 408 (M+)

NMR(CDC15 + ; 3.55 [ s , 8H, N ( C H 2 ) 4 ] , 7 . 2 2 - 7 . 7 (m,

M S 0 - d 6 > 6 8H, Ar-H).

A n a l y s i s f o r • C 2 0 H l 6 N 4 0 2 S 2 (408)

Calcd. j 0 , 5 8 . 8 2 ; H, 3.92

Found s C, 58.46$ H, 4 .26* .

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5. BX^^J;K!,ASi^?lI!S..r?I'

Most of -the compounds were evaluated f->r t h e i r

anthelmint ic and an t imicrobia l a c t i v i t i e s in the

Divis ions of Paras i to logy and Fermentation Technology of

t h i s I n s t i t u t e .

5 • 1 Anthelminti c Te s t ing :

5.11 Antihookworm Testing:

The compounds were t es ted for t h e i r antihookworm

a c t i v i t y agains t experimental i n f ec t ions of ^.p^p^stôn^lus

brâîl iensis in r a t s , Ng^îsjiôi_d.es dubius in mice and

dlG.SLi.2 .i2SLS: ceylanicum in hamsters by standard methods ' '

with s l i g h t modif icat ions to s u i t loca l condi t ions .

Methodology;

Young male r a t s weighing 25-40 g (Universi ty

of Fre iburg s t r a i n ) were inoculated subcutaneously or

o r a l l y with 500 i n f ec t i ve larvae of N. b r a s i l i e n s i s . Only

those r a t s showing eggs in t he i r s tool on 8th day, were

used for screening. An ora l dose of the compound was

given in a s ingle or mul t ip le dose on the day 9 post

i n j e c t i o n . The animals were starved over night p r io r to

adminis t ra t ion of drugs. This was done t o ensure closure

contact of the given chemotherapeutic agents with the

p a r a s i t e s in absence of food m a t e r i a l . I n i t i a l l y a

s ingle dose of 250 mg/kg of the compounds was used. The

http://i_d.es

216

compounds, insoluble in water , were made in to fine

suspension with tween 80. For each compound, 3 in fec ted

animals were used and a group of 3 amimals was kept as

un t rea ted conbrol . All the experimental end cont ro l led

r a t s were s tarved overnight before they were sac r i f i ced on

the day 3 post t rea tment . The t o t a l number of wwms

present in the i n t e s t i n e of a r a t was counted on autopsy.

The therapeut ic eff icacy of the compounds was assessed

by comparing average number of the worms recovered from

the t r ea t ed group to t h a t from the control group. I f N

i s the average number of worms found in control group of

animals and n i s the average number of worms found in the

t r ea t ed group of animals, then the $ depa ras i t i za t ion was

ca lcu la ted by the formula N -n x 100.

A s imi l a r method was adopted when th - screening was

ca r r i ed out aga ins t NomâJbo^pJ^qi^^ dub_ius_ in mice and

A?l?il£stoma p.p.yjjî£^m i n hamsters .

Itesuljsând^^di^scugsion:

The compounds were i n i t i a l l y t e s t ed for t h e i r

antihookworm a c t i v i t y against NejmaJjp_sîroid:esi du_b_iuj3 in

mice and Hippostrangyla s brasi l i jensis , in r a t s but nme of

them sh-.'wed any notevrorthy a c t i v i t y upt "> an oral dose of

250 mg/kg given for th ree days except 229 and 2J50 which

showed 6 2-70/& reduction o£ worms a t dose of 250 mg/kg x 3

days. At a lower dose-schedule, compound _23_D was found to

217

be e f fec t ive in removing 60$ of the worms at a dose of

100 mg/kg given o r a l l y for 3 days. The antihookworm

t e s t i n g of compounds car r ied out against Aacylp.stp_ma

ceylanicum showed severa l compounds to possess high a c t i v i t y .

Thus, compounds 6.2, 6j£, 72, 90, 110, 111, 127 and l6_8

cleared 100$ of the A.£ejrlanjLcuni worms from hamsters a t an

o ra l dose of 12.5-250 mg/kg given once or t h r i ce dai ly for

3 days. The bes t compounds of the s e r i e s are 110 and 1S_8

which cleared 100$ worms a t a s ingle ora l dose of 12.5 mg/kg.

Compounds 16_9_ and 2!11 showed moderate a c t i v i t y and caused

only 61.5 and 83.5f° reduct ion in worm load a t single o ra l

dose of 250 mg/kg and 50 mg/kg r e spec t ive ly . Rest nf the

compounds were i n a c t i v e upto 250 mg/kg given for 3 days.

The anthelmint ic t e s t i n g r e s u l t s of the compounds are

summarised in Tabic 6 .

