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STUDIES ON CHEMICALENTITIES OF THERAPEUTIC

INTERESTA THESIS

SUBMITTED TO THE

SAURASHTRA UNIVERSITY

FOR THE DEGREE OF

Doctor of PhilosophyIN

THE FACULTY OF SCIENCE (CHEMISTRY)

BY

Dinesh J. Paghdar

UNDER THE GUIDANCE

OF

Dr. H. S. Joshi

DEPARTMENT OF CHEMISTRY

SAURASHTRA UNIVERSITY

RAJKOT - 360 005.

INDIA

2005

P X

PQ

Gram : UNIVERSITY Phone : (R) 2584221Fax : 0281-2577633 (O) 2578512

SAURASHTRA UNIVERSITYUniversity Road.Rajkot - 360 005.

Dr. H. S. Joshi Residence :M.Sc., Ph.D.F.I.C.S. B-1,Amidhara AppartmentAssociate Professor, 2- Jalaram Plot,Department of Chemistry University Road,

Rajkot - 360 005.No. GUJARAT (INDIA)

Dt. -06-2005.

Statement under O. Ph. D. 7 of Saurashtra University

The work included in the thesis is my own work under the supervision of

Dr. H. S. Joshi and leads to some contribution in chemistry subsidised by a number of

references.

Dt. : -06-2005 (Dinesh J. Paghdar)Place : Rajkot.

This is to certify that the present work submitted for the Ph.D. Degree

of Saurashtra University by Dinesh J. Paghdar is his own work and leads to advance-

ment in the knowledge of chemistry. The thesis has been prepared under my supervi-

sion.

Date : -06-2005 Dr. H. S. Joshi Place: Rajkot. Associate Professor

Department of ChemistrySaurashtra UniversityRajkot - 360 005.

Dedicated toMy Family

ACKNOWLEDGEMENTS“ Shree Ganeshay Namah “

Hats off to the Omnipresent, Omniscient and Almighty God, the gloriousfountain and continuous source of inspirations! I offer salutations to himand my head bows with rapturous dedication from within my heart, to theOmnipotent Lord “Shree Krishna”.

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. H. S. JOSHI. Associate Professor, Department ofChemistry, Saurashtra University, Rajkot, who held the torch of excellentguidance high and lighted up the darkness, with perpetual affectionateencouragement and occasional constructive criticism when needed, towardsthe goal of my academic journey.

I also owe to, from the deepest corner of heart, deepest sense of gratitudeand indebtedness to Dr. (Mrs.) H. H. Parekh, Professor and Head, Departmentof Chemistry, Saurashtra University, Rajkot, as I have been constantlybenefited with her lofty research methodology and the motivation as well ashis highly punctual, affectionate, yet noncompromising nature which alwaysinspired me in heading rapidly towards my goal and helped me achieving theaim of my present task very speedily.

I wish to thank Dr. R. C. Khunt, for her constant guidance and moralsupport during the course of my research work.

Who in this world can entirely and adequately thank the parents whohave given us everything that we possess in this life? The life it self is theirgift to us, so I am at loss of words in which to own my most esteemed fatherShri Jayntibhai and My loving mother Late Smt. Chaturaben and mostvenerated grand father Laxmanbhai, grand mother Jeeviben. Through the stressand strain of this study, my younger brother Vimal, has encouraged me toreach my destination.P X

PQ

As with the completion of this task, I find myself in difficult positionon attempting to express my deep indebtedness to Praful Chovatia . I wish tothank Zalavadia Paresh for his most willing co-operation and comprehensiveexchange of ideas during the course of my research work.

I offer my heart full gratitude to Purohit Dushyant, Manavar Dinesh,Kachhadia pankaj, Rokad Sunil, Ladani Mahesh, Joshi Mayur, Akabarijignesh, Arun Mishra, Gothalia vrajlal, Dhaduk , Khunt Rupesh, Dr.Kachhadia, Dr.Tapan, Dr.Vyas Dipen, Dr.Mayur, Dr. Nagaji, Dr. K.Bhimani,Dr. Harshad and my research colleagues for their support and much fruitfuldiscussion at various stages. I am most thankful to all my Juniors for theirvaluable co-operation and help during the course of my work.

I am thankful to Mr. Harshad Joshi and Mrs. Namrata for their kindsupport and providing chemicals and glasswares on time his co-operation inmagnifying the presentation of my work in the form of thesis.

I Gratefully acknowledge the most willing help and co-operation shownby CDRI Lucknow, CIL, Chandigarh for spectral studies and TuberculosisAntimicrobial Acquisition Co-ordinating Facility, Alabama, U. S. A. for kindco-operation extended by them for antitubercular activity.

Finally, I express my grateful acknowledgment to Department ofChemistry, Saurashtra University for providing me the excellent laboratoryfacilities , jounior research fellowship and kind furtherance for accomplishingthis work.

DINESH J. PAGHDAR

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CONTENTS

.

SYNOPSIS . . . . . . 01

STUDIES ON CHEMICAL ENTITIES OF THERAPEUTICS INTEREST

Introduction . . . . . . 10

PART - I : STUDIES ON PYRAZOLINES


Section - I : Synthesis and biological screening of (2E)1-[4-(methylsulfonyl)phenyl]-

3-aryl-2-propene-1-ones

Introduction and Spectral studies... . . . . 27

Experimental . . . . . . 33

Graphical data of In Vitro Evaluation of Antitubercular Activity . . 38

In Vitro Evaluation of Antimicrobial screening . . . . 39

Section - II : Synthesis and biological screening of 1-Acetyl-3-[4-methylsulfonyl)phenyl]-

5-aryl-4,5-dihydro-1H-pyrazoles



Graphical data of In In Vitro Evaluation of Antitubercular Activity . . 46


Section - III : Synthesis and biological screening of 3-[4-(Methylsulfonyl)phenyl]-

5-aryl-4,5-dihydro-1H-pyrazoles



Graphical data of In Vitro Evaluation of Antimicrobial screening . . 54

Reference . . . . . . 55

PART - II : STUDIES ON CYANOPYRIDINES


Section - I : Synthesis and biological screening of 2-Methoxy-6-[4-(methylsulfonyl)

phenyl]-4-arylnicotinonitriles


Page No



Reference . . . . . . 76

PART - III : STUDIES ON CYNOPYRIDONES


Section - I : Synthesis and biological screening of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-

4-aryl-1,2dihydropyridine-3-carbonitriles





Reference . . . . . . 91

PART - IV : STUDIES ON CYANOPYRAN


Section - I : Synthesis and biological screening of 2-Amino-6-[4-(methylsulfonyl)phenyl]-

4-aryl-4H-pyran-3-carbonitriles





Reference . . . . . . 107

PART - V : STUDIES ON PYRIMIDINES


Section - I : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl

pyrimidin-2(1H)-ones





Section - II : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl

pyrimidin-2(1H)-thiones





Section - III : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl

pyrimidin-2-amines




Reference . . . . . . 143

PART - VI : STUDIES ON INDAZOLES


Section - I : Synthesis and biological screening of Ethyl-4-[4-methylsulfonyl)phenyl]-2

-oxo-6-arylcyclohex-3-ene-1-

carboxylates




Section - II : Synthesis and biological screening of 6-[4-(Methylsulfonyl)pheny]-4-aryl

-2,3a,4-5-tetrahydro-3H-indazol-3-ones




Reference . . . . . . 169

PART - VII : STUDIES ON ISOXAZOLES DERIVATIVES


Section - I : Synthesis and biological screening of 3-[4- (Methyl sulfonyl)phenyl]-5-aryl

i soxazoles




Reference . . . . . . 187

PART - VIII : STUDIES ON THIAZOLIDINONES DERIVATIVES


Section - I : Synthesis and biological screening of 3-Amino-5-arylidine-2-methyl

-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4-ones

Introduction and Spectral studies. . . . . 198



Reference . . . . . . 206

LIST OF NEW COMPOUNDS . . . . . . 211

SYNOPSIS

1

The work is incorporated in the thesis with the title “STUDIES ON CHEMICAL

ENTITIES OF THERAPEUTIC INTEREST” has been described as under.

STUDIES ON CHALCONE DERIVATIVES

The chemistry of chalcones containing an active keto-ethylenic linkage has

assumed importance because of their versatility in the synthesis of many heterocyclic

compounds. Furthermore, they are also associated with wide spectrum of pharma-

cological activities and industrial applications. The chalcones are reported to pos-

sess antibacterial, antiviral, agrochemical and diuretic activities. They have been found

to be applicable for photosensitive materials, polymerization catalysts fluorescents

brightening agents, pigments etc. With a view to supplement these valid observa-

tions, it was contemplated to synthesize some novel chalcone derivatives using 1-(4-

methanesulfonyl-phenyl)-ethanone with better biological activities which have been

described as under.


Pyrazoline derivatives are endowed with different therapeutic activities such

as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular etc. These

valid observations led us to synthesize some novel pyrazoline derivatives bearing

methylsulfonyl moiety, which have been described as under.

SECTION-I : Synthesis and biological evaluation of 1-[4-(Methyl

sulfonyl)phenyl]-3-aryl-2-propene-1-ones

Type (I) R = Aryl

O

S

O

CH3

O

R

2

The chalcone derivatives of Type (I) have been synthesized by the

reaction of 1-[4-(methylsulfonyl)phenyl]-ethanone with different aryl aldehyde in

presence of 40% NaOH.

SECTION -II : Synthesis and biological evaluation of 1-Acetyl-3-[4-

(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles

The pyrazoline derivatives of Type(II) have been synthesized by the

condensation of the chalcones of Type(I) with hydrazine hydrate in glacial acetic

acid.

SECTION - III: Synthesis and biological evaluation of 3-[4-(Methyl

sulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles

The synthesis of pyrazoline derivatives of Type(III) have been undertaken by

the cyclocondensation of the chalcones of Type(I) with hydrazine hydrate.

Type (II) R = Aryl

SCH3

O

O NN

R

CH3

O

Type (III) R = Aryl

SCH3

O

O NNH

R

3


Cyanopyridine derivatives have attracted considerable attention in view of

their great therapeutic importance as anticonvulsant, antifungal, antibacterial,

antidiabetic and hypertensive agents. In order to developing therapeutically importnat

compounds, it was considered of interest to synthesize some new canopyridine de-

rivatives shown as under.

SECTION-I : Synthesis and biological evaluation of 2-Methoxy-6-[4-

(methylsulfonyl)phenyl]-4-arylnicotinonitriles

Cyanopyridine derivatives of Type(IV) have been prepared by the

reaction of chalcones of Type(I) with malononitrile and sodium methoxide.

PART - III : STUDIES ON CYANOPYRIDONES

Cyanopyridone derivatives are endowed with different therapeutic activities

such as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular etc.

These valid observations led us to synthesize some new cyanopyridone derivatives

bearing m ethylsulfonyl moiety, which have been described as under.

SECTION - I: Synthesis and biological evaluation of 6-[4-(Methyl

sulfonyl)phenyl]-2-oxo-4-aryl-1,2dihydropyridine-3-

carbonitriles

Type (IV) R = Aryl

SCH3

O

O N

O CH3

R

N

4

Cyanopyridone derivatives of Type(V) have been prepared by the

reaction of chalcones of Type (I) with ethyl cyano acetate in presence of basic

catalyst like pyridine.

PART - IV : STUDIES ON CYANOPYRANS

Cyanopyran derivatives exhibit various interesting biological properties such

as antimicrobial, antifungal, antiviral, antifilarial and antisecretory. In view of these

facts, it was contemplated to synthesized some new pyrans, which have been

described as under.

SECTION-I : Synthesis and biological evaluation of 2-Amino-6-[4-

(methylsulfonyl)phenyl]-4-aryl-4H-pyran-3-carbonitriles

Cyanopyran derivatives of Type (VI) have been prepared by the reaction of

chalcones of Type (I) with malononitrile in pyridine.

Type (V) R = Aryl

Type (VI) R = Aryl

SCH3

O

O NH

O

R

N

SCH3

O

O O

NH2

R

N

5


Pyrimidine nucleus possess remarkable pharmaceutical importance and

biological activities, some of their derivatives occur as natural product, like nucleic

acids and vitamin B. Pyrimidine derivatives used for the treatment of AIDS and as

antitumor agents, These valid observations led us to synthesize some novel

pyrimidine in search of agents having more medicinally activities which have been

described as under.

SECTION - I: Synthesis and biological evaluation of 4-[4-(Methyl

sulfonyl)phenyl]-6-arylpyrimidin-2(1H)-ones

Pyrimidinone derivatives of Type (VII) have been prepared by the

condensation of chalcones of Type (I) with urea in presence of acidic catalyst like

HCl.

SECTION-II : Synthesis and biological evaluation of 4-[4-(Methyl

sulfonyl)phenyl]-6-arylpyrimidin-2(1H)-thiones

Type (VII) R = Aryl

SCH3

O

O

NH

N

O

R

SCH3

O

O

NH

N

S

R

Type (VIII) R = Aryl

6

Pyrimidine thione derivatives of Type (VIII) have been prepared by the

condensation of chalcones of Type(I) with thiourea in presence of acidic catalyst

like HCl.

SECTION-III : Synthesis and biological evaluation of 4-[4-(Methyl

sulfonyl)phenyl]-6-arylpyrimidin-2-amines

Aminopyrimidine derivatives of Type (IX) have been synthesized by the

condensation of chalcones of Type (I) with guanidine hydrochloride.


Biological importance of indazole derivatives is well known. They have been

reported to be active as cardiovasscular, sedative, antifungal and antibecterial. In

order to develop medicinally importnat compounds, it was considered of interest to

synthesized some new indazoles which have been described as under.

SECTION - I : Synthesis and biological evaluation of ethyl-4-[4-(methyl

su l fony l )pheny l ] -2 -oxo -6 -ary l cyc lohex -3 -ene -1 -

carboxylates

SCH3

O

O

N

N

NH2

R

SCH3

O

O

O

O

O

CH3

R

Type (IX) R = Aryl

Type (X) R = Aryl

7

Cyclohexenones of Type (X) have been prepared by the cyclocondensation

of chalcones of Type (I) with ethylacetoacetate in the presence of basic catalyst

K2 CO3

SECTION-II : Synthesis and biological evaluation of 6-[4-(Methylsulfo

nyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-indazol-3-ones

Indazole derivatives of Type(XI) have been prepared by the reaction of

cyclohexenones of Type(X) with hydrazine hydrate.

PART - VII : STUDIES ON ISOXAZOLES

Isoxazole derivatives represent one of the modest classes of compound

possessing wide range of therapeutic activities, such as antidepressants, skeleton

muscle relaxant, antidiabetic, anti-inflammatory, analgesic etc. With a view to

mapping better medicinal value and to evaluate its pharmacological profile, we have

synthesized some new isoxazole derivatives, which have been described as under.

SECTION - I : Synthesis and biological evaluation of 3-[4-Methyl

s u l f o n y l ) p h e n y l ] - 5 - a r y l i s o x a z o l e s

SCH3

O

ON

NH

O

R

NO

S

O

O

CH3

R

Type (XII) R = Aryl

Type (XI) R = Aryl

8

Isoxazole derivatives of Type(XII) have been prepared by the reaction of

chalcones of Type(I) with hydroxylamine hydrochloride in presence of sodium

acetate in acetic acid.

PART - VIII : STUDIES ON THIAZOLIDINONES

Compounds bearing thiazolidinone nucleus show wide range of biological

activity such as antimicrobial, CNS depressant, antiinflammatory, antitubercular,

sedative, anticonvulsant, analgesic and antihypertensive. With a view to suppliment

these valid observations, the synthesis of some new thiazolidinones have been

undertaken which have been descried as under.

SECTION - I : Synthes i s and b io log ica l eva luat ion of 3 -Amino-5-

arylidine-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-

thiazolidin-4-ones

The thiazolidinone derivatives of Type (XIII) have been undertaken by the

condensation of 3-amino-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4-

one with different aldehydes in glacial acetic acid.

The constitution of the synthesised compounds have been characterised

using elemental analysis, infrared and 1H nuclear magnetic resonance spectroscopy

and further supported by mass spectrometry. Purity of all the compounds have been

checked by thin layer chromatography.

SCH3

O

O N

S

NH2

CH3

O

R

Type (XIII) R = Aryl

9

In vitro studies on multiple biological activities.

(I) Selected compounds have been evaluated for their in vitro biological assay

like antitubercular activity towards a strain of Mycobacterium tuberculosis

H37Rv at a concentration of 6.25 µg/ml using Rifampin as standard drug,

which have been tested by Tuberculosis Antimicrobial Acquisition

Co-ordinating Facility (TAACF), Alabama, U.S.A.

(II) All the compounds have been also evaluated for their antibacterial activity

towards Gram positive and Gram negative bacterial strains and antifungal

activity towards Aspergillus niger at a concentration of 40µg/ml. The

biological activity of the synthesized compounds have been compared with

standard drugs.

INTRODUCTION

STUDIES ON

CHEMICAL ENTITES OF

THERAPEUTIC INTEREST

Studies on chemical entities...

Introduction...

10

Research programs for the discovery of new drugs and for improving the

evolution criteria are under way in many laboratories. In addition knowledge of

specific constituents of the mycobacterium cell and their biochemical roles has

advanced considerably in the recent years and may permit a more rational approach

to the design of new drug action on specific targets. Also, recent improvements in

the knowledge of the mechanism of action of available drugs and the biochemical

mechanism of resistance to them may be used as a basis for design new and better

weapons to fight the mycobacterial diseases.

The cur ren t env i ronment fo r d i scovery and deve lopment o f new

pharmaceuticals agents could hardly be ware challenging. Public policies and

attitudes are requiring reduction in health care expenditures and increase efficiencies,

resulting in major health care reform in the United States. At the sometime, major

diseases remain untreated and paradoxically, scientific progress continues with ever

increasing acceleration.

The last few decades have witnessed massive advances in biochemistry,

physiology, pharmacology and genetics. This has to a better understanding of working

the body at the molecular level. This in turn has resulted a much better understanding

of the structure and function of important drug targets e.g. enzymes and receptors

and that how drugs can be designed for these targets.

Advances in genetics engineering have been used to produce human proteins

and enzymes in fast growing microbial cells, allowing these molecules to be obtained

in far greater yields than if they were extracted from human tissue. This makes it

easier to study these micro molecules and to design drugs that will interact with

them. Mapping of human DNA through human genome project has immense

implications for medicinal chemistry.

INTRODUCTION


Introduction...

11

Advances in chemistry have made possible the synthesis of complexes

molecules. Enantiometry is an important process in medicinal chemistry since life is

inherently chiral and the drug targets within the body are chiral. As such, they can

distinguish between the enantiomers of a chiral drug, so the use of recemic drug is

inherently wasteful, since only one enantiomer is ideally designed to interact with

its target. Moreover, the existences of the “wrong” enantiomer could create problems

if it interacted with a different receptor, resulting inside effects.

The focus of drug design has switched from structure oriented to target

oriented research, e.g. development of the antiulcer agent cimetidine . Histamine

was the lead compound for the project and various strategies were used to find an

analog that would prevent it fitting its receptor. Once an antagonist was developed,

a theory was proposed on how it might interact with the histamine receptor at a

molecular level. Further analogs were then synthesized to test theory and the theory

was continusally modified as required.

In the nineteenth century, chemistry developed as a science, both in terms of

experimental procedures and scientific theory. Scientist isolated and purified single

compounds from natural extracts. Method of organic synthesis were developed that

helped chemists altering structures in a predictable way.

The chemists started separating out the various components of ancient

positions to discover whether a single compound was responsible for the medicinal

effect known as the active principle.

Drugs are chemicals of low molecular weight (~100-500) which interact with

macromolecular targets to produce a biological response. The biological response

may be therapeutically useful in the case of medicines or harmful in the case of

poisons. Most drugs used in medicine are potential poisons if taken in higher doses

than recommended.


Introduction...

12

Drugs are classified by their chemical structures. Drugs classified in this way

share a common structural feature and often share similar pharmacological activity.

For example, all penicillin’s contain a β-lactum ring and kill bacteria by the same

mechanism, as a result, this classification can sometimes be useful in medicinal

chemistry. However, it is not foolproof. Sulfonamides have a similar structure and

are mostly antibacterial. However some sulfonamides are useful in the treatment of

diabetes. Similarly all steroids have a tetracyclic structure, but the pharmacological

effect of different steroids can be quite different e.g. testosterone is a sex hormone.

Spironolactone is a diuretic .

Finally classifying drugs according to their molecular target is the most useful

classification as far as medicinal chemist is concerned, since it allows a rational

comparison of the structure involved.

Any drug must ideally have a broad spectrum of activity, with a rapid

bactericidal action. Some bacteria produce enzymes that can inactivate or modify

antibiotics action. Some bacteria produce enzymes that can inactivate or modify

antibiotics and insusceptibility of a drug to such degradation or modification could

result in its playing an important part in therapy. Likewise, some bacteria possess

an outer membrane that acts as a permeability barrier to the entry of some, but not

all, antibiotics. Drugs that can readily penetrate this barrier might again be expected

to be of possible clinical importance.

The modern concept of drug discovery supported in 1933 by Gerhand Dumagk

penicillins sulfonamides steroids

N

SCH3

CH3

O

NHH H

COOH

R

O

S

NH2

NHR

OOR''

R'

CH3

H

H

H

CH3R

H


Introduction...

13

with his finding of prontosil red a compound responsible for the antibacterial activity.

In 1939 Florey and Chain investigate penicillin-G which was discovered ten years

earlier by Alexander Fleming.

The word drug is described from the french word drogue which mean a dry

herb. According to WHO a drug may be define as “Any substance or product which

is used or intended to be used for modifying on exploring physiological system or

pathological status for the benefit of the recipient.” There are two main division of

medicinal chemistry. The first chemotherapy, concern with the treatment of

infections, parasite or malignant disease by chemical agents, usually substance that

shows selective toxicity towards the pathogen.

During the period of 1940 to 1960 a large number of important drugs have

been introduced and this period is regarded as “Golden Period” of new drug

discovery. These are some of the specific examples representing new therapeutics.

NAME OF DRUGS YEAR USES

Sulfa drugs 1933 First

antibacterial drug

Penicillin 1940 Antibiotics

Chloroquine 1945 Antimalarial

Methyldopa 1950 Antidiabetic

Chlorthiazide 1957 Diuretic

Adrenergic betablockers 1958 Coronary

Vasodilatory

Semi synthetic penicillins 1960 Antibacterial

Trimethoprim 1965 Antimicrobial

Disodium chromoglycoate 1967 Antiallergic

The other division relates to diseases of bodily disfunctioning of enzymes,

the transmission of impulses on the action of hormones on receptors. Heterocyclic


Introduction...

14

compounds are used for all these purpose, because they have a specific chemical

reactions. The introduction of heterocyclic groups in to drugs may effect their

physical properties, for examples the disscociation constants of sulpha drugs or

modify their patterns of absorption, metabolisam or toxicity.

During the period of 1930-1950 there was an urgent need for new drugs for

treat diseases which had a high mortality rate, there was only limited appreciation

of the hazard. Such drugs might present and toxicological studies before cinical

trials were fairly radimenting proving the proverb “Necessity is the mother

invention”, during the dacade of 30 and 40s.

Taking in view of the applicability of heterocyclic compounds, we have

undertaken the preparation of heterocycles bearing pyrazole nucleus. The placement

of a wide variety of substituents of these nuclei have been designed in order to

evaluate the synthesised products for their pharmacological profile against several

strains of bacteria and fungi.

AIM AND OBJECTIVES

In the pharmaceutical field, these have always been and will continue to be a

need for new and novel chemical inhibitors of biological function. Our efforts are

focused on the introduction of chemical diversity in the molecular from work in

order to synthesizing pharmacologically interesting compound of widely different

composition.

During the course of our research work, looking to the application of het-

erocyclic compounds, several entities have been designed, generated and character-

ized using spectral studies. The details are as under.

1. To synthesize therapeutically active compounds like pyrazolines,

cyanopyridines, cyanopyridones, cyanopyrans, pyrimidines, indazoles,

isoxazoles and thiazolidinones bearing methylsulfonyl moiety.


Introduction...

15

2. To generate several intermediates, like chalcones, cyclohexenone bearing

methanesulfonyl acetophenone moiety.

3. To characterize these products for structure elucidation using several spec-

troscopic techniques like IR, PMR and Mass spectral studies.

4. To assess the reaction and purity of the compounds were done by TLC.

5. To evaluate these products for better drug potential against different strains

of bacteria and fungi.

6. All the compounds have been sent to TAACF, southern Research institute,

and USA; for antitubercular testing.

Taking in to consideration the applicability of heterocyclic compounds, the

placement of variety of substituted in these nuclei has been designed in order to

evaluate the synthesized products for their better pharmaceutical profile.


Pyrazolines...

16

INTRODUCTION

The term “chalcone” was first coined by Kotanecki, who did pioneering

work in the synthesis of natural coloring compounds. They are characterized by

their possession of a C6(A)-CO-CH=CH-C6(B), structure in which two aromatic

ring A and B, are linked by an aliphatic three carbon chain.

Chalcones are phenyl styryl ketones containing reactive keto-ethylinic group

(-CO-CH=CH-). They are also known as benzalacetophenones or benzylidene

acetophenones the alternatively names given to chalcone are β-phenyl acrylophenone,

α -oxo-α,β -diphenyl- β-propylene and α -phenyl- β-benzoyl ethylenes.

