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1
CHAPTER-1
INTRODUCTION
&
LITERATURE REVIEW
2
1.1 INTRODUCTION
The Research in the field of pharmaceutical chemistry has its most important task in the
development of new and better drugs and their successful introduction into clinical practice.
Central to these efforts, accordingly stand the search for pharmaceutical substances and
preparation which are new and original. In addition to these objectives, we may search for newer
drug like entities which exhibit some clear advantages over a drug already known. Such
advantages may be qualitative or quantitative improvement in activity, the absence of
undesirable side effects, lower toxicity, improved stability or decreased cost.
A prerequisition for the design of safe drug is, knowledge about the various metabolic
reactions that xenobiotics and endogenous compounds undergo in the organism. Because
pharmacological activity associated with molecular structure, medicinal chemist is restricted in
the choice of functional groups for designing new drugs. Often he finds or she encounters a
situation where a structure has adequate pharmacological activity but has an inadequate
pharmacokinetic profile (i.e. absorption, distribution, metabolism and excretion). This is because
pharmacology and pharmacokinetic departments in the pharmaceutical industry often do not
collaborate at the early stage of drug development. It is only later, when the new compound is
tested in animals or in humans, that pharmacokinetic disadvantages become obvious. The
binding of a drug to the active or other sites of an enzyme usually has the effect of preventing the
normal operation of that enzyme. The drug’s therapeutic effect is dependent on the drug-enzyme
complex as well as the fraction of active and allosteric sites occupied by the drug. The stronger
the binding of the drug to the enzyme and greater the number of sites occupied, the more
effective the drug is likely to be in inhibiting the action of the enzyme. The factors affecting this
can be classified into two phases.I
(I) The pharmacokinetic phase
(II) The pharmacodynamic phase
Heterocyclic chemistry and medicinal chemistry share a venerable common history.
Many of the founders of heterocyclic systems had an intense interest not only in molecules from
nature but also in the effects of synthetic compounds on living systems.There are two main
divisions of medicinal chemistry.The first chemotherapy, concerns the treatment of infections,
3
parasite or melignant disease by chemical agents, usually substances that show selective toxicity
towards the pathogen. The other division relates to diseases of bodily disfunction and the agents
employed are mainly compounds that effect the functioning of enzymes, the transmission of
impulses or the action of hormones on receptors.
Heterocyclic compounds have great applicability in pharmaceutics because they have
specific chemical reactivity and provide false synthons in biosynthetic process or block the
normal functioning of biological receptors. The inhibition of amide resonance resulting into
more susceptibility of β-lactum to nucleophile is considered at least in part responsible for
antibacterial property, apparently by acetylating transpeptidase and heterocyclic compounds are
used because they have a specific clinical reactivity.With the number of known organic
compounds approaching five million, more than half of which are heterocyclic and out of these
more than half of heterocyclic system attach with another ring system and give pharmacological
activity.Most of the alkaloids which are nitrogenous bases occurring in plants and many
antibiotics including penicillin and streptomycin have also heterocyclic ring system. Many
natural pigments such as indigo, haemoglobin and anthocyanin are heterocycles. Most of the
sugars and their derivatives including Vitamin-C for instance, exist largely in the form of five
membered ring. Vitamin B-6 (Pyridoxine) is a derivative of pyrimidine essential in amino acid
metabolism.I
Drugs in general, can thus be divided into:
* Pharmacodynamic agents: These are chemical substances designed to have pharmacodynamic
effect in the recipient.
* Chemotherapeutic agents: These are chemical substances designed for the treatment of
infectious diseases or by the proliferation of malignant cells.
Essential Drug Concept:
The defination states “those that satisfy the healthcare needs of majority of the
population; they should therefore be available at all times in adequate amounts and in appropriate
dosage form”.It has been realized that only a handful of drugs out of the multitude available that
may be well tested and cheaper drugs are equally (or more) efficient and safe as their newer
more expensive congeners. For optimum utilization of resources, governments (especially in
4
developing countries) should concentrate on these drugs by identifying them as Essential Drugs.