The antihookworm t e s t i n g r e s u l t s would c l ea r ly

ind ica t e to the fac t t ha t a benzimidazole nucleus

s u b s t i t u t e d with a 2-carbmetb.oxyamino function i s an

e s s e n t i a l requirement for b io log ica l a c t i v i t y . This was

evident from the fac t tha t none of the benzthiazole

de r i va t i ve s of the type I , I I showed any order of anthelmintic

a c t i v i t y . However,the presence of a su i t ab le pharmacophore

a t 5 (6 ) -pos i t ion of methyl benzimidazole-2-carbamate has

a key role in a l t e r i n g (enhancement or lowering) of the

b io log ica l a c t i v i t y . Thus, in t roduc t ion of a he te rocyc l ic

218

Table.J>: Ef f i cacy of compounds a g a i n s t Ancylpstoma 5eZiaI1.4-.SuJS. i n f e c t i o n i n h a m s t e r s ,

Compd. No. Name

62 2 ,2 i -D ica rbome thoxyamino -5 ,5 1 -d i b e n z i m i d a z o l y l s u l p h i d e

§3L 2,2»-Dicarbethoxyamino-5,5'-d i b e n z i m i d a z o l y l su lph ide

72 2 ,2^ -Dica rbe thoxyamino -5y5 ! - , • d i b e n z i m i d a z o l y l sulphone

90 2 ,2^-Dicar 'bomethoxyamino-5 > 5 , -"" d ibenz imidazoly lmethane

110 2 ,2<-Dicarbomethoxyamino-5,5>-d i b e n z i m i d a z o l y l oxide

111 2 , 2 ' - D i c a r b e t h o x y a m i n o - 5 , 5 I -"~ " d i b e n z i m i d a z o l y l oxide

12J E t h y l 5 ( 6 ) - p h e n y l b e n z i m i d a z o l e -~ 2-carbamate

16_8 Methyl 5 ( 6 ) - ( 4 - i s o t h i o c y a n a t o - 12 .5x1 100 p h e n y l t h i o ) b e n z i m i d a z o l e - 2 -carbamate

16_9_ E t h y l 5 ( 6 ) - ( 4 - i s o t h i o c y a n a t o - 250x1 61 .5 p h e n y l i M o ) b e n z i m i d a z o l e - 2 -carbamate

211 l , 2 - D l - ( 4 - i s o t h i o c y a n a t o - 50x1 83 .3 p h e n y l s u l f o n o ) e t h a n e

r s .

Dose mg/kg

50x1 25x1

100x3 50x3

250x3 250x2

100x1 50x1

25x1 12 .5x1

50x1 25x1

50x3 25x3

7" c l e a r a n c e of worms

100* 6 4-1'.) J

100 90

100 50-90

100 93 .5

100 94-100

100 77

100 87-100

Al l the exper iments showing 100$ c l e a r a n c e of worms by a p a r t i c u l a r compound, were r e p e a t e d twice o r t h r i c e u s i n g 3 an imals p e r e x p e r i m e n t a l group and 3 were used as c o n t r o l s ,

213

system such as a benz imidazo le a t the 5 ( 6 ) - p o s i t i o n of a

benz imidazo le r i n g g i v e s r i s e t o compounds devoid of any

antihookworm o r a n t i c e s t o d e a c t i v i t y . Fu r the rmore ,

i n c o r p o r a t i o n of the benzimidazole r i n g i n p o l y n u c l e a r

h e t e r o c y c l i c s such as I may g e n e r a l l y l e a d to lower ing o r

l o s s of a c t i v i t y . The b e s t r e s u l t s a r e o b t a i n e d when an

a p p r o p r i a t e l y s u b s t i t u t e d pharmacophore such a s phenyl o r

benz imidazo le r i n g a r e l i n k e d a t the 5(6 ) -pos i t i .on of

a l k y l benz imidazo le -2 -ca rbamate v i a a he teroatom l i k e

s u l p h u r o r oxygen. Attempts t o r e p l a c e t h e s e he te roa toms

by o t h e r groups l i k e S0 2 , CO, CHp, S-CE^-CH^S-or p i p e r a z i n e

i n the d ibenz imidazo l e s ( i l l ) l e a d s t o compounds having

moderate to poor ant inematode a c t i v i t y . The conc lu s ions

drawn from t h i s s tudy i s i n the c l o s e resemblance w i t h the

e a r l i e r s t u d i o s d e s c r i b i n g the high a n t h e l m i n t i c a c t i v i t y

and the m o l e c u l a r frame-work d i s p l a y e d by a s e r i e s of

benz imidazo le a n t h e l m i n t i c s 1 -11 .

5 . 12 CeLS^to^ci^dal^Te s t ing?

The c e s t o d i c i d a l t e s t i n g of a l l the compounds

was c a r r i e d out a g a i n s t exper imen ta l i n f e c t i o n of 64 Hymenoiepis. nana i n r a t s u s i n g the technique of Steward

wi th s l i g h t m o d i f i c a t i o n s .

E®^£dol°_iSZ. '•

Newly weaned male r a t s of U n i v e r s i t y of F r e i b u r g

s t r a i n were i n f e c t e d by feed ing them with 200 v i a b l e ova

220

of H.jiarxa. On day 15, a f t e r incubation of v iab le ova,

r a t s which were found pos i t ive of H.nana ova in t h e i r s tool

were t r e a t e d a f t e r being s tarved overnight . I n i t i a l l y a

s ing le o ra l dose of 250 mg/kg of the compound was given

o r a l l y to 3 animals and 3 were kept as con t ro l . All the

animals including cont ro ls were again s tarved overnight

before being sac r i f i ced on day 3 post t rea tment . The

small i n t e s t i n e of ind iv idua l animal was removed separa te ly ,

washed and the worms co l lec ted and scored. Compounds

removing 100$ of the worms along with t h e i r sco l iccs

wore considered ac t ive in t h i s t e s t .