SYNTHETIC ASPECT

A variety of a methods are available for the synthesis of chalcones. The most

convenient method is the one that involves the Clasien-Schmidt condensation of

equimolar quantities of a aryl methyl ketones with aryl aldehyde in the presence of

alcoholic alkali.1-3

Various condensing agent used are alkali of different strength.4,5

Hydrogen chloride6,7

, Phosphorous oxychloride8, Piperidine

9, Anhydrous aluminium

chloride10

, Boron trifluoride11

, Borax12

, Aminoacids13

, Perchloric acid14

etc.

MECHANISM

The following two mechanisms have been suggested for the synthesis of

chalcones.

O

A B

(I)


Pyrazolines...

17

REACTIVITY OF CHALCONES

The chalcones have been found to be useful for the synthesis of many

heterocyclic compounds.

1. Chalcone contain a Keto-Ethylenic group and therefore reactive towards a

number of reagents yielding various heterocyclic compounds exhibiting

s ignificant biological activities viz. pyrazolines15

, cyanopyridines16

,

cyanopyrans17

, cyanopyridones18

, pyrimidines19-21

, isoxazoles22

,

indazoles23

etc.

2. Chalcones are intermediate compounds for the synthesis of some naturally

occuring heterocyclic compounds like flavones, flavanones, flavanoids,

dihydro flavanols, benzal coumarinones, anthocyanins etc.

3. The structure of some naturally occurring pigments like chrysin, galangin,

kaempferol and quercetrol were established by their synthesis from suitably

substituted chalcones.24

4. They have been useful in providing structure of some natural products like

cyanomulcurin25

, eviodictoyl26

, hemlocktanin27

, narighenin28

,

plioretin29

etc.

5. Chalcones are also useful for the detection of Fe(II)30

and Ca(II)31

ions in

presence of Ba and Sr as it reacts with number of metal ions. Trihydroxy

chalcones were used as an analytical reagents for amperometric estimation

PhC

O

CH 2

H

+ OH-

PhC

O

CH 2-+

PhC

O

H PhC

O

Ph

O-

PhC

O

PhPh

C

O

Ph

O H -H 2 O

H+

-OH -

OH-


Pyrazolines...

18

of copper32

and for spectrophotomatric study of the germanium.33

6. The chalcones are natural biocides34,35

and are well-known key intermidiate

in the synthesis of heterocyclic compounds possessing biodynamic

behaviour.36-38

7. Chalcone and their derivatives are also found to be applicable as light

stabilizing agent39

, sweetening agent40

, oganic brightening agent, photo

sensitive material, polymerisation catalyst, scintillators as well as fluorescent

whitening agent.

THERAPEUTIC IMPORTANCE

Chalcones derivatives have been found to possess wide range of therapeutic

activities as shown below.

1. Antitumor41,42

2. Antispasmodic43

3. Antiulcer44,45

4. Anthelmintics46,47

5. Bactericidal48,49

6. Cardiovascular50

7. Fungicidal51-53

8. Germicidal54

9. Herbicidal55

10. Insecticidal56-58

11. Antiallergic59

12. Anticancer60,61

13. Antiinflammatory62,63

14. Antimalarial64,65

15. Antitubercular66,67

16. Antiviral68


Pyrazolines...

19

Chalcones are potential biocides, because some naturally occurring

antibiotics69

and aminochalcones70,71

probably owe their biological activity in the

presence of the α ,β-unsaturated carbonyl group. Nelson G. L. et al.72

synthesized

the analogs of prostaglandin (II).

The compound 4-[1-oxo-3-(3,4,5- t r imethoxyphenyl)-2-propenyl]-1-

piperazine acetic acid ethyl ester (III) has been marketed under the name of

‘Cinepazet’ used as vasodilator. The other 5-methoxy-2-methyl-1-(1-oxo-7-phenyl)-

1H-indole-3-acetic acid (IV) has been marketed under the name of ‘Cinmetacin’

and useful as antiinflammatory drug.

O

R1O

R

O

N

N COOCH2CH3

H3CO

H3CO

H3CO

N

O

CH3

COOH

H3CO

(II)

(III)

(IV)


Pyrazolines...

20

Some dihydrochalcones are well known for their sweetening property73,74

and appear

to be non-nutritive sweeteners. A dihydrochalcone ‘Uvaretin’ from Uvaria

acuminata has shown antitumor activity75

in lymphocytic leukemia test. V. K.

Ahluwalia et al.76

have noted that 5-cinnamoylchalcones (V) have shown good as

antibacterial activity.

Chalcones have served as starting material for several synthetic manipulations

and a versatile synthon in organic synthesis.

Moreover, Khatib S. et a1.77

synthesized some novel chalcones as potent

tyrosinase inhibitors(VI). Ko H. H. et al.78

have prepared chalcones and found active

against potent inhibition of platelet aggregation. Ziegler H. L. et al.79

reported some

novel chalcones as antiparasitic.

Go M. L. et al.80

have described the synthesis and biological activities of

chalcones as antiplasmodial. Xue C. X. et al.81

synthesized and reported chalcones

as antimalarial agents. Fu Y. et al.82

have synthesized Licochalcone-A

Furthermore, Alcaraz M. J. et al.83

have described the role of nuclear

factor-kappaB and heme oxygenase-1 in the mechanism of act ion of an

anti-inflammatory chalcone derivative in RAW 264.7 cells. Nerya O. et al.84

have

prepared chalcones as potent tyrosinase inhibitors.

OO

R

R1

R

R1

OH

OH

OH

(V)

O

OH

OH

OH

OH

(VI)


Pyrazolines...

21

STUDIES ON CHALCONE DERIVATIVES



PART - III : STUDIES ON CYANOPYRIDONES

PART - IV : STUDIES ON CYANOPYRANS



PART - VII : STUDIES ON ISOXAZOLES

PART - VIII : STUDIES ON THIAZOLIDINONES

Sabzevari O. et al.85

have constructed some new chalcone derivatives as

molecular cytotoxic mechanisms for anticancer activity (VII).

Recently, Ban H. S. et al.86

synthesized some novel chalcones as inhibition of

lipopolysaccharide-induced expression of inducible nitric oxide synthase and tumor

necrosis factor-alpha by 2'-hydroxychalcone derivatives in RAW 264.7 cells. Hollosy

F. et al.87

have prepared some new chalcones as plant-derived protein tyrosine kinase

inhibitors as anticancer agents.

Chalcone have been proved to be an important intermediate for the synthesis

of many heterocyclic compounds in organic chemistry. These facts pormpted us to

sythesize some novel chalcone derivat ives bearing 1-[4-(methylsulfonyl)

phenyl]ethanone, in order to achiving better therapeutic agents, we have undaertaken

the synthesis of chalcones and its derivatiaves, which have been described in fol-

lowing part.

O

OOMe

OH

OMe (VII)


Pyrazolines...

22

INTRODUCTION

Amongst nitrogen containing five membered heterocycles, pyrazolines have

proved to be the most useful framework for biological activities, Pyrazolines have

attracted attention of medicinal chemists for both with regard to heterocyclic

chemistry and the pharmacological activities associated with them. In 1967 Jacobe,

reviewed the chemistry of pyrazolines, which have been studied extensively for their

biodyndmic behaviour88

and industrial applications.89

SYNTHETIC ASPECT :

Different methods for the preparation of 2-pyrazoline derivatives documented

in literature are as follows.

1. Dipolar cycloaddition of nitrilimines of dimethyl fumarate, fumaronitrile

and the N-aryl maleimides yields the corresponding pyrazolines90

.

2. Epoxidation of chalcones i.e. epoxy ketones which reacted with hydrazine

and phenyl hydrazine to give pyrazolines91

. Furthermore, B. Gyassi et al.92

investigated the one pot synthesis of some pyrazolines in dry media under

microwave irradiation. S. Paul et al.93

and Dandia Anshu et al.94

have

also described the microwave assisted synthesis of 2-pyrazolines.

3. 2-Pyrazolines can be constructed by the cyclocondensation of chalcones with

hydrazine hydrate95

.

4. 2-Pyrazolines can also be prepared by the condensation of chalcone dibromide

with hydrazine96

.

NH

N

(I)


Pyrazolines...

23

5. 2-Pyrazolines synthesised by the cycloaddition of diazomethane with

substituted chalcones.97

MACHANISIM

The following mechanism seems to be operable for the condensation of

chalcones with hydrazine hydrate.98

Nucleophilic attack by hydrazine at the β-carbon of the α,β -unsaturated

carbonyl system forms species, in which the -ve charge is mainly accomodated by

the electronegative oxygen attom.

Proton transfer from the nitrogen to -ve oxygen produces an intermediate

enol which simultaneously ketonises to ketoamine. 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 carbonyl

amine. The later with a hydroxy group and amino group on the same carbon lose

water molecule to yield the pyrazolines.

R R1

O

N

NH

R

R1

NH 2NH 2.H2O

R1 R

O

NH2 NH R2CH

-R1

C+ R

O-NH

+

R2 NH2

(i) Proton transfer(ii) Ketonization R1 R

ONR2 NH2

intermolecularneucleophilic attack

R1 R

OHN

R2

NH

R1 R

N

R2

N

-H2O


Pyrazolines...

24


From the literature survey, it was revealed that 2-pyrazolines are better

therapeutic agents some of them are as shown bellow.

1. Antiallergic99

2. Anticonvulsant100,101

3. Antidiabatic102

4. Antiimplantation103

5. Antiinflammatory104

6. Antitumor105

7. Antineoplastic106

8. Antimicrobial107

9. Analgesic108,109

10. Bactericidal110,111

11. Cardiovascular112

12. Diuretic113

13. Fungicidal114

14. Herbicidal115

15. Hypoglycemic116

16. Insecticidal117

17. Tranquilizer118

Moreover F. Manna and co-worker119

have described 1-acetyl-5-(2'-

bromophenyl)-4,5-dihydro-3-(2'-hydroxyphenyl)-1H-pyrazoline and its derivatives

which acts as potent antiinflammatory, analgesic and antipyratic agents.Udupi R.

H. and Bhatt A. R.120

have reported the synthesis and biological activity of Mannich

bases of certain 1,2-pyrazolines. Nugent Richard121

investigated pyrazolines bis

phosphonate ester as novel antiinflammatory and antiarthritic agent. Fuche Rainer

et al.122

have prepared some new 1H-pyrazoline derivatives and reported them as


Pyrazolines...

25

pes t ic ides . Fur thermore , Tsubai e t a l .123

have syn thes ized some new

(phenylcarbamoyl) pyrazolines as an insecticides and at 40% concentration shows

100% mortality of spodopetra litura larve after seven drops.

Shulabh Sharma et al.124

have synthesized pyrazolines and tested their

antiinflammatory activity (II).Ashok Kumar et al.125

have synthesized pyrazolines

as anticonvulsant agents (III). Maurer Fritz et al.126

have synthesized pyrazoles and

screened for their pesticidal activity.

E. Palska et al.127

have prepared 3,5-diphenyl-2-pyrazolines (IV) and cited

their antidepressant activity. B. Shivrama et al.128,129

have synthesized pyrazolines as

antibacterial agents. Hiremath S. P. et al.130

have reported pyrazolines as analgesics,

antiinflammatory and antimicrobial agents. Malhotra V. et al.131

have synthesized

new pyrazolines as a cardiovascular agents (V).

NN

NH

N

N

R

NH S

COCH3

NH

NH

NN

O

O

S

OCH3

COCH3

R1

NNH R2

OMe

OMe N

N

NHR2 S

Ph

R1

(II) (III)

(IV) (V)


Pyrazolines...

26

Moreover, T. M. Stivensen et al.132

have also investigated N-substituted pyrazoline

type insecticides. Tanka Katsohori133

have patented pyrazoline derivatives as

herbicides and Johannes et al.134

as insecticides. Moritaz Z. and Hadol135

investigated

a semi emperial molecular orbital study on the reaction of aminopyrazolinyl azodye

with singlet molecular oxygen. Shivnanda M. K. and co-workers136

have

prepared substituted pyrazolines and reported their antibacterial activity.

Almstead J. et al.137

have prepared pyrazolines as vascularization agents. Guniz

Kuchkguzel et al.138

have synthesized pyrazolines as a antimicrobial and

anticonvalsant agents. Gulhan T. Z. and co-workers139

have prepared pyrazolines

as a hypotensive agent.

S. S. Sonarc et al.140

have synthesized-3-(2-acetoxy-4-methoxyphenyl)-5-

(substituted phenyl)-pyrazolines and tested their antimicrobial activity. H. H.

Parekh141

et al. have also synthesized some new pyrazolines as an antimicrobial agent.

G. N. Mishirika et al.142 have also prepared 2-pyrazolines of salicyclic acid possessing

antimicrobial properties. Tunfawy, Atif and co-workers143

have patented 3-methyl-

4'-(substituted phenylazo)-pyrazol-5-ones as antibacterial agents.

Thus, significant biological properties associated with pyrazoline derivatives

have aroused considerable interes to design the compounds with better drug

potentials and to study their pharmacological profile, which have been described as

under.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF (2E)1-

[ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 3 - A RY L - 2 -

PROPENE- 1-ONES

SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING O F 1 -

A C E T Y L - 3 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 5 -

ARYL-4,5-DIHYDRO-1H-PYRAZOLES

SECTION-III : SYNTHESIS AND BIOLOGICAL SCREENING OF 3-[4-

( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 5 - A RY L - 4 , 5 -

DIHYDRO-1H-PYRAZOLES


Pyrazolines...

27

SECTION - I

SYNTHESIS AND BIOLOGICAL SCREENING OF ( 2 E ) - 1 - [ 4 -

(METHYLS U L F O N Y L ) P H E N Y L ] - 3 - A RYL-2-PROPENE-1-ONES

Chalcone derivatives occupy a unique place in the field of medicinal

chemistry due to wide range of biological activities exhibited by them, prompted

by these facts, the preparation of chalcones of type (I) have been carried out by

condensation of 1-[4-(methylsulfonyl)phenyl]ethanone with various aldehydes in

presence of catalytic amount of alkali.

The structure elucidation of synthesized compounds has been done on the

basis of elemental analyses, Infrared and 1H nuclear magnetic resonance spectroscopy

and further supported by Mass spectrometry.

All the compounds have been evaluated for their in vitro biological assay

like antibacterial activity towards gram positive and gram negative bacterial strains

and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.

The biological activities of synthesized compounds were compared with standard

drugs.

Moreover, some selected compounds have been evaluated for their in vitro

biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a

concentration of 6.25 µg/ml using Rifampin as a standard drug which have been

tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),

Alabama, U. S. A.

S

O

O

CH3

O

CH3

in 40% alkali

R-CHO

R

O

S

O

O

CH3

Type(I)R=Aryl


Pyrazolines...

28

S

CH3

AlCl3

(CH3CO)2O

S

CH3

O

CH3

Alcoholic KOH R

O

H

H2O2 in glacial aceticacid

S

CH3

O

R

SCH3

O

O

O

R

REACTION SCHEME

Type-(I) R = Aryl


Pyrazolines...

29

ANTIMICROBIAL ACTIVITY

Method : Cup-Plate146

Gram positive bacteria : Bacillus cocus

Bacillus subtillis

Gram negative bacteria : Proteus Vulgaris

Escherichia Coli

Fungi : Aspergillus niger

Concentration : 40µg/ml

Solvent : Dimethyl formamide

Standard drugs : Amoxicillin, Ampicillin, Benzyl penicillin,

Norfloxacin, Greseofulvin

The antimicrobial activity was compared with standard drug viz Amoxicillin,

Ampicillin, Benzyl penicillin, Norfloxacin, Greseofulvin and antifungal activity was

compared with viz Greseofulvin. The inhibition zones measured in mm.

ANTITUBERCULAR ACTIVITY

The antitubercular evaluation of the compounds was carried out at

Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF) U.S.A.

Method : BACTEC 460 Radiometric system.

Bacteria : Mycobacterium Tuberculosis H37Rv

Concentration : 6.25 µg/ml

Standard drug : Rifampin.

MICROBIOLOGICAL EVALUATION


Pyrazolines...

30

Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400

cm-1 (KBr disc.)

0.0

20.0

40.0

60.0

80.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

495.7

532.3 596.0

736.8 775.3

815.8 987.51012.6

1031.8

1089.71182.3

1209.3

1224.7

1276.8

1301.9

1330.8

1382.9

1407.9

1490.9

1564.2

1602.71654.8

2916.23028.03087.8

3292.3

3388.7

Type Vibration Frequency in cm-1 Ref. Mode Observed Reported

Alkane C-H str. (asym.) 2916 2975-2950 144-CH3 C-H str. (sym.) 2870 2880-2860 ,,

C-H def. (asym.) 1460 1470-1435 ,,C-H def. (sym.) 1382 1390-1370 ,,

Aromatic C-H str. 3087 3090-3030 145C=C str. 1490 1540-1480 ,,

1089 1125-1090 ,,Halide C-Cl str. 775 800-600 144Sulfonyl SO2 str. 1182 1185-1165 ,,Vinyl CH=CH str. 3028 3050-3000 ,,Chalcone C=C str. 1564 1580-1550 ,,

C=O str. 1654 1672-1652 ,,

IR SPECTRAL STUDIES OF (2E)-1-[4-(METHYLS U L F O N Y L )

PHENYL]-3-(p-CHLOROPHENYL)-2 -PROPENE-1-ONE

SCH3

O

O

O

Cl


Pyrazolines...

31

Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER

Spectrometer (300 MHz)

1 2.5 3 H singlet -SO2CH3 -

2 7.28-7.31 2 H doublet Ar-H b,b Jba=8.1

3 7.35-7.40 2 H doublet Ar-H c,c Jcd=8.7

4 7.47-7.52 1 H doublet CHe -

5 7.55-7.58 2 H doublet Ar-H a,a Jab=8.4

7 7.71-7.76 1 H doublet CHf -

8 7.91-7.94 2 H doublet Ar-H d,d Jdc=8.1

Signal No.

Signal Position (δppm)

Relative No. of protons

Multiplicity Inference J Value In Hz

NMR SPECTRAL STUDIES OF (2E)-1-[4-(METHYLS U L F O N Y L )

PHENYL]-3-(p-CHLOROPHENYL)-2 -PROPENE-1-ONE

SCH3

O

O O

Cl

a b

a' b'

c

d

c'

d'

e f


Pyrazolines...

32

TA

BL

E-1

:M

ASS

SP

EC

TR

AL

ST

UD

IES

OF

(2E

)1-[

4-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

3-(P

-CH

LO

RO

PH

EN

YL

)-2

-

PR

OP

EN

E-1

-ON

E

m/z

=32

0


Pyrazolines...

33

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL SCREENING OF (2E)-1-[4-(METHYL

SULFONYL)PHENYL]-3-ARY L-2-PROPENE-1-ONES

(A) Synthesis of 1-[4-(methylsulfonyl)phenyl]ethanone

To the solution of 1-[4-(methylthio)phenyl]ethanone in glacial acetic acid

(10 ml), H2O2 (6 ml, 30%) was added and stirred for 5 hr. The stirred content was

kept at room temperature for 24 hr till a crystalline solid was seperated. The

seperated solid was filtered and recrystallized from ethanol Yield 80%, m.p118oC,

Anal. Calcd. for C9H10O3S : Require: C, 54.53, H, 5.08; Found: C, 54.51, H, 5.06

%.

(B) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -

propene-1-one

Dissolve 1-[4-(methylsulfonyl)phenyl]ethanone (1.98gm, 0.01mol) in (25 ml)

methanol, to this add p-chlorobenzaldehyde (1.40gm, 0.01mol) in (25 ml) methanol

and stirred at room temperature for 24 hr. in presence of catalytic amount of 40%

KOH. The resulting solution was poured on to crushed ice, thus the solid seprated

was filterated and crystallized from ethanol, Yield 58%, m. p. 120oC, Anal. Calcd.

for C16H13ClO3S Require: C, 59.91, H, 4.08 ; Found: C, 59.89, H, 4.05 %.

Similarly, other compound were prepared. The physical data are recorded in

Table No. 1

(C) Biological screening of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl- 2 -

propene-1-ones

(a) Antibacterial activity146

The purified products were screened for their antibacterial activity using

cup-plate agar diffusion method. The nutrient agar broth prepared by the usual

method was inoculated aseptically with 0.5 ml of 24 hrs. old subcultures of Bacillus


Pyrazolines...

34

Subtilis, Bacillus Coccous, Escherichia coli, Proteus Vulgaris in separate conical

flasks at 40-50oC and mixed well by gentle shaking. About 25 ml content of the

flask was poured and evenly spreaded in a petridish (13 cm diameter) and allowed

to set for 2 hrs. The cups (10 mm diameter) were formed by the help of borer in

agar medium and filled with 0.04ml (40mg) solution of sample in DMF. The plates

were incubated at 37oC for 24 hrs. and the control was also maintained with 0.04ml

of DMF in a similar manner and the zone of inhibition of the bacterial growth were

measured in millimeter and recorded in Graphical Chart No. 1

(b) Antifungal activity146

Aspergilus niger was employed for testing antifungal activity using cup-plate

agar diffusion method. The culture was maintained on sabourauds agar slants

sterilized sabourauds agar medium was inoculated with 72 hrs. old 0.5ml suspension

of fungal spores in a separate flask. About 25ml of the inoculated medium was

evenly spreaded in a petridish (13cm diameter) and allowed to set for 2 hrs. The

cups (10mm diameter) were punched. The plates were incubated at 30oC for 48

hrs. After the completion of incubation period, the zone of inhibition of growth in

the form of diameter in mm was measure. Along the test solution in each petridish

one cup was filled up with solvent, which acts as control. The zone of inhibition of

test solution are recorded in Graphical Chart No. 1

(C)Antitubercular activity

The antitubercular evaluation of the compounds was carried out at

Tuberculosis Antimicrobial Acquisition and Co-ordination Facility (TAACF), USA.

Primary screening of the compounds for the antitubercular activity have been

conducted at 6.25 mg/ml towards Mycobacterium tuberculosis H37Rv in BACTEC

12B using the BACTEC 460 radiometric system. The compounds demonstrating


Pyrazolines...

35

atleast>90% inhibition in the primary screening has been tested at lower

concentration towards Mycobacterium tuberculosis H37Rv to determine the actual

minimum inhibitory concentration (MIC) in the BACTEC-460.

The antitubercular data have been compared with standard drug Rifampin at

6.25 mg/ml concentration and it showed 98% inhibition. The primary screening

method is described as under.

Antitubercular activity was determined using the BACTEC 460 system as

modi f i ed be low. S tock so lu t ions as t e s t compounds were p repared in

dimethylsulfoxidie (DMSO) at 1 mg/ml and sterilized by passage through 0.22 mm

PFTE filters (Millex-FG, Millipore, Bedford MA). Fifty microliters was added to

4ml radiometric 7H12 broth (BACTEC 12B; Becton Dickinson Diagnostic

Instrument System, Sparks, MD ) to achieve a final concentration of 6.25 mg/ml.

Controls received 50 ml DMSO. Rifampin(Sigma Chemical Co., St. Louis, MO)

was included as a positive drug control. Rifampin was solublized and diluted in

DMSO and added to BACTEC-12 broth to achieve a range of concentration for

determination of minimum inhibitory (MIC, lowest concentration inhibiting 99% of

the inoculum).

M. Tuberculosis H37Rv (ATCC 27294; American type culture collection,

Rockville, MD) was culture at 37oC on a rotary shaker in middlebrook 7H9 broth

(Difco Laboratories, Detroiet, MI) supplemented with 0.2 v/v glycerol and 0.05%

v/v Tween 80 until the culture turbidity achieved an optical density of 0.45-0.55 at

550nm. Bacteria were then pelleted by centrifugation, washed twice and resuspended

in one fifth the original volume in dulbecco’s phosephate buffered saline (PBS, Irvine

Scientific Santa, Nalgene, Rochester, NY) and aliquots were frozen at 80oC. Cultures

were showed and an appropriate dilution performed such that a BACTEC-12B vial

inoculated with a 0.1 ml would reach a growth index (GI) of 999 in 5 days.


Pyrazolines...

36

One tenth of diluted inoculum was used to inoculate 4 ml fresh BACTEC

12B broth containing the compounds. An additional control vial was included which

received a further 1;100 diluted inoculam (as well as 50 ml DMSO) use an calculating

the MIC of Rifampin, respectively by establishing procedures.

Cultures were incubated in 37oC and the GI determined daily until control

cultures achieved a GI og 999. Assays were usually completed in 5-8 days. Percent

inhibition was defined as-1-(GI of test sample/GI of control)x100. Minimum

inhibitory concentration of compound effecting a reduction in daily chang in GI,

which was less than that, observed with a 1:100 diluted control culture one day the

letter reached a GI of at least 30.

The percentage of inhibition data of compounds are recorded in Table No. 2


Pyrazolines...

37

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10

1aC

6H5-

C16

H14

O3S

286

9660

--

0.51

S 1

1b4-

Cl-

C6H

4-C

16H

13C

lO3S

320

120

58-

-0.

48S 2

1c2-

Cl-

C6H

4-C

16H

13C

lO3S

320

135

65-

-0.

50S 1

1d3-

Cl-

C6H

4-C

16H

13C

lO3S

320

105

62-

-0.

44S 1

1e4-

OC

H3-

C6H

4-C

17H

16O

4S31

615

456

--

0.52

S 2

1f3,

4-(O

CH 3

) 2-C

6H3-

C18

H18

O5S

346

118

58-

-0.

56S 2

1g4-

F-C

6H4-

C16

H13

FO3S

304

180

55-

-0.

