I 1111111111111111111111111111111 1111111111111111111111111111111 llll llll llll
`US007465836B2
`
`c12i United States Patent
`Lee et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,465,836 B2
`Dec. 16, 2008
`
`(54) HYDROl,YTICALl,Y-RESIS'I>\NT
`BORON-CON1P.INI:-IG THERAPEUTICS AND
`MI<:'rHODS OJI USE
`
`(75)
`
`Inventors: Ying Lee, Los Altos, CA (US)_; Jacob J.
`Plattner, Berkeley. CA (US)~ Stephen .J.
`Bcnkovic, State College, PA (US);
`Stephen J. Baker, Mountain View, CA
`(US); Kirk R. Maples, San Jose, CA
`(US); Carolyn Bellinger-Kawahara,
`Redwood City, CA (US); Tsutomu
`Akama, Sunnyvale, CA (US);
`Yong-Kang Zhang. San Jose, CA (US);
`Rajcshwar Singh, Echnonton (CA);
`Vittorio A. Sauro, Ed111onton (CA)
`
`(73) Assignee: Anacor Pharmaceuticals, Inc., Palo
`Alto, CA(US)
`
`( *) Notice:
`
`Subject to any disclahner, the tenn of this
`patent is extended or adjusted under :15
`U.S.C. 154(b) by 627 days.
`
`(21) Appl. No.: 111/868,268
`
`(22) Filed:
`
`Jun.15, 2004
`
`(65)
`
`US 2005/0054644 Al
`
`Prior Publication Data
`Mar. 1 0, 2005
`
`Related U.S~ .. Application Data
`
`(5 I)
`
`(52)
`(58)
`
`(56)
`
`Int. Cl.
`C07F 9102
`(2006.01)
`U,S. CI. ..................................................
`568/8
`Field of Classification Search ...................... 568/8
`See application file for co1nplete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,880,188 A
`
`311999 Austin et al.
`
`OfHER PUBLICATIONS
`
`Haynes ct al (Journal of Organic Chemistry (1964), 29(11), 3229-
`33.•
`Zhdankin et al. "Synthesis and strncture of bcnzoboroxoles: novel
`organoboron hctcrocyclcs" Tetrahedron Letlers 40:6705-6708
`(1999).
`Koster et al. "Cyclisierungen von Bor-Stickstoff-Verbindugen in der
`Hictz" Liebigs.Ann. Chem. 720:23-31 (1968).
`
`"'cited by exruniner
`
`Priniary Examiner-Dnn.iel M Sullivan
`Assistant Exa111iner-Kellette Gale
`(74) Auorney, Agent, or Finn-Morgan, Lewis & Bockius,
`LLP
`
`(57)
`
`ABSTRACT
`
`Co1npositions and methods of use of borole derivatives.
`including benzoxaboroles, benzazaboroles and benzthi(cid:173)
`aboroles, as therapeutic agents for treaunent of diseases
`caused by bacteria or viruses are disclosed, as well as n1eth(cid:173)
`ods.for synthesis of said agents and co1npositions thereat:
`
`(60)
`
`Provisional application No. 60/478,921, filed on J\ln.
`16, 2003.