Resul t s and Di_scu_s_si on,s:

Most of the compounds were a lso t es ted for t h e i r

ant ices tode a c t i v i t y against H.nana when some of the

compounds showed high a c t i v i t y aga ins t the above tapeworms

in r a t s and mice. Thus, compounds 62, 90, 91 , 110» 111,

!§.§» l£2» 187 and 210 caused 100$ e l iminat ion of worms

along with t h e i r s co l i ce s from r a t s and mice a t s ingle

o r a l dose of 30-250 mg/kg. Poor a c t i v i t y was shown by

compound 172 which removed 50$ of the worms at a s ingle

o ra l dose of 250 mg/kg from r a t s . The best compounds of

the s e r i e s are 6_2_ which cleared 100$ of H.nana worms from

r a t s a t s ingle o ra l dose of 70 mg/kg and 168 which

caused 100$ reduction in worm load at a s ingle ora l dose

of 30 mg/kg. However, 6_2_ and 168 el iminated 100 and 80$

221

worms respec t ive ly from mice a t s ing le ora l dose of 100

mg/kg. p raz iquan te l was used as s tandard drag which removed

100^ of the H.nana worms along with sco l ices at a s ingle

dose of 5 mg/kg given o r a l l y . Rest of the compounds were

found to be i n a c t i v e upto an ora l dose of 250x3 mg/kg. The

d e t a i l r e s u l t s of the ces tod ic ida l a c t i v i t y i s summarized

in Table 7.

The f a c t , t ha t a number of benzimidazzle anthelmint ics

such as mebendazole and fenbendazole exhib i t marked a c t i v i t y

aga ins t d i f fe ren t ces todes , led us to evaluate t h e i r

ce s tod ic ida l a c t i v i t y agains t a common human tapeworm,

H.nana (dwarf tapex^orm). The t e s t i n g r e s u l t s showed tha t

the s t r u c t u r a l parameters required for b io log i ca l a c t i v i t y

in methyl benzimidazole-2-oarbamates i s complementary to

those needed for antihookworm a c t i v i t y described in

Sec. 5.11.

5 • 2 Antimicrobial Ac t iv i ty :

Most of the compounds were also evaluated for

t h e i r in v i t r o growth i nh ib i t o ry a c t i v i t y aga ins t d i f fe ren t

s t r a i n s of b a c t e r i a and fungi and r e s u l t s are summarized

in Table 8. The b a c t e r i a and fungi were maintained on

n u t r i e n t and Sabouraud's agar s l a n t s respec t ive ly and

t e s t i n g was done using the two fold s e r i a l d i lu t ion

technique by d isso lv ing the compounds in e thanol . The

b a c t e r i a used were Staph/locoecus aureus (gram p o s i t i v e ,

Table n J.: E f f i c a c y of compounds a g a i n s t gZB2S2 i2£ iS £ § £ £ ~"'~n" i n f e c t i o n s i n r a t s .

Compd. No . Name

Dose mg/kg c l e a r a n c e

o f worms

6_2 2 , 2 » - M c a r b o m e t h o x y a m i n o - 5 > 5 '• d i b e n z i m i d a z o l y l s u l p h i d e

<g0 2 , 2 ' - D i c a r b o m e t h o x y a m i n o - 5 j 5 ' ' ~"~ d i b e n z i m i d a z o l y l m e t h a n e

^ 1 2 , 2 i - D i c a r b e t h o x y a m i n o - 5 > 5 ' -" d i b e n z i m i d a z o l y l m e t h a n e

110 2 , 2 ' - D i c a r b o m e t h o x y a m i n o - 5 , 5 , ;

d i b e n z i m i d a z o l y l o x i d e

111 2 , 2 ' - • D i c a r b e t h o x y a m i n o - 5 , 5 , -d i b e n z i m i d a z o l y l o x i d e

16_8 M e t h y l 5(6 ) - ( 4 - i s o t h i o c y a n a t o -p h e n y l t h i o ) b e n z i m i d a z o l e - 2 -c a r b a m a t e

1§9 E t h y l 5 ( 6 ) - ( 4 - i s o t h i o c y a n a t o -"" p h e n y l t h i o ) b e n z i m i d a z o l e - 2 -

c a r b a m a t e

172 M e t h y l 5(6 ) - ( 4 - i s o t h i o c y a n a t o -p h e n y l s u l f ono )ben z i m i d a z o l e - 2 -c a r b a m a t e

187 E t h y l 5 ( 6 ) - ( 4 - i s o t h i o c y a n a t o -phenoxy)b en z i m i d a z o l e - 2 -c a r b a m a t e

210 l , 2 - D i - ( 4 - i s o t h i o c y a n a t o -"" p h e n y l t h i o ) e t h a n e

70x1 1 0 0 x 1

50x1

250x1

100 100 '

250x1

250x1

250x1

60

100

250x1 100x1

250x1 100x1 50x1

250x1 100x1

30x1 100x1 50x1

250x1 100x1 50x1 25x1

100 50

100 60 66

100 60

100 80,

55.5'

100 101)

33 33

a

50

100

100

a , i n m i c e .

223

r e s i s t a n t to 2500 u n i t s of p e n i c i l l i n / m l ) , Streptococcus

•SSSSaiis, Salmonella tv_p_hi (gram nega t ive ) , Escher ichia

Goli> Agrobacterium tumefaj.ciens, K lebs i e l l a pnêumojiiae,

pêudomonas aerujgôsa and Proteus Jjilgari_s, while the

fungi used were Candida a lb icans , Trichophyton

mentagrophy t e s , Crypto coccus neoformans, Microsporum canis^

Aspergi l lus njêr , Aspergi l lus fumigatus and

Sporotrichum schenjckii. Tetracycline and amphotericin B

were used as standard drugs in a n t i b a c t e r i a l and ant i fungal

t e s t i n g s r e spec t ive ly .