49S 2

1h3-

Br-

C6H

4-C

16H

13Br

O3S

365

140

65-

-0.

59S 2

1i3-

C6H

5-O

-C6H

4-C

22H

18O

4S37

894

62-

-0.

47S 1

1j4-

N(C

H3)

2-C

6H4-

C18

H19

NO

3S32

914

260

4.25

4.24

0.46

S 1

1k2-

OH

-C6H

4-C

16H

14O

4S30

213

257

--

0.54

S 2

1l2-

C4H

3O-

C14

H12

O4S

276

184

56-

-0.

43S 2

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

TA

BL

E :

1P

HY

SIC

AL

CO

NST

AN

TS

OF

1-[4

-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

3-A

RY

L-2

-PR

OP

EN

E-1

-ON

ES


Pyrazolines...

38

1a 182264 PD-61 C6H5 - Alamar H37R v >6.25 00

1b 182265 PD-62 4-Cl-C6H4 - Alamar H37R v >6.25 00

1c 182266 PD-63 2-Cl-C6H4 - Alamar H37R v >6.25 00

1d 182267 PD-64 3-Cl-C6H4 - Alamar H37R v >6.25 00

1e 182268 PD-65 4-OCH3-C6H4 - Alamar H37R v >6.25 55

1f 182269 PD-66 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18

1g 182270 PD-67 4-F-C6H4 - Alamar H37R v >6.25 42

1h 182271 PD-68 4-Br-C6H4 - Alamar H37R v >6.25 00

1i 182272 PD-69 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11

1j 182273 PD-70 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00

1k 182274 PD-71 2-OH-C6H4 - Alamar H37R v >6.25 00

1l 182275 PD-72 2-C4H3O - Alamar H37R v >6.25 10

SrNo.

Sample ID

Corp ID

R Assay MtbStrain

%Inhibi.

MIC µg/ml

TABLE NO-1TAACF, Southern Research Insitute

Primary Assay Summary Report

NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State

University proprietary Information

R

O

S

O

O

CH3

ANTITUBERCULAR ACTIVITY OF (2E)- 1-[4-(METHYL S U L F O N Y L )

PHENYL]-3-ARY L-2-PROPENE-1-ONES


Pyrazolines...

39

GR

AP

HIC

AL

CH

AR

T N

O.

1 :

(2E

)1-[

4-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

3-A

RY

L-2

-PR

OP

EN

E-1

-ON

ES


Pyrazolines...

40

SECTION - II

SYNTHESIS AND BIOLOGICAL SCREENING OF 1 - A C E T Y L - 3 - [ 4 -

(METHYLSULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES

The broad spectrums of pharmacological properties have been demonstrated

by the pyrazoline nucleus. Inspired by these facts, new pyrazoline derivatives of

Type (II) have been investigated. The 1-[4-(methylsul fonyl )phenyl] -3-ary l -2-

propene-1-ones of type-(I) on treatment with hydrazine hydrate in acetic acid

yielded 1- ace ty l -3- [4-(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles

derivatives of type (II).


basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy






drugs.





Alabama, U. S. A.

Type(I)Type(II)

NH2-NH2 H2O. S

O

O

CH3

NN R

CO-CH3

in glacial CH3COOH

R

O

S

O

O

CH3

R=Aryl


Pyrazolines...

41





1093 1125-1090 ,,1010 1070-1000 ,,

Halide C-Cl str. 819 800-600 144Sulfonyl SO2 str. 1188 1185-1165 ,,Pyrazoline C=O str. 1658 1612-1593 145

C=N str. 1593 1612-1593 ,,N-H str. 3427 3400-3200

0.0

20.0

40.0

60.0

80.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

424.3 484.1

542.0

580.5 624.9

673.1

713.6

783.0

819.7

844.8 871.8

960.51010.6

1093.6

1147.6

1188.11245.9

1299.9

1326.91357.8

1400.21415.7

1490.9

1544.9

1593.1

1658.7

2850.6

2920.0

3047.33303.8

3427.3

IR SPECTRAL STUDIES OF 1-ACETYL-3-[4- (METHYLSULFONYL)

PHENYL]-5-(p-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE

SCH3

O

O NN O

CH3

Cl


cm-1 (KBr disc.)


Pyrazolines...

42



1 2.3 3 H singlet Ar-COCH3 -

2 2.4 3 H singlet Ar-SO2 CH3 -

3 3.03-3.11 1 H d,d Ar-Hf -

4 3.65-3.75 1 H d,d Ar-Hg -

5 5.49-5.55 1 H d,d Ar-He -

6 7.13-7.24 2 H doublet Ar-H b,b' Jba=8.1

7 7.24-7.26 2 H doublet Ar-H c,c' Jcd=8.6

8 7.27-7.28 2 H doublet Ar-H a,a' Jab=8.7

9 7.61-7.63 2 H doublet Ar-H d,d' Jdc=8.1

Signal No.




NMR SPECTRAL STUDIES OF 1 -ACETYL-3- [4 -(METHYLSULFONYL)

PHENYL]-5-(p-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE

SCH3

O

O NN O

CH3

Cl

HfHg

a b

a' b'

c

d

c'd'

e


Pyrazolines...

43

TAB

LE

-2 :

MA

SS

SP

EC

TR

AL

ST

UD

IES

OF

1

-AC

ET

YL

-3-[

4-(

ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-5

-(M

-

BR

OM

OP

HE

NY

L)-

4,5-

DIH

YD

RO

-1H

-PY

RA

ZO

LE

m/z

= 4

21


Pyrazolines...

44

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL SCREENING OF 1 - A C E T Y L - 3 - [ 4 -

(METHYLSULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES

(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-1-

ones

See Part-I, Section-I (B).

(B) Synthesis of 1-Acetyl-3-[4-(methylsulfonyl)phenyl]-5-(p-chlorophenyl)-

4,5-dihydro-1H-pyrazole

A mixture of 1- [4-(Methyls u l f o n y l ) p h e n y l ] - 3 - (p-chlorophenyl)- 2 -

propene-1-on e (3.20 gm, 0.01 mol) in glacial acetic acid (25 ml) and hydrazine

hydrate (0.5gm, 0.01 mol) was refluxed for 8 hrs. The product was isolated and

crys ta l l ized f rom e thanol . Yie ld 56%, m.p . 125o C, Anal . Ca lcd . for

C18H17ClN2O3S; Requires: C, 57.35; H, 4.55; N, 7.43 %; Found: C, 57.32; H,

4.53; N, 7.45 %.

Similarly, other 1-acetyl-3-[4-(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-

1H-pyrazoles were prepared. The physical data are recorded in Table No.2

(C) Biological screening of 1-Acetyl-3-[4-(methylsulfonyl)phenyl]-5-aryl-

4,5-dihydro-1H-pyrazoles.

Antimicrobial testing were carried out as described in Part-I Section-I(C).

The zones of inhibition of test solutions are recorded in Graphical Chart No.2


Pyrazolines...

45

3aC

6H5-

C18

H18

N2O

3S34

211

865

8.18

8.19

0.40

S 2

3b4-

Cl-

C 6H

4-C

18H

17C

lN2O

3S37

612

556

7.43

7.45

0.55

S 2

3c2-

Cl-

C 6H

4-C

18H

17C

lN2O

3S37

618

556

7.43

7.44

0.40

S 1

3d3-

Cl-

C 6H

4-C

18H

17C

lN2O

3S37

616

552

7.43

7.42

0.52

S 2

3e4-

OC

H3-

C6H

4-C

19H

20N

2O4S

372

134

597.

527.

510.

56S 2

3f3,

4-(O

CH 3

) 2-C

6H3-

C20

H22

N2O

5S40

211

848

6.96

6.97

0.42

S 1

3g4-

F-C

6H4-

C18

H17

FN2O

3S36

012

661

7.77

7.76

0.41

S 1

3h3-

Br-

C 6H

4-C

18H

17B

rN2O

3S42

114

068

6.65

6.68

0.49

S 2

3i3-

C6H

5-O

-C6H

4-C

24H

22N

2O4S

434

126

496.

456.

420.

46S 1

3j4-

N(C

H3)

2-C

6H4-

C20

H23

N3O

3S38

514

666

10.9

010

.91

0.58

S 1

3k2-

OH

-C6H

4-C

18H

18N

2O4S

358

165

577.

827.

810.

51S 2

3l2-

C4H

3O-

C16

H16

N2O

4S33

213

655

8.43

8.44

0.45

S 1

TA

BL

E :

3P

HY

SIC

AL

CO

NST

AN

TS

OF

1-

AC

ET

YL

-3-[

4-(M

ET

HY

LSU

LF

ON

YL

)PH

EN

YL

]-5-

AR

YL

-4,5

-DIH

YD

RO

-

1H-P

YR

AZ

OL

ES

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Pyrazolines...

46

2a 182204 PD-1 C6H5 - Alamar H37R v >6.25 00












SrNo.

Sample ID

Corp ID

R Assay MtbStrain

%Inhibi.

MIC µg/ml





S

O

O

CH3

NN R

CO-CH3

ANTITUBERCULAR ACTIVITY OF 1 - A C E T Y L - 3 - [ 4 - (METHYL

SULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES


Pyrazolines...

47

GR

AP

HIC

AL

CH

AR

T N

O.

2 :

1-A

CE

TY

L-3

-[4-

(ME

TH

YL

SUL

FO

NY

L)P

HE

NY

L]-

5-A

RY

L-4

,5-D

IHY

DR

O-1

H-

PY

RA

ZO

LE

S


Pyrazolines...

48

SECTION - III

SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - [ 4 -

( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 5 - A R Y L - 4 , 5 - D I H Y D R O - 1 H -

PYRAZOLES

Therapeutic important of pyrazolines aroused considerable intrest to

synthes ize pyrazol ines of type ( I I I ) by the cyclocondensa t ion of 1 - [ 4 -

(Methylsul fonyl)phenyl] -3-aryl -2-propene-1-ones of type-(I) with hydrazine

hydrate in order to study their biodynamic behaviour.








drugs.

NH2 -NH2 H2Oin ethanol

S

O

O

CH3

NNH

RR

O

S

O

O

CH3

Type(I) Type(III)R=Aryl


Pyrazolines...

49

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

536.2

584.4

617.2

709.8

788.8

812.0

935.4

975.91004.8

1028.0

1066.61095.5

1172.6

1245.9

1296.1

1350.1

1398.3

1436.9

1510.2

1583.4

1606.6

2839.02879.52958.63074.3

3340.5

IR SPECTRAL STUDIES OF 3-[4-(METHYLSULFONYL)PHENYL]-5-

(p-METHOXYPHENYL)- 4 , 5 - D I H Y D R O - 1 H - P Y R A Z O L E





1095 1125-1090 ,,1066 1070-1000 ,,

Ether C-O-C str. 1245 1260-1200 144Sulfonyl SO2 str. 1172 1185-1165 ,,Pyrazoline N-H str. 3340 3400-3200 145

C=N str. 1606 1612-1593 ,,

SCH3

O

O NNH

O

CH3


cm-1 (KBr disc.)


Pyrazolines...

50




2 3.9 3 H singlet Ar-OCH3 -

3 2.95-3.04 1 H d,d Ar-Hc -

4 3.36-3.45 1 H d,d Ar-Hg -

5 4.84-4.90 1 H d,d Ar-He -

6 6.85-6.89 2 H doublet Ar-H b,b' Jba=8.1

7 7.22-7.25 2 H doublet Ar-H c,c' Jcd=8.6

8 7.26-7.30 2 H doublet Ar-H a,a' Jab=8.7

9 7.56-7.60 2 H doublet Ar-H d,d' Jdc=8.1

Signal No.




NMR SPECTRAL STUDIES OF 3-[4-(METHYLSULFONYL)PHENYL]-5-

(p-METHOXYPHENYL)- 4 , 5 - D I H Y D R O - 1 H - P Y R A Z O L E

SCH3

O

O NNH

O

CH3

HfHg

a b

a' b'

c

d

c '

d'

e


Pyrazolines...

51

TAB

LE

-3 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 3

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-5-

(M-P

HE

NO

XY

PH

EN

YL

)-4

,5-

DIH

YD

RO

-1H

-PY

RA

ZO

LE

m/z

=39

2


Pyrazolines...

52

EXPERIMENTAL


( M E T H Y LS U L F O N Y L ) P H E N Y L ] - 5 - A R Y L - 4 , 5 - D I H Y D R O - 1 H -

PYRAZOLES

(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-

1-ones


(B) Synthesis of 3-[4-(Methylsul fonyl)phenyl] -5-(p-methoxyphenyl)-4,5-

dihydro-1H-pyrazole

A mixture of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -(p-methoxyphenyl) - 2 -

propene-1-one (3.16 gm, 0.01 mol) in methanol (25 ml) and hydrazine hydrate

(0.5gm, 0.01 mol) was refluxed for 8 hrs. The product was isolated and crystallized

from ethanol. Yield 63%, m.p. 168oC, Anal. Calcd. for C17H18N2O3S; Requires:

C, 61.80; H, 5.49; N, 8.48 %; Found: C, 61.78; H, 5.48; N, 8.46 %.

Similarly, other 3-[4-(methylsulfonyl)phenyl]-5-aryl-4 ,5-dihydro-1H-

pyrazoles were prepared. The physical data are recorded in Table No.3

(C) Biological screening of 3-[4-(Methylsulfonyl)phenyl] -5-aryl-4 ,5-

dihydro-1H-pyrazoles .




Pyrazolines...

53

2aC

6H5-

C16

H16

N2O

2S30

012

260

9.33

9.34

0.44

S 2

2b4-

Cl-

C6H

4-C

16H

15C

lN2O

2S33

416

478

8.37

8.36

0.61

S 2

2c2-

Cl-

C6H

4-C

16H

15C

lN2O

2S33

414

562

8.37

8.35

0.56

S 1

2d3-

Cl-

C6H

4-C

16H

15C

lN2O

2S33

413

258

8.37

8.38

0.52

S 2

2e4-

OC

H3-

C6H

4-C

17H

18N

2O3S

330

168

638.

488.

460.

55S 2

2f3,

4-(O

CH 3

) 2-C

6H3-

C18

H20

N2O

4S36

011

852

7.77

7.76

0.64

S 1

2g4-

F-C

6H4-

C16

H15

FN2O

2S31

819

266

8.80

8.81

0.41

S 1

2h3-

Br-

C6H

4-C

16H

15Br

N2O

2S37

914

045

7.39

7.40

0.59

S 2

2i3-

C6H

5-O

-C6H

4-C

22H

20N

2O3S

392

165

627.

147.

120.

44S 1

2j4-

N(C

H3)

2-C

6H4-

C18

H21

N3O

2S34

312

672

12.2

312

.24

0.51

S 2

2k2-

OH

-C6H

4-C

16H

16N

2O3S

316

160

578.

858.

870.

61S 2

2l2-

C4H

3O-

C14

H14

N2O

3S29

014

562

9.65

9.67

0.42

S 1

TA

BL

E :

2P

HY

SIC

AL

CO

NST

AN

TS

OF

3-[4

-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

5-A

RY

L-4

,5-D

IHY

DR

O-1

H-

PY

RA

ZO

LE

S

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Pyrazolines...

54

GR

AP

HIC

AL

CH

AR

T N

O.

3 :

3-[4

-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

5-A

RY

L-4

,5-D

IHY

DR

O-1

H-P

YR

AZ

OL

ES


Pyrazolines...

55

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Chem. Ber., 32, 1921 (1899).

2. B. S. Holla and S. Y. Ambekar;

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3. K. Kazauki, K. Htayama, S. Yokomor and T. Soki;

Japan Kokai 75 , 140, 429, (Cl. C07 C A61K) 11 Nov.

1975, Appl. 74, 44, 152, 19 Apr. 1974; 4, p.p.; Chem. Abstr. , 85, 5913 (1976).

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Chem. Ber. , 34, 3527 (1901).

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140411d (1972).

15. A. M. Fahmy. M. Hussan, A. A. Khalt; R. A. Ahmedi,


Pyrazolines...

56

Rev. Roum-Chim., 33(7), 755-61 (1988); Chem. Abstr., 111, 77898 (1989).

16. A. Sakari and H. Midorikawa;

Bull. Soc. Japan 41, 430 (1968); Chem. Abstr., 69, 18985 (1968).

17. A. Samour, Y. Akjnoukh nd H. Jahine (Pal. Sci. Ain Sharm Uni. Cario UAK);

J. Chem. 1970 pub. (1971) 13(4), 421-37 (Eng.); Chem. Abstr., 77 , 101348 (1977).

18. Hartann R. W., Reichert N and Grzarinh S;

Eur. J. Med. Chem., 29(11) , 807-817 (1994); Chem. Abstr. , 122 , 239500n (1995).

19. N. Latif, N. Mishriky and N. S. Girgis;

Indian Journal Of Chemistry, 20B, 147-149 (1981).

20. H. G. Garg and P. P. Singh;

J. Med. Chem., 11, 1104 (1968).

21. B. S. Hastak and B. J. Ghiya;

Indian Journal of Heterocyclic Chemistry, 2, 135-136 (1992).

22. S. B. Lohiya and B. J. Ghiya;

Indian J. Chem., 279-82 (1986).

23. A. C. Jain, A. Mehta and P. Arya;

Indian Jornal of Chemistry. 26B, 150-153 (1987).

24. Hutchins and Wheeler;

J. Chem. Soc., 91 (1939).

25. Arito et al.;

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Pyrazolines...

57

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Pyrazolines...

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Cyanopyridines...

65

INTRODUCTION

Pyridine is the parent of the series of compounds that is important in

pharmaceutical, agriculture and industrial chemistry. Among a wide range of pyridines

3-cyanopyridines acquired a special attention due to their wide range of therapeutic

activities. 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 cyclization of aliphatic raw

materials.

The pyridine nucleous is found in a large number of commonly used drugs

which have diverse pharmacological activities. Interest in the synthesis of

multicyclic pyridine containing compounds have increased in recent years because

of their biological and pharmacological activities. In our continuation work in the

chemistry of pyridine nucleous, we have undrtaken the synthesis of methylsulfonyl

derivatives such as 2-methoxy-6-[4-(methylsulfonyl)phenyl]-4-phenylnicotinonitrile

via chlacones.

SYNTHETIC ASPECT :

Preparation of 3-cyanopyridines have been cited in literature1-6

with different

methods.

1. Samour and co-worker7 have prepared substi tuted cyanopyridines by

th e condensation of chalcones with malononitrile in presence of ammonium

acetate.

N

COOCH3

H3CO

CNR


Cyanopyridines...

66

H2C

CN

CNNaOCH3

HC

CN

CN_

R O

R1

HC

CN

CN_

R O

R1

CN

N

H+

R O

R1

CN

N

R

R1

CN

OCH3ONN

R1

R OCH3

CN

OH

H

N

R1

R OCH3

CN

N

R1

R OCH3

CN-2H

NaOCH3

+

-OH-

H+

H+

NaOCH3

-

-R

R1

CN

OCH3OHN

NaOCH3

MECHANISM :

The reaction proceeds through conjugate addition of active methylene

compounds to the α,β -unsaturated system as shown below.

R1R

O

CH2(CN)2CH3CONH4

N

NH2

R

N

R1


Cyanopyridines...

67


The extensive use of cyanopyridine derivatives have been established in medicine

due to its antihypertensive, anticholestemic, antidiabetic, antifungal and antibacterial

properties.Few of them reported as shown below.

1. Antifungal8

2. Antiepileptic9

3. Antibacterial10

4. Anticonvulsant11

5. Antitubercular12

6. Analgesic13

7. Insecticidal14

8. Antisoriasis15

9. Antihypertensive16

The synthesis of cyanopyridines are of current interest owing to their

enormous occurence in biologically active derivaties. Hence, considerable attention

has been focused on the study of efficient and pharamaceutical important

cyanopyridines bearing benzimidazole nucleus.

El-Nabawia et al.17

have prepared 2-amino-3-cyano pyridine derivatives (I)

and studied their antimicrobial activity. S. Guru et al.18

have synthesized various

cyanopyridyl derivatives (II) and documented their multiple biological activities.

O

N

NH2

R

N

NN CH3

CCH3

O

RC

NH2

N

(I) (II)


Cyanopyridines...

68

The insecticidal activity of cyanopyridines have been screened by Y. Sasaki19

et al. Umed Ten et al.20

have prepared cyanopyridines as agrochemical fungicides.

The oxide activator bleaching activity of cyanopyridine has been proved by

Rees M.21

, Oshida M.22

prepared cyanopyridine derivatives which inhibit cerebral

edema and delayed neuron death. hence, they are useful as cerebral edema inhibitors

or cerebrovascular disorder remedies.

S. S. Verma et al.23

and M. D. Ankhiwala24

have synthesized 2-amino-3-cyano-

2,6-disubstituted pyrimidines and studied their biological activities. Several workers

have prepared cyanopyridine derivatives and reported their cholinesterase

inhibi tors ,25

ant ihis taminic and ant ia l lergic ,26

adernerg ic ,27

herbicidal ,28

antiinflammatory29

and insecticidal30

activities. Some new 3-cyanopyridine derivatives

synthesized by Hammama A. and coworkers31

showed anticancer and anti HIV-I

activity. Abdallah N. et al.32

have synthesized and reported analgesic and

antiinflammatory activity.

Moreover Miertus et al.33

synthesized 2-formyl pyridine thiosemicarbazone

as a carcinostatic agent. Adriano Afonso et al.34

have found cyanopyridines are

Fernesyl protein t ranferase inhibi tors . Hussain et a l .35

have synthes ized

cyanopyridines as antimicrobial agent. Wu Wenxue et al.36

have synthesized

cyanopyridines as histamine H3 antagonists. Saudi Manal N. S. et al.37

have found

that cyanopyridines have fascialicidal property. Harada Hironori et al.38

have prepared

cyanopyridines and screened for their large conductance calcium activated

potassium channel opener activity.

Dipeptidyl peptidase (DPP-IV) inhibition has the potential to become a

valuable therapy for diabetes. Edwin B. Villhauer and co-worker39

have reported

the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor

class and a solution-phase synthesis that is practical up to the multikilogram scale.

One compound, NVP-DPP728 (III), is profiled as a potent, selective and shortacting


Cyanopyridines...

69

DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic

activity.

Marco J. L. et al.40

have synthesized of acetylcholinesterase inhibitors.

Moustafa M. A. et al.41

have prepared antibacterial agents. Rosentreter Ulrich et

al.42

have synthesized a new cyanopyridine as receptor agonists in the treatment of

cancer disease , inflammation, neurodegenerative disease(IV). Gary T. Wang and

co-worker43

have synthesized of o-trifluoromethylbiphenyl substituted 2-amino-

nicotinonitriles as inhibitors of farnesyltransferase(V).

Thus, diverse biological activities have been encountered in compounds

containing cyanopyridine ring system. Therefore it was considered wothwhile to

synthesise cyanopyridine derivatives which have been described as under.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 2 -

METHOXY-6-[4-(METHYLSULFONYL)PHENYL]-4-

A R YLNICOTINONITRILES

N NHNH

O

N

CN

NC

(III)

N

CN

CNR2CH2S

NH2

O(CH2)n OR1

NO

N

N

NC

NR1

R2

F3C

CN

CH3

(IV) (V)


Cyanopyridines...

70

SECTION - I

SYNTHESIS AND BIOLOGICAL SCREENING OF 2-METHOXY-6-[4-

(METHYLSULFONYL)PHENYL]-4-ARYLNICOTINONITRILES

Cyanopyridines play a vital role owing to their range of biological and

physiological activites. In the light of these biological activities and variety of

industrial applications, some new 2-methoxy-6-[4-(methylsulfonyl)phenyl]-4-

a ry ln i co t inon i t r i l e s derivatives of type (IV) have been prepared, by the

cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones of

type (I) with malononitrile in presence of sodium methoxide.








drugs.

Type(I)Type(IV)R=Aryl

CH2(CN)2

NaOCH3 in methanol N

R

O

S

O

O

CH3

CH3

N

R

O

S

O

O

CH3


Cyanopyridines...

71

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

482.2

534.2

779.2

819.7

900.7

1010.6

1091.6

1184.2

1209.3

1263.31307.6

1357.8

1380.9

1409.9

1448.41494.7

1546.8

1577.7

1606.6

2221.8

2852.5

2923.9

3222.8

3327.0





1091 1125-1090 ,,1010 1070-1000 ,,

Halide C-Cl str. 819 800-600 44Sulfonyl SO2 str. 1184 1185-1165 ,,Ether C-O-C str. 1209 1260-1200 ,,Pyridine C=C str. 1606 1650-1520 45

C=N str. 1577 1580-1550 ,,Nitrile C=N str. 2221 2240-2120 ,,

IR SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)

PHENYL]-4-(p-CHLOROPHENYL)NICOTINONITRILE

SCH3

O

O N

O CH3

N

Cl


cm-1 (KBr disc.)


Cyanopyridines...

72




2 3.9 3 H singlet Ar-OCH3 -

3 7.25-7.31 2 H doublet Ar-H b,b Jba=7.8


5 7.43 1 H singlet Ar-He -



Signal No.




NMR SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)

PHENYL]-4-(p-CHLOROPHENYL)NICOTINONITRILE

SCH3

O

O N

O CH3

N

Cl

a b

a'

c

d

c'

d'

He

b'


Cyanopyridines...

73

TAB

LE

-4 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 2-

ME

TH

OX

Y-6

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-4-

AR

YL

NIC

OT

INO

NIT

RIL

E

m/z

= 3

64


Cyanopyridines...