`
`30 Claims, No Drawings
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1055 - Page 1 of 24
`
`

`
`US 7,465,836 B2
`
`2
`
`-continued
`
`Vims Category
`
`Pertinent Human Infections
`
`Fl:wivirict.'lc
`Coronnviridac
`
`R11abduvirn.l:u:
`P;-imrnyxovindac
`
`Yellow fever
`H1umrn respiratory coron:i.vims (HCV)
`Severe :1.1::utc respir:ltory syndrome (SAR)
`Lyss:1virns - R.:1bics
`Panmyxovims - Mumps
`Morbilivims - menslcs
`Pncurno\'ims - rcspim1ory syncyti:i.I vims
`Orthomyxovirid:u: Jnflm·nz01 A-C
`Bunynviridae
`Bunyavin.is - Bwiy:unwcm (BUI\)
`Hantnvims - H:rnta:m (HTN)
`N:iircvin1s - Crimc:rn-Congo l1cm01;h:igic fever
`(CCHF)
`Phldxwirus - Sand.fly fevo:r (SFNJ
`Unkuvims - Uukunicmi (UUK)
`Rift \.:i.lley F1-•ver (RVFN)
`Junin -Arge11tim: hemorrl1agh: kver
`Machupo - Bolivillll l1cmorrlmgic fovcr
`Lnssll - Lassa fever
`I.CM - aseptic lymphocyctic choriomc11ingitis
`Roto\'ims
`Reovirns
`Orbivirus
`Hmnil.!1 immunodeficiency vims I (HIV-I)
`Hmnil.11 immunodeficiency vims 2 (HIV-2)
`Simi:rn immunodeficiency \'illrn (SIV)
`DNA Vimses
`
`Arenaviridae
`
`Reoviridae
`
`Retroviridae
`
`Papo\'avirid:i.c
`Adenovindac
`
`Piuvo\'indae
`Herpes\•ind.i.c
`
`Pediatric viruses that reside in kidney
`Hmnru1 respiutoiy distress il.11d some deep-sested
`eve infections
`1-ium1U1 gnstro-intestinal distress (Norwlllk Vims)
`Herpes simplex vims l (HSV-1)
`He1pes simplex vims 2 (HSV-2)
`Human 1:yto111egaluvirus (HC:vfV)
`Varicell:i zostcr vints (VZV)
`Epstein· Bllrr vims (EBVJ
`H\lfnan herpes vinis 6 (HHV6)
`Orthopoxvin1s is sub-genus for sm~llpox
`· Hepatitis B virus (H.BV) __
`HepatitiS C vims (HCV)
`
`JS Poxvindae
`Hepil.Chuvlrlda.c
`
`1
`HYDROLYTICALLY-RESISTANT
`BORON-CONTAINING THERAPEUTICS AND
`METHODS OF USE
`
`TI1is <1pplication cktitns priority of U.S. Provisional Appli(cid:173)
`cation Ser. No. 60/478,921, filed 16 Jun. 2003, the disclosure
`of which is hereby incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`TI1e present invention relates to novel compounds and
`con1positions which have selective therdpeutic activities, pro(cid:173)
`cesses for inaking such compounds, synthetic intennediates
`e1nployed in these processes and a 1nethod for treating human
`or other inanunal in need of1nedical treahnents.
`
`10
`
`15
`
`BACKGROUND OF THE INVENTION
`
`20
`
`25
`
`30
`
`Many advances in 1nedicine in the 2CY" century have been
`due to the discovery of new classes of small 1nolecular weight
`effectors for various therapeutic needs. Herein .. ,,.e disclose
`the diverse, but selective pham1acologically active boron(cid:173)
`·
`containing entities.
`()ne hallmark of the modern erd of medicine has been the
`decline in 1norbidity and mortality associated with bacterial
`and fi.1ngal infections. However, misuse of conventional anti(cid:173)
`biotics and nan1ral selection of the infectious bacterial popu(cid:173)
`lation has resulted in the development of varying degrees of
`dnig resistance by most bacterial infectious agents to most
`antibiotic agents. In severe cases, such as MRSA (Multidrug(cid:173)
`Resistant StaphA), one or only a few antibiotics are currently
`effective. In addition, the existence of inununodeficiency
`syndro1nes results in additional incidences of opportunistic
`inf1.><.:tions requiring intensive antibiotic treatment.
`Vin1scs arc i1nplicated in a variety of ru1i1nnl and htunan
`disease. Ntunerous approaches have been proposed to combat
`these pathogens which include, but are not litnited to herpes(cid:173)
`vin1ses 1 and 2 (HSV-1 and HSV-2), influenza viruses A, B
`and<:, parainfluen;r.1.1vin1ses14, syncytial virus, Epstein-Barr
`vin1s, rhinovin1scs, hu111an im1nunodcficicncy vin1ses (Hl\l), 40
`poliovin1ses, coxsackievin1ses, echovin1ses, n1bella vin1s,
`varicella-zoster vin1s, neurodenna-tropic vin1s, variola virus,
`cyto1negalovin1s, hepatitis A, B and C vin1ses, papovin1ses,
`rabies virus, yellow fever vin1s, dengue vin1s, West Nile vin1s
`and SARS vin1s.
