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Kanpariya, Ramesh K., 2009, “Synthesis, Spectral Studies and Therapeutic
Activity of Heterocyclic Compounds”, thesis PhD, Saurashtra University
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Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SYNTHESIS, SPECTRAL STUDIES AND
THERAPEUTIC ACTIVITY
OF
HETEROCYCLIC COMPOUNDS
A THESIS
SUBMITTED TO
SAURASHTRA UNIVERSITY
FOR THE DEGREE OF
Doctor of PhilosophyIN
THE FACULTY OF SCIENCE (CHEMISTRY)BY
Ramesh K. KanpariyaRamesh K. KanpariyaRamesh K. KanpariyaRamesh K. KanpariyaRamesh K. Kanpariya
UNDER THE GUIDANCEOF
Dr. V. N. Patolia
KAMANI SCIENCE COLLEGE
CHEMISTRY DEPARTMENT
AMRELI - 365601
GUJARAT - INDIA
2009
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
DedicatedtoMy Belove d Pare nts
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Acknowledgements
"Oum Shree Ganeshay Namah"
Hats off to the omnipresent, omniscient and almighty god, the glorious
fountain and continuous source of inspiration! I offer salutations to him and
may to him and may head bows with rapturons dedication from within my
heart, to the omnipotent lord "Jay Khodiyar Ma".
My head bows with fullest devotion reverence, heartfelt obeisance,
deep sense of respect and admiration to, my most esteemed mentor, my
co-traveler and guide Dr. V. N. Patolia, Head, Chemistry Department Kamani
Science and Prataprai Arts College-Amreli who held the torch of excellent
guidance high and lighted up the darkness, with perpetual affectionate
encouragement and occasional constructive criticism when needed, towards
the goal of my academic journey.
I owe the deepest of heart deepest sense of gratitude and indebtendness
of Dr. D. M. Purohit chemistry Department, Shree M & N Virani Science
College, Rajkot as I have been constantly benefited with his lofty research
methodology and the motivation as well as his highly punctual affectionate,
yet noncompromising nature which always inspired me in heading rapidly
toward my good and helped me achieving the aim of my present task very
speedily.
I am thankful to principal Shree D. P. Virani Sir, for kind support and
providing research facility in Kamani Science College - Amreli.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Who in this world can entirely and adequately thank the parents. Who
have given us everything that we possess in this life. The life itself is
their gifts to us, So I am at loss of words in which to own my must
esteemed father late Kanubhai and my loving mother Smt. Bhanuben,
brothers Dineshbhai and Mukeshbhai has encouraged me to reach my
destination.
As with the completion of this task. I find myself in difficult position
on attempting to express my deep indebtedness to Mr. K. T. Sinojia,
Dr. R. V. Zala, Dr. G. B. Vadher, Dr. V. R. Shah, Mr. J. J. Travadi,
Mr. V. R. Danger, Mr. J. R. Dodia, Mr. Vipulbhai Gohel, Chetanbhai
Vyas, Shankarbhai, Gaffarbhai, Atulbhai, I wish to thank Devachanbhai
Kanpariya for his most willing co-operation stage.
I am most thankful to all my senior Dr. J. G. Dobariya,
Dr. V. R. Radadia and Dr. Sunil Rokad for their valuable co-operation
and help during the course of my work.
I feel lucky and very proud to have intimate friends like Vipul, Jayesh,
Jagdish, Vikram, Nilesh, Sanjay, Kalpesh who have been always
participating with any my problem and disppointment and rebuilt my
confidence at appropriate stages.
Finally, I express my greatful acknowledgement to chemistry
department, Kamani Science College Vidhya Sabha of Amreli for
providing me the excellent laboratory facilities and kind furtherance for
accomplishing this work.
Ramesh K. Kanpariya
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SYNTHESIS, SPECTRAL STUDIESAND
THERAPEUTIC ACTIVITYOF
HETEROCYCLIC COMPOUNDS
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
CONTENTSPage No.
SYNOPSIS ..... ..... 01
STUDIES ON HETEROCYCLIC COMPOUNDS.Introduction ..... ..... 14
PART- I : STUDIES ON CHALCONES.Introduction ..... ..... 18Section - I : Synthesis and antimicrobial activity of
5-{4'-[(3"-aryl)-2"-propene-1"-onephenyl carbmido} - dibenz [b,f] azepines.
Introduction and spectral studies... 24Experimental ...... ...... 31
PART- II : STUDIES ON ISOXAZOLES.Introduction ...... ...... 38Section - I : Synthesis and antimicrobial activity of
5-{4'-[(5"-aryl)-isoxazole-3"-yl]-phenylcarbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 42Experimental ...... ...... 49
PART- III : STUDIES ON PYRAZOLINES.Introduction ...... ..... 53Section - I : Synthesis and antimicrobial activity of
5-{4'-[(5"-aryl) 4",5" dihydro-1"(H)pyrazol-3"-yl]- phenyl carbamido}-dibenz [b,f] azepines
Introduction and spectral studies... 58Experimental ...... ...... 65
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Section - II : Synthesis and antimicrobial activity of5-{4'-[(5"-aryl)-4",5"-dihydro-1"N-acetylpyrazol-3"-yl]- phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 68Experimental ...... ...... 75
Section - III : Synthesis and antimicrobial activity of5-{4'-[(5"-aryl)-4",5"-dihydro-1"-N-phenyl pyrazol-3"-yl]- phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 78Experimental ...... ...... 85
PART - IV : STUDIES ON PYRIMIDINE DERIVATIVES.Introduction ....... ....... 89Section - I : Synthesis and antimicrobial activity of
5-{4'-[(6"-aryl)-2"-mercapto-3"-4"-dihydropyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 95Experimental ...... ...... 102
Section - II : Synthesis and antimicrobial activity of5-{4'-[(6"-aryl)-2"-hydroxy-3"-4"-dihydropyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 105Experimental ...... ...... 112
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Section - III : Synthesis and antimicrobial activity of5-{4'-[(6"-aryl)-2"-amino-3"-4"-dihydropyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 115Experimental ...... ...... 122
PART - V : STUDIES ON CYANO PYRIDINES.Introduction ...... ...... 126Section - I : Synthesis and antimicrobial activity of
5-{4'-[(6"-aryl)-2"-amino-3"cyano pyridine-4"-yl]phenyl carbamido}- dibenz [b,f] azepines.
Introduction and spectral studies... 131Experimental ...... ...... 138
Section - II : Synthesis and antimicrobial activity of5-{4'-[(4"-aryl)-3"-cyano-2"-methoxy pyridine-6"-yl]phenyl carbamido}- dibenz [b,f] azepines.
Introduction and spectral studies... 141Experimental ...... ...... 148
Section - III : Synthesis and antimicrobial activity of5-{4'-[(4"-aryl)-3"-cyano-2"-ethoxy pyridine-6"-yl]phenyl carbamido}- dibenz [b,f] azepines.
Introduction and spectral studies... 151Experimental ...... ...... 158
Section - IV : Synthesis and antimicrobial activity of5-{4'-[(4"-aryl)-3"-cyano-2"-hydroxy pyridine-6"-yl]phenyl carbamido}- dibenz [b,f] azepines.
Introduction and spectral studies... 161Experimental ...... ...... 168
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - VI : STUDIES ON CYANO PYRANS.Introduction ...... ...... 172Section - I : Synthesis and antimicrobial activity of
5-{4'-[(2"-amino)-(4"-aryl)-4"(H) pyran3-carbonitrile-6"-yl]phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 177Experimental ...... ...... 184
PART- VII : STUDIES ON QUINOXALINES.Introduction ....... ...... 188
Section - I : Synthesis and antimicrobial activity of2"-aryl[(3"-methyl phenyl carbamido)]5-dibenz [b,f,] azepines quinoxalines.
Introduction and spectral studies... 192Experimental ...... ...... 199
PART- VIII : STUDIES ON CYCLOHEXENONES.Introduction ....... ...... 204
Section - I : Synthesis and antimicrobial activity of ethyl[(6"-aryl) 4"-phenyl carbamido]-5-dibenz [b,f,]azepines -2"-oxo cyclohex-3"-ene-1"-carboxalate.
Introduction and spectral studies... 208Experimental ...... ...... 215
PART- IX : STUDIES ON BARBITONES.Introduction ....... ...... 219Section - I : Synthesis and antimicrobial activity of
5-{4'-[(3"-aryl)-2"-propene-1"-barbituric acid]-phenl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 223Experimental ...... ...... 230
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART- X: STUDIES ON THIOSEMICARBOXIMIDES.Introduction ....... ...... 234
Section - I : Synthesis and antimicrobial activity of5-{4'[(3"-aryl)-2"-propene-1"-thio semicarboximides]-phenyl carbamido}-dibenz [b,f] azepines.
Introduction and spectral studies... 238Experimental ...... ...... 245REFERENCES ...... ...... 248
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SYNOPSIS
1
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
"SYNTHESIS, SPECTRAL STUDIES AND THERAPEUTICACTIVITY OF HETEROCYCLIC COMPOUNDS
The work presented in the thesis with the title "SYNTHESIS,SPECTRAL STUDIES AND THERAPEUTIC ACTIVITY OFHETEROCYCLIC COMPOUNDS" included substituted Dibenz [b,f]azepines derivatives.
The aim research is to be devlop new bioactive entitles, especially withantimicrobial activities bearing heterocyclic ring system namely dibenz [b,f]azepine.
Dibenz [b,f] azepine represent one of the most class of compoundspossessing a wide spectrum of bactericidal, fungicidal, antitumar, antiinflammetry, antihypertensive activities etc. Keeping in association with dibenz[b,f] azepines of various activities, it was worthwhile to synthesise some newdibenz [b,f] azepines derivatives, which have been described as under.
PART - I STUDIES ON CHALCONES
Chalcones are phenyl strylketones contaning reactive keto ethylenicgroup (-C-CH=CH-) literature reveals that chalcone derivaties possessantibacterial, antiviral, antispasmodic activities. Hence it was thought worthwhile synthesis chalcone derivaties, which have been described are as under.SECTION - I : Synthesis and antimicrobial activity of 5-{4'-[(3''-aryl)
-2''- propene-1''-one] - Phenyl carbamido} - dibenz[b,f] azepines.
R
O
N
NH
O
Type (I) R=Aryl
2
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
The chalcone derivatives of Type -(I) have been synthesised by thecondensation of 5-[(4'-acetyl Phenyl) carbamido] dibenz [b,f] azepine witharomatic aldehyde in presence of 40% NaOH solution
PART - II STUDIES ON ISOXAZOLESIsoxazole derivatives are the potent biological activities. These have
been reported to be active as antibacterial, antifungal, insecticidal andantiallergic. In order to achieving better potency different isoxazolederivatives have been described as under.
SECTION - I Synthesis and antimicrobial activity of 5-{4'-[(5"-aryl)-isoxazole-3''-yl] Phenyl carbamido} - dibenz[b,f] azepines.
Isoxazoles of Type -(II) have been synthesised by chemoselectivecyclisation between chalcones of Type (I) with hydroxy amine hydrochloride.
PART - III STUDIES ON PYRAZOLINESPyrazoline derivatives possess broad spectrum of
pharmacological activities which are reflected by their use as analgesic,antiinflammatory, anticonvulsant, insecticidal, herbicidal, antimicrobialand antipyretic agents. With a view of above facts some new pyrazolineshave been synthesis which have been described as under.
SECTION - I Synthesis and antimicrobial activity of 5-{4'-[(5"-aryl)- 4"-5"- dihydro - 1"-(H)- pyrazol-3"-yl]phenyl carbamido} - dibenz [b,f] azepines.
Type (II) R=Aryl
O
N
NH
ON R
3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Type (III) R=Aryl
Type (V) R=Aryl
Type (IV) R=Aryl
O
N
NH
NH
N R
O
N
NH
NN R
O
N
NH
NN R
O CH3
Pyrazoline derivatives of Type : (III) have been synthesised by thecondensation of chalcones of Type (I) with hydrazine hydrate.
SECTION - II : Synthesis and antimicrobial activity of of 5-{4'-[(5"-aryl)- 4"-5"- dihydro-1"- acetylpyrazole-3"-yl] phenyl carbamido}-dibenz[b,f]- azepines.
Acetyl pyrazoline derivatives of Type : (IV) have been synthesisedby the condensation of chalcones of Type (I) with acetyl hydrazide.
SECTION- III Synthesis and antimicrobial activity of 5-{4'-[(5"-aryl)-4"-5"- dihydro-1"-Phenyl pyrazole-3"- yl]-phenyl carbamido}-dibenz [b,f]azepines.
4
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Phenyl pyrazoline derivatives of Type (V) have been synthesised by thecondensation of chalcones of Type (I) with phenylhydrazine.
PART - IV STUDIES ON PYRIMIDINE DERIVATIVESPyrimidine derivatives are biologically important products and their
synthesis and chemistry have received remarkable attention. It has beenreported that pyrimidine derivatives are associated with variousbiological activities like antifungal, antituberculer, antibacterial, herbicidaletc. This valid observation led us to synthesis some new medicinally activecompounds synthesised, which have been described as under.
SECTION : I Synthesis and antimicrobial activity of 5-{4'-[(6"-aryl)-2"- mercapto-3",4"- dihydro pyrimidine - 4"-yl] -phenyl carbamido} - dibenz [b,f] azepines.
Pyrimidine derivatives of Type : (VI) have been synthesised by thereaction of the chalcones of Type (I) with thiourea in presence ofalcoholic potassium hydroxide.
SECTION : II Synthesis and antimicrobial activity of 5-{4'-[(6"-aryl)-2"- hydroxy-3",4"- dihydropyrimidine - 4"- yl]- phenyl carbamido} -dibenz [b,f] azepines.
Type (VI) R=Aryl
R
O
N
NH
NH N
SH
5
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Pyrimidine derivatives of Type : (VII) have been synthesised by thereaction of the chalcones of Type (I) with urea.SECTION : III Synthesis and antimicrobial activity of 5-{4'-
[(6''- aryl)- 2''- amino -3'',4''- dihydropyrimidine - 4''- yl]-phenyl carbamido} -dibenz [b,f] azepines.
Pyrimidine derivatives of Type : (VIII) have been synthesized by thereaction of the chalcones of Type-(I) with guanidine hydrochloride.
PART - V STUDIES ON CYANO PYRIDINESIn recent years, much interest have been focused on the
synthesis of pyridines as the pyridine ring system is associated withvaluable pharmacological activity like antibacterial, antimalarial,antihypertensive, antifungal, anticonvalsant etc. considering these factswe thought it is worth while to synthesise some new pyridine derivativesin association with dibenz [b,f] azepine nucleus in search of better poten-tial drugs.SECTION - I Synthesis and antimicrobial activity of 5-{4'-[(6''-
aryl)- 2''- amino -3''- cyano pyridine 4''-yl] phenylcarbamido} dibenz [b,f] azepines.
Type (VIII) R=Aryl
R
O
N
NH
NH N
NH2
Type (VII) R=Aryl
R
O
N
NH
NH N
OH
6
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Pyridine derivatives of Type : (IX) have been synthesised by thereaction of the chalcones of Type (I) with malononitrile in presence ofammonium acetate.
SECTION : II Synthesis and antimicrobial activity of 5-{4'-[(4''- aryl)- 3''-cyano-2''-methoxy pyridine-6''-yl] phenyl carbamido} - dibenz [b,f] azepines.
Pyridine derivatives of Type : (X) have been synthesised by thereaction of the chalcone of Type (I) with malononitrile in presence ofsodium methoxide.
SECTION : III Synthesis and antimicrobial activity of 5-{4'-[(4''- aryl)- 3''- cyano-2''-ethoxy pyridine-6''-yl-]-phenyl carbamido} - dibenz [b,f] azepines.
Type (IX) R=Aryl
Type (X) R=Aryl
R
O
N
NH
N
O CH3
N
R
O
N
NH
N
NH2N
R
O
N
NH
N
O
N
CH3Type (XI) R=Aryl
7
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Pyridine derivatives of Type : (XI) have been synthesised by thereaction of chalcones of Type (I) with malononitrile in presence ofsodium ethoxide.SECTION : IV Synthesis and antimicrobial activity of 5-{4'-
[(4''- aryl)-3''- cyano-2''-hydroxy pyridine - 6''-yl]-phenyl carbamido}-dibenz [b,f] azepines.
Pyridine derivatives of Type : (XII) have been synthesised by thereaction of chalcones of Type-(I) with ethyl cyano acetate in presenceammonium acetate.
PART - VI STUDIES ON CYANO PYRANS
Cyanopyran derivatives have been reported to have variouspharmacological activities like antibacterial, antiviral, antifungal etc. Inorder to develop better medicinally important compounds, it wasconsidered of interest to synthesise some cyanopyran derivatives shownas under.
SECTION : I Synthesis and antimicrobial activity of 5-{4'-[(2''-amino)-(4''-aryl)-4'' (H) pyran-3-carbonitrile-6''-yl]phenyl carbamido}-dibenz [b,f] azepines.
Type (XIII) R=Aryl
Type (XII) R=Aryl
O
N
NHR
O
NH2
N
R
O
N
NH
N
OH
N
8
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Cyanopyaran derivatives of Type (XIII) have been synthesised bythe reaction of chalcones of Type-(I) with malono nitrile in pyridine.
PART - VII STUDIES ON QUINOXALINESQuinoxlines have been found to possess wide range of
therapeutic activities and industrial importance. These significantbiological properties have aroused considerable interest to design thecompounds in which dibenz [b,f] azpines nucleus is incorporated with aview to getting compounds with better drug potential.
SECTION : I Synthesis and antimicrobial activity of 2''-Aryl[(3''-methylphenyl carbamido)-5-dibenz [b,f]azepine quinoxalines
Quinoxalines derivatives of Type (XIV) have been synthesised by thereaction of chalcones of Type (I) with bromine in gla. acetic acid ando-phenylene diamine
Type (XIV) R=Aryl
O
N
NHN
NR
9
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART : VIII STUDIES ON CYCLOHEXENONES
Various derivatives of cyclohexenones exhibit interesting biologicalproperties like anticancer, antiinflammatory anticonvulsant, antipyretic etc.With a view to synthesis more potential drug value compounds. We havecarried out the synthesis of cyclohexenones derivatives, which have beenrepresented as under.
SECTION : I Synthesis and antimicrobial activity of ethyl-[(6''-aryl)-4''-phenyl carbamido}-5- dibenz [b,f] azepine-2''-oxo cyclohex-3''-ene-1''- carboxalate.
Cyclohexenone derivatives of Type : (XV) have been synthesised ofthe cyclocondesation of the chalcones of Type (I) with ethyl acetoacetatein presence of sodium ethoxide.
PART : IX STUDIES ON BARBITONESBarbituric acid derivtives showed a wide spectrum of biological
activites. dibenz [b,f] azepine heterocyclic moiety possess diversifiedbiological properties. Considering all the above facts, it was thought thatbarbituric acid group could be introduced to moiety, the resultingcompounds might have some significant biologically active compoundssynthesised, which have been described as under.
Type (XV) R=Aryl
O
N
NH
O
R
O
OCH3
10
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I Synthesis and antimicrobial activity of 5-{4'-[(3''-aryl)- 2''- propene - 1'' - barbituric acid] -phenyl carbamido}-dibenz [b,f] azepines
Barbituric acid derivative of Type (XVI) have been synthesised bythe reaction of chalcones of Type (I) with barbituric acid in gla. aceticacid.
PART : X STUDIES ON THIOSEMICARBOXIMIDESThiosemicariboximides derivatives possess broad spectrum of
therapeutic activity like antidiabatic, bactericidal, anticonvalsant, anti-pyretic etc. With a view of above facts to synthesised variousthiosemicarboximides derivatives are represented as under.
SECTION : I Synthesis and antimicrobial activity of 5-{4'-[(3''-aryl)- 2''- propene-1''-thiosemicarboximides]-phenyl carbamido}-dibenz [b,f] azepine
Type (XVI) R=Aryl
O
O
N
NH
NHNH
R
O
O
Type (XVII) R=Aryl
O
N
NH
N
R
NH S
NH2
11
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Thiosemicarboximes derivatives of Type (XVII) have beensynthesised by the reaction of the chalcones of Type-(I) withthiosemicarbazide in alcohol.
The structure elucidation of the synthesized compound have been doneon the basis of element analyses. IR 1HNMR spectroscopy and further sup-ported by mass spectroscopy. The purity of the synthesised compundschecked by TLC.
All the compounds have been also evaluted for their antimicrobialactivity towards Gram +ve and Gram -ve bacteria and also evaluatedantifungal activity at a concentration of 50 μg/ml. The antimicrobialactivity of the synthesised compounds have been compared with knownstandard drugs. e.g. ampicillin, chloramphenicol, norfloxacin and gresioflulvin.
12
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SYNTHESIS, SPECTRAL STUDIESAND
THERAPEUTIC ACTIVITYOF
HETEROCYCLIC COMPOUNDS
13
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SYNTHESIS, SPECTRAL STUDIES ANDTHERAPEUTIC ACTIVITY OF HETEROCYCLIC
COMPOUNDS
INTRODUCTION
Heterocyclic chemistry has been unparalled progress owing to their
wide natural occurance, specific chemical reactivity and broad spectrum
utility.
Hetrocyclic compounds have great applicability in pharmaceutical,
because they have specific chemical reactivity and provides false synthons
in biosynthetic process.
Some heterocyclic compounds must ideally have a. broad spectrum of
activity with a rapid bactericidal action. We must always continue search
new heterocyclic moleculer and identify its respective drugs activity. To
take the care for synthesis new heterocyclic moleculer a lower toxicity, a
partial or total absence of undesirable side effects, more neutritive value,
improved stability, a decrease in production cost and chek the qualitative or
quantitative improvement in activity with standard drugs. Dibenz [b,f]
azepines derivatives have been reported as a valuable medicine in the treat-
ment anthelmintic, antihistamine activity and also used in the treatment of
parkinson's disease. Dibenz [b,f] azepines substituents serves as nucleus to
a host of compound which are associated with wide spectrum of therapeutic
activity
Heterocyclic compound have great biological significance properties.
(1) They have a specific chemical reactivity.
14
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
(2) They resemble essential metabolism and can also provide false synthons
in biosynthetic process.
(3) They fit receptors and block their normal working.
(4) They provide convenient building blockers to which biologically active
substituents can be attached.
The interesting biological activities of heterocycles have stimulated
considerable research work in recent years including to the synthetic utillity.
Heterocyclic compounds can be synthesised by cyclization
reactions(accompanied by elemination of small molecules) addition
reactions; (adduct formation), ring transformation reactions or replacement
involving groups. Formation of heterocycle from acylic compounds alters
the reactivity.
AIMS AND OBJECTIVITSPoupulation of our country is skyrockating number of diseases are
uncoured eg. cancer, Aids etc.
In the pharmaceutical field, there is a need for new and novel chemical
inhibitors of biological functions. Our efforts are focused on the
introduction of chemical diversity in the molecular frame work in order to
synthesising pharmacologically interesting heterocyclic compounds of widely
different composition. During the course of research work looking to the
applications of heterocyclic compounds, several entities, have been designed,
generated and characterised using spectral studies. The aims and objectives
of the work carried out are as under.
15
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
(1) To synthesise pharmacologically active entities like chalcones,
isoxazoles, pyrazolines, pyrimidines derivatives, cyanopyrans,
quinoxalines, cyclohexanones, barbitones, thiosemicarbaximides bear
ing dibenz [b,f] azepines moiety.
(2) To characterize these products for structural elucidation using
spectroscopic technque like IR,1H NMR and Mass spectral studies.
(3) To check the the purity of all compounds using thin layer chromatography.
(4) To evalute these new products for better drug potential against
different strain of bacteria and fungi activity and compare with known
standard drugs.
The research work is presented as studies on dibenz [b,f] azepines
derivatives are synthesis.
PART - I : STUDIES ON CHALCONESPART - II : STUDIES ON ISOXAZOLESPART - III : STUDIES ON PYRAZOLINESPART - IV : STUDIES ON PYRIMIDINE DERIVATIVESPART - V : STUDIES ON CYANO PYRIDINESPART - VI : STUDIES ON CYANO PYRANSPART - VII : STUDIES ON QUINOXALINESPART - VIII : STUDIES ON CYCLOHEXENONESPART - IX : STUDIES ON BARBITONESPART - X : STUDIES ON THIOSEMI CARBOXIMIDES
16
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 17
PART - I
STUDIES ON CHALCONES
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON CHALCONES
INTRODUCTIONThe chemistry of chalcones (M) have generated intensive scientific
studies throughout the world specially interesting are their biological and
industrial applications. Chalcones are coloured compounds because of the
presence of the chromophore, auxochromes. They are known as
benzalacetophenones or bnzylidene acetophenones. S.V. Kostanecki and
J. Tambor1 gave the name chalcone".
Chalcone are characterised by their possession of a structure in which
two aromatic rings A and B are linked by an aliphatic three carbon chain.
The alternative names given to chlacones are phenyl styryl ketones,
benzalacetophenones. β-phenyl acrylphenone, γ-oxo-α-γ-diphenyl-α-propyl-
ene and α-phenyl-β-benzoethylene.
SYNTHTIC ASPECT:A considerable variety of methods are available for the synthesis of
chalcones. The most convenient method is one that involves the
Claisen-Schmidt condensation of equimolar quantities of an aryl methyl ketones
with aryl aldehyde in presence of alcoholic alkali.2
18
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Several condensing agents used are alkali of different strength3-4, hydrogen
chloride5,6 ,Phosphorous oxychloride7, Piperidine8, anhydrous Aluminium
choride9, Boron trifluoride10, aqueous solution of borax11, amino acid12 and
perchloric acid13 etc.
MECHANISM:Chalcone formation proceeds through aldol type of condensation and
the process is catalysed by the presence of alkali14, following steps of the
reaction mechanism are as under.
The intermediate Aldol type of products formed readily undergoes
dehydration even under mild condition, particularly when R and R' are aryl
groups.
REACTIVITY OF CHALCONES:The chalcone have been found to be useful for the synthesis of variety
of heterocyclic compounds are as under.
(a) Pyrazolines15 and its derivatives can be prepared by the condensation
of chalcones with hydrazine hydrate and acetic acid.
(b) Chalcones on condensation with malononitrile and ammonium acetate
yields 2-amino-3-cyano pyridines16.
(c) Isoxazoles17 can be prepared by the treatment of chalcones with
19
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
hydroxylamine hydrochloride and sodium acetate.
(d) Chalcone on condensation with malononitrile in pyridine forms 2-amino
3-cyanopyrans.18
(e) Chalcones on treatment with urea in presence of alkali affords 2-oxo
Pyrimidines19
(f) Chalcones on reaction with thiourea in presence of alkali/acid yields 2-
thiopyrimidines.20
(g) Chalcones on treatment with guanidine hydrochloride in presence of
alkali affords 2-amino pyrimidines.21
(h) Chalcones reacts with P2S5 yielding 2-isothiazolines.22
(i) Chalcones with sodium nitrile in presence of glacial acetic acid in
ethanol produces 2-(H)-pyrimidines.23
(j) Chalcones with monoethanolamine in ethanol gives 1,4-oxazipines.24
(k) Chalcones with 2-amino thiophenol in acetic acid produces 1,5-
thiazepines.25
(l) Chalcones on reaction with semicarbazide hydrochloride in ethanol
affords 1-caroxamide pyrazolines.26
(m) Chalcones on reaction with 2-aminopyrimidine in glacial acetic acid
affords pyrido pyrimidines.27
(n) Oxiran28 can be prepared by the reaction of chalcone with H2O2 in
basic media.
(o) Cyanopyridone29 derivatives can be prepared by the condensation of
Chalcone with ethalcyanoacetate.
(p) Chalcones gives imine derivatives with amine in presence of sulphuric
acid as a catalyst.30
(q) Chalcone on reaction with barbituric acid gave barbitone derivatives.31
20
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
THERAPEUTIC INTEREST:Chalcones are potential biocides, some naturally occuring antibiotics
and aminochalcones probably own their biological activity to the presence
of α,β- unsaturated carbonyl group.
(a) Insecticidal32,33
(b) Antiulcer34
(c) Antiinflammatory35,36
(d) Bactericidal37,38
(e) Fungicidal39,40
(f) Antiviral41
(g) Anthelmintics42
(h) Antiallergic43
(i) Carboxygenase inhibitor44
(j) Antitumor45,46
(k) Antimalarial47
(l) Anticancer48
(m) Antileishmanial49
Moreover, synthesis and antibacterial activity of substituted chalcone
derivatives have been reported by S.R. Modi et al.50 and A. Attia51, V. R.
Mudalir et al52 have prepared phenoxy chalcones and observed their
insecticidal activity. Kammei et al53. have been synthesised phenoxychalcones
and observed their insecticidal activity. R. De vincenzo et al54. and Han et al.55
have chalcone derivatives for their anti-inflammatory activity. Okuyana et al56.
have been reported chalcone derivatives reductase inhibitor activity. Antitumor
and antifungal activity as reported by A. Tsotitus and co-worker57. Antifeedant
activity of chalcones have been observed by P. N. Sharma and Sreenivasulu58.
21
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ezio Bombardelli et al59. have demonstrated that chalcone possess a
valuable antiproliferation activity both on sensitive cancereous cell and on
cell which are resistant to common chemotherapeutic drugs. S.Elichi etal. of
the have been patented chalcones for their use for treatment of glaucoma60.
B. B. kailashnikov etal61. and S.Santoshi etal62 showed antifungal activity,
P. Walavalker etal63. showed aldose reductase inhibitor, O. tory etal64
evaluated anticancer activity, and J. R. Dimmock. et al65 and T.M.
Abdelr rahman66 evaluated antimicrobial activity.
Recently, Ni Liming et al.67 have synlhesised chalcones and screened
for heir their antiinflammatory and cardiovascular activity. Kumar Srinivas et
al68. have synthesised chalcones as a antitumor agent. Ko Horng Huey et al69.
have prepared chalcones as antiinflammatory agent. Nakahara Kazuhiko et
al70. have synthesised chalcones as carcinogen inhibitors. Antitubercular agents
of chalcone.
Lin Yah meei et al71 have synthesis chalcones derivatives.
B. R. Das et al72. have found that chalcones possesses larvicidal
properties. Kirm Min Young et al73. have synthesised chalcones and tested
for their matrixmetalloproteinase inhibitor activity.
Liu Mei et al74. have been prepared chalcones and evaluated antimalarial
activity. O. veronika et al75, have synthesised chalcones and screened as car-
diovascular agent.
Moreover, it has been found that chalcone derivatives possesses nitric oxide
inhibitor76,77 and anti-HIV78,79 activities.
22
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Chalcone bearing a very good synthon, variety of novel heterocycles
with good pharmacological profile can be designed. These valid
observation led us to explore chalcone chemistry by synthesizing several
derivatives like isoxazoles, pyrazolines, pyrimidine, bearing different
heterocyclic ring systems for medicinal Value, in order to achieving better
therapeutic agents, this study described as under.
SECTION : I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-ONEPHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
23
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-ONE PHENYL CARBAMIDO}-DIBENZ[b,f] AZEPINES.
Recently much interest has been focoused on the synthesis and
biodynamic activities of chalcones and it is a good synthon for various
heterocyclic rings, with a view to obtained compounds havings better thera-
peutic activity 5-{4"-[(3"-aryl)-2" propene-1"one] phenyl carbamido} - dibenz
[b,f] azepines have been synthesis by the condensation of 5-{4' acetyl phe-
nyl carbamido}-dibenz [b,f] azepines with aromatic aldehyde in presence of
alkali. The latter was 5-{4'-acetyl phenyl carbamido}-dibenz [b,f] azepines
have been synthesis by the condensation of 5- dibenz [b,f] azepines methanoyl
chloride with 4-aminoacetophenone.
The constitution of the synthesised products have been characterised
by elemental analysis, IR,1H NMR and Mass spectra study. The product were
screened for antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section : I, Page No: 32-34
Type (I) R=Aryl
R
O
N
NH
O
24
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
5001000150020003000400040
50
60
70
80
90
100
%T
3547
.21
3470
.06
3454
.62
3379
.40
3367
.82 32
98.3
832
75.2
432
46.3
132
19.3
029
43.
472
899.
1128
06.5
225
42.2
6
1705
.13
1498
.74
1446
.66
1313
.57
1226
.77
1170
.83
1045
.45
557.
453
418
57
IR SPECTRAL STUDY OF 5-{4'-[3"-(4"'-METHOXYPHENYL)-2"-PROPENE-1"-ONE] PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
O
N
NH
O
O
CH3
Type
Alkane
Aromatic
Amide
KetoneEtherVinyl
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H def. bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.pC-N str.N-H str.N-H bending> C=OC-O-C-CH=CH str.
Observed2943.47
48991446.66
29431498, 14461226,1170
78013133470149817051170
1446.66
Reported2975-29505890-28501470-14503090-30301600-14501300-1100890-750
1380-13303550-33501650-15501750-16501200-11001400-1600
Frequency in cm.-1
Ref.445-458
"""
446,447""
449446,447
"447450445
25
1770
.34-
780.
10-
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-400 cm-1 (KBrdisc)
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
NMR SPECTRAL STUDY OF 5-{4'-[3"-(4"'-METHOXYPHENYL)-2"-PROPENE-1"-ONE] PHENYL CARBAMIDO} - DIBENZ [b,f] AZEPINES.
Intrenal standard : TMS; solvent :CDCl3 : Instrument : BRUKER spectrometer
(300 MHz)
26
SignalNo
12345
Signal Position(δ δ δ δ δ ppm)
3.656.336.96
7.2-7.56.97
Relative No.of protons Multiplicity Inference
3 H1 H2 H16 H2 H
SingletSingletSinglet
MultipletDoublet
Ar-OCH3a
-CONH2b
-CH=CHc
Ar-Hd
Ar-He
O
N
NH
O
O
CH3a
b
c c
d d d
d
d
d
d
d d ddd
dd
d
d
e
e
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
O
N
NH
O
OCH
3O
N
NH
O
+
m/z
=441
O
N
NH
O
O-
m/z
=457
O
N
NH
O
OCH
3
m/z
=448
O
N
NH m
/z=2
87
O
OCH
3
m/z
=238
O
OCH
3
+m
/z=1
61m
/z=1
03C
H+
m/z
=372
m/z
=180
m/z
=472
O
NH
NH
O
OCH
3
MA
SS F
RE
GM
EN
T S
TU
DY
OF
5-{4
'-[3"
-(4"
'-ME
TH
OX
Y P
HE
NY
L)-
2"-
PRO
PEN
E-1
"-O
NE
]-PH
EN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
27
m/z
=196
O
N +
m/z
=252
NH
-
O
OCH
3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
PEC
TR
AL
ST
UD
Y O
F 5-
{4'-[
3"-(
4"'-M
ET
HO
XY
PH
EN
YL
)-2"
- PR
OPE
NE
-1"-
ON
E]-
PHE
NY
LC
AR
BAM
IDO
}-DIB
ENZ
[b,f]
AZE
PIN
ES.
