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INTRODLICTION :
Pharmacology (derived from Greek words. pharmacon-drug; logos-discourse in) consists
of detailed study of drugs - its source. physical and chemical properties. compounding,
biochemical and physiological effects. pharmacodynamics (its mechanism of action).
pharmacokinetics (absorption. distribution. biotransformation and excretion), therapeutic
and other uses of drugs.
According to WHO definition 'Drug is any substance or product that is used or intended
to be used to modify or explore physiological system or pathological states for the
benefit of the recipient'.
Medicinal or pharmaceutical chemistry is a scientilic discipline at the intersection of
chemistry and pharmacology involved with designing, synthesizing and developing
pharmaceutical drugs. Medicinal chemistry involves the identilication, synthesis and
development of new chemical entities suitable for therapeutic use. It also includes the
study of existing drugs, their biological properties, and their quantitative structureactivity relationships (QSAR). Pharmaceutical chemistry is focused on quality aspects of
medicines and aims to assure fitness for the purpose of medicinal products.
Medicinal chemistry is a highly interdisciplinary science combining organic chemistry
with biochemistry, computational chemistry, pharmacology. pharmacognosy, molecular
biology, statistics, and physical chemistry.
Fighting disease with drugs is the timeless struggle; its begging echoed out of the
primeval jungle. Man' s survival on the planet has depended upon its success. Today the
conflict continues unabated in the laboratory and clinic. The scientific approach to this
struggle is pharmacology. In return for the contributions of fundamental science to
medicinal chemistry, the latter has given the chemical. biological and engineering
science a new input in many fields. The discovery of the medicinal usefulness of a
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compound has always stipulated inquiry into the chemical reaction and improved
methods of preparation of similar substances.
Chemists have created new drugs and hormones, as well as vitamins and other essential
biochemicals, and have developed methods of substances available at reasonable cost.
Investigations in medicinal chemistry are undertaken as an adventure of the human spirit,
essentially an artistic enterprise, stimulated largely by curiosity and served disciplined
imagination. Moreover. most medicinal scientists do their work for the fun of it, in spite
of the uncertainty of the out come of their experiments. This uncertainty is great enough
even in the most carefully planned scientific research programmes, but it becomes
overpowering in medicinal chemistry. We still do not know, in a single instance, the
details of the events by which a drug or metabolite exerts its biological effects. This
greatly impairs prediction of the action of drugs and success in their design.
This dilemma has both stimulating and sobering effects on the progress of medicinal
chemistry. The need for better and more effective drug has greatly increased research on
medicinal science because both scientists, and the sponsors of their work. realise that the
odds of success may be proportional to the amount of work performed.
As Schiller wrote "To one man science is the highest, the heaven goddess; to another it is
a proficient cow that supplies him with butter". In balancing the low chances of practical
clinical success in medicinal research against necessity to build up our store house of
knowledge, medicinal scientists have to rely on inner strength and purposeful
determination. The small club of medicinal scientists gratefully seized upon. the few
prototypes of therapeutically active compounds provided by nature or by sheer chance
observation. The main concern of pharmaceutical chemistry has remained the analyses
and preparation of drugs. Medicinal chemistry tries to hope that biochemical rationales
for drugs discovery may be found. The interpretation of drugs action at the molecular
level is the intellectual goal of medicinal chemistry. It has provided professional
excitement, dedication and scicntific fuel to the best of medicinal scientists.
Drug use and abuse is as old as mankind itself Human beings have always had a desire
to eat or drink substances that make them feel relaxed. stimulated, or euphoric. The
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oldest records of therapeutic plants and minerals stem from the ancient Chinese, the
Hindus, the South American and the Mediterranean peoples of antiquity. The earliest
references about medicinal preparation in writing come from India in RIGVEDA and
from China in their MATERIA MEDICA 2500 - 3000 B.C. In India later on, a large
number of medicinal preparations including A YURVEDA were described by physicians
such as CHARAK, SUSHRUTA, VAAGBHATT and others.
