09 Chapter 1

1

1 INTRODUCTION

The approach for the practice of medicinal chemistry has been

developed by synthesizing new compounds based largely on

modification of known activity. In the search for safer and more potent

therapeutic agents, popular approach is synthesis and evaluation of

biologically active compounds. Literature survey reveals that majority

of pharmacologically active agents are heterocyclic compounds.

Heterocyclic compounds constitute the largest and most varied

family of organic compounds, and it has been estimated that more

than half of the organic chemistry publications are devoted to this

field. About 70% of all the drug molecules used in therapy are

heterocyclics. This is probably a reflection of the fact that many

heterocylclics can be included in the privileged scaffolds category

because they comply with the definition proposed by Evans in that

ligands for diverse receptors. In the light of these observations our

attention was drawn towards synthesis and study of pharmacological

activities of heterocyclic compounds containing halogens.

1.1. Introduction to halogenated heterocyclic Compounds:

Halogen containing drugs have entered into usage only since

1820. The incorporation of halogen atoms into a lead results in

anologues that are more lipophilic and so less water soluble.

Consequently halogen atoms are used to improve the penetration of

lipid membranes. However, there is an undesirable tendency for

halogenated drugs to accumulate in lipid tissue.

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The chemical reactivity of halogen atoms depends on both their

point of attachment to the lead and nature of the halogen. Aromatic

halogen groups are far less reactive than aliphatic halogen groups,

which can exhibit considerable chemical reactivity. The most popular

halogen substituents are the less reactive aromatic fluorine and

chlorine groups. However, the presence of electron withdrawing ring

substituents may increase their reactivity to unacceptable levels. The

change in potency caused by the introduction of a halogen or halogen

containing group will, as with substitution by other substituents,

depend on the position of the substitution. For example, the

antihypertensive clonidine with its o,o-chloro substitution is more

potent than its p,m-dichloro analogue1.

Clonidine ED20 0.01mg kg-1 ED20 3.00mg kg-1

1.1.2. The importance of the halogens in the exploration of

structure-activity relationships:

The replacement of a hydrogen atom in an active molecule by a

substituent (alkyl, hydroxyl, nitro, cyano, alkoxy, amino, halogen, etc.)

can deeply modify the potency, duration, perhaps even the nature of

the pharmacological effect2. The perturbations brought by the

substituent can affect various parameters of a drug molecule, such as

its partition coefficient, electronic density, steric environment,

3

bioavailability, pharmacokinetics and finally its capacity to establish

direct interactions between the substituent and the receptor or the

enzyme.

Solubility, Electronic M H M X modifies: density, Steric factors Bioavailability, Interactions

Steric effects:

The obstruction of a molecule by means of halogen substitution

can impose certain conformations or mask certain functions. In the

case of clonidine the bulky halogen atom prevent free rotation and

maintain the planes of the aromatic rings in a perpendicular position

to each other.

Electronic effects:

The electronic effects of the halogens are ascribed to their

inductive electron attractive properties. These later are maximal for

chlorine and bromine, less marked for iodine, and very weak for

fluorine. The mesomeric donor effect of the halogen atoms is usually

not involved in biological media. The influence of halogens on the

potency of monoamino oxidase inhibition and of dopamine uptake

blockade in-vitro are as below:

Monoamino Oxidase Inhibition IC50 (nM)

X = H : 1200 X = Br : 200 X = CF3 : 100

X = SO2 CF3 : 27

[3H] Dopamine uptake: IC50 (nM)

R1 = R2 = CH3O : 2876 R1 = H, R2 = Cl : 115 R1 = R2 = Cl : 75

4

The choice of the optimal substituent allows noticeable gains in

potency, compared with the parent molecule.

Hydrophobic effects:

The predominantly lipophilic influence of halogen substitution is

seen in the classical cases of the halocarbon anaesthetics, the

halogenophenol antiseptic and the halogenated insecticides. For these

compounds there is direct correlation between biological activity and

certain physicochemical parameters such as partition coefficient,

surface tension or vapour pressure. The accumulation of halogen

atoms favours the passage of the biomembranes and access to the

CNS.