O
N
NH
O
OCH
3
m/z
=472
28
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
4-O
H-C
6H4-(
20)
3-O
CH
3,4-O
H-C
6H3-(
25)
2-C
l-C6H
4-(20
)
30 30 35 -
A.n
iger
R
3-O
CH
3, 4-
OH
-C6H
3-(20
)4-
OC
H3-C
6H4-(
21)
3-N
O2-C
6H4-(
22)
2-C
l-C6H
4-(20
)
- - - 27
E.c
oil
R
2-O
H-C
6H4-(
20)
3-O
H-C
6H4-(
21)
3-N
O2-C
6H4-(
23)
2-C
l-C6H
4-(21
)
32 28 30 -
S. a
ureu
sR
2-O
H-C
6H4-(
19)
3-O
H-C
6H4-(
26)
3-N
O2-C
6H4-(
20)
29 32 31 -
S. ta
phim
ariu
mR
2-O
H-C
6H4-(
22)
3-O
H-C
6H4-(
23)
4-O
CH
3- C
6H4-(
27)
3-N
O2-C
6H4-(
21)
2-C
l-C6H
4-(23
)
30 29 27 -
Ampic
ilin
50
μgCh
loro
mph
enico
l "
Nor
floxa
cin "
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
29
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
40% NaOH,24 hrs.,stirringR-CHO
30
PyridineReflux
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
Type : (I) R = Aryl
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-ONE]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
(A) Synthesis of 5-(4'-Acetylphenyl carbamido)-dibenz [b,f] azepines.A mixture of 5-dibenz [b,f] azepines methanoyl chloride (2.55g, 0.01M),
4-amino acetophenone (1.35g, 0.01M) in ethanol (25 ml) and pyridine (5 ml)was refluxed on a oil bath at 120oC at 12 hrs. The content was cooled andpoured into crushed ice, filtered and washed with water. The isolated productwas crystallized from ethanol yield 85.42 %, M.P :170oC (Found : C:77.85,H: 5.02; N: 7.82, C23 H18N2O2 required C: 77.96; H : 5.08; N : 7.90 %)
(B) Synthesis of 5-{4'-[3"-(4'''-methoxy phenyl)-2"-propene-1"-one]-phenyl carbamido}-dibenz [b,f] azepines.A mixture of 5- (4'-Acetyl phenyl carbamido)-dibenz [b,f] azepines (3.54
g, 0.01M), 4-methoxy benzaldehyde (1.36g, 0.01M) ethanol 40% NaOH tillthe solution vigorously stirring at basic medium at 24 hrs. The contents werepoured into ice, acidified filtered and crystallized from ethanol yield 79.86%M.P. 105oC, (found : C : 75.80; H:5.01; N:5.80; C31 H24 N2O3 required : C:75.86; H:5.08; N: 5.93%)
Simillary other chalcones were prepared and their physical data arerecorded in table No. 1
(C) Antimicrobial activity of 5-{4'-[(3"-Aryl)-2"-propene-1"-one]-phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,section: I, page No. : 32-34
The zone of inhibition of the test solution are recorded in Table No. : 1
31
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
(D) Antimicrobail activity of 5-(4'-Acetylphenyl carbamido)-dibenz[b,f] azepines.Method: It was carried out using the cup-plate method which has beendescribed as under.
Antibacterial activity : 80
The purified products were screened for their antibacterial activity. Theneutrient agarbroth prepared by the usual method, was inoculated speciallywith 0.5 ml for 24 hours, old subsclture of B. megaterium S.aureus,Escherichia coli, S. taphimarium, in separate conical flasks at 40-50°C andmixed well by gentle shaking. About 25 ml of the contents of the flask werepoured and evenly spread in a petridish (13 cm in diameter) and allowed toset for 2 hrs. The cups (10 mm in diameter) were formed by the help of borerin a agar medium and filled with 0.10 ml (1.0 μg/ml) solution of sample indimethyl formamide.
The plates were incubated at 32°C for 24 hrs. and the control was alsomaintained with 0.1 ml of DMF in similar manner and the zone of inhibitionof the bacterial growth are measured in mm diameter and are recorded inTable No. A.
Antifungal activity 81
Aspergillus niger was employed for testing fungicidal activity usingcup-plate method the cultures were maintained on subouraud's agar slants.Purified compounds were used for testing the fungicidal activity, sterlisedsubouraud's agar medium was inoculated with 72 hours old 0.5 ml suspen-sion of fungal spores in a sterilised separate flask. About 25 ml of the inocu-lated medium was evently spreaded in a petridish and allowed to set for 2 hrs.The cups (10 mm in a diameter) were punched in petridish and loded with 0.1ml (1.0 mg/ml) of solution of a sample in DMF
32
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
The plate were incubated at room temp. 37° C for 48 hrs. After thecompletion of incubation period. The zone of inhibition or growth in the formof diameter in mm was measured. Along the test solution in each petridish onecup was filled up with solvent acts as control. The zone of inhibition arerecorded in Table No. A.
ANTIMICROBIAL ACTIVITY
Product : 5-(4'-Acetylphenyl carbamido)-dibenz [b,f]azepines.
Method : Cup PlateGram Positiv Bacteria : B. megaterium
S.aureus,Gram Negative Bacteria : Escherichia coli,
S. taphimarium,Fungi : Aspergillus nigerConcentration : 50 μ gSolvent : Dimethyl formamideStandard Drug : Ampicillin, Chloramphenicol, Norfloxacin,
Greseofulvin
The antibacterial activity was compared with standard drugs viz.Ampicillin, Chloramphenicol, Norfloxacin and antifungal activity was com-pared with standard drug viz. Greseofulvin. The Zones of inhibition weremeasured in mm. The Zones of inhibition that displayed by standard drugsare recorded in Part - I, Page No. 34
33
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
S. ta
phim
ariu
mR 30 29 27 -
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
A.n
iger
R - - - 27
E.co
ilR 32 28 30 -
TABL
E N
O. :
A
: AN
TIM
ICR
OBI
AL
AC
TIV
ITY
ZO
NE
OF
INH
IBIT
ION
FO
R S
TAN
DA
RD
DR
UG
S
Stan
dard
Dru
gs
Am
pici
lin (5
0 μg
)
Chl
orom
phen
icol
(50
μg)
Nor
floxa
cin
(50
μg)
Gris
eofu
lvin
(50
μg)
B. m
egat
eriu
mR 30 30 35 -
S. a
ureu
sR 29 32 31 -
34
Sr.
No.
1 2 3 4
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TAB
LE
NO
: 1
PHY
SIC
AL
CO
NST
AN
T O
F 5-
{4'-[
(3"-
AR
YL
)-2-
PRO
PEN
E-1
"-O
NE
] PH
EN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
ES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C30
H22
N2O
2
C30
H22
N2O
3
C30
H22
N2O
3
C30
H22
N2O
3
C31
H24
N2O
4
C31
H24
N2O
3
C31
H24
N2O
3
C30
H21
N3O
4
C30
H21
N3O
4
C30
H21
N2O
2Cl
C32
H27
N3O
2
C28
H20
N2O
3
C34
H24
N2O
2
C38
H26
N2O
2
M.P
. O
C 4 110
95 128
115
110
73 105
120
130
95 80 90 110
180
Yie
ld% 5
70.0
269
.00
68.7
265
.15
70.3
275
.18
79.8
676
.09
87.3
973
.65
68.9
069
.55
78.1
078
.89
% o
f Nitr
ogen Fo
und
7 6.25
6.00
6.05
6.01
5.70
5.85
5.80
8.49
8.42
5.70
8.61
6.42
5.60
5.05
Cal
cd.
6 6.33
6.11
6.11
6.11
5.73
5.93
5.93
8.62
8.62
5.87
8.65
6.48
5.69
5.16
35
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 36
TABL
E N
O :
2A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(3"-
AR
YL)
-2-P
RO
PEN
E-1"
-ON
E] P
HEN
YL
CA
RB
AM
IDO
}-D
IBE
NZ
[b,
f] A
ZE
PIN
ES.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R
2
C6H
5-2-
OH
-C6H
4-3-
OH
-C6H
4-4-
OH
-C6H
4-3-
OC
H3,4
-OH
-C6H
3-2-
OC
H3-C
6H4-
4-O
CH
3-C6H
4-2-
NO
2-C6H
4-3-
NO
2-C6H
4-2-
Cl-C
6H4-
4-N
,N-(
CH
3) 2C6H
4-C
4H3O
(Fur
fura
l)-C
10H
7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 14 17 18 20 25 17 18 14 17 20 18 14 12 15
S. a
ureu
s4 16 19 26 14 18 13 14 17 20 18 17 15 12 17
S. ta
phim
ariu
m5 19 22 23 16 15 19 27 14 21 23 18 16 17 15
A.n
iger
7 14 17 15 16 20 17 21 19 22 20 16 15 18 19
E.c
oil
6 18 20 21 17 19 14 17 19 23 21 14 17 16 14
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - II
STUDIES ON ISOXAZOLES
37
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON ISOXAZOLES
INTRODUCTIONIsoxazoles-(N) are a group of heterocyclic compounds containing two
hetero atoms : oxygen and nitrogen.
In 1888 claisen first suggest in isoxazoles (N) for a product from the
reaction of 1,3 diketone with hydroxylamine82 subsequently a solid
foundation for the chemistry of isoxazoles was laid down by claisen and his
students. It was shown to possess typical properties of an aromatic system
but under certain reaction conditions, particularly in reducing or basic
media, it becomes very highly labile. The next important contribution to the
chemistry of isoxazoles was made by Quelico in 1946 when he began to
study the formation of isoxazoles from nitrile N-oxides and unsaturated com-
pounds.83
SYNTHETIC ASPECT:Isoxazole may be prepared by the reaction between hydroxylamine and
α,β (3-unsaturated compounds the reaction proceeds Via the formation of an
oxime. which possibiy undergoes cyclization.
38
H
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Isoxazole can be prepared by various methods which are described as
under. L.S. Crawly etal84 prepared isoxazole from chalcones hydroxylamine
hydrochloride and KOH in methanol.
THERAPEUTIC IMPORTANCEIsoxazole possess wide therapeutic activities which are as under.
(a) Antiinflammatory85,86,87,88,
(b) Antivonvulsant89,90
(c) Muscle relaxant91,92
(d) Antipyretic93
(e) Anticholestemic94
(f) Antibacterial95,96,97
(g) Diabetic98
(h) Nematocidal99
(i) Fungicidal100,101
(j) Antiviral102
(k) Herbicidal103,104,105
(l) Anthelmintics106
(m) Antileukemia107
(n) Antitumor108
(o) Hypoglycemic109
(p) Analgesic110
39
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
B.Maggio et al111 synthesised novel. 3-(isoxazol-3-yl)-quinazolin-4-(3H)-
one derivatives and tested for their analgesic and antiinflammatory activities,
as well as for their acute toxicity and ulcerogenic effect. Some of them had a
very low ulcerogenic effect.
C. B. Xue et al112 reported the replacement of the benzamide in XUO57
(potent inhibitor) with an isoxazole carboxamide resulted in significant
improvernent in vitro potency. More importanty the analogue XXUO65
showed on excellent oral antiplatelet effect in dogs.
M. Masui et al.113 have prepared isoxazoles having pesticidal activity.
Some excellent herbicidal results obtained by K.V. Reddy et al.114 Moreover
isoxazoles found to possess remarkable anxiolytic and antihypenensive
effect, reported by J. Nyitrai et al.115, A. Mishra et. al.116 have synthesised and
reported isoxazoles as useful agents for analgesic and antiinflammatory
activities. T. D. Aicher et al.117 cited some isoxazole derivatives possessing
hypoglycemic agents.
S. Ozkan et al.118 have prepared 3-(l-phenyl-l,2,3-triazol-4-yl)
benziscreazoles (O) and studied their insecticidal acitvity.
40
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
M. Dauria119 studied photochemical behaviour of isoxazole derivatives.
Y. N. Manohara et al.120 investigated thermal decomposition kinetics of Co
(II) and Ni (II) complexes of substituted isoxazole and their antibacterial
activity. A.R. Parikh and co worker121 have prepared isoxazole derivatives
and documented antitubercular activity. Some isoxazoles are found to
possess herbicidal122-124 Potential anti-inflammatory125,126 and antimicrobial
agents127,128 estrogen receptor modulators129 and inhibitor of P38 MAP kinose
activities.130
N. Lal et al.131 have synthesised isoxazole derivatives (P) and reported
their adrenergic antagonist activity.
When an intension of the compounds possessing better therapeutic
activity we have undertaken the synthesised of isoxazoles bearing Dibenz
[b,f] azepines moiety which have been described as under.
SECTION-I : SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(5"-ARYL)-ISOXAZOLE-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
41
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(5"-ARYL)-ISOXAZOLE-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.
Taking into consideration of wide therapeutic activity of isoxazole
derivatives. The synthesis of 5-{4'-[(5"-aryl) -isoxazole 3"-yl]-phenyl
carbamido}-dibenz [b,f] azepines have been synthesised by the
condensation of 5-{4'-[(3"-aryl)-2"- propene -1"-one] phenyl carbamido}-
dibenz [b,f] azepines with hydroxyamine hydrochloride.
The constitution of the products have been characterised by elemental
analyses, IR,1H NMR and Mass spectral study. The product were screened
for antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section : I, Page No.32-34
Type (II) R=Aryl
O
N
NH
ON R
42
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Type
Alkane
Aromatic
Amide
KetoneEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H def. (bending)C-H str.C=C Ring skeletalC-H i.p. defC-H o.o.pC-N str.N-H str.N-H bending> C=OC-O-CN=C
Observed2956283914383028
1519, 1492,12307711329339015191716
1112,12221492
Reported2975-29502890-28501470-14353080-30101600-14501300-1100735-700
1380-13303550-33501650-15501750-16501300-11001600-1400
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[5"-(4'''-METHOXYPHENYL)-ISOXAZOLE-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450448
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBrdisc)
50010001500200030004000-25
0
25
50
75
100
125
%T30
28.3
429
56.9
728
39.
312
781.
44
192
8.8
8
171
6.70
170
5.13
1519
.96
1492
.95
143
8.94
136
3.7
213
29.0
013
13.5
712
30.
631
222.
91
1112
.96
1055
.10
949.
0186
8.00
771.
55
3390
.24-
43
O
N
NH
ON O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SignalNo
12345
Intrenal standard : TMS; solvent :CDCl3 : Instrument : BRUKER spectrometer
(300 MHz)
NMR SPECTRAL STUDY OF 5-{4'-[5"-(4'''-METHOXYPHENYL)-ISOXAZOLE-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.
Signal Position(δ δ δ δ δ ppm)
3.756.76.8
7.0 - 7.76.9
Relative No.of protons
3 H1 H1 H16 H2 H
Multiplicity
SingletSingletSinglet
MultipletDoublet
Inference
Ar-OCH3a
N-Hb
Ar-Hc
Ar-Hd
Ar-He
44
a
bc
d d d
d
d
d
d
d dd
dd
dd
d
d
e
eO
N
NH
ON O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 45
MA
SS F
RA
GM
EN
T S
TU
DY
OF
5-{4
'-[5
"-(4
'''-M
ET
HO
XY
PHE
NY
L)-
ISO
XA
ZO
LE
-3"-
YL
]-PH
EN
YL
CA
RB
AM
IDO
}-D
IBE
NZ
[b,
f] A
ZE
PIN
ES.
O
N
NH
ON
+
m/z
=454
O-
O
N
NH
ON
m/z
=470
O
N
NH
ON
+
m/z
=446
O
N
NH
ON
O
CH
3
m/z
=461
O
NH
NH
ON
O
CH
3
m/z
=385
O
N
NH
CH
2+
m/z
=339
O
N
NH
CH
2+
m/z
=325
O
N
NH
m/z
=311
O
N
NH
ON
OC
H3
m/z
=485
O
N
NH
m/z
=105
CH
2+
m/z
=287
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 46
MA
SS S
PEC
TR
AL
ST
UD
Y O
F 5-
{4'-
[5"-
(4'''
-ME
TH
OX
YPH
EN
YL
)-IS
OX
AZ
OL
E-3
"-Y
L]-
PHE
NY
LC
AR
BA
MID
O}-
DIB
EN
Z [
b,f]
AZ
EPI
NE
S.
O
N
NH
ON
OC
H3
m/z
=485
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 47
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
4-O
H-C
6H4-(
22)
2-N
O2C
6H4-(
19)
2-C
l-C6H
4-(28
)
30 30 35 -
A.n
iger
R
3-O
H-C
6H4-(
22)
4-O
H-C
6H4-(
21)
3-N
O2-C
6H4-(
21)
2-N
O2-C
6H4-(
22)
2-C
l-C6H
4-(23
)
- - - 27
E.c
oil
R
4-O
H-C
6H4-(
23)
4-O
CH
3-C6H
4-(20
)
3-N
O2-C
6H4-(
21)
2-C
l-C6H
4-(23
)
32 28 30 -
S. a
ureu
sR
2-O
H-C
6H4-(
19)
4-O
H-C
6H4-(
20)
3-N
O2-C
6H4-(
27)
2-C
l-C6H
4-(20
)
29 32 31 -
S. ta
phim
ariu
mR
3-O
H-C
6H4-(
23)
4-O
H-C
6H4-(
22)
2-N
O2-C
6H4-(
21)
3-N
O2-C
6H4-(
20)
2-C
l-C6H
4-(22
)
30 29 27 -
Ampic
ilin50
μg
Chlo
rom
phen
icol
"N
orflo
xacin
"G
riseo
fulv
in "
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
Type (II) R=Aryl
NH2OH.HClCH3COONa
PyridineReflux
O
N
NH
ON R
48
R-CHO40% NaOH, 24 hrs., Stirring
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(5"-ARYL)-ISOXAZOLE-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepines.. For synthesis see part-I, section : I ,Page No. : 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: 1, section : I, Page No : 31
(c) Synthesis of 5-{4'-[5"-(4"'-methoxy phenyl)-isoxazole-3"-yl]phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine . (4.72g,0.01M); hydroxy
amine,hydrochloride (0.69g, 0.01M) and ethanol (20 ml.). The reaction mix-
ture was reflux at 120OC for 5 hrs. The reaction mixture was cooled, poured
into crushed ice, filtered, dried. The isolated products was crystallised from
ethanol, yield 72.68%; M.P. 120OC ,(Found:C, 76.65 ; H, 4.70 ; N, 8.60
C31H23N3O3 required C , 76.70 ; H, 4.74 , N, 8.65 %).
Similary other isoxazoles were synthesised and their physical data are
recorded in table No. : 3
(D) Antimicrobial activity of 5-{4'-[(5"-aryl)-isoxazole-3"-yl] phenylcarbamido}-dibanz [b,f] azepines.
Antimicrobial testing was carried out as described in part : I,
section: I ,Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. : 4
49
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
3 P
HY
SIC
AL
CO
NST
AN
T O
F 5-
{4'-[
(5"-
AR
YL)
- ISO
XA
ZOLE
-3"-
YL]
-PH
ENY
LC
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
(64)
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C30
H21
N3O
2
C30
H21
N3O
3
C30
H21
N3O
3
C30
H21
N3O
3
C31
H23
N3O
4
C31
H25
N3O
3
C31
H23
N3O
3
C30
H20
N4O
4
C30
H20
N4O
4
C30
H20
N3O
2Cl
C32
H28
N4O
2
C28
H19
N3O
3
C34
H23
N3O
2
C38
H25
N3O
2
M.P
. O
C 4 102
98 95 120
78 130
120
95 42 60 110
78 85 80
Yie
ld% 5
77.6
581
.39
72.7
371
.68
74.0
059
.81
72.6
860
.55
62.5
875
.10
77.6
382
.80
78.1
279
.01
% o
f Nitr
ogen Fo
und
7 9.07
5.81
8.86
8.83
8.28
8.51
8.60
11.1
011
.11
8.51
11.0
99.
418.
257.
45
Cal
cd.
6 9.23
8.91
8.91
8.91
8.38
8.65
8.65
11.2
011
.20
8.58
11.2
09.
458.
317.
56
50
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 51
TABL
E N
O :
4; A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(5"-
AR
YL)
- ISO
XA
ZOLE
-3"-
YL]
-PH
ENY
LC
AR
BA
MID
O}-
DIB
EN
Z [
b,f]
AZ
EPI
NE
S.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 15 17 18 22 18 15 17 19 16 28 14 16 15 13
S. a
ureu
s4 17 19 14 20 12 15 14 17 27 20 14 13 15 17
S. ta
phim
ariu
m5 14 17 23 22 18 17 20 21 20 22 18 17 15 14
A.n
iger
7 19 20 22 21 19 17 16 21 22 23 14 17 19 16
E.c
oil
6 15 12 20 23 18 17 20 12 21 23 19 18 16 15
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - III
STUDIES ONPYRAZOLINES
52
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON PYRAZOLINES
INTRODUCTIONAmongst nitrogen containing five membered heterocycles, pyrazolines
(Q) have proved to be the most useful frame work for biological activities,
pyrazolines have attracted attention of medicinal chemistry for both with
regard to heterocyclic chemistry and the pharmacological activities
associated with them in 1967 Jarobe, reviewed the chemistry of pyrazolines,
which have been studied extensively for their132-133 and industrial
applications.
SYNTHETIC ASPECT :Different methods for the preparation of 2-pyrazoline derivatives
documented in literature are as follows.
(1) 2-pyrazolines can be constructed by the cyclocondensntion of chalcones
with hydrazine hydrate.134
(2) 2-Pyrazoline can also be prepared by the condensation of chalcone
dibromide with hydrazines.135
53
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
(3) 2-Pyrazolines can be synthesised by the cycloaddition of diazomethane
to substituted chalcone.136
(4) Dipolar cycloaddition of nitrilimines of dimethyl fumarate fumaronitrile
and the N-aryl maleimides yields the corresponding pyrazolines.137
(5) Epoxidation of chalcones have epoxy kelones which reacted with
hydrazine and phenyl hydrazine to give pyrazolines.138
Furthermore, B. Gyassi et al.139 investigated the one pot synthesis of
some and pyrazolines in dry media under microwave irradiation S. Paul et.
al.140 D. Dandia et.al.141 have also described the microwave assiled synthesis
of 2-pyrazolines.
MECHANISM:The following mechanism seems to be operable for the condensation of
chalcones with hydrazine hydrate.142
Nucleophilic attack by hydrazine at the β-carbon of the α−β
unsaturated carbonyl system forms species (II) in which the-ve charge is
mainly accomodated oy the electro nagative oxygen atom.
54
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Proton transfer from the nitrogen to -ve oxygen produces an
intermediate enol which simultaniously ketonise to ketoamine (III). Another
intramolecular nucleophilic attack by the primary amino group of ketoamine
on its carbonyl carbon followed by proton transfer from nitrogen to oxygen
leads ultimately to amine (IV). The later with a hydroxy group and amino
group on the carbon lose water moleculer to yield the pyrazolines.
THERAPEUTIC IMPORTANCE:From the literature survey, it was reveled that 2-pyrazolines are better
therapeutic agents,
(a) Analgesic143,144
(b) Bactericidal145,146
(c) Cardiovascular147
(d) Diuretic148
(e) Fungicidal149
(f) Herbicidal150
(g) Hypoglycemic151
(h) Insecticidial152
(i) Tranquilizer153
(j) Antiallergic154
(k) Anticonvalsant155-156
(i) Antidiabetic157
(m) Antiimplantation158
(n) Antiinflamatory159
(o) Antitumor160
(p) Antineoplastic161
(q) Antimicrobial162
55
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
S. S. Sonarc et al.163 have synthesised-3-(2-acetoxy-4-methoxy phenyl)-
5-(substituted phenyl)-pyrazolines (R) and tested their antimicrobial activity.
Moreover, T. M. Stivenson el al.164 have also investigated N-subsliluled
pyrazoline type insecticides, T. Katsuhori165 have patented pyrazoline
derivatives as herbicides and K. Johannes, et. al.166 as insecticides. Z. Moritaz
and S. Hadol167 to investigated a semi emperial molecular orbital study on the
reaction of aminopyrazolinyl azodye with singlet molecular oxygen.
M. K. Shivnanda and co-worker168 have prepared pyrazolines and
reported their antibacterial activity. B. Shivarama Holla et. al.169-170 have
sunthesised pyrazolines as antibacterial agent. S. P. Hiremath et al.171 have
synthesised pyrazolines as analgesic, antiinflammatory and antimicrobial
agent. V. Malhotra et. al.172 have synthesised new pyrazolines as a
cardiovascular agent.
Ji-Inkim Almstead et. al.173 have prepared pyrazolines as vascularization
agent.Guniz Kucukguzel et. al.174 have synthesised pyrazolines as a
antimicrobial and anticonvulsant agents.
56
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
T. Z. Gulhan and co-workers175 have prepared pyrazolines as a
hypoiensive agent. S. Sharma et. al.176 have synthesised pyrazolines and
tested their antiinflammatory activity. Ashok Kumar et. al.177 have
synthesised pyrazolines as anticonvulsant agent B. Jayshankara et al.178 have
synthesised pyrazoles and screened for their epilepsy activity.
In view of therapeutic activities shown by pyrazolines, it was
contemplated to synthesis some new pyrazolines in search of agent
possessing higher biological activitiy with least side effect have been
described as under.
SECTION-I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(5"-ARYL)-4", 5"-DIHYDRO-1"(H)PYRAZOL -3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.
SECTION-II SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(5"-ARYL)-4",5"-DIHYDRO-1"-N-ACETYL PYRAZOL-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
SECTION-III SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(5"-ARYL)4",5"-DIHYDRO-1"N-PHENYLPYRAZOLE -3"-YL] PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
57
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(5"-ARYL)-4",5"-DIHYDRO-1"(H)PYRAZOL -3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES
Pyrazoline derivatives posses broad spectrum of pharmabiological
activity which are reflected by their use as analgesic, antiinflammatory,
anticonvalsant, antimicrobial and antipyretic agents. prompted by above facts
5-{4'-[(5"-aryl)-4",5"-dihydro-1"-(H)-pyrazol-3"-yl]-phenyl carbamido}-
dibenz [b,f] azepines type (III) have been synthesised by the condensation of
5-{4'-[(3"-aryl) 2"-propene-1"-one]-phenyl carbamido}-dibenz [b,f] azepines.
with hydrazine hydrate.
The constitution of the synthesized products were supported by IR, 1H,
NMR and Mass spectral study. The products were screened for their
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section : I, Page No. : 32-34
Type (III) R=Aryl
O
N
NH
NH
N R
58
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14503080-30101600-14501300-1100830-750
1380-13303550-33501650-15501750-16501270-12001660-1630
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'- [5"-(4'''-METHOXY PHENYL)-4"-5"-DIHYDRO-1"-(H)-PYRAZOL-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450449
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBrdisc)
Observed2953284714643005
1570,1527,148712788021348341915701722
1236, 12191697
Type
Alkane
Aromatic
Amide
KetoneEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H def. (bending)C-H str.C=C Ring skeletalC-H i.p. defC-H o.o.pC-N str.N-H str.N-H bending> C=OC-O-CC=N
50010001500200030004000
0
25
50
75
100
125
%T
3419
.90
3005
.20
2953
.12
2847
.03
1925
.02
1784
.21
174
3.71
172
2.49 16
97.4
115
70.1
115
27.
671
487.
17
1464
.02
1437
.02
134
8.29
131
1.6
412
78.8
512
36.4
112
19.
051
157.
33
1112
.96
1060
.88
979.
8794
9.01
877.
6480
2.41
O
N
NH
NH
N O
CH3
59
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SignalNo
1234567
Intrenal standard : TMS; solvent :CDCl3 : Instrument : DPX-200 Spectrometer
(200MHz)
NMR SPECTRAL STUDY OF 5-{4'-[5"-(4'''-METHOXY PHENYL)-- 4 " - 5 " - D I H Y D R O - 1 " - ( H ) P Y R A Z O L - 3 " - Y L ] - P H E N Y LCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Signal Position(δ δ δ δ δ ppm)
3.906.335.21
6.9-7.46.82.151.86
Relative No.of protons Multiplicity Inference
60
3 H1 H1 H16 H2 H2 H1 H
SingletSingletSinglet
MultipletDoubletDoubletTriplet
O
N
NH
NH
N O
CH3
a
b
c
dd d d
dd
d d
dd
d d
d
d
e
e
f
g
Ar-OCH3a
-CONH2b
Ar-NHc
Ar-Hd
Ar-He
Ar-Hf
Ar-Hg
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 61
MA
SS F
REG
MEN
T ST
UD
Y O
F 5
-{4'
-[5"-
(4'''
-MET
HO
XY
PH
ENY
L)-4
"-5"
-DIH
YD
RO
-1"-
(H)-P
YR
AZO
L-3"
-YL]
-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N H
N
OCH
3
m/z
=486
O
N
NH
N H
N
O-
m/z
=471
O
N
NH
N H
N
OCH
3
m/z
=462
O
N
NH
N H
N
m/z
=431
O
N
NH
N H
N
m/z
=455
O
N
NH
N H
N
O-
m/z
=447
O
N
NH m
/z=4
30
O
N
NH
m/z
=311
CH
2+
m/z
=105
O
N
NH
CH
2+
m/z
=353
O
NH
NH
N H
N
OCH
3
m/z
=386
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
PEC
TR
AL
ST
UD
Y O
F 5
-{4'
-[5"
-(4'
''-M
ET
HO
XY
PH
EN
YL
)-4"
-5"-
DIH
YD
RO
-1"-
(H)-
PYR
AZ
OL
-3"
-YL]
-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N H
N
OCH
3
m/z
=486
62
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 63
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
4-O
H-C
6H4-(
25)
3-O
CH
34-O
H-C
6H3-(
26)
3-N
O2-C
6H4-(
23)
30 30 35 -
A.n
iger
R
2-O
H-C
6H4-(
24)
2-O
CH
3-C6H
4-(22
)2-
Cl-C
6H4-(
23)
C4H
3(Fur
fura
l)-(2
3)
- - - 27
E.co
ilR
C4-
H3O
(Fur
fura
l)-(1
8)C
10H
7 (N
epth
al)-
(21)
C14
H19
(Ant
hral
)-(2
3)
32 28 30 -
S. ta
phim
ariu
mR
2-C
l-C6H
4-(21
)4
N,N
(CH
3) 2C6H
4-(22
)
C14
H9(A
nthr
al)-
(23)
30 29 27 -
Ampic
ilin50
μg
Chlo
rom
phen
icol
"
Nor
floxa
cin
"G
riseo
fulv
in
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
Com
para
bale
activ
ity w
ith k
now
n sta
ndar
d dr
ugs
S. a
ureu
sR
3-O
CH
3-4-O
H-C
6H3-(
23)
3-N
O2-C
6H4-(
25)
4-N
,N(C
H3) 2-C
6H4-(
23)
C10
H7 (N
eapt
hal)-
(23)
29 32 31 -
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
Type (III) R=Aryl
NH2NH2.H2O
PyridineReflux
R-CHO40% NaOH, 24 hrs., Stirring
O
N
NH
NH
N R
64
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-(5"-ARYL)-4",5"-DIHYDRO-1"-(H)-PYRAZOL-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido}-dibenz [b,f] azepine
For synthesis see part-I, section : I, Page No.: 31
(B) Synthesis of 5-{4'-[3"-(4"'-Methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: 1 section : I Page No : 31
(c) Synthesis of 5-{4'-[5"-(4"'-methoxy phenyl)-4",5" dihydro-1"(H)pyrazlo-3"-yl] phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72.g 0.01M); hydrazine hydrate
(1.0ml) in methanol (15ml) was refluxed for 12 hrs. The product was poured
into crushed ice filtered, washed with water and crystallised from dioxane
yield : 78.68 % M.P. 60oC (Found : C 75.40; H: 5.23; N: 11.50, C31H26N4O2
Required : C 76.54; H: 5.34; N: 11.52 %)
Simillary other pyrazole derivatives have been synthesised and their
physical data are recorded in Table No. : 5
(D) Antimicrobial activity of 5-{4'-[(5" aryl)-4",5"- dihydro -1"-(H)pyrazol-3"-yl] phenyl carbamido}-dibenz [b,f] azepines.
The antimicrobial testing was carried out as described in part : I,
section: I Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 6
65
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
5
PH
YSI
CA
L C
ON
STA
NT
OF
5-{
4'-[(
5"-A
RY
L)-4
",6"
-DIH
YD
RO
-1"(
H)-
P
YR
AZO
L-3"
-YL]
-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C30
H24
N4O
C30
H24
N4O
2
C30
H24
N4O
2
C30
H24
N4O
2
C31
H26
N4O
3
C31
H26
N4O
2
C31
H26
N4O
2
C30
H23
N5O
3
C30
H23
N5O
3
C30
H23
N4O
Cl
C32
H29
N5O
C28
H22
N4O
2
C34
H26
N4O
C38
H28
N4O
M.P
. O
C 4 90 120
111
125
140
95 60 95 98 70 115
78 85 80
Yie
ld% 5
77.6
581
.39
72.7
371
.68
74.0
059
.81
78.6
860
.55
62.5
875
.10
77.6
382
.80
78.1
279
.01
% o
f Nitr
ogen Fo
und
712
.28
11.8
011
.80
11.8
011
.10
11.5
111
.50
13.9
513
.94
11.4
014
.01
12.5
411
.04
10.0
6
Cal
cd.
612
.28
11.8
611
.86
11.8
611
.15
11.5
211
.52
13.9
713
.97
11.4
214
.02
12.5
511
.06
10.0
7
66
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
6 A
NTI
MIC
RO
BIO
AL
AC
TIV
ITY
OF
5-{
4'-[(
5"-A
RY
L)-4
",6"
-DIH
YD
RO
-1"(
H)-
PYR
AZO
L-3"
-YL]
-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 15 17 18 25 26 15 17 19 23 20 14 16 15 13
S. a
ureu
s4 17 19 14 20 23 15 14 17 25 20 23 13 23 17
S. ta
phim
ariu
m5 14 17 19 15 18 17 20 18 20 21 22 17 15 23
A.n
iger
7 19 24 21 21 19 22 16 21 20 23 14 23 18 16
E.c
oil
6 15 12 15 17 16 17 16 12 11 10 14 18 21 23
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
67
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : II
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(5"-ARYL)-4",5"-DIHYDRO-1"N-ACETYLPYRAZOL-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Acetyl pyrazoline derivatives procuring better therapeatic and
antimicrobial activity looking at their versatile therapeutic importance and
with an aim to getting better drug, it was considered worthwhile to synthesis
some new pyrazoline. The synthesis of 5-{4'-[(5"-aryl)-4"-5"-dihydro-1"-
acetyl pyrazol-3-yl]-phenyl carbamido}-dibenz [b,f] azepines have been syn-
thesis by the cyclocondensation of chalcones of type: (I) with hydrazine
hydrate and glacial acetic acid
The constitution of the products have been characterised by elemental
analyses IR,1H NMR and Mass spectral study. The products were screened
for their antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section I, Page No. 32-34
Type (IV) R=Aryl
O
N
NH
NN R
O CH3
68
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14503080-30101600-14501300-1100830-750
1380-13303550-33501650-15501750-16501270-12001660-1630
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[5"-(4"'-METHOXY PHENYL)-4"-5"-DIHYDRO-1"-N-ACETYL PYRAZOL-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES
Ref.445-458
"""
446,447""
449446,447
"447450449
Instrument : SHIMADZU-IR-8400 Spectrophotometer frequency range : 4000-400
cm-1 (KBrdisc)
Observed2951286515663040
1626,1591,15661270823135033961591171811241626
Type
Alkane
Aromatic
Amide
KetoneEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H def. (bending)C-H str.C=C Ring skeletalC-H i.p. defC-H o.o.pC-N i.p. str. def.N-H str.N-H bending>C=OC-O-CC=N
50010001500200030004000
30
45
60
75
90
105
%T
3543
.35
3460
.41
3396
.76
336
5.90
295
1.19
1718
.63
1626
.05
1591
.33
1566
.25
823
.63
686.
6865
5.82
599.
8855
9.38
559.
38
O
N
NH
NN
O CH3
O
CH3
69
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(200MHz)
NMR SPECTRAL STUDY OF 5-{4'-[5"-(4"'-METHOXY PHENYL)-4"-5"-DIHYDRO-1"-N-ACETYLPYRAZOL-3"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
70
SignalNo
1234567
Signal Position(δ δ δ δ δ ppm)
3.606.402.97
6.9-7.66.932.52.9
Relative No.of protons Multiplicity Inference
3 H1 H3 H16 H2 H2 H1 H
SingletSingletSinglet
MultipletDoubletDoubletTriplet
a
b
c
d d dd
d
d
d
dO
N
NH
NN
O CH3
O
CH3d
dd
ddd
d
e
ed
fg
Ar-OCH3a
-CONH2b
-COCH3c
Ar-Hd
Ar-He
Ar-Hf
Ar-Hg
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 71
MA
SS
FR
EG
ME
NT
ST
UD
Y
OF
5-
{4'-
[5"-
(4"'
-ME
TH
OX
Y
PH
EN
YL
)-4"
-5"-
DIH
YD
RO
-1"-
N-
AC
ETY
LPY
RA
ZOL-
3"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
ES.