Humans have used drugs of one sort or another for thousands of years. Wine was used at
least from the time of the early Egyptians; narcotics from 4000 B.C.; and medicinal use
of marijuana has been dated to 2737 BC in China.
As time went by, "home remedies" were discovered and used to alleviate aches, pains
and other ailments. Most of these preparations were herbs, roots, mushrooms or fungi.
They had to be eaten, drunk, rubbed on the skin, or inhaled to achieve the desired effect.
One of the oldest records of such medicinal recommendations is found in the writings of
the Chinese scholar-emperor Shen Nung, who lived in 2735 BC. He compiled a book
about herbs, a fore runner of the medieval pharmacopoeias that listed all the then-known
medications,
He was able to judge the value of some Chinese herbs. ror example, he found that
Ch'ang Shan was helpful in treating fevers. Such fevers were, and still are, caused by
malaria parasites.
South and Central American Indians made many prehistoric discoveries of drug-bearing
plants. Mexican Aztecs even recorded their propcrties in hieroglyphics on rocks, but our
knowledge of their studies comes mainly from manuscripts of Spanish monks and
medical men attached to the forces of the conquistador Hernan Cortes (1485-1547).
Pre-Columbian Mexicans used many substances, ii'om tobacco to mind-expanding
(hallucinogenic) plants, in their medicinal collections. The most fascinating of these
substances are sacred mushrooms, used in religious ceremonies to induce altered states
of mind, not just drunkenness.
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These were all naturally occurring substances. No refinement had occurred. and isolation
of specific compounds (drugs) had not taken place.
As the centuries unrolled and new civilizations appeared. cultural. artistic. and medical
developments shifted toward the new centers of power. A reversal of the traditional
search for botanical drugs occurred In Greece in the fourth century Be when
Hippocrates (estimated dates, 460-377 BC). the "Father of Medicine" became
interested in inorganic salts as medications.
Hippocrates' authority lasted throughout the Middle Ages and reminded alchemists and
medical experimenters of the potential of inorganic drugs. In fact, a distant descendant of
Hippocrates' prescriptions was the use of antimony salts in elixirs (alcoholic solutions)
advocated by Basilius Valentius in the middle of the 15th century and by the medical
alchemist Phillippus Aureolus Paracelsus (born Theophrastus Bombast von Hohenheim,
in Switzerland, 1493-1541).
South American Indians. especially those in the Peruvian Andes mountains, made
several early discoveries of drug-bearing plants. Two of these plants contain alkaloids of
worldwide importance that have become modern drugs. They are cocaine and quinine.
Cocaine's potential for addiction was known and used with sinister intent by South
American Indian chiefs hundreds of years ago.
In sixteenth century. extracts of cinchona bark had been used against malaria and
ipecacuanha roots for treatment of amebiasis. which are now-a-days. known to contain
quinine and emetine respectively.
The real growth of the systematic study of drugs in relation to their chemical nature had
to await the isolation of pure compounds. Seturner in 1816 isolated morphine from
opium, and since that time the isolation of active principles from crude drugs has
proceeded until the present time and even now is being actively pursued. The only
difference made by the passage of 192 years is that where the early workers concentrated
themselves with isolating alkaloids from materials containing them in fair quantity
present day researchers obtain very minute quantities of active compounds from
materials which contain only the smallest trace as for example. isolation of Vitamin B 12.
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a naturally occurring cobalt compound present in liver only to an extent of a milligram or
so per kilogram of liver. Perhaps the most beneficial medicinal innovation of the
nineteenth century was the discovery of general anesthesia. Davy (1778 - 1829)
intruduced nitrous oxide (laughing gas) as an inhalation anesthetic, and this was followed
by the first clinical experiments with ether in surgical amphitheater.
