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`

`
`Journal of
`Medicinal
`Chemistry
`
`© Copyright 2006 by the American Chemical Society
`
`Volume 49, Number 15
`
`July 27, 2006
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Letters
`
`Discovery of a New Boron-Containing Antifungal
`Agent, 5-Fluoro-1,3-dihydro-1-hydroXy—2,1-
`benzoxaborole (AN2690), for the Potential
`Treatment of Onychomycosis
`
`Stephen J. Baker,* Y°“g~Kat1g Zhang, Tsutomu Akama,
`Agnes Lau, Huchen Z'h.ou, Vincent Hernandez, Weimin Mao,
`M. R. K. Alley, Virginia Sanders, and Jacob J. Plattner
`
`Anacor Phurnmcemicals Inc, 1060 East Meadow Circle
`Palo Alto, California 94303
`
`Receiz/ed March 29, 2006
`
`Abstract: A structure-activity relationship investigation for a more
`efficacious therapy to treat onychomycosis, a fungal infection of the
`toe and fingernails, led to the discovery of a boron-containing small
`molecule, 5-fluoro— l ,3~dihydro- l —hydroxy—2, l -benzoxaborole (AN2690),
`which is currently in clinical trials for onychomycosis topical treatment.
`
`One of the most common fungal infections remains one of
`the most difficult to treat.” Onychomycosis is a fungal infection
`of the toenails and fingernails and has an incidence of 14% of
`the population in the U.S.3 In diabetic and elderly patients the
`incidents ranges from 33% to 50%.“
`Onychomycosis is caused mainly by dermatophytes, a class
`of fungus that dwells on skin, hair, and nails and is the cause
`of other cutaneous fungal infections such as athlete’s foot.-5 The
`major dermatophytes involved are Trichophyton rubrum and
`Triclzophyton merztagropltytes, accounting for approximately
`60~90% of all cases.‘‘’‘7 There are few treatments available,
`and these include oral terbinafine, oral itraconazole, topical
`ciclopirox, and topical amorolfine. However, topical treatments
`have poor clinical efficacy and oral treatments have a high level
`of recurrence and concerns of systemic safety.3"5
`Previously, we reported the development of borinic acid
`quinoline ester compounds as novel antibacterials (1, Figure
`l).‘6 Further structural modification of these boron—containing
`compounds led to the 1,3-dihydro-2,1-benzoxaborole class as
`illustrated by 2. Focused screening of our library revealed these
`dihydrobenzoxaboroles had good antifungal activity against C.
`albicans. Further screening against yeast, filamentous fungi, and
`
`* To whom correspondence should be addressed. Phone:
`0711. Fax:
`(650) 739-0139. E-mail: sbaker@anac0r.com.
`
`(650) 739-
`
`Rii
`l,o
`., \ B
`RI‘:
`/
`
`\
`N
`I /
`
`1
`
`Rm
`I
`7
`,
`." , \ B\1
`Rl__|_
`O 2
`4
`5 / 3
`2
`
`_
`R'=H.C|,F,MeO,CN
`Rn _ -
`l
`_H- viny, aryl
`R"' = vinyl, aryl, OH
`
`Figure 1. Boron-containing small-molecule library.
`
`dermatophytes showed these compounds had broad spectrum
`activity against all these fungal pathogens including the major
`dermatophytes that cause onychomycosis, T.
`rubrzmz. and T.
`nzemagrop/tyres. Herein, we report
`the focused medicinal
`chemistry effort to develop a first-in-class boron-containing
`antifungal agent for the topical treatment of onychomycosis.
`The dihydrobenzoxaborole class (2) emerged as a result of a
`directed effort to expand the chemical diversity of the borinic
`acid quinoline esters (1), all of which contained a boron-
`nitrogen dative bond.”
`Dihydrobenzoxaboroles bearing aryl, heteroaryl, or vinyl
`substituents at the 1-position (9-15) were synthesized starting
`from 2-bromo—5-tluorobenzaldehyde (3) or 2-bromobenzyl
`alcohol (4a) as shown in Scheme l. The hydroxy groups of 4a
`and 4b were protected as the methoxymethyl ether to give 5a
`and 5b, respectively. Compounds 5 were treated with butyl-
`lithium at -78 °C, and the anion formed was trapped by a
`boronic acid ethylene glycol ester (7), prepared from the
`corresponding boronic acid and ethylene glycol,
`to give the
`borinic acid (8). For 11 and 15, intermediate 5b was converted
`into the glycol ester 6, which was reacted with Grignard reagents
`to give 8. Finally, the protecting group was removed under acidic
`conditions and the free alcohol spontaneously cyclized to give
`the target compounds (9— 15).
