Sthi fPd Synthesis of Prodrugs - Nevalainen 24.2.2012 1 Sthi fPd Drug synthesis II Tapio...

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Transcript of Sthi fPd Synthesis of Prodrugs - Nevalainen 24.2.2012 1 Sthi fPd Drug synthesis II Tapio...

  • Tapio Nevalainen 24.2.2012

    1

    S th i f P d

    DrugsynthesisIITapioNevalainen2012

    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 RR

    can 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)

    2

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    Promoieties for carboxylic acids

    CO

    OR

    drug

    HC

    OCC

    Odrug R

    Simple esters

    CR'

    CCO

    g

    O

    CO

    HN

    Rdrug

    CO

    OHdrug Acyloxyalkyl esters

    Amides

    HCR'

    OPC

    O

    Odrug

    OOH

    OH

    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

    5

    Rautio et al. J. Med. Chem. 2000, 43, 1489-1494

    Synthesis of Acyloxyalkyl Esters

    HCR'

    OCC

    O

    Odrug

    O

    RCO

    OHdrug HCR'

    CO

    Odrug ClCR'

    HO

    KI/DMF

    -OCO

    R

    CO

    Cldrug

    SOCl2or(COCl)2

    IZnCl2

    Cl

    I

    CO

    Odrug Cl

    TEA

    CO

    Odrug

    I

    acetone O CO

    R

    COdrug

    -OCO

    R

    Cl OS OOCl

    n-Bu4NHSO4

    A. Nudelman et al. Eur. J. Med. Chem. 36 (2001) 6374

    O O

    O1. ZnCl2 + CaCl2, CH2Cl2

    2. 1,3,5-trioxane

    chloromethyl-chlorosulfonate

    OPO

    OH

    CO

    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

    CHR'

    OC

    Odrug

    O

    R

    O NH

    drugO

    ROHdrug

    Acyloxyalkyl ethers

    Carbamates

    O Odrug

    OR

    CarbonatesO

    OHdrug

    OH

    R1R2

    O

    R1R2

    Odrug

    O

    Acetals

    8

    OPdrugO

    OHOH

    Phosphate esters

    OPCH

    R'

    Odrug O

    OHOH

    Phosphonooxyalkyl ethers

  • Tapio Nevalainen 24.2.2012

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    Promoieties for Hydroxyl Group

    OOH

    O OH HN CHCl2

    OHO

    ONCH3

    H3C

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    OHN

    O

    Dipivefrine(prodrug of adrenaline)

    NO2 OO

    OO

    O-

    Chloramphenicol succinate

    HN

    H3C

    CH3

    CH3O

    O

    NCH3

    H3C

    Bambuterol(prodrug of terbutaline)

    Synthesis of Phosphates

    Drug OH +H2O

    pyridine

    DrugOP

    OH

    O

    HO

    Drug OH

    (EtO)2P(O)ClBase

    OP

    OO

    ODrug

    POCl3TMS-Br

    Drug OH +catalyst

    2. Tetrazole,3. H2O2

    DrugOP

    OO

    O1. Di-tert-butyl N,N-diisopropyl-phosphoramidite

    NP OO

    Di-tert-butylN,N-diisopropyl-phosphoramidite

    O O

    ODrug

    ClOOP

    O O

    ODrug

    TFA

    H3PO4HCl

    t-BuOt-BuO

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    POO P OHHO

    Odi-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

    ClOP

    OO

    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

    OF

    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 aminesN-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 CH3Cl

    -

    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

    CH3Cl

    50C

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    3

    CH3

    HN

    ON+

    CH3

    O

    O

    CH3CH3

    pivaloyloxymethyl prodrugof lidocaine

    CH3

    N

    ON

    CH3

    O3

    lidocaine

    50C

    The synthesis of water-soluble phenytoinprodrugs

    NH

    O

    O O OO

    O OO

    RCHO

    HNNH

    Opyr

    HNN

    O

    HCR

    OH HNN

    O

    HCR

    O OH

    HNN

    O

    O

    HCR

    O

    O

    NN

    O

    OHNN

    DCC, DMAP

    HNN

    O

    O

    HCR

    Cl

    O P O-

    O

    OBn

    Ag+

    Phenytoin glutaratePCl3

    22Bioorg. Med. Chem. Lett. 9 (1999) 1859-1862

    OBn

    OPOO

    OBn

    Bn

    HNN

    O

    O

    HCR

    H2, Pd-C

    OHPOHO

    O

    HNN

    O

    O

    HCR

    R=H, Phosphenytoin

  • Tapio Nevalainen 24.2.2012

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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 CyclicprodrugconsistingofphenylpropionicacidlinkerbetweenthepiperidinylamineandtheCOOHgroup

    Improvemembranepermeation

    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. . 163163173)173)

    Rolitetracycline liberates tetracycline in vivo

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    Imidazolidin-4-one Derivatives of Primaquine

    Mechanism of hydrolysis

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