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STUDIES ON CHEMICAL
ENTITIES OF THERAPEUTIC
INTEREST
A THESIS
SUBMITTED TO THE
SAURASHTRA UNIVERSITY
FOR THE DEGREE OF
DoctorofPhilosophy
IN
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
X
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Gram : UNIVERSITY
Fax : 0281-2577633
Phone : (R) 2584221
(O) 2578512
SAURASHTRA UNIVERSITY
University Road.
Rajkot - 360 005.
Dr. H. S. Joshi
M.Sc., Ph.D.F.I.C.S.
Associate Professor,
Department of Chemistry
No.
Residence :
B-1,Amidhara Appartment
2- Jalaram Plot,
University Road,
Rajkot - 360 005.
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
Place : Rajkot.
(Dinesh J. Paghdar)
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 advancement in the knowledge of chemistry. The thesis has been prepared under my supervision.
Date :
-06-2005
Place: Rajkot.
Dr. H. S. Joshi
Associate Professor
Department of Chemistry
Saurashtra University
Rajkot - 360 005.
Dedicatedto
My Family
Q
ACKNOWLEDGEMENTS
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“ Shree Ganeshay Namah “
Hats off to the Omnipresent, Omniscient and Almighty God, the glorious
fountain and continuous source of inspirations! I offer salutations to him
and my head bows with rapturous dedication from within my heart, to the
Omnipotent Lord “Shree Krishna”.
My head bows with fullest devotion, reverence, heartfelt obeisance,
deep sense of respect and admiration, to my most esteemed mentor, my cotraveler and guide Dr. H. S. JOSHI. Associate Professor, Department of
Chemistry, Saurashtra University, Rajkot, who held the torch of excellent
guidance high and lighted up the darkness, with perpetual affectionate
encouragement and occasional constructive criticism when needed, towards
the goal of my academic journey.
I also owe to, from the deepest corner of heart, deepest sense of gratitude
and indebtedness to Dr. (Mrs.) H. H. Parekh, Professor and Head, Department
of Chemistry, Saurashtra University, Rajkot, as I have been constantly
benefited with her lofty research methodology and the motivation as well as
his highly punctual, affectionate, yet noncompromising nature which always
inspired me in heading rapidly towards my goal and helped me achieving the
aim of my present task very speedily.
I wish to thank Dr. R. C. Khunt, for her constant guidance and moral
support during the course of my research work.
Who in this world can entirely and adequately thank the parents who
have given us everything that we possess in this life? The life it self is their
gift to us, so I am at loss of words in which to own my most esteemed father
Shri Jayntibhai and My loving mother Late Smt. Chaturaben and most
venerated grand father Laxmanbhai, grand mother Jeeviben. Through the stress
and strain of this study, my younger brother Vimal, has encouraged me to
reach my destination.
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As with the completion of this task, I find myself in difficult position
on attempting to express my deep indebtedness to Praful Chovatia . I wish to
thank Zalavadia Paresh for his most willing co-operation and comprehensive
exchange 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, Akabari
jignesh, 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 fruitful
discussion at various stages. I am most thankful to all my Juniors for their
valuable co-operation and help during the course of my work.
I am thankful to Mr. Harshad Joshi and Mrs. Namrata for their kind
support and providing chemicals and glasswares on time his co-operation in
magnifying the presentation of my work in the form of thesis.
I Gratefully acknowledge the most willing help and co-operation shown
by CDRI Lucknow, CIL, Chandigarh for spectral studies and Tuberculosis
Antimicrobial Acquisition Co-ordinating Facility, Alabama, U. S. A. for kind
co-operation extended by them for antitubercular activity.
Finally, I express my grateful acknowledgment to Department of
Chemistry, Saurashtra University for providing me the excellent laboratory
facilities , jounior research fellowship and kind furtherance for accomplishing
this work.
DINESH J. PAGHDAR
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CONTENTS
Page No
SYNOPSIS
..
..
..
01
STUDIES ON CHEMICAL ENTITIES OF THERAPEUTICS INTEREST
Introduction
..
..
..
10
..
..
16
PART - I : STUDIES ON PYRAZOLINES
Introduction
..
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
Introduction and Spectral studies...
..
..
40
Experimental
..
..
44
Graphical data of In In Vitro Evaluation of Antitubercular Activity
..
46
In Vitro Evaluation of Antimicrobial screening
..
47
..
..
Section - III : Synthesis and biological screening of 3-[4-(Methylsulfonyl)phenyl]5-aryl-4,5-dihydro-1H-pyrazoles
Introduction and Spectral studies...
..
..
48
Experimental
..
..
52
Graphical data of In Vitro Evaluation of Antimicrobial screening
..
54
Reference
..
..
55
..
..
65
..
..
PART - II : STUDIES ON CYANOPYRIDINES
Introduction
..
Section - I : Synthesis and biological screening of 2-Methoxy-6-[4-(methylsulfonyl)
phenyl]-4-arylnicotinonitriles
Introduction and Spectral studies...
..
..
69
.
Experimental
..
..
73
Graphical data of In Vitro Evaluation of Antimicrobial screening
..
75
Reference
..
..
76
..
..
79
..
..
PART - III : STUDIES ON CYNOPYRIDONES
Introduction
..
Section - I : Synthesis and biological screening of 6-[4-(Methylsulfonyl)phenyl]-2-oxo4-aryl-1,2dihydropyridine-3-carbonitriles
Introduction and Spectral studies...
..
..
83
Experimental
..
..
87
Graphical data of In Vitro Evaluation of Antitubercular Activity
..
89
In Vitro Evaluation of Antimicrobial screening
..
..
90
Reference
..
..
91
..
..
94
..
..
PART - IV : STUDIES ON CYANOPYRAN
Introduction
..
Section - I : Synthesis and biological screening of 2-Amino-6-[4-(methylsulfonyl)phenyl]4-aryl-4H-pyran-3-carbonitriles
Introduction and Spectral studies...
..
..
Experimental . . . . . .
99
103
Graphical data of In Vitro Evaluation of Antitubercular Activity
..
105
In Vitro Evaluation of Antimicrobial screening
..
..
106
Reference
..
..
107
..
..
111
..
PART - V : STUDIES ON PYRIMIDINES
Introduction
..
Section - I : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2(1H)-ones
Introduction and Spectral studies...
..
..
120
Experimental
..
..
124
Graphical data of In Vitro Evaluation of Antitubercular Activity
..
126
In Vitro Evaluation of Antimicrobial screening
..
127
..
..
Section - II : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2(1H)-thiones
Introduction and Spectral studies...
..
..
128
Experimental
..
..
132
Graphical data of In Vitro Evaluation of Antitubercular Activity
..
134
In Vitro Evaluation of Antimicrobial screening
..
135
..
..
Section - III : Synthesis and biological screening of 4-[4-( Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2-amines
Introduction and Spectral studies...
..
..
136
Experimental
..
..
140
Graphical data of In Vitro Evaluation of Antimicrobial screening
..
142
Reference
..
..
143
..
..
146
..
..
PART - VI : STUDIES ON INDAZOLES
Introduction
..
Section - I : Synthesis and biological screening of Ethyl-4-[4-methylsulfonyl)phenyl]-2
-oxo-6-arylcyclohex-3-ene-1carboxylates
Introduction and Spectral studies...
..
..
155
Experimental
..
..
159
..
161
..
Graphical data of In Vitro Evaluation of Antimicrobial screening
Section - II : Synthesis and biological screening of 6-[4-(Methylsulfonyl)pheny]-4-aryl
-2,3a,4-5-tetrahydro-3H-indazol-3-ones
Introduction and Spectral studies...
..
..
162
Experimental
..
..
166
Graphical data of In Vitro Evaluation of Antimicrobial screening
..
168
Reference
..
169
..
175
..
..
..
PART - VII : STUDIES ON ISOXAZOLES DERIVATIVES
Introduction
..
..
Section - I : Synthesis and biological screening of 3-[4- (Methyl sulfonyl)phenyl]-5-aryl
isoxazoles
Introduction and Spectral studies...
..
..
180
Experimental
..
..
184
Graphical data of In Vitro Evaluation of Antimicrobial screening
..
186
Reference
..
187
..
191
..
..
..
PART - VIII : STUDIES ON THIAZOLIDINONES DERIVATIVES
Introduction
..
..
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
..
..
202
Graphical data of In Vitro Evaluation of Antimicrobial screening
..
205
Reference
Experimental
..
..
..
..
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 pharmacological activities and industrial applications. The chalcones are reported to possess 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 observations, it was contemplated to synthesize some novel chalcone derivatives using 1-(4methanesulfonyl-phenyl)-ethanone with better biological activities which have been
described as under.
PART - I
: STUDIES ON PYRAZOLINES
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
O
H3C
O
S
O
R
Type (I)
R = Aryl
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
R
O
H3C
S
N
O
N
O
H3C
Type (II)
R = Aryl
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
R
O
H3C
S
O
Type (III)
N
NH
R = Aryl
The synthesis of pyrazoline derivatives of Type(III) have been undertaken by
the cyclocondensation of the chalcones of Type(I) with hydrazine hydrate.
3
PART - II
:
STUDIES ON CYANOPYRIDINES
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 derivatives shown as under.
SECTION-I :
Synthesis and biological evaluation of 2-Methoxy-6-[4(methylsulfonyl)phenyl]-4-arylnicotinonitriles
R
O
H3C
S
N
N
O
O
Type (IV)
CH3
R = Aryl
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-3carbonitriles
4
R
O
H3C
S
N
H
O
N
O
Type (V)
R = Aryl
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
R
O
H3C
S
O
O
N
NH 2
Type (VI)
R = Aryl
Cyanopyran derivatives of Type (VI) have been prepared by the reaction of
chalcones of Type (I) with malononitrile in pyridine.
5
PART - V
:
STUDIES ON PYRIMIDINES
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
R
O
H3C
S
NH
N
O
O
Type (VII)
R = Aryl
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
R
O
H3C
S
NH
N
O
S
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
R
O
H3C
N
S
N
O
Type (IX)
R = Aryl
NH2
Aminopyrimidine derivatives of Type (IX) have been synthesized by the
condensation of chalcones of Type (I) with guanidine hydrochloride.
PART - VI
:
STUDIES ON INDAZOLES
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
sulfonyl)phenyl]-2-oxo-6-arylcyclohex-3-ene-1carboxylates
R
O
H3C
O
CH3
S
O
O
O
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 CO 3
SECTION-II : Synthesis and biological evaluation of 6-[4-(Methylsulfo
nyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-indazol-3-ones
R
O
O
H3C
S
O
NH
N
Type (XI)
R = Aryl
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
sulfonyl)phenyl]-5-arylisoxazoles
R
O
H3C
S
O
N
Type (XII)
O
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 :
S y n t h e s i s a n d b i o l o g i c a l e v a l u a t i o n o f 3 -Am i n o - 5 arylidine-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3thiazolidin-4-ones
R
O
H3C
H3 C
S
S
N
O
O
H2N
Type (XIII)
R = Aryl
The thiazolidinone derivatives of Type (XIII) have been undertaken by the
condensation of 3-amino-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4one 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.
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
H 37 Rv 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
10
Studies on chemical entities...
INTRODUCTION
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 current environment for discovery and development of 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...
11
Studies on chemical entities...
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
Studies on chemical entities...
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 .
NH2
R
H
CH 3
H
NH
H
S
CH3
CH3
O
N
CH 3
R'
O
O
S
H
H
H
O
COOH
penicillins
R
R''
NHR
sulfonamides
steroids
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
Introduction...
13
Studies on chemical entities...
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
Studies on chemical entities...
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 heterocyclic compounds, several entities have been designed, generated and characterized 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
Studies on chemical entities...
2.
To generate several intermediates, like chalcones, cyclohexenone bearing
methanesulfonyl acetophenone moiety.
3.
To characterize these products for structure elucidation using several spectroscopic 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.
Introduction...
16
Studies on chemical entities...
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.
O
A
B
(I)
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
4,5
Various condensing agent used are alkali of different strength.
6,7
8
9
Hydrogen chloride , Phosphorous oxychloride , Piperidine , Anhydrous aluminium
10
11
12
13
chloride , Boron trifluoride , Borax , Aminoacids , Perchloric acid
14
etc.
MECHANISM
The following two mechanisms have been suggested for the synthesis of
chalcones.
Pyrazolines...
17
Studies on chemical entities...
O
+
C
Ph
CH
HO
O
-
+
-
C
Ph
2
CH 2
Ph
O
O
C
C
H
O
-
H
+
-OH -
Ph
Ph
H
O
O
OH
HO
-
-H 2 O
C
C
Ph
Ph
Ph
Ph
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
15
16
s ignificant biological activities viz. pyrazolines , cyanopyridines ,
17
18
cyanopyrans , cyanopyridones , pyrimidines
indazoles
2.
23
19-21
22
, isoxazoles ,
etc.
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.
4.
24
They have been useful in providing structure of some natural products like
25
26
27
28
cyanomulcurin , eviodictoyl , hemlocktanin , narighenin ,
plioretin
5.
29
etc.
30
Chalcones are also useful for the detection of Fe(II) 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
Pyrazolines...
18
Studies on chemical entities...
of copper
6.
32
33
and for spectrophotomatric study of the germanium.
The chalcones are natural biocides
34,35
and are well-known key intermidiate
in the synthesis of heterocyclic compounds possessing biodynamic
behaviour.
7.
36-38
Chalcone and their derivatives are also found to be applicable as light
39
40
stabilizing agent , sweetening agent , 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. Antitumor
41,42
2. Antispasmodic
3. Antiulcer
43
44,45
4. Anthelmintics
5. Bactericidal
46,47
48,49
6. Cardiovascular
7. Fungicidal
51-53
8. Germicidal
9. Herbicidal
50
54
55
10. Insecticidal
11. Antiallergic
12. Anticancer
56-58
59
60,61
13. Antiinflammatory
62,63
64,65
14. Antimalarial
15. Antitubercular
16. Antiviral
66,67
68
Pyrazolines...
19
Studies on chemical entities...
Chalcones are potential biocides, because some naturally occurring
antibiotics
69
and aminochalcones
70,71
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).
O
R1
R
(II)
O
The compound 4-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-1piperazine 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.
H3 CO
H3CO
N
COOCH2CH3
N
H3CO
(III) O
O
N
CH3
H3CO
(IV)
COOH
Pyrazolines...
20
Studies on chemical entities...
73,74
Some dihydrochalcones are well known for their sweetening property
and appear
to be non-nutritive sweeteners. A dihydrochalcone ‘Uvaretin’ from Uvaria
acuminata has shown antitumor activity
Ahluwalia et al.
76
75
in lymphocytic leukemia test. V. K.
have noted that 5-cinnamoylchalcones (V) have shown good as
antibacterial activity.
R1
R1
R
R
OH
HO
OH
O
O
(V)
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.
OH
HO
OH
OH
Go M. L. et al.
80
O
(VI)
have described the synthesis and biological activities of
chalcones as antiplasmodial. Xue C. X. et al.
as antimalarial agents. Fu Y. et al.
82
81
synthesized and reported chalcones
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 action of an
anti-inflammatory chalcone derivative in RAW 264.7 cells. Nerya O. et al.
84
have
prepared chalcones as potent tyrosinase inhibitors.
Pyrazolines...
21
Studies on chemical entities...
Sabzevari O. et al.
85
have constructed some new chalcone derivatives as
molecular cytotoxic mechanisms for anticancer activity (VII).
OMe
O
OH
OMe
Recently, Ban H. S. et al.
O
86
(VII)
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 derivatives 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 following part.
STUDIES ON CHALCONE DERIVATIVES
PART - I
:
STUDIES ON PYRAZOLINES
PART - II
:
STUDIES ON CYANOPYRIDINES
PART - III
:
STUDIES ON CYANOPYRIDONES
PART - IV
:
STUDIES ON CYANOPYRANS
PART - V
:
STUDIES ON PYRIMIDINES
PART - VI
:
STUDIES ON INDAZOLES
PART - VII :
STUDIES ON ISOXAZOLES
PART - VIII :
STUDIES ON THIAZOLIDINONES
Pyrazolines...
22
Studies on chemical entities...
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 behaviour
88
and industrial applications.
89
N
N
H
(I)
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
90
and the N-aryl maleimides yields the corresponding pyrazolines .
2.
Epoxidation of chalcones i.e. epoxy ketones which reacted with hydrazine
91
and phenyl hydrazine to give pyrazolines . 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
95
hydrazine hydrate .
4.
2-Pyrazolines can also be prepared by the condensation of chalcone dibromide
96
with hydrazine .
Pyrazolines...
23
Studies on chemical entities...
R1
O
NH 2NH 2.H 2O
R
NH
R1
N
R
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
O
H 2N NH R 2 R 1
R1
CH
-
C
R
+
intermolecular
neucleophilic attack
R1
R
(i) Proton transfer
(ii) Ketonization
R1
-
NH
R2
+
N
O
NH 2
R2
R1
R
R
O
NH2
R
-H2O
N
R2
OH
N
H
N
N
R2
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.
Pyrazolines...
24
Studies on chemical entities...
THERAPEUTIC IMPORTANCE
From the literature survey, it was revealed that 2-pyrazolines are better
therapeutic agents some of them are as shown bellow.
1. Antiallergic
99
2. Anticonvulsant
3. Antidiabatic
100,101
102
4. Antiimplantation
103
5. Antiinflammatory
6. Antitumor
104
105
7. Antineoplastic
106
107
8. Antimicrobial
9. Analgesic
108,109
10. Bactericidal
110,111
11. Cardiovascular
12. Diuretic
112
113
13. Fungicidal
14. Herbicidal
114
115
15. Hypoglycemic
16. Insecticidal
116
117
17. Tranquilizer
118
Moreover F. Manna and co-worker
119
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 Richard
121
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
Studies on chemical entities...
pesticides. Furthermore, Tsubai et al.
123
have synthesized 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.
as anticonvulsant agents (III). Maurer Fritz et al.
125
126
have synthesized pyrazolines
have synthesized pyrazoles and
screened for their pesticidal activity.
N
N
O
S
NH
H
N
NH
OCH3
S
N
N
H
N
COCH3
(III)
(II)
E. Palska et al.
127
COCH3
O
N
R
N
have prepared 3,5-diphenyl-2-pyrazolines (IV) and cited
their antidepressant activity. B. Shivrama et al.
antibacterial agents. Hiremath S. P. et al.
130
128,129
have synthesized pyrazolines as
have reported pyrazolines as analgesics,
antiinflammatory and antimicrobial agents. Malhotra V. et al.
131
have synthesized
new pyrazolines as a cardiovascular agents (V).
Ph
N
R1
NH
R2
N
N
OMe R1
R2
(IV)
OMe
NH
S
(V)
Pyrazolines...
26
Studies on chemical entities...
Moreover, T. M. Stivensen et al.
132
have also investigated N-substituted pyrazoline
133
type insecticides. Tanka Katsohori
herbicides and Johannes et al.
134
have patented pyrazoline derivatives as
135
as insecticides. Moritaz Z. and Hadol
investigated
a semi emperial molecular orbital study on the reaction of aminopyrazolinyl azodye
136
with singlet molecular oxygen. Shivnanda M. K. and
co-workers
have
prepared substituted pyrazolines and reported their antibacterial activity.