`l—Hydroxydihydrobenzoxaboroles (19b-m) were synthesized
`as shown in Scheme 2. The protected 0-bromobenzyl alcohol
`derivative (18), prepared from 16 or 17, was converted into the
`corresponding phenylboronic acid. Deprotection of the meth-
`oxymethyl ether using hydrochloric acid followed by spontane-
`ous cyclization gave the target compounds 19b-m ( 19c, R" =
`Me, was prepared as a racemate). When compounds have
`functional groups sensitive to butyllithium, such as a nitrile
`group, an in situ trap method was applied.”
`The 7—fluoro derivative (19n) was synthesized through
`directed ortho metalation of 3—tluorobenzy1 alcohol
`(20)
`(Scheme 3). 19
`
`© 2006 American Chemical Society
`10.1021/_jm0603724 CCC: $33.50
`Published on Web 06/27/2006
`
`CFAD V. Anacor, |PR201 5-01 776 ANACOR EX. 2157 - 3/6
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`

`
`4448
`
`Jam‘/ml of Medicinal C/zemisngv, 2006, Vol. 49, Na. [5
`
`Scheme 1"
`
`F
`
`Ru
`
`Ri
`
`(b)
`V B’
`(a)
`4» | 4
`R‘
`/
`OH
`4a(R'_=H)
`4b(R'=F)
`(C) (d)
`
`
`0
`’
`\ B~/o>
`I / \/O.,\/OMe
`6
`
`F
`
`3'
`
`‘CHO
`
`Br
`
`3
`‘ \
`‘/“\/Ox/OM‘?
`5a(R'_=H)
`5b(R'=F)
`o
`(6) R'”-B: j
`o
`7
`
`(f)
`
`Rm
`.
`I \ 3.0+:
`/ /O\/OMe
`3
`
`<9)
`
`Rim:
`
`Rlll
`.
`
`R.
`
`/
`9-15
`
`Scheme 4"
`
`F
`
`3
`
`(c) «M
`
`Lerlers
`
`(a) (b) ,
`
`B’
`CHO
`
`Bl
`
`R‘
`
`CH0
`21a (R'_ = F)
`21b (R' = H)
`
`R‘
`
`8'
`/(D:/\
`O/\OM e
`22a (R‘ = F)
`22!) (R' = H)
`/O
`GB»?
`O
`
`'
`B
`(e) (f)
`jp *
`£1;
`R‘
`iii
`3
`
`(9) (f)
`
`H
`\
`
`24
`
`(at) Ph3PCl~IgOMeCl, /-BUCK, DMF. 0 “C to room temp;
`" Conditions:
`(b) 6 N HCl, THF, reflux: (c) NaBH4, MeOH. room temp; (d) MCQCHZCL
`i-Pr2NEt, Cl'l2Cl3. room temp: (e) n—B_uLi, 7a, THF. "73 °C to room temp:
`(f) 6 N HCl, room temp; (g) n-BuL1. l"P"0)3l3. THF, -78 “C to room
`temp.
`
`.
`.
`_
`.
`-
`['
`Table 1. Minimum Inhibitory Concentr:ti<>néug/1iiiL£;)t'
`Boron-Containing Compounds Con1P‘"e
`[0
`‘C 0p
`A
`C.
`T.
`C.
`mgnmgI‘()— uII):— neo_/'(1r— _fi;m,‘.
`/2/zynav
`CCIIIS mans
`gurus
`
`RI
`
`other
`
`11
`rubriml.
`
`ta) NaBH4, MeOI-I, room temp; (b) MeOCHgCl, 1'-PrgNEt,
`"Conditions:
`CH;Cl3, room temp: (c) .yec—BuLi, (MeO)3B, THF. -78 “C to room temp;
`(d) ethylene glycol. THF or toluene, rellux; (e) 11- or r—BuLi, 7, THF, -78
`°C to room temp; (f) 3»bromopyridine, i—I-’rMgCl, THF, 0 “C (ref 17), or
`vinylmagnesium bromide, THF. -78 “C to room temp: (g) 6 N HCl, THF,
`room temp.