1.1.3. Reactivity of the halogens:

In terms of bond strength, all C-halogen bonds, except C-F are

weaker than C-H.

Bond

Bond Strength (Kcal mol-1)

C-H

C-F

C-Cl

C-Br

C-I

93

114

72

59

45

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1.1.4. Usefulness of the halogens and of cognate functions3:

Depending upon their physical properties and their reactivity,

the derivatives of fluorine, chlorine, bromine and iodine present

various degrees of usefulness.

1) The most utilized halogens in medicinal chemistry are chlorine

and fluorine attached to a nonactivated carbon atom. Fluorine

presents the advantage of its small bulkiness (Vander Waals

radius comparable to that of hydrogen). It will be used

essentially to block metabolically sensitive positions of a

molecule. The CF3 group is comparable in size to chlorine and

can advantageously replace it when it is placed in an activated

position (e.g. R-CO-Cl R-CO-CF3). A chlorine substituent

simultaneously produces an increase in lipophilicity, an electron

attracting effect and a metabolic obstruction.

2) In certain active molecules the role of the fluorine or chlorine

atoms is not apparent at first glance. Thus for example two

compounds, chemically as m- trifluoromethylphenylethylamine

and 5-hydroxy tryptamine, show many pharmacological

analogies. In this case the explanation lies in the similitude of

the electrostatic potential maps.

3) Bromine is the less used halogen, and is usually incorporated

as a bromoaryl. The disadvantage of using bromine is that it

generates alkylating reactive intermediates more easily than

chlorine or fluorine and therefore it can confer, during long term

treatment, toxic potentialities to the molecule that bears it. This

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was the case for the anti-inflammatory-analgesic drug

bromfenac sodium withdrawn from the US market due to

reports of hepatotoxicity.

1.1.5. Biologically active halogenated compounds:

Introduction of the halogen atom into an organic molecule cause

dramatic changes in its biological profiles, mainly due to high

electronegativity of halogen. The changes in potency caused by the

introduction of a halogen by other substituents depend on the

position of the substitution. Halogen containing drugs with high

therapeutic value are presented in the following tables:

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Table 1.1: Therapeutic agents with Fluorine

S.No. Name Structure Activity

01

Flucloxacillin

Antibiotic

02

5-

Fluorocytosine

Antibiotic

03

Mefloquine

Antibiotic

04 Bicalutamide NH C C CH2

CH3

OH

O2N

CF3

SO2 F

O

Antineoplastic agent

05 Flumazenil N

NF

CH3O

N

C O

O

C2H

5

CNS depresent

06 Midazolan

Cl

F

N

N

NCH3

CNS depressant

07 Haloperidol F C CH2CH2CH2 N

OH

Cl

O

Anti psychotic

08 Penfluridol

N

CF3

ClOH

F

F

Antipsychotic

09 Fluoxetine

O

CF3

NHCH3

CNS stimulant

8

10 Atorvastatin F

N

NH

OH

OHOH

O

O

Cardiovascular

agent (for inhibition of HMG-CoA

reductase)

11 Sulindac CH2COOHFCH

3

CH

SCH3

O

Analgesic agent

12 Progabide

C NCH2CH

2CH

2CONH

2

OH

Cl

F

Antiepileptic

13 Diflunisal

F

OH

COOH

F

Analgesic Antiinflammatory agent

14 Enoxacin NHN

F

N

CH2CH

3

COOH

O

In the treatment of Urinary tract inflections

15 Flutrimazole

CF

N

N

F

Antifungal

16 Fluconazole

CH2

CH2COH

F

F

N

N

N

NN

N

Antifungal

17 Fluorouracil

N

N

O

OF

H

H

Antineoplastic

agent

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Table 1.2: Therapeutic agents with Chlorine

