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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


DedicatedtoMy Belove d Pare nts


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.


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 STUDIESAND

THERAPEUTIC ACTIVITYOF



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.


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



Section - II : Synthesis and antimicrobial activity of5-{4'-[(5"-aryl)-4",5"-dihydro-1"N-acetylpyrazol-3"-yl]- phenyl carbamido}-dibenz [b,f] azepines.


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.


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.


Section - II : Synthesis and antimicrobial activity of5-{4'-[(6"-aryl)-2"-hydroxy-3"-4"-dihydropyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.



Section - III : Synthesis and antimicrobial activity of5-{4'-[(6"-aryl)-2"-amino-3"-4"-dihydropyrimidine-4"-yl] phenyl carbamido}-dibenz [b,f] azepines.


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.


Section - II : Synthesis and antimicrobial activity of5-{4'-[(4"-aryl)-3"-cyano-2"-methoxy pyridine-6"-yl]phenyl carbamido}- dibenz [b,f] azepines.


Section - III : Synthesis and antimicrobial activity of5-{4'-[(4"-aryl)-3"-cyano-2"-ethoxy pyridine-6"-yl]phenyl carbamido}- dibenz [b,f] azepines.


Section - IV : Synthesis and antimicrobial activity of5-{4'-[(4"-aryl)-3"-cyano-2"-hydroxy pyridine-6"-yl]phenyl carbamido}- dibenz [b,f] azepines.



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.


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.


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.


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.



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


SYNOPSIS

1


"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


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


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


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


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


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


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


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


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


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


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 STUDIESAND

THERAPEUTIC ACTIVITYOF


13


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


(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


(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


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


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


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


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


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


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


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


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)


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


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


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


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


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


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


(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


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


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


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


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.


PART - II

STUDIES ON ISOXAZOLES

37


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


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


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


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


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


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


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.


3.756.76.8

7.0 - 7.76.9

Relative No.of protons

3 H1 H1 H16 H2 H

Multiplicity


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


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


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


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


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


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


49


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


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.


PART - III

STUDIES ONPYRAZOLINES

52


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


(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


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


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


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


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


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


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


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.


3.906.335.21

6.9-7.46.82.151.86


60

3 H1 H1 H16 H2 H2 H1 H


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


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


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


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 -


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


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.


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


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


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


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


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


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


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


3.606.402.97

6.9-7.66.932.52.9


3 H1 H3 H16 H2 H2 H1 H



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


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


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


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


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


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.


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


75


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


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.


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.


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


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


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


3.656.32.9

6.9-7.46.82.22.8


3 H1 H3 H18 H2 H2 H1 H



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


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


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


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


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


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.


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.


section: I, Page No. 32-34


85


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


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.


PART - IV

STUDIES ONPYRIMIDINE DERIVATIVES

88


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


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


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


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


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


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


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 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


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

"


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


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


3.606.16.2

7.1-7.56.97.12.5


3 H1 H1 H16 H2 H2 H1 H


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


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


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


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

.


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


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.


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


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


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.


SECTION : II

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(6"-ARYL)2"-HYDROXY-3",4"-DIHYDRO PYRIMIDINE-4"-YL] PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES


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.


analyses IR, 1H NMR, Mass spectral study. The products were screened for



Type (VII) R=Aryl

105

R

O

N

NH

NH N

OH


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


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


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


3.036.176.11

6.9-7.36.77.32.16


3 H1 H1 H16 H2 H2 H1 H


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


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


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


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


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


EXPERIMENTAL

SYNTHESIS OF 5-{4'-[(6"-ARYL)-2"-HYDROXY-3",4"-DIHYDROPYRIMIDINE-4"-YL]-N-PHENYLCARBAMIDO}-DIBENZ [b,f]AZEPINES.


(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.


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,



112


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


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


SECTION : III

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(6"-ARYL)2"-AMINO-3",4"-DIHYDRO PYRIMIDINE-4"-YL] PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.


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.


analysis IR,1H NMR, Mass spectral study. The products were screened for



Type (VIII) R=Aryl

R

O

N

NH

NH N

NH2

115


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


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



(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


3.796.24.864.80

7.1 - 7.56.97.0


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineReflux


Guanidine Hydrochloride

Type (VIII) R=Aryl

R

O

N

NH

NH N

NH2

120


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


EXPERIMENTAL

SYNTHESIS OF 5-{4'-[(6"-ARYL)-2"-AMINO-3",4"-DIHYDROPYRIMIDINE-4"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES.


(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


122


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


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


PART - V

STUDIES ONCYANO PYRIDINES

125


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


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


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


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


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


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 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


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

"


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



(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


3.906.35.3

7.0-7.66.76.4


3 H1 H2 H16 H2 H1 H



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


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineReflux


CH2(CN)2

CH3COONH4

Type (IX) R=Aryl

R

O

N

NH

N

NH2N

137


EXPERIMENTAL

SYNTHESIS OF 5-{4'-[(6"ARYL)-2"-AMINO-3"-CYANO PYRIDINE-4"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.


(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,


The zone of inhibition of the test solutions are recorded in Table No. 18

138


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


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


SECTION : II

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(4"-ARYL)3"-CYANO-2"-METHOXY PYRIDINE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.


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.


analysis IR,1H NMR,Mass spectral study. The products were screened for


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


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

"


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



(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


3.646.33.44

6.9-7.36.86.3


3 H1 H3 H16 H2 H1 H



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


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineRefulx


CH2(CN)2

CH3ONa

Type (X) R=Aryl

R

O

N

NH

N

O CH3

N

147


EXPERIMENTAL

SYNTHESIS OF 5-{4'-[(4"ARYL)-3"-CYANO-2"-METHOXYPYRIDINE 6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES


(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.