74

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL SCREENING OF 2-METHOXY- 6 - [ 4 -

(METHYLSULFONYL)PHENYL]-4-ARYLNICOTINONITRILES

(A) Synthesis of 1-[4-(Methyl su l fony l )pheny l ] -3 -aryl-2 -propene -

1 -ones


(B) Synthesis of 2-Methoxy-6-[4-(methylsulfonyl)phenyl]-4-(p-chloro-

phenyl)nicotinonitrile

To a solution of 1-[4-(methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -

p r o p e n e - 1 - o n e (3.20 gm, 0.01 mol), malononitrile (0.60gm, 0.01 mol) in

methanol (10ml) and sodium methoxide, which prepared from sodium (46mg) and

absolute methanol (20ml) was added. The content was heated under reflux with

stirring for 12 hr. The reaction mixture was diluted with water and extracted with

chloroform. The excess solvent was distilled off and residue was crystallized from

ethanol. Yield 48%, m.p. 165oC, Anal. Calcd. for C20H15ClN2O3 S; Requires:

C,60.22; H, 3.79; N, 7.02; Found: C, 60.20 ; H, 3.78; N, 7.01 %.

S i m i l a r l y , o t h e r 2 - m e t h o x y - 6 - [ 4 - ( m e t h y l s u l f o n y l ) p h e n y l ] - 4 -

arylnicotinonitriles were prepared. The physical data are recorded in Table No.4

(C) Biological screening of 2-Methoxy-6-[4-(methylsul fonyl )phenyl] -4-

arylnicot inonitr i les

Antimicrobial testing were carried out as described in Part-I Section-1 (C).

The zones of inhabition of test solution are recorded in Graphical Chart No 4.


Cyanopyridines...

75

4aC

6H5-

C20

H16

N2O

3S36

412

554

7.69

7.68

0.51

S 1

4b4-

Cl-

C6H

4-C

20H

15C

lN2O

3S39

816

548

7.02

7.01

0.56

S 2

4c2-

Cl-

C6H

4-C

20H

15C

lN2O

3S39

813

253

7.02

7.03

0.41

S 2

4d3-

Cl-

C6H

4-C

20H

15C

lN2O

3S39

814

258

7.02

7.04

0.45

S 1

4e4-

OC

H3-

C6H

4-C

21H

18N

2O4S

394

115

627.

107.

120.

42S 1

4f3,

4-(O

CH 3

) 2-C

6H3-

C22

H20

N2O

5S42

411

858

6.60

6.62

0.56

S 2

4g4-

F-C

6H4-

C20

H15

FN2O

3S38

216

362

7.33

7.34

0.52

S 2

4h3-

Br-

C6H

4-C

20H

15Br

N2O

3S44

314

068

6.32

6.35

0.51

S 2

4i3-

C6H

5-O

-C6H

4-C

26H

20N

2O4S

456

192

596.

146.

150.

42S 1

4j4-

N(C

H3)

2-C

6H4-

C22

H21

N3O

3S40

717

845

10.3

110

.32

0.59

S 2

4k2-

OH

-C6H

4-C

20H

16N

2O4S

380

170

567.

367.

350.

51S 2

4l2-

C4H

3O-

C18

H14

N2O

4S35

414

565

7.90

7.92

0.49

S 1

TA

BL

E :

4P

HY

SIC

AL

CO

NST

AN

TS

OF

2-

ME

TH

OX

Y-6

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-4-

AR

YL

NIC

OT

INO

NIT

RIL

ES

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Cyanopyridines...

76

GR

AP

HIC

AL

CH

AR

T N

O.

4 :

2-M

ET

HO

XY

-6-[

4-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

4-A

RY

LN

ICO

TIN

ON

ITR

ILE

S


Cyanopyridines...

77

REFERENCES

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Chem. Heterocycl. Compd. (N. Y.) (1999).

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VEB Leund-Werke “Walter Ulbricht” Ger. 1, 193, 506 (1965); Chem. Abstr., 63, 6979

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13. Thiele Kurt, Von Be Benburg and Walter E.;

S. African 6, 905, 06, 13 Feb. (1970).

14. B. John ED., Freeman and Peter F. M.;

Ger. Often., 2, 029, 079 (Cl. A 01 N007d) (1971); Brist. Appl. (1969); Chem. Abstr., 74,

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15. V. Scott and Joseph;

Jap. Pat., 2, 803, 592 (1979); Chem. Abstr., 92, 47216 (1980).

16. J. J. Baldwin, A. Scrialrine, G. S. Ponticeello, E. L. Engelhardt and C. S. Sweeti;


Cyanopyridines...

78

J. Heterocycl. Chem., 17(3), 425 (1980); Chem. Abstr., 93, 186222, (1980).

17. El-Nabawia El-Said Goda, F. Alexandria;

S. Pharm. Sci., 1999; Chem. Abstr., 132, 151650g (2000).

18. Guru S. Goda Ginamath, Ashok S. Shya digeri and Rajesh R. Kavall;

Ind. J. Chem., 37(B), 1137C (1998).

19. Y. Sasaki, J. Takuro, M. Ooishi, M. Sekine and S. Imaki;

Jpn. Kokai Tokkyo Koho JP., 06, 315, 390 (1994); Chem. Abstr., 122, 131184y (1995).

20. Umed Ten, Kusunoki, M. Takuro, M. Shinya;

Jpn. Kokai Tokkyo Koho JP., 09, 95, 489 (1997); Chem. Abstr., 127, 17699y (1997).

21. Rees Wayne M. (S. C. Johnson and son Ime., USA);

PCT Int. Appl. WO 97, 42295 (1997); Chem. Abstr., 128, 4928t (1998).

22. Oshida Mario, M. Yogi, S. Hiroaki, Y. Shinji;

PCT Int. Appl. WO 98, 22, 439; Chem. Abstr., 129, 4582w (1998).

23. S. S. Verma, P. Taneja, L. Prakash, A. L. Mittal;

J. Ind. Chem. Soc., 65, 798 (1988).

24. M. D. Ankhiwala;

J. Ind. Chem., Soc., 69, 16 (1992).

25. Villatobos Anabella, N. Arthur A., C. Yuppyng L.;

U.G. US 5, 750, 542; Chem. Abstr., 129, 4661w (1998).

26. Yoshida Hirashi, O. Kiyoshi, Y. Yasujuki, F. Kensaku;

Jpn. Kokai Tokkyo Koho JP 10, 120, 677; Chem. Abstr., 129, 16062q (1998).

27. Devries Keith Michael, D. R. Lee, W. S. Wayne;

PCT Int. Appl. WO 98, 21, 184; Chem. Abstr., 129, 27896r (1998).

28. Nebel, Kurt, Brunner, H. Geary, S. Rolf;

PCT Int. Appl. WO 98, 21, 199; Chem. Abstr., 129, 27898t (1998).

29. Mama Fedele, C. Franco, B. Adriana, B. Bruna, F. Walter, F. Amelia;

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30 K. M. Hussain, H. Ruzial, S. Ahmed, Nizamuddin;

Ind. J. Chem. Sect. B Org. Incl. Med. Chem., 37B(10), 1069-1074 (1998); Chem. Abstr.,

(131), 237504h (1999).

31. Hammama Abou Elfatoon G., El-Hafeza N. A., M. Wandall; Z. Naturforsch B.;

Chem. Sci., 2000.

32. Abdallah Nevine A., Zakimagdi E. A.;

Acta Pharm (Zagreb) 1999; Chem. Abstr., 132, 137287n (2000).


Cyanopyridines...

79

33. Miertus S., Filipovic P., Majek P.;

Chem. Zvesti, 37(3), 311-19 (1983); Chem. Abstr., 99, 104479t (1983).

34. Atonso Adriano, Kelly J. M. Weinstein J. Wolin R. L., Rosenblum S. B.;

PCT Int. Appl. WO 98 59,950 (Cl. C07D (401/04); Chem. Abstr., 130, 81408s (1999).

35. Hussain M. M. M., and M. K. Mona;

Indian J. Chem., 42(B), 2136-2141 (2003).

36. Wu Wenxue, Liao Honghiclo, Tsai D. J. S.;

PCT Int. Appl. WO 03 33488 (2003) (Cl. C07D 401-06); Chem. Abstr., 138, 337996 (2003).

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Alexandria J. Pharm. Sci., 16(2), 75-82 (2002); Chem. Abstr., 138, 385269 (2003).

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Jpn. Kokai Tokkyo Koho JP., 03 2,06,230 (2003). (Cl. A61K 031-4418); Chem. Abstr.,

139, 41663 (2003).

39. Edwin B. Villhauer, John A. Brinkman, Goli B. Naderi, Beth E. Dunning, Bonnie L.

J. Med. Chem. 2002, 45, 2362-2365

40. Marco J. L., Carreiras M. C.;

Mini Rev Med Chem. 3(6), 518-24, (2003).

41. Moustafa M. A., Nasr M. N., Gineinah M. M., Bayoumi W. A.;

Arch Pharm (Weinheim). 337(3) , 164-70, (2004).

42. Rosentreter Ulrich, Kraemer Thomas et al.;

Ger. Otten. DE 10, 238, 113 (Cl,CO 7D213/60) (2003).

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45. A. R. Kartizky and R. Alans Jones;




Pyridones...

80

INTRODUCTION

Pyridone, which belongs to an important group of heterocyclic compounds

have been extensively explored for their applications in the field of medicine.

Pyridones, with a carbonyl group at position 2 (I) have been subject of extensive

study in recent past. Numerous reports have appeared in the literature, which

highlight their chemistry and use.

Pyridones are derivatives of pyrimidines with carbonyl group at 2-position (I).

Some 2-pyridones are physiologically as well as pharmacologically important which

are as under, eg. amrinone (II), ciclopirox (III) and methylprylon (IV).

SYNTHETIC ASPECT :

1. G. Simchen and G. Entemman1 have synthesised 2-pyridone in which the ring

nitrogen comes from a nitrile group in acyclic precursor.

2. K. Folkers and S. A. Harris2 have synthesised 3-cyano-2-pyridone by

the condensation of cyano acetamide with 1,3-diketone or 3-ketoester.

3. M. A. Sluyter and co-workers3 have prepared fused 2-pyridones.

NH

O

N

NH

NH2

O

N

CH3

OH

ONH

O

O

CH3

CH3

CH3

(I)

(II) (III) (IV)


Pyridones...

81


Pyridone derivatives have been found to possess variety of therapeutic activities

as shown below.

1. Anticancer4

2. Herbicidal5

3. Pesticidal6 ,7

4. Antimicrobial8

5. Angitensin II antagonist9-11

6. Antiviral12

7. AntiHIV13

Collins et al.14

have prepared heteroaryl pyridones as GABA α,β ligands (V).

Pednekar15

synthesized fused 2-pyridone derivatives (VI), (VII) and (VIII) as useful

heterocyclic moieties as they possess broad spectrum of biological activities such

as antiviral, CNS depressant, bactericidal and ulcer inhibitor.

Moreover, several co-workers have prepared 2-pyridones as S3 site of

thrombin inhibitor16

, herbicidal 17

, SH2 domain inhibitor

18, antimicrobial

19, GABA-A

receptor 20

and antiinflammatory21

.

O

CH3

O

H5C2OH2C

+N

NH2

O NH

CH3

N

CH2OC2H5

O

NH

Z

Y

X

O

NH

O

NC

CH3

N

N

R

N

N

O

NC

CH3

O

CH3

NH

O

NC

O

Ph

Ph

CH3

(VI)(V) (VII) (VIII)


Pyridones...

82

Morishita Koji et al. 22

have synthesized m-(2-oxo-l,2-dihydropyridyl) urea

derivatives (IX) possessing cholesterol acyltransterase (ACAT) inhibitory activity

and are useful for the treatment of hyperlipidemia and arteriosclerosis.

Moreover, several co-workers have prereported 2-pyridones as S3 site of

thrombin inhibitors23

, herbicidal24

, SH2 domain inhibitor25

and GABA-A receptor26

.

Peter et al.27

have prepared pyridinyl methyl substituted pyridines and pyridones as

angiotensin II antagonists. H. Posnes28

reported 2-pyridones as physiologically active

compounds. Devdas Balekudru et al.29

prepared substituted pyridinones (X) as

modulators of P38 NAP kinase.

Furthermore, Stenzel Wolfgang et al.30

reported some pyridone derivatives

(XI) as cardiotonic, hypnotics, antiasthematics and antithrombotic. Fischer Reiner

et al.31

prepared (thiazolyl) dihydro-1H-pyridinones (XII) as pesticides and herbicides.

N

NH NH

O

Pr

OCH3

Bu

PrO

N

O

Br

O

Et

(IX)

(X)


Pyridones...

83

Peter and co-workers32

have prepared pyridinylmethyl substituted pyridines

and pyridones as angitensin II antagonist. Mukhtar Hussain Khan and co-workers33,34

have prepared 2-pyridone derivatives (XIII) and (XIV) which possess insecticidal

and pesticidal activity.

These observations prompted us to combine this nucleous into well known

pharmaceutical properties of cyanopyridone nucleous so as to enhance the over all

activities of resulting moiety, which have described as under.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 6-[4-

(METHYLSULFONYL)PHENYL]-2 -OXO-4-ARYL-

1,2-DIHYDROPYRIDINE-3-CARBONITRILES

O

OH

N

N

NH

R1

O

NCR2

W

S

N

A B

Q1

Q2

O

X

OG

Y

NH

N

S CN

O

S

R

R

NH

NH

N

R

O

CN

OR

(XI)(XII)

(XIII) (XIV)


Pyridones...

84

SECTION - I


(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-

3-CARBONITRILES

In view of powerful biological activities shown by cyanopyridones, like

antimicrobial and antitubercular, it was worthwhile to synthesized some cyano

pyridone derivatives possessing better biological activity. Synthesis of some new 6-

[4-(methylsulfonyl)phenyl]-2-oxo-4-aryl-1,2dihydropyridine-3-carbonitriles of

type(V) car r ied out by cyclocondensat ion of chalcones of type(I ) wi th

ethylcyanoacetate in presence of ammonium acetate as under.








drugs.





Alabama, U. S. A.

Type(I) R=Aryl Type(V)

CN-CH2-COOC2H5

CH3COONH4NH

R

O

S

O

O

CH3

N

R

O

S

O

O

CH3


Pyridones...

85

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

495.7

561.2 715.5

813.9

894.9

977.8

1010.6

1031.8

1091.6

1186.11224.7

1336.6

1363.6

1402.21436.9

1490.9

1529.4

1589.2

1635.5

1652.9

1739.7

1921.0

2218.02856.4

2918.1

3249.8

3406.1





1091 1125-1090 ,,1031 1070-1000 ,,

Halide C-Cl str. 813 800-600 35Sulfonyl SO2 str. 1186 1185-1165 ,,Amide C=O str. 1739 1740-1690 ,,Amine N-H str. 3249 3180-3140 ,,Nitrtile C=N str. 2218 2240-2120 ,,


O X O - 4 - ( p - C H L O R O P H E N Y L ) - 1 , 2 - D I H Y D R O P Y R I D I N E - 3 -

CARBONITRILE

SCH3

O

O NH

O

Cl

N


cm-1 (KBr disc.)


Pyridones...

86



1 2.4 3 H singlet Ar-SO2CH3 -


3 6.69 1 H singlet Ar-NH -

4 7.32-7.39 2 H doublet Ar-H b,b Jbc=8.1




Signal No.





O X O - 4 - ( p - C H L O R O P H E N Y L ) - 1 , 2 - D I H Y D R O P Y R I D I N E - 3 -

CARBONITRILE

S

CH3

OO

NH

O

N Cl

a

b

a'

b'

cd

c'd'

ef


Pyridones...

87

TAB

LE

-5 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 6

-[4-

(ME

TH

YL

SUL

FO

NY

L)P

HE

NY

L]-

2-O

XO

-4-(

P-C

HL

OR

OP

HE

NY

L)-

1,2-

DIH

YD

RO

PY

RID

INE

-3-C

AR

BO

NIT

RIL

E

m/z

= 3

84


Pyridones...

88

EXPERIMENTAL


(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-

3-CARBONITRILES


1-ones


(B) Synthesis of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-4-(p-chlorophenyl)-

1,2dihydropyridine-3-carbonitrile


propene-1-one (3.20 gm, 0.01 mol), ethylcyanoacetate (1.13 gm, 0.01 mol) and

ammonium acetate (5.92gm, 0.08mol) in dioxan(25ml) was refluxed for 8 hr. The

resulting mixture was poured on to crushed ice. The product was isolated and

crys ta l l ized f rom e thanol . Yie ld 52%, m.p . 185o C, Anal . Ca lcd . for

C19H13ClN2O3S; Requires: C, 69.30; H, 3.40; N, 7.28; Found: C, 69.28; H, 3.49

N, 7.25 %.

S i m i l a r l y , o t h e r 6 - [ 4 - ( m e t h y l s u l f o n y l ) p h e n y l ] - 2 - o x o - 4 - a r y l -

1,2dihydropyridine-3-carbonitriles were prepared. The physical data are recorded

in Table No.5

(C) Biological screening of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-4-aryl-

1,2dihydropyridine-3-carbonitriles


The zones of inhibition of test solution are recorded in Graphical Chart No 5.


Pyridones...

89

5aC

6H5-

C19

H14

N2O

3S35

013

465

7.99

7.98

0.45

S 2

5b4-

Cl-

C6H

4-C

19H

13C

lN2O

3S38

418

552

7.28

7.25

0.55

S 1

5c2-

Cl-

C6H

4-C

19H

13C

lN2O

3S38

413

242

7.28

7.25

0.48

S 1

5d3-

Cl-

C6H

4-C

19H

13C

lN2O

3S38

415

453

7.28

7.24

0.45

S 2

5e4-

OC

H3-

C6H

4-C

20H

16N

2O4S

380

136

597.

367.

350.

42S 1

5f3,

4-(O

CH 3

) 2-C

6H3-

C21

H18

N2O

5S41

011

850

6.83

6.84

0.56

S 2

5g4-

F-C

6H4-

C19

H13

FN2O

3S36

816

064

7.60

7.61

0.59

S 2

5h3-

Br-

C6H

4-C

19H

13Br

N2O

3S42

914

068

6.53

6.54

0.59

S 1

5i3-

C6H

5-O

-C6H

4-C

25H

18N

2O4S

442

194

726.

336.

340.

57S 2

5j4-

N(C

H3)

2-C

6H4-

C21

H19

N3O

3S39

317

861

10.6

810

.67

0.44

S 1

5k2-

OH

-C6H

4-C

19H

14N

2O4S

366

162

557.

657.

660.

45S 1

5l2-

C4H

3O-

C17

H12

N2O

4S34

013

868

8.23

8.24

0.51

S 2

TA

BL

E :

5P

HY

SIC

AL

CO

NST

AN

TS

OF

6-

[4-(

ME

TH

YL

SUL

FO

NY

L)P

HE

NY

L]-

2-O

XO

-4-A

RYL

-1,2

-DIH

YD

RO

PY

RID

INE

-3-C

AR

BO

NIT

RIL

ES

S 1

Hex

ane:

Ethy

l ac

etat

e(5:

5),

S2

Hex

ane:

Ethy

l ac

etat

e(6:

4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Pyridones...

90

5a 182252 PD-49 C6H5 - Alamar H37R v >6.25 00












SrNo.

Sample ID

Corp ID

R Assay MtbStrain

%Inhibi.

MIC µg/ml





NH

R

O

S

O

O

CH3

N

ANTITUBERCULAR ACTIVITY OF 6-[4-(METHYLSULFONYL)PHENYL]-

2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-3-CARBONITRILES


Pyridones...

91

GR

AP

HIC

AL

CH

AR

T N

O.

5 :

6-[4

-(M

ET

HY

L S

UL

FO

NY

L)P

HE

NY

L]-

2-O

XO

-4-A

RY

L-1

,2D

IHY

DR

OP

YR

IDIN

E-3

-

CA

RB

ON

ITR

ILE

S


Pyridones...

92

REFERENCES

1. G. Simchen and G. Entenmann;

Angew. Chem. Int. Edn Engl, 12 , 119 (1973).

2. K Folkers, S. A. Harris;

J. Am. Chem. Soc., 61 , 1245 (1939).

3. M. A. Sluyter, U. K Pandit, W. N. Speckamp and H. O. Huisman;

Tetranedron Lett., 87 (1966).

4. Hu Zhiyong, Wang Huicai;

Chem. Abstr., 119 , 72465d (1993).

5. U. Toru, T. Susumu, E. Masayuki and S. M. Saharu;

Eur. Pat. Appl. EP. 4 88 , 220 (Cl. C07D 413/04) (1992); Chem. Abstr., 118 , 80944d (1993).

6. R. W. Hartann, N. Reichert and S. Gozhring;

Eur. J. Med. Chem., 29(11), 807-17 (1994); Chem. Abstr., 122 , 239500n (1995).

7. K. Jonhannes, F. Rainer, J. R. Jansen and S. Nichael;

Ger. Offen. DE 4, 309 , 552 (Cl. C07/D 213/85); Chem. Abstr., 122, 9877m (1995).

8. D. D. Erol, N. Yulung and A. Turk;

Eur. J. Med. Chem., 29(11), 893-7 (1994); Chem. Abstr., 122, 13650a (1995).

9. P. Fey, H. K Rudolf, H. Walter and K Thomas;

Eur. Pat. Appl. Ep. 62, 3611, (Cl. C07D 401/14); Chem. Abstr., 122, 55897r (1995).

10. H. Rudolf, H. Walter, D. Juergen and F. Peter;

Eur. Pat. Appl. Ep. 5 57 , 843 (Cl. C07D 401/12); Chem. Abstr., 120 , 8478d (1994).

11. H. Michael, Haesslein Jean-Iuc and H. Bertrand ;

PCT Int. Appl. WO 93 16, 149 (Cl. C07D211/86); Chem. Abstr., 120 , 106778w (1994).

12. R. Bernd, P. A. Schirwan, R. Dieter, R. Guenther;

PCT. Int. Appl. WO 96 30, 342 (Cl. C07D 213/89); Chem. Abstr., 126 , 7993e (1997).

13. F. Al-Omar, A. Abdul Zahar, A. El-Khair, A. Adel;

Chem. Abstr ., 136 , 309834q (2002).

14. I. J. Collins, L. P. David and M. C. Richard;

PCT Int. Appl. WO 98 55 , 480 (1998); Chem. Abstr., 130 , 38376t (1999).

15. Pedneker;

PCT Int. Appl. WO 98 30 , 342 (1998); Chem. Abstr., 130 , 487191 (1999).

16. J. E. Reiner, Lim-Wilby, R. S. Marge, T. K Brunck and Ha-Vong;

Chem. Lett., 9(6), 895-900 (1999); Chem, Abstr., 131 , 286379a (1999).

17. Y Mikio, I. Voshiniro, S. Atsushi, Y. Mitsuhiro and H. Rgo;

Jpn. KokaiTokkyo Koho JP II 140 , 054 (Cl. C07D 213/64); Chem. Abstr., 131 , 44738a


Pyridones...

93

(1999).

18. R. Betageri, L. Beaulieu, B. Pierrel ;

PCT Int. Appl. WO 99 31, 066 (Cl. C07D213/75); Chem. Abstr., 131 , 59136a (1999).

19. S. Asmaa, S. Salem;

Pharmazie 54(3), 178-183 (1993); Chem. Abstr., 130 , 281907k (1999).

20. H. Timothy, M. Christopher, R. laewis, R. Thomas;

PCT Int. Appl. WO 98 10 , 384 (Cl. C07D 471/14); Chem. Abstr., 130 , 13918h (1999).

21. B. Shivakumar and L. G. Nargund;

Indian J. Heterocyclic Chem., 8(1), 27-36 (1998); Chem. Abstr., 130 , 66428e (1999).

22 M. K Morishita, A. Nagisa and J. Masashi;

PCT Int. Appl. WO 99 43, 659 (Cl. C07D 213/72); Chem. Abstr., 131 ,

170353h (1999).

23 Reiner John E., Lim Wilby, Margeu Rita S., Bruncj Terence K. and Ha-Vong Theresa;

Chem. Lett ., 9(6) , 895-900 (1999); Chem. Abstr ., 131 , 286379a (1999).

24. Yamagudi Mikio, Ito Voshiniro, Shibaytama Atsushi, Yomaji, Mitsuhiro and Hanai Rgo;

Jpn. Kokai Tokkyo Koho JP 11 140,054 (Cl. CO7D 213/64) ; Chem. Abstr ., 131 , 44738a

(1999).

25. Betageri Rajashekhar, Beaulieu Llinas Brunet, Pierrel;

PCT Int. Appl . WO 99 31,066 (Cl. CO7D 213/75); Chem Abstr. , 131 , 59136a (1999).

26. Harison Timothy, Moyes Christopher, Richard Laewis, Richard Thomas;

PCT Int. Appl . WO 98 10,384 (Cl. CO7D 471/14); Chem. Abstr ., 130 , 13918h (1999).

27. Peter Fey, Dressel Juergem, Kanko Rudolf, Huebsch Walter and Kraemer Thomas;

Eur. Pat. Appl. EP 62 3611 (Cl. CO7D 401/14); Chem. Abstr ., 122 , 55897x (1995).

28. H. Gary Posnes;

Org. Synth ., 177 (1994). chem. Abstr. , 123 , 167349g (1996).