O
N
NH
NN
OC
H3
OCH
3
m/z
=528
O
N
NH
NN
OC
H3
O-
m/z
=513
O
N
NH
NN
OC
H3
OCH
3
m/z
=504
O
N
NH
NN
OC
H3
m/z
=498
O
N
NH
NN
OC
H3
O-
m/z
=489
O
N
NH
NN
OC
H3
m/z
=474
O
NH
NH
NN
OC
H3
OCH
3
m/z
=428
CH
3
O
N
NH
NH
-N
m/z
=381
O
N
NH
CH
3
m/z
=302
O
N
NH
CH
3
NH
2m
/z=3
30
CH
3
O
N
NH
NH
-N
m/z
=357
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 72
MA
SS
SPE
CT
RA
L
STU
DY
O
F
5-{4
'-[5
"-(4
"'-M
ET
HO
XY
P
HE
NY
L)-
4"-5
"-D
IHY
DR
O-1
"-N
-A
CET
YLP
YR
AZO
L-3"
-YL]
-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
NN
OC
H3
OCH
3
m/z
=528
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 73
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
C6H
5-(25
)2-
OH
-C6H
4-(23
)3-
OH
-C6H
4-(23
)4-
OH
-C6H
4-(23
)
30 30 35 -
A.n
iger
R
2-C
l-C6H
4-(24
)4-
N,N
-(C
H3) 2C
6H4-(
25)
- - - 27
E.co
ilR
4-O
CH
3C6H
4-(24
)2-
NO
2-C6H
4-(25
)C
14H
9 (A
nthr
al)-
(23)
32 28 30 -
S. ta
phim
ariu
mR
4-O
CH
3 (C
6H4-(
29)
2-N
O2C
6H4)-
(25)
C14
H9(A
nthr
al)-
(23)
30 29 27 -
Ampic
ilin 5
0 μg
Chlo
rom
phen
icol
"N
orflo
xacin
"G
riseo
fulv
in "
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
2-C
1-C
6H4(2
1)4-
N,N
,(CH
3) 2-C6H
4-(22
)C
4H3O
- (Fur
fura
l)-(2
3)
29 32 31 -
Com
para
ble a
ctiv
ity w
ith k
now
n st
anda
rd d
rugs
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
NH2-NH2.H2OCH3COOH
PyridineReflux
Type (IV) R=Aryl
O
N
NH
NN R
O CH3
74
R-CHO40% NaOH, 24 hrs. Stirring
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-(5"-ARYL)-4",5"-DIHYDRO-1"-N-ACETYL PYRAZOL-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]-AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-Methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I, Page No : 31
(c) Synthesis of 5-{4'-[5"-(4"'-methoxy phenyl)-4"-5"-dihydro-1"-N-Acetyl pyrazol-3"-yl]-phenyl carbamido} dibenz [b,f] azepines.
A mixture of 5-{4'-[5"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72.g,0.01M); hydrazine hydrate
(1.0ml), glacial acetic acid (2.0 ml) and methnol (20 ml) was refluxed for 12
hrs. The reaction mixture is poured into crushed ice, filtered, washed with hot
water and crystalised from dioxane yield : 78.68 % M.P. 68OC (Found :
C:74.85; H: 5.14; N:10.45; C33H28O3N4 Required : C:75.00; H: 5.30; N: 10.60 %)
Simillary other acetyl pyrazolines have been synthesised and their
physical data are recorded in Table No. : 7(D) Antimicrobial activity of 5-{4'-[(5"-aryl)-4",5"- dihydro -1"-N-
acetyl pyrazole-3"-yl]-phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,
section: I, Page No. : 32-34
The zone of inhibition of the test solution are recorded in Table No. : 8
75
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
7PH
YSI
CA
L C
ON
STA
NT
OF
5-{4
'-[(5
"-A
RY
L)-
4'',5
"-D
IHY
DR
O-1
"-N
- AC
ET
YL
PYR
AZO
LE-3
"-Y
L] P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
ES.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C32
H26
N4O
2
C32
H26
N4O
3
C32
H26
N4O
3
C32
H26
N4O
3
C33
H28
N4O
4
C33
H28
N4O
3
C33
H28
N4O
3
C32
H25
N5O
4
C32
H25
N5O
4
C32
H25
N4O
2
C34
H31
N5O
2
C30
H24
N4O
3
C36
H28
N4O
2
C40
H30
N4O
2
M.P
. O
C 4 70 70 90 98 115
70 68 110
105
75 60 80 122
75
Yie
ld% 5
80.2
075
.11
85.1
090
.11
71.8
078
.68
78.6
883
.80
90.6
850
.72
70.1
275
.15
84.1
588
.24
% o
f Nitr
ogen Fo
und
711
.20
10.7
010
.70
10.7
010
.23
10.4
510
.45
12.7
012
.70
10.4
512
.80
11.4
310
.11
9.18
Cal
cd.
611
.24
10.8
910
.89
10.8
910
.29
10.6
010
.60
12.8
912
.89
10.5
212
.93
11.4
710
.21
9.36
76
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 77
TABL
E N
O :
8
AN
TIM
ICR
OBI
AL
AC
TIV
ITY
OF
5-{4
'-[(5
"-A
RY
L)-4
'',5"
-DIH
YD
RO
-1"-
N-
AC
ETY
L PY
RA
ZOLE
-3"-
YL]
PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 25 23 23 23 19 17 16 17 19 17 18 19 11 22
S. a
ureu
s4 20 20 19 19 18 17 17 18 20 21 22 23 19 10
S. ta
phim
ariu
m5 14 13 8 12 21 21 29 25 11 12 11 13 11 23
A.n
iger
7 20 21 11 12 15 16 11 20 13 24 25 19 22 21
E.c
oil
6 10 13 11 12 14 15 24 25 11 11 13 12 20 23
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : III
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(5"-ARYL)-4",5"-DIHYDRO-1"-N-PHENYL PYRAZOLE-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Looking to the interesting therapeutic activities of pyrazoline, it was
considered worth while to synthesize compounds bearing 5-{4'-[(5"-aryl)-
4"-5"-dihydro-1"-phenyl pyrazole-3"-yl]-phenyl carbamido}-dibenz [b,f]
azepines. of Type (V) have been synthesis 5-{4'-[(3"-aryl)-2"-propene-1"-
one]-phenyl carbamido}-dibenz [b,f] azepines with phenyl hydrazine.
The constitution of the products have been characterised by elemental
analyses IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg.
The details have been cited in the part : I, section I, Page No. : 32-34
Type (V) R=Aryl
O
N
NH
NN R
78
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14403080-30101600-14501300-1100830-750
1380-13303550-33501650-15501750-16501270-12001660-1630
Frequency in cm.-1
IR SPECTRAL STUDY OF-5-{4'[5"-(4"'-METHOXY PHENYL)-4",5"-DIHYDRO-1"-N-PHENYL PYRAZOL-3"-YL]-PHENYLCARBAMIDO}- DIBENZ [b,f] AZEPINS.
Ref.445-458
"""
446,447""
449446,447
"447450449
Instrument : SHIMADZU-IR-8400 Spectrophotometer frequency range : 4000-400
cm-1 (KBr-disc)
Observed2953287014403030
1491, 14401225769132534581491171812221620
Type
Alkane
Aromatic
Amide
KetoneEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H def. (bending)C-H str.C=C Ring skeletalC-H i.p. defC-H o.o.pC-NN-H str.N-H bending>C=OC-O-CC=N
50010001500200030004000
45
60
75
90
105
%T
362
4.37
358
5.79
3535
.64
3493
.20
345
8.48 3
390.
97
3367
.82
3030
.27
2953
.12
1718
.63 14
91.0
214
40.8
7
132
5.14
1222
.91 10
55.1
0
769.
62
704.
0466
3.5
35
63.2
3
408.
92
O
N
NH
NN O
CH3
79
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :CDCl3: Instrument : BRUKER Spectrometer
(200MHz)
NMR SPECTRAL STUDY OF-5-{4'[5"-(4"'-METHOXY PHENYL)-4",5"-DIHYDRO-1"-N-PHENYL PYRAZOL-3"-YL]-PHENYLCARBAMIDO}- DIBENZ [b,f] AZEPINS.
80
SignalNo
1234567
Signal Position(δ δ δ δ δ ppm)
3.656.32.9
6.9-7.46.82.22.8
Relative No.of protons Multiplicity Inference
3 H1 H3 H18 H2 H2 H1 H
SingletSingletSinglet
MultipletDoubletDoubletTriplet
Ar-OCH3a
-CONH2b
-Ar-Hc
Ar-Hd
Ar-He
Ar-Hf
Ar-Hg
a
b
dd d
d
d
d
d
dd
dd
ddd
d
O
N
NH
NN O
CH3e
df
g
e
d d
cc c
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 81
MA
SS F
REG
MEN
T ST
UD
Y O
F-5-
{4'[5
"-(4
"'-M
ETH
OX
Y P
HEN
YL)
-4",
5"-D
IHY
DR
O-1
"-N
-PH
ENY
L PY
RA
ZOL-
3"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
S.
O
N
NH
NN
OCH
3
m/z
=562
O
N
NH
NN
OCH
3
m/z
=538
O
N
NH
NN
O-
m/z
=547
O
N
NH
NN
m/z
=532
O
N
NH
NN
O-
m/z
=523
O
NH
NH
NN
OCH
3
m/z
=462
O
N
NH
CH
3
NH
-
m/z
=354
O
N
NH
CH
3
NH
-
m/z
=330
O
N
NH
CH
3
m/z
=302
m/z
=77
O
N
NH m
/z=2
86
O
N
NH
NN
m/z
=508
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 82
MA
SS S
PEC
TRA
L ST
UD
Y O
F-5-
{4'[5
"-(4
"'-M
ETH
OX
Y P
HEN
YL)
-4",
5"-D
IHY
DR
O-1
"-N
-PH
ENY
L PY
RA
ZOL-
3"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
S.
O
N
NH
NN
OCH
3
m/z
=562
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 83
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
3-O
H-C
6H4-(
23)
4-O
H-C
6H4-(
16)
3-O
CH
3 4-O
HC
6H3(1
9)
30 30 35 -
A.n
iger
R
C6H
4-(19
)2-
OH
-C6H
4-(20
)3-
OC
H3,4
-OH
-C6H
4-(21
)2-
OC
H3-C
6H4-(
22)
4-N
,N-(
CH
3) 2-C6H
4-(19
)
- - - 27
E.co
ilR
2-O
H C
6H4-(
18)
4-O
H-C
6H4-(
22)
2-C
l-C6H
4-(19
)4-
N,N
(CH
3) 2C6H
4-(18
)
32 28 30 -
S. ta
phim
ariu
mR
C6H
4-(22
)2-
OH
-C6H
4-(19
)2-
NO
2-C6H
4-(21
)4-
N,N
(CH
3) 2C6H
4-(20
)
30 29 27 -
Ampic
ilin
50
μg.
Chl
orom
phen
icol
"
Nor
floxa
cin
"
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
3-O
CH
34-O
HC
6H3-(
25)
2-O
CH
3C6H
4-(17
)4-
OC
H3 C
6H4-(
19)
3-N
O2-C
6H4-(
19)
2-C
l-C6H
4(18)
29 32 31 -
Com
para
ble a
ctiv
ity w
ith k
now
n st
anda
rd d
rugs
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
Ph-NH-NH2
PyridineReflux
Type (V) R=Aryl
O
N
NH
NN R
84
R-CHO40% NaOH, 24 hrs stirring
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(5"-ARYL)- 4",5"-DIHYDRO-1"-N-PHENYLPYRAZOL-3"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]-AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No.: 31
(B) Synthesis of 5-{4'-[3"-(4"'-Methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: 1 section : I, Page No : 31
(c) Synthesis of 5-{4'-[5"-(4"'-methoxy phenyl)-4"-5"-dihydro-1"-N-phenyl pyrazol-3"-yl]-phenyl carbamido} dibenz [b,f] azepines.
A mixture of 5-{4'-[5"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72.g,0.01M); phenyl hydrazine
hydrate (1.0ml) and methanol (20 ml) was refluxed for 12 hrs. The reaction
mixture is poured into crushed ice, filtered, washed with hot water and crys-
talised from dioxane yield : 62.78 % M.P. 70OC (Found : C:78.74; H: 5.20;
N:9.88; C37H30O2N4 Required : C:79.00; H: 5.33; N: 9.96 %)
Simillary other phenyl pyrazolines have been synthesised and their physical
data are recorded in table No. : 9
(D) Antimicrobial activity of 5-{4'-[(5"-aryl)-4",5"- dihydro -1"-N-phenyl pyrazole-3"-yl] phenyl carbamido}-dibenz [b,f] azepines.
The antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 10
85
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 86
TAB
LE
NO
: 9
PHY
SIC
AL
CO
NST
AN
T O
F 5-
{4'-[
(5"-
AR
YL
)-4'
'-5"-
DIH
YD
RO
-1"-
N-
PHE
NY
LPY
RA
ZOL-
3"-Y
L] P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
ES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C36
H28
N4O
C36
H28
N4O
2
C36
H28
N4O
2
C36
H28
N4O
2
C37
H30
N4O
3
C37
H30
N4O
2
C37
H30
N4O
2
C36
H27
N5O
3
C36
H27
N5O
3
C36
H27
N4O
Cl
C38
H33
N5O
C34
H26
N4O
2
C40
H30
N4O
C44
H32
N4O
M.P
. O
C 4 78 90 102
102
78 105
70 62 95 76 96 50 60 90
Yie
ld% 5
70.6
185
.80
90.1
170
.71
81.1
165
.71
62.7
883
.12
65.1
272
.18
67.7
182
.83
70.8
277
.18
% o
f Nitr
ogen Fo
und
710
.45
10.1
110
.11
10.1
19.
589.
589.
8812
.09
12.0
99.
7012
.10
10.6
69.
508.
70
Cal
cd.
610
.52
10.2
110
.21
10.2
19.
689.
969.
9612
.13
12.1
39.
8912
.17
10.7
29.
618.
86
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 87
TABL
E N
O :
10 A
NT
IMIC
RO
BIA
L A
CT
IVIT
Y O
F 5-
{4'-[
(5"-
AR
YL
)-4"
-5"-
DIH
YD
RO
-1"-
NPH
ENY
L-3"
-YL]
PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 11 10 23 16 19 12 11 13 12 14 15 11 13 12
S. a
ureu
s4 10 13 14 16 25 17 19 16 19 18 13 12 11 16
S. ta
phim
ariu
m5 22 19 16 15 14 11 12 21 10 11 20 17 15 15
A.n
iger
7 19 20 17 16 21 22 12 13 17 16 19 16 18 11
E.c
oil
6 16 18 13 22 11 10 12 13 15 19 18 16 10 11
Ant
ibec
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - IV
STUDIES ONPYRIMIDINE DERIVATIVES
88
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON PHYRIMIDINE DERIVATIVES
INTRODUCTIONPyrimidine derivatives occur in natural products179 like nucleic acid
and vitamin-B have remarkable pharmaceutical importance because of thier
biological180-183 several analogs of nucleic acids have been used as compound
that interfere with the synthesis and functioning of nucleic acids, and
example is fluorouracil which has been used in cancer treatment. Pyrimidines
are among those molecules that make life possible as being same of the
building blocks of DNA and RNA.
Some pyrimidines of physiologically as well as pharmacologically
importance are as under : e.g. cytosine, beclmeihrin(S), blasticidin (T).
Synthetic pyrimidine derivatives contribute much to the searchable
literature of pyrimidine derivtives, in huge libraries owing to their wide
applicability in different fields.
SYNTHETIC ASPECT:Different methods for the synthesis of pyrimidine have been cited in
the literature.184
1. F. Bigi and co-worker185 have synthesised as shown below under
solvent free condition.
89
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MECHANISM :The reaction of α,β - unsaturated system with urea to the formation of
4-oxo-pyrimidine by 1,2 and 1,4 michal addition.
90
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
THERAPEUTIC IMPORTANCEPyrimidine derivatives have proven to be of great importance in
exhibiting and enhancing the biological activities such as.(a) Antitumor186
(b) Carcinostatic187
(c) antiinflammatory and anticonvulsant188-189
(d) Antimalarial190
(e) Antithyroid191
(f) Anthelmintic192
(g) Anti - HIV193-194
(h) Antilishmenial195
(i) Antiviral196
(j) Antimicrobial197
(k) Herbicidal198-204
(1) Antagonists205-209
Moreover, L. V. Azarayan et al.210 have synthesised pyrimidine diones asantitumor agent. V. P. Krivongov and co-worker211 have synthesisedpyrimidinone derivatives possessing immunotropic and antiinflammatoryactivitiy. M. Refai and co-worker212 have prepared some new pyrimidine de-rivatives showed moderate activity against the growth of Bacillus substilis,Staphylococus aureus and Aspergillus niger. A. Kofies et. al.213 haveseggested that pyrimidinone (UV) as herbicidal and plant growthregulators.
91
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
K. Mogilaiah214 have prepared spiropyrimidinones as antibacterial. M.wilhelm215 have synthesised pyrimidinones as herbicidal agents.
C. D. Timothy and co-worker216 have suggested imidazolyl pyrimidinonesas antiviral T. Nagamatsu et. al.217 have prepared some new triazolo [3,4-c]pyrimidine as xanthin oxidase inhibitors. A. Roland et. al.218 have preparedoxazolyl uracil as herbicidal and insecticidal. M. M. Yari and co-worker219
have investigated the pyrimidinone derivatives which possess calciumantagonist activity.
M. A. Bruce and co-worker220 prepared The dihydropyrimidinones asNPY antagonist.
D. R. Sidler221 have reported pyrimidinone derivatives, useful as an α-adrenergic receptor antagonist.
92
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Mona Mahram and co-worker222 have synthesied pyrimidine derivativesas potent antimicrobial and antitumor agents.
K.A. Gupta and co-worker223 have prepared 2,6-disubstitutedpyrimidinones as CNS agent.
Pyrimidinone derivatives 224-225 have found to be calcium channel blockerM.M.Barbuliene et. al.226 have synthesised pyrimidinones as antiinflammatoryagent.
Recently. Amjad Ali et. al.227 have synthesised new fused pyrimidinonesas antimicrobial agents. Abd El-Galil et. al.228 have synthesised pyrimidineas androgenic, anabolic and antiinflammatory agents, martin Bolli et.al.229
have synthesised pyrimidines as endothelin receptor antagonists. G. Z. Hanget. al.230 have synthesised and screened for their leukocyte functions inhibitoractivity. yamamo to et al.231 have synthesised pyrimidines and tested theirhyderproliferative disorder activity. Adenosine receptor antagonistpyrimidinones have been prepared by Tsytsumi Hideo et. al. 232
93
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'- [(6"-ARYL)-2"-MERCAPTO-3"-4"-DIHYDROPYRIMIDINE 4"-YL] PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
SECTION : II SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'- [(6"-ARYL)-2"-HYDROXY-3"-4"-DIHYDRO PYRIMIDINE 4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
SECTION : III SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'- [(6"-ARYL)-2"-AMINO -3"-4"-DIHYDRO PYRIMIDINE 4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
94
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(6"-ARYL)2"-MERCAPTO-3"-4"-DIHYDRO PYRIMIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Looking to the interesting pharmacological and agricultural activity of
pyrimidine ring system, it was considered worthwhile to synthesise
compounds bearing phenyl carbamido dibenz [b,f] azepine nucleus linked to
the pyrimidine nucleus 5-{4'-[(6"-aryl)-2"-mercapto-3"-4"-dihydro pyrimidine-
4"-yl] phenyl carbamido}-dibenz [b,f] azepines have been synthesis by the
condensation of 5-{4'-[(3"-aryl)-2"-propene-1"-one] phenyl carbamido}-
dibenz [b,f] azepines of Type (I) with thiourea in presence of catalytic amount
of alcoholic pottasium hydroxide.
The constitution of the products have been characterised by elemental
analyses IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section : I, Page No. 32-34
Type (VI) R=Aryl
95
R
O
N
NH
NH N
SH
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-13203080-30301600-14501300-1100890-750
1350-13303550-33501650-15501750-17002600-28001270-1030
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[6"-(4'"-METHOXY PHENYL)]- 2"-MERCAPTO-3"-4"-DIHYDRO PYRIMIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450
"
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBrdisc)
Observed2985295313323047
1523, 1491130980013323583152317142659
1227, 1222
Type
Alkane
Aromatic
Amide
KetoneThiolEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.pC-NN-H str.N-H bending>C=OS-H str.C-O-C
50010001500200030004000
0
25
50
75
100
125
%T
3583
.86
304
7.63
2985
.91
2953
.12
2659
.93
171
4.77
1523
.82
1491
.02
1440
.87
1332
.86
1309
.71 12
71.1
312
22.9
111
80.4
711
12.9
61
060.
8810
37.7
480
0.49
96
O
N
NH
NH N
SH
O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Internal standard : TMS; solvent :CDCl3: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF 5-{4'-[6"-(4"'-METHOXY PHENYL)]-2"-MERCAPTO-3"-4"-DIHYDRO PYRIMIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
97
SignalNo
1234567
Signal Position(δ δ δ δ δ ppm)
3.606.16.2
7.1-7.56.97.12.5
Relative No.of protons Multiplicity Inference
3 H1 H1 H16 H2 H2 H1 H
SingletSingletSinglet
MultipletDoubletSingletSinglet
Ar-OCH3a
-CONHb
-N-Hc
Ar-Hd
Ar-He
Ar-Hf
Ar-SHg
a
b
d d dd
d
d
d
d d d
O
N
NH
NH N
SH
O
CH3
dd
ded f
g
ed
cc
df
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 98
MA
SS F
RE
GM
EN
T S
TU
DY
OF
5-{4
'-[6"
-(4"
'-ME
TH
OX
Y P
HE
NY
L)]
-2"-
ME
RC
APT
O-3
"-4"
-DIH
YD
RO
PYR
IMID
INE-
4"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
NH
N
SH
OCH
3
m/z
=530
O
N
NH
NH
N
SH
OCH
3
m/z
=506
O
N
NH
NH
N
SH
m/z
=476
O
NH
CH
2+
NH
NH
N
SHm
/z=4
12
O
NH
NH
NH
N
SH
OCH
3
m/z
=430
O
N
NH
NH
O-
m/z
=456
CH
2+
OCH
3
m/z
=135
O
N
NH
NH
N
SH
O-
m/z
=515
O
N
NH
NH
N
SH
OH
m/z
=516
CH
2
OCH
3
m/z
=176
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 99
MA
SS S
PEC
TR
AL
ST
UD
Y O
F 5-
{4'-[
6"-(
4"'-
ME
TH
OX
Y P
HE
NY
L)]
-2"-
ME
RC
APT
O-3
"-4"
-DIH
YD
RO
PYR
IMID
INE-
4"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
NH
N
SH
OCH
3
m/z
=530
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 100
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
3-O
H-C
6H4-(
21)
4-O
H C
6H4-(
19)
3-O
CH
34-O
H-C
6H3-(
20)
30
30
35
-
E.c
oil
R
C6H
5-(20
)3-
NO
2-C6H
4-(20
)2-
Cl-C
6H4-(
21)
C10
H7 (N
apth
a)-(
21)
32 28 30 -
S. ta
phim
ariu
mR
C6H
5-(27
)2-
OH
-C6H
4-(28
)2-
OC
H3-C
6H4-(
24)
4-O
CH
3-C6H
4-(26
)
30 29 27 -
Ampic
ilin50
μg
Chlo
rom
phen
icol
"
Nor
floxa
cin "
Gris
eofu
lvin
"
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.
S. a
ureu
sR
3-O
H-C
6H4(2
5)4-
OH
-C6H
4-(26
)2-
Cl-C
6H4-(
22)
29 32 31 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
A.n
iger
R
C6H
5-(24
)2-
OH
-C6H
4-(25
)4-
N,N
,(CH
3) 2-C6H
4-(26
)
- - - 27
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CH0 40% NaoH, 24 hrs Stirring
Type (VI) R=Aryl
NH2 NH2
S
101
R
O
N
NH
NH N
SH
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-(6"ARYL)-2"-MERCAPTO-3",4"-DIHYDROPYRIMIDINE-4"-YL]-N-PHENYLCARBAMIDO}-DIBENZ [b,f]AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepine.
For synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propen-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: 1 section : I , Page No : 31
(C) Synthesis of 5-{4'-[6"-(4"'-methoxy phenyl)-3"-mercapto 3"-4"-dihydro pyrimidine -4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f] azepine. (4.72.g, 0.01M) and thiourea (0.66g,
0.01M) was refluxed at 90oC for 14 hrs. in presence of basic medium like
alcoholic KOH and methanol. The reaction mixture was poured in to crushed,
ice, filtered and dried. The product was isolated, and crystalised from dioxane
yield : 68.71, % M.P. 80oC (Found : C : 70.08; H: 4.88; N:10.52; C32H26N4SO2
Required : C; 70.18; H; 4.90; N; 10.56 %)
Simillary other compounds were prepared an their physical data are
recorded in table No. : 11
(D) Antimicrobial activity of 5-{4'-[(6"-aryl)-2"mercapto 3",4"-dihydro-pyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,
section: I, Page No. 12
The zone of inhibition of the test solution are recorded in Table No.12
102
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 103
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C31
H24
N4O
SC
31H
24N
4O2S
C31
H24
N4O
2SC
31H
24N
4O2S
C32
H26
N4O
3SC
32H
26N
4O2S
C32
H26
N4O
2SC
31H
23N
5O3S
C31
H23
N5O
3SC
31H
23N
4OC
lSC
33H
29N
5OS
C29
H22
N4O
2SC
35H
26N
4OS
C39
H28
N4O
S
M.P
. O
C 4 70 96 108
78 118
115
80 90 122
75 150
62 80 170
Yiel
d% 5
60.7
275
.01
77.8
679
.81
71.2
969
.32
80.7
179
.28
70.6
569
.96
86.0
979
.83
80.0
071
.04
% o
f Nitr
ogen Fo
und
711
.00
10.7
810
.79
10.8
210
.15
10.4
710
.52
12.8
112
.83
11.8
412
.82
11.3
910
.15
9.32
Cal
cd.
611
.20
10.8
510
.85
10.8
510
.25
10.5
610
.56
12.8
412
.84
11.8
712
.89
11.4
210
.18
9.33
TABL
E N
O :
11
PHY
SIC
AL
CO
NST
AN
TS
OF
5-{4
'-[(6
"-A
RY
L)-
2"-M
ER
CA
PTO
-3",
4"D
IHY
DR
O P
YR
IMID
INE-
4"-Y
l] PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 104
TABL
E N
O :
12
AN
TIM
ICR
OBI
AL
AC
TIV
ITY
OF
5-{4
'-[(6
"-A
RY
L)-2
"-M
ERC
APT
O-3
",4"
D
IHY
DR
O P
HEN
YL-
4"-Y
L] P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
E
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 11 16 21 19 20 11 12 13 14 15 11 12 13 14
S. a
ureu
s4 11 15 25 26 20 16 16 10 11 22 13 12 12 13
S. ta
phim
ariu
m5 27 28 11 12 23 24 26 23 10 10 10 12 14 15
A.n
iger
7 24 25 16 19 20 23 21 23 16 19 26 13 12 13
E.c
oil
6 20 12 10 11 12 12 14 16 20 21 10 12 21 11
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : II
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(6"-ARYL)2"-HYDROXY-3",4"-DIHYDRO PYRIMIDINE-4"-YL] PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES
Looking to the interesting pharmacological and agricultural activity of
pyrimidine ring system, it was considered worthwhile to synthesis
compounds bearing phenyl carbamido dibenz [b,f] azepine nucleus linked
to the pyrimidine nucleus 5-{4'-[(6"-aryl)-2"-hydroxy-3",4"-dihydro pyrimidine
4"-yl] phenyl carbamido}-dibenz [b,f] azepines of type (VII) have been
synthesised by the condensation of 5-{4'-[(3"-aryl)-2"-propen-1"-one]
phenyl carbamido}-dibenz [b,f] azepines one of Type-(I) with urea in
presence of catalytic amount of conc. HCl.
The constitution of the products have been characterised by elemental
analyses IR, 1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section I, Page No. 32-34
Type (VII) R=Aryl
105
R
O
N
NH
NH N
OH
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100890-750
1380-13303550-33501650-15501750-17001270-10303550-3300
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[6-(4'"-METHOXY PHENYL]- 2"-HYDROXY 3",4"-DIHYDRO PYRIMIDINE-4"-YL] PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450454
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr disc)
Observed2985295314403047
1523, 149112228001332 354515231714
1222, 11803583
Type
Alkane
Aromatic
Amide
KetoneEther
Hydroxy
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p. defC-NN-H str.N-H bending>C=OC-O-CO-H broad
500100015002000300040001/
0
25
50
75
100
125
%T
3583
.86
304
7.63
2985
.91
2953
.12
2659
.93
171
4.77
1523
.82
1491
.02
1440
.87
1332
.86
1309
.71 12
71.1
312
22.9
111
80.4
711
12.9
61
060.
8810
37.7
480
0.49
103
106
O
N
NH
NH N
OH
O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : DPX-200 Spectrometer
(200MHz)
NMR SPECTRAL STUDY OF 5-{4'-[6-(4'"-METHOXY PHENYL)]-2"-HYDROXY-3",4"-DIHYDRO PYRIMIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
107
SignalNo
1234567
Signal Position(δ δ δ δ δ ppm)
3.036.176.11
6.9-7.36.77.32.16
Relative No.of protons Multiplicity Inference
3 H1 H1 H16 H2 H2 H1 H
SingletSingletSinglet
MultipletDoubletSingletSinglet
Ar-OCH3a
-CONHb
-N-Hc
Ar-Hd
Ar-He
Ar-Hf
Ar-OHg
a
b
d d dd
d
d
d
d d d
O
N
NH
NH N
OH
O
CH3
dd
ded f
g
ed
cc
df
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 108
O
N
NH
NH
N
OH
OCH
3
m/z
=514
O
N
NH
NH
N
OH
O-
m/z
=499
O
N
NH
NH
N
OH
m/z
=483
O
N
NH
NH
N
OH
OCH
3
m/z
=490
O
N
NH
NH
N
OH
m/z
=460
O
NH
NH
NH
N
OH
OCH
3
m/z
=414
m/z
=470
O
N
NH
NH
OCH
3
m/z
=311
O
N
NH
m/z
=408
O
N
NH
NH
N
OH
m/z
=288
O
N
NH
MA
SS F
RE
GM
EN
T S
TU
DY
OF
5-{4
'-[6
-(4'
"-M
ET
HO
XY
PH
EN
YL
]-2"
-HY
DR
OX
Y-3
",4"
-DIH
YD
RO
PYR
IMID
INE-
4"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
NH
CH
2+
NH
NH
N
OH
m/z
=396
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 109
MA
SS S
PE
CT
RA
L S
TU
DY
OF
5-{4
'-[6
-(4'
"-M
ET
HO
XY
PH
EN
YL
]-2"
-HY
DR
OX
Y-3
",4"
-DIH
YD
RO
PYR
IMID
INE-
4"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
NH
N
OH
OCH
3
m/z
=514
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 110
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
2-O
CH
3-C6H
4-(26
)4-
OC
H3-C
6H4-(
27)
3-N
O2-C
6H4-(
29)
C14
H9 (
Ant
hra)
-(27)
30 30 35 -
A.n
iger
R
C6H
5-(22
) 3
-OH
-C6H
4-(22
) 2
-Cl-C
6H4-(
23)
- - - 27
E.c
oil
R
4-N
,N(C
H3) 2C
6H4-(
25)
32 28 30 -
S. ta
phim
ariu
mR
4-O
H-C
6H4-(
22)
4-N
,N-(
CH
3) 2C6H
4-(24
)C 4H
3O (F
urfu
ral)-
(23)
30 29 27 -
Ampic
ilin50
μg
Chlo
rom
phen
icol
"
Nor
floxa
cin
"
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
C6H
5-(25
)2-
NO
2-C6H
5-(26
)
29 32 31 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CHO40% NaOH, 24 hrs Stirring
Type (VII) R=Aryl
NH2 NH2
O
111
R
O
N
NH
NH N
OH
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(6"-ARYL)-2"-HYDROXY-3",4"-DIHYDROPYRIMIDINE-4"-YL]-N-PHENYLCARBAMIDO}-DIBENZ [b,f]AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propen-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: 1, section : I, Page No : 31
(C) Synthesis of 5-{4'-[6"-(4"'-methoxy phenyl)-2"-Hydroxy 3"-4"-dihydro pyrimidine -4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and urea (0.60g,
0.01M) was refluxed at 90oC for 14 hrs. in presence of acid catalyst like HCl
in methanol the reaction mixture was poured into crushed ice, filtered and
dried the product was isolated, crystallised from dioxane: yield : 70.19 %
M.P. 112OC (Found:C:74.60; H: 5.01; N: 10.81; C32H26N4O3
Required: C:74.70; H: 5.05; N: 10.89 %)
Simillary other pyrimidine derivatives have been synthesised and their
physical data are recorded in table No.: 13
(D) Antimicrobial activity of 5-{4'-[(6"-aryl)-2"-hydroxy 3",4"-dihydroxy pyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f]azepines.The antimicrobial testing was carried out as described in part : I,
section: I Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 14
112
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
13 P
HY
SIC
AL
CO
NST
AN
TS
OF
5-{4
'-[(6
"-A
RY
L)-
2"-H
YD
RO
XY-
3",4
"D
IHY
DR
O P
YR
IMID
INE-
4"-Y
l] PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C31
H24
N4O
2
C31
H24
N4O
3
C31
H24
N4O
3
C31
H24
N4O
3
C32
H26
N4O
4
C32
H26
N4O
3
C32
H26
N4O
3
C31
H23
N5O
4
C31
H23
N5O
4
C31
H23
N4O
2Cl
C33
H29
N5O
2
C29
H22
N4O
3
C35
H26
N4O
2
C39
H28
N4O
2
M.P
. O
C 4 82 90 100
124
130
120
112
118
110
80 118
85 105
178
Yiel
d% 5
72.1
269
.72
65.6
978
.99
76.8
781
.11
70.1
975
.26
79.3
283
.58
79.9
265
.89
69.6
773
.00
% o
f Nitr
ogen Fo
und
711
.50
11.1
811
.15
11.1
510
.51
10.8
110
.81
12.9
012
.92
11.9
912
.91
11.7
910
.42
9.53
Cal
cd.
611
.57
11.2
011
.20
11.2
010
.56
10.8
910
.89
12.9
812
.98
12.0
013
.00
11.8
110
.48
9.58
113
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
14A
NT
IMIC
RO
BIA
L A
CT
IVIT
Y O
F 5-
{4'-[
(6"-
AR
YL
)-2"
-HY
DR
OX
Y-3"
-4"
DIH
YD
RO
PY
RIM
IDIN
E-4"
-YL]
PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 23 21 13 14 15 26 27 23 29 14 21 11 23 27
S. a
ureu
s4 25 21 21 22 18 19 11 26 19 18 20 20 18 18
S. ta
phim
ariu
m5 15 16 10 22 21 12 14 13 19 21 24 23 10 12
A.n
iger
7 22 20 22 20 19 18 19 18 21 23 18 19 18 20
E.c
oil
6 10 13 13 15 12 13 12 13 10 15 25 11 10 10
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
114
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : III
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(6"-ARYL)2"-AMINO-3",4"-DIHYDRO PYRIMIDINE-4"-YL] PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Looking to the interesting pharmacological and agricultural activity of
pyrimidine ring system, it was considered worthwhile to synthesis
compounds bearing phenyl carbamido dibenz [b,f] azepine nucleus linked
to the pyrimidine nucleus 5-{4'-[(6" aryl)-2"-amino-3",4"-dihydro pyrimidine
4"-yl] phenyl carbamido}-dibenz [b,f] azepines of type (VIII) have been
synthesised by the condensation of 5-{4'-[(3"-aryl)-2"-propene-1"-one] phe-
nyl carbamido}-dibenz [b,f] azepines of Type (I) with guanidine hydrochlo-
ride in presence of alcohol potassium hydrochloride.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, section I, Page No. 32-34
Type (VIII) R=Aryl
R
O
N
NH
NH N
NH2
115
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
50010001500200030004000
0
25
50
75
100
125
%T
3583
.86
304
7.63
2985
.91
2953
.12
2659
.93
171
4.77
1523
.82
1491
.02
1440
.87
1332
.86
1309
.71 12
71.1
312
22.9
111
80.4
711
12.9
61
060.