The “WHO” has laid down criteria guide of an essential drug:
Drug Development I
Many natural products by trial and error came into practice for combating human
ailments existent during early human observation. With the advent of modern scientific
approach, various plant medicines came under chemical scrutiny, ultimately leading to the
isolation of active principles since early.Such compounds either in extract form or in pure form
became a part of pharmacopoeias. For instance, though the Chinese drug, Mauhang was in use
for over 5000 years for the treatment of various types of fever and respiratory ailments, its active
principle, Ephidrine was isolated in 1887. In 1925 chemical investigations followed by
pharmacological evaluation led this compound into the modern medicine. Similarly during this
period, urea stibamine was introduced as the first drug in 1920 for the treatment of Kala-azar. In
1930, De Rauwolfia preparation was first employed for sedative and hypotensive properties. A
drug is a substance having abnormal effect on certain body functions eg. Strychnine stimulates
the action of heart and aspirin retards its action. Since both of them effects abnormally, the two
substances are known as drugs. Chemical sciences contributed extensively new discoveries
leading to useful drugs since after 1930. The modern concept of drug discovery started in 1933
by Gerhand Domagk with his finding of “Prontosil Red”, a compound responsible for the
antibacterial activity. The advent of sulphonamides drew the attention for the different activities
of various chemicals for bacterial and human cells, this important factor prompted Florey and
Chain in 1939 to investigate penicillin which was discovered ten years earlier by Alexander
Fleming. The spectacular chemotherapeutical properties of penicillin and its dramatic war-time
development for the treatment of wounds made penicillin, a most commonly used inexpensive
drug.
A large number of important drugs have been introduced during the period of 1940 to
1980. This period is known as “Golden period” of new drug discovery. Thus starting from 1933 -
the first antibacterial drug prontosil leading to various sulpha drugs ; 1940 – penicillin ; 1945 –
chloroquine – antimalarial ; 1950 – Methyldopa – anti-hypertensive; 1967 – chlorothiazine -
diuretic;1958 - adrenergic beta blockers coronary vasodilatory; 1960 - semi synthetic penicillin -
antibacterial; 1965 -trimethoprim-antimicrobial;1967- disodium chromoglycoate - antiallergic;
1972 - cimetidine H2 – antagonist; 1975-verapamil- calciumantagonist and 1981 - captopril -
5
antihypertensive eg. Metormine glipizide-anti diabetic.There are some specific examples
representingnew therapeutic agent.
Latest Drug Developments
The current interest in the creation of large, searchable libraries of organic compounds
has captured the imagination of organic chemists and the drug discovery community. In
numerous laboratories the Efforts are focused on the introduction of chemical diversity, which
have been recently reviewed and pharmacologically interesting compounds have been identified
from libraries of widely different compositions.
Today, the chief sources of agents for the cure, the mitigation or the prevention of diseases are
the organic compounds, natural or synthetic, together with so-called organometallics. Such
agents have their origin in a number of ways (a) from naturally occurring materials - of both
plant and animal origin, and (b) from the isolation of organic compounds synthesized in
laboratory whose structures are closely related to those of naturally occurring compounds for eg.
atropine, steroids, morphine, cocaine etc. that have been known to possess useful medicinal
properties.
The process of drug design is extensively driven by the instinct and experience of pharmaceutical
research scientists. It is often instructive to attempt to “capture” these experiences by analyzing
the historical record that are successful drug design projects of the past. From this analysis, the
inferences are drawn which play an important role in shaping our current and future projects.
Towards this region, we would like to analyse the structures of a large number of drugs - the
ultimate product of a successful drug design effort. Our goal for this is to begin to deconvolute
this information in order to apply it to design of new drugs. Different kinds of drugs are
developed for different types of diseases viz which can be defined with their names of the
modern drugs are as under.
(a) Anticancer drugs
Drugs, which stops the abnormal growth of cell tissues in human body, are termed as
anticancer drug. Vinblastin and Busulphan are the novel anticancer drugs.
(b) Hepatoprotective drugs
Drugs, which gives vitality to liver and protects liver by giving immunity power against
antibodies, are termed as Hepatoprotective drug.
6
(c) Antimalarial drugs
Drugs, which kills the plasmodium causing malaria are called antimalarial drug.
Combination of Sulphamethoxazole with Pyrimethamine is a novel antimalarial drug.