S.No. Name Structure Activity

01

Chloroquine

NCl

N

H CH

CH3

CH2

CH2

CH2

N

CH2CH

3

CH2CH

3

Antimalarial

02 Amodiaquine

NCl

N

OH

CH2H

N

C2H

5

C2H

5

Antimalarial

03 Pyrimethamine CH3

N

NH2

CH2

N

Cl

NH2

Antimalarial

04 Proguanil

NH

NH

NH

NH

NH

CH3

CH3

Cl

Antimalarial

05 Dicloxacillin

ON

Cl

Cl

NH

N

O

CH3

S

CH3

COOHO

CH3

Antibacterial

06 Cefachlor O

CH

NH2

NH

NO

S

Cl

COOH

Antibacterial

07 Mitotane CH Cl

Cl

CHCl2

Antineoplastic

agent

08 Clonidine

NH

Cl

Cl

N

N

H

H

Antihypertensive

10

09 Ticlopidine Cl

CH2 N

S

Cardiovascular

agents (Anti

Angina)

10 Diuril Cl

SO2 S

NH

N

NH2

O O

Diuretic

11 Mefruside Cl

SO2 SO

2

OCH

3NH

2

N

CH3

CH2

Diuretic

12 Dichloroisoproterenol Cl

Cl

OH

NHCH(CH3)2

Adrenergic

agent

13 Guanabenz

CH NNHCNH2

NHCl

Cl

Antihypertensive

agent

14 Diazepam

Cl

N

N

OCH3

CNS depressant

15 Oxazepam

Cl

N

CHOH

N

OH

CNS depresents

16 R=NH2 ,

Aproclonidine,

R=H, Clonidine,

R=OH,

4-hydroxyclonidine

N

Cl

Cl

R

N

NH

H

Antihypertensive

agent

11

17 Chloropheniramine

maleate CH CH

2CH

2N(CH

3)2

Cl

N CHCOOH

CHCOOH

Antihistaminic

agent

18 Niclosamide

CONH

Cl

NO2

OH

Cl

Anthelmintic

19 Zomepirac

CClN CH

2COONa

OCH

3

CH3

Analgesic

20 Chlorcyclizine

CH N N

Cl

CH3

Antihistamine

21 Lamotrigine

Cl

ClN

NN

NH2NH

2

Antiepileptic

22 Chloroquine Cl N

NHCHCH2CH

2CH

2N

CH3

CH2CH

3

CH2CH

3

Antimalarial

23 Miconazole

Cl

Cl

CH2

OCH

Cl

Cl

CH2

N

N

Antifungal

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Table 1.3: Therapeutic agents with Bromine

S.No. Name Structure Activity

01 Sulphobromoph

thalein

Br

Br

BrO

SO3Na

OH

SO3Na

OH

OBr

Diognastic

agaent

02 Remoxipride

Br

MeO OMe

NH

CH2

NC

2H

5

O

D2 recedptor

blocker (CNS

depressant)

03 Bretylium

Torsylate

CH

2

N

Br

CH2CH

3

CH3

CH3

SO3- CH

3.

Adrenergic agent

(Antiarrhythmic)

04 Pyridostigmine

Bromide N

O N

CH3

CH3

O

CH3

Br+

Treating in

Myastheniagravis

05 Demecarium

Bromide N

O N (CH2)10

N

CH3

CH3

CH3

CH3

CH3

O

NCH

3

CH3

CH3

O O

BrBr+

+

To treat wide

angle glaucoma

06 Bromodiphenly

dramine

Hydrochloride

Br

CHOCH2CH

2N(CH

3)2 . HCL

Antihistaminic

agent

07 Bromophnirami

ne Maleate NCH

Br

CH2CH

2N(CH

3)2 .