29. Devdas, Balekudru, Walker, John, Selnes, Shaun R., Boehm, Terril., Durley, Richard C.,

Devraj, Rajesh, Hickory, Brian S., Rucker, Paul V., Jerome, Kevin D.;

PCT Int. Appl. WO 03 68 , 230 (Cl. A61K31/4412), 21 Aug 2003, US Appl.

PU 436,915, 30 Dec 2002; 1052 pp.

30. Stenzel, Wolfgang; Hofferber, Eva.;

Eur. Pat. Appl. E.P. 167,121 (Cl. CO7D213/85), 08 Jan 1986, DE Appl. 3,424,685, 05

Jul 1984; 26 pp.

31. Fischer, einer, Ullmann, Astrid, Trautwein, Axel, Drewes, Mark-Wilhelm, Erdelen,

Christoph, Dahmen, Peter, Feucht, Dieter, Pontzen, Rolf, Loesel, Peter.;


Pyridones...

94

Der. Offen. DE 10 , 100,175 (Cl. C07D417/04), 11 Jul 2002.

32. F. Peter, D. Juergem, H. Rudolf, H. Walter and K Thomas;

Eur. Pat. Appl. EP. 62 3611 (Cl. C07D 401/14); Chem. Abstr., 122 , 55897r (1995).

33. Mukhtar Hussain Khan, Raizul Haque;

Indian J. Chem., 37(B) , 1069 (1998).

34. Mukhtar Hussain Khan, Raizul Haque, Taruna Agrawal;

Indian J. Chem., 38(B) , 452-456 (1999).

35. V. M. Parikh;



Jaipur 11-36 (2000).





Cyanopyrans...

95

INTRODUCTION

The chemistry of pyran with different functional group exhibit wide range of

applications in the field of pharmaceuticals, dyes, insecticides and sweet smelling

substances. Pyran ring system is also present in large number of natural coloured

compounds in Vitamin E, hemorrhagic compound in cloves, in fish poisions, in certain

alkaloids and in other substances.

Pyran is a doubly unsaturated six membered ring system with a single oxygen

as hetero atom. The two double bonds may be conjugated as α,β or 1,2-pyran or

isolated as in α,δ or 1,4-pyran.

A degree of stabilisation of the pyran nucleus is achieved by substituting

phenyl group in the 2 or 4 and preferably also in the 6 position.

SYNTHETIC ASPECT

Various methods for the preparation of pyran derivatives have been cited

in the literature1-10

.

1. Reaction between (A) and CH2(CN)2 led to corresponding 2-amino-3-

cyano-4H-pyrans (B)11

.

(A) (II) (B)

O4H-pyran

O2H-pyran

N

O

R1

O O

RCH2(CN)2

N

O

O

O

R

NH2

R1

N

(I)


Cyanopyrans...

96

MECHANISM :

The reaction of malononitrile with α,β -unsaturated system leads to the

formation of cyano 4H-pyran via Michael addition as shown in figure.


Literature survey revealed that various pyrans have resulted in many potential

drugs and are known to possess a broad biological spectrum such as,

1. CNS active agent12

2. Cytotoxic 13

3. Inhibitors of cell proliferation14

4. Gastric acid secretion inhibitor15

5. Antimicrobial16

6. Hypolipidemic17

7. Antipyretic18

8. Antiinvasive19

9. Anti HIV20,21

10. Antifungal22-24

11. Antiallergic25

R

R1

OCH2(CN) 2

N

N

R1 R1

O

R R1

N

N OH

O

NH

R

N

R1

O

NH2

R

N

R1


Cyanopyrans...

97

12. Analgesic26

13. Antagonist27,28

14. Antitumor29

El-Subbagh and co-workers30

have synthesized cyanopyran derivatives and

showed their antiviral activity. Corbou Romuld et al.31

have reported cyanopyran

derivatives (III) which have significant pharmacological activity.

Some of the pyran derivatives(IV) have been patented for their use as

antihypertensive32

, antiestogens33

, antagonist34,35

, antitumor36

and antiviral37

activities.

Synthesis and biological activity of pyran ring system have been reported by O’Brien

et al.38

Sharanin Y. U. A. et al.39

have suggested new 2-amino-3-cyano-4H-pyran

derivatives (V).

O

N

NH

NH2

OCH3

O

CH3

N

O NH2

NN

N

(III)

(IV)


Cyanopyrans...

98

Zwaagstra Mariel40

have newly synthesized pyran derivatives show

antiashamatic activity. Boyer Frederick et al.41

have prepared some new 2-amino-3-

cyano-4H-pyran and reported for anti HIV agent and antiviral activity.

Synthesis and anticancer activity of pyran (VI) containing flourine have been

reported by Mohamed S. Abd et al.42

4H-pyran of type (VII) were prepared to

enhance the anticancer and anti HIV activity.

Moreover, Fathy F. Abdel-Latif et al.43

have reported the synthesis of 2-amino-

3-cyanopyran derivatives and studied their biological activity. Piao Minz, Zhu et.

al.44

have prepared biologically active 2-amino pyran derivatives.

Recently, Hanafusa T, et al45

have reported some new cyanopyran as functional

promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor

specific methylation. Williamson H. S. et al46

have described pyran as a truncated

O

O

O

CH3 NH2

N

R

N

N S

O

CH3

HOOC

F

Cl

NH2

N

X

ONH2

N

(V)

(VI) (VII)


Cyanopyrans...

99

protein from enteropathogenic Escherichia coli acts as an antagonist. Yeo H. and Li

Y. et al.47

have described the synthesis and antiviral activity of helioxanthin analogues.

David-Cordonnier M. H. et al.48

have synthesized as antitumor agents.

Morever, Asche C. et al.49

have reported some novel cyanopyran as antitumour

activity and structure-activity relationships of 5H-benzo[b]carbazoles. Moon C.H.

et al.50

have found some novel benzopyran analog, attenuates hypoxia-induced cell

death via mitochondrial KATP channel and protein kinase C-epsilon in heart-derived

H9c2 cells. Howe A.Y. et al.51 have described some novel nonnucleoside inhibitor

of hepatitis C virus RNA-dependent RNA polymerase. Kim KY et al.52

Anti-apoptotic

action of (2S,3S,4R)-N”-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-

dimethoxymethyl-2H-benzopyran-4-yl)-N’-benzylguanidine.

Thus, diverse biological activities have been encountered in compounds

containing cynopyran ring system. Therefore it was considered wothwhile to

synthesized cyanopyran derivatives containing methylsulfonyl derivatives which have

been descried as under.

SECTION-I :SYNTHESIS AND BIOLOGICAL SCREENING OF 2-AMINO-

6 - [ 4 -(METHYLSULFONYL)PHENYL]-4-ARYL-4H-PYRAN-3-

CARBONITRILES


Cyanopyrans...

100

SECTION - I

SYNTHESIS AND BIOLOGICAL SCREENING OF 2 - A M I N O - 6 - [ 4 -

(METHYLSULFONYL)PHENYL]-4-ARYL-4H-PYRAN-3-CARBONITRILES

Cyanopyran derivatives have been found to be associated with various

pharmacological activities. These findings encouraged us to synthesized, some new

2-amino-6-[4-(methylsulfonyl)phenyl]-4-aryl-4H-pyran-3-carbonitrile derivatives of

type (VI) by the cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-

propene-1-ones of type-(I) with malononitrile in pyridine.








drugs.





Alabama, U. S. A.

R=ArylType(I) Type(VI)

CH2(CN)2

in pyridine O

R

NH2

S

O

O

CH3

N

R

O

S

O

O

CH3


Cyanopyrans...

101

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

530.4 561.2

777.3

821.6

966.3

1028.0

1095.5

1180.4

1247.9

1305.71346.2

1407.91436.9

1461.91494.7

1514.01566.1

1583.41606.6

2046.3

2150.5

2185.22204.5

2372.3

2837.12922.0

3004.9

3352.1

Type Vibration Frequency in cm-1 Ref.

Mode Observed Reported

Alkane C-H str. (asym.) 2922 2975-2950 53

-CH3 C-H str. (sym.) 2837 2880-2860 ,,

C-H def. (asym.) 1461 1470-1435 ,,

C-H def. (sym.) 1346 1390-1370 ,,

Aromatic C-H str. 3004 3090-3030 54

C=C str. 1514 1540-1480 ,,

1095 1125-1090 ,,

1028 1070-1000 ,,

Halide C-Cl str. 821 800-600 53

Sulfonyl SO2 str. 1180 1185-1165 ,,

Pyran C=C str. 1566 1650-1520 54

Nitrile C=N str. 2204 2240-2120 53

Amine N-H str. 3352 3380-3350 ,,

IR SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)

PHENYL]-4-(p-CHLOROPHENYL)-4H-PYRAN-3-CARBONITRILE

SCH3

O

O O

NH2

Cl

N


cm-1 (KBr disc.)


Cyanopyrans...

102



Signal No.



Multiplicity Inference



3 7.33-7.36 2 H doublet Ar-Hb,b’ Jba=8.4

4 7.46-7.49 2 H doublet Ar-H c,c’ Jcd=8.1

5 7.49 2 H singlet Ar-NH2 -

6 7.55-7.56 2 H doublet Ar-H a,a’ Jab=8.7

7 7.56-7.62 2 H doublet Ar-H d,d’ Jdc=8.3

NMR SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)

PHENYL]-4-(p-CHLOROPHENYL)-4H-PYRAN-3-CARBONITRILE

SCH3

O

O O

NH2

Cl

N

a b

a' b'

c

d

c'

d'

e f

J Value In Hz


Cyanopyrans...

103

TAB

LE

-6 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 2

-AM

INO

-6-[

4-(

ME

TH

YL

SUL

FO

NY

L)P

HE

NY

L]-

4-(P

-ME

TH

OX

Y

PH

EN

YL

)-4H

-PY

RA

N-3

-CA

RB

ON

ITR

ILE

m/z

= 3

82


Cyanopyrans...

104

EXPERIMENTAL


1-ones


B) Synthesis of 2-Amino-6-[4-(methylsulfonyl)phenyl]-4-(p-chlorophenyl)-

4H-pyran-3-carbonitrile

To a solution of 1-[4-(Methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -

propene-1-one. (3.20 gm, 0.01 mol) and malononitrile (0.66gm, 0.01 mol) dissolved

in pyridine (20 ml). The content was heated under reflux for 10 hr. on oilbath. The

reaction mixture was cooled and poured on to crushed ice. The residue was

neutralized with 20% HCl, where upon a solid separated out, which was filtered

and crys ta l l ized f rom ethanol . Yie ld 58%, m.p .143o C Anal . Ca lcd . for

C19H15ClN2O3S; Requires: C,58.99; H, 3.91; N, 7.24 %; Found: C, 58.98; H,

3.89; N, 7.23 %.

Similarly, other 2-amino-6-[4-(methylsulfonyl)phenyl]-4-aryl-4H-pyran-3-

carbonitriles were prepared. The physical data are recorded in Table No.6

(C) Biological screening of 2-Amino-6-[4-(methylsulfonyl)phenyl]-4-aryl-

4H-pyran-3-carbonitriles

Antimicrobial testing were carried out as described in Part-I, Section-I(C).

The zones of inhibition or test solution are recorded in Graphical Chart No.6


Cyanopyrans...

105

6aC

6H5-

C19

H16

N2O

3S35

216

568

7.95

7.92

0.56

S 2

6b4-

Cl-

C6H

4-C

19H

15C

lN2O

3S38

614

358

7.24

7.23

0.44

S 1

6c2-

Cl-

C6H

4-C

19H

15C

lN2O

3S38

616

862

7.24

7.25

0.50

S 1

6d3-

Cl-

C6H

4-C

19H

15C

lN2O

3S38

615

546

7.24

7.22

0.55

S 2

6e4-

OC

H3-

C6H

4-C

20H

18N

2O4S

382

170

567.

337.

340.

53S 1

6f3,

4-(O

CH 3

) 2-C

6H3-

C21

H20

N2O

5S41

211

854

6.79

6.80

0.46

S 2

6g4-

F-C

6H4-

C19

H15

FN2O

3S37

016

064

7.56

7.57

0.49

S 2

6h3-

Br-

C6H

4-C

19H

15Br

N2O

3S43

114

069

6.50

6.52

0.49

S 1

6i3-

C6H

5-O

-C6H

4-C

25H

20N

2O4S

444

194

516.

306.

320.

55S 2

6j4-

N(C

H3)

2-C

6H4-

C21

H21

N3O

3S39

517

860

10.3

610

.37

0.46

S 1

6k2-

OH

-C6H

4-C

19H

16N

2O4S

368

142

577.

607.

620.

54S 1

6l2-

C4H

3O-

C17

H14

N2O

4S34

213

965

8.18

8.19

0.55

S 2

TA

BL

E :

6P

HY

SIC

AL

CO

NST

AN

TS

OF

2-

AM

INO

-6-[

4-(M

ET

HY

LSU

LF

ON

YL

)PH

EN

YL

]-4-

AR

YL

-4H

-PY

RA

N-3

-

CA

RB

ON

ITR

ILE

S

S 1

Hex

ane:

Ethy

l ac

etat

e(5:

5),

S2

Hex

ane:

Ethy

l ac

etat

e(6:

4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Cyanopyrans...

106

6a 182240 PD-37 C6H5 - Alamar H37R v >6.25 00












SrNo.

Sample ID

Corp ID

R Assay MtbStrain

%Inhibi.

MIC µg/ml





O

R

NH2

S

O

O

CH3

N

ANTITUBERCULAR ACTIVITY OF 2-AMINO-6-[4-(METHYLSULFONYL)

PHENYL]-4-ARYL-4H-PYRAN-3-CARBONITRILES


Cyanopyrans...

107

GR

AP

HIC

AL

CH

AR

T N

O.

6 :

2-A

MI

NO

-6-[

4-(

ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-4

-AR

YL

-4H

-PY

RA

N-3

-

CA

RB

ON

ITR

ILE

S


Cyanopyrans...

108

REFERENCES

1. A. M. El-Sayed, A. M. El-Saghier, M. M. Abbas Ali, El-Shafei Ahmed Kamal;

Gaaz. Chim. Ital , 1997; Chem. Abstr. , 129 , 4604c (1998).

2. M. R. Hallet, J. E. Painter, Q. Peter, R. Deam;

Tetrahedron Lett. 1998; Chem. Abstr. , 129 , 16105f (1998).

3. A. Chan Seng H., Brlinble margaret;

Aust. J. Chem. , 1998; Chem. Abstr. , 129 , 16105f (1998).

4. P. M. Zhu, I. Kimiaki;

Tetrahedron Lett. 38(30) , 5301-62 (1997); Chem. Abstr. , 127 , 190659h (1997).

5. M. R. Selim Al-Azhar

Bull. Sci. 1997; Chem. Abstr. , 130 , 110131d (1999).

6. F. M. A. El-Taweel, M. A. Selan, S. N. Ayaad, T. M. El-Maati, A. A. Abu El-Agamey;

Biol. Chim Farm. , 1998; Chem. Abstr. , 131 , 73530f (1999).

7. A. A. Hassanien, M. D. Zahran, M. S. A. El-Gaby, M. M. Ghorab;

J. Indian Chem. Soc. , 1999; Chem. Abstr. , 131 , 214249k (1999).

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J. Org. Chem., 1999; Chem. Abstr. , 132 , 49557f (2000).

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Chem. Heterocycl. Compd. (N. Y.) (1999); Chem. Abstr. , 133 , 43477t (2000).

10. S. P. Anatoliy, M. Niazimbetova, Z. I. Evans, H. Dennis, M. E. Nizazymbetor;

Heterocycles (1999); Chem. Abstr. , 131 , 44712m (2000).

11. M. Augustin, P. Jeschke;

J. Peact. Chem ., 1987; Chem. Abstr. , 111 , 7246d (1989).

12. Y. D. Kulkarni, D. Srivastava, A. Bishnoi, P. R. Dua;

J. Indian Chem. Soc. , 73(45) ; Chem. Abstr. , 125 , 86440c (1996).

13. R. Judith, B. Geneviere, T Francois, R. Pierre, L. Stephane, P. Alan, A. Gharem;

Chem. Pharm.Bull. 1998; Chem. Abstr. , 128 , 180349p (1998).

14. Dell Colin Peter, Williams Andrew Carwyn;

Eur. Pat. Appl. EP 599, 514; Chem. Abstr. , 121 , 108765j (1994).

15. L. H. Jochem, V. W. E. Gerlach, B. J. Chim, E. H. Christian, M. Hropot;

Eur. Pat. Appl. EP 807, 629; Chem. Abstr. , 128 , 34684c (1998).

16. A. Dandia, V. Sehgal and P. Singh;

Indian J. of Chem. , 32B , 1288-91 (1993).

17. A. Orjales; A. Berisa and L. Alonso-Cires;


Cyanopyrans...

109

Indian J. of Chem. , 33B , 27-31 (1994).

18. H. I. El-Diwani, H. El-Sahrawi, S. S. Mohmoud & T. Miyase;

Indian J. of Chem. , 34B , 2731 (1995).

19. V. S. Parmar, S. C. Jain, A. Jha, N. Kumar, A. Kumar, A. Vats, S. K. Singh;

Indian J. of Chem. , 36B , 872-879 (1997).

20. X. Zhang, B. Hinkle (a), L. Ballantyne (a); S. Gonzales (a) and M. R. Pena;

J. Heterocycl. Chem. , 34 , 1061 (1997).

21. T. P. Kosta, B. M. Turner, S. Ronald, D. John et. al.;

Eur. Pat. Appl. WO 807, 629; Chem. Abstr. , 128 , 34684c (1998).

22. M. J. Anne, O’Mahony Mary Josephine, L. Stephen, D. Jacqueline;

PCT Int. Appl. WO 98 27, 080; Chem. Abstr. , 129 , 81666d (1998).

23. A. Z. Elassar, A. Abdel Zaher;

Pharmazie 1998; Chem. Abstr. , 129 , 4562a (1998).

24. R. M. Shaker;

Pharmazie 1996, 51(3) ; Chem. Abstr. , 125 , 10762p (1996).

25. D. B. Shinde, M. S. Shingare;

Indian J. Chem. , 30B , 450 (1991).

26. P. Pere, G. Elisa;

Span ES 511, 501.

27. G. A. Kileigil and R. Ertan;

J. Heterocycl. Chem. , 35, 1485 (1998).

28. Saheyla Ozbey and Engin Kendi;


29. W. Wuri, Li Tiechao, M. Robert, J. Yares, E. Hinnart, M. J. Luzzio, S. A. Noble.;

Bio. Org. Med. Chem. Lett. 1998; Chem. Abstr. , 129 , 202833s (1998).

30. El-Subbagh, I. Hussein, Abu-Zaid, M. Sunair;

J. Med. Chem ., 2000, 43(15) , 2915-2921 (2000).

31. Carbou Romuald, Mowbary, Charles Erie, Perros Manoussos;

Chem. Abstr. , 136 , 118423v (2002).

32. A. A. Miky Jehan, H. H. Sharaf;

Indian J. Chem. , 37B , 1998; Chem. Abstr. , 129 , 95421g (1998).

33. J. J. Chon, P. S. Dae, L. H. Sukim Ju Su, K. S. Jin, M. Kuzumi;

PCT Int. Appl. WO 98 25, 916; Chem. Abstr. , 129 , 81667q (1998).

34. F. Katsumi, M. Isamu, T. Natsuku, I. Y. Iijima;


Cyanopyrans...

110

Jpn. Kokai Tokkyo Koho JP 09 , 301, 915; Chem. Abstr. , 128 , 13147q (1998).

35. K. A. Jacobson, Jiang Ji-Long, K. Y. Chul; K. Yishi, A. M. Van Rhee;

PCT Int. Appl. WO 97 27, 177 (1996); Chem. Abstr. , 127 , 190650y (1997).

36. A. Tsutomu, V. Kimihisa;

Saito Synthesis 1997; Chem. Abstr. , 128 , 14002e (1998).

37. T. Mladen, L. Zrinlca, K. Zeljko, P. Ljerka;

Eur. Pat. Appl. EP 820, 998; Chem. Abstr ., 128 , 15401g (1998).

38. O’Brien, John E, Mc. Murry et. al.;

Chem. Abstr ., 130 , (1999).

39. Y. U. A. Sharanin, L. Y. U. Sukharevskaya, V. V. Shelyakin;

Russ. Journal of Org. Chem., 1998; Chem. Abstr. , 130 , 209617d (1999).

40. M. E. Zwaagstra, R. E. M. Korthouwer, T. Henk, Z. Ming-Quinng;

Eur. J. Med. Chem. , 1998; Chem. Abstr. , 129 , 16039n (1998).

41. E. Boyer Frederick Jr., D. J. Michael, E. E. Lee, G. C. Andrew, H. S. Elizabeth;

PCT Int. Appl. WO 98 (1997); Chem. Abstr. , 129 , 16055q (1998).

42. M. S. El-Gaby, Abd. El-Aal, S. G. Abdel-Hamide, M. M. Ghorab;

Acta. Pharm. (Zagreb) 1999; Chem. Abstr. , 132 , 93278d (2000).

43. F. F. Abdel-Latif; R. M. Shanker, N. S. Abdel-Aziz;

Heterocyclic Communication, Vol. 3 , 245-252 (1997).

44. P. M. Zhu, I. Kimiaki;

Chem. Abstr. , 127 , 190659h (1997).

45. Hanafusa T., Shinji T., Shiraha H., Nouso K.;

Cancer. 5(1) , 9 (2005).

46. Williamson H. S., Free A.;

Mol Microbiol. 55(3) , 808-827 (2005).

47. Yeo H., Li Y., Fu L., Zhu J. L., Gullen E. A., Dutschman G. E.;

J Med Chem. 48(2) , 534-546 (2005).

48. M. H., Laine W., Lansiaux A., Rosu F., Colson P.;

Mol Cancer Ther. 4(1) , 71-80 (2005).

49. Asche C., Frank W., Albert A., Kucklaender U.;

Bioorg Med Chem. 13(3), 819-37 (2005).

50. Moon C. H., Baik E. J., Jung Y. S.;

Eur J Pharmacol. 506(1), 27-35 (2004).

51. Howe A. Y., Bloom J., Baldick C. J., Benetatos C. A., Cheng H., Christensen J. S.;


Cyanopyrans...

111


52. Kim K. Y., Lee J. H., Park J. H., Yoo M. A., Kwak Y. G., Kim S. O.;

Eur J Pharmacol. 497(3) 267-77 (2004).

53. V. M. Parikh;



Jaipur 11-36 (2000).





Pyrimidines...

112

INTRODUCTION

Pyrimidine is the most important member of all the diazines as this ring system

occurs widely in living organisms. Pyrimidine and its derivatives have gained

prominence bacause of their potential pharmaceutical values. Many pyrimidine

derivatives play vital role in many physiological action. They are among those

molecules that make life possible as being some of the building blocks of DNA and

RNA.

Pyrimidine is considered to be a resonance hybrid of the charged and

uncharged cannonical structures, its resonance energy has been found to be less

than benzene or pyridine. The naturally occuring pyrimidine derivatives was first

isolated by Gabrial and Colman in 1870, and its structure was confirmed in 1953 as

5-β-D-gluco-pyranoside of divicine.

SYNTHETIC ASPECT

A very important general method for preparing pyrimidines is the condensation

between a three carbon compounds of the type YCH2Z, where Y and Z = COR,

CO2R, CN, and compounds having the amidine structure R(C=NH)NH2, where R

= R (an amidine), OH (urea), SH or SR (thiourea or its s-derivative), NH2

(guanidine); the condensation is carried out in the presence of sodium hydroxide or

sodium ethoxide. This general reaction may be illustrate by the condensation of

acetamidine with ethylacetoacetate to form 4-hydroxy-2,6-dimethylpyrimidine.

NN

NH2 NH

NH2

+ CH2

CCH3O

O

H5C2O NaOC2H5

N

NH

NH2 CH3

O

N

N

OH

NH2 CH3

(I)


Pyrimidines...

113

Pyrimidines can also be prepared by cycloaddition reaction of 1,3,5-

triazines,which act as electron deficient dienes.

There are many other methods of pyrimidine ring synthesis which are of more

limited scope. The reaction of 1,3-dicarbonyl compound or an equivalent reagent

with formamide provides a route of several pyrimidine which are unsubstituted at

the 2-position.

Some other examples of pyrimidine synthesis are as under.

REACTION MECHANISM

The reaction mechanism for the formation of pyrimidine derivatives described

as under.

N

N

N CH3 C N(C2H5)2 N

N

CH3

(H5C2)2N

(PhCO)2CH2 +

CHO

NH4OAc

Me2SO, 80C

N

N

Ph

Ph Ph

N

N

Ph

Ph Ph

CH3 C N3KOMe

140C

N

N

CH3

NH

CH3

N

NCH3 CH3

NH2

PhNMeCH=CH-CHOHCONH 2

200'CHCONHCH=CH-CHO

HCONH 2

N

N


Pyrimidines...

114


It is revealed from the literature survey that pyrimidine derivatives have been

found possessing biological activities reported as under.

1. Fungicidal1

2. Insecticidal2

3. Anticonvulsant3

4. Antitubercular4

5. Tranquilizing5

6. Antidiabetic6

7. Antihypertensive7

8. Analgesic8

9. Antibacterial9

10. Diuretic10

S. S. Sangapure and S. M. Mulagi11

have tested the antimicrobial activity of

benzofuro[3,2-d]pyrimidine derivatives (II). El Sayed12

and A. M. Badaway have

synthesized alkylated substituted mercapto pyrimidine derivatives (III) and studied

RC

CHCH

R1

O

+NH2NH2

R2

Alkali RC

R1

O NH

R2

NH2

R CR1

OH

NH

R2

NH

R CR1

N

R2

N

R CR1

N

R2

N

OH-

-H+_

-H

R2 = SH, NH 2


Pyrimidines...

