MEDC 527 Fall 20081 Heterocycles Nomenclature Hetero-atom is to be counted as 1 or as low as...
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Transcript of MEDC 527 Fall 20081 Heterocycles Nomenclature Hetero-atom is to be counted as 1 or as low as...
MEDC 527 Fall 2008 1
Heterocycles
Nomenclature
Hetero-atom is to be counted as 1 or as low as possible When there is more than one hetero-atom, preference is given to O, then S, then N,
then C. Also N-H presides over –N=. Mnemonic: Old Soldiers Never Cry When there is more than one hetero-atom, numbering should be as direct as possible
from one to the other Substituents are numbered as low as possible Acceptable prefixes include O=Oxa; S=Thia; N=Aza Common suffixes for N- and non-N-heterocycles For partially unsaturated systems, H
is(are) are used to indicate the location of saturation Hantzsch-Widman System of systematic name of heterocyclic compounds
MEDC 527 Fall 2008 2
Heterocycles
Hantzsch – Widman Nomenclature (adopted by IUPAC)
Ring Size
Saturated
Partly Saturated Unsaturated
3 -irane - -irene
4 -etane (dihydro) -ete
5 -olane (dihydro) -ole
6 -inane (di or tetrahydro) -ine
7 -epane (di or tetrahydro) -epine
8 -ocane (di, tetra, or hexahydro)
-ocine
OCommon name : ethylene oxideSystematic name : Oxa + irane …. Oxirane
OCommon name : furanSystematic name : Oxa + ole …. Oxole
MEDC 527 Fall 2008 3
Heterocycles
Hantzsch – Widman Nomenclature (adopted by IUPAC)
NH Common name : pyrroleSystematic name : H at 1 position + Aza + ole …. 1H-Azole
HN
Common name : piperidineSystematic name : Aza + inane …. 1H-Azinane
N
N Common name : pyrimidineSystematic name : two aza at 1, 3 positions + ine …. [1,3]-diazine
MEDC 527 Fall 2008 4
Heterocycles
HN
Azocane
NH
O
[1,3]-Oxazocane
S
NH
O
[1,3,7]-Oxathiazocane
S
N
O
4,5-dihydro-2H,8H-[1,3,7]-oxathiazocine
6-Methyl-2-phenyl-2H,8H-[1,3,7]-oxathiazocine
6-Methyl-2-phenyl-2H,3H,8H-oxocine
S
N
O
CH3
Ph
O
CH3
Ph
Hantzsch – Widman Nomenclature (adopted by IUPAC)
MEDC 527 Fall 2008 5
Oxygen Containing Heterocycles
3-Membered Ring :: Ethylene Oxide or oxirane
O
H
H
H
H
Oxirane formation in our body
Structure? Form at room temperature? Reactivity? Usage? Toxicity?
R
H
H
H
R
H
H
H
O
Oxidizing Enzymes
MEDC 527 Fall 2008 6
Oxygen Containing Heterocycles
O
O
O
CH3CH3
CH3
CH3
3
Vitam in K epoxide
O
Squalene Epoxide
Epoxides in our system
Role of Vitamin K epoxide?
Role of Squalene epoxide?
MEDC 527 Fall 2008 7
Oxygen Containing Heterocycles
Reactions of Epoxides
Acid Opening of Epoxides
O HR
H H
O HR
H H
OHH
HH
ROH
HR
H H
OHHClH+
+
H2O
MEDC 527 Fall 2008 8
Oxygen Containing Heterocycles
Reactions of Epoxides
Enzymatic opening of epoxides
O HR
H H
O HR
H H
OHHR
H H
OHEpoxideHydrase
H+
H2O
Opening of epoxides with amines (lysine mimics) and alcohols (serine mimics)
R’ÖH
O
H
H
R
HO
H
H
R
H
H+
OH
H
R
OR'
R'O
H
R
OHH++
R’NH2
O
H
H
R
HO
H
H
R
H
R'H2N
H
R
O
O
H
R
NH2R'+
R'HN
H
R
OH
OH
H
R
NHR'+
+ -
-+
MEDC 527 Fall 2008 9
Oxygen Containing Heterocycles
Higher Oxides
O
O
O O
O
Oxetane oxolane oxane 1,4-dioxane
Structure? Reactivity? Usage? Toxicity?