`One approach in the develop1nent of antiviral compounds
`has been to identify con1pounds which interfere with the
`nonnal viral rnetabolis1n and replication in infected host cells.
`During the screening of new borinic ester co1npounds, we
`lmvc found that certain of these compounds show antiviral 50
`activity in cell culture assay syste1ns. Many existing con1-
`pounds currently in use for treating viral diseases are subject
`to resistance 1nechanis111s, are expensive to n1ake, do not
`ndequately treat patients or have adverse side effects. There(cid:173)
`fore, there is a continuing need for new co1npounds which act 55
`to kill viruses, to inl1ibit viral replication or to block the
`pathogenic action ofvin1ses.
`
`Boron containing con1pounds have received increasing
`attention as therapeutic agents over the past few years as
`technology in organic synthesis has expanded to include this
`ato1n. [Boron Therapeutics on the horizon, Groziak, M. P.;
`An1erican Journal of Therapeutics (2001) 8, 321-328] The
`nlost notable boron containing therapeutic is the boronic acid
`45 bortczo1nib which was recently launched for the treat1ncnt of
`1nultiple n1yelo111a. This breakthrough demonstrates the fea(cid:173)
`sibility of using boron containing con1pounds as phannaceu(cid:173)
`tical agents. Boron containing co1npo1111ds have been shown
`to huve various biological activities including herbicides l<>r(cid:173)
`ganic boron coin pounds as herbicides. Ban1slcy, G. E.; Eaton,
`J. K.; Airs. R. S.; (1957). DE 1016978 I9571003], boron
`neutron capn1re therapy [Molecular Design and Synthesis of
`1-3-10 Ctirriers for Neutron Capture Then1py. Ymnmnoto, Y.;
`Pure Appl. Che1n., (1991) 63, 423-4261, serine protease inhi(cid:173)
`bition [Borinic acid inhibitors as probes of the factors
`involved in binding at the active sites of subtilisin Carlsberg
`and a-chy1notiypsin. Si111pelkan1p, J.; Jones, J. B.; Bioor(cid:173)
`ganic & Medicinal Chemistry Letters, (1992), 2(11 ), l 391-4j,
`[Design, Synthesis and Biological Evaluation of Selective
`60 Boron-containing Tiiron1bin
`Inhibitors. Weinand, A.;
`Elirhardt, C.; Metten1ich. R.; Tapparelli, C.; I3ioorganic and
`Medicinal Che111istty, (1999), 7, 1295-1307}, acetylcho(cid:173)
`linesterase inhibition [New, specific and reversible bifiu1c(cid:173)
`tional alk-ylborinic acid inhibitor of acetylcholinesterase.
`65 Koehler, K. /\ .. ;Hess, G. P.; Bioche1nistiy (1974), 13, 5345-
`50} and as antibacterial agents [I3oron-Containing A.ntibac(cid:173)
`terial Agents: Effects on Growth and Morphology of Bacteria
`
`Vims Category
`
`Portincnt Human Infections
`
`RNA Viruses
`
`Picomaviridru:
`
`Togavind:ie :u1d
`
`Polio
`IIwmrn hepatitis A
`HtUl13ll rhinovirns
`Rubdla - Gcm1:ll1 measles
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1055 - Page 2 of 24
`
`

`
`US 7,465,836 B2
`
`3
`Under Various Culture Conditions. Bailey, P. J.; Cousins. G.;
`Snow, G. A.; <Jnd White, A. J.; Anli1nicrobial .A.gents nnd
`Che1notherapy, (1980), 17, 549-553]. The boron containing
`con1pounds v.1ith antibacterial activity can be sub-divided into
`two mnin cfasses, thediriz..1borinines, which have been known s
`since the 1960's, and dithienylborinic acid co1nplexes. This
`latter class lrns been expanded to include nmny different dia(cid:173)
`rylborinic acid cotnplexes with potent antibacterial activity
`[Preparation of diarylborinic acid esters as DNA n1cthyl
`transfemse inhibitors. Benkovic, S. J.; Shapiro. L.; Bnker, S. 10
`J.; Walu1on, D. C.; Wall, M.: Shier, \'. K.; Scott, C. P.;
`Baboval, J.; PCT Int. Appl. (2002), WO 2002044184]. Syn(cid:173)
`thetic develop1nents described in Benkovic et al. enabled
`creation or a much 1nore diverse class or unsy1nnH~tricul di(cid:173)
`substituted borinic acid co1nplexes not possible before.
