Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology
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522 Fluorine in Medicinal Chemistry and Chemical Biology
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Appendix
Approved Active Pharmaceutical
Ingredients Containing Fluorine
Elizabeth Pollina Cormier , * Manisha Das , and Iwao Ojima
The following tables list drugs containing fl uorine that have been approved by the U.S.
Food and Drug Administration (FDA) for use in either humans or animals. For human
products, we used the FDA Orange Book, 27th edition ( http://www.fda.gov/cder/orange/ ),
which covers drug products approved under Section 505 of the Federal Food, Drug, and
Cosmetic Act up to 2007. Thus, the updated version may include more fl uorine - containing
drugs. Specifi cally, sections 3.0, 4.0, and 6.0, covering prescription, OTC, and discontin-
ued drug products, respectively, were considered. Information was verifi ed for complete-
ness using the Electronic Orange Book ( http://www.fda.gov/cder/ob/ ), which is updated
on a monthly basis, as well as Drugs@FDA ( http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/ ).
For veterinary products, we used the FDA Green Book ( http://www.fda.gov/cvm/
Green_Book/elecgbook.html ), which covers animal drug products approved under section
512 of the Federal Food, Drug and Cosmetic Act up to 2007. Thus, the updated version
may include more fl uorine - containing drugs. Sections 2 and 6 containing active ingredient
and voluntary withdrawals were reviewed to compile the relevant compounds. Information
was elaborated with the Database of Approved Animal Drugs ( http://dil.vetmed.vt.edu/ )
as well as the Freedom of Information (FOI) Summaries ( http://www.fda.gov/cvm/FOI/
foidocs.htm ).
Other chemical information was obtained from:
* Dr. Cormier ’ s contribution was performed on her own time, and does not represent offi cial policy or views of the U.S.
Food and Drug Administration. No offi cial support or endorsement by the FDA is intended or should be inferred.
Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima
© 2009 Blackwell Publishing, Ltd. ISBN: 978-1-405-16720-8
526 Fluorine in Medicinal Chemistry and Chemical Biology
• National Library of Medicine ’ s ChemIDplus ( http://chem.sis.nlm.nih.gov/chemidplus/
chemidlite.jsp )
• National Center for Biotechnology Information ’ s PubChem ( http://pubchem.ncbi.nlm.
nih.gov/ )
• The Merck Index ( http://themerckindex.cambridgesoft.com )
Section 1 Fluorine - containing Drugs for Human Use Approved by FDA in the United
States
Section 2 Fluorine - containing Drugs for Veterinary Use Approved by FDA in the United
States
Section 1. Fluorine - containing Drugs
for Human Use Approved by FDA
in the United States
Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima
© 2009 Blackwell Publishing, Ltd. ISBN: 978-1-405-16720-8
528 Fluorine in Medicinal Chemistry and Chemical Biology
Active ingredient/
trade name
Chemical name Structure
Alatrofl oxacin Mesylate/
Trovan
7 - [(1 R ,5 S ) - 6 - [[(2 S ) - 2 - [[(2 S ) - 2 -
amino - propanoyl]amino]
propanoyl]amino] - 3 -
azabicyclo[3.1.0]hexan - 3 - yl] -
1 - (2,4 - difl uorophenyl) - 6 -
fl uoro - 4 - oxo - 1,8 -
naphthyridine - 3 -
carboxylic acid;
methanesulfonic acid
F
F
N
O
HO
O
N
F
N
N
H
O
H
N
O
NH
2
S
O
O
OH
Amcinonide
pregna - 1,4 - diene - 3,20 - dione,
21 - (acetyloxy) - 16,17 -
[cyclopentylidenebis (oxy)]
- 9 - fl uoro - 11 - hydroxy - ,(11 β ,
16 α )
O
O
O
HO
H
F
H
O
O
O
Aprepitant/
Emend
5 - [[(2 R ,3 S ) - 2 - [(1 R ) - 1 - [3,5 - bis -
(trifl uoromethyl)phenyl]
ethoxy] - 3 - (4 - fl uorophenyl) - 4 -
morpholinyl]methyl] - 1,2 -
dihydro - 3H - 1,2,4 - triazol - 3 - one
HN
N
H
N
N
O
O
O
F
CF
3
CF
3
Atorvastatin Calcium/
Lipitor
Caduet
[ R - ( R * , R * )] - 2 - (4 - fl uorophenyl) -
β , δ - dihydroxy - 5 - (1 -
methylethyl) - 3 - phenyl - 4 -
[(phenyl - amino)carbonyl] -
1 H - pyrrole - 1 - heptanoic
acid,calcium salt (2 : 1)
trihydrate
N
H
C
O
N
O
O
HO
HO
F
2
Ca
2+
3H
2
O
Bendrofl umethiazide/
Corzide
3 - benzyl - 5,5 - dioxo - 9 -
(trifl uoromethyl) - 5 λ
6
- thia -
2,4 - diaza - bicyclo[4.4.0]
deca - 7,9,11 - triene - 8 -
sulfonamide
N
H
HN
S
O
O
S
CF
3
NH
2
O
O
Fluorine-containing Drugs for Human Use Approved by FDA in the United States 529
Formula Pharmaceutical action Dosage form CAS No. Approval date/
drug sponsor
C
27
H
29
F
3
N
6
O
8
S Anti - infective agent Injectable 157605 - 25 - 9
Dec. 1997/
Pfi zer
C
28
H
35
FO
7
Anti - infl ammatory
agent
Antipruritic agents
Glucocorticoid
Topical cream,
lotion and
ointment
51022 - 69 - 6
Oct. 1979/
Altana
Taro Pharm Inds
C
23
H
21
F
7
N
4
O
3
Antiemetic Oral capsule 170729 - 80 - 3
March 2003/
Merck
(C
33
H
34
FN
2
O
5
)
2
Ca
⋅ 3H
2
O
Anticholesteremic
agent
Oral tablet 344423 - 98 - 9
Dec. 1996/
Pfi zer
C
15
H
14
F
3
N
3
O
4
S
2
Diuretic
Anihyertensive agent
Oral tablet 73 - 48 - 3
May 1983/
King Pharms
Impax Labs
530 Fluorine in Medicinal Chemistry and Chemical Biology
Active ingredient/
trade name
Chemical name Structure
Betamethasone Benzoate/
Uticort
∆
[(8 S ,9 R ,10 S ,11 S ,13 S ,14 S ,
16 S ,17 R ) - 9 - fl uoro - 11 -
hydroxy - 17 - (2 - hydroxy -
acetyl) - 10,13,16 - trimethyl -
3 - oxo - 6,7,8,11,12,14,15,16 -
octahydro - cyclo - penta[a]
phenanthren - 17 - yl] benzoate
O
HO
H
OH
O
O
F
O
Betamethasone
Dipropionate
V
/
Diprolene
Lotrisone
Taclonex
[(8 S ,9 R ,10 S ,11 S ,13 S ,14 S ,
6 S ,17 R ) - 9 - fl uoro - 11 -
hydroxy - 10,13,16 - trimethyl -
3 - oxo - 17 - (2 -
propanoyloxyacetyl) - 6,7,8,
11,12,14,15, 16 -
octahydrocyclo -
penta[a]phenanthren - 17 - yl]