MEDC 527 Fall 2008 10
Oxygen Containing Heterocycles
Higher Oxides
Stability of these oxides change drastically on -substitution
O O OHCOOHH+, H2O
O OO OO O
OO H -, H 2 O
_ _
O OH OH OHH2O
O OMe OH OHH3O
+
Lactones anhydrides
Hemi-acetals acetals
MEDC 527 Fall 2008 11
Oxygen Containing Heterocycles
Examples of Acetals or Hemi-Acetals in Nature
CH2OH
OHH
OHH
OHH
CHO
O
H
OH
H
OH
HOH2C
HOH
Same side = Opposite side =
ribose hemiacetal
MEDC 527 Fall 2008 12
Oxygen Containing Heterocycles
Interconversion of - and -forms of sugars The phenomenon of mutarotation
O HH
HOH
O HH
C H O
C H 2 O H
O HH
O HH
HOH
O HH
C H 2 O H
OH
O HH
O HH
HOH
O HH
C H 2 O H
OH
HOH
HOH
HOH
O HH
C H O
C H 2 O H
O HH
glucose -g lucose g lucose -g lucose
OH
H
H
H
HOH
H
O
OHOH
O
H
H
H
HOH
H
OH
OHOH
O
H
H
H
HOH
H
OH
OHOH
H
H
H
H
OHOH
H
O
OHOH
D -glucose -glucose D -glucose -glucose
CH 2OH CH 2OH CH 2OH CH 2OH
OH
H
H
H
HOH
H
O
OHOH
O
H
H
H
HOH
H
OH
OHOH
O
H
H
H
HOH
H
OH
OHOH
H
H
H
H
OHOH
H
O
OHOH
D -glucose -glucose D -glucose -glucose
CH 2OH CH 2OH CH 2OH CH 2OH
MEDC 527 Fall 2008 13
Oxygen Containing Heterocycles
Examples of sugars in natural systems Deoxynucleic Acids and Ribonucleic Acids
O
H
OH
H
O
OH2C
H
Base
H
H = DNA= RNA
O
H
OH
H
O
OH2C
H
Base
H
H = DNA= RNA
N
NN
N
NH2
Sugar
N
NNH
NSugar
O
NH2
N
N
NH2
O
Sugar
NH
N
O
O
Sugar
CH3
Adenine Guanine Cytidine Thymidine
Live link: http://www.bmrb.wisc.edu/referenc/nomenclature/
MEDC 527 Fall 2008 14
Oxygen Containing Heterocycles
Sugars and Diabetes
OHH
HOH
OHH
CH2OH
OHH
HO
NH2
OHH
HOH
OHH
CH2OH
OHH
HOH
NHR
OHH
HOH
OHH
CH2OH
OHH
H
NR
..
Glycated Hemoglobin (HbA1c or GHb)Also called glycosylated hemoglobin. The saccharide equilibrium is the reason for the formation of
glycated hemoglobin in diabetic patients. Excess free plasma sugar, and therefore the open-chain aldehyde, reacts with the N-terminal NH2 group of hemoglobin (or lysine side chains) to form glycated
adducts, which are detected to confirm and monitor diabetes. The upper limit for a normal individual is 7% HbA1c.