One imp0l1ant period of development in this subject was the two decades from 1880 1890, which saw the introduction of Knorr's antipyrine (1883) and Dresser's aspirin
(1899), together with the accidental discovery in 1888 of the earliest synthetic hypnotic
sulphonal, although it was not until 1904 that V.Morning and E.Fischer discovered
diethyl barbituric acid (Veronal). At the turn of century Stotz synthesized the first
honnone Adrenaline (1904) and Burger and Dale in 1909 made a fundamental study of
the eIIect of chemical structure in the series of sympathomimetic amines on the
physiological effects of the compounds.
One of the greatest practitioners of medicinal Chemistry, PAUL EHLRICH (1854 1915), laid the foundation of chemotherapy and dispelled the widely held view of the
immunologist Bering that chemical were more toxic to the host than to pathogenic
microbes.
During the nineteenth century, a number of natural products were isolated and subjected
to detailed investigation of their structure and pharmacological action. Some of the
compounds were found to possess a definite physiological activity and later it was
observed that the physiological activity of a compound is associated with a particular
structural unit or group and if this structural unit or group presents in other compound the
latter also becomes biologically active. Such a part of the drug which is responsible for
the actual physiological activity is known as pharmacophore group. The pharmacophoric
group is then somewhat modified by the commen and simple unit process to give more
active compounds with low toxicity. Although there is no broad relationship between the
structure and biological activity of the various groups, yet some physiological effect is
often associated with a particular structure.
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CHEMOTHERAPY:
The term chemotherapy was introduced by Paul Ehrlich to indicate the treatment of
microbial disease by the administration of a drug which has a lethal or inhibitory effect
on the microbe responsible and was described as a "Magic bullet" which when
introduced into the body, would destroy only the bacteria at which it was aimed. He also
pronounced many of the current concepts of chemotherapy.
A chemotherapeutic agent is defined in terms of its function rather than its origin. The
science of chemotherapy rests on many disciplines, which includes, organic chemistry,
natural product research, biology of the invader and host, pharmacology, toxicity and
therapeutics. Prontosll (2, 4 - diaminoazobenzene - 4'-sulphanamide) introduced by
Domagk in 1932 was the first chemotherapeutic agent active against bacteria. In spite of
its therapeutic effects had no in vitro antibacterial activity.
The chances of devising a clinically useful medicinal chemical are indeed very slim,
since several restrictive conditions are super imposed, even on the best laboratory
findings high potency, should have a minimum of side effects and acute toxicity and
virtually no chronic toxicity. No wonder that only small number of novel drugs are
introduced into clinical practice. Every kind of drug needs improvement and should be
replaced by more specific agents with fewer side effects. One cannot abandon the hope
of perfecting the action of existing compounds on structural modifications.
The systematic research work in pharmaceutical laboratories had led to the introduction
of more systematic drugs in the modern times. The synthetic work is carried out more or
less along the following lines:
O. Compounds are synthesized whose structures are more or less similar to naturally
occurring substances. This some times produces drug whose price is much less
than the naturally occurring one.
O. Attempts are made to prepare the compounds with simplified structures based on
the structures of natural drugs.
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O. Attempts are made to synthesize new drug which have the properties of certain
natural products, but have no relation to them in structure.
O. Attempts are made to synthesize new drug which are unrelated in structure and
properties to natural products.
Different types of drugs generally used are designated as anesthetic, analgesic.
antipyretic,
antituberculostatic,
antihistamine,
antihypertensive,
anticonvulsant,
anticoagulant, Anthelmintic, antimalarial, anti leprotic, anti-inflammatory, antiallergic,
antithyroid, sedative and hypnotics, etc .. which prompted us to synthesize several new
Naproxen derivatives.
Aims and objectives of present investigation are as under:
() To
generate
several
Naproxen
derivatives
bearing
biologically
active
heteromonocycles like thiazolidinones and 5-arylidines.