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


(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,



148


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


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


SECTION : III

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-ETHOXY PYRIDINE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.



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 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


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

"


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



(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


3.826.31.3

7.0-7.56.86.43.31


3 H1 H3 H16 H2 H1 H2 H

SingletSingletTriplet


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


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineReflux


CH2(CN)2

C2H5ONa

Type (XI) R=Aryl

R

O

N

NH

N

O

N

CH3

157


EXPERIMENTAL

SYNTHESIS OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-ETHOXYPYRIDINE 6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f]AZEPINES


(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.


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


(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,



158


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


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


SECTION : IV

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-HYDROXY PYRIDINE-6"-YL]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.



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



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



(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


3.756.162.13

6.8-7.76.96.6


3 H1 H1H

16 H2 H1 H



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


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineRefulx


Type (XII) R=Aryl

(1) Ethyl cyano acetate(II) CH3COONH4

R

O

N

NH

N

OH

N

167


EXPERIMENTAL

SYNTHESIS OF 5-{4'-[(4"-ARYL)-3"-CYANO-2"-HYDROXYPYRIDINE-6"-YL]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.


(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.


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


168


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


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


PART - VI

STUDIES ONCYANO PYRANS

171


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


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


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


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


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


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 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


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

"


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



(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


3.626.74.85

6.9-7.86.66.91


3 H1 H2 H16 H2 H3 H



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


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


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


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 -


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineRefulx


CH2(CN)2

in Pyridine

Type (XIII) R=Aryl

O

N

NHR

O

NH2

N


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.


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,



184


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


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.


PART - VII

STUDIES ONQUINOXALINES

187


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


(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


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


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


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 details have been cited in the part : I, Section I. Page No. 32-34

Type (XIV) R=Aryl

O

N

NHN

NR

192


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

"


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


NMR SPECTRAL STUDY OF 2"-[(4"'-METHOXY PHENYL)-(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f] AZEPINEQUINOXALINES.

194

SignalNo

12345


3.606.923.06

7.0-7.76.93


3 H1 H2 H20 H2 H


MultipletDoublet

Ar-OCH3a

-NHb

-CH2c

Ar-Hd

Ar-He


(300MHz)

a

b

d d ddd

d

d dd

dd

d

e

e

dcd

dO

N

NHN

N

OCH3

dd

d

d


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


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


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


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


Br2 ingl. CH3 COOH

O

N

NHN

NR

NH2

NH2

198


EXPERIMENTAL

SYNTHESIS 2"-(4"'-ARYL) [(3"-METHYL PHENYL CARBAMIDO)]-5-DIBENZ [b,f] AZEPINE QUINOXALINES.



(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


Simillary other componds were prepared and their physical data are


(E) Antimicrobial activity of (2"-aryl)-[(3"-methyl phenyl carbamido)-5-dibenz [b,f] azepine quinoxalines..




200


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


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.


PART - VIII

STUDIES ONCYCLOHEXENONES


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


(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


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


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


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 .


analysis IR,1H NMR, and Mass spectral study. The products were screened


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


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


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



(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


3.646.51.2

7.0-7.76.93.87.085.96.9


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


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineReflux


Type (XV) R=Aryl

O

N

NH

O

R

O

OCH3

(1) E. A.A.(2) C2H5ONa

214


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


(C) Synthesis of ethyl[6"-(4'"-methoxy phenyl)-4"-phenyl carbamido]-5-dibenz [b,f] azepines-2"-oxo-cyclohex-3"-ene-1"-carbaxalate


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,



215


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


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.


PART - IX

STUDIES ON BARBITONES


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.


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


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


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


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 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


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


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



(300MHz)

NMR SPECTRALSTUDY OF 5-{4'-[3"-(4"'-METHOXY PHENYL)-2"-PROPENE-1"-BARBITURIC ACID]-PHENYL CARBAMIDO}-DIBENZ [b,f] AZEPINES.

225

SignalNo

123456


3.646.46.91

7.0-7.46.83.72


3 H1 H2 H16 H2 H2 H


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


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


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


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineRrflux


Type (XVI) R=Aryl

O

OO

NHNH

in gla. CH3COOH

229

O

O

N

NH

NHNH

R

O

O


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


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,



230


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


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.


PART - X

STUDIES ONTHIOSEMICARBOXIMIDES

233


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


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


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


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


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 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


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


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



(300MHz)

NMR SPECTRAL STUDY OF 5-{4'-[3"-(4"'-METHOXY PHENYL)-2"-PROPENE-1"-THIOSEMICARBOXIMIDES]-PHENYLCARBAMIDO}-DIBENZ [b,f] AZEPINES.

240

SignalNo

1234567


3.596.76.91

7.0-7.76.913.212.32


3 H1 H2 H16 H2 H1 H2 H


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


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+


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.


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


Reaction Scheme

N

OCl

O

CH3

NH2+

N

O NHO

CH3

R

N

O NHO

PyridineReflux


Type (XVII) R=Aryl

O

N

NH

N

R

NH S

NH2

RefluxThiosemicarbazide

244


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


(C) Synthesis of 5-{4'-[(3"-(4'"-methoxy phenyl)-2"-propene1"-thiosemicarboximides]-phenyl carbamido}-dibenz [b,f] azepines


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,



245


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


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.


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


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


28. Rasaki Abayomi Osisany, James Olabisi Oluwadiya;


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


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


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


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


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 ;


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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).


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).


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).


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).

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