Studies on the Syntheses of Possible Antifertility and ...
Transcript of Studies on the Syntheses of Possible Antifertility and ...
Studies on the Syntheses of Possible Antifertility and Anthelmintic Agents
( SUMMARY )
A THESIS SUBMITTED TO THE
ALIGARH MUSLIM UNIVERSITY, ALIGARH FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY .IN CHEMISTRY
BY Mohammad Shamim Akhtar
M. Phil.
DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE
LUCKNOW-226001 FEBRUARY, 1987
SUMMARY SYNTHESES OF POSSIBLE ANTIFERTILITY AGENTS
In India, one of the pr ior i ty areas of research work in
medicinal chemistry relates to the prevention of pregnancy. A chemical
agent, capable of preventing pregnancy, has greater acceptabili ty u
provided it does not prolong the period of menyistr^tion and does
not cause unwanted side-effects. Search for structural lead to achieve
this objective has resulted in the synthesis and biological evaluation
of thousands of aryl-ethylene der ivat ives . These compounds, though
very effective in preventing pregnancy in experimental animals, are
not suitable for clinical use. Thereafter no useful structural lead
has been identified for the development of a non-steroidal oral contra
ceptive agent. However, various attempts made to identify possible
lead molecules have .suggested that exploratory research act ivi t ies
in the area of heterocycles may provide useful lead for achieving
this objective. The present study i s , therefore, aimed towards identi
fying simpler heterocycles capable of evoking contraceptive ac t iv i ty .
The various molecules identified for the syntheses and biological eva
luation are l isted belbw:-
n ni
IV
R^=H,Ac
R- 0^ VI
In an another approach i t was considered of interest to
design compounds which may selectively alter the permeability of
the decidual cells in uterus and may also interfere with the oxido-
reductive processes of the cell biochemistry. Representative proto
types of such compounds are:
V M2 O2 C V ^ , X X ^ C 0 2 M G
.CO2MG M(2-
vn
H
vni
•Mc2
Syntheses of compounds belonging to prototypes I-III required subst i
tuted aroyl propionic acids as the starting materials. These were
u ni
prepared by the Friedel-Craft reaction of siragfle aromatic substrate
with succinic anhydride. Esterification of the substituted aroyl pro
pionic acids so obtained followed by their reduction with sodium
borohydride gave a mixture of 4-hydroxy-4-substituted phenyl buty-
rates and 2-oxo-5-substitutedphenyl tetrahydrofurans (Prototype I ) .
These were separated by column chromatography over sil ica gel.
Ring closure of methyl-4-substitutedphenyl-4-oxo-butyrates with acetic
anhydride and hydrazine hydrate yielded compounds belonging to
prototypes II and III respect ively.
Synthetic approach towards
fourth prototype, namely 4-aryl i -
dine-3-methyl-isoxazolone-5- invol
ved the reaction of appropriate
aryl aldoximes with methylaceto-
acetate. One representative comp
ound of th is class of compounds
was reduced with sodium borohydride to obtain a stereomeric mixtures
of IVa.
Syntheses of prototypes V and VI namely 3-substitutedphenyl
2-isoxazolin-5-one and 3-substitutedphenyl-5-methyl isoxazole respec
tively required starting materials of the type A.
R'=H,Ac
N - H 9OCH3
^ - - - - -COR.
VI
o A.R^=OMe,M<2
Ar
M G O C O
COM<2
C02MG/COM<2
1
These compounds namely 4-acetyl-3-methoxycarbonyl or acetyl-4-subst i -
tutedphenyl but-3-ene-2-ones, in pr inciple , can be prepared by the
pyridinium chlorochromate (PCC) oxidation of 2,5-dimethyl-3-methoxy-
carbonyl or acetyl-4-substitutedphenylfurans. Results of the PCC oxi
dation of these furans indicated that instead of compound A 4-acetoxy-
3-methoxycarbonyl or acetyl-4-
substitutedphenyl but-3-ene-2-ones
(1 ) were obtained. This oxidation
is novel and the products being
reactive organic intermediates are
of interest for more than one reason.
For example, the reaction of the oxidation products with aqueous
acid to yield acetophenones may evoke interest for vinderstanding reac
tion mechanism. This is precisely why an appropriate intermediate
has been isolated to delineate the reaction pathway of this reaction.
Hydroxylamine reacted smoothly with the PCC oxidation products to
furnish compounds belonging to prototypes V and VI. However, the
facile loss of COCH group even at milder reaction conditions prevented ^ 1
the preparation of other compounds (R = COCH ) of the prototype
V. Besides the chemical reactivity of the PCC oxidation products ,
their behaviour under electron impact was also interesting and a care
ful study of their mass fragmentation pattern has been carr ied out.
The reqiaired starting material for the synthesis of 2,5-dime-
thyI-3-methoxycarbonyI-4-(3-cyano-2-oxo-l , 2 ,3 ,4 - ' tetrahydroqulnollno)
furan (Prototype VII) was obtained by carrying out modified Nef reac
tion of l-(p>acetamldophenyl)-2-nitro propene. The resulting compound
.C02MG
R H
M G O S C
H
vni
'C02Me
namely 2,5-diraethyl-3-methoxycarbonyl-4-(p-acetamidophenyl )fiiran
was subjected to Vilsmier-Haak
reaction and the formyl derivative
so obtained on oximation gave
2 ,5-dimethyl-3-methoxycarbonyl-
4-(3-aldoxiinino-2-chloro quino-
lino) furan. This compound on
reaction with SOCl followed by
sodium borohydride reduction
furnished the desired molecule.
Compounds representing prototype VIII were prepared by
reacting substituted aldehydes
with methyl-3-amino crotonate
in presence of appropriate solvents.
In order to change R, two synthe
tic strategies have been employed.
In the first one, appropriately
substituted aromatic or hetero
cyclic aldehydes were prepared
and in the second one, appropriate
functionalities on the phenyl ring of 2,6-dimethyl-3,5-dimethoxycarbo-
nyl-4-phenyl- l ,4-dihydropyridine were simulated for elaborating them
to heterocyclic ring systems. Aldehydes such as 4-chloro-3-nitro ben-
zaldehyde, 2-chloro-3-formyl-quinoline and 4-formyl tetrazolo [1 ,5-
a] quinoline have been prepared. The heterocyclic ring systems on
the phenyl ring of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-phenyl-l ,4-
dihydropyridine have been made from appropriate 1,4-dihydropyridine
subs t ra te . For example, hydrogenation of 2,6-dimethyl-3,5-dimethoxy-
carbonyl-4-(4-amino-3-nitrophenyl)-l ,4-dihydropyridine gave the expec
ted diamine, which without further purification was reacted with
a variety of reagents such as a ry la ldehydes , sodium nitrite, benzil,
CS, and phthalic anhydride to yield 2-aryl-5(6)-[ 4-{2,6-dimethyl-
3 ,5-dimethoxycarbonyl-l ,4-dihydropyridyl ] - l (3 )-substitutedbenzyl ben-
zimidazole, 5(6)-[4-(2 ,6-dimethyl-3 ,5-dimethoxycarbonyl-l ,4-dihydropy
r idy l ) Ibenztriazole, 6-[4-(2 ,6-dimethyl-3 ,5-dimethoxycarbonyl-l ,4-
dihydropyr idyl ) 1-2 ,3-diphenyl quinoxaline, 5(6)-l4-(2 ,6-dimethyl-
3,5-dlmethoxycarbonyl-l ,4-dihydropyr idyl) ]-2-mercapto benzimidazole
. and 10-H-2-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)-l,4-dihydropyridyl]-
10-oxo- isoindolo [ 3 , 2 - a ] benzimidazole r e s p e c t i v e l y .
Biological Act iv i ty:
Various compoxinds syn thes i s ed as p o s s i b l e a n t i f e r t i l i t y agents
have been screened for t h e i r con t racep t ive eff icacy in r a t s and hams
t e r s . New leads have been generated and signif icant con t r acep t ive
a c t i v i t y in 2 , 6 - d i m e t h y l - 3 , 5 - d i m e t h o x y c a r b o n y l - 4 - s u b s t i t u t e d - l , 4 - d i h y -
d r o p y r i d i n e have been o b s e r v e d .
SYNTHESES OF POSSIBLE ANTHELMINTIC AGENTS
The ex i s t ing medical facilijties in ru r a l a r ea s and the soc io
economic s t r u c t u r e of the endemic populat ion of India cal l for the
development of a b road - spec t rum an the lmin t i c . In p r i n c i p l e , a b r o a d -
spect rum anthe lmint ic agent should possess the a b i l i t y to enter ces tode
and nematode p a r a s i t e s i r r e s p e c t i v e of t h e i r t i s sue locat ions and should
be capable of evoking se l ec t ive in te r fe rence wi th the b i o c h e m i s t r y
of the p a r a s i t e s . In o r d e r to ach ieve t h i s o b j e c t i v e , the iden t i f i ca
tion of the p h a r m a c o p h o r e , which should be a t t ached to the lead
molecule, i s e s s e n t i a l . Ear l i e r work on benz imidazo le -2 -ca rbama tes ,
c a r r i e d out in t h i s l a b o r a t o r y , suggested tha t the or ien ta t ion of the
carbonyl g r o u p ( s ) s imulated in the molecular framework of subs t i t uen t s
a t t a c h e d to pos i t ion 5(6) of benzimidazole nucleus g r ea t l y influences
antineraatodal and an t ices toda l p r o p e r t i e s . Although a large number
of compounds have been s y n t h e s i s e d to ident i fy the pharmacophore
r e s p o n s i b l e for w ide - spec t rum anthe lmint ic a c t i v i t y , t he complete
knowledge of d e s i r e d pharmacophore has not yet been a c h i e v e d . I t
w a s , t h e r e f o r e , cons ide red of i n t e r e s t to ex tend t h i s e x p l o r a t o r y
r e s e a r c h a c t i v i t y and the s y n t h e s i s of p r o t o t y p e s IX-XXII ( F i g . l )
was then unde r t aken . The design of p r o t o t y p e s XVI and XVII i s based
on t h e concept t ha t d i h y d r o p y r i m i d i n e d e r i v a t i v e s may in t e r f e r e s e l e c
t i v e l y wi th the r edox reac t ions of the p a r a s i t e energy metabol ism
and if found a c t i v e may s e rve as lead compounds for drug development
work .
The synthet ic strategy for prototype IX, namely 4 -benzoy l -
N- [5 (6 ) - (2 -me thoxyca rbony lamino)benz imidazo ly l I py r ro l i d in -2 -one r e
qu i red 4 -benzoy l -N-(4-amIno-3-n i t ropheny l ) - p y r r o l i d i n - 2 - o n e as the
s t a r t i ng mater ia l and t h i s was p r e p a r e d by reac t ion of /&-benzoyl-
V-butyro lac tone wi th 2 - n i t r o - £ - p h e n y l e n e d iamine . S t ruc tura l e luc ida t ion
IX
MG02C
N
M c 0 2 C ' ^ \ H
^
NOH
MGO2C/ ^N H
XII
MG02C'^ \ H
XIll
, C 0 2 M G
M G - ^ , ^ > - M C
MG02C
XIV
v<r.
N
N ^ N H C 0 2 M e
H
XV
Contd.
N-M(2
XVI xvn
NH
N ^ N H C 0 2 M e
Me02C
NHCO2MG
CO2MG
XVIll
H
XIX
R
^ " ^ ^ C H ^ N H ^ / NC02M(2
NHC02Me
XX
Me
^NHCq2MG
XXI
M202C-
Ar '
•N / C02Me
/ ; -N
-N
H
CO2M2
XXII
(Fig . 1)
of t h e r e a c t i o n p r o d u c t c a l l e d
for a model r e a c t i o n a n d t h e y
one i d e n t i f i e d for t h i s p u r p o s e II -Nc^v^/'N—i
w a s c o n c e r n e d w i t h t h e r e a c t i o n r y ^ y y \ / / ^ ^ \ i^ i j
of /3 - ( £ - t o l u o y l ) - Y - b u t y r o l a c t o n e s
w
, N ; Y ' ^ ~ - C 0 2 M Q
H
i t h £ ^ - a n i s i d i n e . D e t a i l e d s t u d i e s 13 15
on t h e C and N-NMR s p e c t r a
of t h e r e a c t i o n p r o d u c t in t h i s
mode l r e a c t i o n h e l p e d to i d e n t i f y
i t a s 4 - t o l u o y l - N - ( £ - m e t h o x y p h e n y l ) - p y r r o l i d i n - 2 - o n e . B a s e d on t h i s
r e s u l t , t h e r e a c t i o n p r o d u c t of 0 - b e n o y l - Y - b u t y r o l a c t o n e w i t h 2 - n i t r o -
£ - p h e n y l e n e d i a m i n e w a s i d e n t i f i e d a s 4 - b e n z o y I - N - ( 4 - a m i n o - 3 - n i t r o p h e -
n y l ) - p y r r o l i d i n - 2 - o n e .
The s y n t h e s i s of p r o t o t y p e X, n a m e l y ^ - [ ( 2 - m e t h o x y c a r b o n y l -
a m i n o ) - 5 ( 6 ) - b e n z i m i d a z o l y l ] - a c r y l i c a c i d , w a s i n i t i a t e d b y r e a c t i n g N-~-^^^^'^\^''^^^^^55i./' 2
4 - a c e t a m i d o - 3 - n i t r o b e n z a l d e h y d e
w i t h ma lon ic a c i d in p r e s e n c e
of c a t a l y t i c amount of p y r i d i n e .
The r e s u l t i n g p r o d u c t w a s h y d r o - ^
l y s e d u n d e r a l k a l i n e c o n d i t i o n s
a n d t h e £ - n i t r o a n i l i n e d e r i v a t i v e
so o b t a i n e d w a s h y d r o g e n a t e d u n d e r c o n t r o l l e d c o n d i t i o n s to
f u r n i s h t h e d e s i r e d d i a m i n e . R e a c t i o n of t h i s compound w i t h N , N - d i m e -
t h o x y c a r b o n y l - S - m e t h y l i s o t h i o u r e a y i e l d e d t h e d e s i r e d p r o t o t y p e X.
The s y n t h e s i s of p r o t o t y p e XI, n a m e l y m e t h y l 5{ 6 ) - [ 5 - e t h o x y -
c a r b o n y l - 6 - m e t h y l - 3 , 4 - d i h y d r o p y r i m i d i n - 4 - y l 1 b e n z i m i d a z o l e - 2 - c a r b a m a t e
r e q u i r e d 5 -e t h o x y e a r b o n y 1 - 6 - m e t h y l -
2 - o x o - 4 - ( 4 - a c e t a m i d o - 3 - n i t r o p h e n y l ) f-j>^ >N"
p y r i m i d i n e a s t h e s t a r t i n g m a t e r i a l . M G O O C ^ \ M
T h i s w a s p r e p a r e d b y t h e a c i d \-\
c a t a l y s e d r e a c t i o n of 4 - a c e t a m i d o -
3 - n i t r o b e n z a l d e h y d e w i t h e t h y l -
a c e t o a c e t a t e a n d u r e a . T h e p y r i m i
d i n e so o b t a i n e d a f t e r h y d r o g e n a -
t i o n w a s c y c l i s e d w i t h N , N - d i m e -
t h o x y c a r b o n y l - S - m e t h y l i s o t h i o u r e a to g i v e t h e r e q u i r e d p r o t o t y p e XI .
During the course of present investigation on the preparation of dihy-
drop yri mi dines, it was possible to isolate the intermediate formed
in the acid catalysed reaction of aromatic aldehyde with /3-ketoester
in presence of thiourea. It is noteworthy because earlier attempts
to isolate the intermediate were unsuccessful.
The preparation of the
prototype XII, namely 2-raethoxycar-
bonylamino benzimidazole-5( 6)-aceto-
xime by the direct oximation of
methyl-5{6)-acetyl benzimidazole-
2-carbamate has revealed that MGO2C despite the presence of a carbamate
moiety, the oximation of carbonyl
group was possible.
r>^
XII The synthesis of prototype
XIII (X = NH) owes i ts origin to the observation made during
the upscaling studies of the CDRI compound 83/148, a potent anthelmin
tic agent. It was observed that during the preparation of 2,5-dimethyl-
MGO2C .C02Me
8 3 / 1 4 8 :X = 0 XIII ;X = NH
XIV
N
N'^NHC02M«
3-methoxycarbonyl-4-( 4-amino-3-nitrophenyl) furan, the required inter
mediate for the preparation of 83/148, invariably a small amount of
red compound was formed in the reaction mixture and this was identi
fied as 2 ,5-dimethyl-3-methoxycarbonyl-4-( 4-amino-3-nitrophenyl)pyrrole.
The formation of this pyrrole derivative along with the corresponding
furan in the Nef reaction of l-( 4-amino-3-nltrophenyl )-2-nitro propene
in presence of methylacetoacetate and piperidine suggested that a
careful study of th is reaction may furnish a reaction condition in
which the pyrrole could be obtained as the predominant product.
10
This prompted to study the Nef reaction in presence of pr imary,
secondary and ter t iary amines and the results were monitored by
HPLC. The reactions of 2-nitro-l-substi tutedphenyl propenes with
methylacetoacetate in presence of primary amines gave exclusively
N-substituted pyrrole , while the presence of secondary amines fur
nished a mixture of pyrrole and furan derivatives and the presence
of ter t iary amine exclusively yielded furan der ivat ives . The hydroge-
nation of 2 ,5-dimethyl-3-methoxycarbonyl-4-( 4-amino-3-nitrophenyl )-
N-substituted pyrroles and 2,5-dimethyl-3-methoxycarbonyl-4-substituted
phenyl-N-( 4-amino-3-nitrophenyl )pyrroles followed by the cyclisation
of the hydrogenation products with N .N-dimethoxycarbonyl-S-methyliso-
thiourea yielded compounds of prototypes XIII and XIV respect ively .
The C-NMR spectra of tetrasubstituted furans and tetra or penta-
substituted pyrroles and their comparislon with spectra computed
by a computer on the basis of literature data have yielded useful
information.
The synthetic strategy for prototype XV, namely 2 ,2 ' -d ica rbo-
methoxyamino-5,5'-dibenzimidazolyl methanol involved the following
sequence of reactions. Nucleophilic displacement of chlorine in 4 , 4 ' -
H
XV
dichloro-3,3 ' -dini t ro benzophenone with aqueous ammonia followed
by the sodium borohydride reduction of the resulting nitroamine gave
the secondary alcohol. Hydrogenation of this compound followed by
the cyclisation of the resulting diamine with N ,N-dimethoxycarbonyl-
S-methylisothiourea furnished the required prototype XV,
Synthesis of prototypes XVI-XVII were initiated by carrying
out acid catalysed reaction of aromatic aldehydes with methylaceto
acetate in presence of thiourea. Studies on the alkylation of resulting
compound, namely 5-ethoxy-carbonyl-6-methyl-4-substitutedphenyl-3,4-
dihydropyrimidine-2-thione, gave useful information. Alkylation with
11
me thy l iod ide in presence of sodium h y d r o x i d e in methanol y i e lded
Et02C
N-MG
Et02C
XVI XVII
only S-methyl d e r i v a t i v e and the raethylation of the same subs t r a t e
in DMSO gave the d imethy la ted product namely 1 ,6 -d ime thy l -5 - e thoxy -
ca^bony l -2 -me thy lmercap to -4 -pheny l -4 - ( l - H ) - p y r i m i d i n e . Nucleophi l ic
displacement of methyl mercaptan from S-raethyl d e r i v a t i v e (mono
a l k y l a t e d p roduc t ) by N-methyl p ipe raz ine furnished XVI. In an another
novel a lkylat ion reaction, 5 - e t h o x y c a r b o n y l - 6 - m e t h y l - 4 - s u b s t i t u t e d -
p h e n y l - 3 , 4 - d i h y d r o p y r i r a i d i n - 2 - t h i o n e was r eac t ed with monochloroacetic
ac id in presence of BF - e t h e r a t e in methanol and t h i s r e su l t ed in
the formation of p ro to type XVII.
The synthes i s of prototype XVIII, namely 5( 6 )-N[ {2-methylmer-
c a p t o - 6 - m e t h y l - 4 - p h e n y l p y r i m i d i n - 5 - y l ) methyl Jamino benz imidazole-
2-carbamate invo lved the a romat i sa -
tion of 5 - e t h o x y c a r b o n y l - 2 - m e t h y l -
mercap to -6 -me thy l -4 -pheny l -4 ( IH)-
pyr imid ine wi th manganic ace ta te
as the f i r s t s t ep of the total
s y n t h e s i s . Th i s was followed by
LAH reduc t ion and the resu l t ing
compound namely 5 - h y d r o x y m e t h y l -
2 -me thy lmercap to -6 -me thy l -4 -pheny l
py r imid ine was r eac t ed wi th PBr,
to obtain the d e s i r e d bromo d e r i v a
t i v e . The l a t t e r was r eac t ed wi th
2 - n i t r o - p - p h e n y l e n e d iamine , and the reac t ion product was then h y d r o -
genated to y ie ld the d e s i r e d diamine which was then c y c l i s e d with
N,N-d ime thoxyca rbony l -S -me thy l i so th iou rea to furnish the r e q u i r e d
compound of the p r o t o t y p e XVIII.
NH
N^NHC02M<2 XVIII
12
NHC02Me
Syntheses of molecules belonging to prototype XIX, namely
methyl-5{6)-l4-(2,6-dimethyl-3,5-
dimethoxycarbonyl-1,4-dihydro-
pyridino) ]-N-substituted benzitnida-
zole-2-carbamates, were achieved
by following sequence of 3-Nitro-
4-substitutedamino-chlorobenzal-
dehyde was reacted with methyl-
3-amino crotonate to obtain the
corresponding 1,4-dihydropyridine
der ivat ive . NMcleophilic displace
ment of chlorine by amines followed
by hydrogenation of the resulting
o^-nitro aniline derivatives gave
the desired o^-phenylenediamine derivatives which were then cyclised
with N,N-dimethoxycarbonyl-S-raethylisothiourea to yield XIX.
XIX
R
The compounds representing prototype XX namely N,N-dime-
thoxycarbonyl-N-substitutedbenzyl
auanidines were prepared by react
ing appropriate benzylamines with
N, N-dimethox year bony 1-S-me thy 1-
isothlourea.
CH2NH NCO2MG
NHCOaMe
VNHCO2MG
XX The synthetic strategy for prototype XXI namely methyl-4(5)-
methyl-5( 4)-(3 ,4-methylenedioxy-
phenyl )-4 ,5-dihyd^oimidazole-2-
carbamate, involved the reaction
of 2-nitro-l-(3,4-methylenedioxy-
phenyl )propene with hydroxylamine
hydrochloride as the first s tep.
The compound so obtained was
hydrogenated and the resulting diamine was cyclised with N,N-dirae-
thoxycarbonyl-S-methylisothiourea to yield compounds of the prototype
XXI.
The synthetic strategy for the prototype XXII, namely 1,6-
biscarbomethoxy-2-methoxycarbonylamino-7-methyl-5-(p-methoxyphenyl)-
4,5 ,6 ,7- te t rahydro- l ,3-diazepln.e required 3-amlno-2-^ (p-methoxyphenyU
nltroethyl Jcrotonate as the starting material. This was prepared by
XXI
13
react ing 2 - n i t r o - l - ( p - r n e t h o x y p h e n y l )propene with methyl -3-amino c r o t o -
na te . This compound was reac ted wi th hydroxy lamine to obta in 3 -ca rbo -
methoxy 5 -n i t ro -2 -ox i -M(2
mino- (4 -p -me thoxypheny l ) » P O - i M s
pentane. Evidence for KyloO P / "N
the ass igned s t ruc tu re
MeO ^ >^xjj
was obta ined from s p e c
t roscop ic data and
from the r e s u l t s of
chemical t ransformat ions .
Similar to the reac t ion
of 1-( p- rae thoxyphenyl ) -
propene with methyl-3-araino c ro tona te , reac t ions of o the r 2 - n i t r o -
1-subs t i tu tedphenyl propenes with the same reactant gave 3-amino-
2-[ ( / a - s u b s t i t u t e d p h e n y l )n i t roe thy l I c ro tona tes , which in turn r eac t ed
wi th hydroxylamine to yie ld 5 -n i t ro -2 -ox imino -4 - subs t i t u t edpheny l
pentanes . Oxidation of the l a t t e r c lass of compounds with e i t h e r mono-
p e r p h t h a l i c ac id or m-chloro perbenzoic acid y ie lded 3-ca rbomethoxy-
3 - h y d r o x y - 5 - n i t r o - 4 - s u b s t i t u t e d p h e n y l pen tan-2-ones . Oximation of
t he se compounds gave 3 - c a r b o m e t h o x y - 3 - h y d r o x y - 5 - n i t r o - 2 - o x i m i n o -
4 - subs t i t u t edpheny l pen tanes . On the bas i s of Dreiding model the
s t e r e o c h e m i s t r y of these d ias te reomers was ass igned as R R ( t h r e e ) .
In o r d e r to obta in the p ro to type molecule, 3 -ca rbomethoxy-4- ( p -methoxy-
phenyl ) -5 -n i t ro -2-ox imino pentane was hydrogenated and the produc t
without fu r ther pur i f ica t ion was cyc l i s ed wi th N ,N-d ime thoxyca rbony l -
S-methyl i so th iourea to y ie ld XXII,
Biological Act iv i ty
Compounds r ep resen t ing var ious p r o t o t y p e s were eva lua ted
for t h e i r an t i f i l a r i a l a c t i v i t y against L. cciAinii, cestocidal a c t i v i t y
against H. nana and nematocidal a c t i v i t y against A. cZLj^anicum and N.b^a-
'4-ttten-4-i'4 infec t ions . Compounds exh ib i t i ng signif icant an the lmin t ic
a c t i v i t y were screened for t h e i r a c t i v i t y against developing s tages
of p a r a s i t e s . Sens i t iv i ty of pharmacophores in "benzimidazole carbama
tes" for e l ic i t ing anthelmintic ac t iv i ty has been discussed and a comp
ound e x h i b i t i n g spec i f ic a c t i v i t y against hook-work has a l so been
iden t i f i ed . Compounds r ep resen t ing p r o t o t y p e s X, XII, XVI, XVII,
XVIII, XX and XXII d id not e x h i b i t any anthe lmint ic a c t i v i t y .
Studies on the Syntheses of Possible Antifertility and Anthelmintic Agents
A THESIS SUBMITTED TO THE
ALIGARH MUSLIM UNIVERSITY, ALIGARH FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY
BY lAohammad Shomim Akhtar
M. Phil.
DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE
LUCKNOW-226001 FEBRUARY, 1987
T«lex : 0 5 3 5 - 2 8 6 T«l«gr«m : CENDRUG Phone : 32411-18 PABX
No.
srR jrftrw. Tte inw #<> 173
rtisH* 226001 (TTOT)
CENTRAL DRUG RESEARCH INSTITUTE Chat tar Manz i l . Post Box No. 173
LUCKNOW—226001 (INDIA)
Date 23Kd FzblaoAij 1987
CERTIFICATE
Thi6 i6 to czfitily that thz wofik zmbodizd in tki6 thz6i6
ha6 bzzn ccxAtizd oat by Mt. M. Shamim AkhtoA, hA.Phii., undz^
ouA 'tupzxvi'iion. He ha6 {,a<ilMzd thz izquin-Zmznt^ ^01 thz dzg^zz
oi Doctor oi Phiio'iiophLj o^ thz AttgoAh Mu6tLm UnivZAMty KzgaxdinQ
thz natuAZ and pAZ6CA.ibzd pziiod ol in\JZ6tigationai woik. Thz
woAk inciadzd in thi'i thzM6 uniz^6 othZAwi^z 6tatzd. i6 ait oii-
ginai.
<N\ . S -M-^E^ (M.S. AHMAV) (A.P. BHAVURl)
ACKNOWLEDGEMENT
I •^e.zi plza^zd to izcofid my i.ndzbtnz^^ and pA.o{,ound ^e-n^z
0^ g^atitudz to Vi. A. P. BhaduA^., Sc<.tnt<6t E-U, Mzdicmal Chzm4.6tA.Lj
Viv-tMon, CzntA.al VKUQ Rz^zaxck iMtitutz, Lucknow ^OA. hi6 indi6pzn-
6abiz Qindancz, con6tn.uctiK/z cn.itici6m, a^zctionatz behav-couA and
Z^zxia6ting zncouAagzmznt which 6u6tainzd my z^o^.t'S at all thz ^tagz^
o{j thz oAduoa^ andzitaking^.
I wi6h to convzy my 6inczn.z thanks to Pxo{,. M.S. Ahmad,
Chaiiman, VzpoAtmznt o^ Chzmi6tn.y, AttgoAh Mwtilim LlnivzA.Mty, AligoAh,
•l^ot hi6 kzzn intZA.Z6t and mvaluablz hzlp izndzizd during thz tznuAZ
0^ thi'i woik.
Thank'^ oAZ daz to Vi. M.M, VhoA, f.N.A., DixzctoA., Czntn.al
Vn.ug Rz^za/ich In'ititutz, Lucknow and VA.. V.S. Bhakuni, FNA, Vzputy
ViKZctoi Ion. providing lahoKatoiy iacilitiZ6.
1 am al6o g^atz^ul to all thz mzmbzn6 o^ PoAaMtology and
Endocrinology Division o{, thi^ In^titatz ^o-t providing valuablz ^aizzn-
mg data.
I am thankful to Vi. K.P. Madha6udanan, Sciznti'it, ^ox provi
ding mz thz opportunity o{, Ma^'f^ Spzctromztric ^tudiZ'i.
1 would tikz to acknowlzdgz Pro^. E. Rti'dzr, Pharmaczutical 13 In^dttitutz, Bonn, ^or pro\^iding UtzratuAZ ba^zd computzr data o^ C-
NSAR.
I am indzbtzd to thz 6ta{,i o^ Rzgional Sophi'iticatzd In^trumzn-
tation Czntrz, C.V.R.I., ^or providing ^pzctro^copic and analytical
data.
My warmz-it thanks arz daz to Vr.iMi'i,^) M. Szth ^or many
hzlpiai di^ca^^ion^, zncouragzmznt and a^^zctionatz bzhaviouA daring
thz zntirz cour6z o^ thi4> ^tudy.
A gatorz oi thanks to Vr. U.L. ShoAma •{,or 6pznding hi6 vaia-
ablz timz in zxprz^^ing hi^ {^inz 6zn6Z o^ art.
1 atio acknowlzdgz thz 'Stimulating companion6hip and nzzd-
lui cooperation oi A^hrai, A^hwani, Rahul, Sangzzta, Winzzt, Ranjan,
Anita, Vibyzndu, Raju, Sham-ihad and Pzrwaiz.
I would be {,cUtinQ in my duty i{, I do not mucoid my /iumfa£e
appfizciation ioi thz con^ittant dncouAagzimznt, in my all zndzavouA'^,
I izczivzd ^om my paA.znt6 and otkzn. {,amiiy mzmbzX'i.
finally thz ^nancial a^^i^tancz in thz ^o^m oi {,zliow6hip
oi Council o{j Scizntiiic and Indu^t^ial Rz6zaA.ch (CSIR), Nzw Vzlhi,
i6 g^atz^fully acknowlzdgzd.
