Tapio Nevalainen 24.2.2012 1 S th i fP d Drug synthesis II Tapio Nevalainen 2012 Synthesis of Prodrugs Drug Functional Groups and Synthesis of Prodrugs Drug Drug X R Drug Drug-X-R, where X is the fuctional group in a drug, in which promoiety R can be attached. X can be NH, CO NH, CO 2 H, OH, SH, CONH, SO H, OH, SH, CONH, SO 2 NH, C=O NH, C=O Prodrug should be: – inactive and nontoxic – easily synthesizable – chemically stable outside site of action – bioreversible (parent drug must be regenerated in vivo) 2
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Tapio Nevalainen 24.2.2012
1
S th i f P d
Drug synthesis II
Tapio Nevalainen
2012
Synthesis of Prodrugs
Drug Functional Groups and Synthesis of Prodrugs
DrugDrug XX RRDrugDrug-XX-RR,
where XX is the fuctional group in a drug, in which promoiety RRcan be attached.
XX can be NH, CONH, CO22H, OH, SH, CONH, SOH, OH, SH, CONH, SO22NH, C=ONH, C=O
Prodrug should be:
– inactive and nontoxic
– easily synthesizable
– chemically stable outside site of action
– bioreversible (parent drug must be regenerated in vivo)
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Tapio Nevalainen 24.2.2012
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Promoieties for carboxylic acids
C
O
OR
drug
HC
OCC
Odrug R
Simple esters
C
R'
CC
O
g
O
C
O
HN
Rdrug
C
O
OHdrug Acyloxyalkyl esters
Amides
HC
R'
OPC
O
Odrug
O
OHOH
Phosphonooxyalkyl esters
O
3
O
O
NH
O
NH2
O
Oseltamivir(Tamiflu)
O OH
NNH
O
OO
Enalapril
Synthesis of Esters
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Tapio Nevalainen 24.2.2012
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Synthesis of Naproxen Prodrugs for Topical Drug Delivery
Rautio et al. Eur. J. Pharm. Sci.2000, 11(2), 157-63
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Rautio et al. J. Med. Chem. 2000, 43, 1489-1494
Synthesis of Acyloxyalkyl Esters
HC
R'
OCC
O
Odrug
O
RC
O
OHdrug HC
R'
C
O
Odrug Cl
C
R'
HO
KI/DMF
-OC
O
R
C
O
Cldrug
SOCl2or(COCl)2
IZnCl2
Cl
I
C
O
Odrug Cl
TEA
C
O
Odrug
I
acetone OC
O
R
COdrug
-OC
O
R
Cl O
S OO
Cl
n-Bu4NHSO4
A. Nudelman et al. Eur. J. Med. Chem. 36 (2001) 63–74
O O
O1. ZnCl2 + CaCl2, CH2Cl2
2. 1,3,5-trioxane
chloromethyl-chlorosulfonate
OPO
OH
C
O
Odrug
OH1. AgOPO(OBn)2, toluene2. H2, 10% Pd/C
NaI
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AcyloxymethylAcyloxymethyl esters of esters of nalidixicnalidixic acidacid
Cyclic peptide prodrugsThe two-step activation of peptide prodrugs
23Curr. Pharm. Des. 1999, 5(4):265-87
Cyclic Prodrug of Tirofiban •Cyclic prodrug consisting of phenylpropionic acid linker between the piperidinylamine and the ‐COOH group
• Improve membrane permeation
Synthesis
24Org. Lett., 4 (4), 549 -552, 2002
Tapio Nevalainen 24.2.2012
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Mannich bases as Prodrugs• N-Mannich base prodrugs can be applied to both -NH acids (e.g. amides) and
amines, and undergo bioconversion to release the parent -NH acid or amine and an aldehyde by chemical hydrolysis in aqueous, alkaline, and slightly acidic solutions.
Mannich reaction is nucleophilic addition reaction of an aldehyde and any primary or secondary amine to produce resonance stabilized schiff base (iminium ion). The addition of a carbanion from a CH acidic compound (enolizable carbonyl compound, amide, carbamate, hydantoin or urea) to the schiff base gives another base called the Mannich base.
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Mannich Base Prodrugs
Hetacillin is rapidly hydrolyzed to ampicillin in aqueous solutions and in vivo ((U. U. KlixbullKlixbull and H. and H. BundgaardBundgaard, , IntInt. J. . J. PharmPharm.. 2323 (1985), (1985), pppp. . 163163––173)173)