137
Almstead J. et al.
Kuchkguzel et al.
138
have prepared pyrazolines as vascularization agents. Guniz
have synthesized pyrazolines as a antimicrobial and
anticonvalsant agents. Gulhan T. Z. and co-workers
139
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.
Parekh
141
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-workers
143
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 A N D B I O L O G I C A L SCREENING O F 1 ACETYL-3-[4-(METHYLSULFONYL)PHENYL]-5ARYL-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
Studies on chemical entities...
SECTION - I
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
(2E)-1-[4-
(METHYLS U L F O N Y L ) P H E N Y L ] - 3 - A RY L - 2 - P R O P E N E - 1 - O N ES
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.
O
H3C
O
R-CHO
in 40% alkali
S
O
O
O
H3C
S
R
O
CH3
R=Aryl
Type(I)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, Infrared and 1 H 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 H37 R v a t 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.
Pyrazolines...
28
Studies on chemical entities...
REACTION SCHEME
S
H3C
AlCl 3
(CH3 CO)2O
O
S
H3C
CH3
H
Alcoholic KOH
R
O
O
R
S
H2 O 2 in glacial aceticacid
CH3
O
R
O
S
H3C
O
Type-(I)
R = Aryl
Pyrazolines...
29
Studies on chemical entities...
MICROBIOLOGICAL EVALUATION
ANTIMICROBIAL ACTIVITY
146
Method
:
Cup-Plate
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 H37 Rv
Concentration
:
6.25 µg/ml
Standard drug
:
Rifampin.
Pyrazolines...
30
Studies on chemical entities...
IR
SPECTRAL
STUDIES
OF
(2E)-1-[4-(METHYLS U L F O N Y L )
P H E N Y L ] - 3 -(p-CHLOROPHENYL)- 2 - P R O P E N E - 1 - O N E
100.0
%T
80.0
1276.8
60.0
2916.2
3028.0
3087.8
736.8
775.3
1301.9
1382.9 1209.3
1089.7
1182.3
1224.7
1490.9
987.5
1330.8
O
1012.6
H3C
1031.8
S
532.3
596.0495.7
1564.2 1407.9
40.0
3292.3
3388.7
20.0
1654.8
1602.7
815.8
Cl
O
O
0.0
3250.0
2000.0
1750.0
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Halide
Sulfonyl
Vinyl
Chalcone
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-Cl str.
SO2 str.
CH=CH str.
C=C str.
C=O str.
Frequency in cm -1
Observed
Reported
2916
2870
1460
1382
3087
1490
1089
775
1182
3028
1564
1654
2975-2950
2880-2860
1470-1435
1390-1370
3090-3030
1540-1480
1125-1090
800-600
1185-1165
3050-3000
1580-1550
1672-1652
Ref.
144
,,
,,
,,
145
,,
,,
144
,,
,,
,,
,,
Pyrazolines...
31
Studies on chemical entities...
NMR
SPECTRAL
STUDIES
OF
(2E)-1-[4-(METHYLS U L F O N Y L )
P H E N Y L ] - 3 -(p-CHLOROPHENYL)- 2 - P R O P E N E - 1 - O N E
Cl
d
c
d'
c'
O
H 3C
a
b
a'
b'
e
f
S
O
O
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.5
3H
singlet
-SO 2 CH3
-
2
7.28-7.31
2H
doublet
Ar-H b,b
Jba=8.1
3
7.35-7.40
2H
doublet
Ar-H c,c
Jcd=8.7
4
7.47-7.52
1H
doublet
CHe
5
7.55-7.58
2H
doublet
Ar-H a,a
7
7.71-7.76
1H
doublet
CHf
8
7.91-7.94
2H
doublet
Ar-H d,d
Jab=8.4
Jdc=8.1
Pyrazolines...
PROPENE-1-ONE
m/z =320
TABLE-1 : MASS SPECTRAL STUDIES OF (2E)1-[4-(METHYLS U L F O N Y L ) P H E N Y L ] - 3 -(P-CHLOROPHENYL)- 2 -
Studies on chemical entities...
32
Pyrazolines...
33
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF ( 2 E ) -1-[4-(METHYL
S U L F O N Y L ) P H E N Y L ] - 3 -ARY L- 2 - P R O P E N E - 1 - O N E S
(A)
Synthesis of 1-[4-(methylsulfonyl)phenyl]ethanone
To the solution of 1-[4-(methylthio)phenyl]ethanone in glacial acetic acid
(10 ml), H2 O 2 (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.p118o C,
Anal. Calcd. for C9 H10 O 3 S : Require: C, 54.53, H, 5.08; Found: C, 54.51, H, 5.06
%.
(B)
Synthesis of 1-[4-(Methyl s u l f o n y l ) p h e n y 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. 120o C, Anal. Calcd.
for C 16 H13 ClO 3 S 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-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 propene-1-ones
(a)
Antibacterial activity
146
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
Studies on chemical entities...
Subtilis, Bacillus Coccous, Escherichia coli, Proteus Vulgaris in separate conical
flasks at 40-50 o C 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 37 o C 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 activity
146
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 30o C 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 H 37 Rv in BACTEC
12B using the BACTEC 460 radiometric system. The compounds demonstrating
Pyrazolines...
35
Studies on chemical entities...
atleast>90% inhibition in the primary screening has been tested at lower
concentration towards Mycobacterium tuberculosis H 37 Rv 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
modified below. Stock solutions as test compounds were prepared 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 H37 Rv (ATCC 27294; American type culture collection,
Rockville, MD) was culture at 37 oC 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
Studies on chemical entities...
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 37 oC 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...
C6 H5 -
4-Cl-C 6H4 -
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
2-C4 H3O-
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
S1 Hexane:Ethyl acetate(5:5),
2
R
1
No
Sr.
276
302
329
378
365
304
346
316
320
320
320
286
4
Weight
184
132
142
94
140
180
118
154
105
135
120
96
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C14 H12 O4 S
C16 H14 O4 S
C18 H19 NO3 S
C22 H18 O4 S
C16 H13 Br O3 S
C16 H13 FO3 S
C18 H18 O5 S
C17 H16 O4 S
C16 H13 ClO3 S
C16 H13 ClO3 S
C16 H13 ClO3 S
C16 H14 O3 S
3
Formula
Molecular
56
57
60
62
65
55
58
56
62
65
58
60
6
%
Yield
-
-
4.25
-
-
-
-
-
-
-
-
-
7
Calcd.
-
-
4.24
-
-
-
-
-
-
-
-
-
8
Found
% of Nitrogen
0.43
0.54
0.46
0.47
0.59
0.49
0.56
0.52
0.44
0.50
0.48
0.51
9
Value
Rf
S2
S2
S1
S1
S2
S2
S2
S2
S1
S1
S2
S1
10
System
Solvent
TABLE : 1 PHYSICAL CONSTANTS OF 1-[4-(METHYLS U L F O N Y L ) P H E N Y L ] - 3 - A RY L - 2 - P R O P E N E - 1 - O N E S
Studies on chemical entities...
37
Pyrazolines...
38
Studies on chemical entities...
ANTITUBERCULAR ACTIVITY OF (2E)- 1-[4-(METHYL S U L F O N Y L )
P H E N Y L ] - 3 -ARY L- 2 - P R O P E N E - 1 - O N E S
O
O
H3C
S
R
O
TAACF, Southern Research Insitute
TABLE NO-1
Primary Assay Summary Report
Sr
No.
Sample
ID
Corp
ID
R
Assay
Mtb
Strain
%
MIC
µg/ml Inhibi.
1a
182264 PD-61
C 6 H5 -
Alamar
H37 R v
>6.25
00
1b
182265 PD-62
4-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
1c
182266 PD-63
2-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
1d
182267 PD-64
3-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
1e
182268 PD-65
4-OCH3 - C 6 H4 -
Alamar
H37 R v
>6.25
55
1f
182269 PD-66
3,4-(OCH3 ) 2 -C 6 H3 -
Alamar
H37 R v
>6.25
18
1g
182270 PD-67
4-F-C 6 H4 -
Alamar
H37 R v
>6.25
42
1h
182271 PD-68
4-Br-C6 H4 -
Alamar
H37 R v
>6.25
00
1i
182272 PD-69
3-C 6 H5 O-C 6 H4 -
Alamar
H37 R v
>6.25
11
1j
182273 PD-70
4-N(CH3 ) 2 -C 6 H4 -
Alamar
H37 R v
>6.25
00
1k
182274 PD-71
2-OH-C6 H4 -
Alamar
H37 R v
>6.25
00
1l
182275 PD-72
2-C 4 H3 O -
Alamar
H37 R v
>6.25
10
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
Pyrazolines...
GRAPHICAL CHART NO. 1 : (2E)1-[4-(METHYLS U L F O N Y L ) P H E N Y L ] - 3 - A RY L - 2 - P R O P E N E - 1 - O N E S
Studies on chemical entities...
39
Pyrazolines...
40
Studies on chemical entities...
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-(methyls u l f o n y l ) p h e n y l ] - 3 - a r y l - 2 p r o p e n e - 1 - o n e s of type-(I) on treatment with hydrazine hydrate in acetic acid
yielded 1- ac e t y l - 3 - [ 4 -(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles
derivatives of type (II).
O
O
H3C
O
.
R NH 2-NH2 H2O
S
H3C
in glacial CH3COOH
O
S
O
N
N
Type(I)
R
CO-CH3
R=Aryl
Type(II)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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 H37 R v a t 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.
Pyrazolines...
41
Studies on chemical entities...
IR SPECTRAL STUDIES OF 1 - A C E T Y L - 3 - [ 4 - (METHYLSULFONYL)
PHENYL]-5-(p-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE
100.0
%T
80.0
673.1
2850.6
60.0
713.6
1544.9
3047.3
3303.8
1188.1
1245.9
1299.9
1147.6
2920.0
3427.3
40.0
1490.9
Cl
20.0
1326.9
1357.8
O
H3C
1093.6
1593.1
S
O
580.5
624.9
783.0
424.3
844.8
484.1
871.8
542.0
960.5
1010.6
N
N
O
1658.7
819.7
1400.2
1415.7
H3C
0.0
3250.0
2000.0
1750.0
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Halide
Sulfonyl
Pyrazoline
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-Cl str.
SO2 str.
C=O str.
C=N str.
N-H str.
Frequency in cm -1
Observed
Reported
2920
2975-2950
2850
2880-2860
1490
1470-1435
1357
1390-1370
3047
3090-3030
1544
1540-1480
1093
1125-1090
1010
1070-1000
819
1188
1658
1593
3427
800-600
1185-1165
1612-1593
1612-1593
3400-3200
Ref.
144
,,
,,
,,
145
,,
,,
,,
144
,,
145
,,
Pyrazolines...
42
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 1 - A C E T Y L - 3 - [ 4 -(METHYLSULFONYL)
PHENYL]-5-(p-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE
d
Cl
c
O
H3 C
a
b
Hf
Hg
d'
O
c'
e
S
a'
b'
N
N
O
H3 C
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.3
3H
singlet
Ar-COCH3
-
2
2.4
3H
singlet
Ar-SO 2 CH3
-
3
3.03-3.11
1H
d,d
Ar-Hf
-
4
3.65-3.75
1H
d,d
Ar-Hg
-
5
5.49-5.55
1H
d,d
Ar-He
-
6
7.13-7.24
2H
doublet
Ar-H b,b'
Jba=8.1
7
7.24-7.26
2H
doublet
Ar-H c,c'
Jcd=8.6
8
7.27-7.28
2H
doublet
Ar-H a,a'
Jab=8.7
9
7.61-7.63
2H
doublet
Ar-H d,d'
Jdc=8.1
Pyrazolines...
BROMOPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE
m/z = 421
TABLE-2 : M A S S S P E C T R A L S T U D I E S 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 - ( M -
Studies on chemical entities...
43
Pyrazolines...
44
Studies on chemical entities...
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-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e - 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 - ( M e t h y ls u l f o n y l ) p h e n y l ] - 3 - (p-chlorophenyl)- 2 -
p r o p e n e - 1 - o n 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
crystallized from ethanol. Yield 56%, m.p. 125o C, Anal. Calcd. for
C 18 H17 ClN 2 O 3 S; 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-dihydro1H-pyrazoles were prepared. The physical data are recorded in Table No.2
(C)
Biological screening of 1-Acetyl-3-[4-(methylsulfonyl)phenyl]-5-aryl4,5-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...
C6 H5 -
4-Cl-C6H4 -
2-Cl-C6H4 -
3-Cl-C6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C6H4 -
3-C6 H5-O-C 6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
2-C4 H3O-
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
S1 Hexane:Ethyl acetate(5:5),
2
R
1
No
Sr.
332
358
385
434
421
360
402
372
376
376
376
342
4
Weight
136
165
146
126
140
126
118
134
165
185
125
118
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C16H16N 2O4 S
C18H18N 2O4 S
C20H23N 3O3 S
C24H22N 2O4 S
C18 H17 BrN2 O3 S
C18H17FN 2O3 S
C20H22N 2O5 S
C19H20N 2O4 S
C18 H17 ClN2O3 S
C18 H17 ClN2O3 S
C18 H17 ClN2O3 S
C18H18N 2O3 S
3
Formula
Molecular
1H-PYRAZOLES
55
57
66
49
68
61
48
59
52
56
56
65
6
%
Yield
8.43
7.82
10.90
6.45
6.65
7.77
6.96
7.52
7.43
7.43
7.43
8.18
7
Calcd.
8.44
7.81
10.91
6.42
6.68
7.76
6.97
7.51
7.42
7.44
7.45
8.19
8
Found
% of Nitrogen
0.45
0.51
0.58
0.46
0.49
0.41
0.42
0.56
0.52
0.40
0.55
0.40
9
Value
Rf
S1
S2
S1
S1
S2
S1
S1
S2
S2
S1
S2
S2
10
System
Solvent
TABLE : 3 PHYSICAL CONSTANTS OF 1-ACETYL-3-[4- (METHYLSULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-
Studies on chemical entities...
45
Pyrazolines...
46
Studies on chemical entities...
ANTITUBERCULAR
ACTIVITY
OF
1 - A C E T Y L - 3 - [ 4 - (METHYL
SULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES
O
H3C
S
O
N
N
R
CO-CH3
TAACF, Southern Research Insitute
TABLE NO-2
Sr Sample
No.
ID
Primary Assay Summary Report
Corp
ID
R
Assay
Mtb
Strain
%
MIC
µg/ml Inhibi.
2a
182204
PD-1
C 6 H5 -
Alamar
H37 R v
>6.25
00
2b
182205
PD-2
4-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
2c
182206
PD-3
2-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
2d
182207
PD-4
3-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
2e
182208
PD-5
4-OCH3 - C 6 H4 -
Alamar
H37 R v
>6.25
55
2f
182209
PD-6
3,4-(OCH3 ) 2 -C 6 H3 - Alamar
H37 R v
>6.25
18
2g
182210
PD-7
4-F-C 6 H4 -
Alamar
H37 R v
>6.25
42
2h
182211
PD-8
4-Br-C6 H4 -
Alamar
H37 R v
>6.25
00
2i
182212
PD-9
3-C 6 H5 O-C 6 H4 -
Alamar
H37 R v
>6.25
11
2j
182213
PD-10 4-N(CH3 ) 2 -C 6 H4 -
Alamar
H37 R v
>6.25
00
2k
182214
PD-11
Alamar
H37 R v
>6.25
00
2l
182215
PD-12 2-C 4 H3 O -
Alamar
H37 R v
>6.25
10
2-OH-C6 H4 -
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
Pyrazolines...
PYRAZOLES
GRAPHICAL CHART NO. 2 : 1 - A C E T Y L - 3 - [ 4 - (METHYLSULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-
Studies on chemical entities...
47
Pyrazolines...
48
Studies on chemical entities...
SECTION - III
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
3-[4-
(METHYL S U L F O N Y L ) P H E N Y L ] - 5 - A RY L - 4 , 5 - D I H Y D R O - 1 H PYRAZOLES
Therapeutic important of pyrazolines aroused considerable intrest to
synthesize pyrazolines of type (III) by the cyclocondensation of 1 - [ 4 (Methyls u l f o n y l ) p h e n y l ] - 3 - a r y l - 2 - p r o p e n e - 1 - o n e s of type-(I) with hydrazine
hydrate in order to study their biodynamic behaviour.
H3C
O
O
O
H3C
S
R
NH2 -NH2 H2O
in ethanol
S
O
N
N
H
O
Type(I)
R=Aryl
R
Type(III)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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.
Pyrazolines...
49
Studies on chemical entities...
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
100.0
%T
90.0
80.0
70.0
60.0
935.4
2839.0
2879.5
3074.3
2958.6
975.9
1296.1 1172.6 1004.8
1583.4 1436.9
1066.6
1606.6
1095.5
1350.1
1028.0
50.0
40.0
3340.5
1510.2
O
H3 C
S
30.0
2000.0
1750.0
1500.0
788.8
536.2
617.2
H3C
812.0
O
1245.9
1250.0
NH
N
O
3250.0
709.8 584.4
1398.3
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Ether
Sulfonyl
Pyrazoline
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-O-C str.
SO2 str.
N-H str.
C=N str.
Frequency in cm -1
Observed
Reported
2945
2879
1436
1398
3058
1510
1095
1066
1245
1172
3340
1606
2975-2950
2880-2860
1470-1435
1390-1370
3090-3030
1540-1480
1125-1090
1070-1000
1260-1200
1185-1165
3400-3200
1612-1593
Ref.
144
,,
,,
,,
145
,,
,,
,,
144
,,
145
,,
Pyrazolines...
50
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 3-[4-(METHYLS U L F O N Y L ) P H E N Y L ] - 5 (p-METHOXYPHENYL)- 4 , 5 - D I H Y D R O - 1 H - P Y R A Z O L E
H3C
d
O
c
O
H 3C
a
b
Hf
Hg
d'
S
O
c'
e
N
a'
NH
b'
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.5
3H
singlet
Ar-SO 2 CH3
-
2
3.9
3H
singlet
Ar-OCH3
-
3
2.95-3.04
1H
d,d
Ar-Hc
-
4
3.36-3.45
1H
d,d
Ar-Hg
-
5
4.84-4.90
1H
d,d
Ar-He
-
6
6.85-6.89
2H
doublet
Ar-H b,b'
Jba=8.1
7
7.22-7.25
2H
doublet
Ar-H c,c'
Jcd=8.6
8
7.26-7.30
2H
doublet
Ar-H a,a'
Jab=8.7
9
7.56-7.60
2H
doublet
Ar-H d,d'
Jdc=8.1
Pyrazolines...
DIHYDRO-1H-PYRAZOLE
m/z =392
TABLE-3 : MASS SPECTRAL STUDIES OF 3-[4-(METHYLSULFONYL)PHENYL]-5- (M-PHENOXYPHENYL)- 4 , 5 -
Studies on chemical entities...
51
Pyrazolines...
52
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
3-[4-
( METHYLS U L F O N Y L ) P H E N Y L ] - 5 - A RY L - 4 , 5 - D I H Y D R O - 1 H PYRAZOLES
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e 1-ones
See Part-I, Section-I (B).
