Transcript  5/25/2016 1 Nitrogen Containing Heterocycles

Nitrogen Containing Heterocycles

3-Membered Ring
5/25/2016
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Nitrogen Containing Heterocycles

3-Membered Ring in our system?
H3C
O
Cl
N
H2N
Cl
Mechlorethamine
H3C
O
Mitomycin C

OCONH2
OMe
O
N P
N
N
NH
TEPA
How do these work?
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Higher Heterocycles Containing Nitrogen

Basic Ring Systems
H
N
H
N
azetidine

pyrrolidine
(azolidine)
H
N
H
N
H
N
O
N
H
piperidine
piperazine
morpholine
(perhydroazine) (perhydro-1,4-diazine) (perhydro-1,4-oxazine)
Acid – Base Properties
Ist pKA ?
IInd pKA ?

Stability to Water, Acid and Base
Without substituents ?
With substituents ?
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Higher Heterocycles Containing Nitrogen

Examples of Drugs … 4-membered ring
R
H
N
S
O
N
O
RCONH
CH3
N
NH
CH3
-lactam
COOH
COOH
cephalosporin
CH3
H3C
HO
N
O
S
COOH
meropenem

R'
O
O
penicillin
CH3
S
N
CH3
CH3
HO
N
O
NH
CH3
O
S
NH2
COOH
thienamycin
Importance of -lactam ring in activity …… generation of resistance!!
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Higher Heterocycles Containing Nitrogen

F
Examples of Drugs … 5-membered ring
OH
NH2
O
COOH
N
HO OOC
NH
N
H
NH
H3C
pyrrole
tryptophan
CH3
atorvastatin
(anti-hyperlipidemic agent)
CH3
Cl
H3C
N
N
O
NH
CH3
pyrrolidine
nicotine
clemastine
(anti-histaminic)
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Higher Heterocycles Containing Nitrogen and Another Heteroatom

Five membered Rings
O
N
N
Oxazole
(1,3-oxazole)
O
N
O
Isoxazole
(1,2-oxazole)
NH
Oxazoline
Oxazolidine
(1,3-oxazoline) (1,3-oxazolidine)

HN
O
N
N
Imidazole
(1,3-diazole)
HN
N
HN
N
H
Pyrazole
(1,2-diazole)
NH
Imidazoline
Imidazolidine
(1,3-diazoline) (1,3-diazolidine)
Acid – Base Properties
Ist pKA ?
IInd pKA ?
Why is imidazole not basic ?
pKA with greater substitution ?

Stability to Water, Acid and Base
Without substituents ?
With substituents ?
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Higher Heterocycles Containing Nitrogen and Another Heteroatom

CF3
Examples of such heterocycles in Drugs
N
N
CH3
H3C
O
O
N
S
H2N
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N
H
O
O2 N
HO
N
N
H3C
CH3
Sulfisoxazole
Metronidazole
(anti-biotic agent)
(anti-biotic agent)
SO2NH2
Celecoxib
(pain medication)
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Heterocycles Containing Sulfur

Basic Ring Systems
S
Thiophene
(Thiole)
Tetrahydrothiophene
(thiolane)

S
S
Examples in Drugs
N
1,3-thiazole
O
S
OMe
HN
N
COOH
H2N
N
N
N
N
CH 3
methapyrilene
(Antihistamine)
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O
CH 3
S
S
N
O
H2N
S
NH2
O
S
ceftizoxime
(Antibiotic)
thiazolsulfone
(Antimalarial)
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Complex Heterocycles

Examples in Drugs
OH
O
H2N
O
S
H
N
O
CH3
S
N
H
N N
sulfamethizole
N
N
S
N
CH3
H3C CH
3
timolol
(Antibiotic)
(Antihypertensive)
F
F
OH
N
N
N
N
N
NH
CH3
N
N
Cl
N
N
N
OH
N
fuconazole
(for pneumonia)
O
O
F
N
(Antihypertensive)
O
H
N
N
losartan
NH
O
O
NHAc
linezolid
(Anti-infectious)
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phenytoin
(Anti-seizure)
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6 Membered Nitrogen Containing Heterocycles