^<^^
(M. Shamim AkhtoAJ
LIST OF ABBREVIATIONS
Unless o the rwise s ta ted a l l a r a b l e numbers in BOLD l e t t e r s
re fe r to compounds d i scussed in t h i s d i s s e r t a t i o n .
AlCl^
bs
^^C-NMR
d
DMSO
DMF
Ether
Hz
IR
Jra
Jo
LAH
m
m . p ,
PMR
q
s
t
TEA
UV
Aluminium Chlor ide
Broad s inglet
Carbon nuclear magnetic resonance
Doublet
Dimethyl su lphox ide
Dimethyl formamide
Diethyl e the r
Hertz
Inf rared
Jmeta
Jor tho
Lithium aluminium h y d r i d e
Molecular ion
mult iplet
Melting point
Proton magnetic resonance
quar t e t
s inglet
t r i p l e t
Tr i f luoroacet ic ac id
Ul t ravio le t
CONTENTS
Page
Preface . . . i
CHAPTER 1
1.1 : Non-s tero ida l contragesta t ional he t e rocyc l e s . . . 1
1.2 : Basis of work . . . 9
CHAPTER 2
2 .1 -2 .5 : Syntheses of compounds belonging to p ro to types
I-VIII . . . 12
CHAPTER 3
3.1 : Exper imenta l . . . 37
3.2 : Tables . . . 47
3.3 : Biological a c t i v i t y . . . 69
CHAPTER 4
4 .1 -4 .5 : S tudies on chemotherapy of helminth infec t ions :
Ret rospec ts and p ro spec t s . . . 72
4.6 ; Basis of work . . . 76
CHAPTER 5
5. L-5 .9 a : Syntheses of compounds belonging to p r o t o t y p e s
IX to XXII . . . 100
CHAPTER 6
6.1 : Exper imenta l . . . 138
6.2 : Tab les . . . 154
6.3 : Biological a c t i v i t y . . . 189
REFERENCES . . . 199
PREFACE
In India, the pr ior i ty areas of research work in medicinal
chemistry are two; the first one is concerned v i th parasi t ic infec
tions while the second one relates to the prevention of pregnancy.
The existing medical facility in villages and the socio-economic
structure of the population call for an easy access to a broad-spec
trum antiparasitic agent and if a cheap chemoprophylactic is also
made avai lable , the diseased and those who are succeptible to
the disease would be benefitted and would help in restr ict ing the
endemic areas to a managable situation. Prevention of pregnancy
by a chemical agent would be more acceptable to those who are
motivated for family welfare if the agent causes minimum physiologi
cal insult and if the period of menv/stmtion is not enhanced.
In the light of these concepts the present study has been
init iated. Approach for developing an agent to prevent pregnancy,
therefore, is concerned with the non-steroidal molecules. The failure
of tr iarylethylenes to provide a non-steroidal remedy has prompted
a world wide search for new structural leads. The f irst part of
this dissertation is directed towards this objective. The second
part of this dissertation is aimed towards identifying pharmaco
phores which are responsible for evoking anticestodal and antinema-
todal act ivi t ies i rrespective of their tissue locations. Care has
also been taken to evaluate active compounds for chemoprophylactic
activi ty since this may help to identify the pharmacophore respon
sible for chemoprophylaxis.
Synthesis of desired prototype molecules is often associated
with interesting chemical reactions and a few of the molecules synthe
sized might also offer an opportunity to enrich the present state
of knowledge provided their spectral properties are carefully studied,
The present dissertation has taken a note of this situation.
CHAPTER 1
1.1 : NON-STEROIDAL CONTRAGESTATIONAL HETEROCYCLES
1.1.1 : Monocyclic heterocycles
1.1.2 : Blcyclic heterocycles
1.1.3 : Polycyclic heterocycles
1.2 : BASIS OF WORK
CHAPTER - 1
1 . 1 NON-STEROIDAL CONTRAGESTATIONAL HETEROCYCLES
C h e m i c a l a g e n t s w h i c h p r o v o k e p r e g n a n c y f a i l u r e
by c r e a t i n g a s i tuat ion in which the p r o p e r endocr ine requ i rements
have been d i s tu rbed to cause d i r e c t l y or i n d i r e c t l y an t i zygo t i c ,
b l a s t o l y t i c , ba l s to tox ic or abor t i fac ien t a c t i v i t i e s , a r e te rmed as
contragesta t ional agents . Control of popula t ion , a pr ime need of
the present age , may be ach i eved by these agents but the small
and defini te incidence of se r ious s ide-e f fec t s resu l t ing from these
agents should be careful ly s tud ied since i nh ib i t i on of pregnancy
must lead to minimum phys io log ica l in su l t . The most common type
of contragesta t ional agent effect ive by oral route of admin i s t r a t ion
(oral con t r acep t ives ) r e p r e s e n t a combination of an es t rogen and
a p roges t in since a p roges t in or an es t rogen alone i s c l i n i c a l l y l ess
a c c e p t a b l e . However, the need for a second generat ion of ora l con t ra
c e p t i v e s has been r e a l i s e d because agents which do not e x h i b i t any
hormonal or ant ihormonal effect but a re capab le of evoking s e l ec t i ve
physiologica l imbalance in the u terus to cause pregnancy fa i lu re
would be more a c c e p t a b l e . A d e s i r a b l e choice for designing a such
contrages ta t ional agents a r e he te rocyc les and t h i s has p rompted to
review the e a r l i e r r e p o r t s of the cont rages ta t ional eff icacy of h e t e r o
cyc les and a br ief r e p o r t of the same i s p re sen ted h e r e .
1.1 .1 Monocyclic heterocycles
The most conspicuous non-hormonal con t r acep t i ve agen t s ,
developed by Omodei-sale et_ aj^ , a r e r e p r e s e n t e d by 3 , 5 - d i s u b s t i -
t u t e d - l H - 1 , 2 , 4 - t r i a z o l e s (!.)• These i n h i b i t pregnancy in hams te r s
at a dose of 5 mg/kg P .O . A more effect ive compound of t h i s s e r i e s .
N NH f? -J R = Cj_^-alkyl; R = H. F, CI,
MeO, Etc , Cj_^-alkyl;
2 R = H, F, CI, Cj_^-alkyl or
alkoxy; R R = OCH O
2-
namely 3 - ( 2 - e t h y l p h e n y l - 5 - ( 3 - m e t h o x y p h e n y l ) - l H - l ,2 , 4 - t r i a z o l e {2),
deve loped by Galliani et_ al_ , e x h i b i t s a n t i f e r t i l i t y effect by acting
on the u te roplacenta l unit (UPU), resu l t ing in r e so rp t ion or expuls ion
of the concep tuses . This compound i s ac t ive whe ther given o r a l l y .
OEt OMe
M(2
subcutaneous ly , in t r amuscu la r ly or in t r avag ina l ly but the requ i rement
of a ve ry high ora l dose l imi t s i t s usefulness . Another d e r i v a t i v e
of 2. (R = CH ; R , R , R = H) also e x h i b i t s s ignif icant pregnancy 3
terminat ing a c t i v i t y . The ED values a r e 0.3 mg/kg /day s . c . in
hams te r s and 2 mg /kg /day s . c . in r a t s . Instead of t h r e e ni trogen
atoms in the he t e rocyc l i c r i n g , py razo l e d e r i v a t i v e (3 ) wi th two 4
ni t rogen atoms a lso e x h i b i t s pregnancy terminating a c t i v i t y and
the r e p o r t e d ED values a r e 3 mg/kg /day in hams te r s and 25 mg/kg/
day in r a t s .
Oral admin i s t r a t ion of a r e p r e s e n t a t i v e of s ix -membered
he t e rocyc l e s namely 2 ' , 3 ' , 5 ' - t r i - 0 - a c e t y l - 6 - a z u r i n e (\), at a dose
of 300 mg/kg on days 8, 9, 10, 11 and 12 of pregnancy in r a b b i t s ,
have been r e p o r t e d to i n h i b i t pregnancy in a l l cases whi le d e r i v a
t i v e s of 2 - [ « < - ( o r t h o s u b s t i t u t e d benzimidoyl) benzy l ] p y r i d i n e (5 )
have been found to i n h i b i t ovula t ion .
AcOHoC R^N
1.1.2 Bicyclic Heterocycles
Compared to monocyclic heterocycles, more number of bicyc
lic heterocycles have been evaluated for their ant ifer t i l i ty ac t iv i ty . 7
Of these 3-(2-benzofuranyl )-3-alkyl-2,2-dimethyl propionic acids a
(6^), substituted 2-anilino benzoxazoles (7 ) and 2-benzoyl-3-phenyl 9
benzothiophene (or benzothiophene oxide) derivat ives (8) have
shown pregnancy inhibiting act ivi ty in r a t s .
R R2 ^^C02R^
7
R = H, Me; R = H, OMe;
R^ = Me, Et; R^ = R* = H
R = H, a l k y l , a l k o x y ,
a l k y l o x y , CO H
R,R = OH, H, a l k o x y ;
2
R = H, CI , Br , OH, a l k o x y ;
R = H, Py r ro lod inoe thoxy ;
n = 0, 1
8
Derivatives of 2-aroyl-3-phenyl benzothiophenes {9) at 1 mg/day
S.C. and 1,2-diphenyl-l ,2,3,4-tetrahydroquinoline (2£) at 50-100
mg in ra ts have been reported to prevent pregnancy.
R = H, 4-OMe, 4-OH, 4-Cyclo-p h e n t y l o x y , 3-OMe, 3-OH, 2-OMe, 2-OH, 3-Cl , 4-Cl;
R^ = H, OMe, OH
Bicycl ic compounds such as indazole d e r i v a t i v e s (JLi.) ^^^ 1 ,2 -d iphe 13 . .
ny l indoles (^2^) a lso e x h i b i t con t r acep t ive a c t i v i t y .
NHR R
11
R = Me, Ph, CH :CHCH , Et; 1 I i
R = Me, H, HC; CCH^, H^CtCHCH^Ph
R = Cyc lohexy l , Me2CHCH2Ph
R = H, CN
10I>™
R MeO; R = Et NCH^CH^
A chroman der ivat ive namely 3 ,4 - t rans -2 ,2 -d lmethy l -3 -pheny l -4 - [2 . -14 (3 -pyrro l id inoethoxy)phenyl ] -7 -methoxychroman (13) prevents con
ception at a single oral dose of 1,25' mg/kg in rats and mice and
2.5 mg/kg in dogs and rhesus monkeys immediately postcoitum. It
also possesses estrogen, antiestrogen and antiprogestational propert i e s .
M G O
13
The isoquinol ine d e r i v a t i v e , l - N - m e t h y l p i p e r a z i n e - 2 - c h l o r o - 4 - n i t r o i s o -15 quinoline (^i.)» e x h i b i t s an t i - implan ta t ion a c t i v i t y in r a t s at '^ 50
mg/kg wi th maximum a c t i v i t y on days 4,5 and 6 of p regnancy . Another
c lass of b i cyc l i c n i t rogen he t e rocyc le s such as 3 - l2 . - (W-subs t i tu t ed
aminoalkoxy)benzoyl l indo les (15) and o i - m e t h y l a r y l a m i d o - P - n a p h t h y l ( 1-
raethylamino-2-methylbenziraidazolyl) e t h e r s
lantat ion a c t i v i t y in a lb ino female r a t s .
17 (16) pos ses s an t i - imp-
0-eCH2] R^ .NHCOPh
15 16
R = H; R = NEt^, NMe^, N(CHMe ) , p i p e r i d i n o , morpholnio , p y r r o l i d i n e ;
R^ = R^ = CH^O^S n = 2-3
: R,R = CH CH^OCH^CH^
: R = Me; R = Ph
A b i cyc l i c su lphur containing h e t e r o c y c l e , 2 - P h e n y l - 3 - a r o y l benzoth io-
phenes ( r z ) . a t 1 mg /kg /day S.C. in r a t s for 15 days complete ly 18 i n h i b i t s fetus development
17
1.1.3 Polycyclic Heterocycles;
A wider variety of tr icyclic and/or polycyclic heterocycles
exhibit ant lfert i l i ty ac t iv i ty . Tricyclic nitrogen containing compounds 19 such as 18-24 are reported to be useful contraceptives.
18
^ H
19
20 21
22 23 24
Of the polycyclic oxygen containing heterocycles, benzofurobenzopyra-
nones (25 ) cause ^83 .3% inhibition of fetal implantation at 10 mg/kg
i . p . in ra ts and several derivatives of the nitrogen containing
heterocycle 2^ are luteolytic in rabbi t s at a dose of 1 mg/day for 1^ A 21 14 days
25 26
R = H, aminoalkyl
Several subs t i t u t ed indeno, naphtho and cyc lohep ta py razo le s (27) 22
e x h i b i t a n t i f e r t i l i t y a c t i v i t y in r a t s at a dose of 1-100 tug/day
and t r i azo lo i so indo le d e r i v a t i v e s (2^) are pos tco i ta l con t racep t ives
in r a t s . The ED va lues range between 1-10 mg/kg s . c .
R'
R' m^ hi 11 N-^R
27 28
R = 4-pyr idy l
R = R = H;
n = 2
R = Subs t i tu tedpheny l
Nitrogen and sulfur containing heterocycles such as thieno l 2 , 3 - g ] 24 indazoles (29) at 50 mg/day , 2H[ 1 ]-benzothiepino [4 ,5-C] pyrazoles
(30) at 2 mg/day and methanobenzo [b] thiophenes (21) at 5 mg/
kg exhib i t ant i fert i l i ty a c t i v i t y .
Eight membered tr icyclic nitrogen containing heterocycle such as 27 dibenzodiazocine {^) and the angular benzo [4,5] pyrano [2 ,3-
C] pyrroles (3^ ) with two different heteroatoms are reported to
be useful contraceptives.
32 33
X = 2,8-Cl2; R = 2-thienyl R,R = H, a lky l , a lkoxy, OH, halo, acyloxy;
2 R = H, a lky l , a r a lky l ,
aminoalkyl
Another class of compounds namely pyrazolo [5,1-a] isoquinoline
(34; 2 mg/kg/day in hamsters) and aminoindolobenzodiazepines
(35) have been found to possess contraceptive efficacy.
34
The con t racep t ive eff icacy of the members of the n i t rogen containing
t r i c y c l i c he te rocyc les (36-38) a r e as follows ' .
36
H
H S»5 H m-(OCH, )C,H.
3 6 4
CH,OH C,H_
CH3 C^H^
H S"5
CH2-CH3
CH = CH
CH = CH
CH^-CH^
CH^-CH^
CH,
ED
Hamster
3 .5
1
> 5
- 1 0
>3
10
50 (mg / k g / d a y)
Rat
20
5
25
- 2 0
20
>5
1.2
N-^Ph
BASIS OF WORK
3.5 1.8
16
The tex t of the p receed ing sect ion suggests t ha t h e t e r o c y c l e s
a re capable of terminat ing pregnancy but the a v a i l a b l e r e p o r t s do
not pro jec t a c l ea r p i c t u r e about t h e i r con t r acep t ive eff icacy by
ora l route of admin i s t r a t ion and the r e s u l t s of the follow up act ion
in la rge number of cases have p o s s i b l y remained u n r e p o r t e d . However,
the d e s i r e d de t a i l s concerning the prof i le of a n t i f e r t i l i t y a c t i v i t y
a r e a v a i l a b l e for t r i a z o l e d e r i v a t i v e s and t h i s p rompted an e a r l i e r
effort in t h i s l a b o r a t o r y to a s c e r t a i n whe the r the i somer ic t r i a zo l e s
(A&B) and the rep lacement of one of the ni trogen atom In t h e s e com
pounds by o the r he teroatoms could influence the con t r acep t ive e f f i cacy .
10
It has been found tha t i someric t r i azo le s (A&B) and oxadiazole d e r i
v a t i v e s (C) e x h i b i t con t racep t ive a c t i v i t y but t h e i r eff icacy by 31 32 oral route of admin i s t r a t ion is ex t r emely poor '
The present s tudy r e p r e s e n t s an extension of the work in i t i a t ed
e a r l i e r in t h i s l a b o r a t o r y and is d i r ec t ed to exp lo re the con t racep
t ive efficacy of o the r s impler he te rocyc les possess ing only one phenyl
r i ng . The s t r e s s on having a single phenyl r ing in the molecular
framework of s imple r he t e rocyc l e s is based on the assumption tha t
tw.o phenyl r ings in s imple r he te rocyc les at h igher doses may lead
to o e s t r o g e n i c i t y . In view of these c o n s i d e r a t i o n s , the syn theses
and the evalua t ion of con t r cep t ive efficacy of p r o t o t y p e s I-VI were
under taken .
u ni
«^a?r
R'=H,Ac VI
11
Another approach in the present s tudy for obtaining second
generat ion con t racep t ive agents r e l a t e s to the design of compounds
which simulate two d i s t i nc t type of pharmacophores in t h e i r molecular
s t r u c t u r e s ; the f i r s t one i s concerned with i t s a b i l i t y to a l t e r mem
brane pe rmeab i l i t y whi le the second one i s concerned with i t s capa
b i l i t y to in te r fe re ox ido- reduc t ion p r o c e s s e s . The choice of these
pharmacophores i s based on the assumption tha t compounds capable
of e l i c i t ing these a c t i v i t i e s in uterus would lead to inh ib i t ion of
pregnancy. A s i tuat ion such as t h i s would generate f resh l eads and
th i s approach a p p e a r s to have not been employed by e a r l i e r w o r k e r s .
In the present s tudy two r e p r e s e n t a t i v e c l a s s of compounds namely
1 . 2 , 3 , 4 - t e t r a h y d r o q u i n o l i n e d e r i v a t i v e s (VII) and 1 ,4 -d ihyd ro p y r i d i n e
d e r i v a t i v e s (VIII) have been ident i f ied for s y n t h e s i s and biological
evaluat ion as a n t i f e r t i l i t y agen t s .
V Me O2 C V . ^ / > V ^ C 0 2 M G
.CO2MG H
•Ms
vn vni
CHAPTER 2
2.1 ; Syntheses of 2-oxo-5-substitutedphenyl tetrahydrofurans,
5-Substituted phenyl-2,3-dihydrofuran-2-ones and 6-oxo-
3-substitutedphenyl-l ,4,5 ,6- tetrahydro-lH-pyridazines
2.2 : Syntheses of 4-Arylidine-3-methyl-4,5-dihydroisoxazolin-
2-ones and 4-(3 ,4-Dimethoxybenzyl )-3-niethyl-2 ,3 ,4 ,5 -
tetrahydroisoxazolin-5-one
2.3 : Syntheses of 5-Substitutedphenyl-2-isoxazolin-5-ones and
3-substitute dp henyl-5-methyli so xazoles
2.4 : Synthesis of 2,5-Dimethyl-3-niethoxycarboxyl-4-( 3-cyano-
2-oxo-l ,2,3 ,4-tetrahydroquinolino)furan
2.5 : Syntheses of 2,6-Dimethyl-3,5-ditnethoxycarbonyl-4-substi-
tuted-1,4-dihydropyridines
12
CHAPTER - 2
2.1 Substituted aroyl propionic acids (jL.- ) were identified as
the starting materials for the syntheses of compounds belonging to
prototypes I-III . Benzoyl propionic acid (Jl ) was easily prepared
by the Friedel-Craft reaction of benzene with succinic anhydride
I II m while 4-( 3-nitrophenyl)-4-oxo butyric acid (2) was obtained by the
nitration of \_ with fuming nitr ic acid. Esterification of these acids
with dry methanol in presence of BF -etherate furnished the methyl
esters (3^-^) which on reduction with sodium borohydride gave a
mixture of 4-hydroxy-4-substituted phenyl butyrates (^-^) and 2-
oxo-5-substituted phenyl tetrahydrofurans (Z"^' Scheme 1) . These
were separated by column chromatography over silica gel using chlo
roform, hexane (1:1) as the eluent. The dehydro derivat ives of
7 -8 , the second prototype of the present study, were obtained by
the ring closure of 2"*. with acetic anhydride (9-10; Scheme 1).
Similar ring closure of 2.~JL with hydrazine hydrate furnished 11-
12, the representatives of prototype III (Scheme 1).
2.2 Compounds representing the molecular framework of prototype
IV were prepared by reacting appropriate aromatic aldoximes (19-
24) with methyl acetoacetate in methanol
(Scheme 2 ) . The resulting compounds
(25-30) were obtained as non-separable
mixture of Z and E isomers. The stereo-
meric mixture was evident from the
PMR spectrum which indicated the p re
sence of two singlets for ethylenic proton at around 8.50 - 9.00
ppm.
One representative compound of prototype IVa was prepared
by the sodium borohydride reduction of the benzylidene derivative
CH3
13
CO2H
1:R = H 2:R=N02
C02Me
1:R=H j4;R=N02
CO^MG
5:R=H 6;R=N02
9:R=H 10:R= NO2
ri:R=H 12;R=N02
7:R=H 8.:R=N02
a,Dry MeOH/BF3cth2ratG; b,NaBH4/M<20H; c,Ac20; d,NH2NH2H20/MeOH
ScherriG 1
14
13R=H
14:Rr3,4-diOMe
1 5 . R = 4 - O H - 3 - O M G
16.R=4-NH2-3-N02
17:R=4-NHAc
18.R=4-NH2
a •> R
19-24
Substitucnt R
as in 13-18
Mc
Substituent R
as m 13-18
2 6 . c
OMe
6 OMe
M2 HH^'
HH^ O
H
31
a, NH2OH / McO H; b, AcCH2C02Me / MeOH;
c ,NaBH4/M20H
Scheme 2
15
26 in methanol (Scheme 2 ) . The compound 31^ so obtained was a mix
ture of isomers, which could not be separated by preparat ive TLC
or column chromatography.
2.3 A retro-synthetic analysis for obtaining compounds repre
senting prototypes V and VI suggests the preparation of starting
materials of the type A (Fig. A), which in turn can be obtained
V:R = H,Ac VI
from tetrasubstituted furans (B). Since substantial quantity of tetra-
substituted furans were available in the laboratory, efforts were
directed to obtain compounds of the type A from these furans (B).
Oxidation of substituted furans (C) have been reported earl ier to 33 34 yield oC,|3-unsaturated ketones (D; Fig.A) ' . In the present study
it was observed that the oxidation of 3-methoxycarbonyl-2,5-dimethyl-
4-substituted phenyl furans (32-36) with pyridinium chlorochromate
gave compounds which exhibited sixteen mass units more than the
expected mass of 0(,/3-unsaturated ketones (G). The ir spectra of
these compounds showed carbonyl bands at around 1660, 1720 and
1760 cms . The nmr spectra indicated the presence of two acetyl
groups and one methoxy group besides the required aromatic protons.
On the basis of these data, three tentative structures E, F or H
may be proposed for these oxidation products. Structures E and
F were ruled out on the basis of C-nmr spectra of the oxidation
products. The two quaternary carbon atoms of three membered ring
in E and the quaternary sp carbon atom in F are expected to appear
between 65-70 ppm but the C-nmr signals for the two quaternary
carbon atoms at around 160 ppm and the absence of any peak between
65-70 ppm supported the structure H (37-41; Scheme 3) . Since these
compounds were the enol acetates of the desired starting material
(A), they were reacted with aqueous acid . Instead of the desired
ketones (A; R = OMe) substituted acetophenones 42-46 were obtained.
The possible mechanism by which these compounds (37-41) broke
down to substituted acetophenones is described in Scheme 4. The
16
R- s COCH3
COR'
O
.1 A R = O M G . M ( 2
R COR'
B R^rOMG. Me
'f v . . o
SR' FCC
•^ ^^^o o^^^^
D
R- s O.
H3COC COR^
E R ' ^ = O M G , M 2
COCH3 R
COCH3 COCH3 CORI
O
.1 FR'=OMe,Me
COCH3
C02M(2
COCH3
G
Fig A
17
Rv ^C02Me PCC
}2_
li 36
Rv /COM(2
CH2CI2 M G O C O Q'Z^OMe - >
37-41
Subst i tuent R as in 32-36 R = 3 ,4 -d ime thoxypheny l
R = 3 ,4 -methy lened ioxypheny l
R = 4-methoxyphenyl
R = 4 -e thoxy-3 -me thoxy-pheny l
R = 4 -benzy loxy-3 -me thoxy-pheny l
(Scheme 3)
R
O
Me 42-46
Substi tuent R as in 32-36 47
CO2MG
R ,C0M(2
H / Me
Rv R h—Me
O^ O
-CO2
C02Me O C02Me
(Scheme 4)
18
c o n v e r s i o n of 2 * °^ a c t i v a t e d s u r f a c e to jn[^ p r o v i d e d a d d i t i o n a l e v i
d e n c e fo r t h e p r o p o s e d m e c h a n i s m . T h e s t e r e o c h e m i s t r y of 37 -41
h a s b e e n w o r k e d ou t b y c o m p a r i n g PMR s p e c t r a of t h e s e c o m p o u n d s
w i t h t h e s p e c t r a of STj-bl^ ( T a b l e 8 , p a g e 54 ) . The d o w n f i e l d s h i f t
of t h e -OCOCH s i g n a l s in 37-41 i s o n l y p o s s i b l e if t h e a c e t y l g r o u p 35
a t C-4 a n d m e t h o x y c a r b o n y l a t C-3 a r e o r i e n t e d in a c i s g e o m e t r y
T h e r e a c t i o n of o x i d a t i o n p r o d u c t s ( 3 7 - 4 1 ) w i t h h y d r o x y l -
amine h y d r o c h l o r i d e in me thano l f u r n i s h e d one of t h e p l a n n e d c o m p
o u n d s (R = H) of p r o t o t y p e V (Scheme 5 ) . T h e f a c i l e l o s s of t h e
COCH g r o u p e v e n a t m i l d e r r e a c t i o n c o n d i t i o n s p r e v e n t e d t h e p r e p a -^ 1
r a t i o n of o t h e r c o m p o u n d s (R = COCH ) of t h e p r o t o t y p e V. A d d i
t i o n a l e v i d e n c e for t h e a s s i g n e d s t r u c t u r e s ( 4 8 - 5 1 ) w a s o b t a i n e d
b y an u n a m b i g u o u s s y n t h e s i s of one of t h e r e p r e s e n t a t i v e compound
(49) b y r e a c t i n g 47 w i t h h y d r o x y l a m i n e h y d r o c h l o r i d e .
X - a
32 li 11 40
:
:
:
.
R
R
R
R
3 , 4 - d i m e t h o x y p h e n y l
3 , 4 - m e t h y l e n e d i o x y p h e n y l
4 - m e t h o x y p h e n y l
4 - e t h o x y - 3 - m e t h o x y p h e n y l
48-51.
S u b s t i t u e n t R a s in 37 -40
a , NH^OH/MeOH
(Scheme 5 )
T h e c o m p o u n d s b e l o n g i n g to p r o t o t y p e VI n a m e l y 3 - s u b s t i t u t e d -
p h e n y l - 5 - m e t h y l i s o x a z o l e s ( 6 2 - 6 5 ) w e r e p r e p a r e d b y r e a c t i n g 4 -
a c e t o x y - 3 - a c e t y l - 4 - s u b s t i t u t e d p h e n y l b u t - 3 - e n e - 2 - o n e s ( 5 7 - 6 1 ) , o b t a i n
e d b y t h e p y r i d i n i u m c h l o r o c h r o m a t e (PCC) o x i d a t i o n of 3 - a c e t y l -35
2 , 5 - d i m e t h y l - 4 - s u b s t i t u t e d p h e n y l f u r a n s ( 5 2 - 5 6 ) , w i t h h y d r o x y 36
l a m i n e h y d r o c h l o r i d e in m e t h a n o l ( S c h e m e 6 ) .
19
R ^ .COCH3 a
R COCH3
M H3COCO COCH3
52 : R = 3 ,4 -d i ine thoxyphenyl 57 : R = 3 ,4 -d ime thoxypheny l
53 : R = 3 ,4 -me thy lened ioxy phenyl
58 : R = 3 ,4 -methy lened io-xypheny l
54 : R = 4-methoxyphenyl 59 4-methoxyphenyl
55 4-e thoxy-3-methoxy-phenyl
60 : R 4 -e thoxy-3-metho-xypheny l
56 : R = 4 - b e n z y l o x y - 3 -methoxyphenyl
61 4 - b e n z y l o x y - 3 -methoxy phenyl
62 : R = 3 ,4 -dimethoxy
63 : R = 3 ,4-methylenedioxy
64 : R = 4-methoxy
65 : R = 4-ethoxy-3-methoxy
a, PCC/CH^Cl^; b , NH^OH/MeOH
(Scheme 6)
20
This faci le loss of two carbon atoms from 4-ace toxy-3 -me thoxy-
c a r b o n y l - 4 - s u b s t i t u t e d phenyl bu t -3-ene-2-ones under ac id ic and bas ic
condit ions p r o v i d e d temptat ion to s tudy the behaviour of t h i s c l ass
of compounds under e lec t ron impact . Since t h i s c lass of compounds
is nove l , i t s chemical r e a c t i v i t y and behaviour under e lec t ron impact
a re expec ted to con t r ibu te towards the ex i s t i ng knowledge in t h i s
f i e ld . Only the r e s u l t s of the mass spec t romet r i c s tudy a re d e s c r i b e d
h e r e . The EI and CI behaviour of t e t r a s u b s t i t u t e d e thy lenes (37-
40, 57-60) under pos i t i ve and negative ionizat ion condi t ions employing
techniques such as co l l i s ional ac t iva t ion (CA), metas table scan , exact 37 mass measurements and D^O CI have been s tud ied . The pos i t i ve
ion EI, p o s i t i v e ion CI (CH ) and negat ive ion EI spec t r a of ^
and ^ a re shown in F i g . l and 2 . The metas table t r ans i t ions o b s e r v e d
under p o s i t i v e ion EI condit ions by high voltage scan a re a lso i n d i
ca ted in the EI s p e c t r a of ^ and 3^ (F ig . la and 2 a ) . The molecular
ions are not suff ic ient ly s t ab le to give intense M peaks and they
fragment by loss of CH CO and CH CO. A / - h y d r o g e n rearrangement
followed by the t rans fe r of the acy l group from C to C cou ld
lead to a s t ab l e (M-CH CO) ion (Scheme 7 ) . In the compounds 57-
60, the (M-CH CO) ion decomposed by the loss of r a d i c a l s such
as CH^*, CH^CH^*, HO". CH^O* , CH^CH^O" and CH^CO' whi le in the
compounds 36-39 loss of CH CO from M ' induce fur ther loss of neu
t r a l molecules (CH OH and CO) as shown in Scheme 8. A c h a r a c t e r i s
t ic difference i s o b s e r v e d in the p recu r so r ion s p e c t r a of the a roy l
ion in two groups of compounds (57-60 and 37-40) . The major p r e c u r
sor for a roy l ion in 57-60 is the (M-CH COCH ) ion, whi le in 2 1 "
40 arCO"^ i s formed mainly from (M-CH CO-CH OH) ion (Scheme 8 ) .
Metastable t r ans i t i ons were a lso o b s e r v e d for the d i r ec t decomposi
t ion of the (M-CH CO) ion to ArCO in a l l t he compounds thus su
ppor t ing the generat ion of a carbonyl function on C by the t ransfer
of the acyl group during the loss of CH CO from M .