All the b a c t e r i a were maintained on n u t r i e n t

agar s l a n t s . Testing was done in n u t r i e n t broth. - After

inocula t ion with a loopful of cul ture from the s l a n t ,

the seeded broth were incubated a t 37+l°C for 24 h r .

The two fold s e r i a l d i lu t ion technique was applied. A

s e t of tubes containing only inocula ted broth was kept as

c o n t r o l s . After incubat ion fo r 24 h r , the l a s t tube with

no growth of the microorganism was taken to represent

the minimum i n h i b i t o r y concentrat ion (MIC, expressed in

ug/ml) . A compound i n h i b i t i n g the growth of microbe in

a concentrat ion of 25 ug/ml was considered to be a c t i v e .

5 • 22 An t i f ungal_ As sag;:

All the fungi were maintained on Sabouraiad<s

agar s l a n t s and the compounds were t e s t ed i n Sabnuraud's

b r o t h . Loopfuls of the fungal cu l tu re (C.albicans and

224 c»Se-£?S£a§£:^.) fr°ni "the s l a n t s were inocula ted in to the

broth and the respect ive inocula ted bro ths were used for

t e s t i n g a f t e r incubat ion for 24 hr a t 28+l°C. In the case

of small fungi, small pieces of mycelia were introduced in to

conical f lask conta ining 50 ml of the b ro th . The f lasks

were then incubated with shaking for 24-43 hr and the c lear

broths were taken out of the f l a s k s . The compounds were

t e s t ed by s e r i a l d i l u t i o n technique as described in a n t i

b a c t e r i a l assay. The compounds which inh ib i t ed the growth

of fungus a t 25 ug/ml concent ra t ion , was considered to be

a c t i v e .

5.23 Resu l t s :

The compounds were t e s t e d aga ins t var ious s t r a i n s

of b a c t e r i a and found to be inac t ive except 215 which inh ib i t ed

the growth of Streptococcus f a e c a l i s and Klebs ie l l a

pneumoniae a t minimum i n h i b i t o r y concentra t ions (MIC) of 25

and 25 p.g/ml and 242 which i n h i b i t e d the growth of above

microbes a t MIC«s of 25 and 50 ug/ml r e spec t ive ly . The

growth of r e s t of the s t r a i n s remained unaffected by

e i t h e r of the compounds t e s t e d .

In ant i fungal t e s t i n g the be s t compound of the se r i e s w a s 2 1 4 which i n h i b i t e d the growth of a l l the fungi used at

the MlC's of 3.125-12.5 ug/ml. However, 215. caused the

i n h i b i t i o n of O.albjcarta .T.mentagrophytes and A.fumigatus

a t MICis of 6 .25 , 6.25 and 100 ug/ml. Rest of the compounds

i n h i b i t e d the growth a t h igher concentrat ions and r e s u l t s

are summarized in Table 8.

225

3Ski3L-§ : IS. Z i l £ 2 a n t i f u n g a l a c t i v i t y of t h e compounds

Compd. __ Minimum^ i n h i b i tory, concent r a t i o n X^-PiJ-iLAlgAii N ° * 0 . C- S. T. A.

Si^iSfiSS neoformans a c h e n g k i i merit a p - f J^sisatus rophy tes

i20 i l l

111 i l i

145

214

215.

220

221

222

225,

212

241

244

2 4 1

> 1 0 0

> 1 0 0

> 1 0 0

100

> 1 0 0

3 .125

6 . 2 5

25

25

100

100

25

50

> 1 0 0

100

> 1 0 0

> 1 0 0

50

50

> 1 0 0

3 . 1 2 5

> 1 0 0

100

100

> 1 0 0

> 1 0 0

25

50

100

50

> 1 0 0

> 1 0 0

> 1 0 0

100

> 1 0 0

3 . 1 2 5

> 1 0 0

100

100

^ > 1 0 0

> 1 0 0

50

25

^>100

25

100

100

100

50

100

3 . 1 2 5

6 . 2 5

> 1 0 0

> 1 0 0

100

50

> 1 0 0

25

100

25

> 1 0 0

> 1 0 0

> 1 0 0

50

> 1 0 0

1 2 .

100

> 1 0 0

> 1 0 0

100

50

^>100

> 1 0 0

100

> 1 0 0

226

RBPBRMCE; S:

N . R . S t o l l , J . . _ £ a r a s i t o l . . , 33 , 1 (1947 ) .

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1945.

36 • B e i l s t e i n Handbuch d e r Organischen Chemie, 1 4 ,

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( P u b l i s h e r ) L t d . , London, 1946, p .644 and 988.

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(1940) , 446.

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( P u b l i s h e r s ) L t d . , London, 1946, p .1017 .

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231

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http://Para.si.tol

S U M M A R Y

1

The survey of world-wide incidence of various

helminth infesta t ions in man which appeared time to time

reveals that despite several measures taken to eradicate

helminth infections i t s growing trend has not been

checked . Although helminth infections are not generally

f a t a l , they contribute to the major public health problems 2 3

in tropical and subtropical regions of the world ' and

may also lead to several c l in ica l complications causing

even death of the patient in absence of immediate medical

care. The high prevalence of helminth infections i s

par t ly due to the poor sanitary habi ts and lack of

prophylaxis followed by masses, abundance of proper natural

conditions for the developments of helminth juveniles and

part ly due to the lack of suitable drugs available for the

treatment of different forms of helminthiasis. The present

thesis i s an effort to develop ideal chemotherapeutic

agents for the treatment of infections due to hookworms and

cestodes, the two major helminth diseases of t ropics .