() To characterize these products for their structural assignment uSll1g elemental
analysis and various spectroscopic techniques like IR and NMR.
() To study, the structure - activity relationship and screen these new derivatives for
their antibacterial, antifungal, antitubercular, analgesic and antiinflammatory
activities.
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In the present thesis, it is our modest effort to devise some new organic compounds
containing NAPROXEN moiety, an analgesic and anti-inflammatory agent.
The following types of the compounds have been prepared and tested for their
antimicrobial activities and anti-intlammatory, analgesic activities using in vivo method.
The spectroscopic analysis, elemental analysis and physical properties of the compounds
have been studied.
1. PART - I
: 4-0XO-THIAZOLIDINES
2. PART - II : 5-ARYLIDINES
3. PART - III: FORMAZANS
4. PART - Ill: BIOLOGICAL ACTIVITY, QSAR AND CHARACTERISATION
DATA
3. I:-.ITRODUCTION TO DRUG: NAPROXEN
Naproxen (INN) (pronounced) is a non-steroidal anti-inflammatory drug (NSAID)
commonly used for the reduction of moderate to severe pain, fever, inflammation and
stiffness caused by conditions such as osteoarthritis, rheumatoid arthritis, psoriatic
arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and the
treatment of primary dysmenonhea. It works by inhibiting both the COX-I and COX-2
enzymes. I Only the (S) stereoisomer of naproxen has the desired antiimflammatory
activity and is safe to use. The (R) stereoisomer is reported to be a liver toxin. Since it is
much more expensive to manufacture enantiomerically pure compounds, there is the
potential for counterfeit supplies to enter the market which are not enantiomerically pure.
In other words, the compounds would contain some mixture of two enantiomers (R & S)
instead of being 100 % of the (S) stereoisomer. 2
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1. CHEMICAL NAME: 3
(c) 2-Naphthalene acetic acid. 6-methoxy-a-methyl-.(S)-.
(c) (S)-6-Methoxy-a-methyl-2-naphthalene acetic acid
2. STRllCTURAL FORMULA: 3
COOH
4. MOLECULAR WEIGHT: 3 230.26
5. ELEMENTAL COMPOSION: 3
C = 73.03%
H=6.13%
0=20.84%
6. PHYSICAL PROPERTIES: 3
(d) Melting Point:
The melting point ofNaproxen is 156 ±
iJc
(d) Form. Colour. Odour:
Naproxcn occurs as a white or almost white crystal with characteristic odor.
(d) Solubility:
Being highly hydrophobic Naproxen is practically insoluble in water.
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It is readily soluble in many organic solvents.
Soluble in ethanol (96%) and in methanol
Freely soluble in chloroform
(d) Dissociation constant (pKa) : pKa
=
4.2
7. PHARMACOLOGy:4
Naproxen is a member of the arylacctic acid group of nonsteroidal anti-inflammatory
drugs (NSAIDs). Naproxen has analgesic and antipyretic properties. As with other
NSAIDs, its mode of action is not fully understood; however, its ability to inhibit
prostaglandin synthesis may be involved in the anti-inflammatory effect.
Mechanism of action: 4
The mechanism of action of naproxen, like that of other NSAIDs, is believed to be
associated with the inhibition of cyclooxygenase activity. Two unique cyclooxygenases
have been described in mammals. The constitutive cyclooxygenase, COX-I. synthesizes
prostaglandins necessary for normal gastrointestinal and renal function. The inducible
cyclooxygenase, COX-2, generates prostaglandins involved in inflammation. Inhibition
of COX- I is thought to be associated with gastrointestinal and renal toxicity while
inhibition of COX-2 provides anti-inflammatory activity.
Therapeutic Indications: 4
Naproxen is indicated for the treatment of juvenile rheumatoid arthritis, rheuma~oid
arthritis, ankylosing spondylitis, osteoarthrosis, acute gout, and acute musculoskeletal
disorders (for example sprains and strains, tenosynovitis, fibrositis, lumbosacral pain,
direct trauma, and cervical spondylitis), and dysmenorrhoea.