The CA fragmentation pa t t e rn of the s t ab l e M " r e sembles
the 70 eV EI induced fragmentation of the molecule. However, the
r e l a t i v e abundances of the fragment ions a r e different in the two
s p e c t r a . This difference i s a t t r i b u t a b l e to the difference in the
r e a c t i v i t i e s of the decomposing and non-decomposing M ' ions due
to t h e i r having di f ferent s t ruc tu re s ' . The (M-CH CO)* ion gives
r i s e to the base peak in the CA s p e c t r a , wh i l e the most Intense
24
CH30 CH30
0 nu II ^^
OCH3 - C H j C O * ^ " ' ' ^ " Y ^ \ ° « = " 3 ~'^'^3°" , O'"'
COCH3
5 , M —
m / i 292
-CH3C0
( M - C H j C O ) '
m/z 2S0
•/-CH3 •^
OCH3
(Scheme 8)
25
ion in the normal" EI s p e c t r a is ArCO . This i s unde r s t andab le as
the a roy l ion i s produced in the source from seve ra l p r e c u r s o r s
such as (M-CH^CO)"^, (M-CH CO-CH )"*• and (M-CH^CO-CH CO)"^.
As obse rved from CI(CH ) spec t r a of 57-60 and 37-40, a p a r t
from MH and (M-H) ions , the major fragment ions a r i s e by the
loss of neutra l molecules such as CH CO. CH CO H and CH O (Scheme
9 ) . The methyl e s t e r s 37-40 a r e c h a r a c t e r i s e d by the presence of
peaks corresponding to (MH-CH CO-CH OH)"*" and (MH-CH CO H-CH OH)"^.
The CI ( D O ) spec t r a of t he se compounds show (MD-CH CO)"^ and
(MD-CH CO H) ions indicat ing t h e r e b y that proton a d d e d is not
lost in these p r o c e s s e s . Moreover , metastable peaks cor responding
to these losses a re a lso o b s e r v e d in the CI(D O) s p e c t r a (Table
1 ) . The re tent ion of D in the el iminat ion ion ind ica tes t ha t a mecha
nism such as the one shown in scheme 9 opera tes for loss of ace t ic
ac id resul t ing in a cyc l i s ed p roduc t . In the methyl e s t e r s 37-40
the fur ther fragmentation of t h i s ion r e s u l t s in the loss of CH CO,
Yet another noteworthy feature in the CI spec t ra of these compounds
i s the presence of (M+43) i ons , p resumably due to se l f - acy la t ion 40
reac t ion . The acy l ion is produced from the sample i t se l f as a
r e su l t of which the (M+43) ion abundance increases when the sample
p r e s s u r e inc reases or when acetone i s used as the reagent for CI .
With ace tone-d , both (M+CH,CO)"^ and (M+CD,CO)"^ a re o b t a i n e d . The
(M+CH CO) ion is found to decompose by the loss of CH CO giving
r i s e to MH ions (Scheme 10b ) . A metastable peak i s seen at m/z
240.5 in CI (ace tone , CH or D O ) spectrum of ^ cor responding
to t h i s decomposi t ion.
The CA spectrum of the MH"*" and CI(CH spect rum of 59^
show cons iderab le difference in the r e l a t i v e abundance of the fragment
ions (Table 2 , F i g . l ) . Loss of H from MH (Scheme 10c) l eads
to the most abundant ion in the CA spec t rum, whi le (MH-CH CO)
g ives r i s e to the base peak in i t s CI(CH ) spec t rum. The (MH-Ar-
COCH ) ion i s ve ry prominent in the CA spectrum showing t h e r e b y
tha t the acyl migration i s an important p rocess even under CA condi
t i o n s .
As in the case of p o s i t i v e ion EI s p e c t r a , t he molecular
ions in the negat ive ion EI s p e c t r a a re a lso not v e r y abundant excep t
in iM and 40. However, in the e lec t ron cap ture spectrum of 59 (rvin
26
CH30
C H 3 0 - > f « ^ " V ^ O-COCr.3
3 , M H ' m/2 307
-CH2CC cm
(Mh-CM2C0)* rr./j 265
OCOCH3
C H 3 0 - ^ ^ ^ \ J ^
3 .MH+ m/z 307
CH3O
( M H - C H , C 0 2 H ) m/ z 2 i T
7,(MH-CH2CO) m / i 261
0 I
^ ^ - C H 3 -CH3OH O s C v - ^ O H
7 — * CHaOYTy^O
CH3O'
rr.'i 2iS
_Ch, -CH3OH CH30
CH3O
7 . ( M H - C H 3 C C : -
rr .'7 263
(Scheme 9)
27
T a b l e 1; M e t a s t a b l e P e a k s O b s e r v e d in t h e D O CI S p e c t r a of ^ ,
^ , 2 7 a n d 3 9 .
Compound T r a n s i t i o n m
o b s d C a l c d
52 MD' (MD-CH CO )'^ 199 .8 1 9 9 . 7
m/z 248+60)
58 (M+CH,CO) ' MH"^ 2 4 0 . 5 2 4 0 . 5
MD"*"
( rn /^ 308
(M+CH CO)"^
(m/z_
MD"
(m/z_
MD"
(m/z_
MD"*"
( m / z
319
278
324
324
m/z 277+42)
59 MD' (MD-CH CO)"^ 2 0 0 . 5 2 0 0 . 3
m/z 236+42)
1 2 MD' (MD-CH CO)"^ 2 4 5 . 5 2 4 5 . 4
m/z_ 282+42)
(MD-CH CO^H)"*" 2 1 5 . 0 2 1 5 . 0
ni/_z 264+60)
(MD-CH CO H)"^ (MD-CH CO H- 2 0 2 . 3 2 0 2 . 1
CH^OH)"^
(m/z 264 m/z 231+33)
39 MD"^ (MD-CH CO)"^ 216.0 216.0
(m/z 294 m/z 252-42)
28
CMj.
M j ^ O C « , ^ CH, 0
'4- ~ 0CH3
1
OCOCH3
m/i 07
0 ^ ». 0
1 i: 1:
CH3COO COCH3
CH3O CH3
m/2 2 77
-H2
CH3O
(MH -M j ) mjz 275
(C)
iScheme 10)
29
T a b l e 2 : Ion A b u n d a n c e s ( I ) in t h e CA S p e c t r a of 59
m/z_ P E I , M"*", P C E ( C H J . M H " * " NCI ( C H ^ ) , M '
ra/z 276 m/z 277 m/z 276
35
28
43
44
59
77
83
85
92
107
108
109
121
127
135
141
149
158
159
161
175
177
191
201
203
215
216
217
219
233
234
235
261
275
30
—
—
14
—
—
12
—
15
—
—
—
50
—
16
—
15
—
—
13
20
—
24
—
—
18
26
45
100
—
—
._
20
25
15
18
15
44
10
13
18
35
50 14
26
26.3
15
20
12
23
13
38
54
16
18
30 100
30 31
45 25
25
100
30
CO2M2
under CI(CH,) condit ions) the base peak i s due to M * . Fragmentation 4
occurs mainly by the loss of CH^CO* , CH^CO^H, (CH^CO^H+'H) or
(CH CO H+CH ) as shown in scheme 1 1 . Similar fragmentation pa t t e rn
of the M ' of 59^ i s also o b s e r v e d under col l i s ional ac t iva t ion (Table
2 ) . The methyl e s t e r s 37-40 fragment less r a p i d l y than ST-bO^. The
presence of ace toxy group in these molecules r e s u l t s in the formation
of abundant ace toxy ion, a t m/z 59 which g ives r i s e to the base
peak in the spec t r a of 57-60 (M-ArCO) is a c h a r a c t e r i s t i c fragment
obse rved in t h e i r s p e c t r a . It i s in te res t ing to note tha t the comple
mentary fragment ion, ArCO , g ives r i s e to in tense peaks in the
pos i t i ve ion s p e c t r a . An acyl group migrat ion from C to C as under
pos i t i ve ion condit ions would exp la in the formation of (M-ArCO)
ion (Scheme 11) . This rearrangement ion is a l so o b s e r v e d under
col l i s ional ac t iva t ion of the M * (Table 2 ) .
2 .4 The s y n t h e s i s of p ro to type VII involves Nef react ion of 2-
n i t r o - l - ( p - a c e t a m i d o p h e n y l ) Propene
(66) as the f i r s t s t e p . The r e s u l
ting compound namely 3-methoxy-
carbonyl -2 , 5 -d ime thy l -4 - ( p - a c e t a - iN^ '
midophenyl) furan (6^) was sub jec - M G — ^ V'~~-M<2
ted to v i l smier -Haak reac t ion and
the formyl d e r i v a t i v e {66) so VII
obta ined on oximation gave 69^ which was then reac ted with SOCl
to y i e ld 7^. Sodium b o r o h y d r i d e reduc t ion of ^ in methanol furnished
d e s i r e d compound ^ 1 (Scheme 12) .
2 .5 Compounds represen t ing p ro to type VIII (79-86) were p r e p a r e d
by reac t ing a p p r o p r i a t e l y subs t i t u t ed a l d e h y d e s (72-78 and bS^) wi th
methyl-3-aminocrotonate in presence of a p p r o p r i a t e so lvents (Scheme
13) . In o r d e r to change R in comp
ounds 79-86, two s t r a t eg i e s have
been employed . In the f i r s t one
a p p r o p r i a t e a l d e h y d e s were gene
r a t e d and in the second one , a p p
r o p r i a t e funct ional i t ies on the
phenyl r ing of 2 ,6 -d ime thy l 3 , 5 -
dimethox year b o n y l - 4 - p h e n y l - 1 , 4 - d i h y
d r o p y r i d i n e were simulated for e l abora t ing them to h e t e r o c y c l i c r ing
s y s t e m s .
31
0
OCOCHj
0CM3
C"3 0 ^ « « ^ 3
-COCH3 -CH3CO2H
^**3^^°~ C H 3 \ / 0 C H j v ^ O
6 Jk * 0 ^ " ° COCM3
(Scheme 11)
32
"""10 M G - ' ^ N 0 2
66
a
CO2MG
M G
\^
a , CH COCH2C02CH^, Et^N/MeOH; b , DMF/POCl^; C , NH^OH/MeOH;
d , SOCK/Benzene; e , NaBH./MeOH 2 4
(Scheme 12)
33
R-CHO
72-78 k 68
V M G ' N
H
79-86
^Me
72 : R = 4 'Ch lo ro -3 -n l t ropheny l
73 : R = 4-acetainidophenyl
74 : R = 4-amino-3-n i t rophenyl
75 : R =
CHO
4-ch lo ro -3 -n i t ropheny l
4-acetamidophenyl
29 : R
80 : R
81 : R = 4-amino-3-n i t rophenyl
82 : R =
R^ R' R' = M ( 2 , R 2 = C 0 2 M G
76 : R =
77 : R
N - ^ C I
H H OH OH
OH OH H H
''••''- 0 C X CI
H H OH OH
-CH2OH 3, ^ , ^ -CH2OH
OH OH H H
78 : R = 85
86 : R =
a , Me thy l -3 -aminoc ro tona te / app rop r i a t e solvent
(Scheme 13)
M G - ^ ^ O
34
Appropriately substituted aldehydes were prepared as follows:
Nitration of 4-chloroben2aldehyde with cone. UNO gave
72 while 2-chloro-3-formyl quinoline {Tb), obtained by vilsmier-
Haak reaction of acetanil ide, was reacted with sodium azide to obtain
78 (Scheme 14).
o 76
a, DMF/POCl ; b , NaN 78
(Scheme 14) In order to build heterocyclic ring systems on the phenyl
ring of 2 ,6-dimethyl-3 ,5-dimethoxycarbonyl-4-phenyl-l ,4-dihydro
pyridine, the compound ^ was hydrogenated in presence of Raney-
nickel to obtain the corresponding diamine (90; Scheme 15) and
a
H , Raney-Ni/MeOH
90
(Scheme 15)
the methanolic solution of compound 72 was reacted with aqueous
methylamine and aqueous ammonia under pressure to yield ^ and
89 respect ively. Reaction of 72^ with benzylamine at atmospheric
pressure yielded 88 (Scheme 16).
35
M G 0 2 C
79
NO2
C02Me a
• ^
NO2
MG 02C\^'^^\X02M(2
87
88
89
a. Appropr i a t e amine
(Scheme 16)
MG-H
' M G
R = NHCH
R = NHCH^Ph
R = OH
Ring closure in 90 was evoked ei ther by reac t ing i t with
substituted benzaldehydes in presence of acetic acid (91-95; Scheme
17) or by reacting it with sodium nitrite in p resence of aqueous
acetic ac id . The latter y ie lded 9b^ (Scheme 17) . Synthes i s of a
9 0
HN-N \ \
MGO2C CO2MG
H 92
93
94
95
Substituted benzaldehydes/AcOH;
(Scheme 17)
R = Phenyl
R = p-methoxyphenyl
R = 3 ,4-dimethoxyphenyl
R = 4-methoxy-4-hydroxy-phenyl
R = 3 ,4-methylenedioxy-phenyl
b , NaNO^/aq. AcOH
36
compoxind ^ structurally related to prototype VIII, v/as achieved
by reacting ^ with benzil in presence of methanol (Scheme 18)
whereas the reactioft of 9£ with carbon disulfide yielded ^ (Scheme
18). The tetracyclic heterocycle ^ was obtained by refluxing metha-
nolic solution of 90^ with phthalic anhydride (Scheme 18).
M ( 2 0 2 C \ ^ > \ / C 0 2 M G
CO2MG
99 9 8
a, Benzil/MeOH; b , CS ; c .Phthall ic anhydride/MeOH
(Scheme 18)
37
CHAPTER - 3
EXPERIMENTAL
3.1 The melting points were determined on a sulphuric acid
or an electrically heated block and are uncorrected. All the reactions
were checked by thin layer chromatography over silica gel G or
alumina (basic or neutral) plates using iodine vapours. KMnO spray
or Dragendorf's spray as the developing reagent. The structures
of all the compounds were routinely checked by IR and PMR Spectro-
scopy-IR spectra were recorded on Perkin-Elmer 157 infracord and
Beckman Acculab-1 grating instruments and values are expressed in
cm . PMR spectra were recorded on varion EM 360L or Perkin-Elmer
R-32 using TMS as internal reference (Chemical shift in ppm).
C-NMR spectra were recorded on CFT-20 spectrometer operating
at 20 MHz, 8192 data points were collected and a sweep width of
5000 Hz was used. Pulse delay of 0.5 sec. was essential for record
ing the signals of carbonyl carbons. N-NMR spectrum was recorded
on a Bruker WM-400 FT NMR spectrometer using formamide as the
reference. Mass spectra of these compounds were recorded on Jeol-
D 3000 instrument. The second place after the decimal point in the
required value of C,H,N analyses have been approximated.
jg-Benzoyl propionic acid (1)
This compound was essentially prepared by the method re-
ported earlier
p-O-Nitrobenzoyl) propionic acid (2 , Table 3)
To fuming HNO (d; 1.54, 20 ml) held at 0°C was added
2. (5 gm) in portions to prevent the reaction temperature to rise
above 8-10°. After complete addition of the compound it was stirred
at the same temperature (8-10°) for an additional 1 hr. The reaction
mixture was then poured on to crushed ice under stirring. The sepa
rated solid was filtered and washed with ice-cold water ('^5°).
The compound (2 ) was dried and recrystallized from minimum ethanol.
Methyl-4-substituted^phenyl-4-oxo-butyrate {y-±. Table 3)
A solution of 1_ or 2 (5 gm) in methanol (20 ml) and BE -
etherate (0.1 ml) was refluxed for 3 hrs. After completion of the
reaction, water was added to the reaction mixture and extracted
38
with e t h y l a c e t a t e . The organic l aye r was washed with water t h r e e
t i m e s , d r i e d on anhydrous sodium su lpha te and removed under reduced
p r e s s u r e . The r e s idue on t r i t u r a t i o n with hexane gave the d e s i r e d
compound ^ o^ i_ which was r e c r y s t a l l i s e d from e t h a n o l .
Methyl -4 -hydroxy-subs t i tu ted^pheny l butyrate (5 -6 . Table 4) and
2-oxo-5-subst i tuted phenyl tetrahydrofuran (X"8.» Table 5)
To a solut ion of 3_ or 4 (0.01 mole) in methanol (8 ml) was
added sodium b o r o h y d r i d e (0,02 mole) in por t ions under cooling
(0-5°) and s t i r r i n g . The reac t ion was al lowed to continue at the
same tempera ture for 20 mts . The react ion mixture was then d i lu ted
with water (20 ml) and e x t r a c t e d with chloroform (50 m l ) . Usual
work up of the organic l aye r y ie lded a mixture (^-6^ and T_-B) which
was s e p a r a t e d by column chromatography over s i l i c a gel using a
mixture of ch loroform, e t h y l a c e t a t e (80:20) as e luen t . The comp
ounds ^-6^, ob ta ined as c r y s t a l l i n e , s o l i d s , which were r e c r y s t a l l i s e d
from chloroform-hexane mixture whi le compounds 7^-|[ were o i l s .
5-Substituted phenyl-2,3-dihydTofuran-2-one (9-10)
A mixture of ^ or 2 (0.01 mole) and ace t ic a n h y d r i d e (0.04
mole) was re f luxed for 3.5 h r . After removal of the solvent under
reduced p r e s s u r e , water (20 ml) was added to i t and e x t r a c t e d with
e t h y l a c e t a t e . Usual work up y ie lded dark r e d so l id which was
pur i f i ed by column chromatography over s i l i c a gel using chloroform-
e t h y l a c e t a t e mixture as the e luen t . The compounds 9-10 so ob ta ined
were r e c r y s t a l l i s e d from chloroform-hexane m i x t u r e .
Yield 70%; m . p , 82-83" ; M" at m / i 160
IR (KBr)
PMR (CDCl^)
So»8°2
11 IR (KBr)
PMR (CDCl^)
CioHyNO^
1800 (CO)
3 .36-3 .38 (d ,2H,CH2) , 5 .68-5 .74 ( t , IH, CH),
7 .25-7 .63 (m, 5H, Ar-H) .
Requ i r e s : C, 75.00; H, 5.00
Found: C, 74.62; H, 4.81
Yield 65%; m . p . 105°; M" at m/z 205
1790 (CO)
3 .44-3 .46 ( d , 2H, CH^). 5 .91-5 .97 ( t , IH, CH),
7 .42-8 .33 (m, 4H, Ar-H)
Requ i r e s : C, 58 .53; H, 3 . 4 1 ; N, 6.82
Found: C, 58.70; H, 3 .88 , N, 6.60
39
6-Oxo-3-subst i tuted'^phenyl- l ,4 ,5 ,6- tetrahydro- lH-pyridazine (11-12)
To a solut ion of 2 °^ A (0-01 mole) in methanol (5 ml) was
added hyd raz ine h y d r a t e (0.02 mole) and s t i r r e d at room tempera ture
(25°) for 1.5 h r . Addi t ion of water (10 ml) to the reac t ion mixture
y ie lded 11 or JJ^ as so l id which was r e c r y s t a l l i s e d from hot metha
nol .
Yield 65%; m . p . 120-21°; M" at m/z 174
1680 (CO) 11 '• IR (KBr) :
PMR (CDCl ) :
S0«10N2°
12 :
IR (KBr) :
PMR(CDCl,+DMSO-d, ) : i 0
SoV3°3
2.40-2 .98 (m, 4H, ZxCH^), 7 .20-7.70
5H, Ar -H) , 9 .12-9.40 ( b s , IH, NH)
Requi res : C, 68.96; H, 5.74; N, 16.09
Found: C, 69 .21 ; H, 5 .98; N, 15 .84.
Yield 60%; m . p . 160°; M" at m/z 219
1680 (CO)
(m.
2 .40-2 .60 ( t , 2H, CH^) . 2 .98-3 .19
CH ) , 7 .55-8.21 (m, 5H, Ar-H & NH)
Requi res : C, 54.79; H, 4 ,10; N, 19.17
Found: C, 54.90; H, 4 .45 ; N, 1 8 . 9 1 .
( t . 2H,
Table 6) Aryl id ine-3-methyl -4 ,5-dihydro- i soxazol in-5-one (25-30,
To a solut ion of the r e q u i r e d oxime (19-24; 0.01 mole) in
methanol (10 ml) was added methyl ace toaceta te (0.02 mole) and
ref luxed for 3 h r . Solvent was removed under reduced p r e s s u r e and
the r e s idue was t r i t u r a t e d with water (20 ml) to y ie ld the r e q u i r e d
compound (25-30) as so l id which was r e c r y s t a l l i s e d from aqueous
methanol .
4-(3 ,4-Dimethoxybenzyl ) -3- inethyl -2 ,3 ,4 ,5- te trahydro- i soxazol in-5-one
(31.)
To a suspens ion of £6 (2:47 gm, 0.01 mole) in methanol
(10 ml) was added NaBH (0.57 gm, 0.015 mole) in por t ions vmder
s t i r r i n g and cooling ( 5 - 1 0 ° ) . It was s t i r r e d at the same tempera tu re
for 1.5 h r . Water was a d d e d to the reac t ion mixture and e x t r a c t e d
wi th e t h y l a c e t a t e . Usual work up of the organic l a y e r y i e lded a
r e s idue which on t r i t u r a t i o n wi th petroleum benzene furnished 31
as a c r y s t a l l i n e s o l i d . This was r e c r y s t a l l i s e d from c h l o r o f o r m - p e t
roleum benzene m i x t u r e .
21 IR (KBr)
PMR (CDCl^)
40
Yield 55%; m . p . 130°; M" at m/z 251
1738 (CO)
1.93-1.98 (m, 3H, 3H^), 3 .00-3.90 (m, lOH,
CH , 2XCH, 2X0CH^). 6 .50-6 .98 (m, 4H, Ar
il , NH)
C , , H , , N O , : Requi res : C, 62 .15; H, 6 .77; N, 5.57 13 17 4
Found: C, 62 .48; H. 6 . 3 1 ; N, 5.81 2 , 5 - D i m e t h y l - 3 - m e t h o x y c a r b o n y l - 4 - s u b s t i t u t e d ; ^ p h e n y l furans (32-36) .
Table 7)
To a suspension of a p p r o p r i a t e n i t r o s ty r ene (0 .01 mole)
in methanol (10 ml) was added t r i e thy lamine (0.02 mole) and methyl
ace toace ta te (0.02 mole) under s t i r r i n g and cooling ( 5 - 1 0 ° ) . After
15 minutes the react ion mixture was a l lowed to come to room temp
e r a t u r e (25°) and the s t i r r i n g was continued for 24 h r . Removal of
solvent under reduced p r e s s u r e at 25°C was followed b y the addi t ion
of wate r (20 ml) and the react ion mixture was fur ther s t i r r e d at
room tempera tu re for 1 h r . The s e p a r a t e d so l id was f i l t e r e d , washed
with w a t e r , d r i e d and r e c r y s t a l l i s e d from chloroform-hexane mix tu re .
4 -Ace toxy-3 -me thoxyca rbony l -4 - subs t i t u t ed '^^^ pheny l bu t -3 -ene-2-ones
(37-41,, Table 8)
To a well s t i r r e d solution of t e t r a s u b s t i t u t e d furan (32-
36, 0.01 mole) in d r y dichloromethane (50 ml) was added pyr id in ium
chlorochromate (0.04 mole) and the reac t ion mixture was s t i r r e d
at room tempera tu re (30°) for 10 h r . It was then d i lu ted with e the r
and the organic l aye r was pas sed through a column of s i l i c a ge l .
The column was f ina l ly e lu ted with chloroform-hexane (1:2) and
the usual work up of t h e organic l ayer y i e lded the d e s i r e d compounds
(37-41) as s o l i d s excep t 2*. * 21. which were o i l s . The so l id comp
ounds (2Z» .*?. * Ai) were r e c r y s t a l l i s e d from chloroform-pet ro leum
benzene.
Subs t i tu ted acetophenones (42-46)
To a solut ion of subs t i t u t ed bu t -3 -ene-2-ones (37-41; 0.5
gm) in methanol (1 .5 ml) was a d d e d aqueous h y d r o c h l o r i c ac id (10%,
0.5 ml) and the mixture was ref luxed for 2 h r . The solvent was
removed and the r e s idue was e x t r a c t e d wi th ch loroform. The usual
work up of organic l aye r gave t h e r e q u i r e d acetophenones ( 42 -46) .
These were iden t ica l in a l l r e s p e c t s wi th the authent ic ace tophenones .
41-
Isolation of methyl piperonoylacetate (47)
A solution of 2^ (1 gm) in chloroform (3 ml) was added
to a short band of silica gel and left to stand for 48 h r . There
after it was eluted with a mixture of hexane-chloroform (1 :1) . Re
moval of the solvent furnished oily residue which on tri turation
with hexane gave 4[7 as a solid. This was recrystal l ised from chlo-
roform-hexane mixture, and was found to be indentical in all res
pect with the authentic sample prepared by the method reported ,. 42 earlier
3-Substituted phenyl-2-isoxazoliii-5-ones (48-51, Table 9)
To a solution of subsituted but-3-ene-2-ones (37-41; 0.001
mole) in methanol (10 ml) was added hydroxylamine hydrochloride
(0.003 mole) and sodium acetate (0.003 mole). This mixture was
s t i r red at room temperature (20°) for 6 h r . Water (10 ml) was then
added to the reaction mixture and the separated solid was f i l tered,
washed with water, dried and recrystal l ised from methanol.
2,5-Dimethyl-3-acetyl-4-substituted'^ phenyl furans (52-56, Table 7)
These were essentially prepared by the method described
for compounds 32-36.
4-Acetoxy-3-acetyl-4-substituted^~*'phenyl but-3-ene-2-ones (57-61,
Table 8)
These compounds were prepared by the method described
for compounds 37-41.
3-Substituted phenyl-5-methyl-isoxazole (62-65, Table 10)
The method described for compounds 48-51, was followed
to obtain these compounds.
2-Nitro-l-(£-acetaniidophenyl) propene (66)
This was essentially prepared by the method reported ,. 43 earl ier
2,5-Dimethyl-3-methoxycarbonyl-4-(£-acetainidophenyl) furan (67)
The method of preparation of these compounds was essen
t ia l ly the one reported for compounds 32-36.
42
2,5-Dimethyl-3-methoxycarbonyl-4-(2-chloro-3-formyl qiiinolino) furan
(68, Table 11)
To a precooled flask in an ice-bath for 15 minutes was
added POCl (15.4 ml, C.Ol mole) and it was allowed to stand at
this temperature for another 15 minutes. Dry DMF (6.3 ml, 0.01
mole) was then added under stirring and after 5 minutes the comp
ound 62 (2.87 gm, 0.01 mole) was added. The resulting mixture
was heated at 70-74° under stirring for 16 h r . Finally it was poured
onto crushed ice , and then separated solid was f i l tered, washed
with water and dr ied. It was recrystal l ised from chloroform-hexane
mixture.
2,5-Dimethyl-3-methoxycarbonyl-4-(3-aldoximino-2-chloroquinolino)furan
(69, Table 11)
A solution of bS^ (3.4 gm, 0.01 mole) in methanol (15 ml),
hydroxylamine hydrochloride (1.38 gm, 0.02 mole) and sodium acetate
(1.64 gm, 0.02 mole) was s t i r red at room temperature (25°) for
3 h r . Water (20 ml) was then added to the reaction mixture and
the precipitated solid was f i l tered, washed with water, dried and
recrystal l ised from aqueous DMF.
2,5-Dliiiethyl-3-methoxycarbonyl-4-(2-chloro-3-cyano quinolino) furan
(70. Table 11)
To a suspension of b9^ (1.79 gm, 0.005 mole) in dry benzene
(8 ml) was added SOCl (5.9 ml, 0.025 mole) and the resulting mix
ture was heated at 90° for 3 h r . Finally it was poured on to crushed
ice and the resulting mixture was allowed to come to 90°. After
holding it at this temperature for 45 minutes, it was cooled to room
temperature (25°) and allowed to stay at this temperature for 6
h r . The separated solid was then f i l tered, dried and recrysta l l i sed
from aqueous DMF.
2,5-Dimethyl-3-methoxycarbonyl-4-(3-cyano-2-oxo-l,2,3,4-tetrahydro-
quinolino) furan (71)
To a suspension of 25. (0.35 gm, 0.001 mole) in methanol
(5 ml) was added NaBH (0.15 gm, 0.004 mole) under cooling (5-
10°) and s t i r r ing . It was then s t i r red at th is temperature for 1.5
h r . water was added to it and the mixture was extracted with ethyl
acetate. Usual work up of the organic layer yielded an oil which
43
on t r i t u r a t i o n wi th petroleum benzene furn ished a s o l i d . This was
r e c r y s t a l l i s e d from aqueous DMF.
71 : Yield 92%; m . p . 145-46°
IR (KBr) : 1675, 1700 (CO). 2200 (CN)
PMR (TFA) : 2.00 ( s . 3H. 5-CH^), 2.40 ( s , 3H, 2-CH^),
3 .27-3 .37 ( d , 2H, CH^) , 3.69 ( s , 3H, CO^CH^) ,
3 .89-4.07 ( t , IH. CH), 6 .74-7 .18 (m, 3H, Ar
il)
C , „ H , , N , 0 . : Requi res : C, 66.66; H, 4 .93 ; N, 8.64 18 i o i. 4
Found: C, 66 .51 ; H, 4 .58 ; N, 8 .35 .
4-Chloro-3-nitro benzaldefayde (72)
To fuming HNO (d ; 1.54, 10 ml) he ld at 0° was added
£ - c h l o r o benza ldehyde (1 .4 gm) in por t ions so t h a t t empera tu re r e
mains 0 -5° . After complete add i t ion of the compound i t was s t i r r e d
at the same tempera tu re (0-5°) for 2 h r . The reac t ion mixture was
poured on c r u s h e d ice and the s e p a r a t e d so l id was f i l t e r e d , washed
with water and d r i e d . It was r e c r y s t a l l i s e d from chloroform-hexane
mix tu re .
4-Amliio-3-nitro benzaldehyde (74)
This was p r e p a r e d by following the method r e p o r t e d in 44
the l i t e r a t u r e
2-Chloro-3-formyl quinoline (76)
This compound was p r e p a r e d by the method r e p o r t e d e a r -, . 45
l i e r
4-Formyl tetrazolo [ 1 , 5 - a ] quinoline (78)
This was p r e p a r e d by the method r e p o r t e d in the l i t e r a -45a tu re
2 ,6 -Di inethyl -3 ,5-dimethoxycarbonyl-4-subst i tuted- l , 4 - d i h y d r o p y r i -
dines (79-86, Table 12)
A mixture of the a p p r o p r i a t e a l d e h y d e (72-78 & Ml, 0.01
mole) and methyl -3-amino crotonate in an a p p r o p r i a t e solvent ( e t h y
lene glycol for 79-83, 85 and methanol for 84, ^ ) was hea ted on
water ba th for 24 h r . Thereaf ter water was added to the reac t ion
mixture and s t i r r e d at room tempera ture (25-30°) for 2 h r . , t he
44
separated solid was f i l tered, washed with water and dr ied. In the
case of ^ the work up was different. In this case dry ether was
added to the reaction mixture and the solid obtained after trituration
was filtered and dr ied. The compounds 79-83 and 8b^ were recrys ta-
llised from aqueous methanol while ^ was recrystal l ised from aqueous
DMF.