8810
37.7
480
0.49
Reported2975-29502890-28501470-14503080-30301650-14501300-1100890-750
1350-13303550-33501650-15501750-17001270-1130
Frequency in cm.-1
SPECTRAL STUDY OF 5-{4'-[6"-(4'"-METHOXY PHENYL)]- 2"-AMINO-3",4"-DIHYDRO PYRIMIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2958295314403047
1523,149113098001332358315231714
1180, 1112
Type
Alkane
Aromatic
Pyrimidine
KetoneEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str. (Amino)N-H bending>C=OC-O-C
O
N
NH
NH N
NH2
O
CH3
116
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : DPX-200 Spectrometer
(200MHz)
NMR SPECTRAL STUDY OF 5-{4'-[6"-(4'"-METHOXY PHENYL)]-2"-AMINO-3",4"-DIHYDRO PYRIMIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
117
SignalNo
12
3456
Signal Position(δ δ δ δ δ ppm)
3.796.24.864.80
7.1 - 7.56.97.0
Relative No.of protons Multiplicity Inference
3 H1 H2 H1 H16 H2 H1 H
SingletSingletSingletSinglet
MultipletDoubletSinglet
Ar-OCH3a
-CONHb
-NH2c
-NHc
Ar-Hd
Ar-He
Ar-Hf
a
b
d d dd
d
d
d
d d d
O
N
NH
NH N
NH2
O
CH3
dd
ded f
ed
c
df
c
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS F
REG
MEN
T ST
UD
Y O
F 5-
{4'-[
6"-(4
'"-M
ETH
OX
Y P
HEN
YL)
]- 2"
-AM
INO
-3",
4"-D
IHY
DR
O P
YR
IMID
INE-
4"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
OCH
3
O
N
NH
NH
N
NH
2m
/z=5
13
O
N
NH
NH
N
NH
2
OH
m/z
=499
O
N
NH
NH
N
NH
2m
/z=4
59
O
N
NH
NH
N
NH
2
OCH
3
m/z
=489
O
N
NH
NH
N
NH
2m
/z=4
83OC
H3
O
N
NH
NH
m/z
=473
OCH
3
m/z
=108
OCH
3
O
NH
NH
NH
N
NH
2m
/z=4
13
OCH
3
O
N
NH
NH
m/z
=449
m/z
=311
O
N
NH
O
N
m/z
=220
CH
2+
m/z
=105
118
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
PEC
TRA
L S
TUD
Y O
F 5-
{4'-[
6"-(4
'"-M
ETH
OX
Y P
HEN
YL)
]- 2"
-AM
INO
-3",
4"-D
IHY
DR
O P
YR
IMID
INE-
4"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
OCH
3
O
N
NH
NH
N
NH
2m
/z=5
13
119
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CHO40% NaOH, 24 hrs Stirring
Guanidine Hydrochloride
Type (VIII) R=Aryl
R
O
N
NH
NH N
NH2
120
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
2-O
H-C
6H4-(
23)
3-O
CH
3,4-O
H C
6H3-(
25)
4-O
CH
3-C6H
4-(25
)
3
0
30
3
5
-
A.n
iger
R
3-O
CH
3,4-O
HC
6H3-(
21)
3-O
CH
3-C6H
4-(21
)
- - - 27
E.c
oil
R
2-O
H-C
6H4-(
25)
3-O
H-C
6H4-(
23)
C14
H9 (
Ant
hra)
-(21)
32 28 30 -
S. ta
phim
ariu
mR
3-N
O2-C
6H4-(
23)
C4H
3O- (
Furfu
ral)-
(25)
C14
H9 (
Ant
hra)
-(25)
30 29 27 -
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
2-N
O2-C
6H4-(
23)
2-C
l-C6H
4-(23
)C
10H
7-(N
epth
a)-(
23)
C14
H9 (
Ant
hra)
-(25)
29 32 31 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
Ampic
ilin50
μg
Chlo
rom
phen
icol
"
Nor
floxa
cin "
Gris
eofu
lvin
"
121
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(6"-ARYL)-2"-AMINO-3",4"-DIHYDROPYRIMIDINE-4"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I section : I, Page No : 31
(C) Synthesis of 5-{4'-[6"-(4"'-methoxy phenyl)-2"-amino 3"-4"-dihydro pyrimidine -4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one] henyl
carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and guanidine
hydrochloride (0.95g, 0.01M) was refluxed at 110oC for 12 hrs. in presence
of alco-KOH in methanol the reaction mixture was poured into crushed ice,
filtered and dried the product was isolated, crystallised from dioxane: yield
:69.71 % M.P. 89OC (Found:C:74.62; H: 5.40; N:13.44; C32H27N5O2
Required: C:74.70; H:5.44; N: 13.61 %)
Simillary other pyrimidine were synthesised and their physical data are
recorded in Table No. 15
(D) Antimicrobial activity of 5-{4'-[(6"-aryl)-2"amino-3",4"- dihydro-pyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.Antimicrobial testing was carried out as described in part : I, section: I
Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 16
122
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
15PH
YSI
CA
L C
ON
STA
NT
S O
F 5-
{4'-[
(6"-
AR
YL
)-2"
-AM
INO
3",
4"-D
IHY
DR
OPY
RIM
IDIN
E-4"
-Yl]
PHEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
E.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C31
H25
N5O
C31
H25
N5O
2
C31
H25
N5O
2
C31
H25
N5O
2
C32
H27
N5O
3
C32
H27
N5O
2
C32
H27
N5O
2
C31
H24
N6O
3
C31
H24
N6O
3
C31
H24
N5O
Cl
C33
H30
N6O
C29
H23
N5O
2
C35
H27
N5O
C39
H29
N5O
M.P
. O
C 4 120
135
115
97 95 98 89 145
198
160
200
85 240
170
Yiel
d% 5
81.7
160
.82
70.8
285
.91
71.8
078
.11
69.7
170
.81
88.7
169
.78
78.6
977
.11
59.7
276
.11
% o
f Nitr
ogen Fo
und
714
.23
13.9
613
.98
13.9
313
.11
13.5
013
.44
15.8
515
.70
13.4
015
.88
14.6
013
.10
11.9
6
Cal
cd.
614
.49
14.0
214
.02
14.0
213
.23
13.6
113
.61
15.9
015
.90
13.5
315
.96
14.7
913
.13
12.0
123
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
16A
NTI
MIC
RO
BIA
L A
CT
IVIT
Y O
F 5-
{4'-[
(6"-
AR
YL
)-2"
-AM
INO
-3"-
4" D
IHY
DR
OPY
RIM
IDIN
E-4"
-YL]
PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 19 23 13 21 25 20 25 21 19 18 18 19 21 19
S. a
ureu
s4 9 17 13 19 20 17 20 23 17 23 13 21 23 25
S. ta
phim
ariu
m5 21 19 18 19 21 19 19 19 23 13 21 25 20 25
A.n
iger
7 18 18 18 11 21 18 21 19 12 17 20 17 19 18
E.c
oil
6 20 25 23 13 11 14 12 11 12 13 14 10 14 21
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
124
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - V
STUDIES ONCYANO PYRIDINES
125
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON CYANO PYRIDINES
INTRODUCTIONPyridine and its derivatives represent one of the most active class of
compounds possessing a wide spectrum of biological activities in the field
of medicine, agriculture and industrial chemistry. Pyridine-3-carboxamide
occurs as a component of the structure of the important coenzymes NADP +,
one of the B12 complex of vitamins, occurs in red blood corpuscles and
participates in biochemical redox reaction. Pyridoxol (Vitamin B6) (I),
occurs in yeast and wheatgerm is an important food additive.
The availability of 3-cyanopyridine, nicotinamide and nicotinic acid
make possible their use as synthetic intermediates.
Most derivatives are prepared by manipulation of pyridine and its
simple homologues in a manner similar to chemistry of the benzenoid
chemistry. However the simple pyridine compounds are prepared by the
cyclisation of aliphatic raw material.
SYNTHETIC ASPECTS
Preparation of 3-cyanopyridines have been cited in literature 233-237 with
different methods. The well known method is:
126
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
1. Samour and co-workers238 have prepared substituted cyanopyridines by
the condensation of chalcones with malononitrile in presence of
ammonium acetate.
MECHANISMThe mechanism for the condensation of chalcones with malononitrile is
shown as under.
This reaction proceeds through conjugated addition of active
methylene compounds to the α, β unsaturated system. The α, β-unsaturated
compound is known as acceptors and active methylene compound is known
as addender.
127
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
THERAPEUTIC EVALUATIONCyanopyridines possess wide therapeutic activities listed as under.
1. Antihypertensive239
2. Antisoriasis240
3. Antiepileptic241
4. Anticonvulsant242
5. Antifungal243
6. Antibacterial244
7. Herbicidal245
8. Antiinflammatory246
9. Anti HIV247
S. S. Verma et al.248 have synthesised 2-amino-3-cyano-2,6-disubstituted
pyridines and studied their biological activities. The insecticidal activity of
cyanopyridines has been investigated by Y. Sosaki249, I. Teu and
co-workers250 have shown cyanopyridines as agrochemical fungicides. M.
Hussans and co-workers251 have prepared 3-cyanopyridines and reported their
pharmacological activity. S. Guru evaluated252 cyanopyridine derivatives (III)
have been documented for their multiple biological activities.
F. Manna and co-workers253 have reported the antiinflammatory activity
of 3-cyanopyridines. Some new 3-cyanopyridine derivatives have been found
128
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
to show anticancer and anti HIV activity.254 A. R. Parikh et al.255-256 have
prepared some new cyanopyridines and studied .their antimicrobial activity.
U. D. Pyachenko and co-workers257 have synthesised some
cyanopyridine derivatives (IV) which are useful in the treatment of retroviral
diseases. Cyanopyridine derivatives (V) showing significant biological
activity are described258
H. H. Parekh et al.259 have prepared new cyanopyridines and all
products have been evaluated for their in vitro growth inhibitory activity against
different microbes. T. B. Lowinger et al.260 have prepared some new
cyanopyridines and postulated them as vitro and cellular activities.
Moreover, H. Hiroki et al.261 synthesised 2-acylamino-3,5-
dicyanopyridine derivatives useful as calcium channel opening drugs.
Antimicrobial activity of cyanopyridine derivatives have reported by M. M.
Komal262, E. B. Villhauer et al.263 have prepared novel cyanopyridines which
has been found to be bioavailable dipeptidyl peptidase inhibitors.
The synthesis of cyanopyridines is of current interest owing to their
enormous occurence in biologically active derivatives. Hence,
considerable attention has been focused on the study of efficient and
pharmaceutically important cyanopyridines bearing dibenz [b,f]-azepines
nucleus, which is described as under.
129
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(6"-ARYL)2"-AMINO-3"CYANOPYRIDINE-4"-YL] PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
SECTION : II SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(4"-ARYL)3"-CYANO-2"-METHOXYPYRIDINE-6"-YL] PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
SECTION : III SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(4"-ARYL)3"-CYANO-2"-ETHOXYPYRIDINE -6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
SECTION: IV SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(4"-ARYL)3"-CYANO-2"-HYDROXYPYRIDINE-6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
130
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(6"-ARYL)2"-AMINO-3"-CYANO PYRIDINE-4"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Pyridine nucleus plays in important role in medicine agriculture and
industrial chemistry. To further assess the potential of such a classes of
compounds, cyano pyridine derivative of 5-{4'-[(6"-Aryl) - 2"-amino-3"-
cyano pyridine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines of type (IX)
have been synthesised by the condensation of chalcones of 5-{4'-[(3"-aryl)-
2"-propene -1"one]- phenyl carbamido}- dibenz [b,f] azepines with
malononitrile in presenese of ammonium acetate.
The constitution of the products have been characterised by elemental
analyses IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I,section : I, Page No. 32-34
Type (IX) R=Aryl
R
O
N
NH
N
NH2N
131
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303550-33501650-15501750-17001100-13002500-2200
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[6"-(4'"-METHOXY PHENYL)]-2"-AMINO-3"-CAYNO PYRIDINE-4"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450
"
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2953284714383026
15990,15191111802133434401519170812342220
Type
Alkane
Aromatic
Amide
KetoneEtherNitrile
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) (bending)C-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=O strC-O-CC≡N
50010001500200030004000-25
0
25
50
75
100
125
%T30
26.4
129
53.
1228
47.0
3
2220
.14
1805
.43
1708
.99
1599
.04
1519
.96
1489
.10
1438
.94
141
3.87
133
4.78
1309
.71
1271
.13
123
4.48
121
1.34
1159
.26
111
1.03
105
8.9
688
3.43
802.
4177
3.4
8
3440
.90-
O
N
NH
N
NH2N
O
CH3
132
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : DPX-200 Spectrometer
(200MHz)
NMR SPECTRAL STUDY OF 5-{4'-[6"-(4'"-METHOXY PHENYL)]-2"-AMINO-3"-CAYNO PYRIDINE 4"-YL] PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
133
SignalNo
123456
Signal Position(δ δ δ δ δ ppm)
3.906.35.3
7.0-7.66.76.4
Relative No.of protons Multiplicity Inference
3 H1 H2 H16 H2 H1 H
SingletSingletSinglet
MultipletDoubletSinglet
Ar-OCH3a
-NHb
-NH2c
Ar-Hd
Ar-He
Ar-Hf
a
b
d d dd
d
d
d
d dd
dd
ded f
ed
c
df
c
O
N
NH
N
NH2N
O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS F
REG
MEN
T ST
UD
Y O
F 5-
{4'-[
6"-(4
'"-M
ETH
OX
Y PH
ENY
L)] -
2"-A
MIN
O-3
"-C
AYN
O P
YR
IDIN
E 4"
-YL]
PHEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
NH
2N
O-
m/z
=520
O
N
NH
N
NH
2N
OCH
3
m/z
=511
O
N
NH
N
NH
2N
m/z
=505
O
N
NH
N
NH
2N
m/z
=481
O
NH
NH
N
NH
2N
OCH
3
m/z
=435
O
N
NH
N
NH
2N
OCH
3
m/z
=535
O
N
NH
N
NH
2N
m/z
=428
O
N
NH
NH
-
m/z
=344
O
N
NH
N
NH
2N
m/z
=405
O
N
NH
m/z
=311
OCH
3
m/z
=108
CH
2+
m/z
=105
134
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
PEC
TRA
L ST
UD
Y O
F 5-
{4'-[
6"-(4
'"-M
ETH
OX
Y PH
ENY
L)] -
2"-A
MIN
O-3
"-C
AYN
O P
YR
IDIN
E 4"
-YL]
PHEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
NH
2N
OCH
3
m/z
=535
135
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
S. ta
phim
ariu
mR
4-N
,N(C
H3) 2-C
6H4-(
23)
C4H
3O- (
Furfu
ral)-
(26)
C10
H7 (
Nep
thyl
)-(27
)
30 29 27 -
Ampic
ilin50
μg
Chlo
rom
phen
icol
"N
orflo
xacin
"G
riseo
fulv
in "
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
2-Cl
-C6H
4-(26
)4-
N, N
(CH
3) 2-C6H
4-(27
)
29 32 31 -
B. m
egat
eriu
mR
C 4H3O
(Fur
fura
l)-(2
4)C
10H
7O (N
epth
yl)-(
26)
30 30 35 -
A.n
iger
R
3-O
H-C
6H4-(
23)
3-N
O2-C
6H4-(
22)
2-C
l-C6H
4-(23
)
- - - 27
E.c
oil
R
4-N
,N-(
CH
3) 2C6H
4-(24
)
32 28 30 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
136
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CHO40% NaOH, 24 hrs Stirring
CH2(CN)2
CH3COONH4
Type (IX) R=Aryl
R
O
N
NH
N
NH2N
137
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(6"ARYL)-2"-AMINO-3"-CYANO PYRIDINE-4"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I section : I, Page No. 31
(C) Synthesis of 5-{4'-[6"-(4"'-methoxy phenyl)-2"-amino 3"-4"-cyano pyrimidine -4"-yl] phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]-
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g ,0.01M) and malononitrile
(0.66g, 0.01M) and ammonium acetate (0.77g, 0.001M) was refluxed 10 hrs
at 120.oC in methanol solvent the reaction mixture was poured into crushed
ice, filtered and dried the product was isolated, crystallised from dioxane:
yield 66.75%, M.P. 85OC (Found:C:76.16; H: 4.61; N:12.98; C34H25N5O2
Required: C:76.26; H:4.67; N: 13.08 %)
Simillary other compounds were synthesised and their physical data
are recorded in Table No.17
(D) Antimicrobial activity of 5-{4'-[(6"-aryl)-2"amino-3" cyanopyridine- 4"-yl] phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,
section: I Page No. 32-34
The zone of inhibition of the test solutions are recorded in Table No. 18
138
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
17PH
YSI
CA
L C
ON
STA
NT
S O
F 5-
{4'-[
(6"-
AR
YL
)-2"
-AM
INO
-3"-
CYA
NO
,PY
RID
INE4
"-Y
l] PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C33
H23
N5O
C33
H23
N5O
2
C33
H23
N5O
2
C33
H23
N5O
2
C34
H25
N5O
3
C34
H25
N5O
2
C34
H25
N5O
2
C33
H22
N6O
3
C33
H22
N6O
3
C33
H22
N5O
Cl
C35
H28
N6O
C31
H21
N5O
2
C37
H25
N5O
C41
H27
N5O
M.P
. O
C 4 114
190
130
102
110
120
85 105
130
120
85 120
128
90
Yiel
d% 5
79.7
071
.60
78.5
259
.75
80.1
281
.65
66.7
568
.71
89.9
065
.70
72.7
285
.11
87.2
265
.11
% o
f Nitr
ogen Fo
und
713
.60
13.4
013
.39
13.3
512
.65
13.0
112
.98
15.2
415
.22
12.8
815
.11
14.0
912
.40
11.4
0
Cal
cd.
613
.86
13.4
313
.43
13.4
312
.70
13.0
813
.08
15.2
715
.27
12.9
715
.32
14.1
412
.61
11.5
7
139
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
18A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(6"-
AR
YL)
-2"-
AM
INO
-3"-
CYA
N P
YR
IDIN
E-4"
-YL]
PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 21 22 22 23 27 10 11 12 13 21 22 24 26 23
S. a
ureu
s4 19 16 21 17 18 10 12 18 19 26 27 17 16 18
S. ta
phim
ariu
m5 11 13 12 13 14 15 17 19 20 21 23 26 27 20
A.n
iger
7 21 20 23 12 17 18 19 21 22 23 13 17 18 19
E.c
oil
6 10 11 11 12 13 15 12 11 12 14 24 13 10 12
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
140
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : II
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(4"-ARYL)3"-CYANO-2"-METHOXY PYRIDINE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Pyridine nucleus plays in important role in medicine agriculture and
industrial chemistry. To further assess the potential of such a class of
compounds, cyano pyridine derivative of 5-{4'-[(4"-Aryl) - 3"-cyano -2"-
methoxy pyridine 6"-yl] phenyl carbamido}- dibenz [b,f] azepines by the
condensation of 5-{4'-[(3"-aryl)-2"-propene-1"one]- phenyl carbamido}-
dibenz [b,f] azepines type (I) with malononitrile and sodium methoxide.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR,Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section :I, Page No. 32-34
Type (X) R=Aryl
R
O
N
NH
N
O CH3
N
141
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303550-33501650-15501720-16501100-13002500-2200
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[4"-(4"-METHOXY PHENYL)-3"-CYANO-2"-METHOXY PYRIDINE -6"-YL]- PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450
"
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2985285314403047
1591,15531222800133235831523171411802220
Type
Alkane
Aromatic
Amide
KetoneEtherNitrile
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) (bending)C-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N strN-H str.N-H bending>C=O strC-O-CC ≡ N
50010001500200030004000
0
25
50
75
100
125
%T
3583
.86
304
7.63
2985
.91
2953
.12
2659
.93
171
4.77
1523
.82
1491
.02
1440
.87
1332
.86
1309
.71 12
71.1
312
22.9
111
80.4
711
12.9
61
060.
8810
37.7
480
0.49
O
N
NH
N
O CH3
N
O
CH3
2220
.20-
142
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :CDCl3: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF 5-{4'-[4"-(4"'-METHOXY PHENYL) -3"-CYANO-2"-METHOXY PYRIDINE-6"-YL] PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
143
SignalNo
123456
Signal Position(δ δ δ δ δ ppm)
3.646.33.44
6.9-7.36.86.3
Relative No.of protons Multiplicity Inference
3 H1 H3 H16 H2 H1 H
SingletSingletSinglet
MultipletDoubletSinglet
Ar-OCH3a
-NHb
Ar-OCH3c
Ar-Hd
Ar-He
Ar-Hf
a
b
d d dd
d
d
d
d dd
ddd
eO
N
NH
N
O CH3
N
O
CH3
f
ed
c
c
d
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS F
RE
GM
EN
T S
TUD
Y O
F 5-
{4'-[
4"-(4
"'-M
ETH
OX
Y P
HEN
YL)
-3"
-CYA
NO
-2"-
MET
HO
XY
PY
RID
INE-
6"-Y
L] P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
OC
H3
N
O-
m/z
=535
O
N
NH
N
OC
H3
N
m/z
=520
O
N
NH
N
OC
H3
N
OCH
3
m/z
=526
O
N
NH
N
OC
H3
N
O-
m/z
=511
m/z
=450
O
NH
NH
N
OC
H3
N
OCH
3
O
N
NH
N
OC
H3
Nm
/z=4
44
O
N
NH
N
OC
H3
Nm
/z=4
20
NH
-O
NH
NH
OC
H3
N
m/z
=351
O
N
NH
m/z
=311
CH
2+
m/z
=105
O
N
NH
N
OC
H3
N
OCH
3
m/z
=550
144
m/z
=196
O
N
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
PEC
TR
AL
STU
DY
OF
5-{4
'-[4"
-(4"'
-MET
HO
XY
PHEN
YL)
-3"-
CYA
NO
-2"-
MET
HO
XY
PYR
IDIN
E-6"
-Y
L] P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
OC
H3
N
OCH
3
m/z
=550
145
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
S. ta
phim
ariu
mR
C10
H7 (N
apth
a)-(
25)
C14
H9-
(Ant
hra)
-(26)
30 29 27 -
Ampic
ilin50
μg
Chlo
rom
phen
icol
"N
orflo
xacin
"G
riseo
fulv
in "
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
3-O
H-C
6H4-(
25)
4-O
H-C
6H4-(
27)
3-O
CH
3,4-O
H-C
6H3-(
26)
29 32 31 -
B. m
egat
eriu
mR
3-O
CH
3,4-O
H-C
6H3-(
28)
2-O
CH
3-C6H
4-(27
)
30 30 35 -
A.n
iger
R
C6H
5-(23
)C
10H
7 (N
apth
a)-(
23)
C14
H9 (
Ant
hra)
-(22)
- - - 27
E.c
oil
R
2-O
H-C
6H4-(
18)
C 14H
9(Ant
hra)
-(18)
32 28 30 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
146
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineRefulx
R-CHO40% NaOH, 24 hrs Stirring
CH2(CN)2
CH3ONa
Type (X) R=Aryl
R
O
N
NH
N
O CH3
N
147
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(4"ARYL)-3"-CYANO-2"-METHOXYPYRIDINE 6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I, Page No : 31
(C) Synthesis of 5-{4'-[4"-(4"'-methoxy phenyl)-3"-cyano- 3"-2"-methoxy pyridine -6"-yl]-phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f] azepine. (4.72.g, 0.01M) and malononitrile
(0.66g, 0.01M) and sodium methoxide as solvent was refuxed 10 hrs. at
100.oC. The reaction mixcture was poured into crushed ice, filtered and dried
the product was isolated, crystallised from dioxane: yield :78.80 % M.P.
70OC (Found:C:76.32; H: 4.70; N:10.11; C35H26N4O3
required: C:76.36; H:4.72; N:10.18 %)
Simillary other Compund were prepared and their physical data are
recorded in Table No. 19
(D) Antimicrobial activity of 5-{4'-[(4"-aryl)-3"-cyano-2"-methoxypyridine-6"-yl] phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 20
148
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
19
PHY
SIC
AL
CO
NST
AN
TS
OF
5-{4
'-[(4
"-A
RY
L)-
3"-C
YAN
O-2
"-M
ET
HO
XY
PYR
IDIN
E-6"
-Yl]
PHEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
E
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C34
H24
N4O
2
C34
H24
N4O
3
C34
H24
N4O
3
C34
H24
N4O
3
C35
H26
N4O
4
C35
H26
N4O
3
C35
H26
N4O
3
C34
H23
N5O
4
C34
H23
N5O
4
C34
H23
N4O
2Cl
C36
H29
N5O
2
C32
H22
N4O
3
C38
H26
N4O
2
C42
H28
N4O
2
M.P
. O
C 4 117
120
130
118
120
80 70 98 190
170
112
120
120
110
Yiel
d% 5
70.7
269
.71
78.8
085
.82
89.9
072
.80
78.8
062
.80
49.6
874
.68
84.6
969
.84
59.7
171
.82
% o
f Nitr
ogen Fo
und
710
.60
10.4
010
.42
10.3
89.
7010
.09
10.1
112
.32
12.2
210
.06
12.4
010
.77
9.77
9.01
Cal
cd.
670
.76
10.4
410
.44
10.4
49.
8910
.18
10.1
812
.38
12.3
810
.09
12.4
310
.98
9.82
9.03
149
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
20A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(4"'
-AR
YL
)-3"
-CYA
N-2
"-M
ET
HO
XY
PYR
IDIN
E-6"
-YL]
PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
(Pag
e N
o. 1
84)
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 23 18 10 21 28 27 23 14 13 23 11 17 18 19
S. a
ureu
s4 23 22 25 27 26 16 17 18 12 22 23 19 18 18
S. ta
phim
ariu
m5 11 19 18 23 17 18 19 20 21 20 23 20 25 26
A.n
iger
7 23 20 12 18 10 11 13 13 14 12 20 21 23 22
E.c
oil
6 12 18 12 10 11 13 11 12 10 14 12 15 17 18
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
150
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : III
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-ETHOXY PYRIDINE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Pyridine nucleus plays in important role in medicine agriculture and
industrial chemistry. To further assess the potential of such a class of
compounds, cyano pyridines derivative of 5-{4'-[(4"-Aryl)-3" cyano-2"-
ethoxy pyridine 6"-yl] phenyl carbamido}-dibenz [b,f] azepines by the
condensation of 5-{4'-[(3"-aryl)-2"-propene -1"one]- phenyl carbamido}-
dibenz [b,f] azepines type (I) with malononitrile and sodium ethoxide.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part :I, Section I, Page No.32-34
Type (XI) R=Aryl
R
O
N
NH
N
O
N
CH3
151
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303550-33501650-15501750-17001100-13002500-2200
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[4"-(4"-METHOXY PHENYL) -3"-CYANO-2"-ETHOXY PYRIDINE -6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450
"
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2933287014402985
1485,14401303821137734731485171812242202
Type
Alkane
Aromatic
Amide
KetoneEtherNitrile
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=O strC-O-CC≡N
50010001500200030004000
40
60
80
100
%T
347
3.91
3402
.54
2985
.91
2933
.83
2870
.17
279
8.80
2623
.28
2202
.78
1786
.14
1749
.49
171
8.63
1485
.24
1440
.87 14
02.3
013
77.2
213
03.9
212
24.8
411
18.
751
062.
81
885.
36 831
.35
O
N
NH
N
O
N
CH3
O
CH3
152
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :CDCl3: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF 5-{4'-[4"-(4'"-METHOXY PHENYL) -3"-CYANO-2"-ETHOXY PYRIDINE-6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
153
SignalNo
1234567
Signal Position(δ δ δ δ δ ppm)
3.826.31.3
7.0-7.56.86.43.31
Relative No.of protons Multiplicity Inference
3 H1 H3 H16 H2 H1 H2 H
SingletSingletTriplet
MultipletDoubletSinglet
Quaterate
Ar-OCH3a
-NHb
-CH3c
Ar-Hd
Ar-He
Ar-Hf
-OCH2g
a
b
d d dd
d
d
d
d dd
ddd
ef
ed
c
c
d
O
N
NH
N
O
N
CH3
O
CH3
g
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS F
RE
GM
EN
T ST
UD
Y 5-
{4'-[
4"-(4
'"-M
ETH
OX
Y P
HEN
YL)
-3"-
CYA
NO
-2"-
ETH
OX
Y PY
RID
INE-
6"-Y
L]-
PHEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
O
N
CH
3
OCH
3
m/z
=564
O
N
NH
-
m/z
=211
O
NH
NH
N
O
N
CH
3
OCH
3
m/z
=464
O
N
NH
N
O
N
CH
3m
/z=4
58
O
N
NH
N
O
N
CH
3m
/z=5
34
m/z
=540
O
N
NH
N
O
N
CH
3
OCH
3
m/z
=77
O
N
m/z
=220
154
CH
2+
m/z
=105
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
RE
CT
RA
L S
TUD
Y 5
-{4'
-[4"-
(4'"
-MET
HO
XY
PH
ENY
L)-3
"-C
YAN
O-2
"-ET
HO
XY
PY
RID
INE-
6"-Y
L]-
PHEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
O
N
CH
3
OCH
3
m/z
=564
155
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
S. ta
phim
ariu
mR
2-O
H-C
6H4-(
21)
2-N
O2
C6H
4-(25
)3-
NO
2-C6H
4-(21
)
30 29 27 -
Ampic
ilin
5
0 μg
Chlo
rom
phen
icol
"
Nor
floxa
cin
"
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
C6H
5-(20
)C 4H
3O (F
urfu
ral)-
(20)
C10
H7 (
Nep
thal
) - (2
2)
29 32 31 -
B. m
egat
eriu
mR
2-O
CH
3-C6H
4-(20
)4-
N,N
,(CH
3) 2 C6H
4-(21
)
30 30 35 -
A.n
iger
R
3-O
H-C
6H4-(
18)
3-O
CH
3,4-O
H-C
6H3-(
19)
2-O
CH
3-C6H
4-(21
)
- - - 27
E.c
oil
R
2-O
CH
3-C6H
4-(26
)C 4H
3O (F
urfu
ral)-
(23)
32 28 30 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
156
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CHO40% NaOH, 24 hrs Stirring
CH2(CN)2
C2H5ONa
Type (XI) R=Aryl
R
O
N
NH
N
O
N
CH3
157
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-ETHOXYPYRIDINE 6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I section : I, Page No : 31
(C) Synthesis of 5-{4'-[4"-(4"'-methoxy phenyl)-3"-cyano-2"-ethoxypyridine -4"-yl]-phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and malononitrile
(0.66g, 0.01M) and sodium ethoxide as solvent was poured into crushed ice,
filtered and dried the product was isolated, crystallised from dioxane:
yield :81.10 % M.P. 82OC (Found:C:76.52; H: 4.80; N:9.80; C36H28N4O3
required: C:76.59; H:4.96; N:9.92 %)
Simillary other pyridine were synthesised and their physical data are
recorded in Table No. 21
(D) Antimicrobial activity of 5-{4'-[(4"-aryl)-3"cyano-2"-ethoxypyridine-6"-yl] phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,
section: I Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 22
158
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
21PH
YSI
CA
L C
ON
STA
NTS
OF
5-{4
'-[(4
"-A
RY
L)-3
"-C
YAN
O-2
"-ET
HO
XY
PY
RID
INE-
6"-Y
l]-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2
C6H
5-2-
OH
-C6H
4-3-
OH
-C6H
4-4-
OH
-C6H
4-3-
OC
H3,4
-OH
-C6H
3-2-
OC
H3-C
6H4-
4-O
CH
3-C6H
4-2-
NO
2-C6H
4-3-
NO
2-C6H
4-2-
Cl-C
6H4-
4-N
,N-(
CH
3) 2C6H
4-C
4H3O
(Fur
fura
l)-C
10H
7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C35
H26
N4O
2
C35
H26
N4O
3
C35
H26
N4O
3
C35
H26
N4O
3
C36
H28
N4O
4
C36
H28
N4O
3
C36
H28
N4O
3
C35
H25
N5O
4
C35
H25
N5O
4
C35
H25
N4O
2Cl
C37
H31
N5O
2
C33
H24
N4O
3
C39
H28
N4O
3
C43
H30
N4O
2
M.P
. O
C 4 180
207
98 120
79 80 82 180
115
82 185
58 105
108
Yiel
d% 5
70.2
067
.72
71.6
062
.68
74.1
082
.11
81.1
059
.60
65.6
466
.68
71.1
158
.10
69.1
061
.10
% o
f Nitr
ogen Fo
und
710
.44
10.0
910
.08
10.1
09.
609.
829.
8012
.01
11.9
99.
512
.09
10.6
19.
488.
81
Cal
cd.
610
.48
10.1
810
.18
10.1
89.
659.
929.
9212
.08
12.0
89.
812
.13
10.6
89.
588.
83
159
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
22A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(4"'
-AR
YL
)-3"
-CYA
N-2
"-E
TH
OX
YPY
RID
INE-
6"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
E
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 19 18 16 14 13 20 11 13 16 17 21 10 11 14
S. a
ureu
s4 20 17 16 14 12 10 11 17 16 19 16 20 22 16
S. ta
phim
ariu
m5 16 21 17 18 15 13 11 25 21 17 18 11 12 10
A.n
iger
7 15 16 18 17 19 21 16 14 13 12 11 10 11 16
E.c
oil
6 11 16 18 15 13 26 11 14 15 17 18 23 11 13
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
160
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : IV
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-HYDROXY PYRIDINE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Pyridine nucleus plays in important role in medicine agriculture and
industrial chemistry. To further assess the potential of such a class of
compounds, cyano pyridine derivative of 5-{4'-[(4"-Aryl)-3"-cyano-2"-
hydroxy pyridine 6"-yl] phenyl carbamido}- dibenz [b,f] azepines by the
condensation of 5-{4'-[(3"-aryl)-2"-propene -1"one]- phenyl carbamido}-
dibenz [b,f] azepines type (I) with ethyl cyano acetate in presence of
ammonium acetate.
The constitution of the synthesised products have been characterised
by elemental analysis IR,1H NMR, Mass spectral study. The products were
screened for antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section I, Page No 32-34
Type (XII) R=Aryl
R
O
N
NH
N
OH
N
161
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
500100015002000300040001/
45
60
75
90
105
% T2
995.
55 24
07.2
4
2227
.86
181
1.22
1730
.21
1519
.96
1440
.87
1367
.58
1300
.07
1271
.13
1224
.84
1060
.88 88
7.28
484.