CHCOOH

CHCOOH

Antihistaminic

agent

13

08 Bromhexine

Br NH2

Br

CH

2

N

CH3

Antitussive

09 Bromperidol F CH

2CH

2CH

2

O

NOH

Br

In the

treatament of

Schizophrenia

10 Bromazepam

Br

NH

N

N

O

Anxiolytic

11 Temelastine N

CH3

CH

2

NH

NHCH2CH

2CH

2CH

2

O

N

CH3

Br

Antihistamine

12 Benzbromarone OCH

2CH

3

Br

OH

Br

O

Antiinflammatory

and analgesic

antipyretic

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Table 1.4: Therapeutic agents with Iodine

S.No. Name Structure Activity

01 Idoxuridine

I

NO

OH

O

NH

O

OH

Antiviral

02 Haloprogin

Cl

Cl

Cl

O

I

For the treatment of

superficial tinea inflections

03 Clioquinol

N

OH

I

Cl

Used in atopic dermatitis, eczema,

psoriasis and impetigo

04 Idoquinol N

I

I

Anti-infective

05 Loxaglate

I

II

COO-

OHCH2CH

2NHOC NHOCCH

2NHOC

I

II

CONHCH3

NCH

3CH

3CO

Diagnostic agent

15

06 Lopanoic

acid

I

II

NH2

CH2

CH

COOHC

2H

5

Diagnostic agent

07 Locetamic

acid

I

II

NH2

N CH

2

CH

CH3

COOH

CH3

O

Diagnostic agent

08 Propyliodone

I

O

N

I

CH2CO

2C

3H

7

Diagnostic agent

09 Lav

othyroxine

sodium

O

I

II

I

OH CH

2

CH

NH2

COO-.Na+

Hypothyroidism

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1.2. MICROWAVE CHEMISTRY:

Since 1950s microwave energy has found a variety of technical

applications in chemical and related industries particularly in food

processing, drying, polymer industries, analytical chemistry (micro

wave digestion, ashing, extraction), biochemistry (protein hydrolysis,

sterilization), pathology (histo processing, tissue fixation) and medical

treatments (diathermy). The first academic reports on the use of

microwave heating to mediate organic chemical reactions were

published by the group of Gedye and Giguere in 19864-6. The early

experients on Microwave Assisted Organic Synthesis [MAOS] were

typically carried out on sealed teflon or glass vessels in a domestic

household microwave oven without any temperature and pressure

measurents7-18. In 1990s the first attempts were made by Loupy et. al

at solvent free microwave chemistry (so called dry media reactions)

with eliminated danger of explosions19. Particularly at the beginning of

microwave assisted organic synthesis, the solvent free approach was

very popular since it allowed the safe use of domestic microwave ovens

and standard open vessel technology. A large number of interesting

transformations using dry media reactions has been published.

However technical difficulties relating non-uniform heating, mixing,

precise determination of reaction temperature and scale-up

approaches remained unsolved in dry media techniques. Besides the

dry media attempts, microwave-assisted synthesis in solution has

been carried under open vessel conditions. However, if solvents are

heated by microwave irradiation at atmospheric pressure in an open

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vessel, the boiling point of solvent limits the reaction temperature. In

order to achieve high reaction rates, good microwave absorbing

solvents (DMF, Ethylene glycol) with high boiling points have been

frequently used in open vessel microwave synthesis. However the use

of such solvents presented serious challenges during product isolation

and re-cycling of the solvent. In the mid 1990 christopher R. Strauss

developed a technique i.e. MAOS in dedicated sealed vessels using

standard solvents. Recently published [since 2001] literature in the

area of controlled MAOS reveals that this approach will be the method

of choice due to beneficial combination of rapid heating by microwaves

with sealed vessel technology for performing organic synthesis on a

laboratory scale in future. Since the year 2000, among academic

laboratories number of publications realated to MAOS has increased

dramatically, reaching the overall number of about 3000 by the end of

2005. Besides the drastic-reduction in reaction times, microwave

heating is also known to suppress side reactions, increase yield, and

improve purity and reproducibility20-25. Today dedicated microwave

reactors allow for careful control of time, temperature, pressure

profiles and also ensure reproducible protocol development, scale up

and transfer from laboratory to laboratory and from instrument to

instrument. Therefore, many academic and industrial groups are

already using MAOS as a technology for rapid reaction organization,

efficient synthesis of new chemical entities and for exploring chemical

reactivity.

