Sthi fPd Synthesis of Prodrugs - · PDF fileTapio Nevalainen 24.2.2012 1 Sthi fPd Drug...

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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

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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Imidazolidin-4-one Derivatives of Primaquine

Mechanism of hydrolysis

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