`
`Scheme 2"
`
`R._- \ Br
`' /
`
`X
`
`(a)(b)
`or(c>(b)
`
`0
`16 (X=HorOH)
` ’ d
`e
`mm
`Me
`17
`
`“C
`
`)
`
`||\ BI’
`R7 / O\/We
`13 R"
`l<g)(h)
`
`pH
`I \ B‘
`R'—. / O
`
`19b-m R"
`(21) NaBHi, MeOH, room temp (when X = H), or EH3-
`“ Conditions:
`THF, TI-IF. room temp (when X = OH); (b) MeOCH3Cl, I—PI"_7NEl, CH'_gCl3,
`room temp: (c) MeMgBr, THF, -78 “C to room temp‘, (d) NBS, AIBN,
`CCI4, reflux: (e) NaOAc, DMF. 70 °C; (t) NaOH, MeOH, reflux; (g) n-BuLi,
`(i—PrO)_;B. THF, —78 “C to room temp; (h) 6 N HCl, THF, room temp.
`
`Scheme 3"
`
`F
`
`20
`
`(8)
`T,
`
`on
`
`F
`
`OH
`3'
`
`\O
`
`19n
`
`"Conditions:
`HCI.
`
`ta) sec—BuLi, (i—PrO)3B, THF, -78 °C to room temp, then
`
`Six-mernbered benzoxaborin analogues were synthesized as
`shown in Scheme 4. For 6-fluoro analogues, the benzaldehyde
`(3) was subjected to a Wittig reaction and the resulting enol
`ether was hydrolyzed to give the phenylacetaldehyde (21a).
`Reduction of the carbonyl group, followed by protection of the
`
`ciclopirox
`9a
`9b
`10::
`10b
`11
`12
`13
`14
`15
`19a
`191)
`196
`23a
`23b
`24
`
`Riv — H
`H
`5_F Riv — H
`H
`5-1:
`5—F
`5-F
`5-1:
`5—F
`5-1:
`R" = H
`H
`5-13 R" = H
`5-F R" = Me
`6-F
`H
`6—F
`
`0-5
`4
`]
`8
`51
`4
`4
`I
`l
`I6
`8
`l
`32
`8
`8
`32
`
`0'5
`4
`2
`8
`2
`2
`4
`4
`2
`32
`4
`l
`l6
`8
`8
`32
`
`0'3
`4
`0.5
`2
`0.5
`I
`4
`l
`l
`4
`2
`0.5
`I6
`8
`8
`64
`
`0'3
`8
`2
`4
`0.5
`4
`4
`l
`l
`l6
`l
`0.25
`32
`8
`I6
`>64
`
`1
`4
`2
`4
`1
`2
`4
`l
`l
`l6
`2
`0.25
`I6
`8
`16
`3?.
`
`resulting alcohol gave the methoxymethyl ether (223), which
`was converted to the final products 23a and 24 using the same
`chemistry described previously. The unsubstituted derivative
`(23b) was synthesized from commercially available 2—bro-
`mophenylacetaldehyde (21b).
`To determine the antifungal activity of these compounds, we
`screened for their minimum inhibitory concentrations (MIC)
`against the major dermatophytes that cause onychomycosis, T.
`rubrum and T. menmgrop/iytes, and against the yeasts and molds
`C. albicarzs, C. n.e0f0r17zans, and A. funzjgatus to test for their
`broad spectrum activity. The antifungal agent ciclopirox,
`currently in use for the topical treatment of onychomycosis, was
`used as a reference.
`
`Our initial lead compound was the l—phenyldihydrobenzox—
`aborole (93) (Table 1). This showed modest broad spectrum
`activity with MIC values of 4-8 pig/mL. One of the first
`modifications made was to install a 5-fluoro group, giving 9b.
`This substitution led to a 2- to 8-fold increase in potency against
`the strains tested. Subsequently, most of the following analogues
`synthesized contained this tluoro substitution.
`We set out to determine the effect of replacing the l—phenyl
`group of 9 with various substitutions. The I-styryl—substituted
`dihydrobenzoxaboroles 10a and 1011 led to approximately
`equivalent activity to our leads 9a and 9b, respectively, against
`all fungi tested (Table 1). Again, when R‘ = 5-F (10b). potency
`was improved 4- to 8-fold. Replacing the 1-phenyl group of 9b
`with 1-vinyl (11) or I-(furan-3-yl) (12) led to an approximate
`
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`

`
`Letters
`
`Table 2. Minimum Inhibitory Concentration (,ug/mL) of
`1,3-Dihydro—l—phenyl-2,1-benzoxaborole Compounds (9)
`
`Riv
`z
`B\1O 2
`3
`
`7
`
`A
`
`5
`
`RI
`
`5
`
`compd
`9a
`9b
`9c
`9d
`9e
`9f
`9g
`911
`9i
`9_j
`
`I
`R‘
`H
`F
`H
`I-I
`H
`F
`F
`F
`F
`F
`
`I
`R”
`H
`H
`3'—Cl
`3'—F
`4’-F
`3'—Cl
`3’—F
`4’—F
`3'-Me
`4’-Me
`
`T.