(d) Drug for meningitis
Drugs, which cures the inflammation of meningitis, are termed as meningitis drugs
Cifalexin is a novel meningitis drug.
(e) Drug for typhoid
Drugs, which kills the bacteria of Salmonella typhi causing typhoid are known as typhoid
drugs. A novel drug for typhoid is Ciprofloxacin.
(f) Antidiabetic drugs
Drugs, which converts the excess glucose of blood into glycogen are termed as
antidiabetic drugs. Novel antidiabetic drugs are Metformin,Glipizide and Gliclazide.
(g) Antitubercular drugs
Drugs, which kills the bacteria of mycobacterium tuberculosis and thus cures lesions of
pleural cavity. A novel antitubercular drug is Ethambutol.
(h) Antiasthamatic drugs
Drugs, which prevents the attack of asthama and gives relax respiration are called
antiasthamatic drugs. Novel antiasthamatic drugs are Ethophylline, Theophylline and Asmon.
(i) Antihypertensive drugs
Drugs, which normalizes the blood pressure by dilating blood vessels are called
antihypertensive drugs. Novel antihypertensive drugs are Atenolol, Amlodipine and
Nifedipine.Amlodipine and Nifedipine.
(j) Anti-AIDS drugs
Drugs, which kills the viruses of AIDS i.e., HIV-1 and HIV-2 are called anti-AIDS drugs.
Novel drugs are Zidovudine, Acyclovir and Didanosine.
(k) Antacid drugs
Drugs, which neutralize the acid in stomach and stops excessive secretion of acid, are
called antacid drugs. Novel antacid drugs are Omeprazole and Lansoprazole.
(l) Non steroidal antiinflammatory drugs (NSAID)
A drug, which gives relief from fever, pain and inflammation are called NSAID. Novels
NSAID are Pyroxicam, Meloxicam and Nimesulide.
7
1.2 AIMS AND OBJECTIVES
Taking in view of the applicability of heterocyclic compounds, we have under taken the
preparation of heterocycles bearing Thiadiazine, Sulfamide moieties.The placement of a wide
variety of substituents of these nuclei have been designed in order to evaluate the synthesized
products for their pharmacological profile against several strains of bacteria and fungi.
During the course of research work, looking to the application of heterocyclic compounds,
several entities have been designed, generated and characterized using elemental analyses
spectral studies.
The objectives are as under.
To develop novel heterocyclic 1,2,6-thiadiazine 1,1-dioxide derivatives having different
substitutions at 4th
position of the thiadiazine ring system.
Crystallographic study of some of the novel derivatives.
To evaluate novel derivatives for their batter drug potential against different strains of
bacteria and fungi (MIC).
To characterise these products for stuctural elucidation using spectroscopic techniques
like IR, PMR and Mass spectral studies.
8
1.3 LITERATURE REVIEW
Sulfamide is a simple molecule having the sulfonamide functionality, used by chemists
for the design of clinically active compounds with clinical importance,provides 5 types of
substituents, by changing one to four -H- atoms. Some steroid sulfatase (STS) and protein
tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been
reported. All these moieties reacts either by directly coordinating to a metal ion found in some
metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the
sulfamide motif, or as in the case of the cyclic sulfamides acting as HIV protease inhibitors,
interacting with the catalytically critical aspartic acid residues of the active site by means of an
oxygen atom belonging to the HN-SO2-NH motif, which substitutes a catalytically essential
water molecule. In other cases, the sulfamide moiety is important for inducing desired physico-
chemical properties to the drug-like compounds incorporating it, such as enhanced water
solubility, better bioavailability, etc., because of the intrinsic properties of this highly polarized
moiety when attached to an organic scaffold.1
Cyclic sulfamides, in particular, have been found to be useful as HIV protease inhibitors.
As the need for new and improved inhibitors is warranted by the rampant spread of HIV, the
search for new synthetic pathways to access novel sulfamides is ongoing. To this end, the work
discussed herein focuses on the synthesis of new sulfamides utilizing the ring-closing metathesis
(RCM) reaction to generate novel seven-membered cyclic compounds. These compounds are
being lauded for their biological activities as HIV protease inhibitors.
