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O NH
O
F3C
Cl
O NH
O
F3C
Cl
N
NN
OH
O
HN
OHPh
O NHtBuF
O
O
OHHOOH
F
Et
O O
O OH
OMeOO
HO N
Fluorine in Medicinal Chemistry
Niyi FadeyiLindsley’s Group
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Introduction of fluorine can be highly advantageous in pharmaceutical compounds
Alter chemical properties, disposition and biological activity, including its stability, lipophilicity, and bioavailability
20% of pharmaceuticals on the market are estimated to contain fluorine, including half of the top 10 drugs sold in 2005
Small size with high electronegativity
June 5, 2006 Volume 84, Number 23 pp. 15-24 and pp. 27-32 Chemical & Engineering News
Fabulous Fluorine
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The Effect of Fluorine Substitution on pKa
William K. Hagmann, J.Med. Chem., 2008, 51, 4359–4369Ve´ronique Gouverneur, et al, Chem. Soc. Rev., 2008, 37, 320–330
Lange’s Handbook of Chemistry, 15th ed.; Dean, J. A., Ed.; McGraw-Hill Inc.: New York, 1999.Brown, H. C.; . In Determination of Organic Structures by Physical Methods; Braude, E. A.,
Nachod, F. C., Eds.; Academic Press; New York, 1955
Fluorine have strong effects on the acidity (and basicity) of neighboring functional groups.
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Effect of Fluorine on physicochemical and Conformational Properties
Perturbation of pKa
Strongly modify pharmacokinetic properties of a pharmaceutical agent.
Modify binding affinity : reinforcement of the binding between drug and biological target.
Modulation of pKa may impact bioavailability by affecting transportation and absorption of the drug.
Ve´ronique Gouverneur, et al, Chem. Soc. Rev., 2008, 37, 320–330D. A. Smith, H. van de Waterbeemd and D. K. Walker, Methods and Principles in Medicinal
Chemistry, vol. 31: Pharmacokinetics and Metabolism in Drug Design, Wiley-VCH, Weinheim, 2006.
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Basicity and Bioavailability of 3-piperidiylindole Antipsychotics
Greater affinity for serotonin 5-HT2 receptors than for dopamine D2 receptorsReduce side effects, such as delusions and hallucinations
M. Rowley, et al. J. Med. Chem., 2001, 44, 160. Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330
Moderate bioavailability in rats Good pharmacokinetics in dogsGood selectivity for 5-HT2 receptors
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Basicity and bioavailability in a series of piperidinyl and piperazinyl indoles
Must be selective for 5-HT1D receptors over 5-HT1B receptors, as 5-HT1B receptors are implicated in coronary vasoconstriction
M. B. Van Niel., et. al . J. Med. Chem.,1999, 42, 2087.
Improved oral bioavailability
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The hERG (human ether a-go-go–related gene) is best known for its contribution to the electrical activity of the heart that coordinates the heart's beating
hERG K+ channel is a major component of the toxicity observed with many pharmaceuticals and it is estimated that 25-40% of all lead compounds show some activity towards the hERGion channel.
Introduction of fluorine strongly reduces amine basicity, impacting membrane permeability and interference with the hERG K+ channel associated with cardiovascular toxicity.
hERG K+ Channel
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β and γ fluorine to attenuate amine basicity: J. Med. Chem. 1999, 42, 2087.
hERG Toxicity
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Conformational Changes
Substitution of a hydrogen or hydroxyl group for a fluorine in biologically active molecules is commonly tolerated
Fluorine substitution therefore exerts only a minor steric demand at receptor sites.
William K. Hagmann, J.Med. Chem., 2008, 51, 4359–4369
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Effect on Conformational Changes
Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330A. G. Myers, J. K. Barbay and B. Zhong, J. Am. Chem. Soc., 2001, 123, 7207.
Conformational study on fluorinated analogues of HIV-1 protease inhibitor “Indinavir”
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Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in the treatment of patients with HIV
SAR studies showed that the presence of the trifluoromethyl group improved drug potency by lowering the pKa of the cyclic carbamate
Makes a key hydrogen bonding interaction with the protein.