2,6-Dimethyl-3 ,5-dlmethoxycarbonyl-4-substituted ^^ phenyl-1,4-dihydro
pyridines (87-89, Table 12)
A mixture of the compound J9^ (0.01 mole) and aqueous
methyl amine or aqueous ammonia (0.04 mole) in methanol (20 ml)
was heated in steel bom at 150° for 24 hr . The volume of the reac
tion mixture was reduced to 10 ml and to t h i s , water (20 ml) was
added, and the mixture was allowed to stand at room temperature
for 3 h r . The separated solid was f i l tered, washed with water and
dr ied. These compounds were recrystal l ised from aqueous methanol.
2,6-Dimethyl-3»5-dimethoxycarbonyl-4-{4-benzylaniino-3-iiitro phenyl)-
1.4-dihydropyridine (88, Table 12)
A mixture of the compound 79 (3.8 gm, 0.01 mole) and
benzyl amine (6.3 ml, 0.06 mole) was heated at 110° under stirring
for 8 h r . Water was then added to the reaction mixture and extrac
ted with ethyl acetate. Usual work up of the organic layer gave
an oil which on trituration with petroleum benzene, yielded a solid.
This was recrystal l ised from chloroform-petroleum benzene mixture.
2,6-Dimethyl-3,5-dimethozycarbonyl-4-(3,4-diaiiiinophenyl)-l,4-dihydro-
pyridine (90, Table 12)
To a suspension of 81 (1 gm) in methanol (100 ml) was
added Raney-Ni (~0.2 gm) and hydrogenated at 2.5 kg/cm^ for 2
h r . The catalyst was filtered off, solvent removed under reduced
pressure and the residue tr i turated with water. The solid so obtained
was f i l tered, dried and recrysta l l ised from aqueous methanol.
2-Aryl-5(6)-(4-{2,6-diinethyl-3,5-dimethoxycarbonyl-l,4-dihydropyri-dyl)l-l(3)-substituted2benxyl benzimidazole (91-95, Table 12a).
A mixture of 90 (0.001 mole) and substituted benzaldehyde
(0.002 mole) in glacial acetic acid (2 ml) was heated on a water
bath for 4 h r . Water was then added to the reaction mixture and
45
e x t r a c t e d wi th e t h y l a c e t a t e . Usual work up of the organic l aye r
y ie lded a r e s idua l mass which on t r i t u r a t i o n with petroleum benzene
furnished 90-95 as s o l i d . These were r e c r y s t a l l i s e d from aqueous
methanol ,
5 ( 6 ) - l 4 - ( 2 , 6 - D i m e t h y l - 3 , 5 - d i m e t h o x y c a r b o n y l - l , 4 - d i h y d r o p y r i d y l ) l benz-
triazole (96)
To a solution of 90 (0.662 gm, 0.002 mole) in ace t ic ac id
(2 ml) was added water (2 ml) and to t h i s mixture was added a
solution of sodium n i t r i t e (0.414 gm, 0.006 mole) in water (1 ml)
under cooling (5-10°) and s t i r r i n g . It was s t i r r e d under cooling
for 15 minutes and then i t was hea ted at 80-90° for 1.5 h r . The
reac t ion mixture was poured into c rushed i c e . The s e p a r a t e d so l id
was f i l t e r e d , washed wi th water and d r i e d . It was r e c r y s t a l l i s e d
from aqueous methanol .
5-I4 - (2 ,6 -Di ine thy l -3 ,5 -d l ine thoxycarbony l - l , 4 -d ihydropyr idy l ) ] 2 , 3 -
diphenyl quinoxaline (97)
A mixture of 9£ (0.331 gm, 0.001 mole) and benzi l (0 .21
gm, 0.001 mole) in methanol (5 ml) was ref luxed under s t i r r i n g
for 5 h r . Water was then added to the reac t ion mixture and the
s e p a r a t e d so l id was f i l t e r e d , washed wi th w a t e r , d r i e d and r e c r y s
t a l l i s e d from aqueous methanol .
97 : Yield 65%; m . p . 172-3°; M* at m/z 505
IR (KBr) : 1680 (CO)
PMR(CDCl,+DMSO-d,) :2 .29 ( s , 6H, 2xCH, ) , 3.51 ( s , 6H, 2xCO,CH,) , i o —3 2 3
5.10 ( s , IH, CH), 7.15-7.65 (m, 13H, Ar-H) ,
8.38 (s_, IH, NH)
^ 3 l " 2 7 ^ 3 ° 4 • Requi res : C, 73 .66; H, 5.34; N, 8.31 Found: C, 73.66; H, 5 .37; N, 8 .66.
5 ( 6 ) - I 4 - ( 2 , 6 - D i m e t h y l - 3 , 5 - d i m e t h o x y c a r b o n y l - l , 4 - d l h y d r o p y r i d y l ) ] - 2 -
mercapto benzimidazole (98)
To a solution of 90 (0.331 gm, 0.001 mole) in ethanol (2
ml) and wa te r (2 ml) was added carbon d isu l f ide (2 m l ) . The r e a c
t ion mixture was heated under s t i r r i n g at 60° for 6 h r . Water was
then added to i t and the s e p a r a t e d so l id was f i l t e r e d , washed wi th
w a t e r , d r i e d and r e c r y s t a l l i s e d from aqueous DMF.
46
98^ : Y i e l d 70%; m . p . 2 6 8 - 9 ° ; M"^ a t m/z 373
IR (KBr) : 1660 (CO)
PMR(CDCl,+DMSO-d, ) : 2 . 2 0 ( s , 6H. 2xCH-) , 3 .50 ( s , 6H, 2xCO,CH ) , 3 6 J £ . 5
4 .85 ( s , I H , C H ) , 6 . 6 9 - 7 . 0 5 ( m , 3H, A r - H ) .
C H N O S : R e q u i r e s : C , 5 7 . 9 0 ; H, 5 . 0 9 ; N , 11 .26
F o u n d : C , 5 7 . 6 8 ; H, 4 . 8 1 ; N, 1 1 . 5 8 .
10-H-2 - [4 - {2 ,6 -Dimethy l -3 ,5 -d in i e thoxycarbony l ) - l , 4 -d ihydropyr idy l l -
10-oxo-isoindolo [ 3 , 2 - £ ] benzimidazole (99)
A m i x t u r e of ^ ( 0 . 3 3 1 gm, 0 . 0 0 1 mole ) a n d p h t h a l i c a n h y
d r i d e ( 0 . 1 4 8 gm, 0 .001 mole) in me thano l (5 ml) w a s r e f l u x e d for
10 h r . Wate r w a s a d d e d to t h e r e a c t i o n m i x t u r e , t h e s e p a r a t e d s o l i d
w a s f i l t e r e d , w a s h e d w i t h w a t e r , d r i e d a n d r e c r y s t a l l i s e d from
a q u e o u s m e t h a n o l .
9 i : Y i e l d 55%; m . p . 2 2 5 - 6 ° ; M"^ a t m/z 443
IR (KBr) : 1680, 1650 {CO)
PMR(CDCl,+DMSO-d, ) : 2 . 22 ( s , 6H, 2xCH 1 , 3 .50 ( s , 6H, 2 x C 0 , C H , ) , 3 o —5 Z 3
4 .90 ( s , I H , C H ) , 7 . 0 1 - 7 . 8 0 ( m , 8H, A r - H .
NH) .
C H N O : R e q u i r e s : C , 6 7 . 7 2 ; H, 4 . 7 4 ; N, 9 . 4 8
F o u n d : C , 6 7 . 5 8 ; H, 4 . 9 2 ; N, 9 . 0 5 .
3.2 TABLES
Physical and Analytical data of Compounds, which have not
been included in Experimental section, are described
under vertical columns and their spectral
characteristics have been recorded in
horizontal sequence.
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68
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69
3.2 ANTIFERTILITY ACTIVITY OF COMPOUND SYNTHESISED
Almost a l l the compounds s y n t h e s i s e d as p o s s i b l e an t i f e r -
t i l i t y agents have been screened for t h e i r e a r l y abor t i f ac ien t a c t i v i t y
in the Division of Endocrinology of Central Drug Research I n s t i t u t e ,
Luc know.
Evaluation of Early Abortifacient Act iv i ty Material and Method:
Adult male and female hams te r s and r a t s of p roven f e r t i l i t y ,
maintained under uniform husbandry condi t ions having a regula ted
l igh t and da rk pe r iod were caged for overn igh t and the vaginal smear
was examined following morning. Finding of spermatozoa in smear v/as
cons ide red as day 1 of p regnancy . From days 4-8 of pregnancy in
hamster and days 6-10 in r a t s the compounds were a d m i n i s t e r e d s u b -
cutaneously .
On day 12 of pregnancy in h a m s t e r , animals wre lapro tomized
and examined for imp lan ta t i on / r e so rp t ion s i t e s . Required a rea of the
r e so rp t i on s i t e s was f ixed in Bov in ' s fluid for h i s to log ica l examina
t ions . Results have r e v e a l e d tha t if compounds were admin i s t e r ed
before day 4 of pregnancy in hamster or day 6 in r a t t hey were
not equa l ly effect ive as in the pos t - implan ta t ion s t age . The r e s u l t s
of biological a c t i v i t i e s of var ious compounds s y n t h e s i s e d a r e d e s c r i b e d
in Table 13.
RESULTS AND CONCLUSIONS:
Simpler he t e rocyc l e s possess ing only one phenyl r ing d id
not show any r emarkab l e con t r acep t ive effecacy. The p r e s e n t s tudy
has a lso r e v e a l e d the pregnancy i n h i b i t o r y effect of compounds b e
longing to a new c lass of he t e rocyc l i c sys tem namely 2 , 6 - d i m e t h y l -
3 , 5 - d i r a e t h o x y c a r b o n y l - 4 - s u b s t i t u t e d - l , 4 - d i h y d r o p y r i d i n e . Th i s new
lead i s worth exp lo i t ing and ca l l s for evaluat ion of o the r compounds
of t h i s s e r i e s .
a o
70
c <u > 0) u o. >> y c a c tX) <D U
Ou
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in ( M
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ID eo 00
in eo
CHAPTER 4
STUDIES ON THE CHEMOTHERAPY OF HELMINTH INFECTIONS:
RETROSPECTS AND PROSPECTS
4.1 : The hea l th haza rd of helminth infections in India
4.2 : Development of exper imenta l models
4.3 : Biochemical s t ud i e s
4.4 : Mode of Action
4.5 ; Future development
4.6 : BASIS OF WORK
72
CHAPTER - t\
•STUDIES ON THE CHEMOTHERAPY OF HELMINTH INFECTIONS:
RETROSPECTS AND PROSPECTS"
4 . 1 Helminthiasis, a group of several diseases caused by the
invasion of human body by the roundworms (nematodes), flatworms
(trematodes) and tapeworms (cestodes), may be broadly classified
as gastrointestinal or enteric helminthiasis, schistosomiasis and fila-
riasis. Of these, filariasis alone affects the health and general well-
being of nearly 400 million people in tropical and subtropical regions
of the world . Of the 900 million people around the world living
in the areas endemic to filariasis, 236 million population belong
to India, The picture of endemicity in this country is becoming alarm
ing day by day since 22 million microfilaeramic carriers and about
16 million cases with clinicopathological symptoms have been reported.
The continuous spread of the disease and protracted suffering and
disability caused by the parasites to the infected population have
attracted greater attention and priority has been laid for combating
helminth infection not only in this country but also by the members
of the World Health Organisation.
The enteric or gastrointestinal helminthiasis is also highly
prevalent in different parts of the tropical world. In India it is
endemic in rural masses and the urban population with low standard
of living and poor sanitation. The incidence of ancylostomiasis ranges
from 40% in plains to 90% or even more in the area of tea estate
46,47
and coffee plantation ' . The ever growing dimensions of this dis
ease in this country is evident from the recently published statistical
figures. In Uttar Pradesh alone 20.1% of rural population is affected
by hookworm infection
Helminthiasis, in principle, can be controlled by improving
personal and public hygiene and in the event of less statisfactor y
sanitation conditions, chemoprevention is possibly the most attracting
approach. Any chemical which may evoke selective toxicity to para
sites or is capable of stimulating immunosurveillance mechanism of
the host would be of interest for the treatment of the infected popu
lation. Present state of art in immunology possibly permits immuno-
-diagnosis but specific immunotherapy of various diseases caused
73
by helminth infections is not yet possible and this has prompted
to analyse the retrospects and prospects of the chemotherapy of
helminth infections.
4.2 The retrospective analysis of the chemotherapy of helminth
infections reveals the attempts made by earlier workers to develop
suitable experimental models for the evaluation of possible anthel
mintic agents.
DEVELOPMENT OF EXPERIMENTAL MODELS
A. Filariasis: The search for experimental host-parasite models
has led to investigations on parasites such as L'ttomoAutde s caiin« 49 (Vector, Liponij^^u bacoU), Vipe.taiomma \jitzaz (Vector, Qfini-
thodO'i.ou-t moubata) and Bn-ugia malayi ' (Vector, Aede S azqijpti
The suitable hosts are cotton rats {Stgrnodon hi'^p^tdu^t,) Ma-bto-
my^ nataizn6A.6, albino rats and gerbila { h\e.n.<lonz^ unQuicutatu6 ) .
The difficulty of breeding, handling and maintenance of
cotton rats, the natural infection fori-. CCUiinil, the most commonly used
filarial infection have led to the identification of mostomys as 52
alternative host , Subsequently, mastonys has been found to be
more suitable as a host for V. viteae. and 8. maiayi infections.
The latter can also be infected to cat , rhesus monkey and langoor. B. Intestinal Helminthiasis:
Hookworms and tapeworms are the main targets in intestinal 54
helminthiasis. Albino rats and golden hamsters as laboratory animals
for W. bA.a6ihznM^ , (a trichostrongylid) and Ancijio^toma ce.bjian<curr]
(hookworm) respectively, have been found to be more suitable but
certain advantages and susceptibility of M. nataizn6i6 to N. b^aMtiZn-
-J-t-i infection have furnished yet another model for hookworm infection,
for detailed study of infectivity longevity and fecundity of A.cZytani-58 cum , laboratory rodents have been used. The laboratory models
for tapeworm infections such as Hymznolzpi'f^ nana ' in mice and
H. diminuta, a natural infection in rodents, have been found to be
satisfactory.
The development of suitable experimental models for the
evaluation of possible anthelmintic agents has provided impetus for
the screening of large number of compounds. However, the need for
the replacement of this emperlcal approach has been realised much
74
e a r l i e r and in o r d e r to p rov ide a sc ient i f ic ra t iona le for the drug
des ign , two d i s t inc t app roaches have been made. The f i r s t one is
concerned with the s t u d i e s on the b iochemis t ry of the helminth p a r a
s i t e s and the second one r e l a t e s to the understanding of the mode
of act ion of ac t ive compounds d i scovered during random sc reen ing .
4.3 BIOCHEMICAL STUDIES
The anaerobic h a b i t a t of most of the in tes t ina l he lmin ths
has provoked s t u d i e s on g l y c o l y s i s and the i n h i b i t o r for the key
enzymes of the g lyco ly t i c pa thway in helminth p a r a s i t e s such as
Chandiz/iziia kaujkingi, L. ccuiimi and a^coAciia gaiU has been s e a r
ched . Cyanine 863 , an ac t i ve inh ib i to r of these enzymes , has
not deve loped into a drug because of i t s t o x i c i t y . The b iochemis t ry
of Se.taAia CZX\/i, the p a r a s i t e of the Indian water buffalo, has been
s t u d i e d . A phosphoenol p y r u v a t e (PEP) succinate pa thway requ i r ing
a th io l function for the enzyme a c t i v i t y has also been mapped . Adult
and microf i la r iae of 5 . CZn.'^i a r e ve ry different in biochemical
composi t ions . Unlike mic ro f i l a r i ae , adu l t s have h igher contents of
glycogen and glucose but have lower contents of f ruc tose , l i p i d s ,
nucleic ac ids and phosphorous . Recent obse rva t ions emphas ize t r a n s -
cu l t icu la r abso rp t ion as an ac t i ve t r anspor t p rocess and inh ib i t i on
of t h i s t r a n s p o r t can s t a r v e the p a r a s i t e and p r o b a b l y k i l l i t . P r e
sence of CAMP dependent and independent prote in k inases in B^tuQia ma-
latji and N. b->iaMUe.nM6 ' p l ay a regula tory ro le and the a c t i v i t y
of high molecular weight p h o s v i t i n kinase have been i n h i b i t e d by
suramin and h e p a r i n , indica t ing a r e l a t i onsh ip between drug action
and inh ib i t ion of t h i s enzyme. The p a r a s i t i c in tes t ina l he lmin ths
such as A. iumbxicoidz^ and A. gaiU p ro tec t themse lves from p r o t e o
ly t i c and o the r deg rada t ive enzymes secre ted in the lumen, wi th
the he lp of t r y p s i n and chymot ryps in i n h i b i t o r s . Different organs
of A. gatii contain s e v e r a l amino ac id metabolising enzymes such as
Histamine ammonia- lyase , th reonine d e h y d r a t a s e , glutamate d e h y d r o g e
nase and alanine and a s p a r t a t e amino t r ans fe ra ses of which alanine
and a s p a r t a t e t ransaminases have been found most a c t i v e . Transami
nases for alanine and a s p a r t a t e have been r e p o r t e d i n S . CZn.vi , i.coAi-
nii and v. vitzaz whi le arg in ine and isoleucine t ransaminases a re
a l so p resen t i n S . cz^vi. The p resence of var ious biogenic amines
in helminth p a r a s i t e s has been ver i f i ed as adul t worms of L. caxinii
75
contains a l l the four amines t e s t ed which a r e h i s t amine , 5 -hyd roxy
t r yp t amine , dopamine and no r - ep ineph r ine but dopamine is found
to be absent in the microf i l a r i a ! stage which possess h igher amine
content than adu l t s . S. ce^v-t, N. bia^iUtn^i^, A. iamblicoidz^
v a r , homini't) and A. galti contains al l the four neuro amines but
with varying level of 5-HT and NE in different p a r a s i t e s . The p r e
sence of both type A and type B monoamine ox idase (MAO) in A.gatii
and a l i p h a t i c polyamines such as spe rmid ine , spermine as well as
put resc ine in S. ce.ivi, A. qalii, C. digonopo^a have been shown
4.4 MODE OF ACTION
Biochemical composit ion ot p a r a s i t e s , the enzymes involved
in metabolic reac t ions as well as s u s c e p t i b i l i t y of the p a r a s i t e s
to an the lmin t ics have been inves t iga ted to unders tand the mode of
action of these drugs and to ident i fy target for chemothe rapy . I nh ib i
tion of c h o l i n e s t e r a s e s , in ter ference with fumerate r e d u c t a s e , i n h i b i
tion of mi tochondria l NADH oxid iz ing a c t i v i t y , in te r fe rence with p h o s -
phofructokinase and folate metabolism and d i s rup t ion of ce l lu la r in te
g r i t y a r e the major ta rge t s i t e s for the anthe lmint ic d rugs . Anti-
f i la r ia l drugs have been found to effect the var ious metabolic a c t i v i
t i e s of the p a r a s i t e s which could e i t he r be d i r e c t t a rge t s of the
drug or the secondary effect of t h e i r ac t ion . The capac i ty to syn the
s ize glycogen and p ro te in from glucose and val ine by adul t L. caiinii
i s a l t e r e d by DEC. It a l so affects the ox ida t i ve and metabolizing 70
enzymes of the host . Consequently admin is t ra t ion of DEC to the
host has been fovmd to a l t e r i t s immunological r esponse and to cause
a d v e r s e reac t ion in microf i laraemic h o s t . This drug has shown to
cause the loss of shea th from L. CCiA.inii and the e lec t ron microscopic
s tud ie s have r e v e a l e d tha t the cut ic le of microf i la r iae of 0 . volvulus
a l so undergo changes . Levamisole a l t e r s the ae rob ic glucose metabo
lism of BKugia pahanii and i t has been suggested tha t the effect
of t h i s drug on the metabolism of microf i lar iae a re secondary to 72
the obse rved p a r a l y s i s . Suramin i n h i b i t s the l ac ta t e and malate
dehydrogenase of 0 . \Jol\jaiuA . It a lso i n h i b i t s p ro te in kinase
of the same organism and c i rcumstant ia l ev idence e x i s t s to presume 74 tha t Suramin might have more than one s i t e of act ion . Nic losamide,
Praziquantel and Mebendazole Inh ib i t glucose up take by the p a r a s i t e
and an inc rease in lac ta te formation ind ica tes a change-over to homo-75
lac ta te fermentat ion . Proposed mode of act ions of drugs containing
76
benz imidazole -2-carbamate nucleus (Mebendazole, Albendazole , Fenben-
dazo le , Flubendazole , Oxibendazo le , Pa rbendazo le , e t c . ) th iabendazole
and cambendazole r evea l t h e i r act ions mainly through inh ib i t i ons
of microtubule po lymer i sa t ion and fumerate r e d u c t a s e .
Current ev idence is inadequate to determine whe t he r or
not DEC is capable of invoking a p r o p h y l a c t i c action in the lympha t ic 76
f i l a r i a s i s in man . More than thousand compounds have been eva lua ted
as poss ib l e new macrof i l a r i c ide by the spec ia l programme of WHO
alone and a few compounds which have been ident i f ied for c l in ica l 77
s tud ies a re d e s c r i b e d in f i g . a .
The chemotherapeu t ic agent employed for the t reatment
of nematode and ces tode infections and t h e i r s t r u c t u r e to a c t i v i t y 78 r e l a t i o n s h i p have been r ev iewed . Of the var ious chemothe rapeu t i c ,
agen t s , methyl benz imidazole -2-carbamates occupy a unique pos i t i on .
This is p r i m a r i l y because of t h e i r wider spectrum of anthelmint ic
a c t i v i t y but no a t tempt a p p e a r s to have been made to rev iew the
present s ta tus of benzimidazole anthelmint ics for the t rea tment of
var ious helminth infections for assess ing the spect rum of anthelmint ic
a c t i v i t y . The p resen t s ta tus of benzimidazole an the lmint ics h a s ,
t he r e fo r e , been p resen ted in t ab l e la to p r o v i d e a b i r d ' s eye -v iew
of t h e i r e f f icacy .
4 .5 The t r end of r e s e a r c h a c t i v i t i e s in the area of chemopreven-
t ion of helminth infections suggests t ha t in the coming decade^ p o s s i b l y
more emphas is would be l a id on the development of chemoprophy lac -
t i c s and immuno-regula tors . The l a t t e r v/ould be more concerned with
the development of agents which would enable an immuno-incompetent
host to regain i t s immunocompetence. The c l a s s i ca l chemotherapeu t ic
approach may furnish exc i t ing and in te res t ing data on n i t ro group
bear ing h e t e r o c y c l e s . Development of new lead molecules as GABA
agonist i s a s t rong p o s s i b i l i t y and the de ta i l ed unders tanding of
the mode of act ion of ive rmec t ins would be p o s s i b l y a c h i e v e d .
4 . 6 BASIS OF WORK
The socio-economic problems and inadequate publ ic hea l th
fac i l i t i e s of t h i s country cal l for the development of a b r o a d - s p e c t r u m
77
OCH3
NHCSCH2CH2CO2H
s
CGP 24914
OCH3
NHCSCH2CH2CO2H
S
CGP 20376
O2 N - ^ ^ ) - N - ^ ^ N - C - N ^ - C H 3
CGP 6140
T Furapyriaidone: N-(5-nitro
-2-furfurylidone) amino
tetrahydro-2(lJl) Pyrimidone
^ ^ XH2CHOHCH9OH
^ N 0 2
Desmethylmisindazole:
1,2-Propanediol, 3(2-
nitro-lH-imidazol-l-yl)
OCH3 H
H5C2\J/CH3
73>s
Contd.
78
,CH(CH2)3 CH3
Ive rmic t ine (A mixture of Components I and I I
Component I : 5-0-demethyl-22,23-dihydro avermectin Ala
Component I I : 5 -0 -demethy l -25-de ( l -me thy lp ropy l ) -22 ,23-
d ihyd ro -25 - ( l -me thy l e thy l ) avermectin Ala) ,
'XKl H
NHC02Me
ALBENDAZOLE :
FENBENDAZOLE :
OXIBENDAZOLE :
PARBENDAZOLE :
R = SCH-
R = SC,H, 0 J
R = OC^H^
R = ^"9
THIABENDAZOLE
CAMBENDAZOLE
: R = H
0
: R = NH-C-OCH(CH3)2
LEVAMISOLE N
PRAZIQUANTEL Contd.
79
Na03S
^3^~\ >-CONH SOjNa
NH I CO
NHCONH
S03Na
S03Na
Suramin (Hexa-sodium 3,3'-Ureylene-bis-8-(3-benzimido-£-toluido)-
1,3,5-naphthalene sulphonate)
0 Et / ~ \ II /
Me-N N-C-N. \ , Et
CN
H 0 2 C - C - N H - H ( > ^
CI ^NH-C-C02H
DEC (l-Diethylcarbamyl-
A-methylpiperazine)
Lodoxamide N,N'-(2-Chloro-5-
Cyano-m-phenylene)
0=C'
u
' IV^NHC02Mc
— N
Mebendazole (Methyl 5-benzoyl
-2-bensiniidazole carbamate)
o=c
H Nv^NHCO^Me
Flubendazole (£-fluorobenzoyl)-
2-benzimidazole carbamate
Fig. af
80
Table Iti: Spectrum of anthelmintic activity of caimon antinematode and anticestode drugs
Drug/Dose
1
Albendazole
400 mg ( s i n g l e )
200 mg ( s i n g l e )
400 mg ( s i n g l e )
30 mg/kg ( s i n g l e )
800 mg (Multiple)
- do -
10 mg/kg (Multiple)
- do -
- do -
100 mg/kg (Multiple)
15 mg/kg ( s i n g l e )
400 mg ( s i n g l e )
10 mg/kg (Multiple)
15 mg/kg (Multiple)
10 mg/kg ( s i n g l e )
Parasite
2
KicoA-U iuirhJiicoidoji,
TAichuA-ii tAickuAa.
SViongyloide^ -^WiocoAaJtU
EnteAobiiu veAjnic.aloA'ii
Co-piZZaAia. hzpcutica.
Hym.nolzpiyi nana.
TajtYua. 'iag-Lnata
0-6tZAtagia o^UeAtagl
Coop^Aia oncophoAa
CoopeAicL zuAnabada.
0p-c6-tfeoAdtc4 vivzxxirU.
VicAocoztium taxiaoMXim
Ancylo^toma daodznalz
TA'ichuALi g£oba£o-6a
¥<u>(Uoia he.p<vtica
TAlchinoJLla. pA<Uido^piAaJiLt>
Host
3
Man
Man
Man
Mice
Man
Man
Calves
Hamst e r s
Ewes
Man
Goat
Sheep
Mice
1 —
Anthelmintic efficacy
(%)
4
93 .3 89.7 89.7
100
100
99
69
92
99.99
99.9
99.9
95 .3
94.46
79
41-50
95
36
Bibliography Number
5
79
79
90
81
82
83
84
85
86
87
88
89
81
1
20 mg/lcg (Mul t ip le )
5-10 mg/kg (Mul t ip l e )
7.5 mg/kg (Mul t ip l e )
2 .5 or 3.8 mg/ k g . ( M u l t i p l e )
2.5 mg/kg (Mul t ip le )
4 . 8 mg/kg
2
VicAocoatium dznciAiticum
k^caAidloi Qolti, RcUttiztincL t£.tA.(igona, R. zckLnobothiicUa.
CoopoAia. panctata, NejiiatocLUcui ipauthlQZA, HazmonckvUt ptojioJ., TAicho^tAongyliUi axlz, T. coZuhAi^oAmii),
W. hzZvztyLanuUi, Oe^ophago-dtomm xadiaXim
HazmonchiU coYitoKtuA, TAicko^^tAongyluA cobxbKi-
GalgzAia ovina, UoA^hallaLgia. nwukaZU.
VictyocauZa^ iiJioAla.
FoUicioia gigantioxi
3
Sheep
Fowls
Calves
Sheep
Sheep
Sheep
4
98.61
100
99-100
'V 99.8
99
63.2
5
90
91
92
93
93
93 (Multiple)
FENBENDAZOLE
50 mg/kg iKldnAjnzlla. ^pVujJLtUt Mice 95.1 94 (Multiple)
7.5 mg/kg StAongyloidU UX^tZAi, > 98.5 95 (Multiple) PaAaAicafii^ zquoAum
50 mg/kg TOKOCXlACi CCUtU, (Multiple) Ancyto-itomcL caninum, Dogs 98-100 96
TAlchuAi^ vuZpi^
10 mg/kg KiCOA-ii -iutun Pigs 100 97 (Multiple)
10 mg/kg CyothO'ittomM, (s ingle) CytLco.Ue.phaiuU,
CyticocycMU, Donkey 100 98 CyticodontophoAiu, CkatiAO'itomuin,
82
1
10 mg/kg (Single)
- do -
- do -
7 .5 mg/kg (Mul t ip le )
- do -
100 mg/kg ( s i n g l e )
7.5 mg/kg (Mul t ip le )
15 mg/kg (Multiple)
15 mg/kg ( s i n g l e )
7.5 mg/kg (Multiple)
100 mg/kg (single)
- do -
20 mg/kg (Multiple)
35 mg/kg (Multiple)
- do -
- do -
2
TAiodontophoAu^, StAongyixjU) Zqainu6,
S. vuJigaA.u>
HabAonejna. majuut
H. mtucae
0>s>teJita.Qia o^tuJitagl, CoopeAla ^pp.
TA-Lcho^tAongyZwi axoJ.
VicJiocoe-tum ddndAiticum
VoAomphi^tomm -6pp.
faudOA-ola. hzpatlca.
Monizzia -6pp.
StAongylu^ zdzntatoA, TA.icJionejna. 4pp.
Taenia. >6p.
V<jpytidium canimm
ToxocoJia my^ttax Tox<ii,cjaAU> IzoniiM., UncinaAia. ^znoczphaZa
MzX(utAongyZuA 4pp.
GZoboczphaZu^ uAO^ubuiatiu
TJuchuJiti, 4,vuy6
3
Donkey
Donkey
Donkey
Hei fer
Heifer
Sheep
C a t t l e
Sheep
Sheep
Ponies
Dogs
Dogs
Dogs & Cats
Pigs
Pigs
Pigs
4
55.5-100
81.8-100
47.6-100
100
90
99.3-100
87.2
50
100
100 99.7
>90
<50
100
93-100
70-100
0-100
5
98
98
vS
99
100
101
101
101
101
102
103
103
104
105
105
105
83
1
MEBENDAZOLE
5 mg/kg (double)
70-100 mg/kg ( s i n g l e )
10 mg/kg (Mul t ip le )
5 mg/kg (Mul t ip le )
50 mg/kg (Mul t ip le )
- do -
1.5 g/10 kg
- do -
10 mg/kg ( s i n g l e )
22 mg/kg (Mul t ip le )
25 rag/kg (Mul t ip le )
100 mg (Mul t ip le )
5.7 mg/kg (Mul t ip le )
100 mg ( s i n g l e or M u l t i p l e )
25 rag/kg (Mul t ip le )
0 .5 g/kg ( d a i l y )
2
N. da6m4
P, awb^guuA
Ancy£o4toma cxmimm
TA.'idiinziZa. ndl^oni
VicAocoe.tUm dzntAlticxm
VaudcJ-olx hzpatica.