115

ON

NH

NH2

S

N

N

CH3

Cl

H3CS

NH

NH

O

R

O

N

NH

NH2

O

NNH

O

CH3

O

O

N3

OH

N

N

ClNH2

H5C2 NH2

N

N

O

O

O

NH2NH2

CH3

CH3

CH3

their anticancer and antineoplastic activity. H. Y. Moustafa13

have reported some

pyrimidine derivatives and studied their biological activities.

The pyrimidines uracil (IVa), thyamine (IVb) and cytosine (V) occur very

widely in nature since they are components of nucleic acids, in the form of N-

substituted sugar derivatives. Several analogues have been used as compounds that

interfere with the synthesis and functioning of nucleic acids: examples are fluorouracil

(IVc) and the anti-AIDS drug Zidovudine (AZT) (VI). Some diaminopyrimidines ,

including pyrimethamine (VII) and trimethoprim (VIII) are antimalarial agents;

trimethoprim is also an effective antibacterial agent when used in combination with

a sulphonamide. Minoxidil (IX) is a vasodilator which has been used in the treatment

of hypertension. Vitamine B1(X) is also a pyrimidine.

(II) (III)

(IV) (V) (VI)

(VII) (VIII)


Pyrimidines...

116

NH

N N

NH2

R3

R1

R2

CH3 N N

R4

R3

R2

R1

SH

R5

N

N

N+

O

NH2

NH2

N

N+

CH3

NH2

N+

S

CH3

HOH2CH2C

H

Patil L. R. et al.14

have synthesized some new pyrimidines bearing paracetamol

and imidazolyl moieties. B. J. Ghiya et al.15

synthesized some mercapto pyrimidine

derivatives (XI) and screened for their anticancer, antitubercular and anti HIV

activities.Kaplina N. V. and co-workers16

shows herpes inhibiting activity of some

mercapto pyrimidine derivatives.

Moreover, Chaudhari Bipinchandra et al.17

prepared N6-(2-aminopyrimidin-

4-yl)-quinoline-4,6-diamine (XII) as N-type calcium channel antagonists for the

treatment of pain. Devi E. Sree and co-workers18

have prepared pyrimidine

derivatives and tested for antimicrobial activity. Kovalenko A. L.19

synthesized and

reported antifungal activity of pyrimidine derivatives. Shiv P. Singh and co-workers20

synthesized 4-(4-pyrazolyl)-2-aminopyrimidines(H) and tested them for their

antimicrobial activity.

Some pyrazolo thienopyrimidine derivatives exhibit antiulcer activity21

.

Skolova A. S. and co-workers22

have synthesized 5-amino-6-mercapto pyrimidine

possessing antitumor and cytostatic activity. Hozein Zeinab et al.23

and Khalafallah

(IX) (X)

(XI) (XII)


Pyrimidines...

117

Ali Kamel24

have prepared mercapto derivatives and screened for their antibacterial

and antifungal activity.

H. S. Joshi et al.25 have sythesized some new pyrimidines as antitubercular

and atimicrobial activity(XIII).

Marie Gompel and co-worker26

have showed that meridianins inhibit various

protein kinases such as cyclin-dependent kinases, glycogen synthase kinase-3, cyclic

nucleotide-dependent kinases and casein kinase (XIV). Alistair H et al27

have

synthesized a novel series of aminopyrimidine IKK2 inhibitors which show excellent

in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The

relative potency and selectivity of these compounds has been rationalized using

QSAR and structure-based modelling (XV).

Aleem Gangjee et al.28

have designed and synthesized some novel analogues

of N -{4-[2-(2-Amino-4-ethylpyrrolo[2,3-d ]pyrimidin-5-yl)ethyl]benzoyl}-L-

glutamic acid as potential inhibitors of thymidylate synthase (TS), dihydrofolate

NH

N

N

NH2

R

R

R

R

Meridianin A OH H H HMeridianin B OH H Br HMeridianin C H Br H HMeridianin D H H Br HMeridianin E OH H H BrMeridianin F H Br Br HMeridianin G H H H H

N

N NH

S

N

NH

O O

R

(XIV)

NH

N

Br

R SH

(XIII)

(XV)


Pyrimidines...

118

reductase (DHFR) and as antitumor agents (XVI). Antonello Mai et al.29

have

descr ibed 2 -a lky lamino-6- [1 - (2 ,6 -d i f luorophenyl )a lky l ] -3 ,4 -d ihydro-5-

alkylpyrimidin-4(3H)-ones (F2-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-

benzyl-oxopyrimidine (DABO) family and bearing different alkyl and arylamino side

chains at the C2-position of the pyrimidine ring were active against wild type (wt)

human immunodeficiency virus (HIV-1) and some relevant HIV-1 mutants(XVII).

Viney Lather and co-worker30

have been proposed to predict the anti-HIV

activity of dihydro (alkylthio) (naphthylmethyl) oxopyrimidines. These models are

capable of providing lead structures for development of potent but safe anti-HIV

agents(XVIII).

Gompel M et al.31

have prepared new family of protein kinase inhibitors

isolated from the ascidian aplidium meridianum. Mai A et al.32

have synthesized 5-

alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a

new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors

N

N

NH

NH2

R

NH

O COOH

COOH

CH3

(XVI)

N

NH

O

R

NH

X F F

R1

R = R1 =H, Me ; X = alkyl,aryl, arylalkyl

(XVII)

N

NH

X-S

O

R

R1

(XVIII)


Pyrimidines...

119

belonging to the DABO family. Yamamoto I. et al.33

have reported some

oxopyrimidines searching for the novel antagonist or agonist of barbiturates to the

sleep mechanism based on the uridine receptor. Huang YL et al.34

have synthesized

non-classical antifolates, 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines

and 2,4-diamino-6(5H)-oxopyrimidines as antitumor activity.

Shimizu T., Kimura T. et al.35

have described N3-substituted uridine and

related pyrimidine nucleosides as antinociceptive effects in mice. Sanmartin C et

al.36

have prepared new symmetrical derivatives as cytotoxic agents and apoptosis

inducers. Agarwal A. et al.37

have synthesized 2,4,6-trisubstituted pyrimidine

derivatives as pregnancy interceptive agents.

Whittingham J. L. et al.38

have described pyrimidine ring as a platform for

antimalarial drug for the selectivity of a class of nucleoside inhibitors. Han G. Z. et

al.39

documented the pyr imidine der ivat ives as ant icancer ac t ions of 2-

methoxyestradiol and microtubule-disrupting agents in human breast cancer. Tack

D. K. et al.40

reported anthracycline vs nonanthracycline therapy for breast cancer.

Cano-Soldado P. et al.41

have described pyrimidine nucleous as interaction of

nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside

transporter-1 (SLC28A1). Gompel M. et al.42

have isolated a new family of protein

kinase inhibitors from the ascidian aplidium meridianum. Junmei Wang et al.43 have

prepared and described for HIV-1 Reverse Transcriptase(XIX)

NHNH F

F

F

O

Cl

(XIX)


Pyrimidines...

120

Looking to the diversified activities exhibited and in continuation of our work

on the synthesis of biologically active heterocycles, the synthesis and biological

screening of pyrimidine derivatives have been described as under.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 4 -

[ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 6 -

A RYLPYRIMIDIN-2(1H)-ONES

SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING OF 4-[4-

(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-

2(1H)-THIONES

SECTION-III : SYNTHESIS AND BIOLOGICAL SCREENING OF 4-[4-

(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-

2-AMINES


Pyrimidines...

121

SECTION - I


(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-ONES

In the past years considerable evidence has been accumulated to demonstrate

the efficiency of pyrimidinones. 4-[4-(methylsulfonyl)phenyl]-6-arylpyrimidin-

2(1H)-one of type (VII) have been prepared by the condensation of 1-[4-

(methylsu l fony l )pheny l ] -3 -a ry l -2 -p ropene -1 -ones of type-(I) with urea in

presence of catalytic amount of conc. HCl as shown under.








drugs.





Alabama, U. S. A.

C

O

NH2 NH2 NHN

R

O

S

O

O

CH3R

O

S

O

O

CH3

R=Aryl Type(VII)Type(I)


Pyrimidines...

122

0.0

20.0

40.0

60.0

80.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

474.5 518.8

596.0

657.7

698.2

773.4 810.0

918.1 947.0

995.21029.9

1074.31157.2

1182.3

1247.9

1340.4

1394.4

1431.1

1460.0

1492.8

1514.0

1620.1

2380.0

2675.12738.7

2856.42920.0

3030.03242.1

3404.1



-CH3 C-H str. (sym.) 2856 2880-2860 ,,

C-H def. (asym.) 1460 1470-1435 ,,

C-H def. (sym.) 1394 1390-1370 ,,

Aromatic C-H str. 3030 3090-3030 45

C=C str. 1514 1540-1480 ,,

1089 1125-1090 ,,

1029 1070-1000 ,,

Halide C-Cl str. 773 800-600 44

Sulfonyl SO2 str. 1182 1185-1165 ,,

Vinyl CH=CH str. 3025 3050-3000 45

oxopyri. C=O str. 1654 1672-1652 ,,

IR SPECTRAL STUDIES OF 4-[4-(METHYLSULFONYL)PHENYL]-

6- ( p-CHLOROPHENYL)PYRIMIDIN-2(1H)-ONE

SCH3

O

O

NH

N

O

Cl


cm-1 (KBr disc.)


Pyrimidines...

123




2 7.35 1 H singlet Ar-Hf -

3 7.46-7.51 2 H doublet Ar-H b,b’ Jba=8.1

4 7.66-7.77 2 H doublet Ar-H c,c’ Jcd=7.8


6 7.88-7.91 2 H doublet Ar-H a,a’ Jab=8.4

7 7.94-7.97 2 H doublet Ar-H d,d’ Jdc=7.8

Signal No.





(p-CHLOROPHENYL)PYRIMIDIN-2(1H)-ONE

SCH3

O

O

NH

N

O

Cl

ba

a' b'

c

d

c'

d'

e

f


Pyrimidines...

124

TAB

LE

-7 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 4

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-6-

(P-C

HL

OR

OP

HE

NY

L)

PY

RIM

IDIN

-2(1

H)-

ON

E

m/z

= 3

60


Pyrimidines...

125

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL SCREENING OF

(A) Synthesis of 1-[4-(Methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones


(B) Synthesis of 4-[4-(Methylsul fonyl )phenyl ] -6-(p-chlorophenyl)

pyrimidin-2(1H)-one


propene-1-one. (3.20 gm, 0.01 mol) and urea (0.60gm, 0.01 mol) in dioxane(15

ml) was refluxed in presence of alcoholic KOH for 10 hr. The excess solvent was

distilled off and the residue was neutralized with dilute HCl, the separated solid

was filtered out and crystallized from ethanol. Yield 48 %, m.p. 165oC Anal. Calcd.

for C17H13ClN2O3S Requires: C, 56.99; H, 3.63; N, 7.76 % Found: C, 56.96; H,

3.62, N, 7.74 %.

Similarly, other 4-[4-(methylsulfonyl)phenyl]-6-arylpyr imidin-2(1H)-

ones were prepared.The physical data are recorded in Table No. 7.

(C) Biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl

pyrimidin-2(1H)-ones


The zones of inhibition of test solution are reported in Graphical Chart No. 7.


Pyrimidines...

126

7aC

6H5-

C17

H14

N2O

3S32

613

561

8.58

8.53

0.56

S 2

7b4-

Cl-

C6H

4-C

17H

13C

lN2O

3S36

016

548

7.76

7.74

0.49

S 1

7c2-

Cl-

C6H

4-C

17H

13C

lN2O

3S36

016

952

7.76

7.74

0.54

S1

7d3-

Cl-

C6H

4-C

17H

13C

lN2O

3S36

015

558

7.76

7.75

0.43

S 2

7e4-

OC

H3-

C6H

4-C

18H

16N

2O4S

356

170

567.

867.

870.

53S 2

7f3,

4-(O

CH 3

) 2-C

6H3-

C19

H18

N2O

5S38

611

851

7.25

7.26

0.56

S 1

7g4-

F-C

6H4-

C17

H13

FN2O

3S34

416

062

8.13

8.14

0.48

S 2

7h3-

Br-

C6H

4-C

17H

13Br

N2O

3S40

514

048

6.91

6.90

0.54

S 1

7i3-

C6H

5-O

-C6H

4-C

23H

18N

2O4S

418

194

626.

696.

700.

46S 1

7j4-

N(C

H3)

2-C

6H4-

C19

H19

N3O

3S36

917

851

11.3

711

..34

0.48

S 2

7k2-

OH

-C6H

4-C

17H

14N

2O4S

342

126

578.

188.

190.

54S 2

7l2-

C4H

3O-

C15

H12

N2O

4S31

620

562

8.86

8.87

0.58

S 1

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

TA

BL

E :

7P

HY

SIC

AL

CO

NST

AN

TS

OF

4-[

4-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

6-A

RY

LP

YR

IMID

IN-2

(1H

)-O

NE

S

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Pyrimidines...

127

7a 182216 PD-13 C6H5 - Alamar H37R v >6.25 00












SrNo.

Sample ID

Corp ID

R Assay MtbStrain

%Inhibi.

MIC µg/ml





NHN

R

O

S

O

O

CH3

ANTITUBERCULAR ACTIVITY OF 4-[4-(METHYLSULFONYL)PHENYL]

- 6 - A RYLPYRIMIDIN-2(1H)-ONES


Pyrimidines...

128

GR

AP

HIC

AL

CH

AR

T N

O.

7 :

4-[4

-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

6-A

RY

LP

YR

IMID

IN-2

(1H

)-O

NE

S


Pyrimidines...

129

SECTION - II


(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-THIONES

Thiopyrimidines represent one of the most active classes of compounds

possessing a wide spectrum of biological activities, such as significant in vitro activity

against unrelated DNA and RNA viruses including Polio Viruses, diuretic,

antitubercular spermidical etc. These valid observation led us to synthesize 4-[4-

(m ethylsulfonyl)phenyl]-6-arylpyrimidin-2(1H)-thiones of type (VIII) by


type-(I) and thiourea in presence of HCl as catalyst.


basis of elemental analyses, infrared and 1 H nuclear magnetic resonance

spectroscopy and further supported by Mass spectrometry.





drugs.





Alabama, U. S. A.

NHN

R

S

S

O

O

CH3C

S

NH2 NH2R

O

S

O

O

CH3

Type(VIII)Type(I) R=Aryl


Pyrimidines...

130

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

474.5 493.7

532.3

596.0 669.3

734.8 773.4

812.0

983.6

1014.51031.8

1087.81182.3

1207.4

1224.7

1276.81301.9

1332.7

1382.91406.0

1490.9

1546.8

1564.2

1604.7

1658.7

2339.52362.6

2854.5

2918.1

3342.4




-CH3 C-H str. (sym.) 2854 2880-2860 ,,

C-H def. (asym.) 1490 1470-1435 ,,

C-H def. (sym.) 1382 1390-1370 ,,

Aromatic C-H str. 3045 3090-3030 45

C=C str. 1546 1540-1480 ,,

1087 1125-1090 ,,

1031 1070-1000 ,,

Sulfonyl SO2 str. 1182 1185-1165 44

Amine N-H str. 3342 3300-3150 45

C=C str. 1658 ,,

IR SPECTRAL STUDIES OF 4 - [4 - (METHYLSULFONYL)PHENYL]-6-

AR YLPYRIMIDIN-2(1H)-THIONE

SCH3

O

O

NH

N

S


cm-1 (KBr disc.)


Pyrimidines...

131






4 7.52-7.61 5 H multiplet Ar-H(c-g) -

5 7.94-7.96 2 H doublet Ar-Ha,a’ Jab=8.4


Signal No.




NMR SPECTRAL STUDIES OF 4 - [4 - (METHYLSULFONYL)PHENYL]-6-

AR YLPYRIMIDIN-2(1H)-THIONE

SCH3

O

O

NH

N

S

a b

a' b'

c

d

g

f

e

h

i


Pyrimidines...

132

TAB

LE

-8 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 4-

[4-(

ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-6-

AR

YL

PY

RIM

IDIN

-2(1

H)-

TH

ION

E

m/z

= 3

42


Pyrimidines...

133

EXPERIMENTAL


(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-THIONES

(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2-propene-ones


(B) Synthesis of 4-[4-(Methylsulfonyl)phenyl]-6-(phenyl)pyrimidin-2(1H)-

thione

A mixture of 1-[4-(methylsulfonyl)phenyl]-3-phenyl-2-propene-one (2.86

gm, 0.01 mole) and thiourea (0.78gm, 0.01 mol)in dioxane(15 ml) was refluxed on

a oil-bath in presence of alcoholic KOH for 10 hr. The solvent was distilled off and

the residue was neutralized with dilute HCl, the separated solid was filtered out and

crystallized from ethanol. Yield 62 %, m.p. 182oC Anal. Calcd. for C17H14N2O2S2

Requires: C, 59.63; H, 4.12; N, 8.18 % Found: C, 59.61; H, 4.10, N, 8.19 %.

Similarly, other 4-[4-(m ethylsulfonyl)phenyl]-6-arylpyrimidin-2(1H)-

thiones were prepared. The physical data are recorded in Table No. 8.

(C) Biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-arylpyrimidin-

2(1H)-thiones




Pyrimidines...

134

8aC

6H5-

C17

H14

N2O

2S2

342

182

628.

188.

190.

62S 2

8b4-

Cl-

C6H

4-C

17H

13C

lN2O

2S2

376

165

517.

437.

440.

42S 1

8c2-

Cl-

C6H

4-C

17H

13C

lN2O

2S2

376

162

587.

437.

420.

54S 1

8d3-

Cl-

C6H

4-C

17H

13C

lN2O

2S2

376

155

547.

437.

450.

48S 1

8e4-

OC

H3-

C6H

4-C

18H

16N

2O3S

237

217

046

7.52

7.51

0.56

S 2

8f3,

4-(O

CH 3

) 2-C

6H3-

C19

H18

N2O

4S2

402

118

516.

966.

.97

0.54

S 1

8g4-

F-C

6H4-

C17

H13

FN2O

2S2

360

160

597.

777.

780.

48S 2

8h3-

Br-

C6H

4-C

17H

13Br

N2O

2S2

421

140

676.

656.

640.

51S 1

8i3-

C6H

5-O

-C6H

4-C

23H

18N

2O3S

243

416

558

6.45

5.44

0.47

S 1

8j4-

N(C

H3)

2-C

6H4-

C19

H19

N3O

2S2

385

172

6610

.90

10.9

10.

49S 2

8k2-

OH

-C6H

4-C

17H

14N

2O3S

235

813

654

7.82

7.81

0.54

S 1

8l2-

C4H

3O-

C15

H12

N2O

3S2

332

160

588.

437.

440.

61S 2

TA

BL

E :

8P

HY

SIC

AL

CO

NST

AN

TS

OF

4

-[4

-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

6-A

RY

LP

YR

IMID

IN-2

(1H

)-

TH

ION

ES

S1

Hex

ane:

Ethy

l ac

etat

e(5:

5),

S 2

Hex

ane:

Ethy

l ac

etat

e(6:

4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Pyrimidines...

135

8a 182228 PD-25 C6H5 - Alamar H37R v >6.25 00












SrNo.

Sample ID

Corp ID

R Assay MtbStrain

%Inhibi.

MIC µg/ml





NHN

R

S

S

O

O

CH3

ANTITUBERCULAR ACTIVITY OF 4-[4-(METHYLSULFONYL)PHENYL]-

6-ARYLPYRIMIDIN-2(1H)-THIONES


Pyrimidines...

136

GR

AP

HIC

AL

CH

AR

T N

O.

8 :

4-[4

-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

6-A

RY

LP

YR

IMID

IN-2

(1H

)-T

HIO

NE

S


Pyrimidines...

137

SECTION - III


(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES

Compounds containing pyrimidine ring are widely distributed in nature. Many

amino pyrimidine derivatives are reported to possess different biological activities.

In view of these findings, it was considered worthwhile to synthesize some new 4-

[4 - (methylsulfonyl)phenyl]-6-arylpyrimidin-2-amines of type-(IX) to study their

biological activities. Amino pyrimidine derivatives of type-(IX) have been prepared

by the reaction of the chalcones of type- (I) with guanidine hydrochloride in presence

of potassium tertiary-butoxide in tertiary-butanol shown as under.


basis of elemental analysis, infrared and 1H nuclear magnetic resonance spectroscopy






drugs.

C

S

NH2 NH2 .HClNN

R

NH2

S

O

O

CH3

R

O

S

O

O

CH3

Type(I) Type(IX)R=Aryl


Pyrimidines...

138

50.0

60.0

70.0

80.0

90.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

451.3

491.8

804.3

964.3

1010.6

1089.7

1218.9

1319.2

1355.9

1436.9

1490.9

1527.5

1571.9

1645.2

2339.52360.7

2852.52920.0

3211.3

3336.6





1089 1125-1090 ,,1010 1070-1000 ,,

Halide C-Cl str. 804 800-600 44Sulfonyl SO2 str. 1175 1185-1165 ,,Pyrimidine C=N str. 1571 1580-1520 45Primary Amine N-H str. 3336 3554-3350 ,,

IR SPECTRAL STUDIES OF 4 - [4 - ( METHYLSULFONYL)PHENYL]-6-

(p-CHLOROPHENYL)PYRIMIDIN-2-AMINE

SCH3

O

O

N

N

NH2

Cl


cm-1 (KBr disc.)


Pyrimidines...

139




2 5.25 2 H singlet Ar-NH2 -



5 7.42-7.46 2 H doublet Ar-Hc,c’ Jcd=9.6


7 7.97-8.01 2 H doublet Ar-Hd,d’ Jdc=8.5

Signal No.




NMR SPECTRAL STUDIES OF 4 - [4 - (METHYLSULFONYL)PHENYL]-6-(p-

CHLOROPHENYL)PYRIMIDIN-2-AMINE

SCH3

O

O

N

N

NH2

Cl

a b

a' b'

c

d

c'

d'

e

f


Pyrimidines...

140

TAB

LE

-9 :

MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 4

-[4

-(M

ET

HY

LSU

LF

ON

YL

)PH

EN

YL

]-6-

(M-P

HE

NO

XY

PH

EN

YL

)

PY

RIM

IDIN

-2-A

MIN

E

m/z

= 4

17


Pyrimidines...

141

EXPERIMENTAL


(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES

(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2-propene-ones


(B) Synthesis of 4-[4-(Methylsulfonyl)phenyl]-6-(p-chlorophenyl)pyrimidin-

2-amine

A mixture of 1-[4-(methylsulfonyl)phenyl]-3-(p-chlorophenyl) -2-propene-

1-one. (3.20 gm, 0.01 mol) and guanidine hydrochloride (1.10gm, 0.01 mol) in

dioxane (20 ml) was refluxed on oil-bath in presence of alcoholic KOH for 8 hr. The

excess solvent was distilled off and the residue was neutralized with 20 % HCl, the

separated solid was filtered out and crystallized from ethanol. Yield 51 %, m.p.

166oC Anal. Calcd. for C17H14ClN3O2S Requires: C, 56.74; H, 3.92; N, 11.68 %

Found: C, 56.72; H, 3.91, N, 11.67 %.

Similarly, other 4-[4-(methylsulfonyl)phenyl]-6-arylpyrimidin-2-amines were

prepared. The physical data are recorded in Table No. 9.

(C) Biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-arylpyrimidin-

2-amines




Pyrimidines...

142

9aC

6H5-

C17

H15

N3O

2S32

512

455

12.9

112

.92

0.46

S 1

9b4-

Cl-

C6H

4-C

17H

14C

lN3O

2S35

916

651

11.6

811

.67

0.44

S 1

9c2-

Cl-

C6H

4-C

17H

14C

lN3O

2S35

916

248

11.6

811

.66

0.56

S 2

9d3-

Cl-

C6H

4-C

17H

14C

lN3O

2S35

913

463

11.6

811

.69

0.44

S 1

9e4-

OC

H3-

C6H

4-C

18H

17N

3O3S

355

186

5811

.82

11.8

10.

54S 2

9f3,

4-(O

CH 3

) 2-C

6H3-

C19

H19

N3O

4S38

514

971

10.9

010

.92

0.56

S 2

9g4-

F-C

6H4-

C17

H14

FN3O

2S34

313

759

12.2

412

.26

0.48

S 2

9h3-

Br-

C6H

4-C

17H

14Br

N3O

2S40

414

065

10.3

910

.38

0.58

S 1

9i3-

C6H

5-O

-C6H

4-C

23H

19N

3O3S

417

182

6410

.07

10.0

80.

47S 1

9j4-

N(C

H3)

2-C

6H4-

C19

H20

N4O

2S36

816

453

15.2

115

.22

0.45

S 2

9k2-

OH

-C6H

4-C

17H

15N

3O3S

341

194

5912

.31

12.3

20.

51S 2

9l2-

C4H

3O-

C15

H13

N3O

3S31

516

156

13.3

312

.34

0.62

S 1

TA

BL

E :

9P

HY

SIC

AL

CO

NST

AN

TS

OF

4-[

4-(

ME

TH

YL

SUL

FO

NY

L)P

HE

NY

L]-

6-A

RY

LP

YR

IMID

IN-2

-AM

INE

S

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Pyrimidines...