(B)
Synthesis of 3-[4-(Methyls u l f o n y l ) p h e n y l ] - 5 -(p-methoxyphenyl)-4,5dihydro-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 -
p r o p e n e - 1 - o n e (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. 168 o C, Anal. Calcd. for C17 H18 N 2 O 3 S; Requires:
C, 61.80; H, 5.49; N, 8.48 %; Found: C, 61.78; H, 5.48; N, 8.46 %.
Similarly, other 3-[4-(methyls 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 were prepared. The physical data are recorded in Table No.3
(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 - 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.3
Pyrazolines...
3,4-(OCH3)2- C6H3 - C18H20N 2O4 S
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2f
2g
2h
2i
2j
290
316
343
392
379
318
360
330
334
334
334
300
4
Weight
145
160
126
165
140
192
118
168
132
145
164
122
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C14H14N 2O3 S
C16H16N 2O3 S
C18H21N 3O2 S
C22H20N 2O3 S
C16 H15 Br N2 O2 S
C16H15FN 2O2 S
C17H18N 2O3 S
C16 H15 ClN 2O2 S
C16 H15 ClN 2O2 S
C16 H15 ClN 2O2 S
S1 Hexane:Ethyl acetate(5:5),
2-C4 H3O-
4-OCH3 -C6 H4 -
2e
2l
3-Cl-C 6H4 -
2d
2-OH-C6 H4 -
2-Cl-C 6H4 -
2c
2k
4-Cl-C 6H4 -
2b
C16H16N 2O2 S
C6 H5 -
3
Formula
Molecular
2a
PYRAZOLES
2
R
1
No
Sr.
62
57
72
62
45
66
52
63
58
62
78
60
6
%
Yield
9.65
8.85
12.23
7.14
7.39
8.80
7.77
8.48
8.37
8.37
8.37
9.33
7
Calcd.
9.67
8.87
12.24
7.12
7.40
8.81
7.76
8.46
8.38
8.35
8.36
9.34
8
Found
% of Nitrogen
0.42
0.61
0.51
0.44
0.59
0.41
0.64
0.55
0.52
0.56
0.61
0.44
9
Value
Rf
S1
S2
S2
S1
S2
S1
S1
S2
S2
S1
S2
S2
10
System
Solvent
TABLE : 2 PHYSICAL CONSTANTS OF 3-[4-(METHYLSULFONYL)PHENYL]-5-ARY L - 4 , 5 - D I H Y D R O - 1 H -
Studies on chemical entities...
53
Pyrazolines...
GRAPHICAL CHART NO. 3 : 3-[4-(METHYL S U L F O N Y L ) P H E N Y L ] - 5 - A RY L - 4 , 5 - D I H Y D R O - 1 H - P Y R A Z O L E S
Studies on chemical entities...
54
Pyrazolines...
55
Studies on chemical entities...
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Shulabh Sharma, Virendra Kishor Srivastava, Ashok Kumar;
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125.
Archana V. K. Srivastava, Kumar Ashok;
Arzneimittel. Forschung, 52(11), 787-91 (2002); Chem. Abstr., 138, 353758 (2003).
126.
Maurer Fritz, Fuchs Rainer, Erdelen Chritoph, Turberg A.;
PCT Int. Appl. WO 03, 59, 887 (Cl. C07 D231/28) (2003); Chem. Abstr., 139, 117441z
(2003).
127.
E. Palaska, M. Aytemir, I. T. Uzboy, D. Erol;
Europian Journal of Medicinal Chemistry, 36(6), 539-543 (Eng), 2001;
Chem. Abstr.,136, 18374v (2002).
128.
B. Shivarama Holla, M. K. Shivananda, P. M. Akabar Ali, M. Shalini Shenoy;
Indian J. Chem., 39B, 440-47 (2000).
129.
B. Shivarama Holla, M. K. Shivananda, B. Veerendra;
J. Heterocyclic Chem., 12, 135-138 (2002).
130.
S. P. Hiremath, K. Rudresh and A. R. Saundane;
Pyrazolines...
63
Studies on chemical entities...
Indian J. Chem., 41(B), 394-399 (2002).
131.
Malhotra V., Pathak S., Nath R., Mukherjee D., Shanker K.;
Indian J. Chem., 41B, 1310-13 (2002); Chem. Abstr., 137, 370021j (2002).
132.
T. M. Stavenson, D. W. Piotrowski, M. A. H. Fahmy, R. L. Lowe, K. L. Monaco;
Chem. Abstr., 130, MAR Part - I, 29 AGRO (1999).
133.
T. Katsohori, A. Hiroyuki, K. Masumij;
PCT Int. Appl. WO 98, 56, 760; Chem. Abstr., 130, 66492w (1999).
134.
K. Johannes, J. Fuchs, R. Erdelen;
U.S. US 5, 525, 622 (cl. 514-403; A 0N 43156). Jun. 1996, DE Appl. 4, 128, 564, Aug.
1991; 574; Chem. Abstr., 125, 1427199 (1996).
135.
Z. Moritaz, S. Hadol;
Dyes and Pigmenta, 41, 1-2, 1-10 (1999).
136.
M. K. Shivananda, P. M. Akberali, B. Holla, Shivarama, M. Shenoy, Shalini;
Indian J. Chem. Sec. 13 Org. Chem. Incl. Med. Chem. 39B(6), 440-447 (Eng.); Chem.
Abstr., 134, 86195n (2000).
137.
Almstead Ji - In Kim, 1220 N. J., Jones D. R.;
PCT Int. Appl. WO 02, 89, 799 (Cl. A61K31/4439) (2002); Chem. Abstr., 137, 370086j
(2002).
138.
Guniz Kacukguzel, Sevin Rollas, Habibe Erdeniz, Muammer Kiraz, A. Cevdet Ekinci;
Eur. J. Med. Chem., 35, 761-77 (2000).
139.
Gulhan T. Z., Pierre Chevallet, Fatma S.K., Kevser Eral.;
Eur. J. Med. Chem., 35, 635-41 (2000).
140.
S. S. Sonarc;
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141.
V. J. Fernandes, H. H. Parekh;
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142.
N. Mishrika, N. Assod, F. M. Fawzy;
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143.
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Pyrazolines...
64
Studies on chemical entities...
145.
A. R. Kartizky and R. Alans Jon;
J. Chem. Soc., 2942 (1960). Introduction of Infra fed and Raman spectroscopy by Norman
B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy. Academic Press (1975).
146.
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llluslea & Febiger , (Philadelphia), USA, 180; Biol. Abstr., 1977, 64, 25183
Pyrazolines...
65
Studies on chemical entities...
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.
COOCH3
N
H 3 CO
CN
R
SYNTHETIC ASPECT :
1-6
Preparation of 3-cyanopyridines have been cited in literature
with different
methods.
1.
7
S a m o u r a n d c o - w o r k e r have prepared substituted cyanopyridines by
th e condensation of chalcones with malononitrile in presence of ammonium
acetate.
Cyanopyridines...
66
Studies on chemical entities...
R1
O
N
R
R1
CH2 (CN)2
R
CH3CONH4
N
NH2
MECHANISM :
The reaction proceeds through conjugate addition of active methylene
compounds to the α,β -unsaturated system as shown below.
CN
CN
NaOCH3
_
HC
H2C
CN
CN
R1
R1
R1
CN
CN
+
CN
_
HC
H
CN
R
O
O-
R
R
N
O
N
NaOCH3
NaOCH3
R1
R1
R1
H
CN
CN
CN
+
+
H
R
N
H
OCH3
R
O
HO
HN
OCH3
R
O
N
OCH3
-OH
R1
R1
CN
CN
+
-2H
NaOCH3
R
N
OCH3
R
N
OCH3
Cyanopyridines...
67
Studies on chemical entities...
THERAPEUTIC IMPORTANCE
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. Antifungal
8
2. Antiepileptic
3. Antibacterial
9
10
4. Anticonvulsant
5. Antitubercular
6. Analgesic
11
12
13
7. Insecticidal
8. Antisoriasis
14
15
9. Antihypertensive
16
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.
O
C
CH3
R
H2N
O
N
N
N
CH3
N
N
R
C
NH2
(I)
El-Nabawia et al.
17
(II)
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.
Cyanopyridines...
68
Studies on chemical entities...
19
The insecticidal activity of cyanopyridines have been screened by Y. Sasaki
et al. Umed Ten et al.
20
have prepared cyanopyridines as agrochemical fungicides.
The oxide activator bleaching activity of cyanopyridine has been proved by
21
Rees M. , 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.
23
24
S. S. Verma et al. and M. D. Ankhiwala have synthesized 2-amino-3-cyano2,6-disubstituted pyrimidines and studied their biological activities. Several workers
have prepared cyanopyridine derivatives and reported their cholinesterase
inhibitors,
25
antihistaminic and antiallergic,
29
26
adernergic,
27
herbicidal,
28
30
antiinflammatory and insecticidal activities. Some new 3-cyanopyridine derivatives
31
synthesized by Hammama A. and coworkers 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 tranferase inhibitors. Hussain et al.
35
cyanopyridines as antimicrobial agent. Wu Wenxue et al.
36
have synthesized
have synthesized
cyanopyridines as histamine H3 antagonists. Saudi Manal N. S. et al.
37
have found
38
that cyanopyridines have fascialicidal property. Harada Hironori et al. 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-worker
39
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
Studies on chemical entities...
DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic
activity.
NC
O
CN
NH
N
NH
N
(III)
Marco J. L. et al.
Moustafa M. A. et al.
al.
42
41
40
have synthesized of acetylcholinesterase inhibitors.
have prepared antibacterial agents. Rosentreter Ulrich et
have synthesized a new cyanopyridine as receptor agonists in the treatment of
cancer disease , inflammation, neurodegenerative disease(IV). Gary T. Wang and
co-worker
43
have synthesized of o-trifluoromethylbiphenyl substituted 2-amino-
nicotinonitriles as inhibitors of farnesyltransferase(V).
H 2N
CN
F3C
NC
N
CN
O(CH2)n OR1
R1
R 2CH 2S
CN
O
N
N
R2
(IV)
H3 C
(V)
N
N
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-( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 4 A R YLNICOTINONITRILES
Cyanopyridines...
70
Studies on chemical entities...
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 2-METHOXY-6-[4( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 4 - A RY L N I C O T I N O N I T R I L E S
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-( m e t h y l s u l f o n y l ) p h e n y l ] - 4 a r y l n i c o t i n o n 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.
O
O
O
R
H3C
S
R
CH 2(CN)2
H 3C
NaOCH3 in methanol
O
Type(I)
S
O
N
O
R=Aryl
Type(IV)
N
CH3
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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.
Cyanopyridines...
71
Studies on chemical entities...
IR SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)
P H E N Y L ] - 4 -(p-CHLOROPHENYL)N I C O T I N O N I T R I L E
100.0
%T
90.0
900.7
80.0
779.2
2852.5
482.2
1010.6
1380.9
1448.4
1209.31091.6
1494.7
1577.7
O
1357.8
H3C
S
1546.8
2923.9
50.0
30.0
534.2
1409.9
60.0
40.0
1263.3
1307.6 1184.2
2221.8
70.0
3222.8
3327.0
2000.0
1750.0
1500.0
819.7
N
O
1606.6
3250.0
Cl
N
O
1250.0
1000.0
750.0
CH3
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Halide
Sulfonyl
Ether
Pyridine
Nitrile
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-Cl str.
SO2 str.
C-O-C str.
C=C str.
C=N str.
C=N str.
Frequency in cm -1
Observed
Reported
2923
2975-2950
2852
2880-2860
1448
1470-1435
1380
1390-1370
3028
3090-3030
1494
1540-1480
1091
1125-1090
1010
1070-1000
819
800-600
1184
1185-1165
1209
1260-1200
1606
1650-1520
1577
1580-1550
2221
2240-2120
Ref.
44
,,
,,
,,
45
,,
,,
,,
44
,,
,,
45
,,
,,
Cyanopyridines...
72
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)
P H E N Y L ] - 4 -(p-CHLOROPHENYL)N I C O T I N O N I T R I L E
Cl
d
c
O
H3C
a
b
a'
b'
d'
c'
He
S
O
N
N
O
CH3
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
J Value
In Hz
Inference
1
2.4
3H
singlet
Ar-SO 2 CH3
-
2
3.9
3H
singlet
Ar-OCH3
-
3
7.25-7.31
2H
doublet
Ar-H b,b
4
7.40-7.46
2H
doublet
Ar-H c,c
5
7.43
1H
singlet
Ar-He
6
7.57-7.60
2H
doublet
Ar-H a,a
7
7.97-7.99
2H
doublet
Ar-H d,d
Jba=7.8
Jcd=8.4
Jab=8.1
Jdc=8.1
Cyanopyridines...
NI C O T I N O N I T R I L E
m/z = 364
TABLE-4 : MASS SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)PHENYL]-4-AR YL
Studies on chemical entities...
73
Cyanopyridines...
74
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 2-METHOXY- 6 - [ 4 ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 4 - A RY L N I C O T I N O N I T R I L E S
(A)
Synthesis of 1-[4-(Methyl s u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e 1-ones
See Part-I, Section-I (B).
(B)
Synthesis of 2-Methoxy-6-[4-(methylsulfonyl)phenyl]-4-(p-chlorophenyl)nicotinonitrile
To a solution of 1-[4-(methyls u l f o n y l ) p h e n y 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. 165o C, Anal. Calcd. for C20 H15 ClN 2 O 3 S; Requires:
C,60.22; H, 3.79; N, 7.02; Found: C, 60.20 ; H, 3.78; N, 7.01 %.
Similarly, other 2-methoxy-6-[4-(methylsulfonyl)phenyl]-4arylnicotinonitriles were prepared. The physical data are recorded in Table No.4
(C)
Biological screening of 2-Methoxy-6-[4-( m e t h y l s u l f o n y l ) p h e n y l ] - 4 arylnicotinonitriles
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...
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
4c
4d
4e
4f
4g
4h
4i
4j
4k
C20H16N 2O4 S
C22H21N 3O3 S
C26H20N 2O4 S
C20 H15 Br N2 O3 S
C20H15FN 2O3 S
C22H20N 2O5 S
C21H18N 2O4 S
C20 H15 ClN 2O3 S
C20 H15 ClN 2O3 S
C20 H15 ClN 2O3 S
C20H16N 2O3 S
3
Formula
Molecular
380
407
456
443
382
424
394
398
398
398
364
4
Weight
145
170
178
192
140
163
118
115
142
132
165
125
5
oC
Molecular M.P.
2-C4 H3OC18H14N 2O4 S
354
S1 Hexane:Ethyl acetate(5:5), S2 Hexane:Ethyl acetate(6:4)
4-Cl-C 6H4 -
4b
4l
C6 H5 -
2
R
4a
1
No
Sr.
NITRILES
65
56
45
59
68
62
58
62
58
53
48
54
6
%
Yield
7.90
7.36
10.31
6.14
6.32
7.33
6.60
7.10
7.02
7.02
7.02
7.69
7
Calcd.
7.92
7.35
10.32
6.15
6.35
7.34
6.62
7.12
7.04
7.03
7.01
7.68
8
Found
% of Nitrogen
0.49
0.51
0.59
0.42
0.51
0.52
0.56
0.42
0.45
0.41
0.56
0.51
9
Value
Rf
S1
S2
S2
S1
S2
S2
S2
S1
S1
S2
S2
S1
10
System
Solvent
TABLE : 4 PHYSICAL CONSTANTS OF 2-METHOXY-6-[4-(METHYLSULFONYL)PHENYL]-4-ARYL NICOTINO
Studies on chemical entities...
75
Cyanopyridines...
GRAPHICAL CHART NO. 4 : 2-METHOXY-6-[4-(METHYLSULFONYL)PHENYL]-4-ARYLNICOTINONITRILES
Studies on chemical entities...
76
Cyanopyridines...
77
Studies on chemical entities...
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29.
Mama Fedele, C. Franco, B. Adriana, B. Bruna, F. Walter, F. Amelia;
Eur. J. Med. Chem., 34(3), 245-254 (1999); Chem. Abstr., 131, 352178s (1999).
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
Studies on chemical entities...
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).
37.
Saudi Manal N. S., El. Sayad M. H., El-Hoda M. A.;
Alexandria J. Pharm. Sci., 16(2), 75-82 (2002); Chem. Abstr., 138, 385269 (2003).
38.
Harada Hironori, Takuwa Tomofumi, Okazaki Toshio, Hirano Yusuke;
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).
43.
Gary T. Wang, Xilu Wang, Weibo Wang, Lisa A. Hasvold, Gerry Sullivan, Charles W.;
Bioorganic & Medicinal Chemistry lett. 15(1), 153-158, (2005).
44.
V. M. Parikh;
“Absorption spectroscopy of organic molecules”, Addition-Wesley Pub. Co. London 243,
258 (1978). A. Hand book of spectroscopic data by B. D. Mishtry; 1st ed. ABD Press
Jaipur 11-36 (2000).
45.
A. R. Kartizky and R. Alans Jones;
J. Chem. Soc., 2942 (1960). Introduction of Infra fed and Raman spectroscopy by Norman
B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy. Academic Press (1975).
Cyanopyridines...
80
Studies on chemical entities...
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.
O
N
H
(I)
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).
CH3
O
N
H 3C
CH3
NH 2
CH3
N
N
H
O
O
OH
(III)
(II)
N
H
O
(IV)
SYNTHETIC ASPECT :
1.
1
G. Simchen and G. Entemman have synthesised 2-pyridone in which the ring
nitrogen comes from a nitrile group in acyclic precursor.
2.
2
K. Folkers and S. A. Harris have synthesised 3-cyano-2-pyridone by
the condensation of cyano acetamide with 1,3-diketone or 3-ketoester.
3.
3
M. A. Sluyter and co-workers have prepared fused 2-pyridones.
Pyridones...
81
Studies on chemical entities...
CH 2 OC2 H5
H 5C 2OH 2 C
O
N
+
H3 C
O
H3 C
N
H
O
N
O
H2 N
THERAPEUTIC IMPORTANCE
Pyridone derivatives have been found to possess variety of therapeutic activities
as shown below.
4
1.
Anticancer
2.
Herbicidal
3.
Pesticidal
4.
Antimicrobial
5.
Angitensin II antagonist
6.
Antiviral
7.
AntiHIV
5
6,7
8
9-11
12
13
Collins et al.
Pednekar
15
14
have prepared heteroaryl pyridones as GABA α,β ligands (V).
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.
CH 3
O
CH3
X NC
CH3
Ph
N
H
O
NC
NC
HN
N
Z
O
(V)
N
N
H
O
N
R
(VI)
Y
N
CH3
O
O
Ph
(VIII)
(VII)
Moreover, several co-workers have prepared 2-pyridones as S3 site of
16
thrombin inhibitor , herbicidal
receptor
20
17
18
19
, SH2 domain inhibitor , antimicrobial , GABA-A
21
and antiinflammatory .
Pyridones...
82
Studies on chemical entities...
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.
O
CH3
Pr
NH
NH
O
N
O
Bu
Pr
(IX)
Moreover, several co-workers have prereported 2-pyridones as S3 site of
23
24
thrombin inhibitors , herbicidal , SH2 domain inhibitor
Peter et al.