VictyocjCiuiuu> illoAla.
UorUzzia
RaltUztincL Q-cSUnoboth-Kidd, R. cz^tLcAjUu^
Toxocjvia. auU.
TazrUcL taZruazioA.mii,
SubaZwia. bAumpti
Ent&AobiiLi \}QAmlcuZaAiA>
VlcXyocaaia& oJinilzldu.
A^c/VL-u lujihKlcoldu Tt-cciiuA-ci txidnJbjJia. StAongytoido^ MZKCoAotid
Cy^ttixLtKCMAi tznuicoltu
3
Mice
Rabbits
Dog
Rats
Sheep
Sheep
Sheep
Sheep
Hens
Cats
Chicken
Man
Donkey
Man
Lambs
EdunococcoA mitfctc£ocu£aA.o»iice
4
100
100
100
98
90.6
79.4
99
84
100
100 99 50
100
100
75-100
100 100 75
100
90.5
5
106
107
108
109
110
110
111
111
112
113
114
115
116
117
118
119
84
1 2 3 4 5 _
8.8 mg/kg StAOngylvui vuZgoAti, Ponies 99-100 120 (Mul t ip le )
10-100 mg/kg AncyZo^t^toma ce.yl(ini.ctM Hamsters 99.7-100 121 (Mul t ip le )
100 mg NzcatOA OiJieA COJUUS Man 94.9 122 (Mul t ip le )
20 mg/kg O^itVitagicL o^ejitagi, (Multiple) Haejnonchui contoAtiu,
TA.ickO'UAOngylvUi ^pp., Sheep 100 12 3
ChahOAtia ovlna.
- dO - 02A>ophago^tomum uena£o4tun Sheep 90 i23
- do - tionizzie. ZXparUZ, Sheep 80 123
TA-LchuALi ovina.
100 mg ( s i n g l e ) TZAnidzni, demimXiU, Taznioi ^OLg-Lnata., Man '^100 124
MonitL^OAmLf) monlti^oAmiyi,
- do - Myme.nolzp'U nancL Man '^40 124
FLUBENDAZOLE 600 mg/kg K^COAti, iutvbAlcoidz^ Man 97
(double) 125
300 mg/kg TAichuA-U tAicJliuACL Man 65 .1 125 (double)
5 mg/kg A. COH/Conen^^ Mice 65 .1 125 (Mul t ip le )
50 or 100 mg/kg V. Vlinactl Mice No e f f e c t 126 (Mult ip le) Ht/meno£epc4 Yuxna.
50 mg/kg T. ^plAotu Mice 100 126 (Mul t ip l e )
1.5 mg/kg Oe^ophago-&tomum dojfvtatum, (Mul t ip le ) KiCOAlA 4uum, JAldnWlU> Pigs 100 127
4ac4, Ue.t(UtAongyluuii apAl
85
1
1.5 mg/kg (Multiple)
- do -
50 mg/Kg (Multiple)
150 mg/kg (Multiple)
- do -
150 mg/kg (Multiple)
OXIBENDAZOLE
150 mg/kg (Mul t ip le )
2
StAongyioidi^ Jiayuomi
StzphanuAvui dzntatu^
Eckino-ittoma. capAorU
G. uAo^ubaiattx^
CcLplttaAloL ^pp.
LZtomo^oidz^ caA.ou.-c
L. caAiyuA.
3
Pigs
Pigs
Mice
Mice
Mice
Man
Man
4
88
85
100
67-100
25-86
99
85
5
127
127
128
129
129
130
130
15 rag/kg (single)MccW^4 4uujn Pigs 100 131
40 ppm, in food Od^ophcLQO'itomxm dzntatwn Pigs 66.4 131 (20-29 days)
10 mg/kg StAOngyloidZ^ UX^tSAl Foals > 99 132 (Multiple)
40 mg/kg K^CjlKdia gatU Chicks 98.4 133 (Multiple)
15 mg/kg TAidlOAZma Ponies 97.7 13 4
(Multiple)
- do - StAOngylvUi vlllgoA-U, Ponies 100 134
OxyuAJU e.qai 15 mg/kg Hazmonchu plaxizi, Cattle > 99 135
(single) TJUcho-tttAongliu axil, CoopzJiia 'lipp. T. cotubAlioAnuu, BunO'&toimm pltUbotomm, Oz^ophagO'&tomum Koudlatim
15 mg/kg 0-titllAtagia. O^WLtougl C a t t l e 96 135 ( s i n g l e )
86
1
15 mg/kg ( s i n g l e )
- do -
7.5 mg/kg (Mul t ip le )
15 mg/kg (Mul t ip l e )
- do -
- do -
- do -
40 mg/kg (Mul t ip l e )
10 mg/kg (Mul t ip le )
THIABENDAZOLE
50 mg/kg (Mul t ip l e )
- do -
-do -
- do -
- do -
- do -
2
TA<chuAt6 4p .
UorU^zia -ip.
CoopoJiia oncopkoAa (Larvae)
NmatodiALU 4pp.
StAongytoiddyi pa.p>itto-i>Lui
CapiZZofiia. faou-ci
8ano4-tomiun pklzbotomum
TAlchlmlla ^pltoLU
PAob4>tmcLyA<Ji vlvipoAa, PauiaicaJi'Ui zquoAum
TAlchuAi^ txidviuAa
Kiccui-U bxTthKicioiikJi
EnteAobiu^ voAmicalaAi^
TA.ichO'i>tKongyivii, 4pp,
Necctto-t ojnet^anaA
HymznoZzpLit nana
3
C a t t l e
C a t t l e
C a t t l e
C a t t l e
C a t t l e
C a t t l e
C a t t l e
Mice
Ponies
Man
Man
Man
Man
Man
Man
4
> 80
> 71
98
83
94
92
94
100
'V 100
12
78
83
100
50
Not e f f e c -
5
135
135
136
136
136
136
136
137
138
139
139
139
139
139
139
53 mg/kg
88.0 mg/kg (Multiple)
50 mg/kg (Multiple)
OsteJitag-ia (UAcumcincta
O&WUajQAjoi o^UeJitcLQA., CoopfUcL 4pp.
StA.ongyluu> vaZgoAtii,
t i v e
Sheep 91
Heifer 100
Horses 100
140
100
141
1
87
50 mg/kg (Multiple)
CytLcocyciu^ naMatwi, Cyatho^tomm coAonatum, C. ccLtLntxXum, Cytico^ite.-phwm^ loYiQibuJucubi^, C. go Mi., Cyticocyciwi imignz, CyaUho-itomum labiatum
Horse No 141 effect
50 mg/kg ( M u l t i p l e )
50 mg/kg ( s i n g l e or d o u b l e )
300 mg/kg
CAMBENDAZOLE
10 mg/kg ( M u l t i p l e )
25 mg/kg ( M u l t i p l e )
100 mg/kg ( s i n g l e )
5 mg/kg ( M u l t i p l e )
25 mg/kg ( M u l t i p l e )
- do -
40 mg/kg ( M u l t i p l e )
20 mg/kg
20 mg/kg
15 mg/kg
VAOCUIU^ me(unen4-c4
StA.ongyla6 ^teAcoAotU Ancylo-Ucma, daoduuxJiz
VicAocoztium dzndAitiam
SiAongyloldz^ ux^WU.
P-cctocoeXoun Zanctotatum
AncyZo^oma caninum
StAongyloidu ^^ZAcoAatu
VijcAocodUxm de.ndAiticvum
T)iixiho^UfLon.QyluA axzi ChaJboJiticx. ovina
TxidUneMd ^piJuxULU
PaAdicaA'U zquoAum, OxyuALt zqal
Hojzmonchu (lontoAttu
CoopzA-ia. pijcJUnatcL, C. Punctata, Ot^ophago^^tatum AadiatiM
Man
Man
Sheep
F o a l s
Sheep
Dogs
Man
Ewes
Ewes
Mice
Horses
Zebu
Zebu
100
84 55
< 100
> 99
9 5 . 1
70 .5
95
9 6 . 7
99
100
100
100
100
142
143
144
132
145
146
147
148
148
149
150
151
151
88
15 mg/kg
20 mg/kg
Buno-itomum phtzbotomm Zebu
0-iXeAtagioL (UACumc-mcta, sheep CaplltaAia tongipe^, Bano^omum tAigoncQ.ph(ilum CoopeAla. cwiticeJ.
Inffec-t i v e
100
151
152
- do -
- do -
30 mg/kg
OXFENDAZOLE
7 . 5 mg/kg
12.5 mg/kg ( s i n g l e )
7.5 mg/kg (Mul t ip l e )
- do -
- do -
2 mg/kg (Multiple)
- do -
- do -
- do -
2.5 mg/kg (Multiple)
- do -
- do -
- do ~
- do ~
TAicho^Ufiongyiwi vWiinwi
NimatodiAiu ^paMUgoA
Vixityocatxliu vivipaAoai
HazttzA<jUL4t capiilivi-u
CapiJULoAija. hzpatica
k^cjoJiiAi 4uu»n, Oe^ophago-yf^mum dzntcutum
StAongyloidzAi AoruorU
TA.ichuA4Jt >itu^
Chabzfitia ovina
ViatyocauMU) vivipaMju!>
CcqfVLZocaaltu capKQ.oti
MazZleAivu capltloAli,
Buno^&tomum 4 p .
HaemonchuA ^p.
CoopoAia. 4 p .
TKicho-UAOtiggluuS, 4 p .
WZCAAtOCAAJuX^
Sheep
Sheep
C a t t l e
Goats
Mice
P i g l e t s
P i g l e t s
P i g l e t s
Roe deer & Mufflon
- do -
- do -
- do -
Catt le
Catt le
Catt le
Catt le
Catt le
99.6
90.7
99
90
99
100
80
60
75-100
100
70.9
70.9
99.4
96.4
98.3
99.9
100
152
152
153
154
81
155
155
1.55
156
156
156
156
157
157
157
157
157
89
1
4 . 5 mg/kg
- do -
1.6 mg/kg (S ing le )
10 mg/kg
3 mg/kg
2.5 mg/kg
2.5 mg/kg
1.5-9.0 mg/kg (Mul t ip le )
9.0 mg/kg
(Mul t ip le )
2.8 mg/kg
- do -
PARBENDAZOLE
20 mg/kg (Mul t ip le )
P-CC-tyocoUt tLi iiZoAia. sheep 94-100
MorUez^ sheep 96-100
Tn.ickin<Llia ^p-uiatLU Mice 99
Ponies > 96 OxyaA<y{> tqtxl, St/iongyiwi, vaZgaA-Ut, S. zdzntaiwi, TxlodontjophoKubti, TKicho^tAonglix^ axai
HyoA^ongyZiu Aubidiu Pigs 100
VictyocauMjLi vivipajia^ Calves 100
O^Wltag-i/l O^OAtagi, Calves 97-100 Coop^Aia oncophoAd, C. mo^mcu>tZAl, C. pe-ctinata, C. panctaXa, Hdjnoitodvujud h(ilv(Ltioinu^, T. longi^picuZoA^^, OeAophogo^tomxm KoAiatum
A^COAIA -6UUin Pigs 99.2-100
MztcutAongyiuu apfii S Pigs 99.5 M. pudzndotzctijUi
HaemoyickLU contoAtwii Goats 82
CoopeAia CUAticeJ,, Goats 91 .3 BuA04>tomm tfiigonocz-phaJtum
Ha£jnondiuu!> contoAtwi, Calves 100 TAicho^tAongytuA colub- Calves 100 AlioAiruA, Buno-itomum Goats 100 tAigonoczphalum, Sheep 100 StAongyloid(Li> paplUo^(ju> Dog 100 ToxocoAa cants
111
111
158
159
160
161
162
163
163
164
164
165 165
4 mg/kg (Mul t ip le )
UixAjJ/wdioL iaZcA-iiAn Elephant 100 165
90
20 mg/kg (Multiple)
30 mg/Ig active ingradient
300 mg/kg (Multiple)
41 mg/kg (single)
30 mg/kg
K-iCOAAJt VAXuZoAam Calves Ayicylo^&toma CjOAinum Dog TAldkuALi globaZoMi Goat
O^teAtagicL o^tvitagi Catt le CoopcAia. oncophoAo. Cat t le
A4CaA>C6 4tunm Boar GlobocZfhaMu uAo^ubaiataiBoav
A'&caAidUa. numidaz Guinea-fowls
Q^ZAto-qia. CAAcumcinctn, 0. txliiiAcata., Gcu.Q<iAia. Sheep pachy^cztii, ChahiAtia. ovina, hlejnaZodoLu^ •bpathigoji, Oz^ophago^ttormm coiwrbianum
98.5-100 66.1-88.7 51.6
96 100
100 59-100
99
94.1-100
165
166
167
168
169
PEBENDAZOLE
1.5 mg/kg (Mult iple)
VictyocjOJuZuA vivlpoAiu, HaijmonchLLi, contoKtiu,
Roe deer 100 & mufflons
- do -
- do -
50 mg/kg (Mul t ip l e )
- do -
5 mg/kg (Mul t ip le )
- do -
- do -
- do -
- do -
Capi'iofffufi'A f^p^^fff-i, MueMeAAjii caplUoAii,
MoniizlcL
TOKOC/VLOL ca.ni/i
AncuflostomoL canimm
0. lyAdta
HouLmonchiu placzi
NemotodcAoA hzlvztianu^
T^ichoAtAongyluA coiubAiioAjniA
- d o -
-do -
Puppies
Puppies
Calves
Calves
Calves
Calves
Calves
60.
75
64
88
71.
64,
85,
96
<99
6
3
.9
.9
.7
.9
170
170
170
171
172
173
173
173
173
173
91
1
50 mg/kg (Mul t ip le )
200-500 mg/kg (Mul t ip le )
3 mg/kg (Mul t ip le )
10 mg/kg
100 mg/kg (Mul t ip le)
7.5 mg/kg
- do -
- do -
2.5 mg/kg ( s i n g l e )
7.5 mg/kg (Mul t ip le )
LEVAMISOLE
50 mg/kg (Mul t ip le )
5 mg/kg (Mul t ip le )
3 mg/kg
6 mg/kg
8 mg/kg (Mul t ip le )
10 mg/kg
- do -
- do -
2
TcLZrUa ^^ag-ouita
StKongyloideJi,
Ki)CjaA-ii> ^uaun
KbCjaAidi/i galti
SyngamuA tAocJiZjii, CoupWLaAloi ob^gnaXoL,
CoopQJiia punctata
HaejnoncJuu
Oi^ophago^omum JiadUatum
Hzta^i>tA.ongyluu> ap^i
MoifUzzia ^coticz^
A. matay^zn^i^
TAlcho^tAongyiuu!) axzl, CoopZAia cxpiticzi, NzmvtodUnjUt ^pattigzA,
A.&coA'U
NzcatoA amzJiicanui^
0^6tejLtagla o^UeAtagl
PaAoAcat-cA zqaoAum
TKichonzma 4p.
StAongytiu dzntatwi>
3
Calves
Horses
Pigs
Chicken
Pheasants
Calves
Calves
Calves
Pigs
Calves
Rats
Sheep
Chi ldren
Chi ldren
Calves
Horses
Horses
Horses
4
100
98.5-100
100
100
< 90
75.4
100
100
97.8
91.7
90.77
97 .9 -99 .9
99.99
99.99
99.7
100
9
61
5
174
175
176
177
178
179
179
179
180
181
182
183
184
184
185
186
186
186
92
1
8 mg/kg (Mul t ip le )
10 mg/kg (Mul t ip le )
- do -
- do -
- do -
8 mg/kg (Mul t ip le )
- do -
- do -
0 .6 -2 .4 mg/kg (Mul t ip le )
TETRAMISOLE
10 mg/kg (Multiple)
- do -
- do -
7.5 mg/kg (Multiple)
15 mg/kg
10-100 mg/kg
- do -
- do -
- do -
2 3
O^tteAtagia cltcuMuncta., Lambs 0. tJiiiuJicata, TtiadoA^a-gia davtlcuu., TAidio-!>tA.o-ngyiiU) vitAinwi,, T, cotijd)AA.^oKmli, hl^mcutodVLuUD battai
HaimondiuA pZxKKU.
8uno4^mu/n phZzbotamum
Oojiophago^tormm xadiatim
Victyocauitubi vivipa/m^
KdcaX'ii) 4uuff»
JjiickuJiLd 61x16
MeXoitnongyluui, 6pp.
[micJioiiZoAlxz]
VlgoMAvz 6tJLongyi(U>
Victyocaatiu
PA. oto6tAongylu6
K6caA'i6 6aum J Oe4 ophzgo6tomum de.ntatum
HaemoKidiuA, chabzKiMi
Calves
Calves
Calves
Calves
Pigs
Pigs
Pigs
Man
Sheep
Sheep
Sheep
P i g l e t s
Lambs
GanguZzWcakli 6pumo6<i Mice or rats
Nippo6tAongylu6 bAoMtizn- -do-
r>tcc/uneX£a 6pAAatU -do-
HymeMolzpi^ nana - d o -
4
100
100
98.5
99.6
90.9
100
91
99.5
98.75
85.1
97.1
100
90-100
100
97
90.3
61
Ineffective
5
187
188
188
188
188
189
189
189
190
191
191
191
155
192
193
193
193
193
93
20 mg/Kg Anc£/-£o4^ma caninum, Toxocxfia fixvfiu>, Toxocxvil6 tzorUna
Dogs 100 194
- do TAichuA-Li valpi^, Vipytidium cauoAJUM, Eciru-Yiococcuud gAamiZo4>a^
Dogs Infec- 194 t ive
FEBANTEL
6 mg/kg ( M u l t i p l e )
15 mg/kg ( s i n g l e )
10 mg/kg ( M u l t i p l e )
- do -
- do -
5 mg/kg ( M u l t i p l e )
10 mg/kg
- do -
- do -
5 mg/kg ( M u l t i p l e )
PoAcuccuiAyi, zqaoAwn
TAA.chin.zZta. ipiAOLtUt
HaanoncJuu plauczl, TAichO'itAongylvui axzi, OeMjphagO'&tatim AodlaXum, CoopzAlu pzctinata, C. oncophoACL, NejKVtodiAu^f ^patki.Q(iA.
O-iteAtcLg-ia o^ZAtagl
MonJjz.zia. hzmdini
Hyo-itAongyZtu Aubidiu
VictyocauliLit vivlpoAu^
V. oAndiaMl
ToxocoAa VAJtaloAum
Haemonc/iu4 contoAttJu, O^it&Atagia ciAcumcMicta,
H o r s e s
R a t s
C a l v e s
C a l v e s
C a l v e s
P i g s
Camel
Z e b r a s
B u f f a l o e s
Sheep
100
9 4 . 4
97-100
93 -98
N i l
99
100
100
; 100
99
195
196
197
197
197
198
199
199
199
200
7.5 mg/kg (Multiple)
JAinho^btAongyluuii coZixb-AlioAjnli, Oz^pha.gO'btomum vznulo4>um
ContoAtiu oncophoAa Calves 100 201
PRAZIQDAMTEL
30 mg/kg (single)
HzteAophy^^ hztzAophye^ Rats 100 202
94
30 mg/kg (Double)
40 mg/kg (single)
40 mg/kg (single)
50 mg/kg (Multiple)
25 mg/kg (Multiple)
100 mg/kg (Multiple)
10 mg/kg (Multiple)
15 mg/kg (Multiple)
25 mg/kg (Multiple)
5 mg/kg (Multiple)
5 or 10 mg/kg (Multiple)
40 mg/kg (Multiple)
25 mg/kg (Multiple)
1-0 mg/kg (single)
1.0-2.5 mg/kg (single)
2.0-2.5 mg/kg (single)
Schi6to4>oma joponlcum Man 94.2
Op<yi^OA^dili> \)l\JViKinl Man 95.8
FcuciolofyiAJt ba6ki
SchLito^omcL mcLruoYu.
CtonoKok-Ld ^inznM^
Ta£.nia. M.ginata
T. ^oLLum
Hyrmnole.pZ& nana
Chi ldren lOO
Man
Man
93.3
100
Calves loo
Man
Man
100
88.5
V. pac-Liicum Man 100
Ecft-inococcoA g>ianuZo^a^, Dogs loo TaejfUa nuttice.p4), T, hydatigzna
SchUto4oma haejmtob<im Children »97
ScJvL&to/iOma bou-u
TazrUa ptu.i(Vimi^, VipytidMun caiumm
Dog 100
203
204
205
206
207
174
208
208
VlphytlobotifiKiim iactum Man 95.3 208
208
209
210
Calves 98.9 2 I I
ViphytZobotlnAium ZfiAjnac<u. Cats loo 212
EdvinococcuA muZtAJtocataA-U Dog 99.9 212
212
95
1
1.0 mg/kg ( s i n g l e )
5.0 mg/kg ( s i n g l e )
50 mg/kg ( s i n g l e )
- do -
- do -
- do -
5 mg/kg ( s i n g l e )
50 mg/kg (Mul t ip le )
2.5 mg/kg (Mul t ip le )
2
Taen>ui tazyUciaioAnuu
Uonizzia. e-xpayua
C. iJa4cco-£a-4^
C. t/LnuicoUjU,
HytnznoZe.pi^ micAo-itoma.
VicAocozLLum dzridKltiam
ToLZYUjx hydoutLge.na
3
Cat
Goat
C a t t l e
Rabbit
Mice
Sheep
Mice
Sheep
Dogs
4
100
100
100
100
100
100
100
92.2
100
5
213
213
n 4
214
214
214
215
216
217
96
anthe lmint ic agent . In the l ight of the p r e s e n t l y mapped endemic
a r ea s of t h i s coun t ry , a compound capable of evoking an t i ces toda l
and antinematodal act ions would be an adequate coverage for achieving
the de s i r ed o b j e c t i v e ,
A ra t ional approach for the development of a wide - spec t rum
anthelmint ic i s , t h e r e f o r e , e s s e n t i a l . In p r i n c i p l e , a b r o a d - s p e c t r u m
anthelmint ic agent should possess the a b i l i t y to en ter ces tode and
nematode p a r a s i t e s i r r e s p e c t i v e of t h e i r t i s sue locat ions and should
be capable of binding e f fec t ive ly wi th p a r a s i t e t u b u l i n s . Yet another
approach to ach ieve the same ob jec t ive is concerned with the s imula
tion of pharmacophores in the molecular a r c h i t e c t u r e of compounds
for provid ing c a p a b i l i t y to in t e r f e re wi th more than one t a rge t s i t e s
of the p a r a s i t e s . Besides microtubule po lymer i sa t ion , energy and
l i p i d metabolism of the p a r a s i t e s have been iden t i f i ed by WHO as
effect ive a l t e rna te t a rge t s i t e s for the development of an the lmint ic
agen t s . It i s , t h e r e f o r e , obvious tha t a knowledge of pharmacophores
is of pr ime impor tance . The e a r l i e r work of t h i s l a b o r a t o r y concern
ing the ident i f ica t ion of p r o p e r pharmacophores r e l a t e s to changes
c a r r i e d out in five different a r e a s (F ig .3a) of the Mebendazole mole
cule and the r e s u l t s ob ta ined have suggested tha t subs t i tuen t s at
pos i t ion 5(6) of methyl benz imidazo le -2-carbamates g r e a t l y influence
218
antinematodal and an t i ces toda l p r o p e r t i e s . Minor s t r u c t u r a l v a r i a
t ions in the subs t i t uen t s at pos i t ion 5(6) has been found to influence
the t i s sue nematocidal a c t i v i t y . In continuation of t h i s work i t was
cons idered of i n t e r e s t to s y n t h e s i z e compounds s t r u c t u r a l l y r e l a t e d
to p ro to types IX-XXII and to evalua te them as b r o a d - s p e c t r u m an the l
mintic agen t s . The a c t i v e compounds could then be eva lua ted for
t h e i r a b i l i t y to b ind p a r a s i t e tubulin and as i n h i b i t o r s of p a r a s i t e
energy metabol ism. The p re sen t s tudy has a l so been ex tended to
obta in compounds s t r u c t u r a l l y r e l a t e d to p r o t o t y p e s XVI & XVII. The
design of t he se two p r o t o t y p e molecules is based on the concept
t ha t d i h y d r o p y r i m i d i n e d e r i v a t i v e s may in te r fe re s e l e c t i v e l y wi th
the r edox reac t ions of the p a r a s i t e energy metabolism and if found
ac t i ve may s e r v e as lead compounds for drug development work .
98
^
N ^ N - - C 0 2 M G
MGO2C/ \ N ^ < ^
.CO2H
X
NOH
N
H ^
XII
M G 0 2 C ^ ^ N H
XI
MGO2C'" \ H
XIII
.CO2MG
H
XIV
N
N - ^ N H C 0 2 M G
N ^COpMG H
XV
99
N-Me
XVI XVfl
NH
N ^ N H C 0 2 M e
MGO2C
NHCO2MG
CO2MG
XVIII
H
XIX
R
" ^ ^ C H ^ N H ^ / NCO2MG
NHCO2MG
XX
M G
^ N H C 0 2 M G
M G 0 2 C - •N / CO2MG
-H
/ ; •N :
Ar- -N CO2MG
XXII
CHAPTER 5
5.1 : Syntheses of 4-Benzoyl-N-[ 5( 6)-(2-methoxycarbonylamino)-benzimidazolyl ]pyrrolidin-2-one
5.2 : Syntheses of |3-[ (2-Methoxycarbonylamino)-5(6 )-benzirnida-zolyl ]-acrylic acid. Methyl 5( 6)-[ 5-ethoxycarbonyI-6-methyl-3 ,4-dihydropyrimidin-4-yl lbenziinidazole-2-carba-mate and 2-Methoxycarbonylaniino benzimidazole-5( 6 )-acetoxime
5.3 : Methyl-5(6)-[2 ,5-dimethyl-3-methox year bony 1-N-substituted pyrrolo ]-benzimidazole-2-carbaraates and Methyl-5(6)-N-[2 ,5-dimethyl-3-methoxycarbonyl-4-substitutedphenyl ] -benzi mi dazole-2-carbamates
5.4 : Comparative C-NMR study of tetrasubsti tuted furans and tetra/pentasubsti tuted pyrroles
5.5 : 2 ,2'-Dicarbomethoxyamino-5 ,5'-dibenzimidazol-yl-methanol
5.6 : 5-Ethoxycarbonyl-(2-( l-methylpiperazino )-6-phenyl-4( IH)-pyriraidine and 5-Aryl-6-ethoxycarbonyl-7-methyl-3-oxo-2,3-dihydro-5H-thiazoIo [3,2-a] pyrimidine
5.7 : Methyl 5(6 )-N-[ (2-methylmercapto-6-methyl-4-phenyl pyrimi-din-5-yl )methyl lamino benzimidazole-2-carbamate
5.8 : Methyl-5(6)- l4-(2,6-dimethyl-3,5-dimethoxycarbonyl- l ,4-dihydropyridino) 1-N-substituted benzimidazole-2-carbamate and N ,N-Dimethoxycarbonyl-N-(substitutedbenzyl )quanidine
5.9 : Methyl-4(5 )-methyl-5(4)-[ 3 ,4-methylenedioxyphenyl ]-4 , 5 -dihyd^oiraidazole-2-carbamate
5.9a : 1,6-Bis carbomethoxy-2-methoxycarbonylamino-7-methyl-5-(2^-methoxyphenyl)-4,5 ,6 ,7- te t rahydro- l ,3-diazepine
100
CHAPTER - 5
The synthesis of prototype IX required appropriately substi
pyrrolidine-2-one der i -
o Ph
5.1
tuted
vative as the starting material
and for which a model study
was considered desirable because
substituted butyrolactones after
ring opening with primary aro
matic amines, in pr inciple ,
can recyclize to give compounds structurally related to either 99a
or 100.
100
Benzoyl and (£-toluoyl)- / -butyrolactones (103, 104) , required
for the model s tudies , have been prepared by reacting appropriate
aroyl propionic acid (101, 102) with formaldehyde and hydrochloric
acid. Reactions of 103 and 104 with £-anisidine yielded compounds
which were devoid of IR signals for lactone carbonyls. This suggested
that the lactone ring had part icipated in the reaction and the mass
spectra of the compounds suggested that the opening of lactone ring
must have been followed by a ring closure reaction. In order to
eliminate one of the two possible structures (99a and 100), studies
on the C-nmr spectra of two compounds (105, 106) were undertaken.
The difference in the chemical shifts of methylene carbon attached
to the hetero atom in 104 and 105 (Scheme 19) was of a diagnostic
value for the structural assignment of the reaction product. The
appearance of the methylene carbon attached to the hetero atom in
104 at 69.07 6 ppm and in 105 at 50.58 6 PPm indicated that the
methylene carbon in the reaction products was not attached to oxygen.
This lent support for structure 105 and further support for the ass i
gned structure was obtained from the N signal. The appearance
101
/ « ,
1-Q7 (O)
erx}^' H /H
1Q9
-COOH
1Q1.R=H
102 -R^Me
a". 69.07 103 •.R=H
1 0 4 •R = CH3
"a 5056 b:3fr02 c-35.68 d 171.21 e:5547 f:2165 g:19737
o:5121 b 38A8 c:35J6 d:173A0 e: 55.39 f.2106 g 75.41
a,HCHO/HCi, b,g-Anisidine, c,H2/Pd,C; d,2-Nitro-p-phenytenedianiine,e.H2/Roney-Ni, f,HN=C-NH2/ClC02Me.»)^C-NMR data
S'*'* SCHEME 19
102
of the N signal at 33.689 <5 pprn indicated the amide character of 218a the nitrogen . Catalytic hydrogenation of 105 gave 106 and the
methylene carbon of this compound appeared at 51.27 £ ppm providing
further evidence for the attachment of the methylene carbon with
the nitrogen atom.
These model studies prompted the synthesis of the ninth
prototype molecule namely 4-Benzoyl-N-[ 5( 6 )-(2-methoxycarbonylamino )
benzimidazolyl ] pyrrolidin-2-one (109). Reaction of ^-benzoyl-y-buty-
rolactone (103) with 2~nitro p^-phenylene diamine in presence of t r i -
ethylamine yielded 4-benzoyl-N-( 4-amino-3-nitrophenyl )-pyrrol idin-
2-one (108; Scheme 19). Catalytic hydrogenation of 108 in presence
of Pd/C followed by the ring closure of the resulting diamine with
S-methylisothiouroniumsulphate and methylchloroformate furnished
the desired prototype molecule (109; Scheme 19).
5.2 Unlike the synthesis of IX, the preparation of compounds
relating to prototypes X-XII required the 0-nitroaniline derivat ives
(114, D & 123) as the starting materials, which after catalytic
hydrogenation and ring closure with N ,N-dimethoxycarbonyl-S-methyl-
isothiourea could be expected to furnish the desired compound. Reac
tion of 4-acetamido-3-nitro benzaldehyde (112) with malonic acid
o =c^N-^ OM<2
.C02M<2
X xn
H2N'
NOH
o . ^ M(2
Dl
XI
103
in the presence of c a t a l y t i c amount of p y r i d i n e gave 4-acetarnido-
3-ni t ro cinnamic ac id (113; Scheme 20 ) . Alkaline h y d r o l y s i s of t h i s
compound y i e lded the d e s i r e d s t a r t ing mater ia l (114; Scheme 20 ) .
