I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US007 5 82621 B2
`
`c12) United States Patent
`Baker et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,582,621 B2
`Sep.1,2009
`
`(54) BORON-CONTAINING SMALL MOLECULES
`
`(56)
`
`References Cited
`
`(75)
`
`Inventors: Stephen J. Baker, Mountain View, CA
`(US); Tsutomu Akama, Sunnyvale, CA
`(US); Carolyn Bellinger-Kawahara,
`Redwood City, CA (US); Vincent S.
`Hernandez, Watsonville, CA (US);
`Karin M. Hold, Belmont, CA (US);
`James J. Leyden, Malvern, PA (US);
`Kirk R. Maples, San Jose, CA (US);
`Jacob J. Plattner, Berkeley, CA (US);
`Virginia Sanders, San Francisco, CA
`(US); Yong-Kang Zhang, San Jose, CA
`(US)
`(73) Assignee: Anacor Pharmaceuticals, Inc., Palo
`Alto, CA (US)
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 267 days.
`(21) Appl. No.: 11/357,687
`Feb.16,2006
`(22) Filed:
`Prior Publication Data
`(65)
`
`( *) Notice:
`
`Oct. 19, 2006
`US 2006/0234981 Al
`Related U.S. Application Data
`
`(51)
`
`(60) Provisional application No. 60/654,060, filed on Feb.
`16, 2005.
`Int. Cl.
`A61K 31169
`(2006.01)
`C07F 5104
`(2006.01)
`(52) U.S. Cl. ......................................... 514/64; 558/288
`(58) Field of Classification Search ................... 514/64;
`558/288
`See application file for complete search history.
`
`U.S. PATENT DOCUMENTS
`5,880,188 A *
`3/1999 Austin et al. ................ 524/109
`6,083,903 A *
`712000 Adams et al. .................. 514/2
`FOREIGN PATENT DOCUMENTS
`WO WO 2005/013892 A3
`212005
`OTHER PUBLICATIONS
`Austin et al., 1996, CAS: 124:234024.*
`fungicide: definition from Answre.com, 1998. *
`Sudaxshina Murdan, "Drug Delivery to the Nail Following Topical
`Application," International Journal of Pharmaceutics, 236:1-26
`(2002).
`S. J. Baker, et al., "Progress on New Therapeutics for Fungal Nail
`Infections,"Annual Reports in Medicinal Chemistry, 40:323-335
`(2005).
`* cited by examiner
`Primary Examiner-Rei-tsang Shiao
`(74) Attorney, Agent, or Firm-Morgan, Lewis & Bockius,
`LLP
`
`(57)
`
`ABSTRACT
`
`This invention relates to compounds useful for treating fungal
`infections, more specifically topical treatment of onychomy(cid:173)
`cosis and/or cutaneous fungal infections. This invention is
`directed to compounds that are active against fungi and have
`properties that allow the compound, when placed in contact
`with a patient, to reach the particular part of the skin, nail,
`hair, claw or hoof infected by the fungus. In particular the
`present compounds have physiochemical properties that
`facilitate penetration of the nail plate.
`
`12 Claims, 12 Drawing Sheets
`
`MYLAN - Ex. 1012, p. 1
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 1of12
`
`US 7 ,582,621 B2
`
`.£ ro
`
`L..
`Q)
`~
`~
`0
`LO
`
`3
`"'
`0)
`N
`LI..
`E
`:J
`L..
`.0
`:J
`L..
`..._:
`
`1
`
`8
`
`FIGURE 1A
`
`MIC ug/ml)
`
`00
`N
`0
`0
`O>
`u
`u
`~
`Vl
`c:
`ro
`()
`:.c
`ro
`u
`
`1
`
`2
`
`LO
`co
`N
`LI..
`Vl
`c:
`ro
`E
`.E
`0
`Q)
`c:
`<..)
`
`L..
`
`2
`
`1
`
`"'
`LO
`u..
`Cll
`c:
`ro
`-~
`.0
`ro
`u
`
`2
`
`0.5
`
`,..._
`C')
`0
`C')
`...-
`u
`u
`~
`ro
`.E
`
`Vl
`::J
`
`Cl
`
`::J
`'+-
`<(
`
`1
`
`2
`
`...-
`...-
`(")
`LI..
`Vl
`~
`..c
`Q.
`0
`L..
`Cl
`JY
`c:
`Q)
`E
`..._:
`
`2
`
`4
`
`16
`
`32
`
`32
`
`16
`
`16
`
`64
`
`64
`
`> 64
`
`32
`
`32
`
`O>
`0
`~
`z
`<(
`Q)
`ro
`·c;;
`·:;
`
`Q)
`L..
`Q)
`()
`CJ)
`
`0.5
`
`4
`
`8
`
`"'
`O>
`N
`LI..
`E
`:J
`L..
`.0
`::J
`L..
`i-:
`
`1
`
`8
`
`32
`
`32
`
`4
`
`8
`
`8
`
`16
`
`2
`
`8