27
25
26
and GABA-A receptor .
have prepared pyridinyl methyl substituted pyridines and pyridones as
28
angiotensin II antagonists. H. Posnes reported 2-pyridones as physiologically active
compounds. Devdas Balekudru et al.
29
prepared substituted pyridinones (X) as
modulators of P38 NAP kinase.
O
Br
N
O
Et
(X)
Furthermore, Stenzel Wolfgang et al.
30
reported some pyridone derivatives
(XI) as cardiotonic, hypnotics, antiasthematics and antithrombotic. Fischer Reiner
31
et al. prepared (thiazolyl) dihydro-1H-pyridinones (XII) as pesticides and herbicides.
Pyridones...
83
Studies on chemical entities...
OH
R1
X
O
NH
S
O
Y
O
N
R2
Q1
NC
OG
Q2
N
(XI)
N
W
A
B
(XII)
Peter and co-workers
32
have prepared pyridinylmethyl substituted pyridines
33,34
and pyridones as angitensin II antagonist. Mukhtar Hussain Khan and co-workers
have prepared 2-pyridone derivatives (XIII) and (XIV) which possess insecticidal
and pesticidal activity.
R
N
H
N
R
O
O
N
S
S
H
N
CN
HN
R
O
R
CN
(XIII)
(XIV)
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( 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 RY L 1,2-DIHYDROPYRIDINE-3-CARBONITRILES
Pyridones...
84
Studies on chemical entities...
SECTION - I
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
6-[4-
(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE3-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) carried out by cyclocondensation of chalcones of type(I) with
ethylcyanoacetate in presence of ammonium acetate as under.
O
O
H3C
O
R
S
R CN-CH2-COOC 2H5
O
CH3COONH4
Type(I)
R=Aryl
H 3C
S
O
HN
O
N
Type(V)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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 H37 R v a t 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.
Pyridones...
85
Studies on chemical entities...
IR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-2OXO-4-(p-CHLOROPHENYL)-1,2-DIHYDROPYRIDINE-3CARBONITRILE
Cl
100.0
%T
90.0
O
H3 C
80.0
S
N
H
O
1921.0
N
894.9
O
70.0
2218.0
60.0
2856.4
50.0
2918.1
1739.7
1529.4
40.0
30.0
715.5 561.2
1363.6
977.8
1186.1
1336.6
1031.8
1436.9
1402.2 1224.7
1010.6
3249.8
1652.9
1589.2
1490.9
3406.1
495.7
813.9
1091.6
1635.5
20.0
3250.0
2000.0
1750.0
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Halide
Sulfonyl
Amide
Amine
Nitrtile
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-Cl str.
SO2 str.
C=O str.
N-H str.
C=N str.
Frequency in cm-1
Observed
Reported
2918
2856
1439
1363
3043
1490
1091
1031
813
1186
1739
3249
2218
2975-2950
2880-2860
1470-1435
1390-1370
3090-3030
1540-1480
1125-1090
1070-1000
800-600
1185-1165
1740-1690
3180-3140
2240-2120
Ref.
35
,,
,,
,,
36
,,
,,
,,
35
,,
,,
,,
,,
Pyridones...
86
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-2O 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
CH3
O
S
O
a'
a
b'
b
f
HN
e
c
d
O
c'
N
d'
Cl
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.4
3H
singlet
Ar-SO 2 CH3
-
2
6.6
1H
singlet
Ar-He
-
3
6.69
1H
singlet
Ar-NH
-
4
7.32-7.39
2H
doublet
Ar-H b,b
Jbc=8.1
5
7.41-7.44
2H
doublet
Ar-H c,c
Jcd=8.4
6
7.54-7.57
2H
doublet
Ar-H a,a
Jab=8.4
7
7.66-7.69
2H
doublet
Ar-H d,d
Jdc=8.7
Pyridones...
1,2-DIHYDROPYRIDINE-3-CARBONITRILE
m/z = 384
TABLE-5 : MASS SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-2-OXO-4-(P-CHLOROPHENYL)-
Studies on chemical entities...
87
Pyridones...
88
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
6-[4-
(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE3-CARBONITRILES
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e 1-ones
See Part-I, Section-I (B).
(B)
Synthesis of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-4-(p-chlorophenyl)1,2dihydropyridine-3-carbonitrile
To a solution of 1-[4-(methyls u l f o n y l ) p h e n y l ] - 3 -(p-chlorophenyl) - 2 -
p r o p e n e - 1 - o n e (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
crystallized from ethanol. Yield 52%, m.p. 185o C, Anal. Calcd. for
C 19 H13 ClN 2 O 3 S; Requires: C, 69.30; H, 3.40; N, 7.28; Found: C, 69.28; H, 3.49
N, 7.25 %.
Similarly, other 6-[4-(methylsulfonyl)phenyl]-2-oxo-4-aryl1,2dihydropyridine-3-carbonitriles were prepared. The physical data are recorded
in Table No.5
(C)
Biological screening of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-4-aryl1,2dihydropyridine-3-carbonitriles
Antimicrobial testing were carried out as described in Part-I Section-I(C).
The zones of inhibition of test solution are recorded in Graphical Chart No 5.
Pyridones...
4-Cl-C 6H4 -
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
2-C4 H3O-
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
S1 Hexane:Ethyl acetate(5:5),
3
C19H14N 2O3 S
2
C6 H5 -
1
5a
340
366
393
442
429
368
410
380
384
384
384
4
350
Weight
138
162
178
194
140
160
118
136
154
132
185
5
134
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C17H12N 2O4 S
C19H14N 2O4 S
C21H19N 3O3 S
C25H18N 2O4 S
C19 H13 Br N2 O3 S
C19H13FN 2O3 S
C21H18N 2O5 S
C20H16N 2O4 S
C19 H13 ClN 2O3 S
C19 H13 ClN 2O3 S
C19 H13 ClN 2O3 S
Formula
PYRIDINE-3-CARBONITRILES
R
Molecular
No
Sr.
68
55
61
72
68
64
50
59
53
42
52
6
65
%
Yield
8.23
7.65
10.68
6.33
6.53
7.60
6.83
7.36
7.28
7.28
7.28
7
7.99
Calcd.
8.24
7.66
10.67
6.34
6.54
7.61
6.84
7.35
7.24
7.25
7.25
8
7.98
Found
% of Nitrogen
0.51
0.45
0.44
0.57
0.59
0.59
0.56
0.42
0.45
0.48
0.55
9
0.45
Value
Rf
S2
S1
S1
S2
S1
S2
S2
S1
S2
S1
S1
10
S2
System
Solvent
TABLE : 5 PHYSICAL CONSTANTS OF 6-[4-(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2-DIHYDRO
Studies on chemical entities...
89
Pyridones...
90
Studies on chemical entities...
ANTITUBERCULAR ACTIVITY OF 6-[4-(METHYLSULFONYL)PHENYL]2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-3-CARBONITRILES
O
R
H3C
S
O
HN
O
N
TAACF, Southern Research Insitute
TABLE NO-5
Primary Assay Summary Report
Sr Sample
No.
ID
Corp
ID
R
Assay
Mtb
Strain
MIC
%
µg/ml Inhibi.
5a
182252
PD-49 C 6 H5 -
Alamar
H37 R v
>6.25
00
5b
182253
PD-50 4-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
5c
182254
PD-51 2-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
5d
182255
PD-52 3-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
5e
182256
PD-53 4-OCH3 - C 6 H4 -
Alamar
H37 R v
>6.25
55
5f
182257
PD-54 3,4-(OCH3 ) 2 -C 6 H3 - Alamar
H37 R v
>6.25
18
5g
182258
PD-55 4-F-C 6 H4 -
Alamar
H37 R v
>6.25
42
5h
182259
PD-56 4-Br-C6 H4 -
Alamar
H37 R v
>6.25
00
5i
182260
PD-57 3-C 6 H5 O-C 6 H4 -
Alamar
H37 R v
>6.25
11
5j
182261
PD-58 4-N(CH3 ) 2 -C 6 H4 -
Alamar
H37 R v
>6.25
00
5k
182262
PD-59 2-OH-C6 H4 -
Alamar
H37 R v
>6.25
00
5l
182263
PD-60 2-C 4 H3 O -
Alamar
H37 R v
>6.25
10
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
Pyridones...
CARBONITRILES
GRAPHICAL CHART NO. 5 : 6-[4-(METHYL SULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-3-
Studies on chemical entities...
91
Pyridones...
92
Studies on chemical entities...
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1.
G. Simchen and G. Entenmann;
Angew. Chem. Int. Edn Engl, 12, 119 (1973).
2.
K Folkers, S. A. Harris;
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3.
M. A. Sluyter, U. K Pandit, W. N. Speckamp and H. O. Huisman;
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4.
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K. Jonhannes, F. Rainer, J. R. Jansen and S. Nichael;
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8.
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10.
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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;
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I. J. Collins, L. P. David and M. C. Richard;
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15.
Pedneker;
PCT Int. Appl. WO 98 30, 342 (1998); Chem. Abstr., 130 , 487191 (1999).
16.
J. E. Reiner, Lim-Wilby,
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Pyridones...
93
Studies on chemical entities...
(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;
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20.
H. Timothy, M. Christopher, R. laewis, R. Thomas;
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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;
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170353h (1999).
23
Reiner John E., Lim Wilby, Margeu Rita S., Bruncj Terence K. and Ha-Vong Theresa;
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24.
Yamagudi Mikio, Ito Voshiniro, Shibaytama Atsushi, Yomaji, Mitsuhiro and Hanai Rgo;
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25.
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26.
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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
Studies on chemical entities...
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;
“ Absorption spectroscopy of organic molecules ”, Addition-Wesley Pub. Co. London 243,
258 (1978). A. Hand book of spectroscopic data by B. D. Mishtry; 1st ed. ABD Press
Jaipur 11-36 (2000).
36.
A. R. Kartizky and R. Alans Jones;
J. Chem. Soc., 2942 (1960). Introduction of Infra fed and Raman spectroscopy by Norman
B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy. Academic Press (1975).
Pyridones...
95
Studies on chemical entities...
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.
O
4H-pyran
O
2H-pyran
(I)
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 literature
1.
1-10
.
Reaction between (A) and CH2 (CN) 2 led to corresponding 2-amino-311
cyano-4H-pyrans (B) .
N
O
R1
O
CH2(CN)2
N
O
R
R
(A)
O
N
H2 N
(II)
R1
O
(B)
O
Cyanopyrans...
96
Studies on chemical entities...
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.
N
N
R
O
N
N
O
OH
CH 2(CN) 2
R1
R1
R
R1
NH
NH 2
N
N
O
R
R1
R1
O
R
R1
THERAPEUTIC IMPORTANCE
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 agent
12
2. Cytotoxic 13
3. Inhibitors of cell proliferation 14
4. Gastric acid secretion inhibitor
15
16
5. Antimicrobial
6. Hypolipidemic
7. Antipyretic
17
18
8. Antiinvasive
19
20,21
9. Anti HIV
10. Antifungal
22-24
11. Antiallergic
25
Cyanopyrans...
97
Studies on chemical entities...
12. Analgesic
26
13. Antagonist
14. Antitumor
27,28
29
El-Subbagh and co-workers
30
have synthesized cyanopyran derivatives and
showed their antiviral activity. Corbou Romuld et al.
31
have reported cyanopyran
derivatives (III) which have significant pharmacological activity.
CH3
H
N
O
N
CH3
O
O
NH2
(III)
N
Some of the pyran derivatives(IV) have been patented for their use as
32
33
antihypertensive , antiestogens , antagonist
34,35
, antitumor
36
37
and antiviral activities.
Synthesis and biological activity of pyran ring system have been reported by O’Brien
et al.
38
N
N
N
O
NH2
(IV)
Sharanin Y. U. A. et al.
39
have suggested new 2-amino-3-cyano-4H-pyran
derivatives (V).
Cyanopyrans...
98
Studies on chemical entities...
H3C
O
NH2
O
N
O
R
(V)
40
Zwaagstra Mariel
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.
F
NH2
O
NH2
O
X
HOOC
N
H3C
N
N
N
S
(VI)
(VII)
Cl
43
Moreover, Fathy F. Abdel-Latif et al. have reported the synthesis of 2-amino3-cyanopyran derivatives and studied their biological activity. Piao Minz, Zhu et.
al.
44
have prepared biologically active 2-amino pyran derivatives.
45
Recently, Hanafusa T, et al have reported some new cyanopyran as functional
promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor
46
specific methylation. Williamson H. S. et al
have described pyran as a truncated
Cyanopyrans...
99
Studies on chemical entities...
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.
49
Morever, Asche C. et al. 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
52
of hepatitis C virus RNA-dependent RNA polymerase. Kim KY et al. Anti-apoptotic
action of (2S,3S,4R)-N”-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2dimethoxymethyl-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-AMINO6 - [ 4 -(METHYLSULFONYL)PHENYL]-4-ARYL-4H-PYRAN-3CARBONITRILES
Cyanopyrans...
100
Studies on chemical entities...
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-(methyls u l f o n y l ) p h e n y l ] - 3 - a r y l - 2 p r o p e n e - 1 - o n e s of type-(I) with malononitrile in pyridine.
O
O
O
R
H3C
S
R
CH2(CN)2
in pyridine
O
H 3C
S
O
O
NH 2
Type(I)
R=Aryl
N
Type(VI)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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 H37 R v a t 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.
Cyanopyrans...
101
Studies on chemical entities...
IR SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)
PHENYL]-4-(p-CHLOROPHENYL)-4H-PYRAN-3-CARBONITRILE
100.0
%T
90.0
966.3
80.0
777.3
2046.3
2372.3
70.0
60.0
2837.1
2922.0
3004.9 2150.5
1028.0
1305.7
1095.5
1346.2
1407.9
1180.4
1436.9
1583.4 1461.9 1247.9 O
1606.61494.7
50.0
40.0
30.0
3352.1
2185.2
2204.5
H3C
1566.1
20.0
3250.0
2000.0
1750.0
1514.0
530.4
561.2
821.6
Cl
S
O
O
N
NH 2
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Vibration
Mode
Frequency in cm-1
Observed
Ref.
Reported
Alkane
C-H str. (asym.)
2922
2975-2950
53
-CH 3
C-H str. (sym.)
2837
2880-2860
,,
C-H def. (asym.)
1461
1470-1435
,,
C-H def. (sym.)
1346
1390-1370
,,
C-H str.
3004
3090-3030
54
C=C str.
1514
1540-1480
,,
1095
1125-1090
,,
1028
1070-1000
,,
Aromatic
Halide
C-Cl str.
821
800-600
53
Sulfonyl
1180
1185-1165
,,
Pyran
SO2 str.
C=C str.
1566
1650-1520
54
Nitrile
C=N str.
2204
2240-2120
53
Amine
N-H str.
3352
3380-3350
,,
Cyanopyrans...
102
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)
PHENYL]-4-(p-CHLOROPHENYL)-4H-PYRAN-3-CARBONITRILE
Cl
d
c
O
H3 C
a
b
a'
b'
e
d'
c'
f
S
O
O
N
NH 2
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.5
3H
singlet
Ar-SO 2 CH3
-
2
5.39
1H
singlet
Ar-He
-
3
7.33-7.36
2H
doublet
Ar-Hb,b’
Jba=8.4
4
7.46-7.49
2H
doublet
Ar-H c,c’
Jcd=8.1
5
7.49
2H
singlet
Ar-NH2
6
7.55-7.56
2H
doublet
Ar-H a,a’
Jab=8.7
7
7.56-7.62
2H
doublet
Ar-H d,d’
Jdc=8.3
-
Cyanopyrans...
PHENYL)-4H-PYRAN-3-CARBONITRILE
m/z = 382
TABLE-6 : MASS SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)PHENYL]-4-(P-METHOXY
Studies on chemical entities...
103
Cyanopyrans...
104
Studies on chemical entities...
EXPERIMENTAL
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e 1-ones
See Part-I, Section-I (B).
B)
Synthesis of 2-Amino-6-[4-(methylsulfonyl)phenyl]-4-(p-chlorophenyl)4H-pyran-3-carbonitrile
To a solution of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -(p-chlorophenyl) - 2 -
p r o p e n e - 1 - o n e. (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 crystallized from ethanol. Yield 58%, m.p.143o C A n a l . C a l c d . f o r
C 19 H15 ClN 2 O 3 S; 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-3carbonitriles were prepared. The physical data are recorded in Table No.6
(C)
Biological screening of 2-Amino-6-[4-(methylsulfonyl)phenyl]-4-aryl4H-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...
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
6d
6e
6f
6g
6h
6i
6j
S1 Hexane:Ethyl acetate(5:5),
2-C4 H3O-
2-Cl-C 6H4 -
6c
6l
4-Cl-C 6H4 -
6b
2-OH-C6 H4 -
C6 H5 -
6a
6k
2
342
368
395
444
431
370
412
382
386
386
386
352
4
Weight
139
142
178
194
140
160
118
170
155
168
143
165
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C17H14N 2O4 S
C19H16N 2O4 S
C21H21N 3O3 S
C25H20N 2O4 S
C19 H15 Br N2 O3 S
C19H15FN 2O3 S
C21H20N 2O5 S
C20H18N 2O4 S
C19 H15 ClN 2O3 S
C19 H15 ClN 2O3 S
C19 H15 ClN 2O3 S
C19H16N 2O3 S
3
Formula
CARBONITRILES
R
Molecular
1
No
Sr.
6
65
57
60
51
69
64
54
56
46
62
58
68
%
Yield
8.18
7.60
10.36
6.30
6.50
7.56
6.79
7.33
7.24
7.24
7.24
7.95
7
Calcd.
8.19
7.62
10.37
6.32
6.52
7.57
6.80
7.34
7.22
7.25
7.23
7.92
8
Found
% of Nitrogen
0.55
0.54
0.46
0.55
0.49
0.49
0.46
0.53
0.55
0.50
0.44
0.56
9
Value
Rf
S2
S1
S1
S2
S1
S2
S2
S1
S2
S1
S1
S2
10
System
Solvent
TABLE : 6 PHYSICAL CONSTANTS OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)PHENYL]-4-ARYL-4H-PYRAN-3-
Studies on chemical entities...
105
Cyanopyrans...
106
Studies on chemical entities...
ANTITUBERCULAR ACTIVITY OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)
PHENYL]-4-ARYL-4H-PYRAN-3-CARBONITRILES
O
R
H3C
S
O
O
NH2
N
TAACF, Southern Research Insitute
TABLE NO-6
Primary Assay Summary Report
Sr Sample
No.
ID
Corp
ID
R
Assay
Mtb
Strain
%
MIC
µg/ml Inhibi.
6a
182240
PD-37
C 6 H5 -
Alamar
H37 R v
>6.25
00
6b
182241
PD-38
4-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
6c
182242
PD-39
2-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
6d
182243
PD-40
3-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
6e
182244
PD-41
4-OCH3 - C 6 H4 -
Alamar
H37 R v
>6.25
55
6f
182245
PD-42
3,4-(OCH3 ) 2 -C 6 H3 -
Alamar
H37 R v
>6.25
18
6g
182246
PD-43
4-F-C 6 H4 -
Alamar
H37 R v
>6.25
42
6h
182247
PD-44
4-Br-C6 H4 -
Alamar
H37 R v
>6.25
00
6i
182248
PD-45
3-C 6 H5 O-C 6 H4 -
Alamar
H37 R v
>6.25
11
6j
182249
PD-46
4-N(CH3 ) 2 -C 6 H4 -
Alamar
H37 R v
>6.25
00
6k
182250
PD-47
2-OH-C6 H4 -
Alamar
H37 R v
>6.25
00
6l
182251
PD-48
2-C 4 H3 O -
Alamar
H37 R v
>6.25
10
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
Cyanopyrans...