MEDC 527 Fall 2008 15
Oxygen Containing Heterocycles
Sugars Monosaccharides
CH2OH
OHH
CHO
HOH
CHO
CH2OH
OHH
OHH
CHO
CH2OH
OHH
HOH
CHO
HOH
CH2OH
OHH
OHH
CHO
HOH
CH2OH
OHH
OHH
CHO
OHH
CH2OH
OHH
HOH
CHO
OHH
CH2OH
OHH
OHH
CHO
HOH
HOH
OHH
CH2OH
HOH
CHO
HOH
HOH
OHH
CH2OH
OHH
CHO
OHH
HOH
OHH
CH2OH
HOH
CHO
OHH
HOH
OHH
CH2OH
OHH
CHO
OHH
OHH
OHH
CH2OH
HOH
CHO
OHH
OHH
OHH
CH2OH
OHH
CHO
HOH
OHH
OHH
CH2OH
HOH
CHO
HOH
OHH
OHH
CH2OH
D-Glyceraldehye
D-Threose D-Erythrose
D-Lyxose D-RiboseD-Xylose D-Arabinose
D-Galactose D-AlloseD-Gulose D-GlucoseD-Talose D-AltroseD-Idose D-Mannose
MEDC 527 Fall 2008 16
Oxygen Containing Heterocycles
Reducing and Non-reducing Sugars
OHH
CHO
HOH
OHH
OHH
CH2OH
HOH
CHO
HOH
OHH
OHH
CH2OH
D-Glucose D-Mannose
OHH
CH2OH
HOH
OHH
OHH
CH2OH
HOH
CH2OH
HOH
OHH
OHH
CH2OH
D-Sorbitol D-Mannitol
Sorbitol is 66% as sweet as glucose. It is poorly absorbed and hence does not lead to high sugar levels in blood. It is not as calorific (~70% as calories as glucose) … used as sugar-free sweetner.
Mannitol is a good osmotic diuretic …. Intravenous drip …. Rapidly filtered by kidneys but not reabsorbed resulting in an osmotic effect of water/Na+ excretion
MEDC 527 Fall 2008 17
Oxygen Containing Heterocycles
Derivatized Forms of Monosaccharides
OHH
CHO
HOH
OHH
OHH
CH2OH
HOH
CHO
OHH
HOH
OHH
CH2OH
D-Glucose D-Idose
OHH
HOH
OHH
OHH
CH2OH
COOH
HOH
OHH
HOH
OHH
CH2OH
COOH
D-Gluconic Acid D-Idonic Acid
OHH
HOH
OHH
OHH
CHO
COOH
HOH
OHH
HOH
OHH
CHO
COOHD-Glucuronic Acid D-Iduronic Acid
H
H
H
OHH
O
OHOH
H
OH
COOH
-D-Glucuronic Acid
OH
OH
OH
HH
O
HH
H
OH
COOH
-D-Iduronic Acid
NH2H
CHO
HOH
OHH
OHH
CH2OH
D-Glucosamine
H
H
H
OHH
O
OHNH2
H
OH
CH2OH
-D-Glucosamine
O
O
CH2OSO3
NHSO3
OH
O
OH
OH
O
COO
O
O
CH2OSO3
NHSO3
OH
O
OSO3
OH
O
COOO
O
CH2OH
NHSO3
OH
O
OSO3
OH
O
COO
_
__
__
__ __ _
MEDC 527 Fall 2008 18
Oxygen Containing Heterocycles
Fructose
OHH
HOH
OHH
CHO
CH2OH
OHH
OH
HOH
OHH
CH2OH
OH
OHH
HOH
OHH
CH2OH
CH2OH
OHH
O O OH
CH2OHOH
H
H
OH
HOH2C
H
D-glucose ene-diol fructose (open-chain form) fructose (furanose form)
O
OH
H
H
O H
H O H 2 C
O
H
C H 2 O H
H
H
H
OHH
O
OHO H
C H 2 O H
H
-D -g lu co se -D -fru c to se
Sucrose
MEDC 527 Fall 2008 19
Oxygen Containing Heterocycles
Polysaccharides – Cellulose and Starch
H
HH
HO
H
OH
OC H 2 O H
O HH
H
H
OH
O
OHO H
C H 2 O H
O
H
* *n
1 4
14
C ellu lose (1 4 - -D -g lucose po lym er)
O
H
H
H
OH
O
OHOH
CH2OH
H
H
H
H
OH
O
OHOH
CH2OH
*H
*n
Amylose (14--D-glucose polymer)80% constituent of starch; 20% is amylopectin
MEDC 527 Fall 2008 21
Nitrogen Containing Heterocycles
3-Membered Ring in our system?