`
`2
`
`4
`
`0.25
`
`4
`
`16
`
`16
`
`64
`
`16
`
`> 64
`
`> 64
`
`> 64
`
`> 64
`
`32
`
`2
`
`2
`
`8
`
`2
`
`4
`
`4
`
`2
`
`64
`
`8
`
`> 64
`
`> 64
`
`> 64
`
`> 64
`
`64
`
`>64
`
`64
`
`C1
`
`C2
`
`C3
`
`C4
`
`C5
`
`C6
`
`C7
`
`C8
`
`C9
`
`MYLAN - Ex. 1012, p. 2
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 2of12
`
`US 7,582,621 B2
`
`FIGURE 18
`
`C10
`
`0.5
`
`0.5
`
`0.25
`
`0.25
`
`:::;;Q.5
`
`<0.06
`
`1
`
`2
`
`C11
`
`32
`
`32
`
`32
`
`32
`
`2
`
`2
`
`4
`
`C12
`
`256
`
`C13
`
`16
`
`C16
`
`32
`
`>64
`
`2
`
`8
`
`16
`
`16
`
`C17
`
`64
`
`64
`
`64
`
`16
`
`4
`
`16
`
`8
`
`C18
`
`C19
`
`C20
`
`C21
`
`C22
`
`C23
`
`2
`
`0.5
`
`8
`
`8
`
`4
`
`>64
`
`>64
`
`MYLAN - Ex. 1012, p. 3
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 3of12
`
`US 7 ,582,621 B2
`
`FIGURE 1C
`
`16
`
`>64
`
`>64
`
`>64
`
`<0.06
`
`4
`
`8
`
`C24
`
`C25
`
`C26
`
`C27
`
`C28
`
`C31
`
`MYLAN - Ex. 1012, p. 4
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 4of12
`
`US 7 ,582,621 B2
`
`EXAMPLE2A
`
`MIC u!!/mL
`
`~ -
`= -
`- ~
`0
`·-
`- c..
`~
`·-
`= = =
`- =
`-
`- -
`0
`-
`0
`·-
`-
`CJ
`CJ
`~
`u
`'""-
`nt
`>64
`0.5
`0.25
`nt
`>64
`:::;0.5
`nt
`nt
`::S0.5
`nt
`2
`:::; 0.5
`nt
`:::; 0.5
`nt
`::S0.5
`nt
`4
`nt
`nt
`::S0.5
`:::;0.5
`nt
`nt
`::S0.5
`nt
`1
`:s 0.5
`nt
`:::; 0.5
`nt
`0.5
`32
`1
`1
`
`Fungus
`A.fumiRatus ATCC 13073
`C. albicans A TCC 90028
`C. albicans F56
`C. Klabrata A TCC 90030
`C. krusei A TCC 44507
`C. neoformans F285
`C. parapsilosis A TCC 22019
`C. tropicalis ATCC 13803
`E. jloccosum A TCC 52066
`F. solani ATCC 36031
`M furfur A TCC 44344
`M pachydermatis ATCC 96746
`M sympodialis A TCC 44031
`M audouinii ATCC 42558
`M canis ATCC 10214
`M. RJ!pseum A TCC 24103
`T. menta~rophytes F31 I
`T. rubrum F296
`
`T. rubrum F296
`T tonsurans A TCC 28942
`nt = not tested
`
`Broth used
`RPMI
`RPMI
`RPMI
`RPMI +MOPs
`RPMI + MOPs
`RPMI
`RPMI+ MOPs
`RPMl +MOPs
`RPMI +MOPs
`RPMI +MOPs
`Urea
`Urea
`Urea
`RPM!+ MOPs
`RPMI +MOPs
`RPMI + MOPs
`RPMI + MOPs
`RPMI + MOPs
`RPMI+ MOPS+
`5% keratin powder
`RPMI + MOPs
`
`,,..;
`
`=
`u
`
`0.25
`1
`0.5
`:s 0.5
`I
`0.25
`:s 0.5
`:s 0.5
`:S0.5
`:s 0.5
`1
`I
`1
`2
`2
`2
`I
`I
`
`lo<
`0
`
`0
`CJ
`
`~
`!;:::
`
`.c
`~
`~
`
`nt
`nt
`nt
`64
`64
`nt
`:s 0.5
`256
`::S0.5
`64
`2
`:s 0.5
`:s 0.5
`:::;0.5
`:s 0.5
`:s 0.5
`:::;0.5
`::S0.5
`
`~
`0
`N
`~
`
`i-;
`
`0.25
`<0.12
`0.25
`:s 0.5
`:S0.5
`:s 0.12
`:S0.5
`1
`:s 0.5
`>256
`:S0.5
`:S0.5
`:s 0.5
`:s 0.5
`:s 0.5
`:S0.5
`:s 0.12
`:S0.12
`
`2
`2
`
`1
`:s 0.5
`
`nt
`:s 0.5
`
`1
`nt
`
`nt
`:s 0.5
`
`MYLAN - Ex. 1012, p. 5
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 5of12
`
`US 7 ,582,621 B2
`
`EXAMPLE2B
`
`MFC fue/mL)
`
`gJ -
`0
`=
`!toil
`c
`0
`y
`=
`...
`.....
`
`~
`
`4
`4
`
`Fungus
`T. mentaf!rOJJhytes F3 11
`T. rubrum F296
`
`Broth used*
`RPMI + MOPs
`RPMI + MOPs
`
`~
`
`0
`y
`
`~ =
`0 =
`- Q.;
`....
`=
`·-
`a..
`=
`-
`.c
`·-
`-
`a..
`u
`~
`E--
`1
`S0.5
`S0.5
`2
`
`Q
`...-i
`
`u
`
`16
`8
`
`MYLAN - Ex. 1012, p. 6
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 6of12
`
`US 7 ,582,621 B2
`
`FIGURE 3
`
`Nail Samples
`
`Radioactivitv as mg Eguivalent/g Nail Sam12les
`
`Group A
`(ClO)
`
`Group C
`(Ciclopirox)
`
`Dorsal/intermediate center
`
`25.65 ± 8.80
`
`7.40 ± 3.47
`
`Ventral/intermediate center
`
`20.46 ± 4.72
`
`3.09 ± 2.07
`
`Remainder nail
`
`26.06 ± 12.41
`
`4.38 ± 2.73
`
`*The data represents the mean± S.D. of each group (n = 6).
`
`P value
`(t-test)
`
`0.0008
`
`0.0001
`
`0.0022
`
`MYLAN - Ex. 1012, p. 7
`
`