Pre fe ren t ia l hydrogenat ion of n i t ro group in 114 was p o s s i b l e in
p resence of Raney nickel but i t fa i led for the s t a r t ing mater ia l (D ) .
o
112
H-o=9
OMe
N-</
115 114
a , malonic a c i d , pyridine/MeOH; b , 10% a q . NaOH/MeOH;
c , H , Raney-Ni/MeOH; d , HN=C-NH,/ClCO,CH, SMe
(Scheme 20)
The reac t ion of 4 -ace tamido-3-n i t ro benza ldehyde (116) wi th e t h y l -
ace toace ta te and th iourea under ac id i c condit ion gave 5 - e t h o x y c a r b o -
ny l -6 - r ae thy l -2 -oxo -4 - ( 4 -ace tamido-3-n i t ropheny l ) py r imid ine (117;
o . . - ^
AcHN
a , CHjCOCH^CO^Me, Urea; b , 10% aq.NaOH;
c , H-, Raney-Ni/MeOH; d , MeS-C=NCO,Me '2* NHCO^Me
,N-
OM(2 H NH
M<2 118
(Scheme 21)
104
Scheme 21) which on a lka l ine h y d r o l y s i s y i e lded 118. Hydrogenation
of t h i s compound in p resence of Raney-Ni furn ished the d e s i r e d d i
amine. The diamines p r e p a r e d from 114 and 118 were cyc l i zed by
react ing them with N ,N-d ime thoxyca rbony l -S -me thy l i so th iou rea to
obta in the d e s i r e d p r o t o t y p e compounds 115 and 119 r e s p e c t i v e l y .
Since the p r epa ra t i on of diamine D was not p o s s i b l e , 5 ( 6 ) - a c e t y l
benz imidazole-2-carbamate (124) , p r e p a r e d by the method r e p o r t e d
e a r l i e r , was reac ted wi th hydroxy lamine under cont ro l led condi t ions
to furnish 125 (Scheme 22 ) ,
NOH
AcHN
H 2 N - Y j ^ - ^ ^ M e
D2
Q
AcHN
120
122 121
O2N
123
^ Me02C^
O
124
N
MeOpC^ ^N H
NOH
Me
^
< -
125
a , AC^O; B, Fuming HNO^; c , 10% a q . NaOH/MeOH; d , H , Raney-Ni/MeOH;
e , HN=C-NH2/ClC02CHj; f, NH^OH/MeOH
SMe (Scheme 22)
105
5.3 In o r d e r to s tudy the effect of NH and NR in p lace of the
oxygen atom in the furan r ing of a promising anthelmint ic compound
83/148 (CDRI Code n u m b e r ) , t he syn thes i s of XIII was under taken
and as an extens ion of t h i s s t u d y compounds r ep resen t ing p r o t o t y p e
XIV were a lso s y n t h e s i s e d .
O M G H
CO2MC
83 /148 X=0
X111X=NH,NR XIV N'' f>IH
o=c OMe
The syn the s i s of XIII (X=NH) owes i t s or ig in to the o b s e r v a
t ion made during the upscal ing s tud ies of the compound 83/148. It
was o b s e r v e d tha t during the p r e p a r a t i o n of 2 , 5 - d i m e t h y I - 3 - m e t h o x y -
ca rbony l -4 - ( 4 -amino-3-n i t rophenyl ) furan, ( the r e q u i r e d in t e rmed ia te
for the p repa ra t i on of 83/148) was i n v a r i a b l y a s soc i a t ed wi th a
small amount of a r e d compound formed in the reac t ion mix tu re .
This was ident i f ied as 2 , 5 - d i m e t h y l - 3 - n e t h o x y c a r b o n y l - 4 - ( 4-amino-
3 -n i t ropheny l ) p y r r o l e . The formation of t h i s p y r r o l e d e r i v a t i v e
along wi th the cor responding furan in the react ion of 126 in p resence
of methylace toaceta te and p i p e r i d i n e suggested tha t a careful s t udy
of t h i s reac t ion may furnish a reac t ion condition in which the p y r r o l e
could be obta ined as the predominent p roduc t . This prompted to
s tudy t h e Nef react ion of 126 in presence of p r i m a r y , secondary 219
and t e r t i a r y amines and the r e s u l t s were monitored by HPLC
The reac t ion of 126 wi th methylacetoaceta te in p resence of
p r i m a r y amines gave N-subs t l t u t ed p y r r o l e d e r i v a t i v e s (132-137;
Scheme 23) and the cor responding furan d e r i v a t i v e s could not be
de tec ted in the reac t ion m i x t u r e . This method has a p r e p a r a t i v e
value and g ives be t t e r y i e l d s of the p y r r o l e d e r i v a t i v e s as compared
to the method r e p o r t e d in l i t e r a t u r e which i n v a r i a b l y gave poor
y i e ld s of 2 , 5 - d i m e t h y I - 3 - m e t h o x y c a r b o n y l - 4 - s u b s t i t u t e d phenyl p y r r o
les in our hands . The r eac t ion of 126 and methylace toace ta te In p r e
sence of secondary amines gave different percentage r a t i o s of 128
and 130.
106
129 : R = CI
a 131 : R = CI
CH3
CO I — CH2C02Me
126 : R = NH.
127 R = CI
W
128-129 Nl/
H2N
O2N CONHNH2
CH3 CO2CH3
148 :
148a
^ = NHNH.
R = OMe
a , P i p e r i d l n e ;
132 : R = n - B u
133 ; R = CH^Ph
134 : R = 4 - a n i s y l
135 : R = 3 , 4 , 5 - t r i m e t h o x y p h e n y l
136 : R = 4 - a m i n o - 3 - n i t r o p h e n y l
237 : R = ( C H 2 ) j - N ( C 2 H ^ ) 2
b . P r i m a r y a m i n e ; c , T r i e t h y l a m i n e ;
d . H y d r a z i n e h y d r a t e
(Scheme 2 3 )
i ,0 o
W^ o
@ 2 - 0 4 ^
Q::
O
u X
l O
H cc
X u
W [ / 2 O
o
X
r» X
o u X U
cr o u X
u w
K»
X
109
CO
c o U
I l l
For example in presence of piperidine the percentage ratio
of 128 and 130 was 96:4, in morpholine it was 80:20, in N-methyl-
piperazine i t was 89:11 and in presence of N-phenylpiperazine it
was 87:13. Replacement of piperidine with triethylamine in the reac
tion of 126 and methylacetoacetate gave only 128 and the presence
of 130 in the reaction mixture was not detected.
Recent studies on the mechanism of Nef reaction indicate
the formation of an intermediate 138 (Scheme 24). It is l ikely that
reaction of 126 and methylacetoacetate in presence of triethylamine
also yielded an intermediate structurally similar to 138, which after 220 elimination of H O and HNO as suggested by Boberg , yielded the
tetrasubsti tuted furan. In the presence of piperidine the reaction
of 126 and methylacetoacetate possibly proceeds in three direct ions. 221 The formation of intermediates 138 and enamine (143) possibly
c6ntribute towards the formation of tetrasubstituted furan. The th i rd
pathway might involve the addition of water in 140 which leads
to the ring opening and recyclization of the open product to give
tetrasubsti tuted pyrrole (Scheme 24). This pathway possibly becomes
more facile in presence of primary amines and therefore leads to
exclusively N-substituted pyrrole der ivat ives . Despite a successful
synthesis of N-substituted pyrrole derivatives (132-137) , the synthe
sis of 130 by Nef reaction of 126 in presence of methylacetoacetate
and ammonia was not at all promising due to extremely poor yield
( —10%). An alternate preparation was, therefore, sought and this
prompted the reaction of 126 with 144 (Scheme 25) in different sol
vents. The yield of the compound 130 has been improved upto 90%
by using pyridine as a catalyst and methanol as a solvent.
Me-'^NHR 126 M G ^ ^ N R
1 4 4 : R = H 130 : R = H 1*5 ! R = CH3 146 ; R = CH^
(Scheme 25)
112
Based on t h i s o b s e r v a t i o n , a t t empt s were made to p r e p a r e 2 , 5 - d i m e -
t h y l - 3 - a c e t y l - 4 - ( 4 -amino-3-n i t ropheny l ) p y r r o l e by reac t ing 126 wi th
enamine 147. However, i t fa i led to give the d e s i r e d p roduc t . It
w a s , t h e r e f o r e , cons ide red of i n t e r e s t to a sce r t a in the reason which
led to the fa i lure of t h i s r e ac t i on . One of the logical explana t ions
for the fa i lure of 147 to r eac t wi th 126, would be the lack of a d e
quate nuc l eoph i l i c i t y of the carbon csC to the ace ty l g roup . In p r i n c i
p l e , exper imenta l ev idence for the same may be obta ined from the
chemical shif t of carbon atoms s ince subs tan t ia l difference in nucleo
p h i l i c i t y of the carbon atom c< to methoxycarbonyl and ace ty l groups
in enamines 144 and 147 i s bound to make a s ignif icant difference
b ^0CH3
H3C
• a = b = c = d = e =
^ \r
49.48 170.72 81.56 162.59 18.76
a b c d e
= 28.97 = 196.17 = 95.33 = 162.68 = 21,93
13 C-NMR data
(Fig . 4)
in t h e i r chemical s h i f t s . Th i s prompted a compara t ive s tudy of the 13
C-NMR s p e c t r a of 144 and 147. As would be e x p e c t e d , the carbon
o< to the ace ty l group in 147 was d e s h i e l d e d by almost 14 ppm. This
suggested t h a t the enamine carbon in 147 d id not pos ses s adequa te
nuc l eoph i l i c i t y to r eac t w i th 126. The p r e l im ina ry data of the C-
chemical sh i f t of carbon in enamines 144 and 147 tempted to s tudy
the chemical sh i f t s of carbon
atoms in t e t r a and pen t a subs t i t u t ed
p y r r o l e s (154-158 and 158a-158b).
These p y r r o l e d e r i v a t i v e s may
be cons idered as the E-configura-
t ion (F ig . 5) of enamanine in a | r i g i d geometry . Since p y r r o l e s E-Configuration of
enamine e x h i b i t he te roaromat ic c h a r a c t e r (Fig . 5)
13 wh i l e furans fai led to do s o , t he compara t ive C-NMR s tudy of
..'CO2CH3
H^C
113
tetra or pentasubstituted pyrroles (154-158, 158a, 158b) and tetra
substituted furans (a-q ) was considered interesting. The te t ra-
substituted pyrroles (154-158) were prepared by reacting enamine
144 with appropriate nitrostyrene derivatives (149-153; Scheme 26).
The details of th is study are presented in sec. 5,4.
149
150
151
152
153
144
= R = H
R = 3,4-dimethoxy
R = 3,4-methylenedioxy
R = 4-benzyloxy-3-methoxy
R = 4-acetamido
->
154-158 Substituent R correspondence to 149-153
(Scheme 26)
The next phase of the studies on Nef reaction was concerned
with the reaction of 126 with methylacetoacetate in presence of hy
drazine hydra te . Mechanistic considerations of this reaction suggest
the formation of 148a but the excess of hydrazine hydrate possibly
gave 148 (Scheme 23; page 106 ). Preparation of compounds belonging
to prototype XIV required N-substituted pyrrole derivat ives (171-
175) as the starting material. These were obtained by the reaction
of 166-170 with methylacetoacetate in presence of 2-nitro-£-phenylene
diamine (Scheme 27). Hydrogenation of 130, 132-139 and 171-175 in
presence of Raney-Ni followed by their cyclisation with N,N-dimethoxy
carbonyl-S-methylisothiourea yielded the compounds structurally rela
ted to prototypes XIH and XIV respectively (Scheme 26 & Scheme
27).
5.4 Comparative C-NMR study of 144 and pyrrole derivat ives
154-158 revealed two interesting features. Despite the fact that pyr ro
le has a heteroaromatic character , the C-2 in compounds 154-158,
which corresponds to carbon d of 144 (Fig. 4; page 112 ) , appears
as a shielded carbon while C-3 in 154-158 which corresponds to
114
130.132-137 qb
Me02C
a , H , Raney-Nt/MeOH
h, MeO,CN=C-NHCO-Me 2 / 2
SMe
159 ; R = H
160 : R = CH^
161 : R = n-Bu
162 : R = CH Ph
163 : R = 4-OCH^-Phenyl
164 : R = 3 , 4 , 5 - t r i m e t h o x y p h e n y l
i •" = tty 166
H
NHC02Me
R = (CH^)3-N(C2H^)2
(Scheme 26)
166a
167 !
168 ;
169
170
Mo- HMe? Lv_y.
R = H
R = 3 ,4 -d ime thoxy
R = 4-methyl
R = 4-acetamido
R = 4 -benzy loxy-3 -methoxy
a , 2-Nitro-£^-phenylene diamine
b , H , Raney-Nl/MeOH c , MeO-CN=C-NHCO,Me
2 / 2 SMe
Subst i tuent R co r r e sponds to 166a-170
Subst i tuent R co r r e sponds to 166a-170
N ^ N H C 0 2 M G
(Scheme 27) 176-180
115
carbon C in 144 (Fig.5; page ) appears as deshielded carbon.
This may be explained by assuming that 144 in solution possibly
exists as 144a. This is why the
methyl carbon in 144 appears K-) t ^ "
downfield than the methyl carbon
attached to position 2 in comp-
ounds 154-158. 1 4 4 Q
The comparative study of the C-NMR spectra of te t rasubst i -
tuted furans and tetra or pentasuhstituted pyrroles (Tables A.B)-/as
concerned with the chemical shift of C-Z, C-3, C-4 and C-5 in these
class of compounds. As would be expected C-2 and C-5 in furans
appeared downfield than the corresi^onding pyrrole der ivat ives . How
ever , C-3 and C-4 may be expected to show different chemical shift
in these two class of compounds, because furan lacks heteroaromaticity
while pyrrole possesses the same. Surprisingly the chemical shift
of C-3 and C-4 in furans are marginally different from those of py
r ro les . This would also explain that effect of substituents on the
phenyl ring on C-4 in these class of compounds remains unaltered.
The effect of substituents on C-3, the chemical shifts of C-2 in furans
(a-q) indicated that a methoxycarbonyl or an acetyl residue predomi
nantly deshielded C-2 while an amide function led to a shielding
of almost 9-10 ppm. In continuation of this study the observed
chemical shifts of C-2, C-3, C-4 \ C-5 in furans and pyrroles were
compared with the theorit ical values computed by a computer for
representative compounds (Table C).
5.5 The synthesis of next prototype molecule (XV) namely 2,1'-
Dicarbomethoxyamino-5,5'-dibenzimidaaolylmethanol is based on the
presumption that the carbinol of 82/437 (CDRI Code number) in bio-
phase may slowly get oxidized to the parent compound which has
exhibited significant broad-spectrum anthelmintic ac t iv i ty . In a situa
tion such as this the carbinol may exhibi t longer duration of action.
MG02C-"' \ N ^ L ^ l ^ ^ y ^ N ^ C02M<2
82/437: X = CO XV:X= CHOH
116
to
c Id u b
•a
m 3
1-4
o H
« o
(0 U
tn 3 O • Id >
o
Id
e
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(0 C o X) t-4 (d U )-• (U J3
X u
I i n
•X,
u
in
U
U
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o;
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f\J ro
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i n
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• fo >£)
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o
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CO • *
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u ul (M fM
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in 00
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fv o u
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t--
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po "O
X u o u X 2 I
117
O '^
u I o
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E o u
o I i n
X U
81 2
O^ I—I t— sO ^ r o NO (^ li^ i n
• • • • • o t ^ t ^ f* ^ m f M f M <-! vO
I
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m 0 0 ^ t ^
t ~ t ~ >o "* N fvj
CO
0.00
X ul o u X
- <=> o — i n ^
ol I o
^ X
, O
"a" o >o vO ( M ^
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(\r~ o O MM U == J
rsj i-H vO ( - ) .-H i-H i - l " - '
o
^ Ul X U
o ^ S O
i n (vj rs) r j o * pn psj <M
0 0 0 0 t ^ fvj < U l -o 2 TT -v] r j 04 < U l * .
X " " U - ^ r .
f v r - o^ O '^ . Ul??,in
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pn
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f«» • • • • f - ( I—I ^ o i n r-H t—I o i n i n
t~- (M
. . • I Lr> - o t - <M tr ^ CO Q
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m r o i n f—
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l-i
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118
^ ^ 00 m <-i t~
p l r^ f O r g 1—4 r-H
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(M t^ m (M I - l 1—1
ry oo
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f o
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• 1—1
m r—1
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t—*
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t>-0 0
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• • • • • • po ^ m m m ^
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• • a • • •
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t^ pn in (T-
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119
• • • • r< -^^ i n O* m C^ >0 GO r»T5^ O^ fNj "q* 00 • nC •
• • • • l A f ^ l i T i vO t^ • « f n O X ' ' m (VI (M >-< i-H J-^
• i n
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• • ^ • , CO - O N O C^ ^
fo o o in i n I—I 00 (\j
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in r-i o o ,^ r - t ^ 0 0 <\j . "
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t - ' T t— t ^ i n PO oo >-H
C^ OO NO rsj
u o
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m
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00 o^
m in
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0 O 0 = 0
I ono I
(N) >- o c •<-'
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4-1 4)
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120
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122
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123
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124
It was a lso cons idered d e s i r a b l e to eva lua te the ca rb ino l as a chemo-
p r o p h y l a c t i c . The s y n t h e s i s of 183, r e p o r t e d e a r l i e r in t h i s l abo ra
to ry was s l i g h t l y modified to obta in a be t t e r y i e l d and the main
sequence of reac t ions a r e d e s c r i b e d in Scheme 28 . The reduc t ion
of the carbonyl group in 183 was diff icul t but large e x c e s s of sodium
b o r o h y d r i d e he lped in obta ining . 184. Hydrogenation of t h i s compound
followed by ring c losure wi th N , N - d i m e t h o x y c a r b o n y l - S - m e t h y l i s o t h i o -
urea furnished 185 (Scheme 2 8 ) .
a O2N
• ^
NO2
181 182
184
M G 0 2 C - ^ ^ N H
183
^C02M(2
185
a . Cone. HNO ; b , a q . NH ; c , NaBH4/MeOH; d , H^, Raney-Ni/MeOH e , l/IeO,CN=C-NHCO,Me
2 I SMtt
(Scheme 28)
125
5.6 As an extension of our exploratory research act ivi t ies for
identifying new molecular structures associated with broad-spectrum
anthelmintic ac t iv i ty , the syntheses of prototype XVI-XVII were consi
dered of interest . The starting compounds 192-197 were obtained
by Biginelli reaction.
Et02C
H / \ Nv^/N N-Mc
II "^^ N
Me
XVI xvn
Acid catalysed reaction of aromatic aldehyde with ethylaceto-
acetate in presence of urea to yield 5-ethoxycarbonyl-6-methyl-4-
phenyl-3,4-dihydropyrimidin-2-one (202) , commonly known as Biginelli
reaction , was reinvestigated by Hinkle and Hey and it was
observed that the replacement of urea with thiourea led to the forma
tion of the corresponding 3,4-dihydropyrimidin-2-thione derivatives
(192-197; Scheme 29).
Before undertaking the synthesis of dihydropyrimidine proto
types XVI and XVII, model studies on the alkylation of 5-ethoxycar-
bonyl-6-methyl-4-phenyl-3 ,4-dihydropyrimidin-2-thione (192) , were
considered as essential prerequis i tes . Reaction of 192 with methyl
iodide under various experimental conditions was studied. This reac
tion in presence of sodium hydroxide in methanol yielded 198 (Scheme
29). Earlier workers have prepared th is compound by reacting
5-ethoxycarbonyl-2-methylmercapto-4-methylpyrimidine with phenyl
magnesium halide and the spectroscopic data of the reaction product
reported by them agreed well with that of 198. Reaction of 192 with
methyl iodide in presence of soidum hydroxide in DMSO gave 190
(Scheme 29). Deraercaptation of 199 with strong acid gave 201 (Scheme 225
27). The U.V. absorption maxima at 290 nm supported the assigned
structure. Finally the reaction of 198 with N-methylpiperazine yielded
the prototype molecule 200 (Scheme 29).
126
Q
186
187
188
189
190
191
:
:
:
:
:
R
R
R
R
R
R
=
=
=
=
=
H
3 ,4 -d imethoxy
4-niethoxy
3-niethyl
4-acetaniido
4-n i t ro
\l/
M G
,NH2
K ^NHo
Subst i tuent R co r re sponds to 186-191
\l/
H r-\ N x ^ N N M G
11 ^ N
M G
201
M G
202 a, CH^I, NaOH/MeOH; b , CH I , NaOH/DMSO; c , N - m e t h y l p i p e r a z i n e ;
d , H,SO^/MeOH 2 4
(Scheme 29)
127
In the l ight of t h e s e obse rva t ions a l k y l a t i o n of (192-195)
with monochloroacetic ac id in presence of potassium h y d r o x i d e in
methanol could be expec t ed to y ie ld the p ro to type (XVII) molecules
202-205 but the reac t ion of 192, 194, 195 wi th monochloroacetic ac id
in presence of potass ium h y d r o x i d e y ie lded 205-208 (Scheme 30)
whi le the reac t ion of 192-195 wi th monochloroacetic ac id in presence
192-195
rile COOH
202 :
203 :
204 :
20'5 :
R = H
R = 3 ,4 -d imethoxy
R = 4-OCH^
R = 3-CH,
206
207
R = H
R = 4-OCH.
208 : R = 4-NHCOCH.
a , CICH CO H, BF .Et^O/MeOH; b , CICH^CO^H, NaOH/MeOH
(Scheme 30)
BF e t h e r a t e y ie lded 202-205 (Scheme 30) . The cyclocondensat ion
of 192-196 wi th monochloroacetic ac id i s expec ted to y ie ld two i so
meric b i c y c l i c s , 5 - A r y l - 6 - e t h o x y c a r b o n y l - 7 - m e t h y l - 3 - o x o - 2 , 3 - d i h y d r o -
5H-thiazolo [ 3 , 2 - a ] p y r i m i d i n e s (202-205) and 7 -Ary l -6 -e thoxyca rbony l
5 - m e t h y l - 3 - o x o - 2 , 3 - d i h y d r o - 7 H - t h i a z o l o l 3 , 2 - a l p y r i m i d i n e s . Of t he se
the former could be i so l a t ed from the react ion mix tu re . The s t r u c t u r e
of 202-205 was suppor t ed by t h e i r PMR data (Table 24 , page n ^ )
which r evea l ed a downfield shi f t {—0.70 S ppm) of the methine proton
at posi t ion 6. Th i s can only be exp la ined if 3-N i s invo lved in r ing
c losure to form 202-205.
As a next s t ep towards the s y n t h e s i s of yet another 1,4-
d i h y d r o p y r i m i d i n e d e r i v a t i v e , benza ldehyde was r eac t ed wi th e t h y l
128
t r i f luoromethy lace toace ta te in p resence of t h i o u r e a . It was in t e re s t ing
to note tha t ins tead of 1 , 4 - d i h y d r o p y r i m i d i n e d e r i v a t i v e , t he i n t e r
mediate 209, 210 (Scheme 31) was obta ined as a mixture of d i a s t e r e o -
mer s . Isola t ion of t h e s e compounds has a s ignif icance because no
in te rmedia te a p p e a r s to have been i so la t ed from the Biginel l i r e a c -223 t ion . Ring c losure of 209 wi th p o l y p h o s p h o r i c ac id gave 211
(Scheme 31) .
R = H, 4-NHCOCH.
+ CF3COCH2C02Et
S ^
a
211 H a . Thiourea ; b , Po lyphos
pho r i c ac id
209 H
210 : R = 4-NHCOCH,
MeO
(Scheme 31)
5.7 In o rde r to eva lua te the cont r ibut ion of p y r i m i d i n e moiety
appended with benz imidazo le -2-carbamate nuc leus , the s y n t h e s i s of
p ro to type XVIII namely methyl 5 (6)-N-[ ( 2 - m e t h y l m e r c a p t o - 6 - m e t h y l -
4-phenyl p y r i m i d i n - 5 - y l )raethyl ] amino benz imidazo le -2 -ca rbamate
was under taken . The syn the t i c
s t r a t egy of p ro to type XVIII invo lves
oxida t ion of 198 wi th manganic
ace ta te to obta in 212 (Scheme 32)
which on reduc t ion wi th sodium
b o r o h y d r i d e y ie lded a mixture
of 213 and 214 (Scheme 32) which XVIII
were s epa ra t ed through column
chromatography . However, LAH reduct ion of 212 d id not lead to the
129
Ph>YXN>Y'SCH3
CH3
198
SCH3
Phv,,;;^Nv>^SCH3 II
SCH3
R, , '"Yi^' E t 0 2 C ^ ^ X ^ ^
CH3
213 R:SCH3
214 R=0CH3
IV
216
Ph> -N.
CH3
217
SCH3
N>^SCH3 ;i7 NH CH3
VII,VIII P h \ ^ N ^ S C H 3
NH MU I
VI
H N ~ ^
CH3
NO2 NH2
NHCO2CH3
220 219
Ph. -N.
X- ^ S C H 3
Br CH3
218
I.Mangnic acetate/Benzene. II NaBH^/MeOH.III LAH/Ether,IV Pyridimum
chlorochromate,V.PBr3,Et3N/Benz€ne;VI.H2N-0-NH2,Et3N/ Benzene
VII H2/RQneyNi.VIlI.Me5-C=NC02Me ^^^ NHC02Me
Scheme 32
130
reduction of pyrimidine ring but gave a mixture of 215 and 216 (Sch
eme 32) which were also separated through column chromatography.
The spectroscopic data of these compounds supported the assigned
structures and as an additional evidence 216 was oxidized with pyr i -
dinium chlorochromate to yield 217 (Scheme 32). Reaction of 216
with PBr gave 218 which in turn was reacted with 2-ni tro-p-phenyl-
enediaraine to get 219. Finally hydrogenation of 219 in presence of
Raney-Ni as a Catalyst and cyclisation of the resulting diamine with
N,N-dimethoxycarbonyl-S-methylisothiourea furnished the prototype
molecule 220 (Scheme 32).
5.8 Synthesis of molecules belonging to prototype XIX required
87, 88 and ^ as the starting materials and their synthesis have
already been reported in section
2 .5 . Hydrogenation of 87^ or 88^
gave the desired diamines which
were cyclized with N,N-dimethoxy-
carbonyl-S-methylisothiourea to
obtain the desired benzimidazole
carbamate derivatives (Scheme
33). The compounds representing
prototype XX (227-229) were pre
pared by reacting appropriate
benzylamines with N .N-dimethoxy-
carbonyl-S-methylisothiourea (Sch
eme 33).
/NHCO2MG CHpNHA
\ N C 0 2 M ( 2
XX
5.9 The synthetic strategy employed for the prototype XXI invol
ved the reaction of 2-n i t ro- l -
(3 ,4-methylenedioxyphenyl )-propene
with hydroxylamine hydrochloride
and as would be expected, a
mixture of theo isomers of 1-
hydroxylamino-l-(3 ,4-methylene
dioxyphenyl )-2-nitro propane XX i
was obtained (230; Scheme 34). Separation of these two isomers by
fractional crystallisation or preparat ive TLC was unsuccessful but
the column chromatography of the isomeric mixture over silica gel
revealed an interesting feature. It was observed that only one of
131
M e 0 2 C COoMe
H
90
-^ MGO2C
NHC02Me
CO2MG
H
221
R
.-^^^^2
MGO2C CC^Me
H
87. R = NHM2 88R=NHCH2Ph
a,b
RN'
Q -> MGO2C
NHCOpMe
i N
CO2M2
H
2 2 2 . R = M G
223 R=CH2Ph
^ '
CH2NH2 R-
2 2 4 : R = H
225: R=3,4-m(2thylGnGdioxy 226.R=3.4-dimgthoxy
R- 0 CH2NH^ NCO2MG
NH CO2M2
227-229 SubstituGnt R as in
224-226
a = H2,RaneyNi/MeOH, b= MeS-^'^J^J^'^® ^NHC02M2
Scheme 33
132
Me^ ^N02
a • >
^
CO2MG
NHOH
W
NH2
231
a , NH OH/MeOH; b , H /Raney-Ni; c , MeS-C=NCO Me
NHCO Me
HOHN
N02
230a(FfF^:Thrgo) NHOH
230b(Frs*:Ervthro)
(Scheme 34)
133
the two p o s s i b l e d ia s t e reomers was obta ined in pure s ta te whi le
the second isomer was pos s ib ly involved in a r e t ro r eac t i on leading
to the formation of s t a r t ing n i t r o p r o p e n e . Two p o s s i b l e conclusions
can be drawn from t h i s obse rva t i on . F i r s t l y , t he or ien ta t ion of the
NHOH and H in one of the d ias te reomers must be anti to each o the r
o the rwise the e l iminat ion of NH^OH would not have occured . Secondly,
the isomer which was obta ined in a pure s t a te must possess NHOH
and H groups in o r ien ta t ion which would not allow the e l iminat ion
of NH OH. In a s i tua t ion such as t h i s , two pos s ib l e d i a s t e reomers
(230a and 230b) can be env i saged . The dias tereoraer 230b {R*S*;
e r y t h r o ) would be e x p e c t e d to be ene rge t i ca l ly favoured since the
bu lky groups (Ph & NO^) a re t r ans to each o the r t h e r e b y minimising
the gauche i n t e r a c t i o n s . The s t e r eochemis t ry would a lso permit h y d r o
gen-bonding between NHOH and NO and thus becomes the favoured
d ia s t e reomer , Hydrogenation of 230 wi th Raney-Ni led to the formation
of 231 which was cyc l i zed with N ,N-d ime thoxyca rbony l -S -me thy l i so -
th iourea to ob ta in the r e q u i r e d p ro to type molecule 232 . The i n t e r
mediate diamine 231 was not ve ry s t ab l e and was the re fo re c h a r a c
t e r i z e d as i t s d i h y d r o c h l o r i d e . The r e l a t i v e s t e r e o c h e m i s t r y in 232
was asce r t a ined from the decoupled PMR spec t rum. A doublet (J =
7Hz) at 3.63 - 3.71 d ppm for the methine proton adjacent to methyl
group and a doublet (J = 7 Hz) at 4.23 - 4.31 ef ppm for CH adjacent
to a r y l group suppor t ed t rans s t e r e o c h e m i s t r y for two p r o t o n s .
A r e t r o s p e c t i v e a n a l y s i s of the s t e r eochemis t ry of 230b, on the bas i s
of obse rved r e l a t i v e s t e r eochemis t ry in 232 a l so suppor t s the ass igned
s t e r eochemis t ry of 230b.
5.9a A retro-synthet ic approach for obtaining prototype XXII re
vealed methyl-2-substituted-3-amlno crotonates (233-236) as starting
materials. These were prepared M G p p ^ i .
by reacting l -ary l -2 -n i t ro ethylene M c 0 2 C \ / ' "N 227
with methyl-3-amino crotonate
Nucleophilic displacement of NH Ap
with NHOH group in 233-235 gave ^..