The efforts to substi tute c lass ical anthelmintics by

more effective and safer drugs was unsuccessful t i l l 1961

when Merck came out with the discovery of thiabendazole4,

a new class of anthelmintic possessing broad spectrum of

ac t iv i ty against a variety of nematode parasi tes in man

and domestic animals. This led to the discovery of a series

2

of potent benzimidazole anthelmint ics of which mebendazole

and fenbendazole showed high promise in curing nematode

and cestode i n f e s t a t i o n s and a l so es tab l i shed benzimidazole

heterocycle as a useful pharmacophore for bui ld ing molecules

with broad spectrum of a n t i p a r a s i t i c a c t i v i t y .

The f i r s t chapter of the t he s i s presents a review

dealing with the recent developments in the treatment of

hookworm and cestode i n f e c t i o n s . The second chapter

comprises of the synthes is and b i o l o g i c a l a c t i v i t y of the

d i f f e r en t c l a s ses of the compounds based on the powerful

an the lmint ic a c t i v i t y associa ted with benzimidazoles , d i -6 7

aryl su l f ides and sulfones and b i toscana te . This study

has been car r ied out with a view to develop b e t t e r

an the lmint ics as a l so to de l inea te minimal s t r u c t u r a l

requirements for optimal anthelmint ic a c t i v i t y in the

molecular frame-work exhibi ted by the ' l e a d ' molecules.

Synthesis of 5(6)-N-hoteroarylbenzimidazolos and

benzth iazoles

Several 5(6)-( l -benzimidazolyl)benzimidazoles and

6-( l -benzimidazolyl )bonzthiazoles (<6) have been preoared

s t a r t i n g with the condensation of 5(6)-aminobenzimidazoles

( l a ) and 6-aminobciizthiazoles ( lb ) with 2 ,4 -d in i t roch lo ro -

benzene or 2-ni t robenzoylchlor ide to give 5(6)-{2>4-»

dinitrophenyl)aminobenzimidazoles and benzthiazoles (2)

3

and 6-( 2 - n i t r o b e n z o y l ) a m i n o b e n z t h i a z o l e (3) r e s p e c t i v e l y .

Reduct ion of 2 and J w i t h Raney-n icke l and H2 o r h y d r a z i n e -

h y d r a t e and Raney-n icke l gave the c o r r e s p o n d i n g amines (4 and

5_) which were c y c l i z e d wi th d i f f e r e n t c y c l i z i n g agen t s to

8 9 give the t i t l e p r o d u c t s (6 and 7) ' .

OpNv

l a , X=UH b , X=S

l b

^ N 0 2

\ _ _ / C 0 C 1

H 2 , R =N02 , X=NH,S

4, R1=NH2, X=NH,S

1 . Reduct ion ,12. C y c l i z a t i o n

6 , R=H,CH5, X=S,NH

R1=H,CH,,SH,NHCOOE t

R2=NHC0CH,,NHG0H,NGS, ^COOBt

NH-C^ NNHCOOBt

S y n t h e s i s of 2 , 2 < - d i s u b s t i t u t e d - 5 , 5 ' - d i b e n z i m i d a z o l y l d e r i v a t i v e s

Based on the powerful a n t h e l m i n t i c a c t i v i t y a s s o c i a t e d

w i t h benz imidazo le s , s e v e r a l 2 , 2 i - d i s u b s t i t u t e d - 5 , 5 « -

d i b e n z i m i d a z o l y l d e r i v a t i v e s (1,1) have been prepared i n

o r d e r to studj?" the r o l e of benz imidazole moiety a s a

4

c a r r i e r molecule. The key in te rmedia tes in the synthesis

of above compounds were 3,3»—dinitro (or diamino)-4,4>-

diamino (or d in i t ro )d ipheny l de r iva t i ve s (9) obtained

e i t h e r by hydro lys i s of 4 , 4 ' - d i a c e t a m i d o - 3 , 3 , - d i n i t r o

di phenyl de r iva t ives (8a) or by amination of 4 , 4 ' - d i c h l o r o -

3 , 3 ' - d i n i t r o d i p h e n y l de r iva t ives (8b) or by d i r e c t

reac t ion of 5 - ch lo ro -2 -n i t roace t an i l i de with sodium su l f ide .

Reduction of 8 with hydrazinc-hydrate and Raney-nickel,

Raney-nickel and Ho or ferrous sulphate-ammonia gave the

corresponding 3 , 3 ' , 4 , 4 ' - t e t r a - a m i n o d i p h e n y l de r iva t ives

(10 ) . Reaction of 10 with 1,3-dicarbalkoxy-S-methyliso-

th iou rea s , a c e t i c acid or formic acid yielded the t i t l e

compounds 1 1 .

