Sthi fPd Synthesis of Prodrugs - · PDF fileTapio Nevalainen 24.2.2012 1 Sthi fPd Drug...
Transcript of Sthi fPd Synthesis of Prodrugs - · PDF fileTapio Nevalainen 24.2.2012 1 Sthi fPd Drug...
Tapio Nevalainen 24.2.2012
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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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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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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
Bioorganic & Medicinal Chemistry, 14 (8), 2006, 2569-2580
O
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Synthesis of Amides
Ketorolac amide prodrugs for transdermal delivery
Indomethacin triethylene glycol amide prodrug
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Promoieties for Hydroxyl Group
O Rdrug
O
OOdrug R
Simple esters
CH
R'
OC
Odrug
O
R
O NH
drug
O
ROHdrug
Acyloxyalkyl ethers
Carbamates
O Odrug
O
R
CarbonatesO
OHdrug
OH
R1R2
O
R1
R2
Odrug
O
Acetals
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OPdrug
O
OH
OH
Phosphate esters
OPCH
R'
Odrug O
OHOH
Phosphonooxyalkyl ethers
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Promoieties for Hydroxyl Group
O
OHO OH
HN CHCl2
OH
O
ON
CH3
H3C
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OHN
O
Dipivefrine(prodrug of adrenaline)
NO2 OO
O
O
O-
Chloramphenicol succinate
HN
H3C
CH3
CH3O
O
N
CH3
H3C
Bambuterol(prodrug of terbutaline)
Synthesis of Phosphates
Drug OH +H2O
pyridine
DrugO
POH
O
HO
Drug OH
(EtO)2P(O)ClBase
O
POO
ODrug
POCl3TMS-Br
Drug OH +catalyst
2. Tetrazole,3. H2O2
DrugO
POO
O1. Di-tert-butyl N,N-diisopropyl-phosphoramidite
NP
OO
Di-tert-butylN,N-diisopropyl-phosphoramidite
OO
ODrug
ClOO
PO
O
ODrug
TFA
H3PO4HCl
t-BuO
t-BuO
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POO P
OHHO
O
di-tert-butyl chloromethyl-phosphate
Drug O SCH3
dimethylsulfidebenzoyl peroxide
or DMSO, Ac2O
HOPO(OBn)2/NISTHF/mol. sieves
O
PO
ODrug
OBnBnO
H2, 10% Pd-CAcOEt
Bioorg. Med. Chem. Lett. 6(15), 1837-1842, 1996
t BuO
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Preparation of Chloromethyl Phosphates
Chloromethyliodide with ammonium salt of di-tert-butyl phosphoric acid
Cl
I
O O- ClOO
PO
(n-Bu)4N+
Chloromethyl chlorosulfate with dialkyl and or dibenzyl phosphates
ClO
POO
O ClPO
O
Bioorg. Med. Chem. Lett.13(21), 2003, 3669-3672
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Buparvaquone phosphate prodrugs
Selective Synthesis of Phosphate Monoesters from Phosphoric Acid
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Acetonides and Acetals of Corticosteroids
Ciclesonide (CIC) is both prodrug and softdrug. It is activated by esterases in to active drug desisobutyryl CIC
OHO
O
O
O
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active drug desisobutyryl-CIC Fluocinonide is a prodrug that allow dermal
absorption by “masking” the hydroxyl groups (that can interact with the skin or binding sites in the keratin)
O
O
F
H
HH
F
Fluocinonide(Lidex)
Synthesis of Carbamates and Carbonates
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Synthesis of Capecitabine (Xeloda) a prodrug of antitumor agent 5-fluorouracil
Activation to the antitumor drug 5-fluorouracil
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Promoieties for Thiols
Promoieties for Carbonylgroup
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Example of Enolester: 4,5-dihydroisoxazol-3-yl
fatty acid esters to improve skin permeation of cycloserine
17Cycloserine fatty acid derivatives as prodrugs: Synthesis, degradation and in vitro skin permeability, Chem. Pharm. Bull.50(4):554-7,2002
Promoieties for Aminogroup
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Promoieties for Amino Group Phortess, a water soluble pro-drug of the anti-cancer agent 5F 203
J. J. MedMed. . ChemChem.. 2002, 45, 7442002, 45, 744--747747
Avizafone for diazepam avoids drowsy side effects of diazepamJ. J. PharmPharm, , PharmacolPharmacol. 1990, 42(4), 247. 1990, 42(4), 247--5151
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Ximelagatran, a prodrug form of direct thrombin inhibitor melagatranDrug. Drug. MetabMetab. . DisposDispos. 2003, 31, 645. 2003, 31, 645--651651
Prodrugs for tertiary amines•N-Phosphonooxymethyl Prodrugs of Tertiary Amines
General Synthetic Scheme
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Prodrugs for tertiary amines
N-acyloxymethyl prodrugs of bupivacaine and lidocaine((EurEur. J. Pharm. . J. Pharm. SciSci. 24 (5), 2005, 433. 24 (5), 2005, 433--440)440)
CH3
CH3
NH
O
N+
H3C O O
R
CH3 HCH3 CH3
Cl-
Cl-
bupivacaine prodrugR = -CH2CH2CH3, -CH(CH3)2,-C(CH3)3
CH3
CH3
NH
O
N
H3C
O
O
RCl
bupivacaine
CH3 HN
CH3 OCH3
CH3
CH3
Cl
50°C
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3
CH3
HN
O
N+
CH3
O
O
CH3CH3
pivaloyloxymethyl prodrugof lidocaine
CH3
N
O
N
CH3
O3
lidocaine
50°C
The synthesis of water-soluble phenytoinprodrugs
NH
O
OO OO
O OO
RCHO
HNNH
Opyr
HNN
O
HC
R
OH HNN
O
HC
R
O OH
HNN
O
O
HC
R
O
O
NN
O
OHNN
DCC, DMAP
HNN
O
O
HC
R
Cl
O P O-
O
OBn
Ag+
Phenytoin glutaratePCl3
22Bioorg. Med. Chem. Lett. 9 (1999) 1859-1862
O
Bn
OPOO
OBn
Bn
HNN
O
O
HC
R
H2, Pd-C
OHPOHO
O
HNN
O
O
HC
R
R=H, Phosphenytoin
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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
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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)
Rolitetracycline liberates tetracycline in vivo
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