`

`U.S. Patent
`
`Sep.1,2009
`
`Sheet 7of12
`
`US 7 ,582,621 B2
`
`FIGURE4
`
`Sampling day
`
`Radioactivity as mg Eguivalent/SamQles*
`
`Group A (ClO)
`
`Group C (Ciclopirox)
`
`P-value (t-test)
`
`Day3
`
`Day6
`
`Day 9
`
`Day 12
`
`Day 15
`
`Total
`
`0.0609 ± 0.0605
`
`0.0011 ± 0.0020
`
`0.1551±0.1314
`
`0.0013 ± 0.0027
`
`0.3892 ± 0.3714
`
`0.0018 ± 0.0030
`
`0.6775 ± 0.6663
`
`0.0014 ± 0.0019
`
`0.9578 ± 0.6106
`
`0.0033 ± 0.0041
`
`2.2405 ± 1. 7325
`
`0.0089 ± 0.0131
`
`*The data represents the mean± S.D. of each group (n = 6).
`
`0.0043
`
`0.0022
`
`0.0022
`
`0.0022
`
`0.0022
`
`0.0022
`
`MYLAN - Ex. 1012, p. 8
`
`

`

`

`

`

`

`

`

`

`

`

`

`US 7,582,621 B2
`
`1
`BORON-CONTAINING SMALL MOLECULES
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is related to U.S. Provisional
`Patent Application 60/654,060 filed Feb. 16, 2005, which is
`incorporated by reference in its entirety for all purposes.
`
`BACKGROUND FOR THE INVENTION
`
`Infections of the nail and hoof, known as ungual and/or
`periungual infections, pose serious problems in dermatology.
`These ungual and/or periungual can be caused by sources
`such as fungi, viruses, yeast, bacteria and parasites. Onycho(cid:173)
`mycosis is an example of these serious ungual and/or periun(cid:173)
`gual infections and is caused by at least one fungus. Current
`treatment for ungual and/or periungual infections generally
`falls into three categories: systemic administration of medi(cid:173)
`cine; surgical removal of all or part of the nail or hoof fol- 20
`lowed by topical treatment of the exposed tissue; or topical
`application of conventional creams, lotions, gels or solutions,
`frequently including the use of bandages to keep these dosage
`forms in place on the nail or hoof. All of these approaches
`have major drawbacks. The following discussion is particu- 25
`larly directed to drawbacks associated with current treatment
`ofungual and/or periungual antifungal infections.
`Long term systemic (oral) administration of an antifungal
`agent for the treatment of onychomycosis is often required to
`produce a therapeutic effect in the nail bed. For example, oral
`treatment with the antifungal compound ketoconozole typi(cid:173)
`cally requires administration of 200 to 400 mg/day for 6
`months before any significant therapeutic benefit is realized.
`Such long term, high dose systemic therapy can have signifi(cid:173)
`cant adverse effects. For example, ketoconozole has been
`reported to have liver toxicity effects and reduces testosterone
`levels in blood due to adverse effects on the testes. Patient
`compliance is a problem with such long term therapies espe(cid:173)
`cially those which involve serious adverse effects. Moreover,
`this type of long term oral therapy is inconvenient in the
`treatment of a horse or other ruminants afflicted with fungal
`infections of the hoof. Accordingly, the risks associated with
`parenteral
`treatments generate significant disincentive
`against their use and considerable patient non-compliance.
`Surgical removal of all or part of the nail followed by
`topical treatment also has severe drawbacks. The pain and
`discomfort associated with the surgery and the undesirable
`cosmetic appearance of the nail or nail bed represent signifi(cid:173)
`cant problems, particularly for female patients or those more 50
`sensitive to physical appearance. Generally, this type of treat(cid:173)
`ment is not realistic for ruminants such as horses.
`Topical therapy has significant problems too. Topical dos(cid:173)
`age forms such as creams, lotions, gels etc., can not keep the
`drug in intimate contact with the infected area for therapeu- 55
`tically effective periods of time. Bandages have been used to
`hold drug reservoirs in place in an attempt to enhance absorp(cid:173)