CARBONITRILES
GRAPHICAL CHART NO. 6 : 2 - A M I N O - 6 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 4 - A RY L - 4 H - P Y R A N - 3 -
Studies on chemical entities...
107
Cyanopyrans...
108
Studies on chemical entities...
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Cyanopyrans...
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Studies on chemical entities...
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34.
F. Katsumi, M. Isamu, T. Natsuku, I. Y. Iijima;
Cyanopyrans...
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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.;
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Antimicrob Agents Chemother. 48(12), 4813-21(2004).
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;
“ Absorption spectroscopy of organic molecules ”, Addition-Wesley Pub. Co. London 243,
258 (1978). A. Hand book of spectroscopic data by B. D. Mishtry; 1st ed. ABD Press
Jaipur 11-36 (2000).
54.
A. R. Kartizky and R. Alans Jones;
J. Chem. Soc., 2942 (1960). Introduction of Infra fed and Raman spectroscopy by Norman
B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy. Academic Press (1975).
Cyanopyrans...
112
Studies on chemical entities...
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.
N
N
(I)
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 YCH2 Z, where Y and Z = COR,
CO 2 R, 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.
O
H2N
+
H2N
H5C2 O
O
CH2
NaOC2H5
OH
HN
N
C
NH
O
CH3
H2N
N
CH3
H2N
N
CH3
Pyrimidines...
113
Studies on chemical entities...
Pyrimidines can also be prepared by cycloaddition reaction of 1,3,5triazines,which act as electron deficient dienes.
H3C
N
N
H3C
C
N
N (C2 H5 )2
(H5 C2)2 N
N
N
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.
HCONH 2
PhNMeCH=CH-CHO
HCONHCH=CH-CHO
HCONH 2
N
200'C
N
Some other examples of pyrimidine synthesis are as under.
N
3 H3C
C
N
NH
KOMe
CHO
+
N
140C
H3C
(PhCO)2CH2
NH2
N
CH3
H3 C
Ph
NH4 OAc
N
CH3
Ph
N
N
Me2 SO, 80C
Ph
N
Ph
Ph
N
Ph
REACTION MECHANISM
The reaction mechanism for the formation of pyrimidine derivatives described
as under.
Pyrimidines...
114
Studies on chemical entities...
R
CH
C
R1
CH
+
H2N
NH2 Alkali
O
R1
C
O
H2N
R2
NH
R2
HO
R
R
R1
C
R1
R
R1
-
C
R
HO
C
+
HN
NH
N
R2
N
-H_
-H
N
R2
N
R2
R2 = SH, NH 2
THERAPEUTIC IMPORTANCE
It is revealed from the literature survey that pyrimidine derivatives have been
found possessing biological activities reported as under.
1. Fungicidal
1
2. Insecticidal
2
3. Anticonvulsant
4. Antitubercular
5. Tranquilizing
6. Antidiabetic
3
4
5
6
7. Antihypertensive
8. Analgesic
8
9. Antibacterial
10. Diuretic
7
9
10
11
S. S. Sangapure and S. M. Mulagi have tested the antimicrobial activity of
benzofuro[3,2-d]pyrimidine derivatives (II). El Sayed
12
and A. M. Badaway have
synthesized alkylated substituted mercapto pyrimidine derivatives (III) and studied
Pyrimidines...
115
Studies on chemical entities...
13
their anticancer and antineoplastic activity. H. Y. Moustafa
have reported some
pyrimidine derivatives and studied their biological activities.
H
N
S
Cl
N
N
O
H3 CS
(II)
N
NH2
CH3
(III)
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 Nsubstituted 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.
CH3
O
NH2
O
R
OH
NH
N
HN
N
H
O
N
H
(IV)
N
O
O
O
(VI)
(V)
N3
O
Cl
N
NH2
N
H2N
CH3
N
NH2
O
O
H5 C2
N
(VII)
NH2
CH3
H3C
(VIII)
Pyrimidines...
116
Studies on chemical entities...
NH2
NH2
H3 C
+
+
N
+
N
NH2
(IX)
14
N
S
N
Patil L. R. et al.
N
O HOH2CH2 C
N
(X)
CH3
H
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-workers
16
shows herpes inhibiting activity of some
mercapto pyrimidine derivatives.
R2
R1
R 3 R3
NH
N
R1
R5
N
R4
R2
CH3
N
NH2
(XI)
(XII)
Moreover, Chaudhari Bipinchandra et al.
17
N
SH
prepared N6-(2-aminopyrimidin-
4-yl)-quinoline-4,6-diamine (XII) as N-type calcium channel antagonists for the
18
treatment of pain. Devi E. Sree and co-workers
have prepared pyrimidine
derivatives and tested for antimicrobial activity. Kovalenko A. L.
19
synthesized and
20
reported antifungal activity of pyrimidine derivatives. Shiv P. Singh and co-workers
synthesized 4-(4-pyrazolyl)-2-aminopyrimidines(H) and tested them for their
antimicrobial activity.
21
Some pyrazolo thienopyrimidine derivatives exhibit antiulcer activity .
Skolova A. S. and co-workers
22
have synthesized 5-amino-6-mercapto pyrimidine
possessing antitumor and cytostatic activity. Hozein Zeinab et al.
23
and Khalafallah
Pyrimidines...
117
Studies on chemical entities...
24
Ali Kamel have prepared mercapto derivatives and screened for their antibacterial
and antifungal activity.
25
H. S. Joshi et al. have sythesized some new pyrimidines as antitubercular
and
atimicrobial activity(XIII).
R
N
SH
NH
Br
(XIII)
Marie Gompel and co-worker
26
have showed that meridianins inhibit various
protein kinases such as cyclin-dependent kinases, glycogen synthase kinase-3, cyclic
27
nucleotide-dependent kinases and casein kinase (XIV). Alistair H et al 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).
N
H2 N
NH
R
N
N
N
R
R
N
H
R
R
Meridianin A
Meridianin B
Meridianin C
Meridianin D
Meridianin E
Meridianin F
Meridianin G
H
H
Br
H
H
Br
H
H
Br
H
Br
H
Br
H
H
H
H
H
Br
H
H
O
28
S
O
N
(XV)
(XIV)
Aleem Gangjee et al.
OH
OH
H
H
OH
H
H
N
H
have designed and synthesized some novel analogues
of N -{4-[2-(2-Amino-4-ethylpyrrolo[2,3-d ]pyrimidin-5-yl)ethyl]benzoyl}-Lglutamic acid as potential inhibitors of thymidylate synthase (TS), dihydrofolate
Pyrimidines...
118
Studies on chemical entities...
29
reductase (DHFR) and as antitumor agents (XVI). Antonello Mai et al.
described
have
2-alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-
alkylpyrimidin-4(3H)-ones (F 2-NH-DABOs) 4, 5 belonging to the dihydro-alkoxybenzyl-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).
O
R
O
COOH
HN
CH3
N
R1
NH
H2N
N
N
H
HN
N
X
COOH
F
F
(XVII)
R
R = R1 =H, Me ; X = alkyl,aryl,
arylalkyl
(XVI)
Viney Lather and co-worker
30
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).
O
R1
HN
X-S
N
R
(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
Pyrimidines...
119
Studies on chemical entities...
33
belonging to the DABO family. Yamamoto I. et al.
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 pyrimidine derivatives as anticancer actions 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)
Cl
F
F
HN
NH
O
F
(XIX)
Pyrimidines...
120
Studies on chemical entities...
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-(METHYLSULFONYL)PHENYL]-6A RY L P Y R I M I D I N - 2 ( 1 H ) - O N E S
SECTION-II :
SYNTHESIS AND BIOLOGICAL SCREENING OF 4-[4(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN2(1H)-THIONES
SECTION-III :
SYNTHESIS AND BIOLOGICAL SCREENING OF 4-[4(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN2-AMINES
Pyrimidines...
121
Studies on chemical entities...
SECTION - I
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
4-[4-
(METHYLS U L F O N Y L ) P H E N Y L ] - 6 - A RY L P Y R I M I D I N - 2 ( 1 H ) - O N E S
In the past years considerable evidence has been accumulated to demonstrate
the efficiency of pyrimidinones. 4-[4-(methylsulfonyl)phenyl]-6-arylpyrimidin2 ( 1 H ) - o n e of type (VII) have been prepared by the condensation of 1-[4(methyls u l f o n y l ) p h e n y l ] - 3 - a r y l - 2 - p r o p e n e - 1 - o n e s of type-(I) with urea in
presence of catalytic amount of conc. HCl as shown under.
O
O
O
H3C
O
R
H3C
S
C
R
H2N
O
Type(I)
S
NH2
R=Aryl
O
N
Type(VII)
NH
O
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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 H37 R v a t 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.
Pyrimidines...
122
Studies on chemical entities...
IR SPECTRAL STUDIES OF 4-[4-(METHYLSULFONYL)PHENYL]6- ( p-CHLOROPHENYL)P Y R I M I D I N - 2 ( 1 H ) - O N E
100.0
%T
80.0
2675.1
2738.7
60.0
995.2
1247.9
1029.9
1074.3
1157.2
1394.4
1182.3
1431.1
1492.8
1340.4
1460.0
O
1514.0
2856.4
40.0
20.0
918.1
947.0
2380.0
2920.0
3030.0
3242.1
3404.1
H 3C
0.0
3250.0
2000.0
1750.0
1500.0
474.5
518.8
596.0
773.4
810.0
698.2
S
Cl
NH
N
O
1620.1
657.7
O
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
Vibration
Mode
C-H str. (asym.)
-CH3
C-H str. (sym.)
2856
2880-2860
,,
C-H def. (asym.)
1460
1470-1435
,,
C-H def. (sym.)
1394
1390-1370
,,
C-H str.
3030
3090-3030
45
C=C str.
1514
1540-1480
,,
1089
1125-1090
,,
1029
1070-1000
,,
Aromatic
Frequency in cm-1
Observed
Reported
2920
2975-2950
Ref.
44
Halide
C-Cl str.
773
800-600
44
Sulfonyl
1182
1185-1165
,,
Vinyl
SO2 str.
CH=CH str.
3025
3050-3000
45
oxopyri.
C=O str.
1654
1672-1652
,,
Pyrimidines...
123
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 4-[4-(METHYLS U L F O N Y L ) P H E N Y L ] - 6 (p-CHLOROPHENYL)P Y R I M I D I N - 2 ( 1 H ) - O N E
Cl
d
c
O
H3 C
a
b
a'
b'
e
S
O
d'
c'
NH f
N
O
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.5
3H
singlet
Ar-SO 2 CH3
-
2
7.35
1H
singlet
Ar-Hf
-
3
7.46-7.51
2H
doublet
Ar-H b,b’
Jba=8.1
4
7.66-7.77
2H
doublet
Ar-H c,c’
Jcd=7.8
5
7.62
1H
singlet
Ar-He
6
7.88-7.91
2H
doublet
Ar-H a,a’
Jab=8.4
7
7.94-7.97
2H
doublet
Ar-H d,d’
Jdc=7.8
-
Pyrimidines...
PYRIMIDIN-2(1H)-ONE
m/z = 360
TABLE-7 : MASS SPECTRAL STUDIES OF 4-[4-(METHYLSULFONYL)PHENYL]-6- (P-CHLOROPHENYL)
Studies on chemical entities...
124
Pyrimidines...
125
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF
(A)
Synthesis of 1-[4-(Methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones
See Part-I, Section-I (B).
(B)
Synthesis of 4-[4-(Methyls u l f o n y l ) p h e n y l ] - 6 -(p-chlorophenyl)
pyrimidin-2(1H)-one
To a solution of 1-[4-(methyls u l f o n y l ) p h e n y l ] - 3 -(p-chlorophenyl) - 2 -
p r o p e n e - 1 - o n e. (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. 165o C Anal. Calcd.
for C 17 H13 ClN 2 O 3 S Requires: C, 56.99; H, 3.63; N, 7.76 % Found: C, 56.96; H,
3.62, N, 7.74 %.
Similarly, other 4-[4-(methyls u l f o n y l ) p h e n y l ] - 6 - a r y l p y r i m i d i n - 2 ( 1 H ) ones were prepared.The physical data are recorded in Table No. 7.
(C)
Biological screening of 4-[4-(Methyls u l f o n y l ) p h e n y l ] - 6 - a r y l
pyrimidin-2(1H)-ones
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition of test solution are reported in Graphical Chart No. 7.
Pyrimidines...
3,4-(OCH3)2- C6H3 - C19H18N 2O5 S
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
7f
7g
7h
7i
7j
S1 Hexane:Ethyl acetate(5:5),
2-C4 H3O-
4-OCH3 -C6 H4 -
7e
7l
3-Cl-C 6H4 -
7d
2-OH-C6 H4 -
2-Cl-C 6H4 -
7c
7k
4-Cl-C 6H4 -
7b
316
342
369
418
405
344
386
356
360
360
360
326
4
Weight
205
126
178
194
140
160
118
170
155
169
165
135
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C15H12N 2O4 S
C17H14N 2O4 S
C19H19N 3O3 S
C23H18N 2O4 S
C17 H13 Br N2 O3 S
C17H13FN 2O3 S
C18H16N 2O4 S
C17 H13 ClN 2O3 S
C17 H13 ClN 2O3 S
C17 H13 ClN 2O3 S
C17H14N 2O3 S
C6 H5 -
7a
3
Formula
Molecular
2
R
1
No
Sr.
62
57
51
62
48
62
51
56
58
52
48
61
6
%
Yield
8.86
8.18
11.37
6.69
6.91
8.13
7.25
7.86
7.76
7.76
7.76
8.58
7
Calcd.
8.87
8.19
11..34
6.70
6.90
8.14
7.26
7.87
7.75
7.74
7.74
8.53
8
Found
% of Nitrogen
0.58
0.54
0.48
0.46
0.54
0.48
0.56
0.53
0.43
0.54
0.49
0.56
9
Value
Rf
S1
S2
S2
S1
S1
S2
S1
S2
S2
S1
S1
S2
10
System
Solvent
TABLE : 7 PHYSICAL CONSTANTS OF 4-[4-(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-ONES
Studies on chemical entities...
126
Pyrimidines...
127
Studies on chemical entities...
ANTITUBERCULAR ACTIVITY OF 4-[4-(METHYLSULFONYL)PHENYL]
- 6 - A RY L P Y R I M I D I N - 2 ( 1 H ) - O N E S
O
R
H3C
S
O
N
NH
O
TAACF, Southern Research Insitute
TABLE NO-7
Primary Assay Summary Report
Sr Sample
No.
ID
Corp
ID
R
Assay
Mtb
Strain
%
MIC
Inhibi.
µg/ml
7a
182216
PD-13 C 6 H5 -
Alamar
H37 R v
>6.25
00
7b
182217
PD-14 4-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
7c
182218
PD-15 2-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
7d
182219
PD-16 3-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
7e
182220
PD-17 4-OCH3 - C 6 H4 -
Alamar
H37 R v
>6.25
55
7f
182221
PD-18 3,4-(OCH3 ) 2 -C 6 H3 - Alamar
H37 R v
>6.25
18
7g
182222
PD-19 4-F-C 6 H4 -
Alamar
H37 R v
>6.25
42
7h
182223
PD-20 4-Br-C6 H4 -
Alamar
H37 R v
>6.25
00
7i
182224
PD-21 3-C 6 H5 O-C 6 H4 -
Alamar
H37 R v
>6.25
11
7j
182225
PD-22 4-N(CH3 ) 2 -C 6 H4 -
Alamar
H37 R v
>6.25
00
7k
182226
PD-23 2-OH-C6 H4 -
Alamar
H37 R v
>6.25
00
7l
182227
PD-24 2-C 4 H3 O -
Alamar
H37 R v
>6.25
10
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
Pyrimidines...
GRAPHICAL CHART NO. 7 : 4-[4-(METHYLS U L F O N Y L ) P H E N Y L ] - 6 - A RY L P Y R I M I D I N - 2 ( 1 H ) - O N E S
Studies on chemical entities...
128
Pyrimidines...
129
Studies on chemical entities...
SECTION - II
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
4-[4-
(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 significantin 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
cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones of
type-(I) and thiourea in presence of HCl as catalyst.
O
H3C
S
O
S
R
R
C
H2N
H 3C
S
NH2
O
O
Type(I)
O
N
R=Aryl
NH
S
Type(VIII)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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 H37 R v a t 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.
Pyrimidines...
130
Studies on chemical entities...
IR SPECTRAL STUDIES OF 4 - [ 4 - (METHYLSULFONYL)PHENYL]-6AR YLPYRIMIDIN-2(1H)-THIONE
100.0
%T
90.0
80.0
70.0
60.0
1276.8
1546.8
1301.9
1382.9 1207.4
1406.0
1182.3 983.6
1224.7 1087.8
1564.2
1014.5
1490.9
1332.7
1031.8
2918.12339.5
2362.6
2854.5
3342.4
50.0
596.0
669.3
474.5
734.8
493.7
773.4
532.3
812.0
O
1604.7
40.0
H3 C
1658.7
S
NH
N
O
S
30.0
3250.0
2000.0
1750.0
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Vibration
Mode
Frequency in cm-1
Observed
Reported
Ref.
Alkane
C-H str. (asym.)
2918
2975-2950
44
-CH3
C-H str. (sym.)
2854
2880-2860
,,
C-H def. (asym.)
1490
1470-1435
,,
C-H def. (sym.)
1382
1390-1370
,,
C-H str.
3045
3090-3030
45
C=C str.
1546
1540-1480
,,
1087
1125-1090
,,
1031
1070-1000
,,
SO2 str.
N-H str.
1182
1185-1165
44
3342
3300-3150
45
C=C str.
1658
Aromatic
Sulfonyl
Amine
,,
Pyrimidines...
131
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 4 - [ 4 - (METHYLSULFONYL)PHENYL]-6AR YLPYRIMIDIN-2(1H)-THIONE
d
e
c
O
H3 C
a
b
a'
b'
f
g
h
S
O
NH i
N
S
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.5
3H
singlet
Ar-SO 2 CH3
-
2
7.26
1H
singlet
Ar-NH
-
3
7.26-7.32
2H
doublet
Ar-Hb,b’
Jba=8.4
4
7.52-7.61
5H
multiplet
Ar-H(c-g)
-
5
7.94-7.96
2H
doublet
Ar-Ha,a’
Jab=8.4
6
7.73
1H
singlet
Ar-He
-
Pyrimidines...
THIONE
m/z = 342
TABLE-8 : MASS SPECTRAL STUDIES OF 4-[4-(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-
Studies on chemical entities...
132
Pyrimidines...
133
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
4-[4-
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-THIONES
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e - o n e s
See Part-I, Section-I (B).