propanoate
O
HO
H
O
O
O
O
F
O
Betamethasone Sodium
Phosphate
V
/
Celestone Soluspan
[2 - [(8 S ,9 R ,10 S ,11 S ,13 S ,
14 S ,16 S ,17 R ) - 9 - fl uoro -
11,17 - dihydroxy - 10,13,16 -
trimethyl - 3 - oxo - 6,7,8,11,
12,14,15,16 - octahydrocy -
clopenta[ a ]phenanthren -
17 - yl] - 2 - oxo - ethyl]
phosphate
O
HO
H
O
P
O
O
OH
F
O
O
Na
Na
Betamethasone Valerate
V
/
Luxiq
Valnac
Beta - Val
Dermabet
(1) pregna - 1,4 - diene - 3,20 -
dione, 9 - fl uoro - 11,21 -
dihydroxy - 16 - methyl - 17 -
[(1 - oxopentyl)oxy] - , (11 β ,
16 β ) - ; (2) 9 - fl uoro - 11
β ,17,21 - trihydroxy - 16 β -
methylpregna - 1,4 - diene -
3,20 - dione 17 valerate
O
HO
H
OH
O
O
F
O
Betamethasone/
Celestone
9 - fl uoro - 11,17 - dihydroxy -
17 - (2 - hydroxyacetyl) -
10,13,16 - trimethyl - 6,7,8,9,10,
11,12,13,14,15,16,17 -
dodecahydrocyclopenta
[ a ]phenanthren - 3 - one
O
HO
F
H
H
OH
O
OH
Fluorine-containing Drugs for Human Use Approved by FDA in the United States 531
Formula Pharmaceutical action Dosage form CAS No. Approval date/
drug sponsor
C
29
H
33
FO
6
Glucocorticoid
Topical cream,
gel, lotion, and
ointment
22298 - 29 - 9
Prior to 1982/
Parke - Davis
C
28
H
37
FO
7
Anti - infl ammatory
agent
Glucocorticoid
Topical cream,
gel, lotion, and
ointment
5593 - 20 - 4
Prior to 1982/
Actavis Mid
Atlantic
Fougera
Taro
Teva
Perrigo New York
QLT USA
Schering
Schering
Plough Res
C
22
H
28
FNa
2
O
8
P Injectable 151 - 73 - 5
Prior to 1982/
Schering
C
27
H
37
FO
6
Anti - infl ammatory
agent
Topical cream,
lotion, ointment
2152 - 44 - 5
Prior to 1982/
Connetics
Actavis Mid
Atlantic
Fougera
Taro
Teva
C
22
H
29
FO
5
Anti - infl ammatory
agent
Glucocorticoid
Anti - asthmatic agent
Oral syrup 378 - 44 - 9
April 1961/
Schering
532 Fluorine in Medicinal Chemistry and Chemical Biology
Active ingredient/
trade name
Chemical name Structure
Bicalutamide/
Casodex
N - [4 - cyano - 3 -
(trifl uoromethyl)phenyl] -
3 - [(4 - fl uorophenyl)
sulfonyl] - 2 - hydroxy - 2 -
methyl - , (+/ − )
HN
CF
3
CN
CH
3
OH
S
O
O
2
F
Bromperidol/
Impromen
Tesoprel
Azuren
4 - [4 - (4 - bromo - phenyl) - 4 -
hydroxy - 1 - piperidyl] - 1 -
(4 - fl uorophenyl)butan -
1 - one
F
N
O
HO
Br
Capecitabine/
Xeloda
5 ′ - deoxy - 5 - fl uoro - N -
[(pentyloxy)
carbonyl]cytidine
O
H
3
C
N
HO
OH
N
O
HN
F
O
O
Celecoxib/
Celebrex
4 - [5 - (4 - methylphenyl) - 3 -
(trifl uoromethyl) - 1 H - pyrazol -
1 - yl] benzenesulfonamide
N
N
CF
3
H
3
C
S
O
O
H
2
N
Cerivastatin Sodium/
Baycol
∆
sodium [ S - [ R * , S * - ( E )]] - 7 - [4 -
(4 - fl uorophenyl) - 5 -
methoxymethyl) - 2,6 - bis
(1 - methylethyl) - 3 -
pyridinyl] - 3,5 - dihydroxy -
6 - heptenoate
N
F
COONa
O
OH
OH
Cinacalcet Hydrochloride/
Sensipar
N - [1 - ( R ) - ( - ) - (1 -
naphthyl)ethyl] - 3 - [3 -
(trifl uoromethyl)phenyl] -
1 - aminopropane
hydrochloride
F
3
C
H
N
CH
3
HCl