`tion of the pharmaceutical agent. However the bandages are
`thick, awkward, troublesome and generally lead to poor
`patient compliance.
`Hydrophilic and hydrophobic film forming topical antifun(cid:173)
`gal solutions have also been developed. These dosage forms
`provide improved contact between the drug and the nail, but
`the films are not occlusive. Topical formulations for fungal
`infection treatment have largely tried to deliver the drug to the 65
`target site (an infected nail bed) by diffusion across or through
`the nail.
`
`2
`Nail is more like hair than stratum comeum with respect to
`chemical composition and permeability. Nitrogen is the
`major component of the nail attesting to the nail's proteina(cid:173)
`ceous nature. The total lipid content of mature nail is 0.1-
`1.0%, while the stratum comeum lipid is about 10% w/w. The
`nail is 100-200 times thicker than the stratum corneum and
`has a very high affinity and capacity for binding and retaining
`antifungal drugs. Consequently little if any drug penetrates
`through the nail to reach the target site. Because of these
`10 reasons topical therapy for fungal infections have generally
`been ineffective.
`Compounds known as penetration or permeation enhanc(cid:173)
`ers are well known in the art to produce an increase in the
`permeability of skin or other body membranes to a pharma-
`15 cologically active agent. The increased permeability allows
`an increase in the rate at which the drug permeates through the
`skin and enters the blood stream. Penetration enhancers have
`been successful in overcoming the impermeability of phar-
`maceutical agents through the skin. However, the thin stratum
`corneum layer of the skin, which is about 10 to 15 cells thick
`and is formed naturally by cells migrating toward the skin
`surface from the basal layer, has been easier to penetrate than
`nails. Moreover, known penetration enhancers have not
`proven to be useful in facilitating drug migration through the
`nail tissue.
`Antimicrobial compositions for controlling bacterial and
`fungal infections comprising a metal chelate of 8-hydrox(cid:173)
`yquinoline and an alkyl benzene sulfonic acid have been
`shown to be efficacious due to the increased ability of the
`30 oleophilic group to penetrate the lipoid layers of micro-cells.
`The compounds however, do not effectively increase the abil(cid:173)
`ity to carry the pharmaceutically active antifungal through the
`cornified layer or stratum corneum of the skin. U.S. Pat. No.
`4,602,011, West et al., Jul. 22, 1986; U.S. Pat. No. 4,766,113,
`35 West et al., Aug. 23, 1988.
`Therefore, there is a need in the art for compounds which
`can effectively penetrate the nail. There is also need in the art
`for compounds which can effectively treat ungual and/or
`periungual infections. These and other needs are addressed by
`40 the current invention.
`
`SUMMARY OF THE INVENTION
`
`In a first aspect, the invention provides a compound having
`45 a structure according to Formula I:
`
`(I)
`
`wherein B is boron. R la is a member selected from a negative
`charge, a salt counterion, H, substituted or unsubstituted
`alkyl, substituted or unsubstituted heteroalkyl, substituted or
`60 unsubstituted cycloalkyl, substituted or unsubstituted hetero(cid:173)
`cycloalkyl, substituted or unsubstituted aryl, and substituted
`or unsubstituted heteroaryl. Ml is a member selected from
`oxygen, sulfur and NR 2
`a. R 2
`a is a member selected from H,
`substituted or unsubstituted alkyl, substituted or unsubsti(cid:173)
`tuted heteroalkyl, substituted or unsubstituted cycloalkyl,
`substituted or unsubstituted heterocycloalkyl, substituted or
`unsubstituted aryl, and substituted or unsubstituted het-
`
`MYLAN - Ex. 1012, p. 14
`
`

