Fundamentals of Medicinal Chemistry

O

O N

N NH

O N

O

CH 3 CH 3

CH 3

O N

N

N

N

CH 2 CH 2 OH

O OCH 2 Ph O

Cl OCH 2 Ph

P

ROH

ROH

ROH O

OCH 2 Ph

OCH 2 Ph

P

RO

O

OH

OH

P

RO

O

OH

OH

P

RO

O

OH

OH

P

RO

O O

Cl O

P

O

O

P

O

RO

H 2 / Pd,C

Br 2 / H 2 O

O

N

N

P

N OR

N

P

Br

H+

PHOSPHATE GROUPS

HYDROXY GROUPS

2-Methylphenol Mephenesin (muscle relaxant)

CH 3

CH 3

CH 3

OCH 2 CHCH 2 OH

CH 3 CH 3 OH

CH 3

OH

NaOH

O−Na+ CH

2 ClCHOHCH 2 OH

Etofylline (bronchodilator) Theophylline (bronchodilator) Dyphylline (bronchodilator)

O

O

O

N

N N

CH 2 OH

N

CH 2 CHOHCH 2 OH

SULPHONIC ACID GROUPS

H 2 SO 4

OH OH

SO 3 H

N N I

OH

N

SO 3 H

Various steps

8-hydroxy-7-iodo-5-quinolinesulphonic acid (topical antiseptic)

CH=CH−CH=N SO 2 NH 2

NaHSO 3

SO 2 NH 2

SO 3 Na

SO 3 Na

CH−CH 2 −CH−NH

N 4 -Cinnamylidenesulphanilamide Noprylsulphamide (antibacterial)

Figure 3.7 Examples of water solubilizing structures and the routes used to introduce them into

lead structures. Phosphate acid halides have been used to introduce phosphate groups into lead

structures. The hydroxy groups of the acid halide must normally be protected by a suitable

protecting group. These protecting groups are removed in the final stage of the synthesis to reveal

the water solubilizing phosphate ester. Structures containing hydroxy groups have been intro-

duced by reaction of the corresponding monochlorinated hydrin and the use of suitable epoxides

amongst other methods. Sulphonic acid groups may be introduced by either direct sulphonation

or the addition of bisulphite to reactive C¼C bonds amongst other methods

THE INCORPORATION OF WATER SOLUBILIZING GROUPS IN A STRUCTURE 69