`rubrum
`A
`I
`l 6
`8
`8
`4
`l
`4
`2
`2
`
`A.
`C.
`C.
`T.
`menmgro— albi— ne0for— fumi-
`p/z_vte'.s‘
`cans
`mans
`gm‘u.s'
`4
`4
`8
`4
`2
`0.5
`2
`2
`8
`8
`4
`8
`I6
`4
`4
`8
`4
`4
`2
`2
`8
`0.25
`0.5
`2
`2
`0.5
`l
`l
`4
`I
`l
`2
`4
`l
`0.5
`0.5
`2
`0.5
`0.5
`0.5
`
`to 8-fold decrease in activity, while replacement with
`2-
`1—(thiophen-3-yl) (13) or l-(4-methylthiophen-3-yl) (14) led to
`approximately equal activity against all fungi (Table 1). Interest-
`ingly, replacement of the 1-phenyl group of 9b with l-(pyrid-
`3-y1) (15) showed selectivity toward nondermatophyte strains;
`there was a 16-
`to 64-fold decrease in activity against
`the
`dermatophytes T. rubrum. and T. /Iientagrop/7_vres but no change
`in activity against C. albicans and only a 4-fold reduction in
`activity against C. /zeoformans and A. fumigams (Table 1).
`In another modification to enhance hydrophilicity, we re-
`placed the 1-phenyl group of 9a and 9b with a I-hydroxy group
`to give 19a and 19b, respectively. Compounds 19a and 19b
`proved to have a more broad spectrum profile than 9a and 9b,
`respectively. Both 19a and 19b showed an 8-fold increase in
`activity against C. neoformarzs, and 19b showed an 8-fold
`increase in activity against A. fumigarus. (Table 1).
`In an effort to understand the effect of the 3-substiution on
`the oxaborole ring, we added a methyl group to the 3-position
`to give 19c. However, this modification led to an 8- to 32-fold
`decrease in activity (Table 1).
`We then increased the ring size from a five-membered
`oxaborole of 9a, 9b, and 19b to the conesponding six—membered
`oxaborin, giving 23b, 23a, and 24, respectively. The results of
`these are shown in Table 1. The I-phenyl substituted oxaborin
`23b was only approximately 2-fold less active than the
`oxaborole 9a. In contrast, the 5-fluoro—1-phenyloxaborin 23a
`was 4- to 16-fold less active than the corresponding oxaborole
`9b, showing that
`in this case,
`the 5-fluoro group gave no
`advantage on potency over the unsubstituted oxaborin 23b.
`Finally, the l-hydroxyoxaborin 24, was 32- to 256-fold less
`active than the corresponding oxaborole 19b.
`The results shown in Table I led us to conclude that a five-
`
`the
`membered benzoxaborole ring, with no substitution at
`3-position, was optimum for activity. Furthermore, we found
`that
`the l—phenyl or
`I-hydroxy substituents gave the best
`potency.
`Next, we focused our attention on the l-phenyldihydroben-
`zoxaborole scaffold (9) to determine the effect of substitutions
`
`on the 1-phenyl ring, and examples of these are shown in Table
`2. As before, in all cases, compounds with R‘ = F were more
`potent than compounds with R‘ = H. Compounds 9f—j showed
`activity similar to that of the lead compound 9b; however,
`because of in vitro cytotoxicity of 9f—j compared to 9a (data
`not shown), these compounds were not considered for further
`development.
`
`Journal of Medicilial C/1emistr_v, 2006, Vol. 49, N0. /5 4449
`
`7
`
`Table 3. Minimum Inhibitory Concentration (,ug/mL) of
`l,3—Dihydro- l -hydroxy-2, l—benzoxaborole Compounds (19)
`OHI
`O 2
`
`R'T
`5 /4
`
`3
`
`T.
`
`C.
`
`C.
`
`A.