`

`Rib
`0/
`I
`.,....G2XB'
`Js ~ ....... ~2
`
`E2
`
`":
`
`M2
`
`':A.2
`
`J2
`
`3
`eroaryl. Jl is a member selected from (CR3 aR4 a)n 1 and CR5a.
`R 3 a, R4 a, and R 5 a are members independently selected from
`H, OH, NH2 , SH, substituted or unsubstituted alkyl, substi(cid:173)
`tuted or unsubstituted heteroalkyl, substituted or unsubsti(cid:173)
`tuted cycloalkyl, substituted or unsubstituted heterocy(cid:173)
`cloalkyl, substituted or unsubstituted aryl, and substituted or
`unsubstituted heteroaryl. The index nl is an integer selected
`from 0 to 2. Wl is a member selected from C=O (carbonyl),
`(CR 6aR 7a)m 1 and CR sa. R 6a, R 7 a, and R sa are members inde(cid:173)
`pendently selected from H, OH, NH2 , SH, substituted or 10
`unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
`substituted or unsubstituted cycloalkyl, substituted or unsub(cid:173)
`stituted heterocycloalkyl, substituted or unsubstituted aryl,
`and substituted or unsubstituted heteroaryl. The index ml is 15
`an integer selected from 0 and 1. Al is a member selected
`from CR9
`a and N. D 1 is a member selected from CR IOa and N.
`El is a member selected from CR lla and N. G 1 is a member
`selected from CR12a and N. R9 a, R 10a, R 11 a and R 12a are
`members independently selected from H, OH, NH2 , SH, sub(cid:173)
`stituted or unsubstituted alkyl, substituted or unsubstituted
`heteroalkyl, substituted or unsubstituted cycloalkyl, substi(cid:173)
`tuted or unsubstituted heterocycloalkyl, substituted or unsub(cid:173)
`stituted aryl, and substituted or unsubstituted heteroaryl. The
`combination of nitrogens (Al+Dl+El+Gl) is an integer
`selected from 0 to 3. A member selected from R3
`a, R4
`a and
`a, R7 a and R 8a, together
`R5
`a and a member selected from R 6
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R3
`a and R4
`a, together
`with the atoms to which they are attached, are optionally
`a and R7 a, together
`joined to form a 4 to 7 membered ring. R 6
`with the atoms to which they are attached, are optionally
`a and R 10
`joined to form a 4 to 7 membered ring. R9
`a, together
`with the atoms to which they are attached, are optionally
`a andR11 a, together
`joined to forma4 to 7 membered ring. R 10
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R lla and R 12a, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. The aspect has the
`proviso that when Ml is oxygen, Wl is a member selected
`from (CR3 aR4 a)n 1 , wherein nl is 0, J1 is a member selected
`from(CR 6aR7a)m 1 , wherein ml is l,Al is CR9 a, Dl is CR11a,
`El is CR11 a, Gl is CR12a, then R9
`a is not halogen, methyl,
`ethyl, or optionally joined with R 10
`a to a form phenyl ring;
`R 10
`a is not unsubstituted phenoxy, C(CH3 ) 3 , halogen, CF3 ,
`methoxy, ethoxy, or optionally joined with R9
`a to form a
`phenyl ring; R 11 a is not halogen or optionally joined with
`R IOa to form a phenyl ring; and R 12a is not halogen. The aspect
`has the further proviso that when Ml is oxygen, Wl is a
`member selected from (CR3 aR4 a)nu wherein nl is 0, J1 is a 50
`member selected from (CR 6aR7 a)mu wherein ml is 1, Al is
`CR9 a, Dl is CR 10a, El is CR11 a, Gl isCR12a, thenneitherR6a
`
`nor R 7 a are halophenyl. The aspect has the further proviso that
`when Ml is oxygen, Wl is a member selected from
`(CR3 aR4 a)nu wherein nl is 0, J1 is a member selected from 55
`(CR6aR7a)m 1 , wherein ml is l,Al is CR9a, Dl is CR 10a, El
`is CR11 a, Gis CR12a, and R9
`a, R 10
`a andR11 a are H, thenR6a,
`
`R 7 a and R 12a are not H. The aspect has the further proviso that
`when Ml is oxygen wherein nl is 1, J1 is a member selected