RJ

R X^*^ ^x1

2f R = 3-FH2 o r 3-N02

R = 4~NH2 o r 4-NQ2

8 a , R = 3-N02 , R = 4-NHAc

b , R1 = 3-N02 , R = 4-01 1 1 , R = NHC00R , H, CH3

R ^ CH^, C2H5

X = S,S02 ,C0,CH2 ,0

S(CH2)2S, CON NCO

5

Synthesis of 2 ,5-diarylbenzimidazoles and t h e i r cycl ic

analogs

Synthesis of 2,5-diaxylbenzimidazoles was

undertaken based on the a c t i v i t y of several 2 -ary lbenz i -

midazoles . 4-Amino-3-nitrobiphenyl (12) , on react ion

with n i t robenzoyl chlor ides ,gave 4r-(aroyl)amino-3-

n i t rob ipheny l s (13a) which were reduced with hydrazine-

hydrate and Raney-nickel to y i e ld the corresponding

amines 15b. Cyclizat ion of l j b with acid gave 2 , 5 -

diarylbenzimidazoles (14a) . Reaction of 2-(4-amino-

phenyl)-5(6)-phenylbenzimidazole (14a, B= 4-NH2) with

a lky l chloroformates and thiophosgene yielded 2-( 4-

carbalkoxyaminophenyl and 4- isothiocyanatophenyl) -5(6)-

phenylbenzimidazoles (14b) . Similar react ion of 14a

(R = 2-NHp) with a lky l chloroformates and potassium e thy l

xanthate yie lded the cyc l ic products 1£ while the

reac t ion of l j b with thiophosgene y ie lded l-(2-amino,

2- isothiocyanato and 4- isothiocyanatobonzoyl)-2-

meroapto-5-phenylbenzimidazoles ( I 6 a - e ) . 4-^mino-3-

n i t rob ipheny l (12) was a lso used to prepare e thy l

5(6)-phenylbenzimidazolc-2-carbamate (17) by reduction

followed by cyc l i s a t i on of the r e s u l t i n g amine with

1,3-dicarboth^xy-S-mcthylisothiourea .

6

/VM2 Ph^^X^ NO,

1 . Red.

2. Cycl . ^

12

i 0 H

16 a, R = 2-NH2

b , R = 2-NCS

c , R = 4-NCS

HCOOBt

NR

l ^ a , R = 2 & 4-N02

b , R = 2 & 4-NH2 14a, R = H, 2-NH2,4-NH2

b , R = 4-NHC00CH3, I4a^ 4-NHCOOEt, 4-NCS

Ph'

H

15, X = 3,0

2 - S u b s t i t u t e d - 5 ( 6 ) - ( 4 - s u b s t i t u t e d phenoxy, phenylthio

and sulfono)benzimidazoles

5-(4-Acetamidophenoxy and pheny l th io ) -2 -n i t roan i l i nes

( i § . ) w e r * u s e d to prepare several benzimidazoles of the

type 21 . Reduction of 18 with hydrazine-hydrate and

Raney-nickel and subsequent cyc l iza t ion with formic acid,

a c e t i c acid and 1,3-dicarbalkoxy-S-methylisothioureas gave

7

the co r re spond ing 2 , 5 ( 6 ) - d i s u b s t i t u t e d benz imidazo los ( 1 9 ) .

Oxida t ion of 19 (X=S) wi th KMn04-CH_C00H gave the su l fones

19 (X=30 2 ) . Acid h y d r o l y s i s of l g w i t h 10$ HOI gave the

co r re spond ing amines (£0) which were t r e a t e d w i t h

th iophosgene to g ive 2 - s u b s t i t u t e d - 5 ( 6 ) - ( 4 - i s o t h i o o y a n a t o -

phenoxy, p h e n y l t h i o and su l fono )benz imidazo le s ( 2 1 ) .

X V ; N V N H 2 l.Hed

» XJ^HJJ IX.K xx^N—

1 8 , X = 0 , 3

N' H

1 9 , R = H, CH5, NHCOOB3

C0Hr

f^Yx

2 1 , R = H, CHv>-, NHC00R-1

CSC1

R = CH-r, GpHj-

X =: 0 ,S,S0 2

S y n t h e s i s of 5 (6 ) - th iophenoxymethy l and phenoxymethyl

2 CX" 20, R = H, CH5, I\THC00RJ

$•= CH^, C2H5

X = 0, S, S02

b e n z i m i d a z o l e - 2 - c a r b a m a t a s

The h i g h e r homologue (2£) of fonbendazole was

s y n t h e s i z e d s t a r t i n g from 4 - c h l o r o - 3 - n i t r o b e n z y l bromide

(.22) by the sequence of r e a c t i o n s d e s c r i b e d below. This

has he lped i n e v a l u a t i n g the e f f e c t of i n t r o d u c t i o n of one

8

methylene u n i t a t 5 ( 6 ) - p o s i t i o n of benz imidazo le on

b i o l o g i c a l a c t i v i t y of fenbendazo le .

BrH 2°N^^Y

22

1 . PhXFa N 0 2 2 . NH5

CI 3 . Red. 4. Gycl .

^vC H2 Y lT—N

H 22, X = 0 , S, R = CH3,C2H5

S y n t h e s i s of 1,2 and 1 , 3 - d i s u b s t i t u t e d a l k a n e s and

1 , 4 - d i s u b s t i t u t e d p i p e r a z i n e s

I n o r d e r to s tudy t h e change in biological a c t i v i t y

of 4 , 4 i - d i i s o t h i o c y a n a t o d i p h e n y l s u l f i d e and su l fone by

i n c r e a s i n g the d i s t a n c e between two a r y l f unc t i ons by

i n t r o d u c t i o n of 2 o r 3 CH2 u n i t s , s y n t h e s i s of 1 , 3 - and

1 , 2 - d i s u b s t i t u t e d a l k a n e s (2_7) was u n d e r t a k e n . 4-Acetami-

do th iopheno l (2_4), on r e a c t i o n wi th 1 ,2-dibromoethane and

1 ,3-d ibromopropane , y i e l d e d 1,2 and l , 3 - d i - ( 4 - a c e t a m i d o -

p h e n y l t h i o ) a l k a n e s ( 2 5 j . Oxida t ion of 2£ w i th KMnO4-0H,COOH

gave the c o r r e s p o n d i n g s u l f o n e s 25 (X=S0?) which were

hyd ro ly sed i n presence of ac id t o give the d e s i r e d amines

26. Reac t ion of 26 wi th th iophosgeno y i e l d e d the t i t l e

compounds 27 .