Thiadiazines attract permanent interest because acyclic and cyclic products containing
sulfamide fragments exhibit a broad spectrum of physiological activities. Thus Cyclic Sulfamide
Derivatives acts as 11β-Hydroxysteroid Dehydrogenase 1 Inhibitors2,
sulfamoylamidines possess antiulcerous3 activities, 4-phenyl-derivatives exhibits antispasmodic
activity,4 5-alkyl-2-phosphinyloxymethyl-1,2,5-thiadiazolidin-3-one1,1-dioxides are proposed
for the treatment of rheumatoid arthritis,5 and 1,2,5-thiadiazolidine 1,1-dioxides containing an
indole substituent at position 2 are used for the treatment of migraine.6
5-Alkyl-2-fluoromethyl
derivative inhibit enzymes, viz., human leucocyte elastase and cathepsin G.7
Aryl-substituted
9
seven- and eight membered cyclic sulfamides inhibit HIV-1 protease.8,9
Many sulfamides are
employed as detergents.10
S,S-Dioxides of benzothiadiazine, thiadiazine, and thiatriazine as well
as some acyclic sulfamides can serve as herbicides.11
According to latest inventions its been
reported that this class of compounds exhibits as a new class of hydrogen bond equivalent of
uracil12
,as a trypanocidal agents.13
1,2,6-thiadiazine 1,1-dioxide also possess antiprotozoal14
properties and antiparasitis activity.15
The chemistry of sulfamides has received sufficient attention in the literature. The
synthesis, physicochemical properties and reactions of these compounds have been considered
many times in reviews which were partially or completely devoted to sulfamides. During the last
decade, abundant experimental data have accumulated, which call for further
generalisation.Sulfamide can also be used as catalyst for fromation of β-nitrostyrenes16
,
Pyrrolidinyl-sulfamide derivatives as a new class of bifunctional organo catalysts for direct
asymmetric Michael addition ofcyclohexanone to nitroalkenes17
, Asymmetric conjugate addition
of ketones to nitroalkenes catalyzed by chiral bifunctional sulfamides18
.
In the 1980s, a new class of chiral oxidising agents based on sulfamides was found.
These are 2-sulfamoyloxaziridines which exhibit high enantioselectivity (40% ± 91%) in
asymmetric oxidation of sulfides to sulfoxides.19
It is believed20
that the increased interest in
sulfamide derivatives stems from the fact that these compounds are structurally similar to ureas.
In this connection, thought came it was worthwhile performing a comparative analysis of the
structures and physicochemical properties of sulfamide and urea.However, the major function is
to systematise procedures for the formation of heterocyclic compounds based on sulfamide.
Wherever possible, a comparative analysis of the properties of cyclic sulfamides and of the
corresponding cyclic ureas was carried out.
Akira. Ouchi and T. Moeller21
(1964) reported the reaction of Sulfamide and various
monoketones in presence of hydrogen chloride to yield substituted cyclic thiadiazine 1, 1-
dioxide. Subsequent study had shown that hydrogen chloride is more effective catalyst both for
this reaction and for comparable reaction with 2-pentanone, 3-pentanone, and acetophenone.
10
NS
NH
CH3CH3
OO
H
SN
N R2
R1
O
OO
Figure-1.1
Piller. Goya and M.Stud22
(1978) showed the reaction of these class of derivatives as
shown below.
NS
NH
NH2
O O
CN
S
O
O
NH
NC
CN
NH2
NS
NH
OH
O O
NO2CH3
O
NO2
O
O
CH3
Figure-1.2
John B. Wright23
(1964) reported synthesis of Sulfamide with alpha and beta diketones.
The use of N-monosubstituted sulfamides gave 2-substituted derivatives. The use of ethyl
acylpyruvates as the o-diketones led to the 3-carbethoxy derivatives.
NHS
N
CH3
O O
CH3
CH3CH3
O O
S
OO
NH2NH2
11
Figure-1.3
Gloria, Tabajara S.24
(1974), Garg, H. G. et al
25(1972) reported Synthesis of 4-arylazo
substituted-thiadiazine by condensing 1,3-diphenyl 1,2,3-propanetrione 2-arylhydrazone with
Sulfamide in presence of acid.