237-239 (Scheme 35) , The structural and stereochemical assignments
of these compounds were concerned with three problems. F i r s t ly ,
it was essential to ascertain whether the compounds ex i s ted as oximes
or as the tautomeric hydroxylamines. In case the compounds were
oximes , the stereochemistry across the -C=N, the second problem
.l^^<" CO2MC
1 J 4
R-NO2
.CO2M2
M G ^ ^ N H 2
a
.C02M<2
'^ MG
233 : R = H
234 : R = 3,4-Dimethoxy
235 ; R = 4-Methoxy
236 ; R = 4-Nitro
b V
. 9^C02M2
Me02Cv^X^N-C02M<2 / ^ N H C 0 2 M e N
MsO 249
\|/
248 : R = 4-Methoxy
a , MeOH; b , NH OH/MeOH; c , d i l .H^SO^/MeOH;
d . Mono p e r p h t h a l l i c ac id or m-CPBA; e , H , , Raney-Ni/MeOH;
f, Me§?C=NC02CH2 NHCO^CHj
(Scheme 35)
135
in the present context, had to be ascertained. Thi rd ly , the relat ive
stereochemistry across the two assyrametric carbon centres (in case
the compounds were oximes) had to be worked out. Indirect evidence
for the structure of compounds 237-239 was obtained from the following
chemical reactions. Acid hydrolysis of 233-235 furnished the ketones
240-242 which could then be converted into 237-239 by reacting them
with hydroxylamine hydrochlor ide. The direct evidence for the assign
ed structures of the compounds was obtained from the C-NMR spec-
trum of one of the representative compound (239). The C signal
for -Cj=N at 158.51 i ppm in the NMR spectrum of 239 and the appear
ance of the carbon of methyl group at 12.05 6 ppm indicated it to
be anti oxime . In order to ascertain the stereochemical purity
of compounds 237-239, the multiplicity of the methine proton (Ctl-
CO Me) was studied. However, this methine proton in these compounds
appeared along with the signals of other methine and methylene pro
tons in a 90 MHz PMR spectrum. This prompted to record a 400 MHz
PMR spectrum of one of the representative compound (239). The app
earance of a neat doublet at 3.72 6 ppm in the PMR spectrum sugges
ted stereochemical homogenity and indicated stereoselective formation
of only one diastereomer. The other minor diastereomer could not
be isolated from the reaction mixture and in the absence of this
minor diastereomer, the relat ive stereochemistry of 239 could not
be ascertained. Reaction of 233-236 with ei ther monoperphthalic acid
or m-chloro perbenzoic acid yielded 243-246. It was interesting to
note that the te r t ia ry hydroxyl group in these compounds was not
prone to easy elimination reaction and the reaction of 243-244 with
hydroxylamine hydrochloride yielded oximes 247-248 without eliminat
ing a molecule of water. The presence of a ter t iary hydroxyl group
in these compounds was evident from the PMR signal (DO exchangea
ble) at 4.0 6 ppm. The s tabi l i ty of the te r t ia ry hydroxy groups
in compounds 247-248 suggested that the hydroxyl group was not
placed anti to vicinal CH[. In the light of this observation the Dreid-
ing models of various rotamers of the two possible diastereomers
were studied to ascertain the s ter ic crowding in the molecule. On
the basis of Dreiding model the stereochemically most favoured dia-
stereomer (I ; R R , threo) is described below:
136
OH
HON.
O2NH2C
^ ^ / ^ ^ ./NOH
OMe' 3
I II In order to obtain a representative compound of the desired
prototype XXII, compound 239 was hydrogenated over Raney-Ni and
the resulting solution was reacted with N ,N-dimethoxycarbonyl-S-me-
thyl-isothiourea to yield 249. The appearance of one broad singlet
and a sharp doublet for the methyl protons in the PMR spectrum
(400 MHz) indicated it to be a mixture of stereomers. This was fur
ther supported by the appearance of two extremely close peaks in
the HPLC spectrum. Preparative HPLC to separate the isomers was
not attempted. The possible mechanism of formation of compound 249
is described in scheme 36.
137
H H
O2N-
,C02Me ^^ H H
A r ^ 1 A ^COaMG
• ^
NOH HoN H rt NHOH/NH2
Mc Mc
M G S H ^ NCO2MC
-NH2OH/NH3
Ar CO2MG /^
HN / /V -NHC02Me
N C02Me
NHC02M(2 V
A r C02M<2
H 2 N - ^ ^)~^
M<2
Me
M < 2 0 2 C ^ X N , / .C02Me
-N -H
A r ^ \ ^N / / ' ^ C 0 2 M e
Scheme 36
13TB
CHAPTER - 6
EXPERIMENTAL
6.1 The melting points were determined on a sulphuric acid
bath or an electrically heated block and are uncorrected. All the
reactions were checked by thin layer chromatography over silica
gel G or alumina (basic or neutral) plates using iodine vapours.
KMnO. spray or Dragendorf's spray as the developing reagent. The
structures of all the compounds were routinely checked by IR and
PMR Spectroscopy-IR spectra were recorded on Perkin-Elmerl57 infra-
cord and Beckman Acculab-1 grating instruments and values are expre
ssed in cm . PMR spectra were recorded on varian EM 360L or
Perkin-Elmer R-32 using TMS as internal reference (Chemical shift
in S ppm). C-NMR spectra were recorded on CFT-20 spectrometer
operating at 20 MHz, 8192 data points were collected and a sweep
width of 5000 Hz was used. Pulse delay of 0.5 sec. was essential
for recording the signals of carbonyl carbons. C-NMR spectra were
also recorded on a Bruker WM-400 FT NMR spectrometer. Mass spectra
of these compounds were recorded on Jeol-D 3000 instrument. The
second place after the decimal point in the required value of C,H,N
analyses have been approximated.
P-Aroyl propionic acid (101-102)
These compounds were essentially prepared by the method
reported earlier
/3-Aroyl-/-butyrolactones (103,104)
These compounds were prepared in better yields by modifying 41a
the method reported earlier . The details are as follows:
Formaldehyde (37.41%; 0.30 mole) was added to a stirred
solution of /3-aroyl propionic acid (103, 104; 0.27 mole) in NaOH
solution (0.5N, 60 ml, 0.30 mole). After stirring at room temperature
(25') for 1 hr. the mixture was acidified with cone. HCl (^15 ml)
and stirred at room temperature (25°) for additional 12 hr. The
separated semi solid was triturated with ether to obtain the required
compound. The mother liquor was again stirred at room temperature
(25°) for 4 hr. and the separated solid was filtered. The combined
solid product was recrystallised from hot benzene.
139
41a +
103 : Y i e l d 82%; m . p . 62 -64° ( L i t . m . p , 6 3 - 6 5 ° ) ; M
a t m/z 190
I R ( K B r ) : 1670 & 1775 (CO) PMR ( C D C l , ) : 2 . 7 1 - 2 . 8 8 ( t , 2H, C H , ) , 4 . 2 5 - 4 . 5 3 ( m , 3H, OCH )
3 i ^ & C H ) , 7 . 2 6 - 7 . 5 8 ( m , 3H, 3 , 4 i 5Ar -H) , 7 . 7 2 -7.90 ( m , 2H, 2 & 6 A r - H ) .
41d +
104 : Y i e l d 80%; m . p . 84-85° ( L i t . m . p . 8 5 - 8 7 ° ) ; M
a t m/z 204
IR (KBr) : 1670 & 1760 (CO) PMR(CCK+CDC1,) : 2 . 4 0 ( s , 3H, C H , ) , 2 . 6 9 - 2 . 8 2 ( { t . 2H, CH ) ,
4 3 ~i '^
4 . 1 2 - 4 . 5 8 ( m , 3H, OCH^ & C H ) , 7 . 2 0 - 7 . 2 9 ( d ,
2H, 3 & 5 A r - H ) , Jo = 9 H z ) , 7 . 7 3 - 7 . 8 3 ( d , 2H,
2 & 6 A r - H , Jo = 9 H z ) .
4-Aroyl-N-(£-methoxyphenyl)-pyrrolidin-2-ones (105 & 107; Table 15)
General Procedure:
To a mixture of 103 or 104 (0.1 mole) and £-anisidine (0.1
mole) in alcohol (6 ml) was added triethylamine (0.2 mole) and ref-
luxed for 8 hr. Water was added to it and extracted with ethyl aceta
te. Usual work up of organic layer yielded a residue which was trea
ted with ether to obtain a solid. It was recrystallised from a mixture
of chloroform-hexane.
4-( 0(-Hydroxy-4-methyl) benzyl-N-(£-methoxyphenyl) pyrrolidin-2-one
(106)
A solution of 105 (0.01 mole, 3.0 gm) in methanol (35 ml)
was hydrogenated in presence of Pd/c (10%, 0.3 gm) at 2,5 kg/cm
for 2 hr. The catalyst was filtered off and the filterate was concen
trated under reduced pressure. The residue on trituration with CCl
furnished a crystalline solid which was recrystallised from hot CCl .
106 : Y i e l d 90%; m . p . 1 1 5 - 1 6 ° ; M"^ a t m/z 311
PMR (CDCl^) : 2 . 3 0 ( s , 3H, C H ^ ) , 2 . 5 4 - 2 . 7 2 ( m , 2H, C H - C H ^ ) ,
3 . 4 0 - 3 . 8 0 ( m , 6H, OCH ) , NCH^ & C H ) , 4 . 4 0 -
4 .60 ( m , I H , CHOH), 6 . 7 0 - 7 . 4 5 ( m , 8H, A r - H ) .
4-Benzoyl-N-(4-amino-3-nitrophenyl)-pyrrolidln-2-one (108; Table 15)
The experimental procedure was essentially same as described
for 105 but instead of 2.-anisidine, 2-nitro-£-phenylene diamine was
140
used . The compound 108 was r e c r y s t a l l i s e d from e thy l a c e t a t e - e t h e r
mix tu re .
Catalytic hydrogenation of 108
A solution of 108 (0 .65 gm, 0.02 mole) in methanol (30 ml)
was hydrogena ted a t 2.5 kg/cm in the presence of Raney-Ni ( 0.3
gm) io r 30 minutes . Ca ta lys t was f i l t e red off and the solvent was
removed under reduced p r e s s u r e . The r e s idue without fu r ther pu r i f i ca
tion was u t i l i s ed for the next s t e p .
4-Benzoyl-N-I5(6)-(2-methoxycarbonylainino) benzimidazolyl 1 pyrro l id in-
2-one (109; Table 15)
Aqueous NaOH solution (25%, 3 ml) was added under s t i r r i n g
to a precooled (10-15°) mixture of S-methyl isothiouronium su lpha te
(0 .01 mole) and methylchloroformate (0.02 mole) in water (4 ml)
and the pH of the reac t ion mixture was maintained between 8.0 - 9 .0 .
Glacial ace t i c ac id was then carefu l ly added for readjus t ing the pH
to about 5.0 and to t h i s mix tu re , was then added the r e q u i r e d diamine
(mentioned a b o v e , 0.01 mole) in methanol (15 m l ) . This reac t ion mix
tu re was re f luxed for 3 h r , cooled to room tempera tu re and f inal ly
d i lu ted wi th w a t e r , the so l id so obta ined was f i l t e r e d , washed wi th
water and d r i e d . I t was r e c r y s t a l l i s e d from e thano l .
4-Acetanildo-3-nitro benzaldehyde (112)
This was p r e p a r e d by the method r e p o r t e d e a r l i e r
4-Acetamido-3-nltro cinnamic acid (113)
To a mixture of 112 (2 gm, 0.01 mole) and malonic ac id
(1 gm, 0.01 mole) in ethanol (5 ml) was added p y r i d i n e (0 .1 ml)
and re f luxed for 2 h r . The s e p a r a t e d so l id was f i l t e r e d , washed
wi th hot ethanol (5 m l ) , d r i e d and r e c r y s t a l l i s e d from DMF-H O mix-
Yield 88%; m . p . 254-5°; M* at m/z 250
1620, 1690 (CO)
2.08 ( s , 3H, NHCOCH^), 6 .50-6.58 ( s , IH, =CH,
J = 16Hz), 7 .40-8 .20 (m, 5H, Ar-H, =CH. & NH)
Requires : C, 52.80; H, 4 .00; N, 11.20
Found: C, 52.60; H, 3 .80; N, 11.50.
t u r e .
113
IR(KBr)
PMR (DMSO-
Sl"l0^2°5
•'^6^
141
4-Ani lno-3 -n i t ro c innamic a c i d (114)
To a s u s p e n s i o n of 113 ( 2 . 5 gm, 0 . 0 1 mole ) in m e t h a n o l (8
ml) w a s s l o w l y a d d e d a q u e o u s NaOH s o l u t i o n (10%, 2 . 5 ml) a n d s t i r r e d
a t room t e m p e r a t u r e ( 2 8 ° ) for 30 m i n u t e s . A m i x t u r e of w a t e r (10
ml) a n d a c e t i c a c i d ( 0 . 1 ml) w a s a d d e d to t h e r e a c t i o n m i x t u r e a n d
t h e s e p a r a t e d s o l i d w a s f i l t e r e d , w a s h e d w i t h w a t e r , d r i e d a n d
r e c r y s t a l l i s e d from DMF-H O m i x t u r e .
114
IR (KBr )
PMR (DMSO-d, ) o
S«8^2°4
Y i e l d 9 0 1 ; m . p . 2 0 6 - 7 ° ; M a t m/z 208
1690 ( C O ) , 3350 (NH)
6 . 1 0 - 6 . 4 0 ( d , I H , =CH, J = 1 6 H z ) , 6 . 9 0 - 7 . 0 8
( d , I H , =CH-CO H, J = 1 2 H z ) , 7 . 3 0 - 8 . 0 0 ( m ,
5H, Ar-H & NH^)
R e q u i r e s : C , 5 1 . 9 2 ; H, 3 . 8 4 ; N, 1 3 . 4 6
Found : C , 5 2 . 2 0 ; H, 3 . 5 0 ; N, 1 3 . 1 1
C a t a l y t i c h y d r o g e n a t i o n of 114
T h e e x p e r i m e n t a l p r o c e d u r e w a s e s s e n t i a l l y s ame a s d e s c r i b e d
for t h e r e d u c t i o n of 108 a n d t h e r e s u l t i n g d i a m i n e w a s u s e d for t h e
n e x t s t e p w i t h o u t f u r t h e r p u r i f i c a t i o n .
/ 3 - I ( 2 - M e t h o x y c a r b o n y l a m i n o ) - 5 ( 6 ) - b e n z i m i d a z o l y l ] - a c r y l i c a c i d (115)
T h i s w a s p r e p a r e d b y t h e m e t h o d d e s c r i b e d for 109 a n d
r e c r y s t a l l i s e d f rom DMF-H O m i x t u r e .
115
I R ( K B r )
PMR ( D M S O - d . ) 6
S2«llN3°4
Y i e l d 63%; m . p . > 3 0 0 ° ; M a t m/z 261
1665 ( C O ^ H ) , 1720 (CO)
3 .73 ( s , 3H, CO^CH^) , 6 . 2 4 - 6 . 4 1 ( d , I H ,
J = 16Hz, 7 . 1 0 - 7 . 7 8 ( m , 4H, =CH & A r - H )
R e q u i r e s : C , 5 5 . 1 7 ; H, 4 . 2 1 ; N, 16 .09
Found : C , 5 5 . 1 0 ; H, 4 . 2 6 ; N, 15 .80
=CH,
5 - E t h o x y c a r b o n y l - 5 - m e t h y l - 2 - o x o - 4 - ( 4 - a c e t a i i i i d o - 3 - i i i t r o p h e n y l ) p y r i m i -
d ine (117; T a b l e 16)
T h i s w a s p r e p a r e d b y t h e m e t h o d r e p o r t e d in t h e l i t e r a
t u r e 223
5 - E t h o x y c a r b o n y l - 6 - m e t h y l - 2 - o x o - 4 - ( 4 - a i i i i n o - 3 - n l t r o p h e n y l )
d ine (118; Table 16)
p y r i m l -
T h i s w a s e s s e n t i a l l y p r e p a r e d b y t h e m e t h o d d e s c r i b e d for
114 a n d r e c r y s t a l l i s e d f rom DMF-H O m i x t u r e .
142
Methy l -5 (6 ) - t5 -e thoxycarbony l -5 -methy l -3 ,4 -d ihydropyr imid in-4 -y l ]
benzimidazole-Z-carbamate (119; Table 16)
The method for p r epa ra t i on of 119 was the one r e p o r t e d
for 115.
4-Acetaniido acetophenone (121)
231 This was p r e p a r e d by the method r e p o r t e d e a r l i e r
4-Acetainido-3-iiitro acetophenone (122)
This compound was p r e p a r e d by the method r e p o r t e d e a r -
, . 231
l i e r
4-Amino-3-nitro acetophenone (123)
This was p r e p a r e d by the method d e s c r i b e d for 114.
Methyl -5(6) -acy l benzimidazole-Z-carbamate (124)
This was a lso p r e p a r e d by the method r e p o r t e d in the l i t -232
e r a t u r e 2-Methoxycarbonylamino benzimidazole-5-(6)-acetoxime (125)
A mixture of hydroxy lamine h y d r o c h l o r i d e (0.96 gra, 0.015
mole) and sodium ace ta te (1.36 gm, 0.015 mole) was added to a solu
t ion of 124 (2 .3 gm, 0.01 mole) in methanol (12 ml ) . The mixture
was re f luxed for 5 h r . cooled and d i lu ted wi th water (10 ml ) . The
so l id so obta ined was f i l t e r e d , washed wi th w a t e r , d r i e d and r e c r y s -
t a l l i s e d from DMF-H O mix tu re .
125
IR(KBr)
PMR (DMSO-d, ) 6
Yield 80%; m . p . 281-2°; M" at m/z 248
1640 (C = N) , 1720 (CO), 3300 (NH)
2.22 ( s , 3H, CH^), 3.80 ( s , 3H. CO^CH^) ,
7 .40-7.70 (m, 3H, Ar-H)
*^ll"l2 '^4°3 ' Requires : C, 53.22; H, 4 .83 ; N, 22.58
Found ; C, 53.15; H, 5 .31 ; N, 22.20
2-Ni tro - l - (4 - subs t i tu ted phenyl) propene (^26, 127)
These compounds were p r e p a r e d by the method r e p o r t e d
e a r l i e r
2,5-Dimethyl-3-methoxycarbonyl-4-subst i tuted phenyl fiiran (128, 129;
Table 17) and 2 ,5-dimethyl -3-methoxycarbonyl-4-subst i tuted phenyl
pyrrole (130, 131; Table 17)
145
Method A:
To a suspension of 126, 127 (0 .001 mole) in methanol (10
ml) was a d d e d p i p e r i d i n e (0.002 mole) and methylacetoaceta te (0.002
mole) under cooling (5-10°) and s t i r r i n g . I t was s t i r r e d at room
tempera tu re (25°) for 24 h r . Water was added to the reac t ion mixture
and e x t r a c t e d wi th e t h y l a c e t a t e . Usual work up of organic l aye r
y ie lded an oil containing a mixture of 126, 129 and 130, 131 which
were s e p a r a t e d through column chromatography over s i l i ca gel using
hexane : Chloroform (80:20) as an e luent . These compounds were r e c -
r y s t a l l i s e d from chloroform - hexane mix tu re .
Method B for 128
To a suspension of 126 ( 1 .1 gm, 0.005 mole) in methanol
(8 ml) was added t r i e thy lamine (1 .0 ml, 0.01 mole) and methy lace to
ace ta te ( 1 . 1 . ml, 0.01 mole) under cooling (5-10°) and s t i r r i n g .
I t was then s t i r r e d at room tempera ture (20°) for 24 h r . Water (20
ml) was added to the reac t ion mix tu re , the s epa ra t ed so l id was
f i l t e r e d , washed wi th water and d r i e d . I t was pur i f ied through socc i -
lat ion using benzene as a so lven t .
Method B for 130
A mixture of 126 (1 .1 gm 0.005 mole) , methyl-3-amino c ro to -
nate (1.15 gm, 0.01 mole) and p y r i d i n e (0 .1 ml) in methanol (10
ml) was re f luxed for 36 h r . Water was added to the reac t ion mixture
and af ter 4 hr the s e p a r a t e d so l id was f i l t e r e d , washed wi th water
and d r i e d .
2,5-Dimethyl-3-methoxycarbonyl-4-substituted,_^ phenyl-N-subst i tuted
pyrroles (132-137; Table 17)
General Procedure:
A mixture of 126 (0 .01 mole ) , methylacetoaceta te (0.02 mole)
and p r i m a r y amines (0.02 mole) in methanol (15 ml) was re f luxed
for 12-14 h r . Water was added to the reac t ion mix tu re , the s e p a r a t e d
so l id was f i l t e r e d , washed wi th water and d r i e d . These compounds
were r e c r y s t a l l i s e d from chloroform-pet ro leum benzene mix tu re .
2,5-Diinethyl-3-methoxycarbonyl-4-(4-anilno-3-i i l trophenyl )-N-methyl p y
rrole (146; Table 17)
A mixture of 126 (2 .2 gm, 0.01 mole) and 145 (2 .58 gm.
144
0.02 mole) in methanol (15 ml) was re f luxed for 36 h r . Water was
added to the react ion m i x t u r e , t he s e p a r a t e d sol id was f i l t e r e d ,
washed wi th water and d r i e d . I t was r e c r y s t a l l i s e d from aqueous
methanol .
3,6-Dimethyl-4-hydrazinocarbonyl-5-(4-amino-3-nitrophenyl) pyridazine
(148)
A mixture of 126 (0.002 mole) , methylace toace ta te (0.004
mole) and hydraz ine h y d r a t e (0.004 mole) in ethanol (10 ml) was
re f luxed on a wa te rba th for 3 h r . The reac t ion mixture was d i lu ted
with w a t e r , the s e p a r a t e d so l id was f i l t e r e d , d r i e d and r e c r y s t a
l l i s e d from e t h y l a c e t a t e - h e x a n e .
148
IR(KBr)
PMR (TFA)
Yield 70%; m . p . 170-71°; M+lat m/z 303
1650 (CO)
2.18 ( s , 6H, 2xCH ) , 7 .47-7.61 (m, 3H, Ar-
H)
C, H, N O, : Requires : C, 51 .65; H, 4 .63 ; N, 27.81 13 14 6 J
Found : C , 5 1 . 4 5 ; H, 4 . 3 1 ; N, 2 7 . 9 6
2-Nitro- l - subst i tuted phenyl propene (149-153)
These compoxinds were p r e p a r e d by the method r e p o r t e d ,. 43 e a r l i e r
2 ,5-Dimethyl-3-methoxycarbonyl-4-subst i tuted' '^phenyl pyrro les (154-
158; Table 18)
The exper imenta l p rocedure was e s s e n t i a l l y same as d e s c r i b e d
for 146.
Catolytlc hydrogenation of ^30^, 132-137
The exper imenta l p rocedure was e s s e n t i a l l y same as d e s c r i b e d for
108.
Methyl 5 (6) - I2 ,5 -d imethyl -3-methoxycarbonyl -N-subst i tuted'~ ' pyrrolo]
benzlniidazole-2-carbaiiiates (159-166; Table 19)
To a solution of diamine (mentioned a b o v e , 0,01 mole) in
methanol (10 ml) was added N ,N-d ime thoxyca rbony l -S -me thy l i so th iou rea
(0 .01 mole) and ca t a ly t i c amount of 2.-TSA and ref luxed for 5 h r .
Water (20 ml) was added to the reac t ion mix tu re , the so l id so o b
ta ined was f i l t e r e d , washed wi th water and d r i e d . These were r e c r y s
t a l l i s e d from aqueous methanol .
145
2-Nitro- l -subst i tuted' 'phenyl propene (166-170)
43 These were p r e p a r e d by the method r e p o r t e d e a r l i e r
2,5-Dimethyl-3-methoxycarbonyl-4-subst i tuted ^ ^ phenyl-N-(4-anuno-3-
nitrophenyl) pyrrole (171-175; Table 20)
These compounds were e s s e n t i a l l y p r e p a r e d by the method
d e s c r i b e d for 132-137.
Methyl-5(6)-N-[2 ,5-dimethyl-3-inethoxycarbonyl-4-substituted'^~^ phenyl 1
pyrrolo ben2imidazole-2-carbamates (176-180; Table 21)
The exper imenta l p rocedure was same as d e s c r i b e d for 159-
166.
4 , 4 ' -D ich loro -3 ,3 ' -d in i t ro benzophenone (182)
232a This was p r e p a r e d by the method r e p o r t e d in l i t e r a t u r e
4 ,4 ' -Diamino-3 ,3 ' -d in i tro benzophenone (183)
This compound was also p r e p a r e d by the method r e p o r t e d
2,2 • -1 B i s - (4-ainino-3-nitrophenyl) ] methanol (184)
To a suspension of 183 (3.04 gm, 0.01 mole) in methanol
(10 ml) was a d d e d sodium b o r o h y d r i d e (4.56 gm, 0.12 mole) and
ref luxed for 4.5 h r . Water was then added to the reac t ion mixture
and pH was ad jus ted to 7 by adding glacia l acet ic ac id d r o p w i s e .
The so l id so obta ined was f i l t e r e d , washed with w a t e r , d r i e d and
r e c r y s t a l l i s e d from aqueous DMF.
184 : Yield 85%; m . p . 230-32°; M" at m/z 304
PMR (DMSO-d^) : 5.50 ( s , IH, CH), 6 .88-6 .98 and 7 .23-7.31
(m, 6H, Ar -H) , 7 .70-8.01 ( b s , 4H, 2xNH )
^ 1 3 " l 2 ^ 4 ° 5 ' Requires : C, 51 .31 ; H, 3.94; N, 18.42
Found : C, 51.80; H, 4 .24; N, 18.51
2,2'-Dicarbomethoxyaniino-5,5'-dibenziniidazolylmethanol (185)
This compound was p r e p a r e d by following the method d e s
c r i b e d for 159-166. I t was r e c r y s t a l l i s e d from aqueous DMF.
185 s Yield 78%; m . p . > 300"; M" at m/z 410
IR (KBr) : 1725 (CO)
146
PMR (TFA) : 3.90 ( s . 6H, 2xNHC02CH^), 5.28 ( s , IH. CH)
7.38-7.70 (m, 6H, Ar-H)
C,„H,„N^O^ : Requires : C, 55.60; H, 4 .39; N, 20.48 19 18 6 5
Found : C, 55 .41 ; H, 4 .78; N, 19.94
5-Ethoxycarbonyl-6-methyl-4-subst i tuted'^phenyl-3 ,4-dihydrophyrini idin-
2-thione (192-197; Table 22)
These compounds were p r e p a r e d by the method r e p o r t e d ,. 223
e a r l i e r
5-Ethoxycarbonyl-2-methylmercapto-6-methyl-4-phenyl-4( lH)-pyrimidine
(198; Table 23)
A mixture of 192 (0 .01 mole ) , Potassium h y d r o x i d e (0 .01
mole) and methyl iod ide (0.012 mole) in methanol (5 ml) was s t i r r e d
at room tempera ture (SO'C) for 1 h r . The s e p a r a t e d so l id was f i l t e r e d ,
washed with water (50 ml) and r e c r y s t a l l i s e d from aqueous methanol .
5-Ethoxycarbonyl -2- ( l -methyl p iperaz lno) -6 -methy l -4 -pheny l -4{ lH) -
pyrimidine (200; Table 23)
A mixture of 192 (2 .9 g, 0.01 mole) and N-methyl p i p e r a z i n e
(2 ml , 0,02 mole) was hea ted a t 70-75°C for 5 h r . Water was added
to the reac t ion mixture and e x t r a c t e d wi th e thy l a c e t a t e . Organic
l aye r was washed f ive t imes wi th water and d r i ed on anhydrous
sodium s u l p h a t e . Removal of solvent y i e lded the compound 200 as
an o i l .
l , 6 -Dimethyl -5 -Ethoxycarbonyl -2 -methylmercapto-4-phenyl -4 - [ lHl -pyr i -
mldine (199)
A mixture of 192 (0 .01 mole ) , potassium h y d r o x i d e (0.02
mole) and methy l iod ide (0.022 mole) in N.N-dimethyl su l foxide (3
ml) was s t i r r e d at room tempera tu re (30°C) for 1 h r . Water (5 ml)
was a d d e d to the reac t ion m i x t u r e , the s epa ra t ed so l id was f i l t e r e d ,
washed wi th water (50 ml) and r e c r y s t a l l i s e d from aqueous methanol .
199 : Yield 70%; m . p . 160"; M" at m/z 304
IR (KBr) : 1680 (CO)
1.03-1.19 ( t , 3H, CH^), 2.30 ( s , 3H, CH ) , PMR (CDCl )
2.43 ( s , 3H, SCH^), 2.90 ( s , 3H, NCH ) , 3 .88-
4.10 ( q , 2H, CH^) , 5.11 ( s , IH, CH) , 7.18
( s , 5H, Ar-H)
147
C , , H - - N , 0 , S : Requires : C, 63 .15 ; H, 6 .57; N, 9.21
Found : C, 63.00; H, 6 .25; N, 8.80
1,6-Dimethyl -5-ethoxycarbonyl -4-phenyl -3 ,4-dihydropyrimidin-2-one (201)
To a solution of 16^ (0 .5 g) in methanol (2 ml) was added
cone. H SO (2 d rops ) and ref luxed on steam ba th for 4 h r . Water
was added to i t and e x t r a c t e d with e t h y l a ce t a t e . Usual work up
y ie lded a so l id which was r e c r y s t a l l i s e d from aqueous methanol .
201
IR (KBr)
PMR (CDCl )
Yield 55%; m . p . 160-61°; M"*" at m/z 274
1660, 1690 (CO)
1.03-1.20 ( t , 3H, CH^), 2.27 ( s , 3H, CH^).
2.77 ( s , 3H, N-CH ) , 3 .79-4 .11 ( q , 2H, CH^) -
5.12 ( b s , IH, CH), 7.21 (m, 5H, Ar-H) , 8.50
( b s , IH, NH)
C ,^H, -N-0- : Requires : C, 65 .69; H, 6.56; N, 10.21 15 l o & J
Found : C, 65 .73 ; H, 6 .81 ; N, 9.84
5-Aryl -6-ethoxycarbonyl -7-methyl -3-oxo-2 ,3-dihydro-5H-thiazolo [ 3 , 2 -
a ] pyrimidine (202-205; Table 24)
General Procedure:
A mixture of 192-195 (0 .01 mole ) , monochloroacetic ac id
(0.05 mole) and BF e t h e r a t e (0 .1 ml) in methanol (5 ml) was s t i r r e d
at room tempera tu re (30°C) for 3.5 h r . Water (10 ml) was then added
to the reac t ion mix tu re . Extrac t ion wi th e t h y l ace ta te (10 ml) followed
by usual work-up y ie lded an oil which on t r i t u r a t i on wi th petroleum
benzene furn ished a so l id 202 which was r e c r y s t a l l i s e d from c h l o r o -
form-hexane mix tu re , wh i l e o the r compounds 203-205 were ob ta ined
as o i l .
l -Carboxymethyl-5-ethoxycarbonyl-6-methyl-4-subst i tuted^^~^phenyl-3 ,4-
dih7dropyrlmldin-2-thione (206-208; Table 25)
General Proce dure :
A mixture of ^92, 194-195 (0 .01 mole) , monochloroacetic
ac id (0 .05 mole) and potassium h y d r o x i d e (0 .01 mole) in methanol
(5 ml) was re f luxed on steam ba th for 2 h r . The s e p a r a t e d so l id
was f i l t e r e d , washed wi th water (40 m l ) , d r i e d and r e c r y s t a l l i s e d
from methanol .