15
107
3380
.45
-
IR SPECTRAL STUDY OF 5-{4'-[4"-(4"'-METHOXY PHENYL) -3"-CYANO-2"-HYDROXY PYRIDINE -6"-YL]- PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
3480
.10-
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303550-33501650-15501750-17001100-13002500-22003500-3200
Frequency in cm.-1
Ref.445-458
"""
446,447""
449446,447
"447450
"454
Observed2995288014403030151912718871367338015191730122422273480
Type
Alkane
Aromatic
Amide
KetoneEtherNitrile
Hydroxy
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=O strC-O-CC≡NO-H broad
O
N
NH
N
OH
N
O
CH3
162
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF 5-{4'-[4"-(4'"-METHOXY PHENYL) -3"-CYANO-2"-HYDROXY PYRIDINE-6"-YL]- PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
163
SignalNo
123456
Signal Position(δ δ δ δ δ ppm)
3.756.162.13
6.8-7.76.96.6
Relative No.of protons Multiplicity Inference
3 H1 H1H
16 H2 H1 H
SingletSingletSinglet
MultipletDoubletSinglet
Ar-OCH3a
-NHb
-OHc
Ar-Hd
Ar-He
Ar-Hf
a
b
d d dd
d
d
d
d dd
ddd
ef
ed
c
c
d
O
N
NH
N
OH
N
O
CH3
d
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS F
REG
MEN
T ST
UD
Y O
F O
F 5-
{4'-[
4"-(4
'"-M
ETH
OX
Y PH
ENY
L) -3
"-C
YAN
O-2
"-H
YD
RO
XY
PYR
IDIN
E-6"
-YL]
- PH
ENY
L C
AR
BAM
IDO
}- D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
OH
N
OCH
3
m/z
=536
O
N
NH
N
OH
N
m/z
=482
O
N
NH
N
OH
N
m/z
=430
m/z
=77
O
N m/z
=220
O
N
NH
N
OH
N
OCH
3
m/z
=512
O
N
NH
N
OH
N
m/z
=506
O
N
NH
m/z
=311
O
NH
NH
N
OH
N
OCH
3
m/z
=436
164
CH
2+
m/z
=105
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS S
PEC
TRA
L ST
UD
Y O
F O
F 5-
{4'-[
4"-(4
'"-M
ETH
OX
Y PH
ENY
L) -3
"-C
YAN
O-2
"-H
YD
RO
XY
PYR
IDIN
E-6"
-YL]
- PH
ENY
L C
AR
BAM
IDO
}- D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
N
OH
N
OCH
3
m/z
=536
165
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
Max
imum
ant
imic
robi
al a
ctiv
ity :
S. ta
phim
ariu
mR
C6H
5-(21
)3-
NO
2-C6H
4-(21
)C 3H
4O -(
Furfu
ral)-
(20)
30 29 27 -
Ampic
ilin 5
0 μg
Chlo
rom
phen
icol
"
Nor
floxa
cin
"G
riseo
fulv
in
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
2-O
CH
3 C
6H5-(
21)
4-O
CH
3- C6H
4-(25
)2-
NO
2-C6H
4-(22
)
29 32 31 -
B. m
egat
eriu
mR
C6H
5-(20
)3-
NO
2-C6H
4-(21
) C
10H
7-(N
epth
al)-
(22)
30 30 35 -
A.n
iger
R
2-N
O2-C
6H4-(
22)
C10
H7 (
Nep
thal
)-(24
)
- - - 27
E.c
oil
R
2-N
O2-C
6H4-(
22)
2-C
l -C6H
4-(23
)
32 28 30 -
Com
para
ble
activ
ity w
ith kn
own s
tand
ard d
rugs
166
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineRefulx
R-CHO40% NaOH, 24 hrs Stirring
Type (XII) R=Aryl
(1) Ethyl cyano acetate(II) CH3COONH4
R
O
N
NH
N
OH
N
167
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-HYDROXYPYRIDINE-6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I section : I , Page No : 31
(C) Synthesis of 5-{4'-[4"-(4"'-methoxy phenyl)-3"-cyano-2"-hydroxypyridine -6"-yl]-phenyl carbamido}-dibenz [b,f] azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and ethyl cyano ac-
etate (1.13ml, 0.01M) was refluxed for 10 hrs. at 110oC in presence of ammo-
nium acetate in methanol poured into crushed ice, filtered and washed. The
product was crystallised from ethanol yiled: 80.82 % M.P. 85OC
(Found:C:76.09; H: 4.32; N:10.08; C34H24N4O3 Required: C:76.20; H:4.34;
N:10.44 %)
Simillary other compunds were prepared and their physical data are
recorded in Table No.23
(D) Antimicrobial activity of 5-{4'-[(4"-aryl)-3"cyano-2" hydroxypyridine-6"-yl] phenyl carbamido}-dibenz [b,f] azepines.The antimicrobial testing was carried out as described in part : I,
section: I, Page No.32-34
The zone of inhibition of the test solution are recorded in Table No. 24
168
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
23PH
YSI
CA
L C
ON
STA
NT
S O
F 5-
{4'-[
(4"-
AR
YL
)-3"
-CYA
NO
-2"-
HY
DR
OX
YPY
RID
INE-
6"-Y
l] PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NE.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C33
H22
N4O
2
C33
H22
N4O
3
C33
H22
N4O
3
C33
H22
N4O
3
C34
H24
N4O
4
C34
H24
N4O
3
C34
H24
N4O
3
C33
H21
N5O
4
C33
H21
N5O
4
C33
H21
N4O
2Cl
C35
H27
N5O
2
C31
H20
N4O
3
C37
H24
N4O
2
C41
H26
N4O
2
M.P
. O
C 4 152
200
125
125
125
130
85 145
170
130
160
120
120
125
Yiel
d% 5
62.4
849
.69
29.7
274
.82
82.4
270
.72
80.8
279
.66
66.7
085
.60
86.6
084
.40
69.7
271
.01
% o
f Nitr
ogen Fo
und
711
.02
10.7
010
.69
10.7
010
.11
10.1
010
.08
12.6
512
.59
10.3
012
.70
11.2
810
.02
9.22
Cal
cd.
611
.06
10.7
210
.72
10.7
210
.14
10.4
410
.44
12.7
012
.70
10.3
712
.75
11.2
910
.07
9.24
169
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
TABL
E N
O :
24A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(4"'
-AR
YL
)-3"-
CYA
NO
-2"-
HY
DR
OX
YPY
RID
INE-
6"-Y
L] P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
E.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 20 18 15 12 19 17 14 11 21 16 13 10 22 11
S. a
ureu
s4 11 12 16 18 19 21 25 22 16 11 14 17 19 20
S. ta
phim
ariu
m5 21 16 11 13 10 11 15 16 21 16 13 20 16 11
A.n
iger
7 12 16 14 12 14 16 18 22 13 12 16 18 24 20
E.c
oil
6 10 12 11 17 18 15 14 22 11 23 10 16 17 18
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
170
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - VI
STUDIES ONCYANO PYRANS
171
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON CYANO PARANS.
INTRODUCTIONPyran derivatives are associated with wide range of applications in
various fields like pharmaceutical, dyes, insecticides and sweet smelling
substances. Pyran ring system also occurs in nature abundantly such as in
large number of natural coloured compounds, in vitamine E, in cloves, in
fich poisons, in certain alkaloids and other substances.
Pyran are six member doubly unsaturated compounds containing one
oxygen atom in the ring. The double bonds may be conjugated known as α-
or 1,2-pyran or it may be isolated known as γ -or 1,4-pyran.
SYNTHETIC ASPECTVarious methods for the preparation of pyran derivatives have been
cited in the literature264-273
1. Reaction between α, β− unsaturated carbonyl system with malononitrile
led to correspnding 2-amino-3-cyano-4H-pyran274
2. A. Z. Elssar et al1275 prepared 3-cyano-pyran derivatives by the reac
tion of α-cyano chalcone derivatives with C2H5COCH2COOCH3 in ba
sic medium.
172
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
3. Abdel-Ghany H. et al.276 have been synthesized cyano derivatives by the
reaction of 2-coumariylidene malononitrile with active methylene
containing compounds.
4. β-Siloxy acrylonitrile were reacted with chalcones to furnish the
respective cyano-4H-pyran derivatives277
5. M. G. Assay et al.278 have synthesized some cyanopyran derivatives by
the reaction of cyclohexenone with cinnamon nitriles.
6. R. De Lera Angel and co-workers279 synthesized pyran derivatives by
thermal electrolytic ring closure of divinylallenals.
7. In recent, A. M. Hussein and et al.280 prepared some novel derivatives
of cyanopyran.
173
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
REACTION MECHANISMThe reaction mechanism for the formation of pyran derivatives proceeds
through Micheal addition of active methylene group of malononitrile to the
β-carbon atom of chalcone described as under.
THERAPEUTIC IMPORTANCEPolysubstituted pyran derivatives arc biologically interesting class of
compouds 281-282 They are associated with various pharmaceutical properties
like
1. Anticancer283
2. Antiinvasive284
3. Anti-HIV285,286
4. Antiallergic287,
5. Antifungal 288,289
6. Cytotoxic290
174
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
7. Antitumor291
8. Antiviral292
9. Antipyratic293
10. Analgesic294
M. A. AI-Haiza and co-workers295 prepared some cyanopyran
derivatives (I) and tested their antibacterial and antifungal activities. A. V. Samet296 et al. aynthesized 2-amino-5-azolyl-3-cyano-4H-pyrans (II) and evaluated
for biological activity. A. Z. Elassar et al 297 reported that cyanopyran
exhibited in vitro antifungal and antibacterial activities.
Moreover, R. M. Shaker.298 have prepared some coumarin ring
containing 2-amino-3-cyanopyran (III) derivatives and studied their
antimicrobial activity. Y. D. Kulkarni and co-workers299 synthesized some pyran
derivatives as CNS active agents. A. A. Hassainien et al300 prepared 2-
amino-3-cyano-7,7-dimethyl-4-substitutedphenyl-5-oxo-4,5,6,8-tetrahydro-
pyran and tested for their biological activities.
175
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Further more, A. Krauze, et al301 synthesized 5-(4-pyridyl) derivatives of 2-
amino-4H-pyran (IV) for antimicrobial activity S. Fowzia Al-Saleh302 and
coworkers synthesized some new cyanopyran derivatives and reported them
as antimicrobial agents. Some pyran derivatives have been pantented for their
use as gastric acid secretion inhibitors303 inhibitors of cell proliferation304
antihypertensive305 antitumor306 antagonists307-308 and antiviral agents309
H.S. Joshi et al310 and co-workers recently have synthesized some new
cyano pyran (V) derivatives as anticancer and antimicrobial agents.
Thus with an effort to capitalize the biological potential of the
heterocyclic system and to synthesize interesting compounds having better
biological potential, the titled compounds have been investigated which have
been described as under.
SECTION : I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(2"-AMINO)-(4"-ARYL)-4"(H)-PYRAN-3-CARBONITRILE-6"-YL]- PHENYL CARBAMIDO}-DIBIENZ [b,f,] -AZEPINES.
176
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(2"-AMINO)-(4"-ARYL)-4"-(H)-PYRAN-3-CARBONITRILE-6"-YL]PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Cyanopyran derivatives have been reported to have various
pharmalogical activities like antibacterial, antisecreatery, antiviral, antifungal
etc. In order to develope better medicinally important compounds. It was
considered of interest to synthesised some cyanopyran derivatives shown as
under. cyanopyran derivatives of 5-{4'-[(2"-amino)-(4"aryl)-4"(H) pyran 3-
carbonotrile 6"-yl] phenyl carbamido}-dibenz [b,f] azepines of type (XIII)
have been synthesised by the reaction of the chalcones of 5-{4'-[(3"-aryl)-2"-
Propene -1"-one]-phenyl carbamido}-dibenz [b,f] azepines with malononitril
in pyridine.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section I, Page No : 32-34
Type (XIII) R=Aryl
177
O
N
NHR
O
NH2
N
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303550-33501650-15501750-16501270-12002250-2150
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[(2"-AMINO)-4"-(4"'-METHOXYPHENYL)-4"-(H)-PYRAN-3-CARBONITRILE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450
"
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2991295114383020
1531,14871178800134036221531179312222230
Type
Alkane
Aromatic
Amide
KetoneEtherNitrile
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=O str.C-O-CC/////N
50010001500200030004000
0
25
50
75
100
%T
3622
.44
2991
.69
2951
.19 17
93.8
671
2.85
1531
.53
1487
.17
1438
.94
1340
.57
1303
.92
1222
.91
1178
.55
1111
.03
1057
.03
875.
7180
0.49
439
.78
3020
.15-
2230
.10-
178
O
N
NH
O
NH2
N
O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF 5-{4'-[(2"-AMINO)-4"-(4"'METHOXYPHENYL)-4"-(H)-PYRAN-3-CARBONITRILE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
179
SignalNo
123456
Signal Position(δ δ δ δ δ ppm)
3.626.74.85
6.9-7.86.66.91
Relative No.of protons Multiplicity Inference
3 H1 H2 H16 H2 H3 H
SingletSingletSinglet
MultipletDoubletSinglet
Ar-OCH3a
-NHb
-NH2c
Ar-Hd
Ar-He
Ar-Hf
a
b
d d dd
d
d
d
d dd
ddd
ef
ed
c
dd
O
N
NH
O
NH2
N
O
CH3
f
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
O
N
NH
O
NH
2
N
OCH
3
m/z
=538
O
N
NH
O
NH
2m
/z=4
83
m/z
=514
O
N
NH
O
NH
2
N
OCH
3
O
N
NH
O
NH
2
N
m/z
=508
O
N
NH
m/z
=311
O
N
m/z
=220
O
N
m/z
=196
O
NH
NH
O
NH
2
N
OCH
3
m/z
=438
CH
2+ m/z
=105
180
MA
SS F
RE
GM
EN
T S
TU
DY
OF
5-{4
'-[(
2"-A
MIN
O)-
4"-(
4"'M
ET
HO
XY
PH
EN
YL
)-4"
-(H
)-PY
RA
N-3
-C
AR
BON
ITR
ILE-
6"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
m/z
=108
OCH
3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
MA
SS F
RE
GM
EN
T S
TU
DY
OF
5-{4
'-[(
2"-A
MIN
O)-
4"-(
4"'M
ET
HO
XY
PH
EN
YL
)-4"
-(H
)-PY
RA
N-3
-C
AR
BON
ITR
ILE-
6"-Y
L]-P
HEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
O
NH
2
N
OCH
3
m/z
=538
181
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 182
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
S. ta
phim
ariu
mR
4-O
CH
3-C6H
4-(21
)2-
NO
2-C6H
4-(20
)4,
N,N
,(CH
3)-C
6H4-(
21)
30 29 27 -
Ampic
ilin
5
0 μg
Chlo
rom
phen
icol
"N
orflo
xaci
n
"
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
Com
para
bale
activ
ity w
ith kn
own s
tand
ard d
rugs
S. a
ureu
sR
C6H
5-(20
)2-
C1-
C6H
4-(20
)C 4H
3O (F
urfu
ral)-
(21)
29 32 31 -
B. m
egat
eriu
mR
2-O
H-C
6H4-(
21)
2-O
CH
3-C6H
4-(22
)C 4H
3O (F
urfu
ral)-
(23)
30 30 35 -
A.n
iger
R
3-O
CH
3,-4-
OH
-C6H
3-(21
)4-
N,N
-(C
H3)-
C6H
4-(20
)
- - - 27
E.c
oil
R
2-O
H-C
6H4-(
23)
C 4H3O
(Fur
fura
l)-(2
4)
32 28 30 -
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 183
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineRefulx
R-CHO40% NaOH, 24 hrs Stirring
CH2(CN)2
in Pyridine
Type (XIII) R=Aryl
O
N
NHR
O
NH2
N
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-(2"-AMINO)-4"-(ARYL)-4"-(H)-PYRAN-3-CARBONITRILE-6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f]-azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I Page No. 31
(C) Synthesis of 5-{4'-[(2"- Amino)-4"-(4"'-methoxy phenyl)-4"-(H)-pyran-3-carbonitrile-6"-yl] phenyl carbamido}-dibenz [b,f]azepines.
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and malononitrile
(0.66g,0.01M) in pyridine was refluxed for 12 hrs. at120oC in methanol (10
ml) the reaction mixture was poured into crushed ice, filtered and washed
then crystalized from ethanol yield :80.82 % M.P. 108OC (Found:C:75.73; H:
4.63; N:10.35; C34H26N4O3 Required: C:75.83; H:4.83; N: 10.40 %)
Simillary other pyran derivatives were prepared and their physical data
are recorded in Table No. : 25
(D) Antimicrobial activity of 5-{4'-[(2"-amino)-(4"-aryl)-4"-(H)-pyran3-carbonitrile 6"-yl]-phenyl carbamido}-dibenz [b,f] azepines.The Antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 26
184
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 185
TABL
E N
O :
25
PHY
SIC
AL
CO
NST
AN
T O
F 5-
{4'-[
(2"-
AM
INO
)-(4"
-AR
YL
)-4"-
(H)-P
YR
AN
3-
CA
RB
ON
ITR
ILE
-6"-
YL
]-PH
EN
YL
CA
RB
AM
IDO
}-D
IBE
NZ
[b,
f] A
ZE
PIN
ES.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C33
H24
N4O
2
C33
H24
N4O
3
C33
H24
N4O
3
C33
H24
N4O
3
C34
H26
N4O
4
C34
H26
N4O
3
C34
H26
N4O
3
C33
H23
N5O
4
C33
H23
N5O
4
C33
H23
N4O
2Cl
C35
H29
N5O
2
C31
H22
N4O
3
C37
H26
N4O
2
C41
H28
N4O
2
M.P
. O
C 4 140
120
120
125
135
115
108
115
138
105
98 105
130
108
Yiel
d% 5
72.6
971
.68
68.7
164
.68
84.0
972
.71
80.8
279
.82
71.7
168
.72
79.1
859
.90
86.0
159
.69
% o
f Nitr
ogen Fo
und
711
.01
10.5
510
.65
10.5
910
.09
10.0
710
.35
12.6
012
.59
10.2
212
.59
11.1
110
.01
9.09
Cal
cd.
611
.02
10.6
810
.68
10.6
810
.10
10.4
010
.40
12.6
512
.65
10.3
212
.70
11.2
410
.03
9.21
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 186
TABL
E N
O :
26
AN
TIM
ICR
OBI
AL
AC
TIV
ITY
OF
5-{4
'-[(2
"-A
MIN
O)-(
4"-A
RY
L)-4
"-(H
)-PY
RA
N 3
-C
AR
BO
NIT
RIL
E-6
"-Y
L]-
PHE
NY
L C
AR
BA
MID
O}-
DIB
EN
Z [
b,f]
AZ
EPI
NE
S.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 19 21 18 16 17 22 13 11 10 11 16 23 20 19
S. a
ureu
s4 20 18 13 15 16 17 15 17 19 20 19 21 12 12
S. ta
phim
ariu
m5 11 16 13 12 11 13 21 20 12 13 21 19 16 12
A.n
iger
7 19 16 13 12 21 10 12 16 17 16 20 11 13 16
E.c
oil
6 16 23 17 18 19 16 13 12 14 16 18 24 12 11
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - VII
STUDIES ONQUINOXALINES
187
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON QUINOXALINES.
INTRODUCTIONThe quinoxaline or benzopyrazine (I) are the product formed by
spontaneous condensation of o-phenylene diamines with 1,2-dicarbonyl
compounds.
This reaction was discovered by Korner311 and by Hinsberg312 independ-
ently. Since qnuinoxalino are also obtained when α−β−dihalo ketones
condensed with o-phenyline diamine. The structure of these cyclic base are
obvious from the mode of formatiora and analytical data. The ring structure
was further confirmed by Gabriel and Sonn, who demonstrated experimen-
tally the relationship between the quinoxaline and the pyrazines by
oxidizing quinoxaline to pyrazine-2,3-dicarboxylic acid.
SYNTHETIC ASPECTDifferent methods are available in literature313-316 for the preparation of
quinoxalines. The popular methods are :
(1) M. L. Keshtov and co-worker317 have been prepared dimer type
quinoxaline derivatives (II)
188
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
(2) Quinoxaline derivative318(III) are prepared by reaction of Nitrobenzene
with NH2OR in presence of Cu catalysts and reaction of nitroanilines
and presence of hydrogenation catalyst.
(3) S. K. Kanungo et al.319 have prepared 1,3-Dimethylpyrrolo quinoxaline-
2-ones from chloroacetic acid and o-pheniline diamine.
BIOLOGICAL IMPORTANCEQuinoxaline derivatives have been found to possess wide range of
therapeutic activities.
1. Inhibition of Candida albicans320
2. CNS depressant321-322
3. Antitubercular323
4. Antiulcer324-325
5. Analgesic326
6. Anxiolytic327
189
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
7. Antihypertensive328
8. Antitumor329
9. Cardiovascular330
10. Herbicidal331
11. Antifungal332
1-(Aminoalkyl)-3-quinoxaline-2-one derivatives were prepared as
neuroprotective agents by K. Ehrenberger and F. Dominik333 . A new series of
sulfonamido quinoxaline were synthesised and assessed for various
biological activity334, antibiotics action of some novel quinoxaline derivative
were studied by T. V. Alfreson335 and co-workers.
V.-Gabriella and co-workers336 have formulated some new quinoxaline.
derivative (IV) as in vitro anticancer activity.
Recently, serveral co-workers have been prepared quinoxaline
derivatives by different methods which possess AMPA receptor antaqonist
and antihistaminic337-339,antagonist340-341, human dopamine D4 receptor342,
antibacteriala343, antimicrobial344-346, anticancer347,and antitumor348, activities.
More recently, B. Konig et al.349 have synthesised quinoxaline derivatives
which has activation of PPARa and PPAR gamma reduces triacyglycerol G.
Sarodrick, T. G. Linker et al.350 have prepared quinoxaline. derivatives having
190
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
bactericidal, algecide, fungicide activity for agriculture use. Quinoxaline
derivative used PDGE receptor and LCK tyrosine kinase inhibitors
In order to achieve better therapeutic agent, the preparation of quinoxaline
derivatives has been taken as under.
SECTION : I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 2"-ARYL-[(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f] AZEPINES QUINOXALINES.
191
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 2"-ARYL[(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f,] AZEPINESQUINOXALINES.
Quinoxalines have been found to possess wide range of therapeutic
activity and industrial importance these significant biological properties
have aroused considerable interest to design compounds in which dibenz
[b,f] azepines nucleus is incorporated with a view to getting compounds with
better drug potential. The quinoxalines of 2"-aryl [(3"-methyl phenyl
carbamido]-5-dibenz [b,f] azepines quinoxalines of type (XIV) have been
synthesised by condensation of chalcones of 5-{4'-[(3"-(4"-methyl phenyl))-
2",3"-dibromo-1"-one]-phenyl carbamido}-dibenz [b,f] azepines, with
o-phenylline diamine.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, Mass spectral study. The products were screened for
antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section I. Page No. 32-34
Type (XIV) R=Aryl
O
N
NHN
NR
192
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303550-33501650-15501750-16501270-10301600-1400
Frequency in cm.-1
IR SPECTRAL STUDY OF 2"-[(4"'-METHOXY PHENYL)-(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f] AZEPINEQUINOXALINES.
Ref.445-458
"""
446,447""
449446,447
"447450
"
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1
Observed2915288114423001
1442, 151212658201325362015121713
1057,11841512
Type
Alkane
Aromatic
Amide
KetoneEtherNitrile
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p. defC-N str. bendingN-H Str.N-H bending>C=O strC-O-CC=N
50010001500200030004000
50
60
70
80
90
100
%T
3001
.34
295
1.19
288
1.75 28
39.3
126
34.8
52
517.
19 24
55.4
6
.13 15
12.2
4 1442
.80
1359
.86
1325
.14
1265
.35 11
84.3
3
1057
.03
0
O
N
NHN
N
OCH3
3620
.10-
890.
20-
193
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
NMR SPECTRAL STUDY OF 2"-[(4"'-METHOXY PHENYL)-(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f] AZEPINEQUINOXALINES.
194
SignalNo
12345
Signal Position(δ δ δ δ δ ppm)
3.606.923.06
7.0-7.76.93
Relative No.of protons Multiplicity Inference
3 H1 H2 H20 H2 H
SingletSingletSinglet
MultipletDoublet
Ar-OCH3a
-NHb
-CH2c
Ar-Hd
Ar-He
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(300MHz)
a
b
d d ddd
d
d dd
dd
d
e
e
dcd
dO
N
NHN
N
OCH3
dd
d
d
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 195
MA
SS F
RE
GM
EN
T S
TUD
Y O
F 2"
-[(4"
'-MET
HO
XY
PH
ENY
L)-(3
"-
MET
HY
L PH
ENY
L C
AR
BAM
IDO
)]-5-
DIB
ENZ
[b,f]
AZE
PIN
E Q
UIN
OX
ALI
NES
.
m/z
=560
O
N
NH
N N
OC
H3
m/z
=536 O
N
NH
N N
O-
m/z
=545
m/z
=454
O
N
NH
N N
O
N
NH
NH
NH
m/z
=536
m/z
=354
O
N
NH
NH
-O
N
NH
NH
-m
/z=2
27m
/z=5
06
O
N
NH
N N
CH
2+
m/z
=105
m/z
=460
O
NH
NH
N N
OC
H3
O
N
NH
N N
OC
H3
OCH
3
m/z
=108
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 196
MA
SS
SPE
CT
RA
L
STU
DY
OF
2"-[(
4"'-M
ETH
OX
Y P
HEN
YL)
-(3"-
M
ETH
YL
PHEN
YL
CA
RBA
MID
O)]-
5-D
IBEN
Z [b
,f] A
ZEPI
NE
QU
INO
XA
LIN
ES.
O
N
NH
N N
OC
H3
m/z
=560
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 197
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
3-O
H-C
6H4-(
23)
4-O
H-C
6H4-(
21)
C10
H7 (
Nap
thal
)-(24
)
30 30 35 -
A.n
iger
R
2-O
H-C
6H4-(
22)
4-N
,N (
CH
3) 2C6H
4-(23
)C 4H
3O (F
urfu
ral)-
(21)
- - - 27
E.c
oil
R
4-O
H C
6H4-(
22)
2-N
O2-C
6H4-(
23)
C 4H30
(Fur
fura
l)-(2
3)
32 28 30 -
S. ta
phim
ariu
mR
2-O
H-C
6H4-(
24)
3-N
O2-C
6H4-(
22)
C 4H3O
(Fuf
ural
)-(22
)
30 29 27 -
Ampic
ilin
5
0 μg
Chlo
rom
phen
icol
"
Nor
floxa
cin
"G
riseo
fulv
in
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
S. a
ureu
sR
2-N
O2-C
6H4-(
23)
2-C
l-C6H
4-(22
)
29 32 31 -
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
Br
Br R
N
O NHO
Reaction Scheme
Type (XIV) R=Aryl
PyridineRefulx
R-CHO40% NaOH, 24 hrs Stirring
Br2 ingl. CH3 COOH
O
N
NHN
NR
NH2
NH2
198
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS 2"-(4"'-ARYL) [(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f] AZEPINE QUINOXALINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f] azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I, Page No : 31
(C) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2",3"-dibromo-1"-One]-phenyl carbamido}-dibenz [b,f] azepines.
A chalcone type (I) (0.01M) was dissolved in acetic and (30 ml) a
bromine in acetic acid (1 ml) 10 % was slowely added to it. the reaction
mixture was stirred for 2 hrs. It was poured into water and crystallised from
ethyl alcohol blackish yellow needles.
(D) Synthesis of 2"-(4"'-Methoxy phenyl) [(3"-methyl phenylcarbamido)]-5-dibenz [b,f] azepine quinoxalines.
A mixture of 5-{4'-[3"-(4"-methoxy phenyl)-2",3"-dibromo-1"-one]-
phenyl carbamido}-dibenz [b,f]-azepine (6.30g, 0.01M) and O-pheneline
diamine (1.08g, 0.01M) and taken in methanol (25 ml). A few drops of con.
H2SO4 was added and then reaction mixture was heated at 70-75oC for 30
min on waterbath. It was then diluted with water and crude mass was ex-
tracted with solvent ether to remove insoluble O-phenelinediamine. Ether was
remove and separate solid was crystalised from ethanol, yiled :75.80 % M.P.
80OC 79.14 (Found:C:79.14; H: 4.99; N:9.95; C37H28N4O2 required: C:79.19;
H:5.96; N:10.00 %)
199
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Simillary other componds were prepared and their physical data are
recorded in Table No. 27
(E) Antimicrobial activity of (2"-aryl)-[(3"-methyl phenyl carbamido)-5-dibenz [b,f] azepine quinoxalines..
The antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 28
200
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 201
TAB
LE
NO
: 27
PHY
SIC
AL
CO
NST
AN
T O
F 2"
-AR
YL
-[(3"
-ME
TH
YL
PHE
NY
L C
AR
BA
MID
O)-5
-D
IBEN
Z [b
,f] A
ZEPI
NE]
-QU
INO
XA
LIN
ES.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C36
H26
N4O
C36
H26
N4O
2
C36
H26
N4O
2
C36
H26
N4O
2
C37
H28
N4O
3
C37
H28
N4O
2
C37
H28
N4O
2
C36
H25
N5O
3
C36
H25
N5O
3
C36
H25
N4O
Cl
C38
H31
N5O
C34
H24
N4O
2
C40
H28
N4O
C44
H30
N4O
M.P
. O
C 4 105
70 118
82 90 120
80 105
90 92 150
10 75 90
Yiel
d% 5
70.7
169
.80
82.1
060
.82
49.4
871
.80
75.8
072
.01
66.1
268
.18
59.6
860
.61
73.8
279
.01
% o
f Nitr
ogen Fo
und
710
.49
10.2
910
.20
10.2
29.
709.
959.
9512
.16
12.1
39.
6111
.90
11.4
49.
818.
70
Cal
cd.
610
.56
10.2
510
.25
10.2
59.
7210
.00
10.0
012
.17
12.1
79.
6811
.92
11.4
89.
898.
89
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 202
TABL
E N
O :
28 A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y 2
"-(4
"'-M
ETH
OX
Y P
HEN
YL)
-[(3"
-MET
HY
LPH
ENY
L C
AR
BAM
IDO
) 5-
DIB
ENZ
[b,f]
AZE
PIN
E]-
QU
INO
XA
LIN
ES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 20 19 23 21 14 16 12 10 14 16 18 19 24 11
S. a
ureu
s4 14 16 18 12 10 17 13 23 16 22 10 11 13 12
S. ta
phim
ariu
m5 14 24 16 18 19 17 15 17 22 20 16 22 16 17
A.n
iger
7 16 22 21 18 16 14 12 10 13 15 23 21 17 20
E.c
oil
6 14 16 18 22 16 19 20 23 16 17 19 23 10 17
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 203
PART - VIII
STUDIES ONCYCLOHEXENONES
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON CYSTUDIES ON CYSTUDIES ON CYSTUDIES ON CYSTUDIES ON CYCLCLCLCLCLOHEXENONESOHEXENONESOHEXENONESOHEXENONESOHEXENONES
INTRODUCTIONCyclohexenones are derivatives of cyclohexane with carbonyl grooup
at position -1 and double bond at position -2 (I). There are different types of
cyclohexenone derivatives but the greatest difference in structure and
properties is exerted by the groups attached to carbon atom.
SYNTHETIC ASPECTDifferent methods for the preparation of cyclohexenone derivatives have
been described in literature351-364
(I) A review of the earlier literature by D.Gerald et al.365 described
representative synthetic procedure of cyclohexenone derivative (I).
(II) Page Philip C. and co-workers366 have been prepared substituted
cyclohexenone derivatives (II)
204
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
(III)H.A. Eman et al.367 have been prepared cyclohexenone derivatives
(III) from chalcone.
(IV) Shklyaev et al368 have been synthesized 1-substituted (R,S) -8- methox5-
methylphenyl)-3,3,9-trimethyl-2-azaspiro [4,5] deca-1,7- d i e n - 6 - o n e s
(IV).
205
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
THERAPEUTIC IMPORTANCECyclohexenone have various medicinal applications such as anthelmintic,
hypoglycemic, nematocidal, antibacterial, antifungal, antiviral, analgesic etc.
Antiarhythmic activity369 of some cyclohexenone derivatives have been
investigated. Cyclohexenone possess cardiovascular, osteoporosis, menpausal
symptoms, estrogen dependent, cancer activities, which was reported by
P.Jacobsen et al.370,N.D. Eddington et al 371 synthesize ethyl 4-[(substituted
phenyl) amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylates (I) and screened
their anticonvulsant activity. C. Edward et al.372 also prepared 2,3-dihydro-5-
(3-oxc-2-cyclohexen-1-yl)-2-benzofurancarboxylic acids (II) and their salts
which are used in the treatment of brain injury.
Cyclohexenone and its derivatives have been prepared and reported as
broad. spectrum of physiological properties viz., antibiotics373-374 bactericidal375
herbicidal376 antimicrobial377, anticonvulsant378 etc. L.M.Alekseeva and
co-workers379 have synthesized cyclohexenone derivatives which are as useful
as neurotropic activity. S.Toshiyuki et al.380 have prepared some novel
cyclohexenone and screened for allergy inhibitor, antithrombotic platelet
aggregation inhibitors and fibrinogen antagonist activity.
206
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Recently, antimicrobial activity have been studied by M.A.Salama and
Atshikh381 Cyclohexenone possess neutropeptide γ-receptor antagonist
activity which was reported by F. Takehiro and co-workers382, B. B. Howard383
have demonstrated cyclohexenone as GABA α5 receptor ligands for enhanc-
ing coagulating properties. Cyclohexenone possess inhibitory activity against
the growth of lettuce seeding found by Y. Kimura and co- workers384
The presence of pesticidal activity among cyclohexenone derivatives is
well documented. The compound 2-{(E,Z)-1-[(2R,S)-2-(4-chlorophenoxy)
propoxy imino] butyl}-3-hydroxy-5-thian-3-yl) cyclohex-2-en)-one (III) has
been marketed under the name of 'Profoxydim' as an herbicides.
These valid observation led us to synthesize new cyclohexenone
derivatives bearing cinnoline nucleus in search of agent having better
therapeutic potential which have been described as under.
SECTION - I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF ETHYL -[(6"-ARYL) 4"-PHENYL CARBAMIDO]-5-DIBENZ [b,f] AZEPINES -2"-OXO CYCLOHEX-3"-ENE-1"-CARBOXALATE
207
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF ETHYL -[(6"-ARYL) 4"-PHENYL CARBAMIDO]-5-DIBENZ [b,f] AZEPINES -2"-OXO CYCLOHEX-3"-ENE-1"-CARBOXALATE
Cylohexenone derivatives have considerable attention in view of their
potential pharmacological properties such as antimicrobial, anticonvulsant,
anticancer etc. Led by these consideration the preparation of cyclohexenone
derivaties of Type (XV) has been undertaken. The synthesis was carried out
by the condensation of 5-{4'-[(3"-Aryl)-2"-propene-1"-one]-phenyl
carbamido}-dibenz [b,f] azepines, with ethyl acetoacetate .
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, and Mass spectral study. The products were screened
for antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section I ,Page No. : 32-34
Type (XV) R=Aryl
O
N
NH
O
R
O
OCH3
208
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
50010001500200030004000
20
40
60
80
100
% T
3593
.50
3549
.14
3473
.91
3379
.40
3296
.46
3024
.48
2951
.19
261
1.7
0
192
8.8
8
1815
.08
171
2.85
1521
.89
1491
.02
1440
.87
1303
.92
1274
.99
1222
.91
1176
.62
1116
.82
1053
.17
977.
9494
7.08
881.
50
777.
34
422.
42
Reported2975-29502890-28501470-14353080-30301600-14501300-1100832-750
1380-13303500-33501650-15501735-17001100-1300
Frequency in cm.-1
IR SPECTRAL STUDY OF ETHYL- [6"-(4'"-METHOXY PHENYL)-4"-PHENYL CARBAMIDO]-5-DIBENZ [b,f] AZEPINES-2"-OXOCYCLOHEX-3"-ENE-1"-CARBOXALATE
Ref.445-458
"""
446,447""
449446,447
"447450
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2951287014403024
1491,1521127477713033549152117121222
Type
Alkane
Aromatic
Amide
KetoneEther
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=O strC-O-C
O
N
NH
O O
OCH3
O
CH3
2870
.50-
209
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF ETHYL-[6"-(4'"-METHOXYPHENYL) -4"-PHENYL CARBAMIDO]-5-DIBENZ [b,f] AZEPINES-2"-OXO CYCLOHEX-3"-ENE-1"-CARBOXALATE
210
SignalNo
123456789
Signal Position(δ δ δ δ δ ppm)
3.646.51.2
7.0-7.76.93.87.085.96.9
Relative No.of protons Multiplicity Inference
3 H1 H3 H16 H2 H2 H2 H1 H1 H
SingletSingletTriplateMultipletDoublet
QuaterateSingletDoublet
Quaterate
Ar-OCH3a
-NHb
-CH3c
Ar-Hd
Ar-He
-OCH2f
Ar-Hg
Ar-Hh
Ar-Hi
a
b
d d ddd
d
d d d
d
d
e
e
d
c
d
d
d
O
N
NH
O O
OCH3
O
CH3
f
h
ig
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 211
MA
SS F
REG
MEN
T S
TUD
Y O
F ET
HY
L-[6
"-(4
'"-M
ETH
OX
Y P
HEN
YL)
-4"-
PHEN
YL
CA
RBA
MID
O]-5
-DIB
ENZ
[b,f]
AZE
PIN
ES-2
"-O
XO
CY
CLO
HEX
-3"-
ENE-
1"-C
AR
BOX
ALA
TE.
O
N
NH
OO
OC
H 3OCH3
m/z
=584
m/z
=560
O
N
NH
OO
OC
H3
OCH
3
O
NH
NH
OO
OC
H3
OCH
3
m/z
=484
O
N
NH
CH
2+
OO
OC
H3
m/z
=429
O
Nm
/z=2
20O
N
NH
O
OC
H3
m/z
=440
O
N
NH
OCH
3
m/z
=460
m/z
=105
CH
2+
O
N
NH
OO
OC
H3
m/z
=530
OCH
3
m/z
=108
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 212
MA
SS F
REG
MEN
T ST
UD
Y O
F ET
HY
L-[6
"-(4
'"-M
ETH
OX
Y P
HEN
YL)
-4"-
PHEN
YL
CA
RBA
MID
O]-5
-DIB
ENZ
[b,f]
AZE
PIN
ES-2
"-O
XO
CY
CLO
HEX
-3"-
ENE-
1"-C
AR
BOX
ALA
TE.