S
OO
NH2NH2CH3
CH3
O
O
N
N
R
NHS
N
CH3
O O
NN
CH3
R
Figure-1.4
Goya P et al.26
, (1988) applied the use of factorial design for the study of the reaction
between diamino derivatives and aldehydes to give fused imidazo and pyrazino derivatives.
Reaction between triamino derivatives and aldehydes, in acetic acid or DMF, under anhydrous
conditions. The ratio of both compounds dependent on the nature of the aldehydes used. The
same reaction, in the absence of solvent, affords, only pyrazinothiadiazine derivatives. The
UV, 1H- and
13C-nmr data of the new compounds reported by Herrero, Angela
27 (1988).
NHS
N
NH2
O O
NH2
NH2
+O
O
NO2O
OH
NO2
+NH
N
S
NH
N ONO2
NH2
O
O
Figure-1.5
Prat M et al.28
(1988) reported the synthesis of β-dicarbonyl compounds using Palladium
as a catalyst,the C-allylation of highly acidic carbon and heterocycles which is the useful
precursor for the synthesis of 1,2,6-thiadiazine 1,1-dioxide.
12
NHS
N
CH3
O O
CH3
+
+OCH3
O
NHS
N
CH3
O O
CH3N
SN
O O
CH3 CH3
Figure-1.6
Campillo Nuria et al.29
(1998) reported same class of derivatives with the structural
assignment and tautomeric studies had been reported by them.
NH
N
O2S
NH2
X
N
Figure-1.7
Alkorta I et al.30
(1991) reported the synthesis and biological screening of
aminothiadiazine dioxides related to trimethoprim. The amine derivatives have been synthesized
and their antibacterial, antifungal and DHFR inhibitory activities evaluated. Their chemical
structures have been established by means of analytical and NMR spectroscopic data. Among the
compounds studied, the 4,4-dibromo derivative 11 showed fungistatic activity against C.
albicans.
Alkorta I et al.31
(1990) studied the synthesis and physicochemical properties.
Herrero A et al.32
(1990) reported amine derivatives undergoes intermolecular
cyclization, under different reaction conditions, to give a novel tricyclic system which shows
interesting chelating properties toward ammonium ion. A spectroscopic study of this new
tricycle and a mechanistic study of the reaction using an15
N-labelled intermediate have been
carried out.
13
N
HH
H NH
S
N
N
N
N
NH
S O
O
O
O
NH2
NH2
NH
S
N
NH2
NH2
O
O
NH2
2
Figure-1.8
Klein, Jean F.et al33
(1993) reported below compounds.
N
SN
CH3
O
OCH3
RFVP
-SO2 NN
CH3
CH3
R
Figure-1.9
Chaio-Ho Lee et al.34
(1993) showed that the treatment of esters with alkylamine to give
pyridone derivatives.
NH2SO2NH2
+(EtO)2CHCH2CO2Et
NH
SO2
NH
EtO2C
EtO2C
N
R
O
EtO2C
RNH2
RNH2
NHRCO2Et
CO2Et
NHSO2NH
NHRCO2Et
CO2Et
Figure-1.10
14
Breining Tibor et al.(1995)35
reported the synthesis and anti-HIV-1 activity of these class
of derivatives.
NNS
NH2
OO
O
S
O
O
NNS
NH2
O O
O
SOH
NNS
NH2
O O
O
SOH
+
Figure-1.11
Shin Hyun-So.et al.36
(1995) studied the single crystal XRD of novel derivatives of these
class.
PhCH2NHSO2N=CHAr
+(EtO)2CHCH2CO2Et
TFA
298KNH
S
N
OO
Ph
EtO2C
Ar
Figure-1.12
Clerici Francesca et al.37
(1996) studied the cyclization reactions of these family
affording the thiadiazine derivative and the pyrimidine derivative .
S
N
OO
N
CH3
CH3
OCH3 N
SN
O O
N
CH3
CH3
OCH3
Figure-1.13
The development and X-ray structure of novel thiadiazine has been repoerted by
Chivers.et.al38
(1998). Brouant et al. (1989)39
15
NS
N
ClO
CH3CH3
Cl
Figure-1.14
NS
N
OO
CH3CH3
Figure-1.15
Campillo et.al.40
(2000) recently reported the novel compounds as shown below
NH
N
SO
O
NH2
NH2
NH2
+X R
2
R1
O
NH
N
S
N
N
R1
R2O
O
NH2
X=O,NCH
Figure-1.16
Cerecetto et.al.13
(2000) reported the new molecules which were analysed for their antifungal
activity.