Examples in Drugs
O
O
O
H
N
OEt
O
N
MeOOC
S
N
Cl
CH3
COOEt
N
Rosiglitazone
(pyridine + thiazolidine2,4-dione)
Anti-diabetic
H3C
CH3
Meperidine
(piperidine)
relieves pain,
narcotic analgesic
N
H
CHOCH2CH2NH2
Amlodipine
(dihydropyridine)
Ca2+ channel blocker,
Antihypertensive, antianginal
O
F
O
HN
O
N
H
O
Phenobarbital
(pyrimidine)
controls epilepsy, seizures,
as a sedative to relieve anxiety
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N
C2H5
COOH
N
HN
Ciprofloxacin
(piperazine)
Antibacterial
(anthrax)
O
N
H
CH3
Phenmetrazine
(morpholine)
Appetite suppresant
CNS stimulant
Amphetamine-like
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Barbiturates / Barbituric Acids
O
H
Ph
N
O
O
H
Me
N
O
N
O
H
H
H
H
N
O
H
N
O
H
N
O
H
H
(Keto form)
pKA = ~4
O
HN
O
C2H5
N
H
H
H
N
O
Phenobarbital
(pyrimidine)
controls epilepsy, seizures,
as a sedative to relieve anxiety
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Ph
OH
HO
N
H
OH
(Enol form)
HN
O
Ph
N
H
O
Phenytoin
(anti-psychotic)
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Heterocycles
 More Complex Unsaturated Ring Systems
 6-membered and higher heterocycles
N
N
N
N
N
N
N
Pyridine pyridazine pyrimidine pyrazine
N
O
O
N
N
Quinoline
present in ……
Chloroquine
(antimalarial)
N
N
N
Isoquinoline
Coumarin
Quinazoline
Praziquantel
(anti-worm)
Warfarin
(anticoagulant)
Prazosin
(antihypertensive)
H
N
H
N
O
N
N
Pteridine
Triamterene
(antihypertensive
S
NH
N
Indole
Isoindole
present in …..
Tryptophan
LSD
(common AA) (hypnotic)
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Benzimidazole
Omeprazole
(anti-ulcer)
N
N
Benzoxazole
Benzthiazole
Chlorozoxazone
(relieves pain)
Ethoxzolamide
(diuretic)
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Heterocycles
 More Complex Unsaturated Ring Systems
 6-membered and higher heterocycles
O O
S
N
N
1,2,4-benzothia
diazin-1,1,-dioxide
present in …..
Chlorothiazide
(antihypertensive )
H
N
N
N
N
H
1,3-Dihydro-2H-1,4Phenothiazine
benzodiazepin-2-one
Acridine
Chlordiazepoxide
Diazepam
Chloropromazine
(sedative, hypnotic) (sedative, anxiolytic)
(anxiolytic)
H
N
H
N
Azepine
Quinocrine
(antibiotic)
5H-dibenz
[b,f]azepine
Imipramine
(anti-depressants)
O
N
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H
N
S
N
N
3H-1,4-Benzo
diazepine
O
diazepine
N
oxazepine
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7 and 8 Membered Nitrogen Containing Heterocycles
O
H
N
N O S
O
Tolazamide
(hexahydroazepine)
Oral hypoglycemic
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CH3
CH3
N
CH3
HO
H3C
CH3
Pentazocine
(octahydroazepine)
Pain reliever
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Heterocycles
 Electrophilic Aromatic Substitution in Heterocycles
 heterocycles generally react well with electrophiles; better than benzene
(except for pyridines)
 their stability to metabolic enzymes is generally lower than their carbocyclic
analogs
 EAS occurs at the 2-position of 5-membered heterocycles
 EAS occurs at the 3-position of 6-membered heterocycles
H
H
N
sulfation
N
SO3H
N
N
S
bromination
S
OH
Br
N
O
O
NO2
nitration
metabolic enzyme
N
OH
metabolic enzyme
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