O
N
NH
OO
OC
H 3OCH3
m/z
=584
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
2-O
H-C
6H4-(
22)
4-O
CH
3-C6H
4-(24
)C
4H3O
(Fur
fura
l)-(2
0)
30 30 35 -
A.n
iger
R
4-O
H-C
6H4-(
21)
4-O
CH
3-C6H
4-(20
)
- - - 27
E.c
oil
R
C6H
5-(24
)3-
OH
-C6H
4-(22
)2-
NO
2-C6H
4-(23
)
32 28 30 -
S. ta
phim
ariu
mR
C6H
5-(22
)2-
OC
H3-C
6H4-(
24)
3-N
O2-C
6H4-(
21)
2-C
l-C6H
4-(20
)
30 29 27 -
Ampic
ilin
50
μg
Chlo
rom
phen
icol
"N
orflo
xaci
n
"
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
S. a
ureu
sR
3-O
H-C
6H4(2
3)2-
NO
2-C6H
4-(25
)
C14
H9 (
Ant
hral
)-(21
)
29 32 31 -
213
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CHO40% NaOH, 24 hrs Stirring
Type (XV) R=Aryl
O
N
NH
O
R
O
OCH3
(1) E. A.A.(2) C2H5ONa
214
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF ETHYL -[(6"ARYL)-4''-PHENYL CARBAMIDO]-5-DIBENZ [b,f] AZEPINES-2"-OXOCYCLOHEX-3"-ENE-1"-CARBOXALATE.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f]-azepineFor synthesis see part-I, section : I, Page No: 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I, Page No : 31
(C) Synthesis of ethyl[6"-(4'"-methoxy phenyl)-4"-phenyl carbamido]-5-dibenz [b,f] azepines-2"-oxo-cyclohex-3"-ene-1"-carbaxalate
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and dissolve in 30ml
dioxane and add sodium ethoxide (0.15ml) and ethyl acetoacetate (2.60g,
0.02M) and reaction was refluxed on oil bath for 12 hrs. The reaction mix-
ture was cooled and poured over crushed ice, The product was isolated and
crystalized from toluene yield :79.10 %, M.P. 290OC (Found:C:75.88; H:
5.41; N:4.71; C37H32N2O5 Required: C:75.89; H:5.45; N: 4.79 %)
Simillary other compounds were prepared and their physical data are
recoaded in Table No. 29
(D) Antimicrobial activity of ethyl-[(6"-aryl))-4"-phenyl carbamido]5-dibenz [b,f] azepines-2"-oxo cyclohex-3"-ene-1"-carboxalateThe Antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 30
215
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 216
TABL
E N
O :
29 P
HY
SIC
AL
CO
NST
AN
T O
F ET
HY
L -[(
6"-A
RY
L)-4
"-PH
ENY
L C
AR
BAM
IDO
]-5-
DIB
EN
Z [
b,f]
AZ
EPI
NE
S-2"
-OX
O-C
YC
LO
HE
X-3
"-E
NE
-1"-
CA
RB
OX
AL
ATE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C36
H30
N2O
4
C36
H30
N2O
5
C36
H30
N2O
5
C36
H30
N2O
5
C37
H32
N2O
6
C37
H32
N2O
5
C37
H32
N2O
5
C36
H29
N3O
6
C36
H29
N3O
6
C36
H29
N2O
4Cl
C38
H35
N3O
4
C34
H28
N2O
5
C40
H32
N2O
4
C44
H34
N2O
4
M.P
. O
C 4 95 122
105
130
78 100
290
122
130
90 150
65 145
95
Yiel
d% 5
68.7
349
.98
83.4
268
.69
73.4
249
.68
79.1
061
.42
72.4
159
.71
83.9
069
.68
67.6
667
.72
% o
f Nitr
ogen Fo
und
75.
0.1
4.49
4.60
4.65
4.64
4.71
4.71
6.98
6.98
4.70
6.95
5.12
4.60
4.14
Cal
cd.
6 5.05
4.91
4.91
4.91
4.66
4.79
4.79
7.01
7.01
4.82
7.03
5.14
4.63
4.28
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 217
TABL
E N
O :
30 A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F ET
HY
L -[(
6"-A
RY
L)-4
"-PH
ENY
L C
AR
BAM
IDO
]-5-
DIB
EN
Z [
b,f]
AZ
EPI
NE
S-2"
-OX
O-C
YC
LO
HE
X-3
"-E
NE
-1"-
CA
RB
OX
AL
ATE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 16 22 17 15 10 13 24 14 15 17 18 20 11 17
S. a
ureu
s4 15 12 23 17 20 19 10 25 11 13 16 19 18 21
S. ta
phim
ariu
m5 22 18 10 12 14 24 16 18 21 20 19 16 13 14
A.n
iger
7 14 10 11 21 18 19 20 16 17 12 14 16 17 18
E.c
oil
6 24 16 22 17 19 15 18 23 11 10 13 17 19 15
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 218
PART - IX
STUDIES ON BARBITONES
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 219
STUDIES ON BARBITONES.STUDIES ON BARBITONES.STUDIES ON BARBITONES.STUDIES ON BARBITONES.STUDIES ON BARBITONES.
INTRODUCTIONThe emerging role of barbitones in pharmaceutical chemistry as well as in
biochemistry stimulated tremendous interest in the synthesis of barbitones of
therapeutic interest. Most important is the effect of barbiturates on the central
nervous system. Barbituric acid derivatives constitute an important class of
compounds possessing diverse type of biological properties including
hypnotic, sedative, anticonvulsant, cardiovascular etc.
Derivatives of barbituric acid are perhaps the most widely used pyrimidines
in medicine. Veronal (I) and Luminol (II) possess hypnotic activities, while
pentothiol (III) is used as an anaesthetic.
SYNTHETIC ASPECTDifferent methods for the synthesis of barbitones have been described in
literature385-389
1. M. R. Mahmoud et al.390 have synthesized barbituric acid derivatives from
chalcones.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
2. Cao-Yun et al391 have prepared barbituric acid derivatives by the reaction
of different aldehydes with barbituric acid in basic media.
3. R. K. Roy et al392 have synthesised barbituric acid derivatives by the
reaction of urea derivatives with malonic acid.
THERAPEUTIC EVALUATIONAt present great interest is being taken in barbituric acid derivative be-
cause of its biological activity and their relation with nucleic acids, viz uracil,
thymine and cytosine.
Some barbiturates showing cardiovascular393-394 antiinflammatory395 and
pesticida396 activities have been reported. D. Peters et al397 have synthesised
seme uracil derivatives and screened for antiviral activity. R. Raymond et al398
synthesised some barbiturates (IV) which showed anticancer activity.
220
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Several co-workers have synthesised barbitone derivatives and reported
their antagonist399 antitumor400 anticonvulsant401 and metalloproteinas
inhibitor402ctivities. Abdel-Hamide and co-workers403 have prepared barbituric
acid derivatives (V) having anticonvulsant activity. A. N. Shivanyuk at al404
have demonstrated barbitone derivatives as porphyrin melamine calixarene
receptor. Wolf-Gang et al405have reported 5-(3-benzylthiazoIidine-2-yIidene)-
1,3-dimethyl hexahydro pyrimidine-2,4,6-trione having agricultural activity Some
barbituric acid derivatives used as herbicides and insecticides have beei dem-
onstrated.406
M.T. Omar 407 has synthesised barbitone derivativse showing antimicrobia
activity. Sakai et al408 have synthesised some new barbitones which were
assessed for bone and cartilage disease, F. Grams and G. Zimmermantv409
have prepared barbitones as metalloprotease inhibitors. Some barbitone de-
rivatives have been studied for their antitumor activity410
Moreover, isotylidene barbiturates (VI) showing antibacterial activity have
been synthesised411 D. Geppert and co-workers412 have prepared new pyrimidine-
2,4,6-triones (VII) as metalloproteinase inhibitors.
221
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Keeping in view the important biological activities possessed by
barbituric acid derivatives, we have tried to synthesise some new barbitones
having better biological activities.
SECTION :I SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-BARBITURIC ACID]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
222
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-BARBITURIC ACID]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Barbituric and derivatives are claimed to have a wide spectrum of
biological activities. Dibenz [b,f] azepines moity possess diversified boilgical
properties considering all the above facts it was thought that if barbituric
acid group, the could be introduced to dibenz [b,f] azepines moiety, the
resulting compounds might have some significant biological properties. For
this purpose some new barbituric acid derivatives of 5-{4'-[(3"-Aaryl)-2"-
propene-1"-barbituric acid] - phenyl carbamido}-dibenz [b,f] azepines, of
type (XVI) have been synthesised by the condensation of 5-{4'-[(3"-aryl)-2"-
propene-1"-one]- phenyl carbamido}- dibenz [b,f] azepines with barbituric
acid.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, and Mass spectral study. The products were screened
for antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section I, Page No. 32-34
Type (XVI) R=Aryl
223
O
O
N
NH
NHNH
R
O
O
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100890-750
1380-13303500-33501650-15501735-17001100-13001400-1600
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[3"-(4"'-METHOXY PHENYL)-2"-PROPENE-1"-BARBITURIC ACID]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447450445
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2985287014402933
1485,14021224,1303
831137734731570174911181485
Type
Alkane
Aromatic
Amide
KetoneEtherVinyl
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=O strC-O-C-CH=CH-
50010001500200030004000
40
60
80
100
%T
347
3.91
3402
.54
2985
.91
2933
.83
2870
.17
279
8.80
2623
.28
2202
.78
1786
.14
1749
.49
171
8.63
1485
.24
1440
.87 14
02.3
013
77.2
213
03.9
212
24.8
411
18.
751
062.
81
885.
36 831
.35
1570
.15-
224
O
O
N
NH
NHNH
O
O
O
CH3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRALSTUDY OF 5-{4'-[3"-(4"'-METHOXY PHENYL)-2"-PROPENE-1"-BARBITURIC ACID]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
225
SignalNo
123456
Signal Position(δ δ δ δ δ ppm)
3.646.46.91
7.0-7.46.83.72
Relative No.of protons Multiplicity Inference
3 H1 H2 H16 H2 H2 H
SingletSingletSinglet
MultipletDoublet Singlet
Ar-OCH3a-NHb
-CH=CH-c
Ar-HdAr-He-NHf
a
b
d d ddd
d
d dd
dd
e
e
d
c
d
d
d
f
O
O
N
NH
NHNH
O
O
O
CH3
f
c
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 226
MA
SS F
RE
GM
EN
T S
TUD
Y O
F 5-
{4'-[
3"-(4
"'-M
ETH
OX
Y P
HEN
YL)
-2"-
PRO
PEN
E-1"
-BA
RBI
TUR
IC A
CID
]-PH
ENY
L C
AR
BAM
IDO
}-DIB
ENZ
[b,f]
AZE
PIN
ES. m/z
=582
O
O
N
NH
NH
NH
O
O
OCH
3
O
O
N
NH
NH
NH
O
O
m/z
=552
O
O
N
NH
NH
NH
O
O
m/z
=528
O
O
NH
NH
NH
NH
O
O
OCH
3
m/z
=482
O
N
m/z
=220
O
O
N
NH
NH
NH
CH
2
O
O
m/z
=452
O
O
N
NH
NH
NH
O
O
m/z
=450
m/z
=108
OCH
3CH
2+
m/z
=105
O
N
NH
m/z
=311
O
O
N
NH
NH
NH
O
O
OCH
3
m/z
=558
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 227
MA
SS S
PEC
TR
AL
STU
DY
OF
5-{4
'-[3"
-(4"'
-MET
HO
XY
PH
ENY
L)-2
"-PR
OPE
NE-
1"-B
AR
BITU
RIC
AC
ID]-
PHEN
YL
CA
RBA
MID
O}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
m/z
=582
O
O
N
NH
NH
NH
O
O
OCH
3
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 228
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
4-O
H-C
6H4-(
22)
2-N
O2C
6H4-(
19)
2-C
l-C6H
4-(20
)
30 30 35 -
E.co
ilR
4-O
H-C
6H4-(
21)
4-O
CH
3-C6H
4-(20
)
3-N
O2-C
6H4-(
21)
2-C
l-C6H
4-(22
)
32 28 30 -
S. a
ureu
sR
2-O
H-C
6H4-(
21)
4-O
H-C
6H4-(
20)
3-N
O2-C
6H4-(
21)
2-C
l-C6H
4-(20
)
29 32 31 -
S. ta
phim
ariu
mR
3-O
H-C
6H4-(
23)
4-O
H-C
6H4-(
22)
2-N
O2-C
6H4-(
21)
3-N
O2-C
6H4-(
20)
2-C
l-C6H
4-(22
)
30 29 27 -
Ampic
ilin 5
0 μg
Chlo
rom
phen
icol
"
Nor
floxa
cin
"G
riseo
fulv
in
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
Com
para
ble a
ctiv
ity w
ith k
now
n st
anda
rd d
rugs
A.n
iger
R
3-O
H-C
6H4-(
22)
4-O
H-C
6H4-(
21)
2-N
O2-C
6H4-(
21)
3-N
O2-C
6H4-(
22)
2-C
l-C6H
4-(23
)
- - - 27
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineRrflux
R-CHO40% NaOH, 24 hrs Stirring
Type (XVI) R=Aryl
O
OO
NHNH
in gla. CH3COOH
229
O
O
N
NH
NHNH
R
O
O
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-BARBITURICACID]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f]-azepineFor synthesis see part-I, section : I, Page No. 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I, Page No. 31
(C) Synthesis of 5-{4'-[3"-(4'"-methoxy phenyl)-2"-propene-1"-barbituric acid]-phenyl carbamido}-dibenz [b,f] azepines
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and barbituric acid
(1.28g, 0.01M) was refluxed 12 hrs. in presence of gla. CH3COOH in
methanol. The reaction mixture was poured in crushed ice, filtered washed
and dried, crystallized from ethanol, yield :71.41 %, M.P. 120OC
(Found:C:72.08; H: 4.42; N:9.59; C35H26N4O5 Required: C:72.80; H:4.44; N:
9.62 %)
Simillary other compounds were synthesis and their physical data are
recorded in Table No. : 31
(D) Antimicrobial activity of 5-{4'-[(3"-aryl)-2"-propane 1"-barbituricacid]-phenyl carbamido-dibenz [b,f] azepines
The Antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 32
230
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 231
TABL
E N
O :
31 P
HY
SCIA
L C
ON
STA
NT
OF
5-{4
'-[(3
"-A
RY
L)-
2"PR
OPE
NE
-1"-
BA
RB
ITU
RIC
AC
ID]-P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
ES.
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C34
H24
N4O
4
C34
H24
N4O
5
C34
H24
N4O
5
C34
H24
N4O
5
C35
H26
N4O
6
C35
H26
N4O
5
C35
H26
N4O
5
C34
H23
N5O
6
C34
H23
N5O
6
C34
H23
N4O
4Cl
C36
H29
N5O
4
C32
H22
N4O
5
C38
H26
N4O
4
C42
H28
N4O
4
M.P
. O
C 4 115
110
120
130
160
115
120
142
122
120
180
145
120
202
Yiel
d% 5
72.7
149
.68
76.6
659
.68
71.7
282
.40
71.4
169
.72
65.3
359
.68
81.6
872
.81
79.3
066
.72
% o
f Nitr
ogen Fo
und
710
.10
9.75
9.71
9.70
9.35
9.60
9.59
11.7
111
.71
9.45
11.7
110
.31
9.25
8.54
Cal
cd.
610
.14
9.85
9.85
9.85
9.36
9.62
9.62
11.7
511
.75
9.55
11.7
610
.33
9.30
8.58
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 232
TABL
E N
O :
32A
NTI
MIC
RO
BIA
L A
CTI
VIT
Y O
F 5-
{4'-[
(3"-
AR
YL)
-2"-
PRO
PEN
E-1"
-BA
RBI
TUR
ICA
CID
]-PH
ENY
L C
AR
BAM
IDO
}- D
IBEN
Z [b
,f] A
ZEPI
NES
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 16 14 17 22 11 13 18 19 22 20 18 17 13 15
S. a
ureu
s4 12 21 13 20 18 15 14 13 21 20 11 10 14 16
S. ta
phim
ariu
m5 14 17 23 22 18 17 20 21 20 22 18 17 15 14
A.n
iger
7 19 20 22 21 19 17 16 21 22 23 14 17 19 16
E.c
oil
6 15 12 13 21 18 17 20 11 21 22 19 18 16 15
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
PART - X
STUDIES ONTHIOSEMICARBOXIMIDES
233
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
STUDIES ON THIOSEMICARBOXIMIDES.STUDIES ON THIOSEMICARBOXIMIDES.STUDIES ON THIOSEMICARBOXIMIDES.STUDIES ON THIOSEMICARBOXIMIDES.STUDIES ON THIOSEMICARBOXIMIDES.
INTRODUCTIONThiosemicarbazone derivatives are of special importance because of their
versatile biological and pharmacological activities. Thiosemicarbazone
derivatives have found applications in drug development for the treatment of
central nervous system disorders, of bacterial infections, as well as analgesic
and antiallergic agent. They are potent intermediates for the synthesis of
pharmaceutical and bioactive materials.
The clinically active drug methisazone and related compounds have shown
activity against DNA viruses, principally the Orthopoxviruses, both in vitro
and in vivo.
SYNTHETIC ASPECTNowadays reaction between thiosemicarbazide with ketones or aldehydes
have attracted a great attention, because of their interesting nature of resulting
compounds for their applications and biological activities.
Different methods are used for the synthesis of thiosemicarbazones which
is described in literature413-416
1. A. B. Tomchin417 has synthesised thiosemicarbazones by the recyclisation
of 2-amino-5-{2-aminoaroyl)-l,3,4-thiadiazoles.
234
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
2. Y. Perumal and co-workers418 have prepared thiosemicarbazones by the
condensation of 6-chlorobenzothiazolyI-2-thiosemicarbazide with aldehydes
or ketones.
THERAPEUTIC EVALUATIONThiosemicarbazones exhibit a wide variety of biological activities which
are listed as under.
1. Antibacterial419
2. Anthelmintic420
3. Antifungal421
4. Anticonvulsant422
5. Antirheumatics423
6. Antiherpes424
7. Antimalarial425
8. Antitumor426-427
9. Anticancer428
Antimicrobial activity of thiosemicarbazone derivatives have been
reported429-430,T. Siatra et al.431 have synthesised some new thiosemicarbazones
235
s
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
from 3-acetyl indole and reported its effect on DNA synthesis and cell
proliferation. 5-chloro salicyaldehydic thiosemicarbazone derivatives have been
documented by Z. Quianawin et al.432
N-substituted thiosemicarbazones showing antitumor activity have been
reported433,D. Wang et al.434 patented thiosemicarbazones useful as sodium
channel blockers. KIzabella 435 has prepared thiosemicarbazones (I) from 1,3-
cyclic diamino and reported as anticancer agent. O.V. Fedorova et al.436
synthesised some thiosemicarbazones (II) having potent in vitro tuberculostatic
activity.
Some 3-aminopyrimidine 2-carboxaldehyde thiosemicarbazone
derivatives are reported as novel prodrug forms of ribonucleotide reductase
inhibitors 3-AP and 3-AMP by Li Jun et al.437
Some new thiosemicarbazone derivatives have been studied for their
anticancer activity438 D. Sharma et al. 439 have synthesised thiophene 2-
carboxaldehyde thiosemicarbazones and evaluated their antimicrobial and
antiviral. S.P.R. Rodiriguez and co-workers440 have synthesised 4-substituted
thiosemicarbazones and reported its antiproliferartive activity.
Thiosemicarbazone derivatives as potent antiviral agents nave been investi-
gated.441
236
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Moreover, Jin Shuhui and co-workers442 thiosemicarbazones and
prepared thiosemicarbazones and reported them for antifungal activity.
Thiosemicarbazones (III) showing significant antimicrobial activity are
described.443 Nilgun K.444 have synthesised some thiosemicarbazones (IV)
bearing indol nucleus and evaluated their cytotoxicity.
Due to the physiological and biological activities of thiosemicarbazones,
it was contemplated to synthesise some new thiosemicarbazones with a hope
that these compounds may have better pharmacological activities.
SECTION - I : SYNTHESIS AND ANTIMICROBIAL ACTIVITYOF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-THIOSEMICARBOXIMIDES]-PHENYLCARBAMIDO} -DIBENZ [b,f] AZEPINES.
237
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
SECTION : I
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-THIOSEMICARBOXIMIDES]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
With a view to getting better antimicrobial activity and considering the
association of various biological activites with thiosemicarbazones, we have
synthesised 5-{4'-[(3"-aryl)-2"-propene-1"-thio semicarboximides-phenyl
carbamido}-dibenz [b,f] azepines, of type (XVII) by the reaction of 5-{4'-
[(3"-aryl)-2"-propene-1"-one]- phenyl carbamido}-dibenz [b,f] azepines with
thiosemicarbazide.
The constitution of the products have been characterised by elemental
analysis IR,1H NMR, and Mass spectral study. The products were screened
for antimicrobial activity at a concentration of 50 μg
The details have been cited in the part : I, Section I, Page No. : 32-34
Type (XVII) R=Aryl
O
N
NH
N
R
NH S
NH2
238
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reported2975-29502890-28501470-14353080-30301600-14501300-1100890-750
1380-13303500-33501650-15501750-16511300-11001400-16001200-1050
Frequency in cm.-1
IR SPECTRAL STUDY OF 5-{4'-[3"-(4"'-METHOXY PHENYL)-2"-P R O P E N E - 1 " - T H I O S E M I C A R B O X I M I D E S ] - P H E N Y LCARBAMIDO}-DIBENZ [b,f] AZEPINES.
Ref.445-458
"""
446,447""
449446,447
"447445450
Instrument : SHIMADZU-FT-IR-8400 Spectrophotometer frequency range : 4000-
400 cm-1 (KBr-disc)
Observed2966277714893030
1556,148912908801370
3553, 3585156616491290
1556.61001
Type
Alkane
Aromatic
Amide
KetoneEtherVinyl
Thioamine
Vibrationmode
C-H str. (asym.)C-H str. (sym.)C-H (def.) bendingC-H str.C=C Ring skeletalC-H i.p. defC-H o.o.p.C-N str bendingN-H str.N-H bending>C=OC-O-C-CH=CH str.C=S.
5001000150020003000400060
67.5
75
82.5
90
97.5
%T
3618
.58
3585
.79
3533
.71
3464
.27
3452
.70
3396
.76
335
6.25
3300
.31
2966
.62 27
77.
59
164
9.19
1566
.25
148
9.10
1290
.42
1001
.09
694.
4061
1.4
55
55.5
249
3.79
7
O
N
NH
NNH S
NH2
O
CH3
3030
.25- 13
70.2
0-
880.
14-
239
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Intrenal standard : TMS; solvent :DMSO: Instrument : BRUKER Spectrometer
(300MHz)
NMR SPECTRAL STUDY OF 5-{4'-[3"-(4"'-METHOXY PHENYL)-2"-PROPENE-1"-THIOSEMICARBOXIMIDES]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.
240
SignalNo
1234567
Signal Position(δ δ δ δ δ ppm)
3.596.76.91
7.0-7.76.913.212.32
Relative No.of protons Multiplicity Inference
3 H1 H2 H16 H2 H1 H2 H
SingletSingletSinglet
MultipletDoublet Singlet Singlet
Ar-OCH3a
-NHb
-CH=CH-c
Ar-Hd
Ar-He
-NHf
-NHg
a
b
d d ddd
d
d dd
dd
e
e
d
c
d
d
d
f
cO
N
NH
NNH S
NH2
O
CH3
d
g
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 241
O
N
NH
NN
HSNH
2
OCH
3
m/z
=545
MA
SS F
RE
GM
EN
T S
TU
DY
OF
5-{4
'-[3
"-(4
"'-M
ET
HO
XY
PH
EN
YL
)-2"
-PR
OPE
NE
-1"-
TH
IOSE
MI
CA
RBO
XIM
IDES
]-PH
ENY
L C
AR
BAM
IDO
}-D
IBEN
Z [b
,f] A
ZEPI
NES
.
O
N
NH
NN
HSNH
2
O-
m/z
=530
O
N
NH
NN
HSNH
2
OCH
3
m/z
=521
O
N
NH
NN
HSNH
2
m/z
=514
O
N
NH
NN
HSNH
2
m/z
=491
O
N
NH
OCH
3
m/z
=457
O
NH
NH
NN
HSNH
2
OCH
3
m/z
=445
O
N
NH
N
CH
+
NH
SNH
2
m/z
=438
O
N
NH
N
CH
2
NH
SNH
2
m/z
=415
O
N
NH
NN
HSNH
2
m/z
=413
OCH
3
m/z
=108
m/z
=105
CH
2+
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 242
O
N
NH
NN
HSNH
2
OCH
3
m/z
=545
MA
SS
SPE
CT
RA
L
STU
DY
O
F 5-
{4'-
[3"-
(4"'
-ME
TH
OX
Y
PHE
NY
L)-
2"-P
RO
PEN
E-1
"-T
HIO
SEM
IC
AR
BOX
IMID
ES]-P
HEN
YL
CA
RBA
MID
O}-
DIB
ENZ
[b,f]
AZE
PIN
ES.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 243
Ant
imic
robi
al A
ctiv
ity :
Con
clut
ion
:M
axim
um a
ntim
icro
bial
act
ivity
:
B. m
egat
eriu
mR
4-O
H-C
6H4-(
22)
2-N
O2C
6H4-(
19)
2-C
l-C6H
4-(28
)
30 30 35 -
A.n
iger
R
3-O
H-C
6H4-(
22)
4-O
H-C
6H4-(
21)
2-N
O2-C
6H4-(
21)
3-N
O2-C
6H4-(
22)
2-C
I-C
6H4-(
23)
- - - 27
E.c
oil
R
4-O
H-C
6H4-(
21)
4-O
CH
3-C6H
4-(20
)
3-N
O2-C
6H4-(
21)
2-C
l-C6H
4-(23
)
32 28 30 -
S. a
ureu
sR
2-O
H-C
6H4-(
19)
4-O
H-C
6H4-(
20)
3-N
O2-C
6H4-(
27)
2-C
l-C6H
4-(20
)
29 32 31 -
S. ta
phim
ariu
mR
3-O
H-C
6H4-(
23)
4-O
H-C
6H4-(
22)
2-N
O2-C
6H4-(
21)
3-N
O2-C
6H4-(
20)
2-C
l-C6H
4-(22
)
30 29 27 -
Ampic
ilin
50
μgCh
loro
mph
enico
l
"N
orflo
xacin
"
Gris
eofu
lvin
"
Ant
ifung
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntib
acte
rial
act
ivity
Zone
of i
nhib
ition
in m
.m.
Com
para
ble a
ctiv
ity w
ith kn
own s
tand
ard d
rugs
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Reaction Scheme
N
OCl
O
CH3
NH2+
N
O NHO
CH3
R
N
O NHO
PyridineReflux
R-CHO40% NaOH, 24 hrs Stirring
Type (XVII) R=Aryl
O
N
NH
N
R
NH S
NH2
RefluxThiosemicarbazide
244
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
EXPERIMENTAL
SYNTHESIS OF 5-{4'-[(3"-ARYL)-2"-PROPENE-1"-THIOSEMICA-RBOXIMIDES]- PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.
(A) Synthesis of 5-(4'-Acetyl Phenyl carbamido)-dibenz [b,f]-azepineFor synthesis see part-I, section : I, Page No: 31
(B) Synthesis of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]phenyl carbamido}-dibenz [b,f] azepines.For Synthesis see part: I, section : I, Page No : 31
(C) Synthesis of 5-{4'-[(3"-(4'"-methoxy phenyl)-2"-propene1"-thiosemicarboximides]-phenyl carbamido}-dibenz [b,f] azepines
A mixture of 5-{4'-[3"-(4"'-methoxy phenyl)-2"-propene-1"-one]
phenyl carbamido}-dibenz [b,f]-azepine. (4.72g, 0.01M) and thiosemicarbazide
(0.91 g, 0.01M) was refluxed for 10 hrs at 100oC in presence of alcohol like
ethanol. The reaction mixture was poured in crushed ice, filtered, washed,
dride and crystallized from ethanol, yield :71.72 % M.P. 72OC (Found:C:70.45;
H: 4.95; N:12.72; C32H27N5O2S
Required: C:70.50; H:4.98; N: 12.84 %)
Simillary other compounds were prepared and their physical data are
recorded in Table No. : 33
(D) Antimicrobial activity of 5-{4'-[(3"-aryl)-2"-propane 1"-thiosemicarboximides]-phenyl carbamido-dibenz [b,f] azepines
The Antimicrobial testing was carried out as described in part : I,
section: I, Page No. 32-34
The zone of inhibition of the test solution are recorded in Table No. 34
245
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 246
TABL
E N
O :
33PH
YSI
CA
L C
ON
STA
NT
OF
5-{4
"-[(
3"-A
RY
L)-
2"-P
RO
PEN
E-1
"-T
HIO
SEM
ICA
RB
OX
IMID
ES]
-PH
EN
YL
CA
RB
AM
IDO
}-D
IBE
NZ
[b,
f] A
ZE
PIN
E
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
Mol
ecul
arFo
rmul
a3
C31
H25
N5O
SC
31H
25N
5O2S
C31
H25
N5O
2SC
31H
25N
5O2S
C32
H27
N5O
3SC
32H
27N
5O2S
C32
H27
N5O
2SC
31H
24N
6O3S
C31
H24
N6O
3SC
31H
24N
5OC
lSC
33H
30N
6OS
C29
H23
N5O
2SC
35H
27N
5OS
C39
H29
N5O
S
M.P
. O
C 4 115
88 110
110
125
78 72 108
105
90 142
115
125
125
Yiel
d% 5
59.6
869
.71
71.1
655
.81
70.1
170
.24
71.7
269
.68
58.6
881
.69
59.9
862
.71
71.6
282
.61
% o
f Nitr
ogen Fo
und
713
.56
13.1
113
.13
13.1
612
.40
12.7
012
.72
14.8
214
.92
12.7
015
.44
13.8
112
.32
11.3
2
Cal
cd.
613
.59
13.1
813
.18
13.1
812
.47
12.8
412
.84
15.0
15.0
12.7
515
.49
13.8
612
.38
11.3
8
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 247
TABL
E N
O :
34A
NT
IMIC
RO
BIA
L A
CT
IVIT
Y O
F 5-
{4"-
[(3"
-AR
YL
)-2"
-PR
OPE
NE
-1"-
TH
IOSE
MIC
AR
BO
XIM
IDE
S]-P
HE
NY
L C
AR
BA
MID
O}-
DIB
EN
Z [
b,f]
AZ
EPI
NE
Sr.
No. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
R 2C
6H5-
2-O
H-C
6H4-
3-O
H-C
6H4-
4-O
H-C
6H4-
3-O
CH
3,4-O
H-C
6H3-
2-O
CH
3-C6H
4-4-
OC
H3-C
6H4-
2-N
O2-C
6H4-
3-N
O2-C
6H4-
2-C
l-C6H
4-4-
N,N
-(C
H3) 2C
6H4-
C4H
3O (F
urfu
ral)-
C10
H7 (N
apth
al)-
C14
H9 (A
nthr
al)-
B. m
egat
eriu
m3 15 17 18 22 18 15 17 19 16 28 14 16 15 13
S. a
ureu
s4 17 19 14 20 12 15 14 17 27 20 14 13 15 17
S. ta
phim
ariu
m5 14 17 23 22 18 17 21 20 22 13 18 17 15 14
A.n
iger
7 19 20 22 21 19 17 16 21 22 23 14 17 19 16
E.c
oil
6 15 21 13 20 18 17 19 11 21 23 19 18 16 15
Ant
ibac
teri
al a
ctiv
ityZo
ne o
f inh
ibiti
on in
m.m
.A
ntifu
ngal
act
ivity
Zone
of i
nhib
ition
in m
.m.
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
REFERENCE1. S. V. Kostanecki and J. Tambor;
Chem. ber., 32, 1921 (1899).
2. K. Kazauki, K Htayama, S. Yokomor and T. Soki;
Chem. Abstr., 85 5913 (1976).
3. H. Rupe amd D. Wasserzug;
Chem. Ber., 34 3527 (1901).
4. T. Szell
Chem. Ber., 92 1672 (1959); Chem. Abstr., 53, 21913 (1959).
5. R. B. Lyle and L. P. Paradis;
J. American Chem. Soc., 77 6667 (1955); Chem. Abstr., 50 10057 (1956)
6. S. A. Hermes;
Chem. Abstr., 70 96422h (1969).
7. A. A. Rawal and N. M. Shah;
Indian J. Chem., 21B 234 (1962).
8. P. L. Cheng, P. fournari and J. Tirouflet;
Bull. Soc. Chim., France. 102248 (1963); Chem. Abstr., 60, 1683 (1964).
9. C. Kurodo and T. Matsukuma;
Sci. Papers Inst. Phys. Chem. Res. (Tokyo), 18, 51, (1932) Chem. Abstr.,26,2442(1932).
10. D. S. Breslow and C. R. Houser;
J. American Chem. Soc., 62, 2385 (1940) ; Chem. Abstr., 34. 7875 (1940)
11. G. V. Jadav and V. G. Kulkarni;
Curr. Sci.(1944)
12. L. Reichel;
Naturwissens Chalen 32, 215 (1944); Chem. Abstr., 10, 2441 (1946).
13. V. M. Vlasov;
Izu. Sib. Otd, Akad. Nauk SSSR Ser. Khim Nauk. 2, 96 (1972) ; Chem. Abstr.,76, 140411d (1972).
248
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
14. P. L. Nayak and N K. Rout;
J. Indian Chem. Soc., 52, 801 (1975).
15. M. A. El. Hashan, M. El-kady, M. A. Saiyed, A. A. Elsawy;
Egypt. J. Chem., 26(6), 715-21 (1985). (Eng); Chem. Abstr., 105, 208684
(1986).
16. A. Sammour, Y. Akhnookh and H. Jahine;
U.A.R.J. Chem., 13(4), 421-37 (1970); Chem. Abstr., 77, 1013489 (1972).
17. L. S. Crawley and W.J. Fanshawe;
J. Heterocycl. Chem., 14, 531 (1977).
18. A. Chan Seng H., Brimble Margaret;
Aus. J. Chem., 1998; Chem. Abstr., 129, 16105f (1998).
19. A. Khalafallah;
Asian J. Chem., 8(4), 951-96 (1996).
20 D. J. Brown;
Heterocycl. Compound., 16.
21. E. C. Taylor and R. W. Morrison;
J.Org. Chem., 32, 2379(1967).
22. Ms. B. S. Hastak and B. J. Ghiya;
Indian J. Heterocycl. Chem., 2 133-135 (1992).
23 P. A. Mehta and H. B. Naik;
Oriental J. Chem., 14(1), 159-60 (1998); Asian J. Chem., 10(4), 1017-8(1998).
24. E. A. Mohamed, R. M. Abdel Rahman, A. A. Sayed and M. M. Ismail;
Indian J. Chem. Soc., 69, 82 (1992).
25. K. P. Jadhav. D.B. Ingle;
Indian J. Chem., 22B, 180 (1983).
26. P. S. Utale, P. B. Raghuvanshi, A. G. Doshi;
Asian J. Chem., 10(3), 597-99 (1998).
27. S. W. Pfeidere and H, Mosthafa;
Synthetic Org. Chem., B90, 738 (1957).
249
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
28. Rasaki Abayomi Osisany, James Olabisi Oluwadiya;
J. Heterocycl. Chem., 15, 947 (1989).
29. K. Folkers, S.A. Harris;
J. Am. Chem. Soc., 61, 1245 (1939).
30. M. R. Mahmoud, E. F. E. Awatef, M. S. Abd-EL-Halim, A. M. Radwan;
India J. Heterocyclic.Chem., 4, 131-36 (1994).
31. A. Y. Deshmuch, P. B. Raghuwanshi, A. G. Doshi;
Oriental J. Chem., 18(1), 101-104 (2002).
32. Nissan Chemical Industries Ltd.,
Japan Kokai To Jckyo Koho Japan 58, 08, 035 (1983) ; Chem. Abstr., 98, 178947a
(1983).
33. R. Seele et. al.;
Eur. Pat. Appl EP, 337, 198, (Cl CO7D 249/08) (1989) ; Chem. Abstr., 113,178990s (1990).
34. Tashio Pharmaceutical Co. Ltd.;
Japan, Kokai Tokkyo Koho JP, 59, 12, 094 (84, 12, 094) (Cl A 61 K 31/ 215);
Chem. Abstr., 101. 54722J (1984).
35. J. Serre, J. Rey and J. P. Tarayre;
Fr. Demande 2, 377. 201 (Cl A 61U37/48); Chem. Abstr., 91, 9494a (1979).,
36. A. E. Vanstone, G. K. Maile and L. K. Nalbantogly;
Ger. Offen. DE 3, 537, 207 (Cl. CO7C 65/40) (1986); Chem. Abstr., 106,149778f (1987).