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1.2.1.Mechanism of microwave heating:

There are three specific mechanisms of interaction between

materials and microwaves: [1] dipole interactions [2] ionic conditions

and [3] ohmic heating. All mechanisms require effective coupling

between components of the target material and the rapidly oscillating

electrical field of the microwaves.

Dipole interactions occur with polar molecules. The polar ends

of the molecule tend to align themselves and oscillate with oscillating

electrical field of the microwaves. Collisions and friction between the

moving molecules results in heating. Broadly, the more polar a

molecule, the more effectively it will couple with the microwave field.

Ionic condition is only minimally different from dipole

interactions. Obviously, ions in solution do not have a dipole moment.

They are charged species that are distributed and can couple with the

oscillating electrical field of the microwaves. The effectiveness or rate

of microwave heating of an ionic solution is a function of the

concentration of the ions in solution26-32. The behavior of any material

in a microwave field can be explained by studying its physical

parameters like the dissipation factor, often called the loss tangent.

The dissipation factor is a ratio of dielectric loss [loss factor] to the

dielectric constant.33 In ohmic heating conducting materials, the

conducting species, electrons, ions etc., are moved through

(microwave) field, causing polarization34. These induced currents will

cause heating through electrical (ohmic) resistance.35

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1.2.2.Advantages of Microwave Synthesis36 :

01. Higher reaction temperatures can be obtained by combining

rapid microwave heating with sealed-vessel (autoclave)

technology.

02. In many instances significantly reduced reaction times,

higher yields and cleaner reaction profiles will be

experienced, allowing for more rapid reaction optimization

and library synthesis.

03. Solvents with lower boiling points can be used under

pressure (closed vessel conditions) and be heated at

temperatures considerably highr than their boiling point.

04. Microwave heating allows direct in core heating of the

reaction mixture, which results in a faster and more even

heating of the reaction mixture.

05. Specific microwave effects that cannot be reproduced by

conventional heating can be exploited-for example, the

selective heating of strongly microwave-absorbing catalysts.

06. Easy on-line control of temperature and pressure profiles is

possible, which leads to more reproducible reaction

conditions.

07. Microwave heating is more energy efficient than classical oil-

bath heating because of direct molecular heating and

inverted temperature gradients.

08. It can easily be adapted to automated sequential or parallel

synthesis.

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09. The introduction of microwave energy into a chemical

reaction which has at least one component which is capable

of coupling strongly with microwaves can lead to much

higher heating rates than those which are achieved

conventionally.

10. Chemicals and the container materials for chemical reactions

do not interact equally with the commonly used microwave

frequenciesd for dielectric heating and consequently selective

heating may be achieved. Specifically the container

materials for a chemical reaction may be chosen in such a

way that the microwave energy passes thorugh the walls of

the vessel and heats only the reactants. The very high

temperatures which result when metal powders are exposed

to microwave fields have been used to create hot spots

which accelerate the reactions of the metals with gases, other

inorganic solids and organic substrates.

11. These selective interactions mean that microwave dielectric

heating is an ideal method for accelerating chemical

reactions under increased pressure conditions. Using quite

simple apparatus based either on transparent plastics, e.g.

Teflon or glass, it is possible to increase the temperature of a

reaction in common organic solvents up to 100 degree

centrigrade above the conventional boiling point of the

solvent. For example, ethanol has a conventional boiling

point of 79 degree centrigrade, microwave dielectric heating

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in a closed vessel can rapidly lead to temperatures of 164

degree centrigrade and a pressure of 12 atmospheres. This

higher temperature leads to a thousand-fold acceleration of

the reaction rate, for reactions which are studied in this

solvent.

12. Microwave assisted organic synthesis facilitates more rapid

synthesis and screening of chemical substances to identify

compounds with appropriate qualities.

13. It is useful in the discovery of novel reaction pathways due to

the extreme reaction conditions attainable by microwave

heating.

14. Microwave synthesis is useful in drug discovery process by

generation of a discovery lilbrary, hit-to-lead efforts, and lead

optimization.