(B)
Synthesis of 4-[4-( Methylsulfonyl)phenyl]-6-(phenyl) pyrimidin-2(1H)thione
A mixture of 1-[4-(methylsulfonyl)phenyl]-3-phenyl- 2 - p r o p e n e - o n e (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. 182o C Anal. Calcd. for C 17 H14 N 2 O 2 S 2
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-arylpyrimidin2(1H)-thiones
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition of test solution are reported in Graphical Chart No. 8.
Pyrimidines...
3,4-(OCH3)2- C6H3 - C19 H18 N2O 4S 2
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
8f
8g
8h
8i
8j
S1 Hexane:Ethyl acetate(5:5),
2-C4 H3O-
4-OCH3 -C6 H4 -
8e
8l
3-Cl-C 6H4 -
8d
2-OH-C6 H4 -
2-Cl-C 6H4 -
8c
8k
4-Cl-C 6H4 -
8b
332
358
385
434
421
360
402
372
376
376
376
342
4
Weight
160
136
172
165
140
160
118
170
155
162
165
182
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C15 H12 N2O 3S 2
C17 H14 N2O 3S 2
C19 H19 N3O 2S 2
C23 H18 N2O 3S 2
C17 H13 Br N2O 2S 2
C17H13FN 2O2S 2
C18 H16 N2O 3S 2
C17 H13 ClN2O 2S 2
C17 H13 ClN2O 2S 2
C17 H13 ClN2O 2S 2
C17 H14 N2O 2S 2
C6 H5 -
8a
3
Formula
Molecular
2
THIONES
R
1
No
Sr.
58
54
66
58
67
59
51
46
54
58
51
62
6
%
Yield
8.43
7.82
10.90
6.45
6.65
7.77
6.96
7.52
7.43
7.43
7.43
8.18
7
Calcd.
7.44
7.81
10.91
5.44
6.64
7.78
6..97
7.51
7.45
7.42
7.44
8.19
8
Found
% of Nitrogen
0.61
0.54
0.49
0.47
0.51
0.48
0.54
0.56
0.48
0.54
0.42
0.62
9
Value
Rf
S2
S1
S2
S1
S1
S2
S1
S2
S1
S1
S1
S2
10
System
Solvent
TABLE : 8 PHYSICAL CONSTANTS OF 4 - [ 4 - (METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-
Studies on chemical entities...
134
Pyrimidines...
135
Studies on chemical entities...
ANTITUBERCULAR ACTIVITY OF 4-[4-(METHYLSULFONYL)PHENYL]6-ARYLPYRIMIDIN-2(1H)-THIONES
O
R
H3C
S
O
N
NH
S
TAACF, Southern Research Insitute
TABLE NO-8
Primary Assay Summary Report
Sr Sample
No.
ID
Corp
ID
R
Assay
Mtb
Strain
%
MIC
µg/ml Inhibi.
8a
182228 PD-25
C 6 H5 -
Alamar
H37 R v
>6.25
00
8b
182229 PD-26
4-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
8c
182230 PD-27
2-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
8d
182231 PD-28
3-Cl-C6 H4 -
Alamar
H37 R v
>6.25
00
8e
182232 PD-29
4-OCH3 - C 6 H4 -
Alamar
H37 R v
>6.25
55
8f
182233 PD-30
3,4-(OCH3 ) 2 -C 6 H3 - Alamar
H37 R v
>6.25
18
8g
182234 PD-31
4-F-C 6 H4 -
Alamar
H37 R v
>6.25
42
8h
182235 PD-32
4-Br-C6 H4 -
Alamar
H37 R v
>6.25
00
8i
182236 PD-33
3-C 6 H5 O-C 6 H4 -
Alamar
H37 R v
>6.25
11
8j
182237 PD-34
4-N(CH3 ) 2 -C 6 H4 -
Alamar
H37 R v
>6.25
00
8k
182238 PD-35
2-OH-C6 H4 -
Alamar
H37 R v
>6.25
00
8l
182239 PD-36
2-C 4 H3 O -
Alamar
H37 R v
>6.25
10
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
Pyrimidines...
GRAPHICAL CHART NO. 8 : 4-[4-(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-THIONES
Studies on chemical entities...
136
Pyrimidines...
137
Studies on chemical entities...
SECTION - III
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
4-[4-
(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.
O
S
O
R
O
H3 C
H3 C
C
H2 N
S
S
NH2 . H C l
O
R
N
N
O
NH2
Type(I)
R=Aryl
Type(IX)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analysis, infrared and 1 H 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.
Pyrimidines...
138
Studies on chemical entities...
IR SPECTRAL STUDIES OF 4 - [ 4 - ( METHYLSULFONYL)PHENYL]-6(p-CHLOROPHENYL)PYRIMIDIN-2-AMINE
Cl
100.0
%T
O
H3 C
90.0
S
N
N
O
NH2
964.3
80.0
1319.2
451.3
1218.9
2339.5
2360.7
2852.5
2920.0
70.0
60.0
2000.0
1750.0
1500.0
804.3
1089.7
1645.21527.5
3336.6
3250.0
491.8
1355.9
1571.9
1490.9
3211.3
50.0
1010.6
1436.9
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Halide
Sulfonyl
Pyrimidine
Primary Amine
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-Cl str.
SO2 str.
C=N str.
N-H str.
Frequency in cm-1
Observed
Reported
2920
2852
1436
1355
3085
1645
1089
1010
804
1175
1571
3336
2975-2950
2880-2860
1470-1435
1390-1370
3090-3030
1620-1430
1125-1090
1070-1000
800-600
1185-1165
1580-1520
3554-3350
Ref.
44
,,
,,
,,
45
,,
,,
,,
44
,,
45
,,
Pyrimidines...
139
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 4 - [ 4 - (METHYLSULFONYL)PHENYL]-6-(pCHLOROPHENYL)PYRIMIDIN-2-AMINE
Cl
d
c
O
H3 C
a
b
a'
b'
S
O
d'
c'
e
N
N
f
N H2
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.4
3H
singlet
Ar-SO 2 CH3
-
2
5.25
2H
singlet
Ar-NH2
-
3
7.30-7.34
2H
doublet
Ar-Hb,b’
4
7.37
1H
singlet
Ar-He
5
7.42-7.46
2H
doublet
Ar-Hc,c’
Jcd=9.6
6
7.96-7.97
2H
doublet
Ar-Ha,a’
Jab=8.4
7
7.97-8.01
2H
doublet
Ar-Hd,d’
Jdc=8.5
Jba=8.7
-
Pyrimidines...
PYRIMIDIN-2-AMINE
m/z = 417
TABLE-9 : MASS SPECTRAL STUDIES OF 4 - [ 4 - ( METHYLSULFONYL)PHENYL]-6-(M-PHENOXYPHENYL)
Studies on chemical entities...
140
Pyrimidines...
141
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
4-[4-
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e - o n e s
See Part-I, Section-I (B).
(B)
Synthesis of 4-[4-(Me t h y lsulfonyl)phenyl]-6-(p-chlorophenyl)pyrimidin2-amine
A mixture of 1-[4-(methylsulfonyl)phenyl]-3-(p-chlorophenyl) -2-propene-
1 - o n e. (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.
166 o C Anal. Calcd. for C17 H14 ClN 3 O 2 S 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-(Me t h y lsulfonyl)phenyl]-6-arylpyrimidin2-amines
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition of test solution are reported in Graphical Chart No. 9.
Pyrimidines...
C6 H5 -
4-Cl-C 6H4 -
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
2-C4 H3O-
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
S1 Hexane:Ethyl acetate(5:5),
2
R
1
No
Sr.
315
341
368
417
404
343
385
355
359
359
359
325
4
Weight
161
194
164
182
140
137
149
186
134
162
166
124
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C15H13N 3O3 S
C17H15N 3O3 S
C19H20N 4O2 S
C23H19N 3O3 S
C17 H14 Br N3 O2 S
C17H14FN 3O2 S
C19H19N 3O4 S
C18H17N 3O3 S
C17 H14 ClN 3O2 S
C17 H14 ClN 3O2 S
C17 H14 ClN 3O2 S
C17H15N 3O2 S
3
Formula
Molecular
56
59
53
64
65
59
71
58
63
48
51
55
6
%
Yield
13.33
12.31
15.21
10.07
10.39
12.24
10.90
11.82
11.68
11.68
11.68
12.91
7
Calcd.
12.34
12.32
15.22
10.08
10.38
12.26
10.92
11.81
11.69
11.66
11.67
12.92
8
Found
% of Nitrogen
0.62
0.51
0.45
0.47
0.58
0.48
0.56
0.54
0.44
0.56
0.44
0.46
9
Value
Rf
S1
S2
S2
S1
S1
S2
S2
S2
S1
S2
S1
S1
10
System
Solvent
TABLE : 9 PHYSICAL CONSTANTS OF 4 - [ 4 - ( METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES
Studies on chemical entities...
142
Pyrimidines...
GRAPHICAL CHART NO. 9 : 4 - [ 4 - ( METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES
Studies on chemical entities...
143
Pyrimidines...
144
Studies on chemical entities...
REFERENCES
1.
M. M. Ghorob and S. G. Abdel-Hamid;
Indian J. Heterocycl. Chem ., 4, 103-06 (1994).
2.
Obatokio Fujii, Katsu Toshi, Narita Isami et al.;
Jpn. Kokai Tpkkyo Koho JP, 08,269,021 (1995); Chem Abstr. , 126 74864b (1997).
3.
Henrie Robert N., Peake Clinton J., Cullen Thomas G. et al.;
PCT Int Appl. WO 98,20,878, Appl. 96/08,17748 (1996); Chem Abstr. , 129, 16136s
(1998).
4.
A. S. Noranyan, Oranisyan A. Sr., Grigoryan G. O., Vartanyan S. et al.;
Chem Abstr. , 126 , 70176f (1997).
5.
Ranise Angelo, Bruno Olga, Schenone Silvia, Bondalalli Franceso et al.,
Farmaco 52(8-9) , 547-55 (1997); Chem. Abstr. , 128 , 238986n (1986).
6.
Mochida Pharmaceutical Co. Ltd. JP, 81, 127,383 (1981).
7.
J. B. Press and R. K. Russell;
U. S. Patemt 4,670,560 (1987); Chem Abstr. , 107 , 1156004v (1987).
8.
R. K. Russell, J. B. Press, R. A. Rampulla, J. J. Mc Nally et al.;
J. Med. Chem ., 31, 1786 (1988).
9.
Y. S. Sadanandan, N. M. Shetty and P. V. Diwan;
Chem Abstr., 117, 7885k (1990).
10.
A. K. Khalafallah, F. M. Abd-El Latif and M. A. Salim;
Asian J. Chem., 5, 988-94 (1993).
11.
S. S. Sangopure and A. M. Mulogi;
Indian J. Heterocyclic Chem ., 10, 27-30 (2000).
12.
El-Sayed and A. M. Badaway;
J. Heterocyclic Chem., 33, 229 (1996).7, 273-76 (1998).
13.
H. Y. Moustafa;
Indian J. Heterocyclic Chem ., 7, 273-76 (1998).
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Briel D.;
Pharmazie, 53(4) , 227-31 (1998); Chem. Abstr. , 129 , 4623k (1998).
15.
Patil, L. R.; Ingle, V. S.; Bondge S. P.; Bhingolikar, V. E.; Mane, R. A.;
Indian Journal of Chem., 2001, 40B , 131-134 (2001).
16.
B. J. Ghiya and Manoj Prabjavat;
Indian J. Heterocyclic Chem., 7, 311-12 (1992).
17.
Kaplina N. V., Griner A. N., Sherdor V. I., Fomina A. N. et al.;
Pyrimidines...
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Chem Abstr. , 123 , 228207s (1995).
18.
Chaudhari, Bipinchandra; Chapdelaine, Mare; Hostetler, Greg; Kemp, Lucius; Mc Cauley;
John PCT Int. Appl. WO 02 36,586 (Cl. CO7D401/12), 10 May 2002, SE Appl. 2000/
4,053, 6 Nov 2000; 56 pp. (Eng).
19.
Devi E. Sree; Prakash, E. Om; Rao, J. T.
Journal of the Institution of Chemists (India) 2002, 74(5) , 167-168 (Eng).
20.
Kovalenko A/ L., Krutika V. I., Zolotukhina M. M. and Alekseeva L. E.;
Zh. Obsch. Khim. , 62(6) , 1363-66 (1992);Chem Abstr. , 118, 101909r (1993).
21.
Shiv P. Singh and Hitesh Batra;
Indian J. Heterocyclic Chem ., 9, 73-74 (1999).
22.
Skolova A. S., Ershova Yu A., Ryabokon N. A., Chernov V. A. et al.,
U. S. S. R. SU 939,559 (Cl. CO7D403/14) (1993), Appl. 3, 216,173 (1980).
23.
Hozein Zeinab A., Abdel Wahab A. A., Hassan K. M. M. et al.;
Pharmazie, 52(10) , 753-58 (1997); Chem. Abstr. , 128 , 22879g (1998).
24.
Ali Kamel Khalafallah;
Asian J. Chem ., 8(4), 751-56 (1996); Chem. Abstr. , 126 , 59927f (1997).
25.
K. S. Nimavat, K. H. Popat, S. L vasoya and H. S. Joshi;
Indian J. Heterocycl. Chem., 12, 217(2003).
26
Marie Gompel, Maryse Leost, Elisa Bal De Kier Joffe, Lydia Puricelli,
Bioorganic and Medicinal Chemistry Letteres 14, 1703-1707 ( 2004)
27
Alistair H. Bingham , Richard J. Davenport, Lewis Gowers , Roland L.
Bioorg Med Chem Lett. 14(2) 409-12 (2004).
28
Aleem Gangjee, Jianming Yu, Roy L. Kisliuk, William H. Haile, Giulia Sobrero.
J. Med. Chem., 46, 591-600 (2003).
29
Antonello Mai , Marino Artico, Rino Ragno, Gianluca Sbardella,
Bioorganic and Medicinal Chemistry Letters 13, 2065-2077 (2005).
30
Viney Lather and A. K. Madan
Bioorganic and Medicinal Chemistry Letters 13, 1599-1604, (2005).
31
Gompel M., Leost M., De Kier Joffe E. B., Puricelli L.;
Bioorg Med Chem Lett.14(7) , 1703-7, (2004).
32
Mai A., Artico M., Ragno R., Sbardella G.;
Bioorg Med Chem.13(6) , 2065-2077 (2005).
33
Yamamoto I.;
Yakugaku Zasshi.125(1) 73-120 (2005).
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Studies on chemical entities...
34
Huang Y. L., Lin C. F., Lee Y. J., Li W. W., Chao T. C.;
Bioorg Med Chem . 11(1), 145-57 (2003).
35
Shimizu T., Kimura T., Funahashi T., Watanabe K., Ho I. K., Yamamoto I.;
Chem Pharm Bull (Tokyo). 53(3) , 313-8 (2005).
36
Sanmartin C., Echeverria M., Mendivil B., Cordeu L., Cubedo E., Garcia-Foncillas J.;
Bioorg Med Chem . 13(6) 2031-44 (2005).
37
Agarwal A., Kumar B., Mehrotra P. K., Chauhan P. M.;
Bioorg Med Chem. 13(6) 1893-9 (2005).
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Whittingham J. L., Leal I., Nguyen C., Kasinathan G., Bell E.;
Structure (Camb). 13(2) 329-38 (2005)
39
Han G. Z., Liu Z. J., Shimoi K., Zhu B. T.;
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40
Tack D. K., Palmieri F. M., Perez E. A.;
Oncology (Huntingt). 18(11), 1367-76 (2004).
41
Cano-Soldado P., Lorrayoz I. M., Molina-Arcas M., Casado F. J., Martinez-Picado J.;
Antivir Ther . 9(6) 993-1002 (2004).
42
Gompel M., Leost M., De Kier Joffe E. B., Puricelli L., Franco L. H., Palermo J.;
Bioorg Med Chem Lett.Apr 14(7) 1703-7 (2004).
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Junmei Wang, Xinshan Kang, Irwin D. Kuntz, and Peter A. Kollman.;
Journal of medicinal chemistry 27,(2004).
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V. M. Parikh;
“ Absorption spectroscopy of organic molecules ”, Addition-Wesley Pub. Co. London 243,
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A. R. Kartizky and R. Alans Jones;
J. Chem. Soc., 2942 (1960). Introduction of Infra fed and Raman spectroscopy by Norman
B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy. Academic Press (1975).
Pyrimidines...
147
Studies on chemical entities...
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.
O
(I)
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
8
1.
N. Nanjundaswami et al. have prepared 6,7-dimethoxy-1-aryl-4-oxo-2naphthoate derivatives (II) by the reaction of dimethoxyphenyl aryl ketone
with diethyl succinate in presence of t-potassium butoxide.
O
H2C
COOEt
O
H3C
H2C
R
O
CH3
O
COOEt
O
H3C
O
t-Buok
O
CH3
R
O
CH3
(II)
Indazoles...
148
Studies on chemical entities...
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 K2 CO3 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.
R
+
R
R1
CH
R1
CH C
O
O
[A]
C H COOC2 H5
COOC2 H5 OH H 3C
H3C
R
+
+
O
O
[A]
H
+
C
H
[B]
+
CH
R1
+
R
+
CH
H5C 2OOC
R1
-H2O
O
CH 3
R
R1
O
CH3
H 5C2 OOC
O
H5C 2OOC
O
O
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. Antibacterial
9
2. Antithrombitics
3. Antagonist
4. Antibiotic
10
11
12,13
5. Cardiovascular
14
Indazoles...
149
Studies on chemical entities...
6. Herbicidal
7. Analgesic
15
16
8. Antiinflammatory
9. Anticonvulsant
17
18
Hermann S. et al.
19
have reported cyclohexenones as herbicides.
Anticonvulsant activity of some cyclohexenone derivatives (III) have been reported
by Natalie D. et al.
20
21
Bastiaan and co-workers 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
R
O
O
N
R
N
H3C
NH
CH3
N
R
O
CH3
O
CH3
O
O
O
H3C
(IV)
(III)
CH3
(V)
Cyclohexenone derivatives which possess plant growth regulatory activity
have been reported.
23,24
Nagao et al.
antiarrhythmic.Collins and co-workers
cyclohexenones. Tvanov et al.
27
26
25
have reported cyclohexenones as
have documented estrogenic activity of
have reported antimicrobial activity of some
28
cyclohexenone derivatives. V. K. Ahluwalia and co-workers
have assessed
cyclohexenone derivatives for anti HIV-I, gastric secretion inhibitors and pesticidal
activity. Cyclohexenone derivatives have been reported to be active as allergy
29
inhibitors, platelet aggregation inhibitors and fibrinogen antagonist.
Antimicrobial activity of cyclohexenone derivatives has been studied by
Indazoles...
150
Studies on chemical entities...
30
Salama and Atshikh . Takehiro and co-workers
31
have reported cyclohexenones
possessing neutropeptide β-receptor antagonist activity. Kimura and co-workers
32
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-workers
35
have synthesized new cyclohexenone derivatives possessing
progesteron receptor binding inhibitory activity. The herbicidal activity of
cyclohexenone derivatives (VI) has been investigated.
36
CH3
H3C
OH
Cl
H3C
CH3
O
H2C
(VI)
Zhang C. et al.
37
Cl
O
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.
Indazoles...
151
Studies on chemical entities...
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.