`1ln1s, there continues to be a need in the 1nedical arts for
`novel, 1nore effective, antibiotic co1npo11nds, especially for
`treating infectious diseases, that are resistant to currently
`available ther.apies.
`
`15
`
`BRIEF SUMMARY OF THE INVENTION
`
`In one aspect. the present invention relates to therapeutic
`co1npounds, which are boron-containing. 111ese con1pounds
`include structures that encmnpass henzoxaboroles, ben(cid:173)
`zazaboroies, benzthiaboroles and related analogs.
`1l1ese co111pounds are also provided as pham1aceutical
`con1positions that can be ad1ninistered to an ani1nal, 1nost
`preferably a hun1un, for treahnenl of a disease having either
`bacterial, fungal or viral etiology, 1nost preferably a htunan, in 30
`an i1111nunologically con1pro1nised or debilitated state of
`health.
`In preferred e1nbodi1nents, the co1npounds ofrhe invention
`are those having the structures given by Fonnula I, with
`preferred substin1ents as.disclosed herein.
`_
`_
`·111e invention ulso provides metllods for preparing these
`therapeutic con1pounds <ind plmnn<iceutical co1npositions
`thereof, and 1nethods of using said compounds ther<ipeuti(cid:173)
`cally. Kits and packaged cmbodilnents of these con1pounds
`and phann<iceutical con1positions of the invention are also 40
`conte1nplated.
`111e invention also relates to 1nethods of treating various
`n1edical conditions, using the co1npounds disclosed herein.
`
`35.
`
`4
`unsubstinned alkynyl, substituted or unsubstituted aralkyl,
`substituted or unsubstituted aryl, and substin1ted or unsubsti(cid:173)
`n1ted heteroaryl,
`\Vherein R*"' is H, alkyl, alkyloxy, alkoxyalkyl, ~ubstitute<l
`or unsubstin1ted aryl, substituted or unsubstinited heteroaryi,
`and \\therein.'\. is CH, CR 1
`, or N
`and wherein Dis CH, CR2
`, or N
`and wherein Eis CH, CR3
`, or N
`and wherein G is CH, CR4
`, or N
`and the con1bination of nitrogens {A+D+E+G) is 0-3
`and wherein J is (CH 2 ),, (n=O to 2) or CHR5
`and wherein W is (CH 2 ),,, (111==0 to 1 }, C=() (carbonyl) or
`CHR'
`, R3 and R4 are each independently selected
`, R2
`wherein R 1
`fro111 the group consisting of hydrogen, haloaJk.-yl, alkyl,
`cycloalkyl,
`(CH2)POH
`(p==l
`to 3), halogen, CHO,
`CH=NOH, C02H, C02-alkyl, S-alkyl, SO,-alkyL S-oryl,
`20 (CH 2)qNR18R 19 (wherein R 18 and R 19 are independently
`selected from hydrogen, alkyl, and alkanoyl)(q'°° to 2),
`alkoxy, CF3 , SCF3 , N02, S03H, OH, substituted or unsubsti(cid:173)
`n1ted aryl, substinited or unsubstituted aralkyl, substin1ted or
`unsubstituted heteroaryl, fused substituted or unsubstituted
`25 aryl, fbsed substihlted or unsubstituted heteroaryl,
`wherein R5 is selected fro1n substin1ted or unsubstituted
`alkyl (C 1-C4 ), substituted or unsubstituted cycloalk.")'l
`(C3-C7), substituted or unsubstituted alkenyl, substi(cid:173)
`tuted or unsubstituted alkynyl, substituted or un-.ubsti(cid:173)
`nued aralkyl, substinited orunsubstinued aryl, and sub(cid:173)
`stituted or unsubstinited heteroaryl,
`wherein R6 is selected front substiruted or ln1substituted
`alkyl (C 1-C4 ), substituted or unsubstituted cycloalkyl
`(C3 -C7), substituted or unsubstituted alkenyl, substi(cid:173)
`tuted or unsubstinited alkynyl, substiruted or. u1~substi­
`n1ted aralk.-yl, substinued orunsubstinited aryl, and sub-
`stituted or unsubstituted hcteroaryl, including salts
`thereof, especially all pharmaceutically acceptable salts.