32
Adverse reactions:;
1% to 10%:
Cardiovascular: Edema (3% to 9%), palpitation «3%)
Central nervous system: Dizziness (3% to 9%), drowsiness (3% to 9%), headache (3% to
9%), lightheadedness «3%), vertigo «3%)
Dermatologic: Pruritus (3% to 9%), skin eruption (3% to 9%)
purpura «3%), rash
Endocrine & metabolic: Fluid retention (3% to 9%)
Gastrointestinal: Abdominal pain (3% to 9%), constipation (3% to 9%), nausea (3% to
9%), heartburn (3% to 9%), diarrhea «3%), dyspepsia «3%), stomatitis «3%),
flatulence, gross bleeding/perforation, indigestion, ulcers, vomiting
Genitourinary: Abnormal renal function
Hematologic: Hemolysis (3% to 9%), ecchymosis (3% to 9%), anemia, bleeding time
increased
Hepatic: LFTs increased
Ocular: Visual disturbances «3%)
Otic: Tinnitus (3% to 9%), hearing disturbances «3%)
Respiratory: Dyspnea (3% to 9%)
Miscellaneous: Diaphoresis «3%), thirst «3%)
<I %: Agranulocytosis, alopecia, anaphylactic/anaphylactoid reaction, angioneurotic
edema, arrhythmia, aseptic meningitis, asthma, blurred vision, cognitive dysfunction,
colitis, coma, confusion, CHF, conjunctivitis, cystitis, depression, dream abnormalities,
dysuria, eosinophilia, eosinophilic pneumonitis, erythema multi forme, exfoliative
dermatitis, glossitis, granulocytopenia, hallucinations, hematemesis, hepatitis, hyper/hypoglycemia, hyper-/hypotension, infection, interstitial nephritis, melena, jaundice,
leukopenia, liver failure, lymphadenopathy, menstrual disorders, malaise, MI, muscle
weakness, myalgia, oliguria, pancreatitis, pancytopenia, paresthesia, photosensitivity,
pneumonia, polyuria, proteinuria, pyrexia, rectal bleeding, renal failure, renal papillary
necrosis, respiratory depression, sepsis, Stevens-Johnson syndrome, tachycardia, seizure,
syncope, thrombocytopenia, toxic epidermalnccrolysis ulcerative stomatitis, vasculitis
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Drug Interaction:'
Naproxen is associated with several suspected or probable interactions that affect the
action of other drugs. The following examples are the most common suspected
interactions.
Naproxen may increase the blood levels of lithium (Eskalith) by reducing the excretion
oflithium by the kidneys. Increased levels of lithium may lead to lithium toxicity.
Naproxen may reduce the blood pressure lowering effects of blood pressure medications.
This may occur because prostaglandins playa role in the regulation of blood pressure.
When naproxen is used in combination with aminoglycosides (e.g., gentamicin) the
blood levels of the amino glycoside may increase, presumably because the elimination of
aminoglycosides from the body is reduced. This may lead to more amino glycosiderelated side effects.
Individuals taking oral blood thinners or anticoagulants (e.g .. warfarin) should avoid
naproxen because naproxen also thins the blood, and excessi ve blood thinning may lead
to bleeding.
Con traindica tions:'
Naproxen is contraindicated in patients with known hypersensitivity. active peptic ulcer,
moderate to severe hepatic disease and infants.
LD50 (mg/kg):
The oral LD50 of the drug is 500 mg/kg in rats,
1200 mg/kg in mice.
4000 mg/kg in hamsters and
greater than 1000 mg/kg in dogs.
