化学原料药开发-异构体的分类 ISOMERS

ISOMERS

Definition

Isomers are compounds that have the same molecular (empirical) formula, but different structures, and demonstrate physico-chemical and pharmacological differences

Classification

Structural Isomers

Definition

Compounds with the same empirical formula, but whose atoms are connected in a different sequence

Chain isomers

–have different branching patterns of carbon chains

Position isomers

–the functional group is located on different carbons in the chain

–tend to have similar chemical properties

Functional group isomers

–have different types of bonds and hence different functional groups

–tend to have very different chemical properties

Tautomers

–compounds in which, under differing conditions eg pH, the substituent groupings may alter their position

–structural isomers that readily convert from one isomeric form to another and hence exist in equilibrium

Stereoisomers

Definition

Compounds which have the same empirical formula and whose atoms are attached in the same sequence, but differ in the spatial arrangement of the atoms

Significance

–may have marked pharmacokinetic and pharmacodynamic differences eg levo-bupivacaine is less cardiotoxic than dextro-bupivacaine, only levo isomer of morphine has opioid activity –different 3 dimensional arrangement → different ability to interact with receptors, enzymes and non-specific binding sites

–isomer-specific ability of a drug to produce a pharmacological effect is evidence supporting the presence of receptors

Enantiomers

–stereoisomers that are non-superimposable mirror images (like left and right hands)

–contain a chiral centre (an asymmetric carbon with four different groups attached to it) –identical physical properties, except the direction in which they rotate polarised light

Classification Systems

a) Rotation of polarised light to the:

left: levorotatory l- (-)

right: dextrototatory d- (+)

a racemic mixture contains equal amounts of levo and dextro isomers and therefore has no overall rotating effect on polarised light

b) Cahn Ingold Prelog convention

Ligands around the chiral carbon are assigned a priority based on their atomic number

(higher atomic number = higher priority)

Rectus (R-) priorities increase in clockwise direction

Sinister (S-) priorities increase in anti-clockwise direction

Not important to know the exact priority rules. Note that this system has nothing to do with rotation of polarised light and therefore classification in one system does not always

correspond to the same classification in the other. “Coincidentally”, this seemingly arbitrary nomenclature (R, S) are the initials of Mr R. S. Cahn.

c) Simple sugars and amino acids can be classified as D- or L- according to the clockwise or anticlockwise spatial arrangement of COOH, NH3, H and hydrocarbon chain around the chiral carbon. This is an old classification system, don’t bother learning it, just be aware of it.

(D- and L- are not to be confused with d- and l-!!)

Diastereoisomers

–Stereoisomers with different orientation of substituent groups on either side of a rigid bond (eg double bond or ring structure)

–Alternatively, can be thought of as isomers with two chiral carbons

Classification systems

a) cis- and trans-

cis- functional groups are on the same side of the double bond

trans- functional groups are on opposite sides of the double bond

eg mivacurium is presented as a mixture of isomers:

trans-trans 60%

cis-trans 30%

cis-cis 10%

b) other systems include syn-/anti- and Z-/E- (forget about this crap)

More detailed info on isomers can be found at