NS
NRR
O O
OONH2SO2NH2
+2RNH2
RNHSO2NHRMalonyl Chloride
Aldehyde
PTSA NS
NRR
O O
OO
Y
Y=Heterocycle with N-Oxido function
Figure-1.17
16
Kawahara et al.12
(2003) reported compounds having equivalence of uracil: 2-pyridone
derivatives (U(X2O)X) and 3-oxo-1,2,6-thiadiazine-1,1-dioxide derivatives (U(SO2)X) and as
the result, the hydrogen bond energy of U(X2O)X-A and a complex of UX(SO2)X-A, was about
1.5 kcal/mol more stable than that of the corresponding adenine-uracil derivatives complex,
respectively. The energy difference between the imide tautomer and enol tautomer was smaller
than those of uracil derivatives. U(SO2)F can form a stable complex with A, and its imide
tautomer is stable.
Fernandez-Resa et al.41
(1981) reported the Preparation of alkyl and glycosyl derivatives
of .Reaction of these compounds with dimethyl sulfate gave the 4-methyl and 2,4-dimethyl
derivatives. With benzyl chloride and allyl bromide C-4 substituted compounds were obtained..
The structures of the corresponding nucleosides were elucidated by 1H NMR and UV by
comparing the latter with those of the alkyl derivatives.
Garcia-Munoz, G et al.42,
(1977) Oxidation reactions of these class were studied.
NS
N
O O
NH2 NH2
NOH
NS
NH
O O
NH2
NO2
NH2
Figure-1.18
7-Amino-derivative was prepared by two different ways.
N
N
SO
O
NH2
NH2
NH2
NH
NH
N
SO
O
N
NH2
N
Figure-1.19
Meyer R B Jr 43
(1979) reported cyclization reaction of this class of molecules with their
biological activity.
17
NH
N
NH2
CN
NH
S
N
NH
N
NH2
O
O
Figure-1.20
Helmut Teufel et al.44
(1960) patented the invention which concerns new substituted
derivatives of thiadiazine and the salts thereof which have valuable pharmacological properties,
as well as process for the production of these compounds.It has surprisingly been found that
substituted compounds of the general formula:
NS
N
R3
R4
OO
O O
R2
R1
Figure-1.21
Rupert Stresser et al45
(1995) reported the invention which relates to
thiadiazinecarboxamide derivatives of the general formula I (I) to processes for their preparation,
and to pharmaceuticals comprising them.
NS
N
OO
R2
R4
R3
R2
OH
N
O
R5
R6
Figure-1.22
18
John B.Wright 46
(1963) reported the novel organic compounds and to a novel process for
preparing the same.More particularly, the invention is directed to a novel process which
comprise condensing a sulfamide or an alkylsulfamide with an α,β-diketo ester.The novel
compounds of this invention can be represented by the following structural formula:
NS
N
OO
R1
R
y
O
Figure-1.23
Where R=H or alkyl;R1=alkyl,aryl,or substituted aryl;and Y=alkoxy,hydrazino or amino.
Marta Porcs-Makkay et al 47
(2010) reported the invention which is related to new
derivatives of the Formula (I), medicaments containing said new compounds, process for the
preparation thereof and the use of said derivatives in the medicine.
N
N
S
R7
R6
R5
R4
R3
O O
R1
R2
Figure-1.24
John B Wright reported 48
(1965) A novel process which comprise condensing sulfamide
or alkylsulfamide with α,γ-diketone.The novel compounds of the invention have the following
structural formula
N NS
R2
OO
R
R3
R1
Figure-1.25
19
Where R is selected from the group consisting of hydrogen and lower-alkyl;R1 is selected from
the group consisting of phenyl,benzyl and phenylethyl;R3 is lower alkyl,phenyl,methylphenyl,
halophenyl, lower-alkoxy-phenyl, pyridyl, benzyl and phenethyl.