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8. PHARMACOKINETICS:
Absorption: 6
The absorption of naproxen in a new controlled-release (CR) formulation (1000 mg
tablet) was studied in fasting and postprandial volunteers. The total area under the
plasma
concentration-time
curve
averaged
2221
micrograms.hr/mL
in
fasting
participants and 2111 micrograms.hr/mL in postprandial participants; whereas the
difference was statistically significant (P
=
.025), the 95% confidence intervals indicated
equivalent values. The peak plasma concentration was lower in the fasting state (63.1
micrograms/mL) than in the fed state (86.1 micrograms/mL) (P
=
.0001). There were no
statistically significant differences between fasting versus postprandial values for the
mean absorption time (9.7 hr vs. 7.7 hr) or plasma half-life (17.3 hr vs. 17.6 hr). Hence,
the rate and extent of absorption of CR naproxen was not substantially altered by the
ingestionoffood.
Distribution:'
Naproxen has a volume of distribution of 0.16 Llkg. At therapeutic levels naproxen is
greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is
less than proportional increase in plasma levels due to an increase in clearance caused by
saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and
56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen. respectively). The
naproxen anion has been found in the milk of lactating women at a concentration
equivalent to approximately 1% of maximum naproxen concentration in plasma
Metabolism: '
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both
parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0desmethyl naproxen are further metabolized to their respective acylglucuronide
conjugated metabolites.
35
Excretion: 7
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from
any dose is excreted in the urine, primarily as naproxen « 1%). 6-0-desmethyl naproxen
« 1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in
humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's
metabolites and conjugates are shorter than 12 hours, and their rates of excretion have
been found to coincide closely with the rate of naproxen disappearance from the plasma.
Small amounts, 3% or less of the administered dose. arc excreted in the feces. In patients.
with renal failure metabolites may accllmulate.
Half _ Life: 7
Plasma half - life ofNaproxen is in the range 12 - 17 hours.
36
TABLE
1
PHARMACOKINETICS PARAMETERS OF NAPROXEN
PARAMETRS
VALUE
TIME TO PEAK LEVELS
2-4
HALF LIFE (hrs)
12 - 17
ANALGESIC ACTIVITY
Onset (hrs)
0.5
Duration (hrs)
8 - 12
VOLUME OF DISTRIBUTION
0.16 LlKg
METABOLISM
Approximately 28% of 4 dose
9. ADMINISTRATION AND DOSE
For analgesia or antipyresis in adults: The recommended dose of naproxen is
220 mg every 8 - 12 hr as needed. The maximum daily dose is 660 mg.
For rheumatoid arthritis dose in adults: Naproxen sodium to a maximum of
1100 mg (divided dose every 8 - 12 hr)
Naproxen sodium is not recommended for less than 12 years of age.
37
TABLE-2
DOSE LIMITS
Antirhcmatic
Analgesic I Antipyretic
1.1 gms I day
0.66 gms I day
Infants ( up to 1 year)
Not recommended
Not recommended
Children ( 1 - 12 years)
Not recommended
Not recommended
Adults I Adolescent
Pediatric
10. STORAGE CONDITIONS AND SHELF LIFE:
Always keep the naproxen in the same container it came
111.
Make sure it is tightly
closed. and alit of reach of children. Store this medication at room temperatllre and away
from excess heat and moisture: do not store this medication in the bathroom.
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TABLE-3
PROPREITORY PRODUCTS
No
1
Dosage Form
Tablet (2S0mg)
Name of product
manufacturer
Artagen
Ranbaxy
Movibon
Brown & Burk
Naprosyn
RPG Life science
2
Tablet (SOOmg)
Naprosyn
RPG Life science
3
Tablet (27Smg)
Xenobid
Rallis
4
Tablet (7S0mg)
Xenar-cr
Elder
(a) Melting Point:
The melting point of the drug power was estimated.
The melting point
=
1S6 ± 2
°c
(b) Identification:
The identity of Naproxen sample was established by taking the I.R. of the sample and
I.R. was compared with that given in pharmacopeia.
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