`from (CR 6aR7 a)mu wherein ml is O,Al is CR9a, Dl is CR1a, 60
`El is CR11a, Gl is CR12a, R 9 a is H, R 10a is H, R 11 a is H, R 6a
`is H, R7 a is H, R 12a is H, then Wl isnotC=O (carbonyl). The
`aspect has the further proviso that when Ml is oxygen, Wl is
`CR5 a, J1 is CR8a, Al is CR9a, Dl is CR 10a, El is CR11a, Gl
`isCR2 a,R6a, R7 a, R9 a, R 10a, R 11a andR12a areH, thenR5a and 65
`R 8a, together with the atoms to which they are attached, do
`not form a phenyl ring.
`
`US 7,582,621 B2
`
`4
`In a second aspect, the invention provides a pharmaceutical
`formulation comprising (a) a pharmaceutically acceptable
`excipient; and (b) a compound having a structure according to
`Formula II:
`
`(II)
`
`wherein B is boron. R 16 is a member selected from a negative
`charge, a salt counterion, H, substituted or unsubstituted
`alkyl, substituted or unsubstituted heteroalkyl, substituted or
`20 unsubstituted cycloalkyl, substituted or unsubstituted hetero(cid:173)
`cycloalkyl, substituted or unsubstituted aryl, and substituted
`or unsubstituted heteroaryl. M2 is a member selected from
`. R 26 is a member selected from H,
`oxygen, sulfur and NR 26
`substituted or unsubstituted alkyl, substituted or unsubsti-
`25 tuted heteroalkyl, substituted or unsubstituted cycloalkyl,
`substituted or unsubstituted heterocycloalkyl, substituted or
`unsubstituted aryl, and substituted or unsubstituted het(cid:173)
`eroaryl. 12 is a member selected from (CR36R46)n2 and CR56
`.
`R36
`, R46
`, and R56 are members independently selected from
`30 H, OH, NH2 , SH, substituted or unsubstituted alkyl, substi(cid:173)
`tuted or unsubstituted heteroalkyl, substituted or unsubsti(cid:173)
`tuted cycloalkyl, substituted or unsubstituted heterocy(cid:173)
`cloalkyl, substituted or unsubstituted aryl, and substituted or
`unsubstituted heteroaryl. The index n2 is an integer selected
`35 from 0 to 2. W2 is a member selected from C=O (carbonyl),
`. R 66
`, R76
`, andR86 are members inde(cid:173)
`(CR66R76)m 2 and CR86
`pendently selected from H, OH, NH2 , SH, substituted or
`unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
`40 substituted or unsubstituted cycloalkyl, substituted or unsub(cid:173)
`stituted heterocycloalkyl, substituted or unsubstituted aryl,
`and substituted or unsubstituted heteroaryl. The index m2 is
`an integer selected from 0 and 1. A2 is a member selected
`from CR96 and N. D2 is a member selected from CR 106 and N.
`45 E2 is a member selected from CR 116 and N. G2 is a member
`, R 106
`, R 116 and R 126 are
`selected from CR126 and N. R96
`members independently selected from H, OH, NH2 , SH, sub(cid:173)
`stituted or unsubstituted alkyl, substituted or unsubstituted
`heteroalkyl, substituted or unsubstituted cycloalkyl, substi(cid:173)
`tuted or unsubstituted heterocycloalkyl, substituted or unsub(cid:173)
`stituted aryl, and substituted or unsubstituted heteroaryl. The
`combination of nitrogens (A2+D2+E2+G2) is an integer
`, R46 and
`selected from 0 to 3. A member selected from R36
`R56 and a member selected from R 66
`, R76 and R 86
`, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R36 and R46
`, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R66 and R76
`, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R96 and R106
`, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R 106 andR116
`, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring. R 116 andR126
`, together
`with the atoms to which they are attached, are optionally
`joined to form a 4 to 7 membered ring.
`
`MYLAN - Ex. 1012, p. 15
`
`