NClCH3
Cl
Mechlorethamine NH
NH2
CH3
OCONH2
O
O
OMe
Mitomycin C
O
PN N
N
TEPA
How do these work?
MEDC 527 Fall 2008 22
Higher Heterocycles Containing Nitrogen
Basic Ring Systems
NH N
HNH
NH
NH
O
NH
azetidine pyrrolidine piperidine piperazine morpholine(azolidine) (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 ?
H2+
NH
NH
NH
N
N
N
H2+
H2+
pKA 9.6 pKA 9.9
MEDC 527 Fall 2008 23
Higher Heterocycles Containing Nitrogen
NHO
N
S
O
CH3
CH3
NH
O
R
COOH
N
S
O
RCONH
R'
COOH
NO
S NH2
CH3
CH3
OH
COOHNH
NO
S
CH3
CH3
OH
COOH
O
NCH3CH3
penicillin-lactam
cephalosporin
meropenem thienamycin
Examples of Drugs … 4-membered ring
Hydrolysis of -lactams …… acid/base and enzymatic conditions
NHO
RR'
NH3+
O
RR'
O
MEDC 527 Fall 2008 24
Higher Heterocycles Containing Nitrogen
Importance of -lactam ring in activity …… generation of resistance!!
Clavulinic Acid …… antidote to antibiotic resistance
N
O OH
OCOOH
NH
O OH
OCOOH
H
Nu-Enz-Ser-O
NH
OH OH
OCOOH
Ser-O
O
OSer
Enz Nu
NH
OH OH
COOH
Nu-Enz-Ser-OH
Enz- Nu
.. ..
....
..
Clavulinic acid-lactamase
N
O OH
OCOOH
NH
O OH
OCOOH
H
Nu-Enz-Ser-O
NH
OH OH
OCOOH
Ser-O
O
OSer
Enz Nu
NH
OH OH
COOH
Nu-Enz-Ser-OH
Enz- Nu
.. ..
....
..
Clavulinic acid-lactamase
MEDC 527 Fall 2008 25
Higher Heterocycles Containing Nitrogen
Examples of Drugs … 5-membered ring
atorvastatintryptophanpyrrole
NHNH
N
F
OH
OH
CH3CH3
O OOC
NH
NH2
COOH
clem astinen ico tine
pyrro lid ine
N H
N
O
C H 3
C lC H 3
NCH 3
(anti-hyperlipidemic agent)
(anti-histaminic)
MEDC 527 Fall 2008 26
Five-membered Rings Containing Nitrogen and Another Heteroatom
Nitrogen and Oxygen
NON
O
NO NHO
Oxazole(1,3-oxazole)
Isoxazole(1,2-oxazole)
Oxazoline(1,3-oxazoline)
Oxazolidine(1,3-oxazolidine)
NNHN
NH
NNH NHNH
Imidazole(1,3-diazole)
Pyrazole(1,2-diazole)
Imidazoline(1,3-diazoline)
Imidazolidine(1,3-diazolidine)
Acid – Base Properties
Ist pKA ?IInd pKA ?Why is imidazole not strongly basic ?pKA with greater substitution ?
MEDC 527 Fall 2008 27
Higher Heterocycles Containing Nitrogen and Another Heteroatom
Stability to Water, Acid and Base Without substituents ?
With substituents ?
