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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
SYNTHESIS OF POTENTIAL ANTHELMINTICS
( SUMMARY )
A THESIS SUBMITTED FOR THE DEGREE OF
Doctor of Philosophy IN
Chem/strq TO
THE ALIGARH MUSLIM UNIVERSITY, ALIGARH
BY
SYED ABUZAR M. Phil.
<
1P>°> <r
DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE
LUCKNOW-226001 JUNE, 1982
SYNTHESIS OF POTENTIAL ANTHELMINTICS
( SUMMARY )
A THESIS SUBMITTED FOR THE DEGREE OF
Doctor of Philosophy IN
Chemfstrij TO
THE ALIGARH MUSLIM UNIVERSITY, ALIGARH
BY
SYED ABUZAR M. Phil.
DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE
LUCKNOW-226001 JUNE, 1982
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 ) .
SYNTHESIS OF POTENTIAL ANTHELMINTICS
A THESIS SUBMITTED FOR THE DEGREE OF
Doctor of Philosophy IN
Chemistrq TO
THE ALIGARH MUSLIM UNIVERSITY, ALIGARH
BY
SYED ABUZAR M. Phil.
DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE
LUCKNOW-226001 JUNE, 1982
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,
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
CH2NN
CHoCHoOH
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# CI 2
/ \
CH,
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i n f e c t i o n y> . However, the drug i s t o x i c , b i t t e r in t a s t e
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*
'R= JO 7
HO COGH,
6 , R = V // \C1
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
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«£igi^i2£59iS
(dogs, fj>xes), T.hydatigena (d?gs) , T.^a^ni^ojrmi^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$.
Dichlorophene i s usual ly safe at the rapeu t i c doses and does
not produce any side ef fec ts* however some a l l e r g i c
reac t ions may be not iced . At higher doses the drug may
produce nausea, vomiting, d iar rhea , co l i c and jaundice and
may requi re spec ia l care to p a t i e n t s with hear t and l i v e r
di seases .
or bi 33., Di chlo rophene
IS
M t h i o n o l (34)
This was i n i t i a l l y used as an a n t i m i c r o b i a l and
t o p i c a l a n t i s e p t i c agent bu t l a t e r found to e x h i b i t a c t i v i t y
a g a i n s t a wide range of nes tode p a r a s i t e s i n men and
a n i m a l s . I t caused 70-85$ 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^ T^u ^es 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 ^^yj^ostama 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
U^in^ari^a s^oji^coghaLa, T.^is 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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37
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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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50
185 . C . J . H a t t o n , Vet . R e c , 77 , 408 (1965) .
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51
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52
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53
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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 . )
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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, +
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s fo r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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$, m . p , 1 8 8 ° .
iR(KBr) cm' 1
A n a l y s i s f o r
Calcd.
Found
1 3 3 , y i e l d 61
iR(KBr) cm - 1
A n a l y s i s f o r
Calcd*
Found
m
1620 (CO), 3200-3300 (NH,NH2)
G19H17N3° ( 3 0 3 )
C, 75 .24 ; H, 5.61
C, 75 .62 ; H, 5 . '
p . 2 2 8 ° .
1625 (CO), 3200-3300 (NH,NH2)
C 19 H 17 N 3 0 ( 3 ° 5 )
C, 75 .24 ; H, 5 . 6 l
C, 7 5 . 3 8 ; H, 5 . 46$ .
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
A n a l y s i s f o r
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
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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 +
A n a l y s i s f o r
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
A n a l y s i s fo r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s fo r
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
A n a l y s i s fo r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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 +
A n a l y s i s f o r
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
A n a l y s i s f o r
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
A n a l y s i s f o r
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^st^on^lus
br^a^il iensis in r a t s , Ng^^isji^oi_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
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 Nom^aJbo^pJ^qi^^ dub_ius_ in mice and
A?l?il£stoma p.p.yjj^i£^m i n hamsters .
Itesuljs^and^^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_s^iroid: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 pn^eumojiiae,
p^eudomonas aerujg^osa 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 nj^er , 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:
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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 .