143

GR

AP

HIC

AL

CH

AR

T N

O.

9 :

4-[

4-(

ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-6-

AR

YL

PY

RIM

IDIN

-2-A

MIN

ES


Pyrimidines...

144

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Pyrimidines...

145

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Pyrimidines...

146

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Indazoles...

147

INTRODUCTION

Cyclohexenone is the parent of a series of compounds that is important in

agricultural and medicinal chemistry. Cyclohexenones are derivatives of cyclohexane

with carbonyl group at 1-position and double bond at 2-position (I). Cyclohexenones

can be conveniently synthesized by the treatment of α,β - unsaturated carbonyl

compounds with ethylacetoacetate in basic media.

In recent years cyclohexenone derivatives have gained lots of interest because

of its prominent pharmaceutical properties.

SYNTHETIC ASPECT

Different methods for the synthesis of cyclohexenone derivatives have been

described in literature.1-7

1. N. Nanjundaswami et al.8 have prepared 6,7-dimethoxy-1-aryl-4-oxo-2-

naphthoate derivatives (II) by the reaction of dimethoxyphenyl aryl ketone

with diethyl succinate in presence of t-potassium butoxide.

O

OCH3

O

CH3 O

R

OCH3

O

CH3

O

R

O

O CH3

t-Buok

CH2 COOEt

CH2 COOEt

(I)

(II)


Indazoles...

148

MECHANISM

The addition reaction between ethylacetoacetate and α,β -unsaturated ketone

give cyclohexenone via Michael addition. This reaction has been carried out in basic

media by using sodium ethoxide or anhydrous K2CO3 in acetone. During the reaction

nucleophillic addition of carbanion take place to the C=C of the acceptor. The α,β -

unsaturated compound is known as acceptor and ethylacetoacetate is known as donor.

THERAPEUTIC EVALUATION

Cyclohexenone and its derivatives are widely used in pharmaceutical industry.

Considerable interest has been shown in the chemistry of cyclohexenones due to

their wide spectrum of therapeutic activities which can be listed as under.

1. Antibacterial9

2. Antithrombitics10

3. Antagonist11

4. Antibiotic12,13

5. Cardiovascular14

R

O

R1 R CH

CH C

O

R1+

-

CH3

O

COOC2H5

CH3 C

O

CH COOC2H5-

+ H+OH-

[A]

[A] + H+

R CH

O

R1+

+CH3CH

O

H5C2OOC

-CH3

O

H5C2OOC

R R1

O

O

H5C2OOC

R R1

[B]

-H2O


Indazoles...

149

6. Herbicidal15

7. Analgesic16

8. Antiinflammatory17

9. Anticonvulsant18

Hermann S. e t a l .19

have repor ted cyc lohexenones as he rb ic ides .

Anticonvulsant activity of some cyclohexenone derivatives (III) have been reported

by Natalie D. et al.20

Bastiaan and co-workers21

have synthesized novel cyclohexenone

derivatives (IV) which are useful in the treatment of parkinson’s disease.

Cyclohexenones (V) as anticancer and antiinflammatory agents have been

investigated.22

Cyclohexenone derivatives which possess plant growth regulatory activity

have been repor ted .23,24

Nagao et al.25

have repor ted cyc lohexenones as

antiarrhythmic.Collins and co-workers26

have documented estrogenic activity of

cyclohexenones. Tvanov et al.27

have reported antimicrobial activity of some

cyclohexenone derivatives. V. K. Ahluwalia and co-workers28

have assessed

cyclohexenone derivatives for anti HIV-I, gastric secretion inhibitors and pesticidal

activity. Cyclohexenone derivatives have been reported to be active as allergy

inhibitors, platelet aggregation inhibitors and fibrinogen antagonist.29

Antimicrobial activity of cyclohexenone derivatives has been studied by

O

NR

R

CH3

O

CH3CH3

CH3

O

N

O

CH3 NH

O

O

CH3

N

O

R

(III) (IV) (V)


Indazoles...

150

Salama and Atshikh30

. Takehiro and co-workers31

have reported cyclohexenones

possessing neutropeptide β-receptor antagonist activity. Kimura and co-workers32

have prepared cyclohexenones as inhibitory activity of penienone and remarkable

inhibitory activity against the growth of lettuce seedlings. Broughton H. et al.33

have demonstrated cyclohexenones as GABA α,β−5 receptor ligands for enhancing

cognition properties.

Rheinheimer J . et al .34

have synthesized 5-(dioxabicyclohept-6-yl)

cyclohexenone oxime ethers as herbicides and plant growth regulators. Harimaya

and co-workers35

have synthesized new cyclohexenone derivatives possessing

progesteron receptor binding inhibitory activity. The herbicidal activity of

cyclohexenone derivatives (VI) has been investigated.36

Zhang C. et al.37

have prepared tricyclic heterocycles, containing furan and

cyclohexenone nucleus for treating hyper-proliferative disorders.

With a view to getting better therapeutic agent, it was contemplated to

synthesized cyclohexenones bearing furan nucleus to enhance the overall activity of

resulting compounds, which have been described as under.

CH2

CH3

CH3

OH

O

Cl

Cl

O

CH3CH3

(VI)


Indazoles...

151

INTRODUCTION

Heterocyclic compounds bearing 1,2-diazole ring system i.e. pyrazole ring

system, attached to benzene ring system are known as benzopyrazole or indazole

(I). Indazole was first described by Buchner in 1869.

Although the chemistry of indazoles has been extensively studied, they have

not been found in natural products and are at the present time of little commercial

use.Indazole can be considered as either azaindazoles or azaisoindazoles.The

compounds of medicinal interest in this group so far have been non-steridol

antiinflammatory agents or analgesic.

SYNTHETIC ASPECT

Several methods have been reported in the literature38,39,40,41,42,43

for the

preparation of indazoles.

1. Cyclocondensation of activated acetylenes with hydrazine afforded indazole

derivatives.44

2. B. V. Badami et al.45 have synthesized indazoles from chalcone derivatives

via cyclohexenone derivatives as follow.

N

NH

Cl

N+

O-

O

R

NH2NH2.H2O

N

NH

R

N+

O-

O

(I)


Indazoles...

152

3. A facile synthesis of substituted indazoles from 2-acyl mesylates and

hydrazines has been described by Caron S. et al.46

THERAPEUTIC EVALUATION

It is revealed from the literature survey that indazole derivatives are better

therapeutic agents and they have been found possessing various biological activities

reported as under.

1. Antiallergic47

2. Antiviral48

3. Antipsychotics49

4. Herbicidal50

5. Fungicidal51

6. Antibacterial52

7. Cardiovascular53

8. Antidepressant54

9. Antineoplastic55

10. Antitumor56,57

Balakrishna and co-workers58

have synthesized indazole derivatives and

evaluated them as antiinflammatory and analgesic activity. Malmstroem J.et al.59

have prepared indazoles (II) as inhibitors of Jun N-terminal kinases (JNK).

Aminoindazoles (III) are useful in the treatment of central and peripheral nervous

R R1

O

NH

N

O

R

R1

K2CO3

Ethylacetoacetate

in dry acetone

NH2NH2.H2OOR

R1

COOEt


Indazoles...

153

system diseases have been synthesized.60

Butera J. A. et al.61 have prepared some indazole derivatives which showed

antihypertensive, muscle relaxant and potassium activator activity. Several workers

have patented indazole derivatives useful as hypolipidemic agent62

, 5-HT3

antagonist63

, enzyme inhibitor64

etc. Some indazole derivatives investigated as a

novel antiasthametic agents.65

Ooe T. et al.66

synthesized indazoles which have been

found to possess varied biological activities such as hematinics, immunostimulants

and antitumor agents. The remarkable cytotoxic activity of indazoles have been

reported.67

Some indazoles (IV) have been synthesized by Duzinska-Usarewicz et al.68

and found to possess antiinflammatory activity. Effland R. et al.69

synthesized 3-

(pyridyl amino)-indazoles (V) and reported as antidepressant and anxiolytics.

Newshaw R. and co-workers70

have prepared 4-amino ethoxy indazoles and

reported them as dopamine D2 agonists. Kania R. et al.71

have synthesized indazole

N

NH

RR1

NNH

NH

N

(V)(IV)

NH

N

NH

Cl

Ph

N

NH

NH

O

ClCOOH

(II) (III)


Indazoles...

154

derivatives as protein kinase inhibitors. Indazole derivatives are reported as inhibitors

of cell proliferation.72

The remarkable antipsychotic activity73

of indazoles (VI) have

been reported.

Lavielle G. et al.74

prepared [(pyrolidinyl) methyl]-indazoles and suggested

them for the treatment of migrains. Marfat Anthony75

has patented indazole

derivatives as phosphodiesterase and tumor necrosis factor production inhibitors.

Indazole derivatives have been evaluated as α,β -adrenoreceptor agonists.76

Antiviral

activity77

of indazoles have been reported. Badran M. et al.78

synthesized some novel

indazole derivatives by fusing with triazines and triazoles for exploring their

antiinflammatory activity.

Moreover, Hwang I. T. et al.79

have synthesized some new 2-phenyl-4,5,6,7-

tetrahydro-2H-indazole derivatives as paddy field herbicides. Tanitame A. et al.80

have reported the designed, synthesized and studied structure-activity relationship

of novel indazole analogues as DNA gyrase inhibitors with Gram-positive

antibacterial activity(VII). Nasr M. N. et al.81

have prepared some novel 3,3a,4,5,6,7-

hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory

agents. Pinna G. A. et al.82

have described the synthesis of Chromophore-modified

bis-benzo[g]indole carboxamides.

Recently, Abouzid K. A. et al.83

have Synthesized and demonstrate anti-

inflammatory activity of novel indazolones. Wang Q. et al.84,85

have described the

syn thes i s and he rb ic ida l ac t iv i ty o f 2 -cyano-3-subs t i tu ted-

N

NH

O

O

R1

Z

R

Z = (un)-substituted piperazine

pyridino etc(VI)


Indazoles...

155

pyridinemethylaminoacrylates. Kakimoto T. et al.86

have prepared some novel

3,3a,5,9b-tetrahydro-2H-furo[3,2-c][2] benzopyran derivatives of chiral glycol

benzyl ether herbicides. Ikeguchi M. et al.87

have documented the synthesis and

herbicidal activity of new oxazinone herbicides with a long-lasting herbicidal activity

against Echinochloa oryzicola.

Among variety of pharmacological properties have been encountered with

indazole systems, keeping the above in mind some novel indazole derivatives have

been synthesized which have been described as under.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING O F

ETHYL-4-[ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 2 -

O X O - 6 - A R Y L C Y C L O H E X - 3 - E N E - 1 -

CARBOXYLATES

SECTION - II : SYNTHESIS AND BIOLOGICAL SCREENING OF 6-[4-

(METHYLSULFONYL)PHENY]-4-ARY L - 2 ,3a , 4 - 5 -

TETRAHYDRO-3H-INDAZOL-3-ONES

NH

N NH

EtOOC

O Cl

Cl

(VII)


Indazoles...

156

SECTION - I

SYNTHESIS AND BIOLOGICAL SCREENING OF ETHYL-4-[4-

(METHYLS U L F O N Y L ) P H E N Y L ] - 2 - O X O - 6 - A RY L C Y C L O H E X - 3 -

E N E - 1 -CARBOXYLATES

Cyclohexenones are endowed with variety of pharmacodynamic activities such

as anticonvulsant,antidiabatic etc. Looking to the interesting properties of

cyclohexenones aroused considerable interest to synthesis of e thyl-4-[4-

(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 - a r y l c y c l o h e x - 3 - e n e - 1 -carboxylates of the

type (X) by the cyclocondensation of 1-[4-(methylsu l fonyl )phenyl ] -3-ary l -2-

propene-1-ones with ethylacetoacetate in the presence of anhydrous K2CO3 in

order to study their biodynamic behavior.








drugs.

R

O

S

O

O

CH3

R

O

S

O

O

CH3

O

OC2H5

K2CO3

CH3COCH2COOC2H5

Type(I)Type(I)Type(X)R=Aryl


Indazoles...

157

0.0

20.0

40.0

60.0

80.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

466.7

513.0

538.1 594.0

621.0

702.0 759.9

781.1

813.9

856.3 918.1

956.6

997.1

1031.8

1051.11076.2

1095.5

1159.1

1244.0

1278.71299.9

1315.41353.9

1373.21388.7

1431.1

1494.7

1564.2

1598.9

1741.6

2852.5

2920.0

2976.0

3408.0





1095 1125-1090 ,,1031 1070-1000 ,,

Ether C-O-C str. 1244 1080-1250 88Sulfonyl SO2 str. 1159 1185-1165 ,,Ester C=O-O str. 1741 1735-1717 ,,Hexenone C=O str. 1675 1685-1665 89(cyclo)

IR SPECTRAL STUDIES OF ETHYL-4-[4-(METHYLS U L F O N Y L )

P H E N Y L ] - 2 - O X O - 6 - A RY L C Y C L O H E X - 3 - E N E - 1 -CARBOXYLATE

SCH3

O

O

O

O

OC2H5


cm-1 (KBr disc.)


Indazoles...

158



1 1.04-1.25 3 H triplet Ar-CH2CH3 -

2 1.26-1.30 3 H singlet Ar-SO2 CH3 -

3 2.4 1 H singlet Ar-Hk -

4 2.30 2 H quartet Ar-CH2CH3 -

5 3.99-4.03 1 H doublet Ar-Hh -

6 3.74-3.96 1 H doublet Ar-Hj -

7 2.72-2.76 1 H doublet Ar-Hi -

8 2.77-3.07 1 H doublet Ar-Hl -




Signal No.




NMR SPECTRAL STUDIES OF ETHYL-4-[4-(METHYLS U L F O N Y L )

PHENYL]-2-OXO-6-ARYLCYCLOHEX-3-ENE-1-CARBOXYLATE

SCH3

O

O

O

O

O

CH3

HiHj

a b

a' b'

c

d e

f

g

Hh

Hl

Hk


Indazoles...

159

TAB

LE

-10

:MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F E

TH

YL

-4-[

4-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

2-O

XO

-6-(

P-

FL

UO

RO

PH

EN

YL

)CY

CL

OH

EX

-3-E

NE

-1-C

AR

BO

XY

LA

TE

m/z

= 4

16


Indazoles...

160

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL SCREENING OF ETHYL-4-[4-

(METHYLS U L F O N Y L ) P H E N Y L ] - 2 - O X O - 6 - A RY L C Y C L O H E X - 3 -

E N E - 1 -CARBOXYLATES

(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-1-ones


(B) Preparation of ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -phenyl-

c y c l o h e x - 3 - e n e - 1 -carboxylate

To a solution of 1-[4-(methylsul fonyl)phenyl] -3-(phenyl) -2-propene-1-

one (2.86 gm, 0.01 mol) in dry acetone, anhydrous K2CO3 (5.42gm, 0.04 mol) and

ethyl acetoacetate(2.60 gm, 0.02 mol) was added and the reaction mixture was stirred

at room temperature for overnight and was filtered. The solvent from the filtrate on

distill off gave a solid, which was crystallized from methanol to gave desired product

. Yield 45%, m.p. 164oC, Anal.Calcd. for C22H22O5S; Requires: C, 66.31; H, 5.56;

Found : C, 66.30; H, 5.54; %.

Similar ly, other e thy l -4 - [4- (methy ls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -

a ry lcyc lohex-3-ene-1 - carboxylates were prepared. The physical data are recorded

in Table No.10

(C) Biological screening of ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -

a r y l c y c l o h e x - 3 - e n e - 1 -carboxylates

Antimicrobial testing were carried out as described in Part-I, Section (C).



Indazoles...

161

10a

C6H

5-C

22H

22O

5S39

816

445

--

0.61

S 1

10b

4-C

l-C 6

H4-

C22

H21

ClO

5S43

217

951

--

0.42

S 2

10c

2-C

l-C 6

H4-

C22

H21

ClO

5S43

216

258

--

0.56

S 1

10d

3-C

l-C 6

H4-

C22

H21

ClO

5S43

213

464

--

0.45

S 2

10e

4-O

CH

3-C

6H4-

C23

H24

O6S

428

167

46-

-0.

53S 1

10f

3,4-

(OC

H 3) 2

-C6H

3-C

24H

26O

7S45

811

454

--

0.56

S 1

10g

4-F-

C6H

4-C

22H

21FO

5S41

616

961

--

0.43

S 2

10h

3-B

r-C 6

H4-

C22

H21

BrO

5S47

714

068

--

0.58

S 1

10i

3-C

6H5-

O-C

6H4-

C28

H26

O6S

490

198

45-

-0.

49S 2

10j

4-N

(CH

3)2-

C6H

4-C

24H

27N

O5S

441

184

513.

173.

180.

42S 2

10k

2-O

H-C

6H4-

C22

H22

O6S

414

157

53-

-0.

51S 1

10l

2-C

4H3O

-C

20H

20O

6S38

816

464

--

0.56

S 2

TA

BL

E :

10

PH

YSI

CA

L C

ON

STA

NT

S O

F

ET

HY

L-4

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-2

-OX

O-6

-AR

YL

CY

CL

O

HE

X-3

-EN

E-1

-CA

RB

OX

YL

AT

ES

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Indazoles...

162

GR

AP

HIC

AL

CH

AR

T N

O.

10 :

ET

HY

L-4

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-2

-OX

O-6

-AR

YL

CY

CL

OH

EX

-3-

EN

E-1

-CA

RB

OX

YL

AT

ES


Indazoles...

163

SECTION - II


(METHYLSULFONYL)PHENYL]-4-ARYL-2,3a ,4,5-TETRAHYDRO-3H-

INDAZOL-3-ONES

The synthesis of indazole has attracted the attention of chemists because of

their potential pharmcodynamic properties. Looking to the interesting properties

of indazoles , i t appeared of in te res t to synthes ize a ser ies of 6 - [ 4 -

(methylsulfonyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-indazol-3-ones of type (XI)

for obtaining biologically potent agents, which were prepared by reacting ethyl-4-

[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 - a r y l c y c l o h e x - 3 - e n e - 1 -carboxylates of

the type (X) with hydrazine hydrate in presence of glacial acetic acid.








drugs.

NH2NH2.H2O

R

N

S

O

O

CH3

NH

O

IN CH3COOH

R

O

S

O

O

CH3

O

CH3 R=ArylType(X) Type(XI)


Indazoles...

164

0.0

20.0

40.0

60.0

80.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

501.5

542.0 567.0

596.0 651.9

692.4

723.3 759.9

835.1 869.8

916.1 962.4

1028.01118.6

1176.51282.6

1328.9

1371.3

1465.81573.81672.2

1874.7

1944.1

2802.4

2898.8

2981.7

3105.23176.5

3328.9





1118 1125-1090 ,,1028 1070-1000 ,,

Ether C-O-C str. 1282 1150-1350 88Sulfonyl SO2 str. 1176 1185-1165 ,,Amide NH-C=O-str 1672 1680-1636 ,,Indazole C=N str. 1573 1660-1480 89Amine N-H str. 3228 3300-3140 ,,


ARYL-2,3a,4,5-TETRAHYDRO-3H-INDAZOL-3-ONE

SCH3

O

ON

NH

O


cm-1 (KBr disc.)


Indazoles...

165



1 1.26 1 H singlet Ar-Hl -


3 3.14-3.20 1 H d,d Ar-Hj -

4 3.26-3.30 1 H d,d Ar-Hi -

5 4.31-4.36 1 H d,d Ar-Hh -



8 7.36 1 H singlet Ar-Hk -



Signal No.





ARYL-2,3a,4,5-TETRAHYDRO-3H-INDAZOL-3-ONE

SCH3

O

ON

NH

O

Hi Hja b

a' b'

c

d e

f

g

HhHl

Hk


Indazoles...

166

TAB

LE

-11

:M

ASS

SP

EC

TR

AL

ST

UD

IES

OF

6-[

4-(M

ET

HY

LSU

LF

ON

YL

)PH

EN

YL

]-4-

(P-M

ET

HO

XY

PH

EN

YL

)-2,

3a,4

-

5-T

ET

RA

HY

DR

O-3

H-I

ND

AZ

OL

-3-O

NE

m/z

= 3

96


Indazoles...

167

EXEPERIMENTAL


(METHYLSULFONYL)PHENYL]-4-ARYL-2,3a ,4,5-TETRAHYDRO-3H-

INDAZOL-3-ONES

(A) Synthesis of 1-[4-(Methyl su l fony l )phenyl ] -3 -ary l -2 -propene-1-

ones

See Part-I, Section-I (B),

(B) Preparation of Ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 - a r y l

c y c l o h e x - 3 - e n e - 1 -carboxylates

See Part-VI, Section-I(B).

(C) Preparation of 6-[4-(Methylsulfonyl)phenyl]-4-phenyl-2,3a,4,5-tetra

hydro-3H-indazol-3-one

To a solution of ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -phenyl

c y c l o h e x - 3 - e n e - 1 -carboxylate (3.98gm, 0.01 mol) in ethanol (20 ml), hydrazine

hydrate (0.5gm 0.01 mol) and acetic acid (2 ml) was added. The content was refluxed

at 80oC for 4 hr on water bath. The residue obtained after cooling was filtered and

isolated. The product was crystallized from methanol. Yield 55 %, m. p. 134oC.

Anal. Calcd. for C20H18N2O3S Requires C, 65.95; H, 4.95; N, 7.64% Found C,

65.93; H, 4.92; N, 7.62%.

Similarly other, 6-[4-(methylsulfonyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-

indazol-3-ones were prepared. The physical data are recorded in Table No. 11.

(C) Biological screening of 6-[4-(Methylsulfonyl)phenyl]-4-aryl-2,3a,4,5-

tetrahydro-3H-indazol-3-ones

Antimicrobial testing were carried out as described in Part-I, Section (C).



Indazoles...

168

11a

C6H

5-C

20H

18N

2O3S

366

134

557.

647.

620.

49S 2

11b

4-C

l-C

6H4-

C20

H17

ClN

2O3S

400

167

596.

996.

970.

53S 1

11c

2-C

l-C

6H4-

C20

H17

ClN

2O3S

400

128

486.

996.

960.

58S 2

11d

3-C

l-C

6H4-

C20

H17

ClN

2O3S

400

164

566.

996.

970.

46S 1

11e

4-O

CH

3-C

6H4-

C21

H20

N2O

4S39

619

244

7.07

7.02

0.51

S 2

11f

3,4-

(OC

H 3) 2

-C6H

3-C

22H

22N

2O5S

426

115

496.

576.

570.

57S 2

11g

4-F-

C6H

4-C

20H

17FN

2O3S

384

148

517.

297.

260.

48S 1

11h

3-B

r-C

6H4-

C20

H17

BrN

2O3S

445

142

686.

296.

280.

53S 1

11i

3-C

6H5-

O-C

6H4-

C26

H22

N2O

4S45

818

151

6.11

6.70

0.48

S 2

11j

4-N

(CH

3)2-

C6H

4-C

22H

23N

3O3S

409

175

5610

.26

10.2

40.

44S 1

11k

2-O

H-C

6H4-

C20

H18

N2O

4S38

216

248

7.33

7.32

0.54

S 1

11l

2-C

4H3O

-C

18H

16N

2O4S

356

187

547.

867.

850.

52S 2

TA

BL

E :

11

PH

YSI

CA

L C

ON

STA

NT

S O

F

6-[4

-(M

ET

HY

LSU

LF

ON

YL

)PH

EN

YL

]-4-

AR

YL

-2,3

a,4

,5-T

ET

RA

HY

DR

O-3

H-

IN

DA

ZO

L-3

-ON

ES

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Indazoles...

169

GR

AP

HIC

AL

CH

AR

T N

O.

11 :

6-[

4-(M

ET

HY

LSU

LF

ON

YL

)PH

EN

YL

]-4-

AR

YL

-2,3

a,4

,5-T

ET

RA

HY

DR

O-3

H-I

ND

AZ

OL

-

3-O

NE

S


Indazoles...

170

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Indazoles...

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Jaipur 11-36 (2000).





Isoxazoles...

176

INTRODUCTION

Isoxazole is a five membered heterocyclic compound having two hetero atom:

oxygen at position 1 and nitrogen at position 2. Claisen first reported an isoxazole

(I) for a product from the reaction of 1,3 diketone with hydroxylamine.1 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

Quelico2 in 1945, when he begain to study the formation of isoxazoles from nitrile

N-oxide and unsaturated compounds.

SYNTHETIC ASPECT

Isoxazoles can be prepared by various method, which are described as under.

1. Tayade V. B. et al.3 synthesized some new 3,5-diarylisoxazoles from the

reaction of 2-aryl acetophenones with hydroxyl amine hydrochloride in

presence of alkali.

2. Dawood Kamal et al.4 prepared isoxazole derivatives from enamino

nitriles.

3. Crawley L. S. and Fan shawe W. J.5 prepared isoxazole from α,β -unsaturated

carbonyl compounds, hydroxyl amine hydrochloride and KOH in methanol.

(I)O

N

R R1

O

+ NH2OH.HClKOH

ON

R

R1


Isoxazoles...

177

4. J. F. Hansen and S. A. Strong6 synthesized isoxazole from α,β -unsaturated

ketones and N-bromo succinimide.