148
Ethyl ( c<- tr i f luoroacety l -^- th iour ido) subs t i tu ted^phenyl propionate
(209. 210)
General Procedure;
A mixture of a p p r o p r i a t e benza ldehyde (0.01 mole ) , E t h y l -
t r i f luoromethyl ace toace ta te (0 .01 mole ) , th iourea (0.02 mole) in
HCl (3 ,5 ml , 3N in 1:1 methanol : wa t e r ) was s t i r r e d at room tempe
r a t u r e (20°C) for 48 h r . The s e p a r a t e d so l id was f i l t e r e d , washed
wi th water and d r i e d . I t was r e c r y s t a l l i s e d from chloroform-hexane
mix tu re .
5-Ethoxycarbonyl-6- tr i f luoromethyl -4-phenyl-3 ,4-dihydropyrimidin-
2-thione (211)
0.1 g of 209 was taken in 2 gm of p o l y p h o s p h o r i c ac id and
hea ted on water ba th for 8 h r . water was added and on t r i t u r a t i o n
a so l id was obta ined which was r e c r y s t a l l i s e d from benzene.
5-Ethoxycarbonyl-2-methylmercapto-6-methyl-4-phenyl pyrimidine (212;
Table 26)
A mixture of 198 (5 .8 g, 0.02 mole) and manganic ace ta te
(11.8 g, 0.04 mole) in d ry benzene (50 ml) was re f luxed for 2.5
h r . Manganous ace ta te was f i l t e r ed off. Water was added to the f i l t e -
r a t e and i t was e x t r a c t e d wi th benzene. Usual work up y i e lded an
oil which was pur i f i ed through a shor t band of s i l i ca gel using h e -
xane as e luent .
5-Ethoxycarbonyl-2-methylmercapto-6-methyl-4-phenyl-2-( lH)-pyri inidine
(213) and 5-Ethoxycarbonyl -2-methoxy-5-methyl -4-phenyl -2- ( lH) p y r i
midine (214)
To a solution of 212 (5 .6 g, 0.02 mole) in methanol (8 ml)
was added NaBH (1 .5 g, 0.04 mole) under cooling (5-10°C) and s t i r r
ing . It was s t i r r e d at room tempera ture (20°C) for 1 h r . Water was
added to the react ion mixture and e x t r a c t e d wi th e t h y l a c e t a t e . Usual
work up y ie lded a mixture of two compounds 213 and 214 which were
s e p a r a t e d through a column of s i l i ca gel using hexane , chloroform
as e luent .
5,6-Dimethyl-2-inethylinercapto-4-phenyl-pyrimidine (215; Table 26)
and 5-HydToxymethyl-2-methylmercapto-6-methyl-4-phenyl pyrimidine
(216; Table 26)
149
To a suspension of LAH (1.14 g, 0.03 mole) in d r y e t h e r
(5 ml) was added a solution of 212 (8 .7 g, 0.03 mole) in d r y e t h e r
(20 ml) under cooling (S-IO'C) and s t i r r i n g . I t was s t i r r e d at the
same tempera tu re for 0.5 h r . Ord ina ry benzene was added followed
by add i t ion of w a t e r . It was e x t r a c t e d wi th benzene. Usual work
up y ie lded a mixture of 215 and 216 which were s epa ra t ed through
a column of s i l i ca gel using hexane , chloroform as e luent .
5-Formyl-2-methylmercapto-6-methyl-4-phenyl-pyrini idine (217; Table
26)
To a solution of 216 (2 .4 g, 0.01 mole) in d r y CH CI (15
ml) was added pyr id in ium chlorochromate (2.2 g, 0.01 mole) . I t
was s t i r r e d at room tempera tu re (25''C) for 40 minutes. Solvent e t h e r
was added and eluted wi th e the r through a shor t band of s i l i ca
ge l . Solvent was removed and on t r i t u r a t i o n with hexane a c r y s t a l l i n e
so l id obta ined was r e c r y s t a l l i s e d from chloroform-hexane mix tu re .
5-Bromomethyl-2-methylmercapto-6-methyl-4-phenyl pyrimidine (218;
Table 26)
To a solution of 216 (2 .4 g, 0.01 mole) in d ry benzene (10
ml) was added a mixture of PBr (0.95 ml, 0.01 mole) and t r i e t h y l a -
mine (1 .0 ml , 0.01 mole) in d r y benzene (5 ml) under cooling (5°C)
and s t i r r i n g . It was s t i r r e d at room tempera tu re (25°C) for 1 h r .
Water was added and e x t r a c t e d wi th e t h y l ace t a t e . Usual work up
y i e lded a so l id which was r e c r y s t a l l i s e d from chloroform-hexane
mix tu re .
5-IN-( 4-Amino-3-nitrophenyl) ] aminomethyl-2-methylmercapto-6-methyl-
4-phenyl pyrimidine (219; Table 26)
To a solution of 218 (0 .3 gm, 0.001 mole) in d r y benzene
(5 ml) was added t r i e t hy l amine (0 .1 ml, 0.001 mole) and O-nitro-
£-phenylened iamine (0.15 gm, 0.001 mole) . It was s t i r r e d a t room
tempera tu re (25°C) for 1 h r . Water was added to i t and e x t r a c t e d
wi th e t h y l a c e t a t e . Usual work up y ie lded an oil which on t r i t u r a t i o n
wi th p e t . benzene y i e lded a so l id which was r e c r y s t a l l i s e d from
chloroform-hexane m i x t u r e .
Methyl-5(6)-N-I (2-methyImercapto-6-methyl-4-phenyl pyrimidine-S-
y l ) methyl] amino benzimidazole-2-carbamate (220; Table 26)
To a solution of 219 (0.38 gm, 0.001 mole) in methanol (20
150
ml) was added Raney-Ni (0 .1 gm) and hydrogena ted at 2.5 kg/cm
for 1 h r . The ca t a ly s t was f i l t e r ed off and the solvent was r educed
to 5 ml. N ,N-d imethoxycarbony l -S-methy l i so th iourea (0.2 gm, 0.001
mole) was added to i t and re f luxed for 3.5 h r . Water (20 ml) was
added to i t , the s epa ra t ed so l id was f i l t e r e d , washed wi th water
and d r i e d . It was r e c r y s t a l l i s e d from chloroform-hexane mix tu re .
M e t h y l - 5 { 6 ) - [ 4 - { 2 , 6 - d i m e t h y l - 3 , 5 - d l m e t h o x y c a r b o n y l - l , 4 - d i h y d r o p y r i -
d y l ) ] benzimidiazole-2-carbamate (221; Table Zl)
A mixture of ^ (0.331 gm, 0.001 m o l e ) , N ,N-d ime thoxyca rbo -
ny l -S -me thy l i so th iourea (0.206 gm, 0.001 mole) and c a t a l y t i c amount
of £-TSA in methanol (5 ml) was ref luxed tor 4 h r . The reac t ion
mixture was d i lu ted with w a t e r , t he so l id so obta ined was f i l t e r e d ,
washed with water and d r i e d . I t was r ec r v s t a l l i s e d from aqueous
methanol .
Methy l -5 (6 ) - (4 - (2 ,6 -d imethy l -3 ,5 -d imethoxycarb«myl - l , 4 -d ihydropyr i -
dy l ) I-N-substltuted benziinidazole-2-carbainate (222-223; Table 27)
The exper imenta l p rocedure was e s s e n t i a l l y same as d e s c r i b e d
for 159-166.
N,N-Dimethoxycarbonyl-N-( subst i tuted benzyDguAnldine (227-229; Table 28)
The exper imenta l p rocedure was e s s e n t i a l l y same as d e s c r i b e d
for 221.
l -Hydroxyla in ine- l - (3 ,4 -methylenedloxyphenyl ) -2-n i tro propane (230)
To a solution of l - ( 3 ,4 -me thy lened ioxypheny l ) -2 -n i t ro propene
(2.07 g, 0.01 mole) in methanol (10 ml) was added hyd roxy lamine
h y d r o c h l o r i d e (1.39 g, 0.02 mole) and sodium aceta te (1 .64 g, 0.02
mole) . The react ion mixture was s t i r r e d at room tempera tu re (20°C)
for 5 h r . Water (20 ml) was a d d e d to i t , the p r e c i p i t a t e d so l id
was f i l t e r e d , washed wi th water and d r i e d . It was pur i f i ed through
column chromatography over s i l i ca gel using hexane : chloroform (20
: 80) as e luent . The compound was r e c r y s t a l l i s e d from chloroform-
hexane mix tu re .
230 : Yield 82%; m . p . 123-24 'C; M* a t m/z 240
IR(KBr) : 3000 (NH) & 3320 (OH)
1.18-1.25 ( d . 3H, CIJ^, J = 7Hz), 4 .20-4 .30 PMR(CDCl,+DMSO-d^) i o
151
( d , IH, CH, J = 9Hz) , 4 .79-5.02 (m, IH,'
CH), 5.89 ( s , 2H, OCH^O), 6 .66-6 .87 (m,
3H, Ar-H)
'^ lo"l2 '^2°5 • Requires : C. 50.00; H. 5.00; N. 11.66
Found : C, 50 .41 ; H, 4 ,82 , N, 11.40
1 ,2-Diamino- l - (3 ,4-methylenedioxyphenyl)propane (231)
To a suspension of 230 (1.2 g , 0.005 mole) in methanol (20
ml) was added Raney-Ni {'^0.5 g) and hydrogenated at 2.5 mg/cm
for 2 h r . After removal of the c a t a l y s t solvent was r educed to
--lO ml and t h i s was used for the next s tep as such .
However, for c h a r a c t e r i s a t i o n 231 was i so la ted as i t s d i h y d r o -
c h l o r i d e . 231 : m . p . l O l ' C ; IR (KBr) : 3000 (NH) PMR(D20) : 1.31-1.39 ( d , 3H, CH^), 3 .60-3.85 (m, IH,
CH), 4 .05-4 .17 (m, IH, CH), 6.19 ( s . 2H.
OCH^O), 7 .08-7 .21 (m, 3H, Ar-H)
C ^ Q H ^ ^ C I N ^ O ^ : Requires : C, 52.06; H, 6.50; N, 12.14
Found : C, 52.00; H, 5 .95; N, 11.94
Methy l -4{5 ) -methy l -5 (4 ) - [3 ,4 -methy lened ioxypheny l ] -4 ,5 -d ihydro imida-
zole-2-carbaniate (232)
To a solution of 231 ob ta ined from above in methanol (5
ml) was a d d e d , N ,N-d ime thy lxyca rbony l -S -me thy l i so th iou rea and £ -
TSA in c a t a l y t i c amount. The reac t ion mixture was re f luxed for 5
h r . I t was cooled to room tempera tu re (20''C) water was a d d e d to
i t , the s e p a r a t e d so l id was f i l t e r e d , washed wi th water and d r i e d .
It was r e c r y s t a l l i s e d from aqueous methanol .
232 : Yield 68%; m . p . l 7 1 ° C ; M" at m/z 277
IR(KBr) : 1700 (CO)
PMR(CDCl2) : 1.26-1.32 ( d , 3H, CH^, J = 6Hz), 3.42 ( s .
3H, NHCO^CH^), 3 .58-3 .74 (m, IH, CH),
4 .23-4 .31 ( d , IH, CH, J = 7Hz), 5.89 ( s ,
2H, OCH^O), 6 .65-6.85 (m, 3H, Ar-H)
^13"lfc^3°4 ' Requires : C, 56 .31 ; H, 5 .4 t ; N, 15.16
Found : C, 56.12; H, 5.59; N, 15.06
Methyl-3-ainino-2I j3 - subst i tutedphenyDnitroethyl ] crotonate (233-236; Table 29)
152
General Proce dure :
To a solut ion of l - a r y l - 2 - n i t r o e thy lene (0 .01 mole) in metha
nol (10 ml) was added methyl -3-aminocrotonate (0.02 mole) and s t i
r r e d at room tempera tu re (20°C) for 8 h r . Water (20 ml) was a d d e d ,
the p r e c i p i t a t e d so l id was f i l t e r e d , washed with w a t e r , d r i e d and
r e c r y s t a l l i s e d from chloroform, hexane mix tu re .
3-Carbomethyoxy-5-i i i tro-2-oxiinlno-4-substituted'^ phenyl pentane (237-
239; Tab le 30)
General Procedure:
To a suspension of 233-236 (0 .01 mole) in methanol (10 ml)
was added hydroxy lamine h y d r o c h l o r i d e (0.02 mole) and sodium ace
ta te (0.02 mole) . It was s t i r r e d a t room tempera tu re (20°C) for 5
h r . Water (20 ml) was added to the reac t ion mixture the s e p a r a t e d
so l id was f i l t e r e d , v/ashed wi th w a t e r , d r i ed and r e c r y s t a l l i s e d
from aqueous methanol .
3-Carbomethoxy-5-nitro-4-substituted _ phenyl pentan-2-one (240-242;
Table 30)
General Procedure:
A mixture of the compoiind 233-235 (1 g) and sulfur ic ac id
(2 d r o p s ) in methanol (10ml) was re f luxed on water ba th for 6 h r .
Water was added to the reac t ion mixture and e x t r a c t e d wi th e t h y l
a c e t a t e . Usual work up of organic l aye r y i e lded an o i l .
3-Carbomethoxy-3-hydroxy-5-nitro-4-substituted^ phenyl pentan-2-one
(243-246; Table 30)
Method A:
To a solution of 233-236 (1 g) in d r y CH CI (5 ml) was
added e t h e r i a l solut ion of monophorphtha l l i c ac id (15 ml) and s t i r r e d
at 20''C for 20 h r . The s e p a r a t e d p h t h a l l i c ac id was f i l t e r e d , so lvent
was removed and on t r i t u r a t i o n with pet ro leum benzene a so l id was
ob t a ined . I t wa r e c r y s t a l l i s e d from chloroform, , petroleum benzene
mix tu re .
Method B:
To a solut ion of 233-236 (0 .01 mole) in d r y CH CI (10 ml)
• was added m-ch loroperbenzoic ac id (0.02 mole) and s t i r r e d a t 20°C
for 24 h r . Work up was same as in method A.
153
3-Carbomethoxy-3-hydroxy-5- iutro-2-oxini ino-4-subst i tuted ^ phenyl pen-
tane (247-248; Table 30)
The exper imenta l p rocedure was same as d e s c r i b e d for 237-
239.
1,6-Bis carbomethoxy-2-methoxycarbonylaniino-7-methyl-5-p-methoxyphe-
n y l ) - 4 , 5 , 6 , 7 - t e t r a h y d r o - l , 3 - d i a z e p i n e (249)
This compound was p r e p a r e d e s s e n t i a l l y by following the
method as for 232 but he re ref luxing time was 36 h r . The compound
was pur i f i ed through column chromatography over s i l i ca gel using
hexane : Chloroform (1 : 1) as e luent . It was r e c r y s t a l l i s e d from
ch loroform, hexane mix tu re .
249
I R ( K B r )
PMR(400 MHz, CDCl )
13 C-NMR{DMSO-d, )
6
S9»25^3S
Y i e l d 20%; m . p , 139 ' 'C; M a t m/z 407
1730 (CO)
1 . 5 4 - 1 . 5 5 ( d , 3H, C H ^ ) , 1.59 ( b s , 3H, C H ^ ) ,
2 . 9 0 - 3 . 0 2 ( m , I H , CHG ) , 3 , 50-3 .60 ( m , I H ,
C H ) , 3 . 4 5 ( s , 3H, CO^CH^) , 3 .75 ( s . 6H,
OCH^ & NCO^CH^) , 3 .82 ( s , 3H, NHCO^CH^),
4 . 5 9 - 4 . 7 0 ( m , 2H, CH ) , 6 . 8 6 - 6 . 8 7 ( d , 2H,
3 & 5 A r - H , Jo = 9 H z ) , 7 . 1 9 - 7 . 2 1 ( d , 2H,
2&6 A r - H , Jo = 9 H z ) , 7 .27 ( s , I H , NH)
1 8 . 6 1 ( q , C H ^ ) , 4 5 . 6 4 ( d , A r - C H ) , 51 .78
( q , CO^CH^) , 54, 65 ( t , C H ^ ) , 54 .92 ( q .
NCO^CH^ , NHCO^CH
C=N), 160.95 ( s ,
& OCH^) ,
NCO^CH^ &
1 5 0 . 0 1 ( s ,
NHCO^CH^),
171 .84 ( s , CO^CH^) , 1 1 3 . 8 4 , 1 2 8 . 4 1 , 129 .44
& 158 .39 ( A r - C )
R e q u i r e s : C , 5 6 . 0 1 ; H, 6 . 1 4 ; N , 1 0 . 3 1
Found : C , 5 6 . 5 1 ; H, 6 . 3 5 ; N , 10 .65
6.2 TABLES
Physical and Analytical data of Compounds, which have not
been included in Experimental section, are described
under vertical columns and their spectral
characteristics have been recorded in
horizontal sequence.
154
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189
6.3 BIOLOGICAL ACTIVITY
The compounds syn thes i zed were t e s t ed for t h e i r in v-tvoantifila-
r i a l a c t i v i t y against LitomO'ioidZ'!^ CCUiinii in cotton r a t s , ces toc ida l
a c t i v i t y against Hymznoie-pi^ nana infection in mice and r a t s . Nematoci-
dal a c t i v i t y agains t AncyiO'itoma CZylanicum in hamsters and against
Ni]ppo6tXongLjtu^ b^a'Utizn^i'i in r a t s in the d i v i s i o n of pa ras i to logy
of t h i s i n s t i t u t e .
METHOD OF ANTHELMINTIC SCREENING
1. Antifllarial screening of Compounds;
Litomo^oidz^ caAiini infection in cotton r a t (Sigmodon hi'tpidu^j
was used as exper imenta l model for the de tec t ion of an t i f l l a r i a l a c t i
v i t y . The vector of t h i s infection namely LiponLj^'iu^ bacoti, ob ta ined
o r ig ina l ly from National Ins t i tu te for Medical Resea rch , Mill H i l l ,
London, was maintained in a room in which t empera tu re (26°) and
humidi ty (90%) were automat ica l ly con t ro l l ed . Culturing of the vector
and the propagat ion of infection to h e a l t h y cotton r a t s were c a r r i e d
as 230
229 out as per the methods of Hawking and Sewell and Sewell and Haw
king
(a) Preliminary tox i c i ty s tudies :
Before admin i s te r ing any compound to infected cotton r a t s ,
the p r e l i m i n a r y t o x i c i t y s tudy of each compound was conducted in 231
mice . This s tudy he lped in finding out the maximum to l e r a t ed dose
(MTD) of the t e s t compound in mice. One fifth of the MTD was used
against cotton r a t . (b) Selection of infected cotton rat:
Recently infected cotton r a t (3 months or so) wi th p r o g r e s s i v e
r i s e in p e r i p h e r a l microf i la r iae and having count of 250 mf or more
per 5 cmm of blood were used for sc reen ing .
(c ) Testing of Compotinds:
For p r i m a r y screening two infected cotton r a t s were used for
each compound a t any pa r t i cu l a r dose leve l s t u d y . Suspension of the
t e s t compounds were made wi th 0.1% Tween 80 af ter gr inding i t to
a fine powde r . The pH of a l l the solut ions were f ina l ly ad jus ted
to 7 .0 . Infected cotton r a t s were injected i n t r a p e r i t o n e a l ! y l / 5 t h MTD
190
in mice for six consecutive days. Tail blood of the animals were
examined just before the commencement of treatment and thereafter
at weekly interval upto 42nd day. Generally, 5 cmm of blood were
taken from the tail every time and smeared on a clean glass s l ide .
The smears were air d r ied , dehaemoglobinised, fixed in methanol
and stained with 5% Gilmsa for 1 hr in the usual way. These were
then examined under high power magnification of the microscope and
the number of microfilariae per cmm of blood counted. Compounds
capable of cleaning 90% of the pretreatment circulating microfilariae
were considered as the effective microfilaricidal. The animals were
sacrificed on 42nd day (counted from the day of commencement of
the treatment) and the adult filarial worms were removed from pleural
cavi ty , kept in a petry dish containing normal saline at 37° and incu
bated at this temperature for 15 minutes. Animals were sacrificed
and adult worms were examined for motility, cell adhesion on the
surface and changes in different developmental stages of mf in the
uterus. If the worms were found dead, the compound was considered
as an effective adult icidal .
2. Screening against Ancylo^toma ce.ytanicum
(a) Adulticidal activity:
This nematode was obtained from Sarabhai Research Centre,
Baroda and each hamsters (weighing 40-60 g) was administered 50
to 60 larvae oral ly . The larvae were harvested lO-iS day old faecal
cultures by the Baermann method. The screening technique was essen-232
t ia l ly that of Steward with slight modifications, to suit the local 2'i3
conditions . Animals in different groups were administered the comp
ounds (made to suspension with Tween 80) orally in varying doses
using three infected animals for each dose; the other three infected
and untreated served as controls. The administration of compounds
was initiated on day 18-20 of infection either in single or multiple
doses on successive days . The experimental and control animals were
sacrificed on day three after the last dose, their worms were counted
and compared with control group of animals. The efficacy has been
expressed in terms of percent worm reduction. (b) Larivicidal activity:
Golden hamster of ei ther sex weighing 40-60 g were inoculated
orally with 60 ± 5 infective larvae (L ) and divided into several
191
groups, depending on the number of doses, routes of the drug adminis
tration and the stages of parasites against which the action of the
drug was to be evaluated. L of this parasite moults to L on the 2:34
day 2 and L. to L on day 5 . The test compound and the reference
drug were administered on days 1,3 and 6 post infection ( p . i . ) so
that effect on L . , L. and L_ stages respectively could be evaluated.
Treated and untreated hamsters were necropsied on day 20 p . i . , when
worms reached maturity in the intest ine. . The efficacy was expressed
in terms of absolute worm expulsion from the host and per cent worm
reduction compared to untreated controls
3. Screening against Hyme.note.pi^ nana:
(a) Adulticidal activity:
The screening technique followed was essentially that of Ste
ward with modifications as described by Gupta et aj_ , The test
compounds were screened in male swiss mice (18-20 g) and male albino
rats (40-45 g) . The experimental animals were infected with 20 viable
eggs and 17-20 days after infection, the faeces of the individual ani
mal was examined for the presence of eggs and those found infected,
were used for screening. The animals were then colour marked, weighed
and divided into groups of three animals, each for different compounds
under tes t . The compounds synthesized were administered init ially
at a dose of 250 mg/kg x 3 (given for three consecutive days) . Inso
luble compounds were made into fine suspension with the help of
Tween 80 (the amoiont used just to moisten the compound), gumaccacia
or 0.1% agar. The experimental animals received the initial dose of
the test compounds, after they were starved for 6 hr. On day three
post-treatment, the animals did not receive any food for 5-6 hr before
they were sacrificed for assessing their worm burden. The intestine
from each animal was removed, washed with normal saline and examined
for worms and scolices under dissecting microscope. Absolute clearance
of parasite along with scolices from individual mice was taken as
the cri terian for assessing the act iv i ty . Even, if a single scolex
or worm remained in the intestine, the drug at that dose was consi
dered in-effective for that particular animal (because the range of
adult worms maturing from a particular inoculum is very wide) . The
percentage efficacy of the compound was obtained from the number
of treated animals freed from infection and those which did not r e s
pond to the drug treatment.
192
The compound showing act ivi ty at the initial dose level , were
persued further in lower doses t i l l a reasonable act ivi ty was retained
by the compound.
4. Screening against Nippo^st/LOngytuA bJiaAille.nAi6:
Young male rats of university of Freiburg strain weighing 25-
40 g were used as the host of N. b^a6itLzn6i6. This parasite was
originally obtained from Wellcome Laboratory, Bechenham, London.
Rats were infected by inoculating 500 infective larvae each (harvested
from 6-10 day old copro-cultures) sub-cutaneously.
The screening technique was essentially same as described
for A. cey£a»iicum(adulticidal) but in the case of W. bfia^itidn^i^, the ad
ministration of compounds was initiated on day 9 post-infection either
in single or multiple doses on successive days .
Parameters selected for identifying active compounds
The death of the adult worms was the primary parameter for
monitoring the antifllarial ac t iv i ty . The percentage of worm clearance
(PWC) was monitored for evaluating compounds against A. C£y£an-tcum in
fection. If PWC was less than 100 at a single dose of 250 mg/kg,
the compounds were considered as less active and were not evaluated
further. In cases where PWC was less than 50, the compounds were
considered as inactive against this infection. For evaluating compounds
against H. nana infection, the total clearance of scolex was taken into
consideration. In cases where scolex was not eliminated (SNE), the
compound was considered as inactive and the complete absence of
scolex was considered as 100% act iv i ty .
Profile of anthelmintic activity of the various compounds synthesized
Almost all the compounds were evaluated for their antifllarial
act ivi ty against Litomo^toidz^ caAA.nii in cotton r a t s , nematocidal act ivi ty
against Ancyio6toma ce-ijianicam in hamsters and against Nippo6t^ongytu^
bA.a'SitLzn^i^ in rats and cestocidal act ivi ty against Ht/meno£ep-C'4 nana in
mice and r a t s . Only the active compounds have been described in
tables 31 and 34. Of these two compounds (159 and 185) had been
picked up for larvicidal act ivi ty and the results are described in
tables 32 and 33.
193
T a b l e 3 1 : A c t i v i t y of Compounds a g a i n s t A. cey^an-tcum ( i n h a m s t e r s ) a n d N. b^a'i>itLznM'i> ( i n r a t s ) i n f e c t i o n s .
Compound No.
A. czyianicum
Dose mg/kg
A c t i v i t y %
N. b^aAitizn6i^
Dose m g / k g
A c t i v i t y %
125 250 X 1 100
50 X 1 0
250 X 1
159
160
177
185
221
232
250 X 1 100
100 X 1 100
50 X 1 97 .22
1 2 . 2 5 x 1 7 7 . 7 8
6 . 1 2 x 1 2 7 . 7 7
250 X 1 80.00
250 X 1 80.00
250 X
100 X
50 X
25 X
12.5x1
6.25x1
3.12x1
250 X
100 X
250 X
100 X
50 X
1
1
1
1
1
1
1
1
1
100
100
100
100
91
83.06
78.46
100
0
100
100
50
250 X 1
100 X 1
50 X 1
12.25x1
6.12x1
250 X 1
250 X 1
250 X 1
100 X 1
50 X 1
25 X 1
12.5x1
6.25x1
3.12x1
100
100
97.2
77.7
27.7
0.0
0.00
100
100
100
100
91
83
78
250 X 1
194
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198
CONCLUSION
The sensit ivi ty of pharmacophores in benzimidazole-2-carbamates
for evoking anthelmintic activi ty is evident from the results of the
biological screening listed in tables 31 and 34. For example, the
oxidised form of 1 ^ (CDRI Code No.82/437 page 115 ) is active as
a macrofilaricidal agent by oral route of administration while the
alcohol 185 fails to exhibit antifilarial act ivi ty by oral route. Yet
another striking example of the effect of minor change in the pharma
cophore on the profile of anthelmintic act ivi ty is obvious from the
comparative study of the results of biological screening of compounds
83/148 (prepared earlier in CDRI) and 159. Replacement of the oxygen
atom in the furan ring of 83/148 by a nitrogen atom (compound 159)
has resulted in the abolition of antifilarial ac t iv i ty . However, only
minor differences in the profile of biological act ivi ty against develop
ing stages of A, CS.yianicum of these compounds have been observed.
A comparative study of the anthelmintic act ivi ty of 159 and 177 indi
cates that the orientation of the ester carbonyl, with respect to benzi-
midazole nucleus and the linkage of the C-5 of the benzimidazole
ring significantly influence the profile of biological ac t iv i ty . Similarly
in compounds 221 the benzimidazole nucleus is not planar with the
1,4-dihydropyridine residue and this in turn makes the orientation
of the ester carbonyl different than the other compoiands. Possibly
th is is one of the contributing factor for the deminished anthelmintic
ac t iv i ty . The biological act ivi ty of compound 232 is interesting because
in th is compound the phenyl ring has been dissociated from the benzi
midazole ring system and the resulting substituted imidazole-2-carba-
mate is capable of exhibiting specificity of anthelmintic ac t iv i ty .
This molecule, therefore, provides a good base for undertaking lead
optimisation studies and should there be a need to develop a specific
antlhookworm compound, this exercise may prove to be beneficial.
The antifilarial act ivi ty of 185 is encouraging and calls for undertaking
special drug formulation studies to induce oral absorption. The proto
types XVI, XVII, XX and XXII have failed to yield a new lead for
developing an anthelmintic agent.
199
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LIST OF PUBLICATIONS
Syntheses of 4-Aryl-2 , 5 - d i m e t h y l - 3 - ( N , N - d i s u b s t i t u t e d - c a r b a m o y l )
furans , subs t i t u t ed Isoquinolino [ 1,2-b Iquinol ines & Methyl 5 ( 6 ) -
subs t i t u t ed benz_lmidazole-2-carbamates, S. Niwas, M.S. A k h t a r ,
S. Kumar & A. P. Bhadur i , Indian J . Chetn. , 24B, 754-60 (1985) .
Novel ox ida t ion of t e t r a s ubs t i t u t ed furans by pyr id in ium c h l o r o -
ch romate , M.S. A k h t a r , M. Seth & A. P. B h a d u r i , J . Het. Chem. ,
22, 1323 (1985) .
Syntheses of Methyl 5( 6 ) - s u b s t i t u t e d b e n z i m i d a z o l e - 2 - c a r b a m a t e s ,
M.S. A k h t a r , M. Seth & A. P. B h a d u r i , Indian J . Chem. , 2 5 3 ,
395 (1986) .
Rearrangement r eac t ions in the mass s p e c t r a of t e t r a s u b s t i t u t e d
e t h y l e n e s , K .P . Madhusudanan, M.S. A k h t a r , M. Seth & A. P.
B h a d u r i , Indian J . Chem. , 25B, 915-21 (1986) .
Studies on Nef Reaction Induced by organic b a s e s , M.S. A k h t a r ,
V.L. Sharma & A .P . B h a d u r i , J . Het. Chem. , (In p r e s s ) .
Reaction of cC , f t -unsa tura ted ketones wi th n u c l e o p h i l e s , M.S. A k h t a r ,
M. Seth & A. P. B h a d u r i , Indian J . Chem. , (In p r e s s ) .
Syntheses of T e t r a h y d r o t h i a z o l o [ 3,2-a Ipy r imid ines and t e t r a s u b s t i
tu ted d i h y d r o p y r i m i d i n e d e r i v a t i v e s as p o s s i b l e an the lmin t ic
agen t s , M.S. A k h t a r , M. Seth & A. P. B h a d u r i , Indian J . Chem. ,
(In p r e s s ) .