37. K. Bowden, P. A. Dal and C. K. Shah;
J. Chem. Res. Synop., 12, 2801 (1990); Chem. Abstr., 114, 160570m (1991).
38. Y. Inamori et. al. ;
Chem. Pharm. Bull, 39(6), 1604 (1991); Chem. Abstr., 115, 105547c (1991).
39. V. M. Gaurav and D. B. Ingle;
Indian J. Chem., 25B, 868 (1986); Chem. Abstr, 107, 39321h (1987).
40. A. K. Pedersen and G. A. Fitz Gerald;
J. Pharm. Sci., 74(2), 188 (1985); Chem. Abstr, 103, 87592m (1985).
250
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
41. D. Binder, C. R. Noe, W. Holzer and B. Rosenwirth;
Arch. Pharm. 318(1), 48 (1985); Chem. Abstr, 102,149025u (1985).
42. M. R. Bell;
US Appl, 637, 931 (1984); Chem. Abstr, 113, 211828t (1990).
43. E. T. Ogansyan et. al.;
Khim. Farm. Zh., 25(8), 18 (1991); Chem. Abstr, 115, 24797n (1991).
44. S. Satoshi, N. Yasunori, U. Hiroki;
J. Med. Chem., 1993, 3904-9 (Eng.) Chem. Abstr, 120, 133956] (1994)
45. Y. Satomi;
Ind. J. Cancer 55(3), 506 (1993); Chem. Abstr, 120, 208071 (1994).
46. R. J. Auto et. al. ;
J.Clin Biochem.Nutr., 17(2) 73(1994); Chem.Abstr.,123, 122487x (1995).
47. Li. Rongshi, Chem. Xiawa., Gong Baogung. Qominguez, Jos, N. et. al.;J. Med.
Chem., 38 (26), 5031-7 (1995); Chem. Abstr., 124, 232f (1996).
48. G. Zongru, H. Rui;
Faming Zbuanli Shenquang Gonky Shuominh Shu CN 1, 113, 909; Chem abstr.,125, 10376r (1996)
49. F. S. Nielsen, S. B. Chirstensen;
J. Med. Chem., 41, 4819-4832 (1998).
50. S. R. Modi and H. B. Naik;
Orient J. Chem., 10(1), 85-6 (1994); Chem. Abstr., 112 81186c (1995).
51. Attia A., Abdetsulan
O. J. Abo- Ahalia; Egupt. J. Chem., 1995; Chem. Abstr., 125, 10570z (1996).
52. V. R. Mudaliar and V. Joshi;
Ind. J. of Chem., 34(B) 456 (1995).
53. Kammei, Hideo, Koide, Tatsurou; Hashimato yoko, Kojima, Takashi, Hasegawa,
makoto; Chem. Abstr., 126, 258666v (1997).
54. R. De Vincenzo, G. Seambla, Panici, R. Benedess, F. O. Remelletti ; Anticancer
Drug. Res., 10(6), 481-90 (1995) Chem. Abstr., 124, 247r (1996). 55. Han,
Rui, Guo, Zong, Ru; Chem. Abstr., 128, 110862b (1998).
251
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
55. Han, Raui Guo, Zong, Tu;
Chem. Abstr., 128 11086b (1998)
56. Okuyana torn; Okada Yoshihito, Shibata Shoji et. al.;Jpn Kokai Tokkyo Koho JP,
11 349, 521 (1999); Chem. Abstr.,132, 22752t (2000).
57. A. Tsotitus, K. Theodara et. al.
PCT Int. Appl. WO 99, 54 278 (1999); Chem Abstr., 131, 28260e (1999).
58. P. N. Sharma, B. Sreenivasulu;
J. Indian Chem. Soc., 1197; Chem. Abstr., 128, 88799n (1998).
59. Ezio Bombardelli, V. Piero;
PCT Int. Appl. WO 98, 58, 913; Chem Abstr., 130, 95382r (1999) 12199d
(2000). 423-. B. B. Kalashnikov I. R Kalashnikov;
60. S. Elichi, K. Koji;
PCT Int. Appl. WO 99, 61, 403; Chem Abstr., 132, 12199d (2000).
61. B. B. Kalashnikov I. P. Kalashnikov;
Russ. J. Gen. Chem., 1998; Chem. Abstr., 130, 296596n (1999).
62. S. Satoshi, N. yasunori, V. Hiroki;
J. Med. Chem., 1993, 3904-9 (Eng.); Chem. Abstr., 120, 133956J (1994). 63
63. P. B. Walavalker, S. Pednekar;
J. Heterocycl. Chem., 1999; Chem. Abstr., 131, 257517p (1999).
64. O. Tory, O. Yoshihito, S. Shoji;
Jpn. Kokai Toceyo Koho JP 11, 349, 521; Chem. Abstr., 132 22752t (2000).
65. J. R. Dimmock, M. Elisk;
U. S. US 6, 017, 933; Chem. Abstr., 132, 107880n (2000).
66. T. M. Abdelrahman;
Bull. Chim. Farm. 1998; Chem. Abstr., 132, 93276b (2000).
67. Ni Liming, Worsencrott K. J., Weingarten M. D., Meng C.Q., Sikorski J.A.; U.S.
US WO 02, 41336 (2002) Chem. Abstr., 139, 85160 (2003).
68. Kumar Srinivas K., Hager E., Pettit C.,Gurulingappa H., Davidson N. E., Khan S.
R.; J. Med. Chem., 46(14), 2813-15 (2003); Chem. Abstr., 139, 117464 (2003).
252
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
69. Ko Horng-Huey, Tsao Loli, Yo kun-Lugn, Cheng-Tsung J.P. Wang, C. N. Lin
Bioorg & Med. Chem., 11(1), 105-111 (2003) Chem. Abstr., 139, 30144 (2003).
70. Nakahara Kazuhiko, G. torakoontiwakon, M. Kameyama,
Ono Hiroshi, Yoshida mitsuru; Jpn. Kokai Tokkyo Koho JP 03 040829 (2003);
Chem. Abstr. 138, 158753 (2003).
71. Lin Yuh-meei, Zhou Yasheen, M. T. Flavin, L. M. Zhou, W. Nie., F. C.Cheng;
Bioorg &Med.Chem., 0181 2795-2802 (2002); Chem. Abstr.138, 66146 (2003).
72. B.R.Das, D.N. Chowdhary, K. Ghosh, G.K. Das ;
Environ and Ecolo 20(3), 649-55 (2002) ; Chem. Abstr. 139, 129387 (2003).
73. Kirm Min-Young., B. Y. Park, K. M. Kirn, N. D. Sung, P. K. Myung;
PCT Int.Appl. WO 02 KR 2031 (A61K031-03) (2002) ; Chem. Abstr. 138,368613 (2003).
74. Liu Mei, Wilairat Prapon, Go Mei-Lin;
J. Med. Chem., 45(8), 1735 (2002) ; Chem. Abstr., 139, 94746 (2003).
75. Opletalova Veronika, L. Jahodar, D. Jun, L. Opletal;
Ceska a slovenska Farmacie, 52 (1), 12-19 (2003) ; Chem. Abstr. 138, 265043
(2003).
76. Rojas Javier, M. Paya, J. N. Dominguez, F. M. Luisa;
Bio org & Med.Chem., Letters, 12(15), 1951-54 (2002); Chem. Abstr. 138,39068 (2003).
77. Rojas Javier, J. N. Dominguez J. E. Charris, Lobo Gricela, Paya M., Ferrandiz
M.L; Eur. J. Med. Chem., 37(8), 699-705 (2002); Chem.Abstr.138,122472
(2003).
78. N. N. Mateeva, R. N. Kode, K. K. Redda; J.
Heterocycl. Chem., 39(6), 1251-58 (2002); Chem. Abstr. 138, 401568 (2003).
79. Kang T. H., Tian Y. H., Kim Y. C.,J. Appl. Pharmacol, 13-34 (2005).
80. A. L. Barry;
"The Antimicrobial Suceptibility test, principle and practices (ELBS-4th
Edition) 180-193 (1976)
253
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
81. F. Simoncini R. R.Rengone and C. Calann.
Farmaco D. Part., 23 (10), 559-70 19680; Chem Abstr. 59, 109851d (1968)
82. L. Claisen and O. Lowmann;
Chem. Ber., 21, 1149(1988).
83. A. Quelico;
Chem. Heterocycl. Compd. 17, 1 (1962).
84. L. S. Crawley and W.J. Fanshawe ;
J. Heterocycl. Chem., 14, 531 (1977).
85. Vamanouchi Pharm. Co. Ltd.;
Jpn. Kokai koho JP 58, 148, 858 (1982) (C107D 207/333) (1983) Appl 82/
30045 (1982); Chem. Abstr, 100, 34538 (1984).
86 P. T. Gallagher, T. A. Hicka and G. W. Mullier (Lilly Ind. Ltd.);
Eur. Pat. EP 2, 57, 882 (1988); Chem. Abstr, 108, 6499k (1988).
87. A. Ando and R. W. Stevens ;
PCT Int. Appl. WO 94, 12, 481 (Cl. C07 D 261/04); Chem, Abstr, 122, 56037x
(1995).
88 W. Wells, A. Michele, H. Todd;
Chem. Abstr, 136, 340680] (2002).
89. T. Tochiro, K. Shriji, I. Shinji, M. Hiroshi, S. Akira and V. Hiroshi ;
Ger. Offen. DE 3, 237, 149 (Cl. C07 A 261/14); (1983); Chem. Abstr, 99,88188 (1984).
90. T. U. Quazi;
Pak. J. Sci. Ind. Res., 27, 326 (1984); Chem. Abstr, 103, 12339m (1985).
91. Nippon Chemiphar Co. Ltd.;
Jpn. Kokai Tokkyo koho JP 58, 46, 077 (83,46 , 077) (Cl. C07 A 261/14)
(1983); Chem. Abstr, 99, 17574 (1984).
92. T. Taate, K. Natira and H. Fukhola ;
Chem. Pharm. Bull 35(9), 37769 (1987); Chem. Abstr, 108, 186621e (1988).
254
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
93. B. Victor J. Safir and Sidney R.
(American Cyanamid Co.) Brit. 1, 178064 (Cl C07D) (1970); Chem. Abstr., 72,79017d (1970).
94. R. Maior, B. Eisele, P. Mutler and H. Grube;
Ger, Offen. DE. 3621372 (1988); Chem. Abstr., 108, 67456p (1988).
95. S. Suzuki, K. Ueno and K. Mori; Yakugaku Kenkya,
34, 224-31, (1962); Chem. Abstr., 57, 16754 (1962). 46 458.
96. G. P. Reddy. E. Rajendra and A. K. Murty;
Indian J. Hetrocycl. 3, 233 (1994); Chem. Abstr., 122, 105724e (1995).
97. B. Victor, J. Safir, R. Sidney; American Cyanamide (O). Brit., 1, 178064
(C107D) (1970); Chem. Abstr., 72, 79017d (1970).
98. K. Hass Duane, B. Carr John;
U.S. 3,879,532 (Cl 242-272 A 61k) (1975); Chem. Abstr., 83, 108626n (1975).
99. D. J.David, D.B.Allon and E. A. Frederick;
Ger. Offen. 2, 723688 (CE A 01 N9/28) 22 DCT, 1977; Chem. Abstr., 88,132015k (1978).
100. M. D. Mackie, H. S. Anthony, W. J. R. Howe, S. P. John and W. S. Marry; Brit.;
UK Pat. Appl. GB 2, 265, 371 (Cl. C07 D 261/06); Chem. Abstr, 120, 1641532
(1994).
101. M. Moriyusu, H. Yushi;
PCT. Int. Appl. WO 97 43, 248 (Cl. 07, 25/50 20 NOv. 1997. JPA pp 96/ 117,
370 13 May 1996, 66 pp Japan, Chem. Abstr. 128 14605z (1998).
102. G. D. Diana and C. P Michel ;
S. African ZA 81 03, 105 (1981) ; Chem. Abstr., 98, 16671 (1983).
103. C. P. Alfred, C. David, Herman, D. Nancy, B. Daniel;
PCT. Int. Appl. WO 9522, 9103 (1995); US Appl. 202, 394, 42 pp (1994); Chem.Abstr., 124, 3055m (1996).
104. A. K. Banerjee et al. ;
Arzneim Forsch., 44, 863 (1994); Chem. Abstr., 122, 160522n (1995).
105. H. Katsumasa, N. Shigehide, H. Kenji;
Chem. Abstr., 136, 340672J (2002).
255
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
106. S. Rung and D. Dus.,
Pharmazie 49, 727 (1994); Chem. Abstr., 122, 55934H (1995).
107. M. Scobie and M. D. Threadojill ;
J. Org. Chem., 59, 7008 (1994); Chem. Abstr., 122, 10090f (1995).
108. R. Jain, D. D. Agarwal and Damodharan;
J. Ind. Chem. Soc. 72, 825-827 (1995).
109. Inai, Masatoshi, Tanaka, Akie, Goto, Kyoto;
JPN-Kokai Tokkyo Koho JP 07, 215, 952 (95, 215, 952) (1995)
JP. Appl. 93 1304 921, 19 PP(1993); Chem. Abstr., 124 86995(s) (1996)
110. Inai, Masatoshi, Tanaka, Akie, Goto, Kyoto;
JPN-Kokai Tokkyo Koho JP 07, 215, 952 (95, 215, 952) (1995) JR Appl, 93
1304 921, 19 PP(1993); Chem. Abstr., 124 86995(s) (1996).
111 B. Maggio, G. Daidone, D. Raffa, F. Piescia, VMC Cutuli;
Archiu Der Pharmazic, 332(2), 50-54 (1999).
112. C. B. Xue, J. Roderick, S. Mousa, R. E. Olason, W. F. Degrade;
Bio-organic and Medicinal Chemistry Letters, 8(24), 3499-3504 (1998).
113. M. Masui, H. Yasushi;
Chem. Abstr., 128, 13256z (1998).
114. K. V. Reddy, S. G. Rao, A. V. Subba;
Indian J. Chem., 37B(7), 677-699 (1988); Chem. Abstr., 129, 260397p (1998).
115. J. Nyitrai, N. Joseph, S. Gyala et al.;
Chem. Abstr, 128, 294778h (1998).
116 A. Mishra, J. K. Sanmati, J. Asthana;
Orient J. Chem., 14(1), 151-152 (1998); Chem. Abstr., 128, 216538m (1998).
117. T. D. Aicher, B. Balkam, R A. Bell, L. J. Brand et al.;
J. Med. Chem., 41(23), 4556-4566 (1998); Chem. Abstr., 129, 3434296 (1998).
118. S. Ozkan, D. Kadir, A. Okay, A. Ahmet;
Heterocycl. Commun. 1999; Chem. Abstr., 131, 5221f (1999).
119 M. Dauria;
Hererocycles, 50(2), 1115-1136 (1999).
256
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
120. Y. N. Manohara, P. V. Nayak, S. Mohan;
Asian J. Chem., 11(1), 253-256 (1999).
121. A. H. Bhatt, H. H. Parekh & A. R. Parikh;
Heterocyclic Commun. Vol. 4, No. 4 (1998).
122. De Mesmaker, A. Schaetzer, J. Kunzwalter;
PCT Int. Appl No., 9, 51, 583 (1999); Chem. Abstr., 131, 271872g (1999).
123. A. Hiroyuki, S. Takahiro, A. Toshio;
PCT Int. Appi. WO 99 64, 404; Chem. Abstr., 132, 12313m (2000).
124 K. Masami;
U. S. US 6 100, 421; Chem. Abstr., 133, 150550H (2000).
125. M. Mauro; S. Enzo et al.;
Farmaco 54(7), 452-460 (1999); Chem. Abstr., 131, 299393a (1999).
126. D. A. Jacob, M. A. John, C. L. Stanley;
PCT Int. Appi. WO 00 00, 477; Chem. Abstr., 132, 64256q (2000).
127. S. K. Gudadhe, S. D. Patii, U. S. Jamode;
Orient J. Chem., 15(1), 133-136 (1999); Chem. Abstr., 132, 222481r (2000).
128. Hui-Xin-Ping, Zhang Lin-Mei; Zhang Ziyi;
Indian J. Sec B. Org. Chem. Inci Med. Chem. 1999; Chem. Abstr., 132, 207803c
(2000).
129. V. D. Huebner, Lin Xiaodong, James lan, C. Liya, M, Desai;
PCT Int. Appl WO 00 08, 001.
130. Achanta G. Modzelewska A, Fengl khans S. R., Hang P., Mol Pharmacol April 24,
(2006).
131. N Lal, A. A. Hussein and M. Meyer Fitotera pia, 77(3), 230-232 (2006).
132. J. Elguero; In Comprehensive Heterocyclic Chemistry eds., A. R. Katritzky and
C. W. res., Vol.5, Ch. 404.
133. R. S. Theobald ; Rodd's Chemistry of Carbon Compounds, Ed. M. F Ansell, Vol.
IV, Part C, Ch. 16, 2nd Edition, (Elsenier SciencePublishers B. V, Amsterdam)
59 (1998).
134. A. M. Fahmy, M. Hassan, A. A. Khalf, R. A. Ahmed;
Reu. Roum. Chim. 33(7), 755-61 (1988); Chem. Abstr., 111, 77898 (1989).
257
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
135. A. K. Padya, K. Jaggi, V. Lakshminarayana, C. S. Pande;
J. Indian Chem. Soc., 75(2), 104-105 (1998)
136. V. Gohanmukkala, A. Subbaraju, R. Naykula and D. Parmeswara;
Indian J. of Heterocyclic Chem., 4, 87-92 (1994).
137. M. Hassaneen Hamdi, A. E. Hamad, A. H. M. Hiyam;
Sultur Lett. 8(5), 27582 (1989); Chem. Abstr, 111, 57611 (1989).
138. M. A. El. Hashsh; M. El-Kady; M. A. Saiyed; A. A. Elsawy;
Egypt J. Chem., 27(6), 715-21 (1985); Chem. Abstr., 105, 20868u (1986).
139. G. Gyassi, K. Bourin, M. Lamiri, M. Soufiaoui;
New Journal of Chemistry; 22(12), 1545-1548 (1998).
140. S. Paul, R. Gupta;
Indian J. Chem., 37(B), 1279-1282 (1998).
141. A. Dandia, H. Taneja, C. S. Sharma;
Indian J. Heterocyclic Chem., 1999; Chem. Abstr., 132, 265161d (2000). 142.
142. A. K. Reda, A. A. Khalaf, M. T. Zimaltu, A. M. Khalil, A. M. Kaddah and H. A.
A.l. Rifuie; J. Indian Chem. Soc. 68, 47-51 (1991).
143. Delay Francois(Fermenich S. A.) Patent Schrift (Switz)
144. Aysel G. Seret D., Gultaze C., Kevser E., Kamil V.;
Ear. J.Med. Chem., 35, 359-64 (2000).
145. P. Desaea; A. Nunrich; M. Capderny and G. Devaux;
Ear. J, Med. Chem., 25, 285 (1990).
146. Kalluraya Blakrishna, R. Chimabalkar, G. Rai, R. Gururaja, S. Shenoy;
J. Indian Coun. Chemi., 18(2), 39-42 (2001); Chem. Abstr., 138, 238061(2003).
147. Y. Hiroyuti, O. Mocoto et al.;
Eur. Pat. Appl. Ep 295695 (Cl C07D 401/6) (1988); Chem. Abstr., 111,23510
(1989).
148. K. Zalgislaw and A. Seffan;
Acta. Pol. Pharm., 36(6), 645 (1979); Chem. Abstr., 93, 204525e (1980).
149. S. S. Nayal, C. P. Singh;
Asian J. Chem. 11, 1, 207-212 (1999).
258
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
150. K. Wellinga, H. H. Eussen Jacobus;
Eur. Pat. Ep 269 141 (Cl C07D 231/06) (1988); Chem. Abstr., 110, 8204 (1989).
151. K. Trena and Zolzislaw;
Acta. Pol. Pharm., 36(3), 227 (1979); Chem. Abstr., 93, 4650r (1980).
152. D. Bhaskar Reddy, T. Senshuma, B. Seehaiha & M. V. Ramma Reddy;
Indian J. Chem., 30(B), 46 (1991).
153. B. Hans, R. Rolf and R. Rudolf;
US. Pat., 3, 822, 283 (1974); Chem. Abstr., 81, 105494r (1974).
154. B. Roman;
Pharmazie, 45, 214 (1990).
155. Z. Brozozowsk E. Pormarnacka; .
Acta. Pol. Pharm., 37(4), 1378, 80 (1980); Chem. Abstr., 25, 80807 (1981).
156. Archana Shrivastava V. k.; Chandra Ramesh Kumar Ashok;
Indian J. Chem., 4182371-75(2002); Chem.Abstr., 138, 271582 (2003).
157. H. G. Garg and P. P. Singh;
J. Chem. Soc., 2, 1141 (1936).
158. D. B. Reddy, T. Senshuna and M. V. Ramma Reddy;
Indian J. Chem., 30(B), 46 (1991).
159. Ashok Kumar, R. S. Verma and B. P. Jagu;
J. Ind. Chem. Soc., 67, 120 (1990).
160. W. I. Ronald, A. Adriano;
Chem. Abstr., 126, 181346f (1997).
161. H. M. Mokhtar, H. M. Faidailah;
Pharmazie, 42, 482 (1987).
162. Panda J. Srinivas S. V., Rao M. E.,
J. Indian Chem. Soc., 79(9), 770-1 (2002); Chem. Abstr., 138, 153499n (2003).
163. S. S. Sonarc,
Asian J. Chem., 10(3), 591-593 (1998); Chem. Abstr., 129, 633, 54317J (1998).
164. T. M. Stivenson, D. W. Piotrowski, M. A. H. Fahmy, R. L. Lowe, K. L. Monaco;
Chem. Abstr., 130, Mar Part -1, 29 AGRO (1999).
259
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
165. T. Katsushori, A. Hiroyuki, K. Masumij;
PCT Int. Appl. WO 98, 56, 760; Chem. Abstr., 130, 66492w (1999).
166. K. Johannes, J. Fuchs, R. Erdelen;
U. S. US 5, 525, 622 (Cl 514-403; AON 43/56) Jun. 1996 DE Appl. 4,
128, 564 Aug. 1991; 574; Chem. Abstr., 125 1427199 (1996)
167. Z. Moritaz, S, Hadol;
Dyes arid Pigment, 41, 1-2, 1-10 (1999).
168. M. K. Shivananda, P. M. Akberali, B. Holla, Shivarama, M. Shenoy,
Shalini; Indian J. Chem. 393B(6), 440-447 (Eng).; Chem.Abstr., 134, 86195n
(2000).
169. B. Shivarama Holla, M. K. Shivananda, P.M. Akabar Ali, M. Shalini Shenoy;
170. B. Shivarama Holla, M.K. Shivnanda, B. Veerendra;
Ind. J. Hetrocydic Chem., 12, 135-138 (2002).
171. S. P. Hiremath K. Rudresh and A. R. Saundane;
Indian J. Chem., 41(B), 394-399 (2002).
172. V. Malhotra, S. Pathak, R. Nath, D. Mukherjee, K. Shanker;
Indian J. Chem., 41B, 1310-13 (2002); Chem. Abstr., 137, 370021J (2002).
173. Almstead Ji-In Kim, D. R. Jones;
PCT Int. Appl. WO 02 89, 799 (Cl. A 61K31/4439) (2002); Chem. Abstr., 137,370086J (2002).
174. Guniz Kucukguzel, Sevin Rollas, Habibe Erdeniz, muammer Kiraz, A Cevdet
Ekinci, Aylin Vidin; Eur. J. Med. Chem., 35, 761-77 (2000).
175. T. Z. Gulhan, Pierre Chevallet, S. K. Fatma, Kevser Erol;
Eur. J. Med. Chem., 35, 635-41 (2000).
176. Shalabh Sharma, Virendra Kishor Shrivastava, Ashok Kumar;
Eur. J. Med. Chem., 37 689-97 (2002).
177. V. K. Archana Srivastava, Kumar Ashok;
Arzneimittel. Forschung, 52(11), 787-91 (2002); Chem. Abstr., 138,353758(2003).
178. B. Jayashankara and K. M.Lokanatha Rai F. J. Chem Vol. 5 Number Z P 309-315
10 Nov. 2007.
260
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
179. R. R. Willams and J. K. Cline;
J. Amer. Chem. Soc., 58, 1504 (1936).
180. C. Reidling, R. Dwarczak, W. M. F. Fabian & K. H. June;
Dye & Pigment, 24, 185 (1994).
181. G. E. Hardtman & H. Otto;
US Pat 366369; Chem. Abstr., 77, 52313 (1972).
179. R. R. Williams and J. K. Cline.
J. Amer. Chem. Soc., 58, 1504 (1936)
180. C. Reidling, R. Dwarczak, W. M. F. Fabrian & K. N. Jun.;
Dye & Pigment 24, 185 (1994).
181. G. E. Hardtman, H. Otto;
U. S. Pat. 366369; Chem. Abstr., 77, 52313(1992)
182. D. J. Brown;
The pyrimidines Suppl. II edited by A. Weiss-berger & C. E. Tayloo, The
Chemistry of Heterocycl. Compds., (1985).
183. D. J. Brown;
Pyrimidines, edited by A. R. Kartritzky & C. W. Ress, Comprehensive Hete. Chem.,
Vol. 111, 57, (1984).
184. Y. S. Sadanandam, M. M. Shetty, P. V. Diwan;
J. Med. Chem., 27, 8792 (1992).
185. F. Bigi; C. Silvia; F. Betting, M. Raimando; S. Giovanni;
Tetrahedron Lett., 40(17), 3465-3468 (1999).
186. C. C. Heidelberger, N. C. Chaudhari, P. Dannberg, D. Mooren, L.Griesbach,
R.Duchinsky, R. I. Schnitzer, E. Pleven; Scheiner (1957), Nature 179, 663.
187. F.French;
Proc. Am. Ass. Cancer Res., 3, 319 (1962).
188. W. Hepworth, T. W. Thompson;
Chem. Abstr., 69, 7724 (1968).
189. G. E. Hardtmann;
U.S. 3, 663, 698 (Cl. 424-251; 1972) Appl. 779, 200; Chem. Abstr, 77, (1972)
261
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
190. N. Tokutake;
Brit. Pat. 146836B; Chem. Abstr., 87, 102370 (1977).
191. D. S. Matteson, M. S. Bleenbaum, R. A. Bechtold, R. J. Willsek;
J. Org. Chem., 43, 950 (1978).
192. M. Akhtar, Shamin, M. Seth, A. Baduri;
(Div. Med. Chem. Centre Drug) Res. Ints. Lucknow India; Chem. Abstr., 108, -,43 150408b (1988).
193. J. A. Martin, D. J. Bushnell, Duncan;
J. Med. Chem., 33, 2145 (1990).
194. K. A. Watanabe, K. Hurado, J. Zeidle;
J. Med. Chem., 33, 2145 (1990)
195. V. J. Ram, N. Haque, P. Y. Guru;
Eur. J. Med. Chem., 27, 851 (1992).
196. Liu, Xunyong, Xu, Lijun; Shandong;
Yike Daxue Xuebuo, 31(2), 176-9 (1993).
197. M. T. Omer, H. H. Fahmy, H. S. Mohamad;
Egypt J. Pharm. Sci., 37(1-6), 609-620 (1996).
198. A. Roland, D. M. Wilhelm Dollinger Markus Sentel Hans. Joachim;
Ger. Offen DE 4, 439, 332 (Cl. C07D 403/10) 1996; Chem. Abstr., 125,86635v (1996).
199. M. Olaf, H. Gerhard, H. Elisabeth, K. Ralf;
PCT Int. Appl. WO 97, 35, 845 (Cl. CO7D 239/54) 1997; Chem. Abstr.,127, 318975c (1997).
200. A. Roland, B. M. Wilhelm. D. Markus;
Ger. Offen. DE 19, 528, 186 (Cl. CO7D 239/54); Chem. Abstr., 126, 186101s
(1997).
201. M. Wilhelm, A. Roland, D. Markus;
PCT Int. Appl. WO 98 54, 155 (Cl. CO7D 239/54) 1998; Chem. Abstr.,130.38393w (1999).
202. A. Roland, D. Mark Wilhelm, D. Markus;
PCTInt. Appl. WO 98 55, 462 (Cl. CO7D 239/54); Chem. Abstr., 130, 38397g
(1999).
262
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
203. A. Roland, D, Markus, M. Wilhelm, I. Myers;
PCT Int. Appl. WO 99 38, 851 (Cl. C07D 239/54) 1999; Chem. Abstr.,131,130003n (1999).
204. W. R John, M. M. Christopher, R. R. Anthony, C. M. Vernie;
PCT Int. Appl. WO 99 14, 216 (Cl. CO7D 403/10) 1996; Chem. Abstr.,130,252370e (1999).
205. Nagarathnam, Dhanapalam; Wong Wai C; Maio Shou Wu,
PCT Int. Appl. WO 97 17, 969 (Cl. A61K 31/505); Chem. Abstr., 127, 65783t
(1997).
206. W. C. Wong, L. Bharat, R. Mohammad, G. Charles;
PCT Int. Appl. WO 98, 51, 311 (Cl. A61K 31/505) Chem. Abstr., 130, 25077w
(1999).
207. M. A. Patane, M. G. Bock, H. G. Selnick;
PCT Int. Appl. WO 98 57, 641, (Cl. A61K 31/445) 1998; Chem. Abstr., 130,81519x (1999).
208. M. A. Patane, M. G. Bock, H. G. Selnick;
PCT Int. Appl. WO 98 54, 641 (Cl. A61K 31/445) 1998; Chem. Abstr., 130,81520x (1999).
209. K. Nicholas, M. Premji, T. Stephen;
PCT Int. Appl. WO 98 54, 180 (Cl. CO7D 417/06) 1998; Chem. Abstr.,130,38394 (1999).
210. L. V. Azarayan, S. A. Avetisyan, A. A. Chachoyan, N. S. Buyukyan; Khim. Farm.
Zh., 31(6), 8-10 (1997); Chem. Abstr., 127, 262648d (1997).
211. V. P. Krivongov, G. A. Tolstiko, Ju.I. Murinov, F. A. Zarudil; Khim. Farm. Zh.,
31(6), 23-27 (1997); Chem. Abstr., 127, 262649e (1997).
212. M. Refai, M. T. Omer, M. M. Kamel, N. S. Ismail;
Egypt. J. Pharm. Sci, 37(1-6), 241-249 (1996); Chem. Abstr., 126, 251088z
(1997).
213. A. Kofies, H. Wonpyo, J. E. Semple;
U.S. US 5 602, 077 (Cl. 504-243, CO7D 239/553); Chem. Abstr., 126, 199577s
(1997).
263
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
214. K. Mogilaiah and S. Baburao;
Indian J. Chem., 37(B), 139 (1998).
215 M. Wilhelm, A. Roland, D. Markus;
PCT Int. Appl. WO 97, 45, 418 (Cl. CO7D 239/54); Chem. Abstr., 128, 48237w
(1998).
216. C. D. Timothy, M. Healthrl, J. Juanc, J. P. Powers;
PCT Int. Appl. WO 99 41, 253 (Cl. CO7D 403/04); Chem. Abstr., 131,10013
(1999).
217. T. Nagamatsu;
Japan Kokai Tokkyo JP 11 246, 560 [99,246,560], (CI. CO7D 487/ 14) 199;
Chem. Abstr., 131, 199707n (1999)
218. A. Roland, D. Markus, W. Ingo;
Ger. Offen DE 19, 854, 082 (Cl. CO7D 417/04) (1999); Chem. Abstr., 131,2721883m (1999).
219. M. M. Yari, S. S.Durac, M. Erfan, Batu O, Erol K.,
Farmaco, 54(6), 359-363 (1999); Chem. Abstr., 131, 228701p (1999).
220. M. A. Bruce, G. S. Poindexter, G. Johnson;
U.S. US 5 889, 016 (Cl. 514-274 A 61K 31/505) 1999; Chem. Abstr, 130,237586m (1999).
221. D. R. Sidler, R. D. Larson, M. Chartrain, N. Lkemato, C. M. Roberge;
PCT Int. Appl. WO 99, 07, 695 (Cl. CO7D 401/00) (1999); Chem. Abstr.,130,182478v (1999).
222. A. Mona Mohran, El-Sherbeny, A. Magda, El-Obaid, M. A. Abdul-Rahman, Badria
Farid; J. Pharm. Sci, 12(1), 39-44 (1998); Chem. Abstr., 129, 58397w (1998).
223. Gupta K. A., Saxena A. K., Jain P. C., Dua P. R., Prasad C. R., Anand Nitya;
Indian J. Chem., 22B, 789-94 (1983); Chem. Abstr, 100, 103282f (1984).
224. Hu Chun, Ding Licheng, Xing Guying, Xin Uatian, Warg Shengfu;
Zhongguo Yaown Haaxue Zazhi, 11, 255-58 (2001). Chem. Abstr., 137, 169475a
(2002).
264
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
225. Baldev Kumar, Balbir Kaur, Jatinder Kaur.
I. J. Chem. Vol. 41B, 1526-30 (2002).
226. Barbuliene M. M., Udrenaite E., Gaidelis P., Vainila V. P.;
Polish J. Chem., 76(4), 557-63 (2002); Chem. Abstr, 137, 154892b (2002).
227. Amjad Ali, Ganle E. T., Ken Ellsworth, Georgiana Harris, Ronald Painter,
Lynn L. Silver, and Katherine Young;
J. Med. Chem., 46(10), 1824-30 (2003).
228. Abd El-Gahil, E. Arr and M. M. Abdulla;
Indian J. Heterocycl. Chem., 12, 129-34 (2002).
229. Martin Bolli, Christoph Boss., Fischli Walter, Clozel Martine, Welles Thomas;
Chem. Abstr., 137, 93766q (2002).
230. Hang G. Z., Liu Z. J. Shimojk:, Zhu B. T; Cancer Res; 65(2) 38793 (2005)
231. Yamamoto; yakuguku zasshi;, 125 (1) 73-120 (2005)
232. Tsutsumi Hideo, Vonishi Satoshi, Akhahane Atsushi;
PCT. Int. Appl. WO 03 57, 689 (CL. C07 D 403/05) (2003); Chem, Abstr. 139.117434z (2003)
233. Ibrahim. Ahmed, Mohamad Kamal;
J. Indian Chemical Soc., 66, 393-397 (1989).
234. Jairo Quirogy, Alvarado Mario;
J. Heterocycl. Chem. 1998.
235. Dayochenko U. P.;
Russ. J. Org. Chem.,34 (4), 554-556 (1998): Chem. Abstr., 130. 223222c (1999).
236. Okazoe Takashi;
PCT Int. Appl. WO 00 06, 547; Chem. Abstr., 132, 321784y (2000).
237. Kanded Ez-H-Din M.;
Chin. Pharm, J. 1999): Chem. Abstr., 132, 321784z; (2000)
238. Samour A. V. Akhnookh and H. Jahine, (Pac. Sci. Ain Sharm Uni. Cairy UAK)
J. Chem. 1970 13(4), 421-37(Eng.):Chem. Abstr., 77. 10134g (1972).
265
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
239. V. Scott and E. Joseph;
Jap. Pat., 2, 803, 592 (1979); Cham. Abstr., 92, 4721b (1980).
240. V, Scott and E. Joseph;
Jap. Pat., 7, 998. 338 (1979); Chem. Abstr., 92, 8242f (1980).
241. W. Von Behenburag, J. Engel. J. Heese and K. Thiale;
Ger Offen., D. E., 3, 337, 593 (CIC 07D 213/72) 1984; Chem. Abstr, 101,130595n (1984)
242. M. R. Pavia, C. P. Taylor, F. M. Hershenon and S. J Labbeslael;
J. Med. Chem., 30, 1210 (1987).
243. Omar M. T., Fatima. Hamad, Gl-Deem, Shehab;
J. Pharma Sci. 37(1-6), 233-240 (1996); Chem abstr., 126, 251105c (1997),
244. Dyahenku V. D., Krivokolysko S, G., Neslecou V. N,; Litvnov
Chem. Helsroeycl. compd., 33(12), 1430-1437 (1998); Chem. Abstr., 1129,230617t (1998).
245. Nebel, Kurt, Brunner, H-Geary. S, Rolf;
PCT Int. Appl. WO 98 21 199; Chem. Abstr., 129, 27898t (1998).
246. Abdallah Nevine A., Zamimagdi E. A.;
Acta Phama (Zagreb) 1999; Chem. Abstr, 132, 1372S7n (2000).