`

`US 7,582,621 B2
`
`6
`inhibition (in the order of the cells shown in the figure) of
`74%, 86%, 100%, 82%, 100% and 84% were observed forthe
`growth of T. rubrum.
`FIG. 8 displays the results of a 40 µL/cm 2 aliquot of 8%
`ciclopirox in w/w commercial lacquer applied per day over
`five days. No zone of inhibition observed; full carpet growth
`of T. rubrum.
`FIG. 9 displays the results of a 40 µL/cm 2 aliquot of 5%
`amorolfine w/v in commercial lacquer applied per day over
`10 five days. No zone of inhibition observed; full carpet growth
`of T. rubrum.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`I. Definitions and Abbreviations
`
`5
`In another aspect, the invention provides a method of kill(cid:173)
`ing a microorganism, comprising contacting the microorgan(cid:173)
`ism with a therapeutically effective amount of a compound of
`the invention.
`In another aspect, the invention provides a method ofinhib(cid:173)
`iting microorganism growth, comprising contacting the
`microorganism with a therapeutically effective amount of a
`compound of the invention.
`In another aspect, the invention provides a method of treat(cid:173)
`ing an infection in an animal, comprising administering to the
`animal a therapeutically effective amount of a compound of
`the invention.
`In another aspect, the invention provides a method of pre(cid:173)
`venting an infection in an animal, comprising administering
`to the animal a therapeutically effective amount of a com- 15
`pound of the invention.
`In another aspect, the invention provides a method of treat(cid:173)
`ing a systemic infection or an ungual or periungual infection
`in a human, comprising administering to the animal a thera(cid:173)
`peutically effective amount of a compound of the invention. 20
`In another aspect, the invention provides a method of treat(cid:173)
`ing onychomycosis in a human, comprising administering to
`the animal a therapeutically effective amount of a compound
`of the invention.
`In another aspect, the invention provides a method of syn-
`thesizing a compound of the invention.
`In another aspect, the invention provides a method of deliv(cid:173)
`ering a compound from the dorsal layer of the nail plate to the
`nail bed. The method comprises contacting said cell with a
`compound capable of penetrating the nail plate, under condi(cid:173)
`tions sufficient to penetrate said nail plate, and thereby deliv(cid:173)
`ering the compound. The compound has a molecular weight
`of between about 100 and about 200 Da. The compound also
`has a log P value of between about 1.0 and about 2.6. The
`compound has a water solubility between about 0.1 mg/mL
`and 1.0 g/mL octanol/saturated water.
`
`25
`
`30
`
`The abbreviations used herein generally have their conven(cid:173)
`tional meaning within the chemical and biological arts.
`"Compound of the invention," as used herein refers to the
`compounds discussed herein, pharmaceutically acceptable
`salts and prodrugs of these compounds.
`MIC, or minimum inhibitory concentration, is the point
`where compound stops more than 90% of cell growth relative
`to an untreated control.
`Where substituent groups are specified by their conven(cid:173)
`tional chemical formulae, written from left to right, they
`equally encompass the chemically identical substituents,
`which would result from writing the structure from right to
`left, e.g., -CH20- is intended to also recite -OCH2 - .
`The term "poly" as used herein means at least 2. For
`example, a polyvalent metal ion is a metal ion having a
`valency of at least 2.
`"Moiety" refers to the radical of a molecule that is attached
`35 to another moiety.
`The symbol ...rv"VV', whether utilized as a bond or dis(cid:173)
`played perpendicular to a bond, indicates the point at which
`the displayed moiety is attached to the remainder of the mol(cid:173)
`ecule.
`The term "alkyl," by itself or as part of another substituent,
`means, unless otherwise stated, a straight or branched chain,
`or cyclic hydrocarbon radical, or combination thereof, which
`may be fully saturated, mono- or polyunsaturated and can
`include di- and multivalent radicals, having the number of
`45 carbon atoms designated (i.e. C 1 -C 10 means one to ten car(cid:173)
`bons). Examples of saturated hydrocarbon radicals include,
`but are not limited to, groups such as methyl, ethyl, n-propyl,
`isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
`(cyclohexyl)methyl, cyclopropylmethyl, homologs and iso-
`50 mers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and
`the like. An unsaturated alkyl group is one having one or more
`double bonds or triple bonds. Examples of unsaturated alkyl
`groups include, but are not limited to, vinyl, 2-propenyl,
`crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,
`55 4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and
`the higher homologs and isomers. The term "alkyl," unless
`otherwise noted, is also meant to include those derivatives of
`alkyl defined in more detail below, such as "heteroalkyl."
`Alkyl groups that are limited to hydrocarbon groups are
`60 termed "homoalkyl".
`The term "alkylene" by itself or as part of another substitu(cid:173)
`ent means a divalent radical derived from an alkane, as exem(cid:173)
`plified, but not limited, by --CH2 CH2CH2 CH2- , and further
`includes those groups described below as "heteroalkylene."
`65 Typically, an alkyl (or alkylene) group will have from 1 to 24
`carbon atoms, with those groups having 10 or fewer carbon
`atoms being preferred in the present invention. A "lower
`
`40
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a table of minimum inhibitory concentration
`(MIC) data of CBO against various fungi.
`FIG. 2A displays minimum inhibitory concentration
`(MIC) for ClO, ciclopirox, terbinafine, fluconazole and itra(cid:173)
`conazole (comparator drugs) against 19 test strains of fungi.
`FIG. 2B displays minimum fungicidal concentration
`(MFC) for ClO, ciclopirox, terbinafine and itraconazole
`(comparator drugs) against 2 test strains of fungi.
`FIG. 3 displays a comparison of Normalized ClO and
`Ciclopirox Equivalent in Each Part of Nail Plate Samples
`after 14-day Treatment.
`FIG. 4 displays a comparison of ClO and Ciclopirox
`Equivalent in Cotton Ball Supporting Bed Samples after
`14-day Treatment.
`FIG. 5 displays the results of a placebo for ClO (50:50
`propylene glycol and ethyl acetate) applied per day over five
`days. Full carpet growth of the organism T. rubrum was
`observed.
`FIG. 6 displays the results of a 40 µL/cm 2 aliquot of ClO
`10% w/v solution applied per day over five days. Zones of
`inhibition (in the order of the cells shown in the figure) of
`100%, 67%, 46%, 57%, 38% and 71 % were observed forthe
`growth of T. rubrum. Green arrow indicates the measurement
`of zone of inhibition.
`FIG. 7 displays the results of a 40 µLiem aliquot of ClO
`10% w/v solution applied per day over five days. Zones of
`
`MYLAN - Ex. 1012, p. 16
`
`