REACTION MECHANISM


Isoxazole derivatives exhibit various biological activities such as,

1. Anthelmintics7

2. Adenosine antagonist8

3. Fungicidal9-11

4. Herbicidal12,13

5. Hypoglycemic14

6. Muscle relaxant15,16

7. Nematocidal17

8. Insecticidal18

9. Antibacterial19-21

10. Anticonvulsant22,23

11. Anticholestermic24

12. Antiinflammatory25-28

R O

R1

OH-NH2.HCl

R O

R1

OH

NH2

-H+

R O

R1

O

NH2

_

:

H+

:R

O

R1

O

NH2+

_

ROH

R1

O

NH

H2O_

H +

R

R1

O

NH

R

R1

O

NR

R1

O

N

2H

_

+_ H_ +

OH

proton transfer


Isoxazoles...

178

13. Antimicrobial29

14. Antiviral30

Aicher Thomas D. et al.31

reported isoxazoles (II) as hypoglycemic agents.

H. H. Parekh et al.32

have synthesis 3-(p-methoxyphenyl)-5-(2 '-chloro-7 '-

methylquinolin-3'-yl)-isoxazole (III) and studied thier biologcal activity.

Talley John and co-workers33

and Mishra et al.34

have synthesized isoxazoles

and reported their analgesic and antiinflammatory activities. Masatosh et al.35

have

documented synthesized isoxazole derivatives as analgesic agent. Some other drugs

viz. sulfisoxazoles (IV) is a well known antibiotic and activicin (V)36

is an antitumor

agent having isoxazole moiety.

Moreover, S. Rung and D. Dus37

have synthesized some new isoxazoles as

remedy for leukemia. M. Scobie and co-workers38

have prepared isoxazole

derivatives and studied their antitumor activity. G. Daidone et al.39

synthesized novel

3-(isoxazol-3-yl)-quinazolin-4-(3H)-one derivative and tested for their analgesic

and antiinflammatory activities as well as for their acute toxicity and ulcerogenic

N

O

CH2O

Cl

Cl

Cl N

O

N

R

ClCH3

SO

NH

ON

R1

CH3

O

NH2

ON

Cl

NH2

H

HOOC

(II) (III)

(IV) (V)


Isoxazoles...

179

effect.

Some i soxazo les a re found to possess he rb ic ida l40-42

p o t e n t i a l

antiinflammatory43,44, antimicrobial agents

45,46, estrogen receptor modulators47

and inhibitor of p38 MAP kinase activities.48

Masui et al.49

have prepared isoxazoles having pesticidal activity. Some

excellent herbicidal results obtained by Reddy et al.50

C. B. Xue et al.51

have reported

on oral antiplatelet effect in dogs.

H. S. Joshi et al.52

have synthesized isoxazole derivatives (VI) and reported

their antitubercular and antimicrobial activity.

Salter M. W. et al .53

have prepared some novel isoxazole as cellular

neuroplasticity mechanisms mediating pain persistence. Matringe M. et al.54

have

reported some new p-hydroxyphenylpyruvate dioxygenase inhibitor-resistant plants.

Mehlisch D. R. et al.55

have synthesized isoxazole derivative as analgesic efficacy

of intramuscular parecoxib sodium in postoperative dental pain. Ray W. A. et al.56

have reported isoxazole derivative as cardiovascular toxicity of valdecoxib.

Welsing P. M. et al.57

have documented the isoxazole as tumor necrosis factor-

blocking agents and leflunomide for treating rheumatoid arthritis in the Netherlands.

Bingham S. J. et al.58

have synthesized as antiuclear. Barbachyn M. R. et al.59

have

described the phenylisoxazolines as novel and viable antibacterial agents active

against Gram-positive pathogens.

ON

Br

R

(VI)


Isoxazoles...

180

With an intension of preparing the compounds possessing better therapeutic

activity, we have under taken the preparation of isoxazoles bearing methylsulfonyl

derivatives which have been described as follows.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING O F 3 - [ 4 -

METHYLS U L F O N Y L ) P H E N Y L ] - 5 -ARY LI S O X A Z O L E S


Isoxazoles...

181

SECTION - I

SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - [ 4 - M E T H Y L

S U L F O N Y L ) P H E N Y L ] - 5 - A RY L I S O X A Z O L E S

Isoxazoles have been reported to have various pharmacological activities

like antibacterial, antifungal, insecticidal etc. In order to achieving better drug

potency , we have prepared i soxazole der iva t ives of type (XII ) by the


type(I) with hydroxylamine hydrochloride in presence of sodium acetate in glacial

aletic acid.








drugs.

NH2OH.HCl

gl. CH3COOH

S

O

O

CH3

NO R

R

O

S

O

O

CH3

Type(XII)Type(I) R=Aryl


Isoxazoles...

182

60.0

70.0

80.0

90.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

528.5 565.1

592.1 717.5

779.2 819.7

835.1

891.1

925.8

966.3

1014.51037.6

1058.81097.4

1159.1

1245.91344.3

1411.81512.1

1600.8

1641.3

2362.6

2854.5

2918.13076.23211.3





1097 1125-1090 ,,1037 1070-1000 ,,

Halide C-Cl str. 779 800-600 60Sulfonyl SO2 str. 1159 1185-1165 ,,Isoxazole C=C str. 1641 1680-1550 61

C=N str. 1600 1690-1460 ,,N-O str. 835 850-810 ,,

IR SPECTRAL STUDIES OF 3-[4-METHYLS U L F O N Y L ) P H E N Y L ] -

5 - ( p-CHLOROPHENYL)I S O X A Z O L E

NO

S

O

O

CH3

Cl


cm-1 (KBr disc.)


Isoxazoles...

183





3 7.05-7.07 2 H doublet Ar-Hc,c’ Jcd=7.8



6 7.57-7.58 2 H doublet Ar-Hd,d’ Jdc=8.4

Signal No.




NMR SPECTRAL STUDIES OF 3-[4-METHYLS U L F O N Y L ) P H E N Y L ] - 5 -

(p-CHLOROPHENYL)I S O X A Z O L E

NO

S

O

O

CH3

Cl

a b

a' b'

c

d

c'

d'e


Isoxazoles...

184

TAB

LE

-12

:MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 3

-[4-

ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-5

-(P

-FL

UO

RO

PH

EN

YL

)

ISO

XA

ZO

LE

m/z

= 3

17


Isoxazoles...

185

EXPERIMENTAL


METHYLS U L F O N Y L ) P H E N Y L ] - 5 - A RY L I S O X A Z O L E S

(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-1-ones


(B) Synthesis of 3-[4-Methyl s u l f o n y l ) p h e n y l ] - 5 - (p-chlorophenyl)-

i soxazo le

To a solution of 1-[4-(methyls u l f o n y l ) p h e n y l ] - 3 -(p-chlorophenyl)- 2 -

propene- 1-one (3.20 gm, 0.01 mol) in ethanol (25 ml), anhydrous sodium acetate

(0.739gm, 0.01 mol) and hydroxylamine hydrochloride(0.59 gm, 0.01 mol) in acetic

acid were added. The reaction mixture was refluxed on oil bath for 7-8 hr. The

product was isolated and crystallized from ethanol. Yield 56 %, m.p. 154oC Anal.

Calcd. For C16H12ClNO3S Requires ; C, 57.57; H, 3.62; N, 4.20; Found C, 57.56,

H, 3.61; N, 4.21%.

Similarly, other 3 - [ 4 -methyls u l f o n y l ) p h e n y l ] - 5 - a r y l i s o x a z o l e s were

prepared. The physical data are recorded in Table No.12.

(C) Biological screening of 3-[4-Methyls u l f o n y l ) p h e n y l ] - 5 - a r y l

i s o x a z o l e s


The zones of inhibition of test solution are reported in Graphical Chart No 12.


Isoxazoles...

186

12a

C6H

5-C

16H

13N

O3S

299

162

424.

684.

670.

58S 2

12b

4-C

l-C

6H4-

C16

H12

ClN

O3S

333

154

564.

204.

210.

44S 2

12c

2-C

l-C

6H4-

C16

H12

ClN

O3S

333

148

644.

204.

230.

50S 1

12d

3-C

l-C

6H4-

C16

H12

ClN

O3S

333

193

574.

204.

220.

41S 1

12e

4-O

CH

3-C

6H4-

C17

H15

NO

4S32

917

461

4.25

4..2

60.

52S 2

12f

3,4-

(OC

H 3) 2

-C6H

3-C

18H

17N

O5S

359

163

683.

903.

910.

56S 1

12g

4-F-

C6H

4-C

16H

12FN

O3S

317

160

544.

414.

420.

43S 2

12h

3-B

r-C

6H4-

C16

H12

BrN

O3S

378

170

483.

703.

720.

57S 1

12i

3-C

6H5-

O-C

6H4-

C22

H17

NO

4S39

114

658

3.58

3.59

0.41

S 1

12j

4-N

(CH

3)2-

C6H

4-C

18H

18N

2O3S

342

162

668.

188.

190.

46S 2

12k

2-O

H-C

6H4-

C16

H13

NO

4S31

517

045

4.44

4.45

0.53

S 1

12l

2-C

4H3O

-C

14H

11N

O4S

289

161

564.

844.

850.

51S 1

TA

BL

E :

12

PH

YSI

CA

L C

ON

STA

NT

S O

F

3-[4

-ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-5

-AR

YL

ISO

XA

ZO

LE

S

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Isoxazoles...

187

GR

AP

HIC

AL

CH

AR

T N

O.

12 :

3-[4

-ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-5

-AR

YL

ISO

XA

ZO

LE

S


Isoxazoles...

188

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189

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Isoxazoles...

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Thiazolidinones...

192

INTRODUCTION

Thiazolidinone, which belong to an important group of heterocyclic

compounds have been extensively explored for their applications in the field of

medicine. Thiazolidinones, with a carbonyl group at position 2 (I), 4 (II), and 5

(III), have been subjects of extensive study in the recent past. Numerous reports

have appeared in the literature which highlight their chemistry and use.

4-Thiazolidinones are derivatives of thiazolidine with carbonyl group at 4

position (II) substituent in the 2,3 and 5 position may be varied, but the greatest

difference in structure and properties is exerted by the groups attached to carbon

atom at the 2-position and to nitrogen atom at the 3-position. The cyclic structure

was assigned after recognisation of mercaptoacetic acid as a primary products of

hydrolysis of 2-phenyl-3-phenylamino-4-thiazolidinones.1

The chemistry of 4-thiazolidinones was reviewed in depth by F. Brown2 in

1961 and G. Newkome and A. Nayak3 in 1979.

SYNTHETIC ASPECT

4-Thiazolidinones are synthesized either by cyclisation of acyclic compounds

or by interconversion among appropriately substituted thiazolidinone derivatives.

α -Mercapto alkanoics acids have been extensively used for the synthesis of

4-thiazolidinones.

S

NH

O12

345

S

NH

O

12

345

S

NH

O 12

345

(I) (III)(II)


Thiazolidinones...

193

R = Alky or aryl

R1 = Aryl or heterocyclic

R2 = H or alkyl

R3 = H or alkyl

R2, R3 = Arylidene

The substi tuted and unsubsti tuted α -mercapto alkanoic acids react

conveniently with Schiff’s bases of aromatic heterocyclic aldehyde and aliphatic or

aromatic amines in different solvent to give a variety of 2-substituted-4-

thiazolidinones4-6

(IV).

MECHANISM

The reaction proceeds by the attack of the mercapto acetic acid upon the

C=N group, with the HS-CH2-COOH adding to the carbon atom followed by the

capture of a proton by nitrogen and subsequent cyclisation.

In there reaction, the uncyclised intermediate is formed in several cases. The

uncyclised product has been isolated.7 Phosphorous pentoxide in dioxan was used

R

N

R1

H

+ COOH

R2

SH

R3

S

R2

NH

R

R1

R2COOH

NH

S

R1

O

R3

R2

R

N

R1

H

+OH

O

SH

N

S

OH

O

R1

R

N

SO

R

R1-H2O

(IV)


Thiazolidinones...

194

for subsequent cyclisation of certain uncyclised products.8 In may instance 4-

thiazolidinones can conveniently be prepared by refluxing the mixture of

thioglycolic acid and Schiff’s bases in benzene9 or dry ether

10 or ethanol.

11

The nucleophilic attack of mercapto acetic acid anion on carbon of

azomethine, which has got possitive character while nitrogen has negative character

is evidenced, simultaneously removal of water as it forms in reaction, helps in

condensation and determination of the reaction time.


The thiazolidinones, substituted at 2 and 3 position showed a wide variety of

biologically activity. The frequent occurrence of the group HN-CO-NH or its

tautomer in compounds possess in vitro tuberculostatic activity12

.

The biological activity of following types have been reported.

1. Antiviral13

2. Anthelmintics14,15

3. Cardiovascular16

4. Herbicidal17

5. Hypnotic18-20

6. Insecticidal21

7. Mosquito repellent22

8. Local anaesthetic23

9. Analgesic24

10. Antibacterial25,26

11. Antidiabetic27

12. Antifungal28-30

13. Anti HIV and anticancer31

14. Antimicrobial32,33


Thiazolidinones...

195

15. Antiulcer34,35

16. Antitumor36

17. Antitubercular37,38

Moreover Albuquerque and co-workers39

have prepared 4-thiazolidinones

which show antidiabetic and antiinflammatory activity. Tagami et al.40

have

synthesized thiazolidinone derivatives as allergy inhibitor. Mohammad et al.41

have

prepared substituted thiazolidinones and reported their antibacterial, antifungal,

antithyroid and amoebicidal properties (V).

R. S. Lodhi and co-worker42

have been synthesized and studied antimicrobial,

antiinflammatory and analgesic property of 4-thiazolidinone and arylidene

derivatives (VI). Goel Bhawna et al.43 have documented thiazolidinone derivatives

and compared their antiinflammation potency, ulcerogenic liability, cardiovascular

and CNS effect. Pawar and co-workers44

reported synthesis and in vitro antibacterial

activity of some 4-thiazolidinone derivatives. In other study, some thiazolidinone

derivatives have been found to be promising antibacterial agent.45,46

N

S

S

R1

R2

O R5R4

R3

N

N

O

NH N S

O Z

R1

R1 = (un) Substituted aryl

Z = H2Z = CH2R2R1 , R2 = Substituted aryl

R1 = OH

R2, R4, R5 = H

R3 = Me(V)

(VI)


Thiazolidinones...

196

H. S. Joshi et al.47

have synthesized microwave assisted 4-thiazolidinones

and reported their biological activity.

Tamura et al.48

have reported antimicrobial activity of 4-thiazolidinone

derivatives. B. Lohary et al.49

have documented and reported hypolipidemic activity

of 4-thiazolidinone derivatives. Bhawana et al.50

have assessed some new 4-

thiazolidinones as antiinflammatory agents. Antifungal and antibacterial activity51

of thiazolidinones has been reported. Many workers have reported 4-thiazolidinone

as antibacterial,52

anticancer,53 antiinflammatory and analgesic agent.

54

Mayer et al.55

have prepared thiazolidinones and studied their herbicidal

activity. Archana and Srivastava56

have synthesized 4-thiazolidinones (VII) as potent

anticonvulsant agent. S. K. Srivastava et al.57

have formulated some new 4-

thiazolidinones (VIII) as antibacterial, antifungal, analgesic and diuretic agents.

Dayam R. et al.58

have reported some new thiazolidinone derivative as novel

class of HIV- integrase inhibitors. Sonawane N. D. et al.59

have synthesized some

new thiazolidinone derivatives as in vivo pharmacology and antidiarrheal efficacy

of CFTR inhibitor in rodents. Shih M. H. et al.60

have described the synthesis and

evaluation of antioxidant activity of sydnonyl substituted thiazolidinone and

thiazoline derivatives (IX).

Moreover, Salinas D. B. et al.61

documented the thiazolidinone derivatives

as CFTR inhibitor. Wang X. F. et al.62

have synthesized some novel thiazolidinone

N

N

NNH

O

N

S

O

H

Ar

H

Ar

N

N

NH

O

CH3

N N

S

NS

Ar

O

(VII) (VIII)


Thiazolidinones...

197

derivatives and described as new cystic fibrosis transmembrane conductance

regulator inhibitor on Cl- conductance in human sweat ducts. Ur F. et al.63

have

constructed some new 6-methylimidazo[2,1-b]thiazole-5-carbohydrazide derivatives

and studied their antimicrobial activities.

Furthermore, Reigada D.et al.64

have reported some novel thiazolidinone

derivatives as release of ATP from retinal pigment epithelial cells involves both

CFTR and vesicular transport. Rao A. et al .65

have described some novel

thiazolidinone derivatives as 2-(2,6-dihalophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-

4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. Muanprasat C. et

al.66 have prepared some new thiazolidinone derivatives as CFTR inhibitors.

Recently, Maclean D. et al.67

have reported thiazolidinone library as agonists

of the stimulating hormone receptor (X). Thiagarajah J. R. et al.68,69

have synthesized

a small molecule as CFTR inhibitor. Taddei A. et al.70

have been constructed some

new thiazolidinone as CFTR inhibition.

N

S

NH

OR3

O

R1

R2

(IX)

S

N

O

BnO

NH

O NHO

NH2

Cl

(X)


Thiazolidinones...

198

In view of the therapeutic activities of 4-thiazolidinones and methylsulfonyl

derivatives, it was contemplated to synthesis some new 4-thiazolidinones in search

of agents possessing higher biological activity with least side effect, which have

been described as under.

SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 3- AMINO-

5 - A R YLIDINE-2-METHYL-2- [4 -METHYLSULFONYL)

PHENYL]-1,3-THIAZOLIDIN-4-ONES


Thiazolidinones...

199

SECTION - I

SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - A M I N O - 5 -

A RY LI D I N E - 2 - M E T H Y L - 2 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 1 , 3 -

THIAZOLIDIN-4-ONES

4-Thiazolidinone and its derivatives represent one of the most active classes

of compounds possessing wide spectrm of pharmacological activity. Looking to

their versatile properties, it was planned to genarate a series of 3- am i n o - 5 -

arylidine-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4-ones of type

(XIII) by heterocyclisation of 3-amino-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-

thiazolidin-5-one with arylaldehyde acid.








drugs.

S

O

O

CH3

S

N

CH3

O

NH2

R-CHO

CH3COONa ingla.CH3COOH

S

O

O

CH3

S

N

CH3

O

CHR

NH2

Type(XIII)R=Aryl


Thiazolidinones...

200

0.0

20.0

40.0

60.0

80.0

100.0

%T

500.0750.01000.01250.01500.01750.02000.03250.01/cm

453.2 470.6

516.9

590.2

621.0

717.5

761.8

815.8

958.6

1010.6

1028.0

1070.4

1099.3

1172.6

1253.6

1288.4

1307.6

1357.81398.3

1431.1

1494.7

1512.1

1556.4

1591.21668.3

2312.52769.6

2839.0

2918.12989.5

3325.0




-CH3 C-H str. (sym.) 2839 2880-2860 ,,

C-H def. (asym.) 1431 1470-1435 ,,

C-H def. (sym.) 1398 1390-1370 ,,

Aromatic C-H str. 3035 3090-3030 72

C=C str. 1512 1540-1480 ,,

1070 1125-1090 ,,

1028 1070-1000 ,,

Sulfonyl SO2 str. 1172 1185-1165 ,,

Amide NH-C=O str. 1668 1680-1636 71

Amine NH- str. 3325 3380-3350 ,,

IR SPECTRAL STUDIES OF 3 - AM I N O - 5 -ARYLIDINE-2-METHYL-2-

[4-(METHYLSULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE

SCH3

O

O N

S

NH2

CH3

O


cm-1 (KBr disc.)


Thiazolidinones...

201



1 2.33 3 H singlet Ar-CH3 -


3 3.69-3.71 2 H doublet Ar-NH2 -

4 7.26-7.29 5 H multiplet Ar-H(c,g) -

5 7.65-7.68 2 H doublet Ar-Hb,b’ J=9.

6 7.74-7.77 2 H doublet Ar-Ha,a’ J=9

7 9.02 1 H singlet Hh -

Signal No.




NMR SPECTRAL STUDIES OF 3 - A M I N O - 5 -ARYLIDINE-2-METHYL-2-

[4-(METHYLSULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE

a b

a' b'

SCH3

O

O N

S

NH2

CH3

O

cd

e

fg

h


Thiazolidinones...

202

TAB

LE

-13

:MA

SS S

PE

CT

RA

L S

TU

DIE

S O

F 3

-AM

INO

-5-(

P-C

HL

OR

OB

EN

ZY

LID

EN

E)-

2-M

ET

HY

L-2

-[4-

(ME

TH

YL

SU

LF

ON

YL

)PH

EN

YL

]-1,

3-T

HIA

ZO

LID

IN-4

-ON

E

m/z

= 4

08


Thiazolidinones...

203

EXPERIMENTAL

SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - A M I N O - 5 -

A RY LI D I N E - 2 - M E T H Y L - 2 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 1 , 3 -

THIAZOLIDIN-4-ONES

(A) Synthesis of 3-Amino-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-5-one

To a solution of 1-[4-(methylsulfonyl)phenyl]ethanone hydrazone (2.12 gm,

0.01 mol) and mercaptoacetic acid (0.92 gm, 0.01 mol) in dry toluene(20ml) was

refluxed on heating mentle using dean stark water separator for 10 hr. The reaction

mixture was cooled and excess toluene was distilled in vacuo. An oily liquid was

obtained, which was poured into hexene and kept overnight. The solid separated

was filtered and recrystlized from ethanol.Yield 48%; M.P. 168oC; Anal. Calcd. for

C11H14N2O3S2 Requires: C,46.13; H,4.93; N, 9.78 %; Found: C, 46.11; H, 4.92;

N, 9.76 %.

(B) Synthesis of 3- Amino- 4- benzylidine-2-methyl-2-[4-(methylsulfonyl)

phenyl]-1,3-thiazolidin-5-ones

To a solution of 3-amino-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-5-one

(2.54 gm, 0.01 mol) and benzaldehyde(1.06 gm, 0.01 mol) and anhydrous sodium

acetate(0.79 gm, 0.01 mol) in glacial acetic acid (20 ml) was refluxed on heating

mentle at 120oC for 12 hr. The reaction mixture was cooled and tritruted with 10%

sodiumsulphate solution. The product was crystallized from ethanol. Yield 48%;

M.P. 168oC; Anal. Calcd. for C18H18N2O3S2 Requires: C,57.73; H, 4.84; N, 7.48%;

Found: C, 57.71; H, 4.82; N, 7.49%.

Similarly other 3 - am i n o - 5 - ary lidine-2-methyl-2-[4-(methylsulfonyl)

phenyl]-1,3-thiazolidin-5-ones have been prepared the physical constants are

recorded in Table No. 13.


Thiazolidinones...

204

(C) Biological screening of 3- Amino- 4- benzylidine-2-methyl-2-[4-

(methylsulfonyl)phenyl]-1,3-thiazolidin-5-ones


The zones of inhibition of test solution are reported in Graphical Chart No 13.


Thiazolidinones...

205

13a

C6H

5-C

18H

18N

2O3S

237

416

848

7.48

7.49

0.51

S 2

13b

4-C

l-C

6H4-

C18

H17

ClN

2O3S

240

812

852

6.85

6.84

0.46

S 1

13c

2-C

l-C

6H4-

C18

H17

ClN

2O3S

240

815

244

6.85

6.86

0.58

S 2

13d

3-C

l-C

6H4-

C18

H17

ClN

2O3S

240

818

561

6.85

6.82

0.46

S 2

13e

4-O

CH

3-C

6H4-

C19

H20

N2O

4S2

404

138

466.

936.

920.

54S 1

13f

3,4-

(OC

H 3) 2

-C6H

3-C

20H

22N

2O5S

243

415

867

6.45

6.44

0.56

S 2

13g

4-F-

C6H

4-C

18H

17FN

2O3S

239

219

163

7.14

7.15

0.44

S 2

13h

3-B

r-C

6H4-

C18

H17

BrN

2O3S

245

314

668

6.18

6.19

0.59

S 1

13i

3-C

6H5-

O-C

6H4-

C24

H22

N2O

4S2

462

183

596.

006.

020.

47S 2

13j

4-N

(CH

3)2-

C6H

4-C

20H

23N

3O3S

241

716

459

10.0

610

.07

0.56

S 1

13k

2-O

H-C

6H4-

C18

H18

N2O

4S2

390

172

437.

107.

110.

41S 2

13l

2-C

4H3O

-C

16H

16N

2O4S

236

414

656

7.69

7.70

0.53

S 2

TA

BL

E :

13

PH

YSI

CA

L C

ON

STA

NT

S O

F 3

-AM

INO

-5A

RY

LID

INE

-2-M

ET

HY

L-2

-[4-

(ME

TH

YL

SU

LF

ON

YL

)

PH

EN

YL

]-1,

3-T

HIA

ZO

LID

IN-4

-ON

ES

S 1 H

exan

e:Et

hyl

acet

ate(

5:5)

,

S 2 H

exan

e:Et

hyl

acet

ate(

6:4)

Sr.

R M

olec

ular

M

olec

ular

M

.P.

Yie

ld

%

of N

itro

gen

Rf

Sol

vent

No

For

mul

a

Wei

ght

oC

%

Cal

cd.

Fou

nd

V

alue

Sys

tem

1

2

3 4

5

6

7

8 9

10


Thiazolidinones...

206

GR

AP

HIC

AL

CH

AR

T N

O.

13 :

3-A

MIN

O-5

-AR

YL

IDIN

E-2

-ME

TH

YL

-2-[

4-(M

ET

HY

LS

UL

FO

NY

L)P

HE

NY

L]-

1,3-

TH

IAZ

OL

IDIN

-4-O

NE

S


Thiazolidinones...

207

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