O
NH
OH
NH3+H3O
+
+ HCHO
NH
NH
NH3+
NH3+H3O
+
+ HCHO
O
N
OH
NH3+
NH
N
NH3+
NH3+
O
NH+
O
NH
OH2+H3O
+
+ HCHO
H3O+
+ HCHO
O
N
NH
N
H3O+
H3O+
no degradation
no degradation
MEDC 527 Fall 2008 28
5-Membered Aromatic Heterocycles
Metabolism of Aromatic Rings Containing One Heteroatom 5-Membered heterocycles generally react well with electrophiles; better
than benzene Stability to metabolic enzymes is generally lower than their carbocyclic
analogs EAS occurs at the 2-position of 5-membered heterocycles
N
H
N
HSO3H
S S Br
O O OH
sulfation
bromination
metabolic enzyme
MEDC 527 Fall 2008 29
O
N
NH
N
O
N
OH
NH
N
OH
O
NH
O
NH
NH
O
OH
NH2
NH2
NH2
O
NH2
H
Oxidativemetabolism
Oxidativemetabolism
5-Membered Heterocycles
Metabolism of Aromatic Rings Containing Two Heteroatoms
MEDC 527 Fall 2008 30
NO
CH3CH3
NH
S
NH2
OO
Sulfisoxazole
NN
CH3
OH
O2N
Metronidazole
CH3
NN
SO2NH2
CF3
Celecoxib
Examples of such heterocycles in Drugs
Higher Heterocycles Containing Nitrogen and Another Heteroatom
(anti-biotic agent) (anti-biotic agent) (pain medication)
MEDC 527 Fall 2008 31
Heterocycles Containing Sulfur
Basic Ring Systems
NSS
S
T e t r a h y d r o t h io p h e n e( t h io la n e )
T h io p h e n e( T h io le )
1 , 3 - t h ia z o le
S
N NN
CH3
CH3
S
N NN
CH3
CH3
methapyrilene
N
S
N
NH
O
NH2
OMe
S
O
COOH
ceftizoxime
S
N
NH2SO O
NH2
thiazolsulfone
Examples in Drugs
(Antihistamine) (Antibiotic) (Antimalarial)
MEDC 527 Fall 2008 32
Complex Heterocycles
Examples in Drugs
(Antibiotic) (Antihypertensive)
NH2 SNH NN
S CH3
OO
sulfamethizole
NN
S
NO N
H
OH
CH3 CH3
CH3
timolol
N
O
N O
NHAc
F
O
linezolid
NH
NH O
O
phenytoin
FF
OH
N NN
NNN
fuconazole
N
N
OH
Cl
CH3
N
NHN
N
losartan(for pneumonia) (Antihypertensive)
(Anti-infectious) (Anti-seizure)
MEDC 527 Fall 2008 33
6 Membered Rings Containing One Nitrogen
Examples in Drugs
N N
C H 3
O
S
NHO
O
R o s i g l i t a z o n e( p y r i d i n e + t h i a z o l i d i n e 2 , 4 - d i o n e )
A n t i - d i a b e t i c
N
O
C H 3
O E t
M e p e r id in e(p ip e r id in e )
re lie v e s p a in , n a rc o tic a n a lg e s ic
NH
C l
C H O C H 2 C H 2 N H 2CH 3
C O O E tM e O O C
A m lo d ip in e( d ih y d r o p y r id in e )
C a 2 + c h a n n e l b lo c k e r , A n t ih y p e r t e n s i v e , a n t ia n g i n a l
NH
NH
O
O O
C2H5
Phenobarbital(pyrimidine)
controls epilepsy, seizures,as a sedative to relieve anxiety
NN
NH
O
F C O O H
C i p r o f l o x a c i n( p i p e r a z i n e )A n t i b a c t e r i a l
( a n t h r a x )
NH
O
C H 3
P h e n m e tra z in e(m o rp h o lin e )
A p p e tite s u p p re s a n tC N S s tim u la n t
A m p h e ta m in e -lik e
MEDC 527 Fall 2008 34
6 Membered Rings Containing Two Nitrogens
Diazines
NN
N
N
N
N1,2-diazine 1,3-diazine 1,4-diazine(pyridazine) (pyrimidine) (pyrazine)
Acid – Base Properties
Ist pKA ?IInd pKA ?Why are these dibasic compounds not strongly basic ?