`
`compd
`19b
`19d
`1%
`19f
`19g
`19h
`l9i
`l9j
`19k
`191
`19m
`l9n
`
`_
`R‘
`
`5-F
`5-Cl
`5-Me
`5-CF3
`5-NC
`5—MeO
`5-1-IOCI-I3
`6,7-benzo
`5-F—6-F
`4-F
`6—F
`7—F
`
`T.
`ru/zrmn
`l
`I
`8
`8
`I6
`64
`64
`4
`4
`I6
`I6
`l6
`
`menmgro— uIbi-
`/2/i_vtc.\'
`cum‘
`l
`0.5
`2
`l
`4
`2
`8
`I6
`16
`8
`32
`>64
`64
`> 64
`2
`32
`4
`4
`16
`64
`32
`I6
`I6
`32
`
`neufor-
`mans
`0.25
`2
`8
`16
`8
`>64
`> 64
`32
`2
`32
`32
`32
`
`fumi-
`gurus
`0.25
`I
`2
`8
`16
`>64
`> 64
`32
`2
`32
`8
`4
`
`OHI
`B\
`£:Lo
`19b
`
`F
`
`Figure 2. Structure of AN2690, currently in clinical
`onychomycosis.
`
`trials for
`
`In a final study, we synthesized various analogues of 5-fluoro-
`l,3-dihydro-l-hydroxy-2,1-benzoxaborole (19b) to determine the
`structure~activity relationship of this scaffold. The results of
`this study are shown in Table 3. We first substituted the 5-F
`group with other groups, giving 19d-i,
`to determine the
`optimum substituent for this position. The results showed that
`the 5-F compound 19b remained the most potent with only the
`5-Cl analogue 19d approaching similar activity. The 5-methyl,
`5-trifluoromethyl, and 5-cyano analogues l9e, 19f, and 19g,
`respectively, showed only weak activity, while 5-methoxy and
`5-hydroxymethyl analogues 19h and 19i, respectively, were
`inactive. Interestingly,
`the 6,7-benzo analogue (l9j) showed
`moderate activity toward the dermatophytes but was effectively
`inactive against the nondermatophyte strains.
`In another modification, we found that addition of a second
`fluoro group at the 6-position, giving 19k, effectively offset
`the additional potency provided by the 5-fluoro substituent. In
`a final modification we moved the fluoro group to other
`positions around the benzo ring, giving l9l~n, and found that
`the optimum position for the fluoro group remained at
`the
`5-position.
`From the results shown in Tables 2 and 3, we concluded that
`the l-phenyl- and l-hydroxy- 5-fluoro-1,3-dihydro-2,l-benzox-
`aborole compounds 9b and 19b, respectively, were the most
`active against fungi and especially against the dermatophytes
`T. rubrmn. and T. n1entagr()pIiytes, the primary fungal pathogens
`causing onychomycosis. To evaluate the ability of the dihy-
`drobenzoxaborole antifungals to treat onychomycosis by topical
`application, we have examined these compounds in a number
`of in vitro experiments including nail penetration and keratin
`binding (results to be reported elsewhere). From these preclinical
`studies, 5—fluoro- l ,3-dihydro-1-hydroxy-2, l -benzoxaborole ( 19b)
`(Figure 2) was identified as having a unique profile of in vitro
`antidermatophyte activity, maintenance of this activity in the
`presence of keratin, and exceedingly good penetration of human
`nails. This compound is currently undergoing clinical trials for
`the treatment of onychomycosis.
`
`CFAD V. Anacor, |PR201 5-01776 ANACOR EX. 2157 - 5/6
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2157 - 5/6
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`

`
`4450
`
`Journal 0fMedi'cinal Chemistry, 2006, V01. 49, N0. 15
`
`In conclusion, we present a novel class of boron—containing
`compounds with broad spectrum antifungal activity. We report
`the synthesis and describe the structure-activity relationship
`for in vitro antifungal activity. One member of this new family
`of antifungal compounds, 19b, was identified as our clinical
`candidate for onychomycosis. Future reports from our labs will
`describe other preclinical studies, mechanism of action, ap-
`plication to systemic diseases, and clinical
`trial results for
`onychomycosis.
`
`Acknowledgment. We acknowledge Maureen Kully and
`Jehangir Khan at NAEJA Pharmaceuticals, Inc., for obtaining
`some MIC data.
`
`Supporting Information Available: Experimental procedures
`and characterization data for all compounds. This material
`is
`available free of charge via the Internet at http://pubs.acs.org.
`
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2157 - 6/6