SH ^T\^x(CH2)nX\^\

+ Br(CH~) Br I L '

2£, R=NHAc, X=S,S0 2 ,n=2,3

26_, R=NH2, X=3,S02 , n=2,3

27, R=NCS, X=S,S02 , n=2,3

A c H J r ^ - ^ 24

9

The synthesis of compounds of the type £0 obtained

by replacement of th io and sulfono l inkage of 4 , 4 ' -

d i isothiocyanatodiphenyl sul f ide and sulfone by piperazine

moiety, a more ac t ive pharmacophore for antinematode

a c t i v i t y , was also ca r r i ed out . The synthes is s t a r t s with

the reac t ion of e i t h e r anhydrous piperazine or 4 - n i t r o -

phenylpiperazine (28) with 4-ni trobenzoyl chloride to

give 1 ,4 -d i subs t i t u t ed p iperaz ines (29) . Reduction of 29

gave the corresponding diamines which were converted to

i so th iocyana tes (3Q_) by t r e a t i n g with thiophosgene.

R-N N - H ~ > R-N S-GO ~ \ 7 -N0 2

o^-v y~ coci

v_TH —"—* RA_-r°°A=/" 28_, R=H, 4 - n i t r o p h e n y l 29_, R=4-n i t ropheny l

R= 4-nij.t rob en zoyl 1 . Red.

* 2 . CSC12

\ /

20, R=4-isothiocyanatophenyl

R= 4-iso th io cyanatoben zoyl

Synthesis of s u b s t i t u t e d thiocarboxamides, carboxamides

and th ioureas

Several subs t i t u t ed thiocarboxamides, and e&rfroatfaaldes

have been prepared as s t r u c t u r a l analog of b i to scana te .

Reaction of d i f ferent p iperazines and a n i l i n e s with

10

va r ious phenyl isothiocyanates gave the thiocarboxamides

(j5l) which were reduced to the corresponding amines (3,2),

Conversion of ^2 in to i so th iocyanates by reac t ing with

thiophosgene resu l t ed in an unusual desulphurizat ion of

thiocarboxamides to give carboxamides (32t X=0).

Thiocarboxamides (22, X=S) carrying "the isothiocyanato

function were conveniently prepared by react ion of one

mole of p iperaz ines with ]D-phenylenediisothiocyanate

( b i t o s c a n a t e ) . Several th ioureas were a lso prepared

e i t h e r by reac t ion of 2-aminobenzimidazole or 4-aminoaceta-

n i l i d e on subs t i t u t ed phenylisothiocyanates U

.R RJ o -NCS

/ " A H - N

\ / N-R2

R 1 , ( r~\ s II / \ 2

, NHC - N N - R

\k

r~\ 2 H-N N-R

3 1 , R =3-N02 , 4-N02 , 4-NHAc

Red. M/

51(R1=4-N02)

J V-NH-C- N M2 < — M _ ( / V-HHG- N V

^2

•B?

33, X = 0,S 2S

The unusual desulphurizat ion of thiocarboxamides

and th ioureas with thiophosgene was studied by converting

a number of thiocarboxamides, th ioureas and thiamide to

t h e i r corresponding oxygen analogs with the help of

11

th iophosgene and p o s s i b l e mechanism f o r d e s u l p h u r i z a t i o n

has been proposed

3 n 1

BIH-C-R

csci2 RN^C* CI

o r

EN

* 0

=c

RJ

Gl

I 11 1 H20

RN=C-R i Gl

B i o l o g i c a l A c t i v i t y :

Most of the compounds have been e v a l u a t e d fo r

t h e i r a n t h e l m i n t i c a c t i v i t y a g a i n s t Nippos t ron gy lu s

bragjLliejqsis i n r a t s , Nematosp i ro ides dubius in mice ,

Ancylostoma ceylanicum i n hamste r s and Hymenolepis nana

i n r a t s and mice . A l a r g e number of 2 , 5 - d i s u b s t i t u t e d

benz imidazo le d e r i v a t i v e s showed promis ing antihookworm

and a n t i c e s t o d e a c t i v i t y which i s r e p o r t e d in the t h e s i s ,

The b e s t compounds of t h i s s tudy were found to be 2 , 2 » -

d i c a r b o m e t h o x y a m i n o - 5 , 5 ' - d i b e n z i m i d a z o l y l oxide ( 1 1 ,

X=0,R=NHC00CH,) and s u l p h i d e ( 1 1 , X=S, R=NHC00CH3) which

e x h i b i t e d 100$ removal of A.ceylanicum a t a s ing le o r a l

dose of 12 .5 -25 mg/kg i n hamste r wh i l e 100$ of the

H.njana worms were e x p e l l e d by 2, 2»-di carbomethoxyamino-

5 , 5 ' - d i b e n z i m i d a z o l y l s u l f i d e ( 1 1 , X=S, R=NHC00CH5) and

12

methyl 5(6)- (4- isothiocyanatophenyl th io)benzimidazole-2-

carbamate (21 , X=S, E=NHCOOCH,) a t s ingle o ra l doses

of 70 and 30 mg/kg respec t ive ly from r a t s . Compound 11

(X=0, R=NHC00GH,) was 100$ ef fec t ive in causing complete

e rad ica t ion of H.nana from r a t s at a single o ra l dose

of 250 mg/kg. The r e s u l t s of the in v i t r o ant imicrobial

a c t i v i t y of some of the compounds are also reported in

the the s i s .