MEDC 527 Fall 2008 35
6 Membered Rings Containing Two Nitrogens
Pyrimidines
N
N
O
O
H
H
Three derivatives are important for RNA/DNA
N
N
O
O
H
H CH3 N
NO
H
NH2
Uracil Thymine Cytosine
Forms of Pyrimidines
N
N
O
O
H
HN
N
O
O
H
H
N
N
OH
OH
Urea Imide or Keto form Enol form(neutral) (acidic) (acidic)
MEDC 527 Fall 2008 36
NH
NH
O
O O
C2H5
Phenobarbital(pyrimidine)
controls epilepsy, seizures,as a sedative to relieve anxiety
N
N OO
H
H
O
Me
Ph
N
N OO
H
H
O
H
HN
N OO
H
H
H
H
NH
NH
O O
Ph
Ph
Phenytoin(anti-psychotic)
N
N OHOH
H
H
OH
H
pKA = ~4
(Enol form)
(Keto form)
6 Membered Rings Containing Two Nitrogens
Special Pyrimidines … Barbituric Acid
MEDC 527 Fall 2008 37
Heterocycles
More Complex Unsaturated Ring Systems
6-membered and higher heterocycles
N NN
N
NN
NPyridine pyridazine pyrimidine pyrazine
N
NO O
N
N
N
N
N
N
Q u i n o l i n e I s o q u i n o l i n e C o u m a r i n Q u i n a z o l i n e P t e r i d i n ep r e s e n t i n … … C h l o r o q u i n e P r a z i q u a n t e l W a r f a r i n P r a z o s i n T r i a m t e r e n e( a n t i m a l a r i a l ) ( a n t i - w o r m ) ( a n t i c o a g u l a n t ) ( a n t i h y p e r t e n s i v e ) ( a n t i h y p e r t e n s i v e
NH
N HNH
N
O
N
S
N
I n d o l e I s o i n d o l e B e n z i m i d a z o l e B e n z o x a z o l e B e n z t h i a z o l ep r e s e n t i n … . .T r y p t o p h a n L S D O m e p r a z o l e C h l o r o z o x a z o n e E t h o x z o l a m i d e( c o m m o n A A ) ( h y p n o t i c ) ( a n t i - u l c e r ) ( r e l i e v e s p a i n ) ( d i u r e t i c )
MEDC 527 Fall 2008 38
Heterocycles
More Complex Unsaturated Ring Systems
6-membered and higher heterocycles
N
NS
OON
N
NH
N
O
NH
S
N
NH
1 , 2 , 4 - b e n z o t h i a 3 H - 1 , 4 - B e n z o 1 , 3 - D i h y d r o - 2 H - 1 , 4 - P h e n o t h i a z i n e A c r i d i n e 5 H - d i b e n zd i a z i n - 1 , 1 , - d i o x i d e d i a z e p i n e b e n z o d i a z e p i n - 2 - o n e [ b , f ] a z e p i n ep r e s e n t i n … . .C h l o r o t h i a z i d e C h l o r d i a z e p o x i d e D i a z e p a m C h l o r o p r o m a z i n e Q u i n o c r i n e I m i p r a m i n e( a n t i h y p e r t e n s i v e ) ( s e d a t i v e , h y p n o t i c ) ( s e d a t i v e , a n x i o l y t i c ) ( a n x i o l y t i c ) ( a n t i b i o t i c ) ( a n t i - d e p r e s s a n t s )
NH
NH
N
O
N
Azepine diazepine oxazepine
MEDC 527 Fall 2008 39
7 and 8 Membered Nitrogen Containing Heterocycles
NNH
O
SOO
C H 3
T o l a z a m i d e( h e x a h y d r o a z e p i n e )O r a l h y p o g l y c e m i c
CH 3
C H 3
NC H 3
C H 3
OH
P e n ta z o c in e( o c ta h y d r o a z e p in e )
P a in r e l ie v e r
MEDC 527 Fall 2008 40
Six Membered Aromatic Heterocycles
Metabolism of Pyridines Pyridines are less reactive toward electrophiles than benzene Stability to metabolic enzymes is generally higher than their carbocyclic
analogs EAS occurs at the 3-position of 6-membered heterocycles
N N
NO2
N N
OH
nitration
metabolic enzyme