247. Al-Omran, Fatima. Elassar, Abdel. EI-Khiair Abdel-A.;
PCT Inl Appl. WO 04, 29, 679 (Cl C07D 408/09); Chem. Abstr., 136, 309834q
(2002).
248. S. S. Verma, R Taneja, L. Prakash, A. L. Mittal;
J. Ind.Chem, Soc. 65, 798 (1988)
249. Y. Sosaki, J. Takuro, M. Ooishi, M.Sekine and S. Imaki;
Jpn. Kokal Takkyo Koho J.P., 06, 315. 390 (1994); Chem. Abstr, 122, 131184y
(1995).
250. Ijmde Teu. Kusunoki, Masayuki Takuro. Maechara Shinya, Kutsume Saiikhi;
Jpn. Kokai Tokkyo Koho JP 09. 95,489 (1997) Chem. Abstr., 127, 17690y
(1997).
251. Hussans M., Eman H. A. El., maghruby A. A.;
J. Serb. Chem Soc., 62 (7) 541-549 (1997); Chem., 127, 638p 19069v (1997).
266
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
252. Guru S. Gadaginamath, Ashok S. Shya digeri and Rajesh R. Kavali;
Indian J. Chem., 37B. 1137c (1998).
253. Manna Fedele, Chimenti Franco. Bolasco Adriana Bruna, Filippeli Walter, Filppelli
Amelia, Gansliardi, Luigi;
Eur. J. Med. Chem., 34 (3). 245-254 (1999); Chem. Abstr, 130, 352178s (1999).
254. Hammamma Abou. Elfatoon G., El-Hafeza N.A., M. Wandall, Z. Naturforsch B.;
Chem.'Sci., 2000.
255. Ranjan C. Khunt, N. J. Datta. F M. Bharmal. G. P Mankad and A. R.Parikh;
Indian J. Chem. 10 97 (2000).
256. Akhil Bhait, H. H. Parekh, K, Parikh and A. R. Psrikh;
Indian J. Chem., 40B. 57 (2001).
257. Pyachenko U.D., Roman S.V.;
Visnik Kharkius Kogo. Natsioriol nogo. Uni 495-59-64 (Russ) Chem. Abstr.,136 (21), 325448x (2002).
258. EI-Taweel F. M. Sofan M.A.;
Egyption J. Med. Chem., 36(2), 539-534 (2002); Chem. Abstr., 137.63154w
(2002).
259. A.V. Dobaria, J. R. Patel, H. H. Parekh;
J. Jndidn Chem. Soc, 79, 772-773, (2002).
260. Lowingar Timothy B., Murata Toshiki, Umeda Masaomi Sakakibare;
PCT Int. Appl. WO 02 24, 679 (Cl. C07D 401/04); Cham Abstr., 136, 279345m
(2002).
261. Haruda Hiroki. Moritano Ayako, Takuwa Tomofumi, Hirano Yuruke:
Jpn Kolai Tokkyo Koho.JP 03, 183, 254 (2003) Chem. Abstr., 139,69158p
(2003).
262. Mona M. Kamal, Manal M. Hussein;
Indian J. Chem., 42(B). 2136-2141, (2003).
263. Villhauer Edwin B., Brinkman John A. Naderi Goli B., Burkey Bryan F., Hugher
Thomas E,; J. Med. Chem, Abstr 46 (13), 2774-2789 (2003).
264. Augustin M. and Jeschke P.; J. Prakt. Chem. (1987); Chem. Abstr., 111, 7246d
(1989).
267
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
265. Piao Minz Zhu and Imatake Kimiaki; Tetrahedron Lett., 38 (30), 5301-62(1997);
Chem. Abstr., 127, 190659h(1997).
266. Selim Mohmed R.; AI-Azhar Bull. Sci(1997); Chem. Abstr., 130,110131d
(1999).
267. A. Chan Seng, H. Brrimble Margaret; Aust. J. Chem. (1998); Chem. Abstr., 129,16015f (1998).
268. Hallet Michaei R., Painter James E., Quayle Peter etal.; Tetrahedron Lett.
(1990);Chem. Abstr.,129, 16033f(1998).
269. El-Sayed Ahmed Mohmmad, Mohmed Mournir Abbas Ali et al.;
Gaaz.Chima ital. (1997); Chem. Abstr., 129, 4604c (1998).
270. Hassanien A. A., Zahran M. D., El-Gaby M. S. A. et al.;
J. Indian Chem. Soc. (1999); Chem.Austr., 131, 2142491(1999).
271. Shesto Palov Anotoly M., Niazimbetova Zukhira et al., Heterocycles (1999);
Chem. Abstr., 131, 44172m (1999).
272. Hsung Richard P., Zificsak Craig A., Wei Lin-Li et al.;
J. Org. Chem. (1999); Chem. Abstr., 132, 49557f (2000).
273. Kiokol G. G., Kalovokolysko S. G., Kya Chenko D. V. et al.; Chem. Heterocyclic
Compd, (N. Y.) (1999) Chem. Abstr., 133, 434771 (2000).
274. Emorsy S. S., Habib O. M. and Matwally M. A.; An. Quim., 83(7-8), 711-13
(1993); Chem. Austr., 121, 108724V (1994).
275. Elssar A. Z. and Abdelzaher A.; Pharmazie, 53(4), 223-27 (1998);
Chem. Abstr., 129, 4562q (1998).
276. Abdel-Ghany H., Moustafa H. M. and Khodairy A.; Synth. Commun., 28 (18),
3431-41 (1998); Chem. Abstr., 129, 260360w (1998).
277. Barbero Asuncion, Garcia Carios, Gonalez et al.; Synthesis, (6), 628-30 (1997);
Chem. Abstr., 127, 176325q(1997).
278. Assay M. G., Hassanien M. M. and Zaki S. A.; Pol. J. Chem., 69(3), 371-75
(1995); Chem. Abstr., 123, 32875p (1995).
279. De Lera Angel R., Torrada Alicia, Rey Jose and Lopez Sussana;
Tetrahedron Lett., 38(42), 742-44 (1997); Chem. Abstr., 128, 13179b (1998).
268
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
280. A. M. Hussein, I. S. Abdel Hafez and M. H. Elnagdi. Journal of the Chinese
Chemical Society, 2000, 47,347-350.
281. M. Mittelbach, V. Wagner and C. Kattky; Ann., 889 (1987).
282. M. H. EI-Moghayer, M. A. Kalifa, M. K. Ibrahim and M. H. EI-Nagadi;
Monicch. Chem., 53, 133 (1982).
283. ElagameyAbdel Ghani A., Sawleim Salah Z. etal.; Collect. Czech. Chem. Commun.,
53(7), 1534- 38(1988); Chem. Abstr. 110, 154095m (1989).
284. Shaker R. M.; Pharmazie, 51(3), 516 (1996); Chem. Abstr., 125, 10762p (1996).
285. Xiowei Zhang, Becky Hinkle, Lisa Ballantyne et al.; J. Heterocyclic Chem., 34,
1061 (1997).
286. Tomich Paul Kostam Bohanon Micheal Turner, Steven Ronald et al.;
Eur. Pat.Appl. EP 807,629; Chem. Abstr., 128, 34684c (1998).
287. D. B. Shinde and M. S. Sionmgare; Indian J. Chem., 30B, 450 (1991).
288. Macritchie Jacquline Anne, O'Mahony Mary Josephine etal.;
PCT Int. Appl. WO 98 27,080; Chem. Abstr., 129, 81666d (1998).
289. Gulgan Ayhan Kilcigil and Rabmiye Ertan; , J. Heterocyclic Chem., 35,1485
(1998).
290. Raza Fimbelo Judih, Bandouin Geneviere, Tillequin Francois et al.; Chem. Pharma.
Bull. (1998); Chem. Abstr., 128, 180394p (1998).
291. Wang Wuri, Li Tiechao, Mibbual Robert, Yares J. et al.; Bio. Org. Med. Chem.
(1998); Chem. Abstr., 129, 202833s (1998).
292. Kossakowski Jerzy, Zawadowski Teoderand Saski Slawomir; Acta. Pol. Pharm.
(1998); Chem. Abstr., 129, 230614a (1998).
293 Hodu EI-Diwani, Hend El-Sharawi, Sawsan S. Mahmoud and Toshi Miyasui;
Indian J. Chem., 34(B), 2731(1995).
294. Puidgellivol Pere and Godry Elisa; Spain Patent ES 511,501.
295. M.A.AI-Haiza, M. S. Mostafa and M.Y.EI-Kady; Molecules 2003, 8, 275-286.
296. Samet A. V., Shestopalov A. M. et al., Izv. Akad. Nauk. Ser. Khim., 8,2050-55
(1996); Chem. Abstr., 129, 16039n (1998).
269
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
297. Elssar A. Z. and Abdelzaher A.; Pharmazie, 53(4), 223-27 (1998);
Chem. Abstr., 129, 4562q (1998).
298. Shaker R. M.; Pharmazie, 51(3) (1996); Chem. Abstr., 125, 10762p (1996).
299. Kuikarni Y. D., Srivastava D., Bishnoi Ana und Dua P. R.;
J. Indian Chem. Soc., 73, 45, (1996).
300. A. A. Hassanien, An. A. Zahran, M. S. A. El-Gaby etal.;
J. Indian Chem. Soc., 76, 350-54 (1999).
301. Krauze, A.; Duburs, G.; Chemistry of Heterocyclic Compounds 2002, 38(2),
251-252; Chem. Abstr., 137, 352873j (137).
302. Fowzia S. Al-Saleh and Ezzat-M. Kandeal;
Indian J. Heterocycl. Chem., 3, 273-76 (1994).
303. Lang Hans Jochem, Gerlach Vwe, Brendel Jo Chim et. al.;
Eur. Pat. Appl. EP 807, 629; Chem. Abstr., 128, 34684C (1998).
304. Dell Colin Peter and Williams Andrew Carwyn;
Eur. Pat. Appl. EP 599, 514; Chem. Abstr.; 122, 108765J (1994).
305. Milky Jehan Jehan A. A. and Sharaf Hammonda H.; Indian J. Chem.,Sec. B Org.
Chem. Incl. Med. Chem. (1998); Chem. Abstr., 129, 95421g (1998).
306. Akama Tsutomu, Veno Kimihisha; Synthesis (1997); Chem. Abstr., 128, 14002e
(1998).
307. Fujimoto Katsumi, Mikoshiba Ishamu, Tanaka Natsuki et al.;
Jpn. Kokai Tokkyo Koho JP 09 301, 915; Chem. Abstr., 128, 13147q (1998).
308. Jacobson Kenneth A., Jiang Ji-Long, Kirn-Young et al.,
PCT Int. Appl. WO 97 27, 177 (1996); 309.Chem. Abstr., 127, 190G5y (1997).
309. Jo Jae Chon, Park Sung Dae, Lim Hyan Sul-.in et al.;
PCT Int. Appl. WO 98 25, 916; Chem. Abstr., 129, 81667q (1998).
310. K. H. Popat, V. V. Kachhadia, K. S. Nirnavat and H. S. Joshi;
Indian J.Chem., 81, 1-3 (2004).
311. Korner : Ber., 17. ref. 593. (1884).
312. Hinsberg ; Ber.. 40. 4830. (1907).
270
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
313. Mouslafa. O.S.. Badr M.Z.A. :
Mansoura Sci. Bull. A. chem.. 1997; Chem. Abstr., 128, 102066e (1998).
314. Lu Fangming. Zhang Zheng Fang, Zhang Chunxia, Lin Yuting; H Uaxue Shiji 2000.
315. App Harald. Mimohan Gerald M., Tang Pengcho, Gazir Ajiv, Levitzki Alexander;
US. US 5, 792,771. US Appl. 386,021 ; Chem. Abstr. 129, 175652y (1998).
316. Nasielski Hinkens. Rayrnonde, Leveque Pierre, Caslelel Faniel. Nasieiki Jackeus;
Heterocycles 1987.
317. Keshtor M.L.. Rusanov A.L.. Belomoina N.M. Mikitaev AK.;
Russ. Chem. Bull., 197 ; Chem. Abstr., 128, 127988v (1998).
318. Seko Shinzo :
Jpn. Kokai Tokkyo Koho JP 00. 109,768 (2000); Chem. Abstr., 132, 26520Sa
(2000).
319. Kanungo S.K.. De B.. Samata A. ;
J. inst. Chem.. 1999 ; Chem. Abstr., 187148v (2000).
320. Metzner J.. Lippmann E.. Weber F.G..
Pharmazie 1981. 36(5). 368-70 (Ger.): Chem. Abstr., 95. 55520m (1981).
321. Almanni M.C.. Pirisino G., Savelli. F., Sparator F., Mana P. et al. ;
Farmaco Ed. Sci., 1981. 36(5), 1450-3. (Russ): Chem. Abstr., 108, 146999e
(1988).
322. Hansan Holger;
Euf. Pat. Appl. EP. 344. 943 ; Chem. Abstr.. 112, 216962 (1990).
323. Kartseva T.V.. Oleahko O.N., Lazareva L.I. and co-workers ;
Khim-Farm.Zh 1987.21(2), 1450-3 (Russ); Chem. Abstr., 108,1469996e (1988).
324. Takahashi Tashihiro. Hagihara Koichiro et al. ;
Eur. Pat. Appl. EP. 334-346 ; Chem. Abstr., 112, 216958x (1990).
325. Tokohashi Tashihiro. Hagihara Koichiro et al ;
Eur. Pat. Appi Ep. 338,346 : Chem. Abstr., 112, 216958X (1990).
326. Satto M.. Peana A., Alamanni M.C. et al. ;
Farmaco Ed. Set.. 41(1), 54-8 (1986); Chem. Abstr., 104, 10960J (1986).
271
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
327. Hansen Holger Claus, Watjen Frank ;
Eur. Pat. Appl. E.P. 347. 094 ; Chem. Abstr., 87, 682862 (1977).
328. Sparotor Ann. Biodo Canu, Catenna Boido, Vito Sparatore Fbio ;
Farmaco 44(10), 945-50 (1989); Chem. Abstr, 112, 151264w (1990).
329. Yaso Masao, Suzuki Yukio. Shibala Kensuke, Hayashi Elichi :
Japan. Kokai Tokkyo Koho Jp. 62, 186, 671 ; Chem. Abstr, 108, 1675012 (1988).
330. Foery Werner. Nyffeler Andreas, Gerber Hans-Rudolf, Martin Henry;
Eur. Pat. Appl. Ep. 190. 105 ; Chem. Abstr. 105, 166904j (1986)
331. Enomato-Masayuki, Nagaho Hideyashi, Sakaki Masuharu, Sato Makato;
Jpn Kokai Tokkyo Koho J. 04. 193. 876; Chem. Abstr. 117, 228449y (1992).
332. Carter Geoffrey A. Clark Terence, James Carolyn S.. Loeffler R.S.;
Thomas Pestic Sci. 14(2), 135-44 (1983); Chem. Abstr. 99, 100826m (1983),
333. Ehrenberger Klaus. Fexlix Dominik;
Eur. Pat. Appl. EP. 512, 689 ; Chem. Abstr. 119, 109008k (1993).
334. Mohmed Y.A., AI-Azbar;
Bull. Sci. 2(1). 1-12 (1991); Chem. Abstr. 119, 28101b (1993).
335. Alfreson T.V, Lam W.C.. Maki A.M., Waring M.J. ;
Appl. Magn. Reson. 2(2). 159-78 (1991); Chem. Abstr.. 117 1970f (1993).
336. Vitale Gabriella, Corona Paola. Loriya Mario, Paglietti Giriseppe ;
Farmaco.. 52(2), 150-153 (1998).
337. Nikam Sham S. ;
PCT int. Appl. WO 97. 46,539 : Chem. Abstr. 128, 61527k (1998).
338. Sakamoto Shuichi. Ohnian Junga, Shishikura Zyn Ichi, Okada Masamtchi, Sasanata
Masao; PCT Int. Appl. WO 97. 46, 555 ; Chem. Abstr, 128, 61528m (1998).
339. Huth Andrew. Ottow Eckhard, Schumaner Ingrid. Krueger Martin ;
Ger. Often. DE. 19. 728, 326 : Chem. Abstr. 130, 81529g (1999).
340. Lubisch Wilfried. Behl Berthold. Hoffmann Hans Peter, Szaubo Laszlo;
Ger Often. DE 19.624, 808 ; Chem. Abstr. 128, 102101n (1998).
341. Takada Susumu, Chornei Nobuo, Kihara Tsuyoshi ;
PCT Int. Appl. WO. 99, 62, 667 ; Chem. Abstr, 132, 22977v (2000).
272
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
342. Bourrain Sylvei. Collins lan, Neduveilil Joseph G.;
Bioorg. Med. Chem.1998 : Chem. Abstr. 130, 81487e (1999).
343. Mehta P.A.. Naik H.B. ;
Orient J. Chem. 1998 ; Chem Abstr., 130. 81489u (1999).
344. Otale P.S.. Raghuwanshi P. B. Doshi A.G. ;
Orient J. Chem. 1999; Chem. Abstr. 132, 93074 (2000).
345. El-Hawash S.A., Habib N.S., Fanaki N.H. ;
Pharmazine 1999 ; Chem. Abstr. 132, 1252584A (2000),
346. Mataszczak Barbara. Mercitor Kurt:
Heterocycles 1997, 45(2), 2449-2462: Chem. Abstr. 128, 230350e (1998).
347. Vitale Gabriella, Corono Paola. Loriya Mario. Paglietli Giuseppe : Farmaco
1998 ; Chem. Abstr., 130. 311 768r (1999).
348. S. A. Ahmed, M.D. Silverman, H. Marohe etal, Rheum Apr: 29, 60(5); 1282-
1293 (2009)
349. B. Konig, A. Koch, J. Spielmann etal, Eur. J. pharmacol, Jan 20, (2009)
350. G. Sarodrick, T. Linker, M. Heydenreich etal J. org. Chem., 74(3): 1282-7,Feb;
(2009)
351. GaoDawel, Jia-Jinli Zhang Yumin, Hua Shiying Chen Hiaodong; Jilin Daxue
Ziran Kexue Xuebao (1997); Chem.Abstr, 128, 114845w (1998).
352. Carleno M. Carmen, Parez Gonzale, Manual Ribogordaa Maria, Houk K. N. J.
Org. Chem. 1998; Chem. Abstr, 129 54166J (1998).
353. Newman Christopher Paul, Agarwal Varinder Kumar, Vennale Graham Patrick;
Eur. Pat. Appl. Ep. 854,143; Chem. Abstr, 129, 148908e (1998).
354. Kobayash Yukiwto, Takeshi, Ogita Yoshihiro, Nishimura Kazuaki; Jpn. Kokai
Tokkyo Koho JP 10,87,664; Chem. Abstr, 128, 230234v (1998).
355. Esteban Gemma, Lopez-Sanchez Mighel A., Martinez Maria Engenia, Plumet
Joaquin; Tetrahe- dron, 1998; Chem. Abstr, 128, 114765v (1998).
356. Barlier Daniel, Benhida Rachid, Vazeux Michael; Phosphorus, Sulphur
siliconrelat. Elem. 1993; Chem. Abstr, 120, 322734v (1994).
273
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
357. Kirn in O., Lee sang Gee; Brit. UK Pat. Appl GB 2,210, 040; Chem. Abstr, 120,322784V (1994).
358. Miiura Tooru, Wada Masaru, Faruya Mus?uki, Nagata Terujuki; Jpn..Kokai Tokkyo
Koho Jp 01,160932; Chem.Abstr, 112, 35332t (1990).
359. Ito Nabuhiko, HusebeAlio Takesuki; Jpn. Kokai Tokkyo Koho Jp 10, 237, 008;
Chem. Abstr, 129, 244945k (1998).
360. E. M. Hammouda., Sadek E. G., Khajil A. M. : Indian J. Hetrocyclic Chem.,
1998; Chem. Abstr, 130, 81476n (1999).
361. Taber Douglass F., Kanai Kazuo, Jiang Qin, Bui Gina;
J. Am. Chem. Soc. 2000; Chem. Abstr., 133, 176965(2000).
362. Tateishi Keiichi, Yanagihara Naoto; Jpn. Kodai Tokkyo Koho JP 04, 870,
247; Chem. Abstr, 118, 101554b(1593)
363. Matsuoka Rikitaro, Watanabe Kiyoshi; Jpn. Kokai. Tokkyo Koho JP 01, 316,
556; Chem. Abstr, 118, 14749b (1993).
364. Grenhill John V., Chaaban ibnrahim, steel peter J. J. Heterocyclic chem., 1992;
Chem. Abstr, 118, 169-70k (1993).
365. Duker Gerald, Frundt peter, Markwitz Hardu.-Henkel Gerald; J. Org.Chem. 1998.
366. Page Philip C. Marchington Allan P, Graham Lisa J. Harkin Shaun A.,Wood
William; Tetrahedron, 1993; Chem.Abstr, 120, 2448801d (1994)
367. Eman H. A. Hassan S. M., El- Mayhaby A. A., J. Serb Chem. Soc. 1997;
Chem. Abstr, 127, 190698u(1997).
368. Shldlyaev, Yu- V, ; Nifortov, Yu. V. ; Shashkov, A. S.; Firgang, S. I. Russian
Chemical Bulletin 2002, 51(12), 2234-2237; Chem. Abstr, 139, 36429z (2003).
369. Ahmad Sallem, Stein Phillip D., Ferram rancis N., Atwal Karnils;
PCT Int. Appl. Wox 98,36,740 ; US Appl. 36, 317(1997).
370. Jacobsen Poul, Trappendhi Svend, Bury Paul Stanley Kanstrup Anders,
Christiansen lise Brown;
PCT int. Appl. WO98, 18, 777; Chem. Abstr, 128, 321562s (1998).
274
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
371. Eddington, Natalie D. ; Cox, Donna S.; Khurana, Maoj, Salama, Noha N.;
Stubles, James P,; Hurrison, Sylvia a J.; Negussie, Abraham; Taylor Robert S.;
et al. Eur. Journal of Medicina chemistry 38 (1), 49-64 (2003); Chem. Abstr,109, 36284y (2003).
372. Cragoe, Edward, J. Jr.; Woltersdorf Otto W.; U.S. US 4,654,365 (Cl. 514,469;
A61K31/34), 31 Mar 1987, Appl. 780,144, 26 Sep 1985; 10 pp; Chem. Abstr,,107, 7061g (1986).
373. Alwarz Lilian, Tamaj, Anzik Borut Kuzman Tadeja, Mesar Tomaj, Koczan Darko;
Chem. Commun. 1998; Chem. Abstr., 129, 95339m (1998).
374. Copar Auton, Salmajer Tomeym Anzik Borut Kuzman Tadeja, Mesar Tomaj,
Koczan Darko; Eur. Pat. Appl. EP 854, 143 ; Chem. Abstr, 129, 148908e (1998).
375. Assy M. G., Hutaba A. A.;
J. Indian Chem. Soc., 12997; Chem. Abstr, 127, 5060u (1997).
376. Gilkerson Terence, Shaw Robert William;
Eur. Pat. Appl. Ep. 310, 186; Chem. Abstr, 111, 23259x (1989).
377. Tvanow.E. I., Konul. P., Kenup L. A. ; Stepanou D. E., Grishehak V., Khim-FarmZh.
1993; Chem. Abstr, 121, 35462w(1994).
378. Scott Kenth R., f.'icholson Jtde M., Fdanogho ivan O.
PCT Int. Appl. WO 93 17, 678; Chem. Abstr, 120, 133914U (1994).
379. Krichevshkii E. S., Alekseeva L. M., Anisimova O. S., Parshin V. A., Ashina V. V.,
Granik V. G.; Khjirn. Farm, Zh. 1997; Chem. Abstr, 128, 244027s (1998).
380. Shimazaki Toshiyuki, Yamashita, Hiroyast, Jpn. Kokai Tokkyo Koho JP 09 118,
653; Chem. Abstr, 127, 3410; (1997).
381. Salama M. A. Atshikh M. A.; Egypt. J: Pharm. Sci. 1997; Chem. Abstr 130,81478q (1999).
382. Fukami Takehiro, Fukurofa Takahiro, Kanatani Akiolharo,
Pet Int. Appl Wo. 9915,516; Chem. Abstr, 130, 237476a (1999).
383. Broughton Howard Braff, Bryant Helen Jane, Chambers Mark Stwart,Curtis
NeilTtoy; PCT Int. Appl. WO 99, 62, 889, Chem. Abstr, 132, 12259y (2000).
275
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
384. Kimura Yasuo, Mizuno Takushi, Kowaho Tsuyoshi, Shiimata Aslami;
Naturfursch. B. Chem. Sci. 1999; Chem. Abstr, 132, 355551 b (2000).
385. A. R. Grey and J. B. Dickey;
Org. Syn. Coll. 2, 60 (1943).
386. C. B. Reese and S. R; James;
Tetrahedron Letters, 2915 (1975).
387. Gill G. Bryon, Hidris Muhammad S.;
Tetrahedron, 49, 219-34 (1993); Chem. Abstr., 118, 191669n (1993).
388. Gursu Esin, Vlusoy Nuray;
Acta. Pharma. 38(4), 107-9 (1996); Chem. Abstr., 126, 59802m (1997).
389. Ogus Funda, Dogsn Llknur;
Spectrosc, Lett., 31(2), 469-82 (1993); Chem. Abstr., 129, 16097e (1998).
390. M. R. Mahmoud, Awatef E. F Ebrahim, M. S. Abd EI-Halim,A.M. Radwan;
Indian J. Heterocyclic Chem., 4, 131 36 (1954).
391. Cao-Yun Weu, Chai Xian Dong, Jiang Yup-Shan et al;
GaodenQ Xuexiao Huaxue Xuebao, 16(2), 225-29 (1995); Chem. Abstr., 123,3302lu (1995).
392. R K. Roy Chowdhury, S. Mehrotra, S. SrivaMava, R K. Srivastava;
Indian J. Heterocycic Chem., 12, 221-24 (2003).
393. Y. K. Gupta, K. P. Bhargava, K. Shanker, J, C. Agarwal;
Indian J.Chem., 20B, 714 (1981).
394. J. C. Agrawal, Y. K. Gupta, R Kumar, C. Nath, K. R Bhargava and
K. Shanker; Indian J. Chem., 22B, 955 (1981).
395. Y. Furukawa;
European Potent Appl. EP 88, 413 (1983): Chem. Abstr:, 100, 22688u (1983).
396. Z. H, Khalil, A. I. M. Koroiem and R. M. Abu-El-Hameed;
J. Chem. Technol, Biotechnol., 36, 473 (1986).
397. D. Peters, A. B. Hornfield and S. Gromowitz;
J. Heierocydic Chem., 27, 2165 (1990).
276
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
398. Raymond R, Diane L., Dan-Chang Wei, Wang;
J. Heterocydie Chem., 30, 1399 (1993).
399. R. F. Burns;
J. Heterocyclic Chem., 33, 1025 (1996).
400. A. G. Manukyan, R. G. Malik, B. T. Guri b-dzhanyan;
Khim-Pharm., Zh., 19, 685 (1995); Chem. Abstr., 104, 207622s (1996);
401. Wyzlic 1. M., Tjarks W, Soloway A. H., Perkins D. J., Burgos M.;
Inorg. Chem., 35(16), 4541-47 (1996); Chem. Abstr., 125, 168582a (1996).
402. Bosies Elmar, Eswein Angeiika, Grams Frank, Krellohans Willi;
Ger. Offen. DE 19, 548, 624 (Ci. C07D 401/04) (1997); Chem. Abstr., 127,121746x (1997).
403. Abdel-Hamide S. G., El-Hakim A. E., El-Helby A. A.;
Al-Azhar J. Pharm. Sci., 17, 35-40 (1996): Chem. Abstr., 126, 225269q (1997).
404. Shivanyuk A. N., Rudkevich D. M., Rcinhoudt D. N.;
Tetrahedron Letters, 37(52), 9341-44 (1996); Chem.Abstr., 126, 144028H
(1996).
405. Wolf-Gang, Hanefeld and Helge Hurms:
Indian J. Heterocyclic Chem., 34, 509 (1997).
406. Andre Rolcind, DoIIinger Markus and Erdelen Christopher; Ger. Ojjen DE 19,
715, 017 (Cl. C07D 401/12) (1998); Chem. Abstr., 129, 302655d (1998).
407. Omar M. T.;
Egypt J. Pharma. Sci. 38, 281-89 (1997); Chem. Abstr., 131, 257514k (1999).
408. Sakai, Kunikazu, Satoh, Yusuke;
PCT Int. Appi. WO 99, 50, 252 (Cl. C07D 239/62) (1999): Chem. Abstr.,131,243286a (1999).
409. Grams Frank, Zimmermann Gerd;
PCT Int. Appl WO 98, 58,915 (Cl. C07D 239/00) (1999); Chem. Abstr., 130,95559d (1999).
410. Oliua Ambrogio, De Cillis Gianpiero, Grams Frank, Livi Valeria, Menta Ernesto;
PCT Int. Appi. WO 98, 58, 925 (Cl. C07D 401/12) (1999); Chem. Abstr., 130,95560x (1999).
277
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 278
411. R. J. Pardasani, S. K. Jain, S. K. Yadav, I. Sharrna;
Indian J. Heterocyclic Chem., 12, 179-80 (2002).
412. Geppert Dagmar, Grams Frank, Krell Hans-Willi, Leinert Herbert, Menta
Ernesto; PCT Int. Appl WO 02, 79, 170 (Cl. C07D 239/62) (2002);
Chem. Abstr., 137, 294967e. (2002).
413. Hung Taishng, xiaman Daxye xyebao; ziram Kexueban, 33(G), 827-31 (1994);
Chem Abstr; 123 9277m (1995).
414. Ersher A. U. Gribanov A. V. Gindin V.A.;
Russ. J. Org. Chem. 33(10), 1490-93 (1997); Chem. Abstr. 129 202913t (1998).
415. Hunter Duncan H; M.C, Roberts Chontelle, Vittal Juga dese j; Can. J. Chem.; 76
416. Casas J. S. Castellano E.E. Gracia Tasende M. S.; Sanche Z. A. Polyhedrom, 17
(13-14), 22 49-56 (1998); Chem. Abstr., 129, 15 15678n (1998).
417. Tomchin A. B. Russ. J. Org. Chem.; 33(4), 567-68 (1997) Chem. Abstr. 128,192597t, (1998).
418. Perumai Yogeeswari, Dharmarajan Sriram, Logantha Ramamoorthy,
Sathiyanesan Sathishkumar, James Stables : Eur. J. Med. Chem., 37, 231-236
(2002).
419. E. T. Dickson, J. R Scovill, D. L. Kayman, A. S. Dobek, E. C. Trumoht; Antimi
crobial agents, Chemother., 18, 27 (1980).
420. Rao K, Srinivasa Rastogi K., Sridhar. D. R., Jain M. C.;
Indian J. Chem., 26B, 596-98 (1987); Chem. Abstr., 108, 150395v (1998).
421. Kalyancuoglu M, Rollas S., Yegenoglu Y. et al;
Pharmazie, 47(10), 796-97 (1992).
422. Cesur Nersin, Cesur Zafar and Guersoy Aysel;
Arch-Pharm., 35(9), 623-24 (1992); Chem. Abstr., 118, 6327j (1993).
423. Missbach Martin;
PCT Int. Appl. Wo 14, 686 (Cl. C07D27/06) (1995); Chem. Abstr., 123, 169641d
(1995).
424. Zhong Mehg, Liu Luosheng, Wen Xiao Xia, Ling Pei Xhe;
Huaxi Yaocue Zazhi, 12(2), 85-86 (1997); Chem. Abstr., 127, 65635w (1997).
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 279
425. J. F. Bartoseivch, T. S. Griffin, C. J. Manson, J. R Scovill;
J. Med. Chem., 22, 855 (1997).
426. Kanvechi B., Johnson C. B., Cellik C and Yuksek H.;
Acta Pol. Pharm., 54(4), 307-12 (1997); Chem. Abstr., 128, 396 (1998).
427. E. Silva Maria Joselice, Alves Antonio Jose, D O Nasimento Silene C.;
Formaco, 53(3), 241-43 (1998); Chem. Abstr, 129, 109012p (1998).
428. Hu Wei-Xiao Sun Nan, Yong Zhong Yu;
Goodeng Xuexiao Huaxue Xuebao 22(12), 2014-17 (2001); Chem. Abstr,136, 294802b (2002).
429. Kalyan Couglu K., Rollas S.,Yegenogly Y;
Pharmazie, 47(10), 796-97 (1992).
430. A. M. Abdel-Halim, Fekria S. Sayed, R. M. Abdel-Aziz, H. S. El-Dein;
Indian J. Heterocyclic Chem., 3, 201-204 (1994).
431. Siatra T, Tsotinis A., Sambari C., Thomou H.;
Eur. J. Med. Chem., 30(2), 107-14 (1995); Chem. Abstr, 123, 11798u (1995).
432. Quianawin Zhao, Wan Xinba, Liu Cuiyibang, Wang Defeng;
Chem. Abstr., 129, 336521a (1998).
433. E, Silva Maria Joselice, Alves Antonio Jose, Silence C.;
Farmaco, 53(3), 241-243 (1998); Chem. Abstr, 129, 109012p (1998).
434. wang Deteng. Wan Xinbo, Liu Cuiyibang, Zhao Quianquin;
Huxai Yaoque Zohi 13(2), 75-76 (1998); Chem. Abstr, 129, 336521a (1998).
435. Krezel Izabella;
Acta Pol. Pharma. 55(2), 125-28 (1998).
436. Fedorova O. V, Mordovskoi G.G., Rusinov G. L.;
Khim-farrr. Zh. 32(2), 11-12 (1998); Chem. Abstr., 129, 81555s (1998).
437. Li Jun, Niu Chuhan-Sheng, Li Xiuyan, Doyle Terrenes V.;
U. S. US 5, 767, 134 (Cl. 514-533 A 61k 31/34), (1998); Chem. Abstr, 129,677109.g (1998).
438. Magalhaes Nereide, Stela Santos, Alves Antonio Jose, Alencar et at.;
Reu. Cienc, Farm. 19(1), 49-66 (1998); Chem, Abstr., 130, 223025t (1999).
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 280
439. D. Sharma, B. Narasiman, Pradeepkumar, V. Judge;
Euro J. of medicinal Chemistry Vol. 44, issue 6 P. 2339-2764 (Jan-2009)
440. S.P. Rodriguez M.A. Qrtiz, F. Rodriguez Euro J. or medicinal Chemistry Vol. 44,
Issue 6 P 2434-2446 (Jan-2009)
441. G. E. Iniama. O. E. Offiong, E N-for, A.A. Ayi Global J. of pure and applied sci
ence Vol. 14(4) 2008 PP 411-416.
442. Jin Shuhui, Chen Li, Zhang Zhenye, Liang Xiaomei;.
Nongyaoxue Xnibao 1(3), 88-90 (1999); Chem. Abstr., 135, 92383j
443. Rajasekaran A. and Murugesan S.;
J. Indian Chem. Soc. 79(6), 544-45 (2002); Chem. Abstr., 137, 369945g(2002).
444. Nilgun Karali;
Eur. J, Med. Chem., 37, 909-18 (2002).
445. Siverstein Basler and Mosil;
Spectroscopy Identification of Organic Compounds (1981).
446. M. D.Aptekar, I. I. Korol, E. P. Trilina and I. P. Savich;
Zh(Kivo), 36 (41) 502 (1974).
447. W. F. Bruce;
U. S. 854, 281, (1975), Chem Abstr., 82 980169 (1975).
448. V. M. Parikh,
"Organic - Spectroscopy page (64) and Ind. J. Chem., 27B, 1024 (1988)
449. C. N. Rao;
"Chemical application of infrared spectroscopy" acadamic press, New York,
(1963).
450. V. K. Ahluwalia and Sunita Dhingra;
"Comprehesive Pracical Organic Chem.," Application of Spectroscopy to the
Indentification of Organic Comps., p 73, (2002).
451. F. Cavanth;
"Analytical Microbiology" Academmic press, New York, 126 (1963).
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds 281
452. V. M. Parikh,
"Absorption Spectroscopy of Organic Molecules" Addition Wesley
Publishing Company, London, 243-258 (1978).
453. N. B. Colthum. L. H. Daly and S. E. Wiberley;
"Introduction to infrared and Raman Spectroscopy" Academic Press,
New York (1964).
454. A. R. Kartizky and R. Alan Jones;
J. Chem. Soc., 2942 (1960).
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds
Synthesis, spectral studies and therapeutic activity of Heterocyclic compounds