N
N
H
(I)
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
38,39,40,41,42,43
Several methods have been reported in the literature
for the
preparation of indazoles.
1.
Cyclocondensation of activated acetylenes with hydrazine afforded indazole
derivatives.
44
Cl
R
R
NH 2NH 2 .H2 O
O
2.
-
+
N
+
O
N
-
N
O
N
H
O
45
B. V. Badami et al. have synthesized indazoles from chalcone derivatives
via cyclohexenone derivatives as follow.
Indazoles...
152
Studies on chemical entities...
R1
R1
O
COOEt
R
R1
K2 CO3
NH
Ethylacetoacetate
NH2 NH2.H2O
in dry acetone R
3.
O
O
R
N
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. Antiallergic
2. Antiviral
47
48
3. Antipsychotics
4. Herbicidal
49
50
5. Fungicidal
51
6. Antibacterial
52
7. Cardiovascular
8. Antidepressant
9. Antineoplastic
10. Antitumor
53
54
55
56,57
Balakrishna and co-workers
58
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
Indazoles...
153
Studies on chemical entities...
system diseases have been synthesized.
60
O
Cl
H
N
NH
NH
N
N
COOH
N
H
Cl
Ph
(II)
Butera J. A. et al.
61
(III)
have prepared some indazole derivatives which showed
antihypertensive, muscle relaxant and potassium activator activity. Several workers
62
have patented indazole derivatives useful as hypolipidemic agent , 5-HT3
63
antagonist , enzyme inhibitor
novel antiasthametic agents.
65
64
etc. Some indazole derivatives investigated as a
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.
and found to possess antiinflammatory activity. Effland R. et al.
69
68
synthesized 3-
(pyridyl amino)-indazoles (V) and reported as antidepressant and anxiolytics.
R
R1
NH
N
N
N
H
N
N
H
(IV)
Newshaw R. and co-workers
70
(V)
have prepared 4-amino ethoxy indazoles and
reported them as dopamine D2 agonists. Kania R. et al.
71
have synthesized indazole
Indazoles...
154
Studies on chemical entities...
derivatives as protein kinase inhibitors. Indazole derivatives are reported as inhibitors
72
73
of cell proliferation. The remarkable antipsychotic activity of indazoles (VI) have
been reported.
R
O
Z
O
HN
Z =
N
R1
Lavielle G. et al.
74
(un)-substituted piperazine
pyridino etc
(VI)
prepared [(pyrolidinyl) methyl]-indazoles and suggested
75
them for the treatment of migrains. Marfat Anthony
has patented indazole
derivatives as phosphodiesterase and tumor necrosis factor production inhibitors.
76
Indazole derivatives have been evaluated as α,β -adrenoreceptor agonists. Antiviral
activity
77
78
of indazoles have been reported. Badran M. et al. 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
81
antibacterial activity(VII). Nasr M. N. et al. have prepared some novel 3,3a,4,5,6,7hexahydroindazole 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.
synthesis
and
herbicidal
activity
of
84,85
have described the
2-cyano-3-substituted-
Indazoles...
155
Studies on chemical entities...
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.
H
N
N
EtOOC
NH
O
Cl
Cl
(VII)
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 A N D B I O L O G I C A L 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 OXO-6-ARYLCYCLOHEX-3-ENE-1CARBOXYLATES
SECTION - II :
SYNTHESIS AND BIOLOGICAL SCREENING OF 6-[4( M E T H Y L S U L F O N Y L ) P H E N Y ] - 4 - A RY L - 2 , 3a , 4 - 5 TETRAHYDRO-3H-INDAZOL-3-ONES
Indazoles...
156
Studies on chemical entities...
SECTION - I
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
ETHYL-4-[4-
(METHYL 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
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 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) by the cyclocondensation of 1-[4-(methyls u l f o n y l ) p h e n y l ] - 3 - a r y l - 2 p r o p e n e - 1 - o n e s with ethylacetoacetate in the presence of anhydrous K2 CO 3 in
order to study their biodynamic behavior.
O
O
H3C
O
R
H3C
S
R
O
K 2CO3
S
O
O
CH3COCH2COOC2H 5
Type(I)
O
R=Aryl
OC 2H 5
Type(X)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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.
Indazoles...
157
Studies on chemical entities...
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
100.0
%T
781.1
856.3
918.1
956.6
80.0
1564.2
2852.5
60.0
1598.9 1431.1
2976.0
40.0
1278.7
1299.9
1315.4
1031.8
1353.9
1095.5
1373.2 1244.0
1388.7
O
1159.1
1494.7
2920.0
20.0
0.0
997.1
1076.2
1051.1
3408.0
H3 C
1741.6
813.9
466.7
594.0
538.1
621.0
513.0
702.0
759.9
O
S
OC2 H5
O
O
3250.0
2000.0
1750.0
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Ether
Sulfonyl
Ester
Hexenone
(cyclo)
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-O-C str.
SO2 str.
C=O-O str.
C=O str.
Frequency in cm-1
Observed
Reported
2920
2852
1494
1388
3080
1564
1095
1031
1244
1159
1741
1675
2975-2950
2880-2860
1470-1435
1390-1370
3090-3030
1540-1480
1125-1090
1070-1000
1080-1250
1185-1165
1735-1717
1685-1665
Ref.
88
,,
,,
,,
89
,,
,,
,,
88
,,
,,
89
Indazoles...
158
Studies on chemical entities...
NMR SPECTRAL STUDIES OF ETHYL-4-[4-(METHYLS U L F O N Y L )
PHENYL]-2-OXO-6-ARYLCYCLOHEX-3-ENE-1-CARBOXYLATE
e
d
c
O
H3 C
a
b
g
Hh
S
O
f
Hj
Hi
O
CH3
Hl
a'
b'
O
Hk
O
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
1.04-1.25
3H
triplet
Ar-CH2 CH 3
-
2
1.26-1.30
3H
singlet
Ar-SO 2 CH3
-
3
2.4
1H
singlet
Ar-Hk
-
4
2.30
2H
quartet
Ar-CH2 CH 3
-
5
3.99-4.03
1H
doublet
Ar-Hh
-
6
3.74-3.96
1H
doublet
Ar-Hj
-
7
2.72-2.76
1H
doublet
Ar-Hi
-
8
2.77-3.07
1H
doublet
Ar-Hl
-
9
7.21-7.23
2H
doublet
Ar-Hb,b’
10
7.29-7.31
5H
multiplet
Ar-H(c-g)
11
7.39-7.41
2H
doublet
Ar-Ha,a’
Jba=8.6
Jab=8.4
Indazoles...
FLUOROPHENYL)C Y C L O H E X - 3 - E N E - 1 -CARBOXYLATE
m/z = 416
TABLE-10 : MASS 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 -(P-
Studies on chemical entities...
159
Indazoles...
160
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
ETHYL-4-[4-
(METHYL 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
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e -1-o n e s
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 -phenylc y c l o h e x - 3 - e n e - 1 - carboxylate
To a solution of 1-[4-(methyls u l f o n y l ) p h e n y l ] - 3 -(phenyl) - 2 - p r o p e n e -1-
o n e (2.86 gm, 0.01 mol) in dry acetone, anhydrous K2 CO 3 (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. 164 o C, Anal.Calcd. for C 22 H22 O 5 S; Requires: C, 66.31; H, 5.56;
Found : C, 66.30; H, 5.54; %.
Similarly, other e t h y l - 4 - [ 4 - ( m e t h y ls 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 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).
The zones of inhibition of test solutions are recorded in Graphical Chart No.10
Indazoles...
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 - C24 H26 O7 S
4-F-C6H4 -
3-Br-C6H4 -
3-C6 H5-O-C 6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
10e
10f
10g
10h
10i
10j
10k
S1 Hexane:Ethyl acetate(5:5),
2-C4 H3O-
3-Cl-C6H4 -
10d
10l
2-Cl-C6H4 -
10c
388
414
441
490
477
416
458
428
432
432
432
398
4
Weight
164
157
184
198
140
169
114
167
134
162
179
164
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C20 H20 O6 S
C22 H22 O6 S
C24 H27 NO5 S
C28 H26 O6 S
C22 H21 BrO5 S
C22 H21 FO5 S
C23 H24 O6 S
C22 H21 ClO5 S
C22 H21 ClO5 S
C22 H21 ClO5 S
4-Cl-C6H4 -
10b
C22 H22 O5 S
3
Formula
Molecular
C6 H5 -
2
R
10a
1
No
Sr.
H E X - 3 - E N E - 1 -CARBOXYLATES
64
53
51
45
68
61
54
46
64
58
51
45
6
%
Yield
7
-
-
3.17
-
-
-
-
-
-
-
-
-
Calcd.
-
-
3.18
-
-
-
-
-
-
-
-
-
8
Found
% of Nitrogen
0.56
0.51
0.42
0.49
0.58
0.43
0.56
0.53
0.45
0.56
0.42
0.61
9
Value
Rf
S2
S1
S2
S2
S1
S2
S1
S1
S2
S1
S2
S1
10
System
Solvent
TABLE : 10 PHYSICAL CONSTANTS 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
Studies on chemical entities...
161
Indazoles...
E N E - 1 -CARBOXYLATES
GRAPHICAL CHART NO. 10 : 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 -
Studies on chemical entities...
162
Indazoles...
163
Studies on chemical entities...
SECTION - II
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
6-[4-
(METHYLSULFONYL)PHENYL]-4-ARY L - 2 , 3a ,4,5-TETRAHYDRO-3HINDAZOL-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, it appeared of interest to synthesize a series 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.
O
O
R
H3C
R
H3 C
S
N H2N H2.H2 O
O
O
S
O
O
IN CH3COOH
N
NH
O
Type(X)
H3 C
R=Aryl
Type(XI)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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.
Indazoles...
164
Studies on chemical entities...
IR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-4ARYL-2,3a,4,5-TETRAHYDRO-3H-INDAZOL-3-ONE
100.0
%T
1874.7
80.0
O
O
1944.1
H 3C
S
O
NH
N
60.0
40.0
20.0
0.0
2802.4
869.8
962.4 835.1
916.1
1371.3
1282.6
1328.9 1176.5
1672.2
1118.6
1465.8
1573.8
1028.0
3176.5
3105.2
2898.8
3328.9
2981.7
3250.0
2000.0
1750.0
1500.0
1250.0
1000.0
501.5
542.0
567.0
692.4
596.0
651.9
759.9 723.3
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Ether
Sulfonyl
Amide
Indazole
Amine
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-O-C str.
SO2 str.
NH-C=O-str
C=N str.
N-H str.
Frequency in cm-1
Observed
Reported
2981
2975-2950
2898
2880-2860
1465
1470-1435
1371
1390-1370
3028
3090-3030
1465
1540-1480
1118
1125-1090
1028
1070-1000
1282
1150-1350
1176
1185-1165
1672
1680-1636
1573
1660-1480
3228
3300-3140
Ref.
88
,,
,,
,,
89
,,
,,
,,
88
,,
,,
89
,,
Indazoles...
165
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-4ARYL-2,3a,4,5-TETRAHYDRO-3H-INDAZOL-3-ONE
d
e
c
Hi
O
H3 C
a
b
a'
b'
g
Hh
Hl
S
O
f
Hj
Hk
O
NH
N
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
1.26
1H
singlet
Ar-Hl
-
2
2.5
3H
singlet
Ar-SO 2 CH3
-
3
3.14-3.20
1H
d,d
Ar-Hj
-
4
3.26-3.30
1H
d,d
Ar-Hi
-
5
4.31-4.36
1H
d,d
Ar-Hh
-
6
6.64
2H
singlet
Ar-NH
-
7
7.27-7.34
5H
multiplet
Ar-H(c-g)
-
8
7.36
1H
singlet
Ar-Hk
-
9
7.34-7.43
2H
doublet
Ar-Hb,b’
Jba=8.5
10
7.46-7.60
2H
doublet
Ar-Ha,a’
Jab=8.7
Indazoles...
5-TETRAHYDRO-3H-INDAZOL-3-ONE
m/z = 396
TABLE-11 : MASS SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-4-(P-METHOXYPHENYL)- 2 , 3a ,4-
Studies on chemical entities...
166
Indazoles...
167
Studies on chemical entities...
EXEPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
6-[4-
(METHYLSULFONYL)PHENYL]-4-ARY L - 2 , 3a ,4,5-TETRAHYDRO-3HINDAZOL-3-ONES
(A)
Synthesis of 1-[4-(Methyl s u l f o n y l ) p h e n y l ] - 3 - a r y l - 2 - p r o p e n e - 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 80 o C 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. 134o C.
Anal. Calcd. for C20 H18 N 2 O 3 S 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-3Hindazol-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,4,5tetrahydro-3H-indazol-3-ones
Antimicrobial testing were carried out as described in Part-I, Section (C).
The zones of inhibition of test solutions are recorded in Graphical Chart No.11
Indazoles...
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
11c
11d
11e
11f
11g
11h
11i
11j
11k
2-C4 H3OS1 Hexane:Ethyl acetate(5:5),
4-Cl-C 6H4 -
11b
11l
C6 H5 -
2
R
11a
1
No
Sr.
382
409
458
445
384
426
396
400
400
400
366
4
Weight
187
162
175
181
142
148
115
192
164
128
167
134
5
oC
Molecular M.P.
C18H16N 2O4 S
356
S2 Hexane:Ethyl acetate(6:4)
C20H18N 2O4 S
C22H23N 3O3 S
C26H22N 2O4 S
C20 H17 Br N2 O3 S
C20H17FN 2O3 S
C22H22N 2O5 S
C21H20N 2O4 S
C20 H17 ClN 2O3 S
C20 H17 ClN 2O3 S
C20 H17 ClN 2O3 S
C20H18N 2O3 S
3
Formula
Molecular
INDAZOL-3-ONES
6
54
48
56
51
68
51
49
44
56
48
59
55
%
Yield
7.86
7.33
10.26
6.11
6.29
7.29
6.57
7.07
6.99
6.99
6.99
7.64
7
Calcd.
7.85
7.32
10.24
6.70
6.28
7.26
6.57
7.02
6.97
6.96
6.97
7.62
8
Found
% of Nitrogen
0.52
0.54
0.44
0.48
0.53
0.48
0.57
0.51
0.46
0.58
0.53
0.49
9
Value
Rf
S2
S1
S1
S2
S1
S1
S2
S2
S1
S2
S1
S2
10
System
Solvent
TABLE : 11 PHYSICAL CONSTANTS OF 6-[4-(METHYLSULFONYL)PHENYL]-4-ARYL-2,3a ,4,5-TETRAHYDRO-3H-
Studies on chemical entities...
168
Indazoles...
3-ONES
GRAPHICAL CHART NO. 11 : 6-[4-(METHYLSULFONYL)PHENYL]-4-ARYL-2,3a ,4,5-TETRAHYDRO-3H-INDAZOL-
Studies on chemical entities...
169
Indazoles...
170
Studies on chemical entities...
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73.
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75.
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Indazoles...
175
Studies on chemical entities...
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De Lucca Gerorge V., Liang Jing, Kim VIt-Bacheler Lee T.;
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Farmaco . 58(9) , 749-63 (2003).
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J Agric Food Chem . 51(17) , 5030-5, (2003).
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Indazoles...
176
Studies on chemical entities...
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
1
(I) for a product from the reaction of 1,3 diketone with hydroxylamine. 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.
N
O
(I)
The next important contribution to the chemistry of isoxazoles was made by
2
Quelico 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.
3
Tayade V. B. et al. synthesized some new 3,5-diarylisoxazoles from the
reaction of 2-aryl acetophenones with hydroxyl amine hydrochloride in
presence of alkali.
2.
4
Dawood Kamal et al. prepared isoxazole derivatives from enamino
nitriles.
3.
5
Crawley L. S. and Fan shawe W. J. prepared isoxazole from α,β -unsaturated
carbonyl compounds, hydroxyl amine hydrochloride and KOH in methanol.
R
O
R
R1
+
KOH
NH2OH.HCl
N
O
R1
Isoxazoles...
177
Studies on chemical entities...
6
J. F. Hansen and S. A. Strong synthesized isoxazole from α,β -unsaturated
4.
ketones and N-bromo succinimide.
REACTION MECHANISM
R1
R1
OH-NH2.HCl
OH
+
_
-H
O
R
O
+
O
H
+
NH2
R
R1
R1
: NH2
: NH2
O
R
R
O
_O
proton transfer
R1
_ 2H+
O
OH
N
R
R
R1
R1
R1
O
_
H
+
O
_
N
R
NH
_
O
H2O
H
+
NH
R
OH
THERAPEUTIC IMPORTANCE
Isoxazole derivatives exhibit various biological activities such as,
1. Anthelmintics
7
2. Adenosine antagonist
3. Fungicidal
4. Herbicidal
8
9-11
12,13
5. Hypoglycemic
14
6. Muscle relaxant
7. Nematocidal
8. Insecticidal
15,16
17
18
9. Antibacterial
19-21
10. Anticonvulsant
22,23
11. Anticholestermic
24
12. Antiinflammatory
25-28
Isoxazoles...
178
Studies on chemical entities...
29
13. Antimicrobial
14. Antiviral
30
Aicher Thomas D. et al.
H. H. Parekh et al.
32
31
reported isoxazoles (II) as hypoglycemic agents.
have synthesis 3-(p-methoxyphenyl)-5-(2'-chloro-7'-
methylquinolin-3'-yl)-isoxazole (III) and studied thier biologcal activity.
R
N
CH2 O
O
N
O
Cl
Cl
H3C
N
Cl
Cl
(II)
(III)
33
Talley John and co-workers 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.
Cl
H2N
O
N
H
NH
N
S
O
O
CH3
O
HOOC
R1
(IV)
Moreover, S. Rung and D. Dus
NH2
(V)
37
have synthesized some new isoxazoles as
38
remedy for leukemia. M. Scobie and co-workers
have prepared isoxazole
39
derivatives and studied their antitumor activity. G. Daidone et al. 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
Isoxazoles...
179
Studies on chemical entities...
effect.
Some isoxazoles are found to possess herbicidal
antiinflammatory
43,44 ,
antimicrobial agents
and inhibitor of p38 MAP kinase activities.
Masui et al.
49
45,46
40-42
potential
, estrogen receptor modulators
47
48
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.
R
N
O
Br
Salter M. W. et al.
53
(VI)
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.
Isoxazoles...
180
Studies on chemical entities...
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 A N D B I O L O G I C A L 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
Studies on chemical entities...
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 isoxazole derivatives of type (XII) by the
cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones of
type(I) with hydroxylamine hydrochloride in presence of sodium acetate in glacial
aletic acid.
O
O
O
H3C
H3C
S
R
NH2 OH.HCl
S
O
N
O
gl. CH3 COOH
O
Type(I)
R=Aryl
R
Type(XII)
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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.
Isoxazoles...
182
Studies on chemical entities...
IR SPECTRAL STUDIES OF 3-[4-METHYL S 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
Cl
100.0
%T
O
H 3C
90.0
2362.6
S
N
O
O
80.0
1641.3
891.1
2854.5
1014.5
1159.11037.6
70.0
60.0
3211.3
966.3 779.2
1411.8
1058.8
819.7
1512.1
1245.9 1097.4
835.1
1600.8
1344.3
925.8
2918.1
3076.2
3250.0
528.5
565.1
717.5 592.1
2000.0
1750.0
1500.0
1250.0
1000.0
750.0
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Alkane
-CH3
Aromatic
Halide
Sulfonyl
Isoxazole
Vibration
Mode
C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
C-H str.