Jose Elguero et al.49
(1982) reported the chemical and structural properties of 18 novel
compounds of this class. By comparison with the corresponding pyrazoles it could be established
that there are some analogies between pyrazoles and thiadiazine 1,l-dioxides. As a consequence,
the hypothesis will be made that these similarities are general and could be extended to a whole
variety of heterocyclic and alicyclic structures
N
N
O2S
R1
R2
R
NN
R
R1
R2
Figure-1.26
Liv Ragna Rohde wang et al 50
(1990) introduced the Carbon substituents exclusively into
the electrophilic 5-position in thiadiazine by 1,1-aduct formation with organomagnasium reagent
followed by reoxidation by manganese dioxide to the conjugated 5-substituted
heterocycle.Pd(II)-catalysed coupling reaction between organostannanes and the 4-bromo or 4-
iodo derivatives have been used for the introduction of a 4-carbon substituents.Methods for
chlorination,bromination or iodination in the 4-position are described.
N
N
O2S
R1
X
RMgBr
N
NH
O2S
R1
X
RH
MnO2
N
N
O2S
R1
X
R
Figure-1.27
20
RSnBu3
(Ph3P)2PDCl2
EDC,N2,50°CN
N
O2S
R
CH2-Ph
N
N
O2S
X
CH2-Ph
Figure-1.28
Ana I.Esteban et al 51
(1995) synthesised new acylonucleosides derivatives of thiadiazine.
NH
N
SO
O
NH2
NH2
HMDS/Pyr
OAC
O
OAC OACONN
S
OO
NH2 NH2
+OAC
ONNS
OO
COCH3
NH2 NH2
Figure-1.29
Giorgio A. Pagani 52
(1974) reported three derivatives have been shown to react with
a number of electrophiles affording 4-substituted products. Halogenation, nitrosation, azo-
coupling, and Mannich and Vilsmeier reactions have been performed, and nitration was also
successful provided that the substrates were N-methylated. N-methylation was conveniently
performed with diazomethane. The behaviour of this heterocyclic sulphone is strikingly
analogous to that of 2-pyrimidone.
SO2
NH
NH
SO2
NNHN
O
N
O2SN
R1
R2
R3
NHSO2
NCH3
PhCH3
Figure-1.30
X-Ray crystallography has essentially been used only as a method of structure
determination or confirmation A number of thiadiazine derivatives and fused systems have been
studied by XRD. In some cases, a comparative study with related pyrazole48
derivatives has been
21
carried out.The X-Ray structures of 7-amino derivative (ATTM)53
, 7-amino thiadiazine(ATT)54
,
3,5-diamino-4-hydroxyimino-4H-1,2,6-thiadiazine 1,1-dioxide56
, 7-Amino-3-methyl-4H-
imidazo[2,3-c][1,2,6]thiadiazine 5,5-dioxide57
, metal salt of 1,2,6-thiadiazine derivative58
, 3 and
4 substituted thiadiazine59
, simple thiadiazine 60
are also mentioned in the literature.
These heteroatomic rings are not aromatic and there is no reason to expect them to be
planar. The reported X-ray results demonstrate this nonplanarity and some other common
features emerge from the reported data. A selection of the results is presented here.
Except for some basic compound, all thiadiazine derivatives and fused systems with one or two
double bonds in the ring show the same molecular conformation more or less distorted. Thus, the
six-membered ring, excluding the S atom, is almost planar, the S atom being from 10.1711 to
0.7531 A out of plane. Compounds with no double bond in the ring, such as 2,6-substituted
1,2,6- thiadiazine-3,5-dione derivatives and the monopotassium salt of 2,6-unsubstituted
derivative as well as compound with one ketone group adopt a boat conformation.
The S atom is, in general, a distorted tetrahedron, with the 0-S-0 angle bigger than the
others around the S. In some derivatives, an intermediate character between a double or single
bond for the sulfone group has been found, whereas in other derivatives the two S-0 bonds are
different, showing a single and a double character.
In most derivatives studied, significant differences between the two S-N distances have been
measured. A considerable electron delocalization between the two rings in fused systems has
been detected in some cases.Intramolecular hydrogen bonds between C-5-H ... 0-4 occur in the
3-hydroxy-4-nitro derivative .In most cases, intermolecular hydrogen bonds of type N-H . . . N,0-
H.. . 0, and N-H..0 linked the molecules in the crystal packing.
22
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