`

`US 7,582,621 B2
`
`7
`alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene
`group, generally having eight or fewer carbon atoms.
`The terms "alkoxy," "alkylamino" and "alkylthio" ( orthio(cid:173)
`alkoxy) are used in their conventional sense, and refer to those
`alkyl groups attached to the remainder of the molecule via an 5
`oxygen atom, an amino group, or a sulfur atom, respectively.
`The term "heteroalkyl," by itself or in combination with
`another term, means, unless otherwise stated, a stable straight
`or branched chain, or cyclic hydrocarbon radical, or combi(cid:173)
`nations thereof, consisting of the stated number of carbon 10
`atoms and at least one heteroatom. In an exemplary embodi(cid:173)
`ment, the heteroatoms can be selected from the group con(cid:173)
`sisting ofB, 0, N and S, and wherein the nitrogen and sulfur
`atoms may optionally be oxidized and the nitrogen heteroa(cid:173)
`tom may optionally be quaternized. The heteroatom(s) B, 0, 15
`N and S may be placed at any interior position of the het(cid:173)
`eroalkyl group or at the position at which the alkyl group is
`attached to the remainder of the molecule. Examples include,
`but are not limited to, --CH2--CH2---0-CH3, --CH2-
`CH2-NH--CH3,
`-CH2--CH2-N(CH3)--CH3, 20
`-CH2-S-CH2-CH3, -CH2-CH2,
`-S(O)--CH3,
`-CH2--CH2-S(0)2--CH3,
`--CH=CH-O--CH3,
`-CH2--CH=N---0CH3, and -CH=CH-N(CH3)-
`CH3. Up to two heteroatoms may be consecutive, such as, for
`example, --CH2-NH-OCH3. Similarly, the term "het- 25
`eroalkylene" by itself or as part of another substituent means
`a divalent radical derived from heteroalkyl, as exemplified,
`but not limited by, -CH2-CH2-S-CH2-CH2-
`and
`-CH2-S-CH2-CH2-NH--CH2-. For heteroalkylene
`groups, heteroatoms can also occupy either or both of the 30
`chain termini (e.g., alkyleneoxy, alkylenedioxy, alkylene(cid:173)
`amino, alkylenediamino, and the like). Still further, for alky(cid:173)
`lene and heteroalkylene linking groups, no orientation of the
`linking group is implied by the direction in which the formula
`of the linking group is written. For example, the formula 35
`-C(0)2R'- represents both --C(0)2R'- and -R'C
`(0)2-·
`The terms "cycloalkyl" and "heterocycloalkyl", by them(cid:173)
`selves or in combination with other terms, represent, unless
`otherwise stated, cyclic versions of"alkyl" and "heteroalkyl", 40
`respectively. Additionally, for heterocycloalkyl, a heteroatom
`can occupy the position at which the heterocycle is attached to
`the remainder of the molecule. Examples of cycloalkyl
`include, but are not limited to, cyclopentyl, cyclohexyl, 1-cy(cid:173)
`clohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. 45
`Examples ofheterocycloalkyl include, but are not limited to,
`1-1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,
`3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofu(cid:173)
`ran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahy(cid:173)
`drothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
`The terms "halo" or "halogen," by themselves or as part of
`another substituent, mean, unless otherwise stated, a fluorine,
`chlorine, bromine, or iodine atom. Additionally, terms such as
`"haloalkyl," are meant to include monohaloalkyl and polyha(cid:173)
`loalkyl. For example, the term "halo(C 1 -C4 )alkyl" is mean to 55
`include, but not be limited to, trifluoromethyl, 2,2,2-trifluo(cid:173)
`roethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
`The term "aryl" means, unless otherwise stated, a polyun(cid:173)
`saturated, aromatic, substituent that can be a single ring or
`multiple rings (preferably from 1 to 3 rings), which are fused 60
`together or linked covalently. The term "heteroaryl" refers to
`aryl groups (or rings) that contain from one to four heteroat(cid:173)
`oms. In an exemplary embodiment, the heteroatom is selected
`from B, N, 0, and S, wherein the nitrogen and sulfur atoms
`are optionally oxidized, and the nitrogen atom(s) are option- 65
`ally quaternized. A heteroaryl group can be attached to the
`remainder of the molecule through a heteroatom. Non-limit-
`
`8
`ing examples of aryl and heteroaryl groups include phenyl,
`1-naphthyl, 2-naphthyl, 4-b