Hydrogen Bonding
Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330G. L. Plosker, C. M. Perry and K. L. Goa, PharmacoEconomics, 2001, 19, 421.
J. C. Adkins and S. Noble, Drugs, 1998, 56, 1055.S. R. Rabel, S. Sun and M. B. Maurin, AAPS PharmSci, 2001, 3, 1.
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Rapid oxidative metabolism by liver enzymes (P450 cytochrome enzymes) and/or stomach acidic medium may decompose the drug.
Introducing fluorine atoms has been shown to be a powerful strategy.
P.N. Edwards in Organofluorine Chemistry: Principles and Commercial Applications R.E. Banks, B.E. Smart, J.C. Tatlow Eds, Plenum Press, N-Y 1994, pp. 502-509.
P.N. Edwards in Organofluorine Chem: Principles and Commercial Applications Plenum Press, N-Y 1994, pp. 502-509 F. Chorki, et al. J. Med. Chem. 2004, 47, 1423-1433.
Ki (nM) Plasmatic concentration(M receptor) ng/Kg
(after 1h, 30mg/Kg p.o)
0.45 21
0.40 805
Metabolic stability
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O
O
OHHOOH
Et
O O
O OH
OMeOO
HO N
Erythromycin
Macrolide antibiotic against pathogenic bacteriaUnsuitable for the treatment of the Helicobacter pyloriinfection, which causes gastritis
The drug decomposes under the acidic conditions of the stomach.
Better bioavailabilityLonger biological half lifeReaches tissue concentrations than Erythromycin
Effect of Fluorine on Metabolic Stability
S. Mabe, J. Eller and W. S. Champney, Curr. Microbiol., 2004, 49, 248.M. T. Fera, M. Giannone, S. Pallio, A. Tortora, G. Blandino and
M. Carbone, Int. J. Antimicrob. Agents, 2001, 17, 151.Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330
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Examples of Fluorinating Reagents
N+N+
F2BF4
-
Cl
Selectfluor(1-chloromethyl-4-fluorodiazoniabicyclo [2.2.2]octane
bis(tetrafluoroborate))
SO
ONS
O
O
F
NFSI(N-fluorobenzene-
sulfonimide)
SO2
N F
N-fluorocamphor sultam
NF
R1
R2 R3+
N-fluoropyridinium salt
R1 = H, MeR2 = H, Me, ClR3 = H, Me, ClX = BF4
-, OTf-
X-
ElectrophilicReagents
Unstable to heatExplosive
Stable to heat
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3
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R
O
HTf2O
R CH
OTfOTf
nBu4N+ Ph SnF
F
PhPh
-
RFF
O
R1 R2
DASTR1 R2
F F
ketones Gem-difluorides
OHR1 DFI
FR1
Alcohol
Aldehyde
Examples of Nucleophilc Fluorination
Angew. Chem., Int. Ed. 2005, 44, 214–231.
Tetrahedron Lett. 1992, 33, 7787.Synlett. 1993, 587
J. Org. Chem. 1999, 64, 5264.J. Org. Chem. 1999, 64, 7048.J. Org. Chem. 2000, 65, 4830.J. Am. Chem. Soc. 1997, 119,
11743.
NSF3
DAST
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J. Am. Chem. Soc. 1997, 119, 11743.
Synthesis of Glycosyl Fluoride
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Examples of Nucleophilc Fluorination
Tetrahedron Lett. 1979, 20, 2023.CsF, HF.Pyr, TBAF can be used
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Examples of Electrophilc Fluorination
Acc. Chem. Res. 2005, 38, 803–812.
J. Org. Chem. 1992, 57, 1597.
J. Org. Chem. 1999, 64, 5264.
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J. Org. Chem. 1993, 58, 2791.