P.A.J . J a n s sen , P r o g . Drug R e s . , 18 , 191 (1974 ) .

Mej^cine i n the T r o p i c s , E d i t e d by A.¥.Woodruff,

C h u r c h i l l L i v i n g s t o n e , London, 1974, p .143 and 157.

T rop ica l M e d i c i n e . 5 th E d . , E d i t e d by G.W.Hunter,

J .C .Swar t zwe lde r and D.F .Clyde , W.B.Saunders Co.

P h i l a d e l p h i a , 1976, p . 451-592 and 593.

S.Sharma and E . S . C h a r l e s , p r o g . Drug R e s . , 2%,

( i n p r e s s ) .

S.Sharma and S.Abuzar, p r o g . Drag R e s . , ( i n p r e s s ) .

J . G . K a t i y a r , A.B.Sen and B .K .Bha t t acha rya , Naturae,

214, 708 ( 1 9 6 7 ) .

M.R.Samuel, p r o g . Drug R e s . , 1£, 96 ( 1 9 7 5 ) .

S.Abuzar, S.Sharma and R . N . I y e r , I n d i a ^ J ^ C h ^ m . ,

19B, 599 ( 1 9 8 0 ) .

S.Abuzar and S.Sharma, ,Z...„ffaturforsch., 36b, 108

(1981 ) .

S.Abuzar and S.Sharma, Arch>ii_pharm. ( i n p r e s s ) .

S.Abuzar and S.Sharma, I n d i j n . J ^ C h e m . , 20B,

230 (1981) .

S.Abuzar, S.Sharma and R . N . I y e r , I n d i a n J ^ J J h e m . ,

19B, 211 ( 1 9 8 0 ) .

LIST, OF PUBLICATIONS

A new convenient method of d e s u l p h u r i z a "felon of t h i o u r e a s and t h i o a m i d e s , S.Abuzar, S.Sharma and R.N. I y e r , I n d i a n J . Chem., 19B, 211 ( 1 9 8 0 ) .

S y n t h e s i s of N - a r y l and N - h e t e r o a r y l b e n z i m i d a z o l e s as p o t e n t i a l a n t h e l m i n t i c s , S.Abuzar, S.Sharma and R . N . I y e r , I n d i a n J . Ohem.. 19B, 599 (1980) .

Syn thes i s of 6 -N-a ry l and h e t e r o a r y l b e n z t h i a z o l e s as p o t e n t i a l a n t h e l m i n t i c s , S.Abuzar and S.Sharma, %. N a t u r f o r s c h . . £§b , 108 ( 1 9 8 1 ) .

S y n t h e s i s of s u b s t i t u t e d t h i o c a r b o x a m i d e s , carboxamides and t h i o u r e a s as p o t e n t i a l a n t h e l m i n t i c and a n t i m i c r o b i a l a g e n t s , S.Abuzar and S.Sharma, I n d i a n J . Ohem.,20B, 230 (1981 ) .

S y n t h e s i s of s u b s t i t u t e d benz imidazo le s as p o t e n t i a l a n t h e l m i n t i c s , S.Abuzar aid S.Sharma, Arch^ffharm. ( i n p r e s s ) . ""

The benzimidazole a n t h e l m i n t i c s - Chemistry and b i o l o g i c a l a c t i v i t y , S.Sharma and S.Abuzar, P r o g . Drug R e s . , B i r k h n u s e r V e r l a g , B a s e l , E d i t e d by E . J u c k e r , ( i n p r e s s ) .

A p r o c e s s f o r the s y n t h e s i s of a n t h e l m i n t i c 2 , 2 ' -d i c a r b a l k o x y e m i n o - ^ l j ' - d i b e n z i m i d a z o l y l d e r i v a t i v e s , S.Abuzar, S.Sharma, J . C . K a t i y a r , p . K . S . V i s e n , S.Ram and A.B.Sen, I n d i a n p a t . App ln . . No .379 /De l /81 da ted 1 2 . 6 . 1 9 8 1 A p roces s fo r -foe s y n t h e s i s of a n t h e l m i n t i c 2 , 2< -d ica rba lkoxyamino-5 ,5 ' -diben z imidazo ly l o x i d e s , S.Abuzar, S.Sharma, J . C . K a t i y a r , S .M.Johr i , S. Gupta, S.Ram and A.B.Sen, I n d i a n P a t . Appln. pend ing .

A p r o c e s s far t h e s y n t h e s i s of a n t h e l m i n t i c a l k y l 5 ( 6 ) - ( i s o t h i o c y a n a t o p h e n y l t h i o and su l fono)bonz imi -d a z o l e - 2 - c a r b a m a t e s , S.Abuzar, S.Sharma, S .M.Johr i , S.Gupta, S.Ram, J . C . K a t i y a r and A.B.Sen, I n d i a n p a t . Appln. ponding .

synthesis of potential anthelminticsir.amu.ac.in/2480/1/t 2395.pdf · either by hydrolysis of...

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