C=C str.
C-Cl str.
SO2 str.
C=C str.
C=N str.
N-O str.
Frequency in cm-1
Observed
Reported
2918
2854
1411
1344
3076
1512
1097
1037
779
1159
1641
1600
835
2975-2950
2880-2860
1470-1435
1390-1370
3090-3030
1540-1480
1125-1090
1070-1000
800-600
1185-1165
1680-1550
1690-1460
850-810
Ref.
60
,,
,,
,,
61
,,
,,
,,
60
,,
61
,,
,,
Isoxazoles...
183
Studies on chemical entities...
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
d
Cl
c
O
a
b
e
d'
c'
H3C
S
O
a'
b'
N
O
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
Inference
J Value
In Hz
1
2.47
3H
singlet
Ar-SO 2 CH3
-
2
6.67-6.93
2H
doublet
Ar-Hb,b’
Jba=8.7
3
7.05-7.07
2H
doublet
Ar-Hc,c’
Jcd=7.8
4
7.25
1H
singlet
Ar-He
5
7.45-7.46
2H
doublet
Ar-Ha,a’
Jab=8.4
6
7.57-7.58
2H
doublet
Ar-Hd,d’
Jdc=8.4
-
Isoxazoles...
ISOXAZOLE
m/z = 317
TABLE-12 : MASS SPECTRAL STUDIES OF 3-[4-METHYL S U L F O N Y L ) P H E N Y L ] - 5 -(P-FLUOROPHENYL)
Studies on chemical entities...
184
Isoxazoles...
185
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
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
(A)
Synthesis of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -aryl- 2 - p r o p e n e -1- o n e s
See Part-I, Section-I (B).
(B)
Synthesis of 3-[4-Methyl s u l f o n y l ) p h e n y l ] - 5 - (p-chlorophenyl)isoxazole
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. 154o C Anal.
Calcd. For C16 H12 ClNO3 S 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 w e r e
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
isoxazoles
Antimicrobial testing were carried out as described in Part-I Section-1 (C).
The zones of inhibition of test solution are reported in Graphical Chart No 12.
Isoxazoles...
4-Cl-C 6H4 -
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
2-C4 H3O-
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
S1 Hexane:Ethyl acetate(5:5),
C6 H5 -
2
R
12a
1
No
Sr.
289
315
342
391
378
317
359
329
333
333
333
299
4
Weight
161
170
162
146
170
160
163
174
193
148
154
162
5
oC
Molecular M.P.
S2 Hexane:Ethyl acetate(6:4)
C14 H11 NO 4 S
C16 H13 NO4 S
C18H18N 2O3 S
C22 H17 NO4 S
C16 H12 Br NO 3 S
C16H12FNO3 S
C18 H17 NO5 S
C17 H15 NO4 S
C16 H12 ClNO 3 S
C16 H12 ClNO 3 S
C16 H12 ClNO 3 S
C16 H13 NO3 S
3
Formula
Molecular
56
45
66
58
48
54
68
61
57
64
56
42
6
%
Yield
4.84
4.44
8.18
3.58
3.70
4.41
3.90
4.25
4.20
4.20
4.20
4.68
7
Calcd.
4.85
4.45
8.19
3.59
3.72
4.42
3.91
4..26
4.22
4.23
4.21
4.67
8
Found
% of Nitrogen
0.51
0.53
0.46
0.41
0.57
0.43
0.56
0.52
0.41
0.50
0.44
0.58
9
Value
Rf
TABLE : 12 PHYSICAL CONSTANTS 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
S1
S1
S2
S1
S1
S2
S1
S2
S1
S1
S2
S2
10
System
Solvent
Studies on chemical entities...
186
Isoxazoles...
GRAPHICAL CHART NO. 12 : 3-[4-METHYL 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
Studies on chemical entities...
187
Isoxazoles...
188
Studies on chemical entities...
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PCT Int. Appl. No. 9, 51, 583 (1999); Chem. Abstr., 131 , 2718272g (1999).
41.
A. Hiroyuki, S. Takahiro, A. Toshio;
PCT Int. Appl. WO 99 64, 404; Chem. Abstr., 132, 12313m (2000).
42.
K. Masami;
U. S. US 6 100, 421; Chem. Abstr., 133, 150550h (2000).
43
M. Mauro, S. Enzo;
Farmaco 54(7), 452-460 (1999); Chem. Abstr., 131, 299393a (1999).
44.
D. A. Jacob, M. A. John, C. L. Stanley;
PCT Int. Appl. WO 00, (Cl. C07D 00/477); Chem. Abst., 132, 64256r (2000).
45.
S. K. Gudadhe, S. D. Patil, U.S. Jamode;
Orient J. Chem., 15(1), 133-136 (1999); Chem. Abstr., 132, 222481r (2000).
46.
Hui-Xin-Ping, Zhang Lin-Mei, Zhang Zi-Yi;
Indian J. Sec. B. Org. Chem. Incl. Med. Chem . 1999. Chem. Abstr., 132,
207803c (2000).
Isoxazoles...
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Studies on chemical entities...
47.
V. D. Huebner, Lin Xiaodong, James Ian, C. Liya, M. Desai;
PCT Int. Appl. WO 00 08, 001.Chem. Abstr., 132, 207803c (2000). Chem.
Abstr., 132, 222486w (2000).
48.
M. Nobugoshi, S. Michitaka, H. Kokhi;
Jpn Kokai Tokkyo Koho JP 86, 657 (2000); Chem. Abstr., 132, 251139r (2000).
49.
M. Masui, H. Yasushi;
PCT Int. Appl. WO 97, 43, 248 (Cl. C 07 C 251/50), 20 Nov. 1997, JP Appl. 96/117,
370, 13 May 1996; 68 pp (Japan). Chem. Abstr. 128, 13256z (1998).
50.
K. V. Reddy, S.G. Rao, A. V. Subba;
Indian J. Chemistry, 37(B) , 677-99 (1998); Chem. Abstr., 129, 260397p (1998).
51.
C. B. Xue, J. Roderick, S. Mousa, R. E. Olason, W. F. Degrado;
Bio org. Med. Chem. Lett., 8(24)b, 3499-3504 (1998).
52.
K. S. Nimavat, K. H. Popat and H. S. Joshi;
J. Ind. Chem. Soc. Vol. 80, 707-708 July, (2003).
53.
Salter M. W.;
J Orofac Pain. 18(4), 318-24 (2004).
54.
Matringe M., Sailland A., Pelissier B., Rolland A., Zink O.;
Pest Manag Sci. (2005).
55.
Mehlisch D. R., Desjardins P. J., Daniels S., Hubbard R. C.;
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Ray W. A., Griffin M. R., Stein C. M.;
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Welsing P. M., Severens J. L., Hartman M., van Riel P. L., Laan R. F.;
Arthritis Rheum. 51(6) , 964-73 (2004).
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Bingham S. J., Buch M. H., Kerr M. A., Emery P., Valadao Barcelos A. T.;
Arthritis Rheum. 50(12) , 4072-3 (2004).
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Barbachyn M. R., Cleek G. J., Dolak L. A., Garmon S. A., Morris J., Seest E. P.,
J Med Chem. 46(2), 284-302 (2003).
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V. M. Parikh;
“ Absorption spectroscopy of organic molecules ”, Addition-Wesley Pub. Co. London 243,
258 (1978). A. Hand book of spectroscopic data by B. D. Mishtry; 1st ed. ABD Press
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61.
A. R. Kartizky and R. Alans Jones;
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B. Colthup, Lowrence H. Daly and Stephan E. Wiberluy. Academic Press (1975).
Isoxazoles...
192
Studies on chemical entities...
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.
O
H
N
4 3
5
2
1
S
O
H
N
4 3
5
2
1
S
(I)
O
H
N
4 3
5
2
1
S
(II)
(III)
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
2
The chemistry of 4-thiazolidinones was reviewed in depth by F. Brown in
3
1961 and G. Newkome and A. Nayak 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.
Thiazolidinones...
193
Studies on chemical entities...
R1
R2
R1
HN
+
N
R
HS
R
R3
H
S
COOH
R2
R2
COOH
R = Alky or aryl
R 1 = Aryl or heterocyclic
R 2 = H or alkyl
H
N
O
R 3 = H or alkyl
R 2 , R 3 = Arylidene
R1
R2
(IV)
S
R3
The substituted and unsubstituted 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-4thiazolidinones
4-6
(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.
R1
R
N
R
R
R1
H
OH
+
N
-H2 O
N
S
O
O
HO
R1
S
SH
O
In there reaction, the uncyclised intermediate is formed in several cases. The
7
uncyclised product has been isolated. Phosphorous pentoxide in dioxan was used
Thiazolidinones...
194
Studies on chemical entities...
8
for subsequent cyclisation of certain uncyclised products. In may instance 4thiazolidinones can conveniently be prepared by refluxing the mixture of
9
thioglycolic acid and Schiff’s bases in benzene 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.
THERAPEUTIC IMPORTANCE
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
12
tautomer in compounds possess in vitro tuberculostatic activity .
The biological activity of following types have been reported.
1. Antiviral
13
2. Anthelmintics
14,15
3. Cardiovascular
4. Herbicidal
5. Hypnotic
16
17
18-20
6. Insecticidal
21
7. Mosquito repellent
8. Local anaesthetic
9. Analgesic
22
23
24
10. Antibacterial
11. Antidiabetic
12. Antifungal
25,26
27
28-30
13. Anti HIV and anticancer
31
32,33
14. Antimicrobial
Thiazolidinones...
195
Studies on chemical entities...
15. Antiulcer
34,35
16. Antitumor
36
17. Antitubercular
37,38
Moreover Albuquerque and co-workers
39
have prepared 4-thiazolidinones
which show antidiabetic and antiinflammatory activity. Tagami et al.
40
synthesized thiazolidinone derivatives as allergy inhibitor. Mohammad et al.
41
have
have
prepared substituted thiazolidinones and reported their antibacterial, antifungal,
antithyroid and amoebicidal properties (V).
R1
R4
R5
O
R3
N
S
R2
S
(V)
R1 = OH
R2, R4, R5 = H
R3 = Me
R. S. Lodhi and co-worker
42
have been synthesized and studied antimicrobial,
antiinflammatory and analgesic property of 4-thiazolidinone and arylidene
43
derivatives (VI). Goel Bhawna et al. have documented thiazolidinone derivatives
and compared their antiinflammation potency, ulcerogenic liability, cardiovascular
44
and CNS effect. Pawar and co-workers reported synthesis and in vitro antibacterial
activity of some 4-thiazolidinone derivatives. In other study, some thiazolidinone
45,46
derivatives have been found to be promising antibacterial agent.
O O
N
NH
Z
N
S
N
R1
R1 = (un) Substituted aryl
Z = H2
Z = CH2R2
R1 , R2 = Substituted aryl
(VI)
Thiazolidinones...
196
Studies on chemical entities...
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 451
thiazolidinones as antiinflammatory agents. Antifungal and antibacterial activity
of thiazolidinones has been reported. Many workers have reported 4-thiazolidinone
as antibacterial,
52
anticancer,
Mayer et al.
55
53
antiinflammatory and analgesic agent.
54
have prepared thiazolidinones and studied their herbicidal
56
activity. Archana and Srivastava 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.
Ar
N
N
S
N
H
S
O
NH
N
O
N
N
O
Ar
N
S
N
NH
N
CH3
H
O
(VIII)
(VII)
Dayam R. et al.
Ar
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.
as CFTR inhibitor. Wang X. F. et al.
61
62
documented the thiazolidinone derivatives
have synthesized some novel thiazolidinone
Thiazolidinones...
197
Studies on chemical entities...
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.
R2
O
S
R1
R3
NH
N
O
(IX)
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-thiazolidin4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. Muanprasat C. et
66
al. 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.
a small molecule as CFTR inhibitor. Taddei A. et al.
70
68,69
have synthesized
have been constructed some
new thiazolidinone as CFTR inhibition.
Cl
O
BnO
S
O
NH
N
NH
H2N
O
(X)
Thiazolidinones...
198
Studies on chemical entities...
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- AMINO5-ARYLIDINE-2-METHYL-2-[4-METHYLSULFONYL)
PHENYL]-1,3-THIAZOLIDIN-4-ONES
Thiazolidinones...
199
Studies on chemical entities...
SECTION - I
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
3- AM I N O - 5 -
A RY L I 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]-1,3thiazolidin-5-one with arylaldehyde acid.
O
H3C
S
O
O
CH3
CH3
NH2
N
R-CHO
S
O
H3C
CH3COONa in
gla.CH3 COOH
NH2
S
N
O
S
O
CH
R=Aryl
Type(XIII)
R
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H 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.
Thiazolidinones...
200
Studies on chemical entities...
IR SPECTRAL STUDIES OF 3 - AM I N O - 5 - ARYLIDINE-2-METHYL-2[4-(METHYLSULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE
O
100.0
H3C
H3C
%T
N
O
80.0
O
H2N
2312.5
2769.6
60.0
717.5
2839.0
40.0
S
S
2918.1
2989.5
3325.0
1010.6
1070.4
1556.4
1307.6
1500.0
1250.0
958.6
1398.31288.41172.6 1028.0
1099.3
1357.8
1431.1
1253.6
815.8
1512.1
1668.3 1591.2
20.0
0.0
3250.0
761.8
1494.7
2000.0
1750.0
1000.0
750.0
453.2
470.6
621.0
516.9
590.2
500.0
1/cm
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Type
Vibration
Mode
Frequency in cm-1
Observed
Reported
Ref.
Alkane
C-H str. (asym.)
2918
2975-2950
71
-CH3
C-H str. (sym.)
2839
2880-2860
,,
C-H def. (asym.)
1431
1470-1435
,,
C-H def. (sym.)
1398
1390-1370
,,
C-H str.
3035
3090-3030
72
C=C str.
1512
1540-1480
,,
1070
1125-1090
,,
1028
1070-1000
,,
1172
1185-1165
,,
Amide
SO2 str.
NH-C=O str.
1668
1680-1636
71
Amine
NH- str.
3325
3380-3350
,,
Aromatic
Sulfonyl
Thiazolidinones...
201
Studies on chemical entities...
NMR SPECTRAL STUDIES OF 3 - A M I N O - 5 - ARYLIDINE-2-METHYL-2[4-(METHYLSULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE
O
a
H 3C
H3 C
c
h
b
d
S
S
O
a'
N
b'
e
g
O
f
H 2N
Internal Standard : TMS; Solvent : CDCl 3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal
No.
Signal Position
(δppm)
Relative No. Multiplicity
of protons
J Value
In Hz
Inference
1
2.33
3H
singlet
Ar-CH3
-
2
2.40
3H
singlet
Ar-SO 2 CH3
-
3
3.69-3.71
2H
doublet
Ar-NH2
-
4
7.26-7.29
5H
multiplet
Ar-H(c,g)
-
5
7.65-7.68
2H
doublet
Ar-Hb,b’
J=9.
6
7.74-7.77
2H
doublet
Ar-Ha,a’
J=9
7
9.02
1H
singlet
Hh
-
Thiazolidinones...
SULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE
m/z = 408
TABLE-13 : MASS SPECTRAL STUDIES OF 3 - AM I N O - 5 - (P-CHLOROBENZYLI D ENE)-2-METHYL-2-[4-(METHYL
Studies on chemical entities...
202
Thiazolidinones...
203
Studies on chemical entities...
EXPERIMENTAL
SYNTHESIS
AND
BIOLOGICAL
SCREENING
OF
3- AM I N O - 5 -
A RY L I 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. 168o C; Anal. Calcd. for
C 11 H14 N 2 O 3 S 2 Requires: C,46.13; H,4.93; N, 9.78 %; Found: C, 46.11; H, 4.92;
N, 9.76 %.
(B)
Synthesis of 3- Am i n o - 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 120 o C for 12 hr. The reaction mixture was cooled and tritruted with 10%
sodiumsulphate solution. The product was crystallized from ethanol. Yield 48%;
M.P. 168 o C; Anal. Calcd. for C 18 H18N 2 O 3 S 2 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 - a r y 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
Studies on chemical entities...
(C)
Biological screening of 3- Am i n o - 4- benzylidine-2-methyl-2-[4(methylsulfonyl)phenyl]-1,3-thiazolidin-5-ones
Antimicrobial testing were carried out as described in Part-I Section-1 (C).
The zones of inhibition of test solution are reported in Graphical Chart No 13.
Thiazolidinones...
C6 H5 -
4-Cl-C 6H4 -
2-Cl-C 6H4 -
3-Cl-C 6H4 -
4-OCH3 -C6 H4 -
3,4-(OCH3)2- C6H3 -
4-F-C6H4 -
3-Br-C 6H4 -
3-C6 H5-O-C6H4 -
4-N(CH3 )2-C 6H4 -
2-OH-C6 H4 -
2-C4 H3O-
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
S1 Hexane:Ethyl acetate(5:5),
2
1
No
Sr.
364
390
417
462
453
392
434
404
408
408
408
374
4
Weight
S2 Hexane:Ethyl acetate(6:4)
C16 H16 N2O 4S 2
C18 H18 N2O 4S 2
C20 H23 N3O 3S 2
C24 H22 N2O 4S 2
C18 H17 Br N2O 3S 2
C18H17FN 2O3S 2
C20 H22 N2O 5S 2
C19 H20 N2O 4S 2
C18 H17 ClN2O 3S 2
C18 H17 ClN2O 3S 2
C18 H17 ClN2O 3S 2
C18 H18 N2O 3S 2
3
Formula
146
172
164
183
146
191
158
138
185
152
128
168
5
oC
PHENYL]-1,3-THIAZOLIDIN-4-ONES
R
Molecular
Molecular M.P.
56
43
59
59
68
63
67
46
61
44
52
48
6
%
Yield
7.69
7.10
10.06
6.00
6.18
7.14
6.45
6.93
6.85
6.85
6.85
7.48
7
Calcd.
7.70
7.11
10.07
6.02
6.19
7.15
6.44
6.92
6.82
6.86
6.84
7.49
8
Found
% of Nitrogen
0.53
0.41
0.56
0.47
0.59
0.44
0.56
0.54
0.46
0.58
0.46
0.51
9
Value
Rf
S2
S2
S1
S2
S1
S2
S2
S1
S2
S2
S1
S2
10
System
Solvent
TABLE : 13 PHYSICAL CONSTANTS OF 3 - AM I N O - 5 ARY LIDINE-2-METHYL-2-[4-(METHYLSULFONYL)
Studies on chemical entities...
205
Thiazolidinones...
THIAZOLIDIN-4-ONES
GRAPHICAL CHART NO. 13 : 3 - AM I N O - 5 - ARY LIDINE-2-METHYL-2-[4-(METHYLSULFONYL)PHENYL]-1,3-
Studies on chemical entities...
206
Thiazolidinones...
207
Studies on chemical entities...
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2.
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4.
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5.
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6.
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7.
A. R. Surrey ;
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T. Takematsu, K. Yokohama, K. Ideda, Y. Hayashi and E. Taniyamal;
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15.
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