J. Org. Chem. 1997, 62, 3340.
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NH
Me
NH
Selectfluor
CH3CN/H2O (1:1)RT, 71%
Me F
O
NH
NH
HNO
O
HN
HH Selectfluor
CH3CNTHF44% N
H
NN
HNH
H
H
F
F
H
O
O
Org. Lett. 2000, 2, 639.
Angew. Chem. Int. Ed. 2001, 40, 4461.
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Examples of Trifluoromethylation
J. Med. Chem. 1992, 35, 641.J. Org. Chem. 2002, 67, 7162.
Trifluoromethylated amino alcohol
Trifluoromethyl-L-proline
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Trifluoromethylation
Tetrahedron Lett. 1991, 32, 91.Chem. Rev. 1997, 97, 757-786
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Aromatic Fluorination
Science. 325, 1661. (2009)
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Enantioselective Electrophilic Fluorination
Substrate-controlled fluorination: diastereoselective electrophilic fluorination of chiralenolates or enol ethers
Reagent-controlled fluorination: asymmetric fluorination of enolates using chiralelectrophilic fluorinating agents
Catalytic asymmetric fluorination
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Substrate-controlled Fluorination
NFSI
SO
ONS
O
O
F
Tetrahedron. Lett. 1992, 33, 1153.Tetrahedron. Lett. 1998, 39, 6135J. Org. Chem. 62, 7546
Angew. Chem., Int. Ed. Engl. 1997, 36, 2362.Synthesis. 2001, 2307.
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Reagent-controlled Fluorination
Moderate yields and low to moderate enantioselectivities (<90% ee)
Wong, C.-H., Angew. Chem. Int. Ed., 2005, 44, 192Taylor, S. D.; Kotoris, C. C. and Hum, G. Tetrahedron, 1999, 55,12431-12477
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Reagent-controlled Fluorination
Org. Lett. 2000, 2, 3699. PCT Int. Appl. WO2001090107. 2001J. Am. Chem. Soc. 2000, 122, 10728
N
NOR2
F+ X-
R1
O
BnF
O
CO2EtF O
O
CO2EtF N
H
FPh
O
86% yield, 91% ee 89% yield, 78% ee 92% yield, 80% ee 100% yield, 78% ee
Cinchona Alkaloids Fluorinating Reagents
Fluorobenzofurancarboxylate
Fluoro-indolinoneFluoro-indenecarboxylate
Fluoro-indenone
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Catalytic Asymmetric Fluorination
O
R2
O
R1 OR3
5 mol%catalyst
SelectfluorCH3CN, rt
O
R2
O
R1 OR3F
OO
OTi
OCl
ClMeCN NCMe
1-napt
1-napt1-napt
1-naptO
Me
O
OPhF
O
Me
O
SPhF
O
Me
O
OF
i-Pr
i-Pr i-Pr
O
Cl
O
Ph OEtF
O
O
F
O
Bn
50% yield, 88% ee 76% yield, 91% ee
53% yield, 33% ee89% yield, 90% ee
63% yield, 51% ee
TADDOL-Titanium complexes
TADDOL-Titanium catalyzed asymmetric fluorination
Hintermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 – 4362Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155
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Asymmetric Fluorination Catalyzed by Other Lewis Acids
NFSI
SO
ONS
O
O
F
Tetrahedron: Asymmetry, 2004, 15, 1007Synlett 2004, 1703 –1706
J. Am. Chem. Soc., 2002, 124, 14530–14531.
BINAP-Palladium Complexes
NO
Boc
MeO
Cl
F3C
PAr2PAr2
Pd
2.5 mol%
NFSI, acetone, 0oCii. deboc N
H
OF3C
F
i.
MeO Cl
BMS-204352MaxiPost
Phase III clinical trials for treatment of acute ischemic stroke
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Organo-Catalytic Enantioselective Fluorination
Excellent yields and high enantioselectivity
Beeson, T. D. and MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 – 5
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Organo-Catalytic Enantioselective Trifluoromethylation
J. Am. Chem. Soc. 2009, 131, 10875–10877