`In preferred etnbodiments of Formula I, Mis oxygen, or M
`is sulfur, or Mis NR **.Further preferred e1nbodi1nents of any
`of these three are any of the following.
`In a preferred entbodiment of Fonnula I, R * is a substi(cid:173)
`tuted or unsubstituted alkyl (C 1-C4 ).
`In a preferred embodiment ofFonnula I, R* is a substi-
`n1ted or unsubstituted cycloalkyl (C3 -C7 ).
`111 a preferred en1bodilnent of Fonnula I, R * is a substi(cid:173)
`n1ted or unsubstituted alkenyl. In a further preferred en1bodi-
`1nent thereof, the substituted alkenyl has the structure
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`111is invention provides therapeutic agents, and specifi(cid:173)
`cally antibacterial, antifungal, or antiviral compounds, useful
`in treating and/or preventing conditions due to these patho(cid:173)
`gens.
`The inventionco1nprises a con1poundhaving the following
`stn1ctures
`
`45
`
`50
`
`~::
`
`wherein Bis boron, NI is selected fro1n oxygen, s~1lfur and
`NR*"'
`wherein R* is selected fro111 substituted or unsubstituted 65
`aJl. .. ")'l (C 1-C4 ), substituted or unsubstituted cycloalk.")'l (C,(cid:173)
`C7), substituted or unsubstin1ted alkenyl, substituted ;r
`
`wherein R7, R8, and R9 are each independently selected front
`the group consisting of hydrogen, nlkyl, hnlonlkyl, nryl, sub-
`60 stituted aryl, aralkyl, substinucd aralkyl, (CH 2)rOH (where
`r=l to 3), CII2NR20R21 (v.:herein R20 and R21 are indepen(cid:173)
`dently selected from hydrogen and alkyl), C02H, C02alk.-yl,
`CONH2 , S-alk")'l, S-aryl, S02alkyl, S03H, SCF3 , CN, halo-
`gen, CF :i and N02 •
`In a preferred en1bodiment of Fonnula 1. R * is a substi(cid:173)
`tuted or unsubstituted alk")'nyl. In a further preferred en1bodi-
`1nent thereof the substin1ted a)J...-ynyl has the stn1cnire
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1055 - Page 3 of 24
`
`

`
`US 7,465,836 B2
`
`5
`
`-1-"=~-R'
`
`wherein R7 is defined as before.
`In a preferred e1nbodi1nent of Fonnula I, R * is a substi(cid:173)
`tuted orln1substit11ted aryl. In a further preferred e1nbodiment
`thereof the substituted aryl has the stn1cture
`
`6
`The structures of the invention also pennit solvent interac(cid:173)
`tions that 1nay afford stn1ctures (Ponnula 113) that include
`aton1s derived fron1 the solvent encountered by the con1-
`pounds of the invention during synthetic numipulations and
`thernpeutic uses. Strucn1res l B arise frotn fOnnation of a
`dative bond between the solvent(s) \Vith the LC\\o·is acidic
`boron center. Thus. such solvent co1nplexes I I3 could be
`stable entities with co1nparative bioactivities. Such stn1cn1res
`are expressly conte1uplated by the present invention \Vhere
`10 R*** is Hor <Jik·yl.
`
`Fonnula Ill
`
`15
`
`20
`
`, R13 and R14 arc each independently
`, R12
`, R11
`wherein R10
`selected fro1n the group consisting of hydrogen, alk.-yli aryl,
`substituted aryl, aralk}'l, substituted amlkyl, (CH 2),0H
`(where s-1 to 3), C02I-I, C02aU,-yl, CONH2, CONHalkyl,
`C<)N(alkyl)2, ()H, alkoxy, aryloxy, SH, S-alkyl, S-aryl, 25
`SO,~lkyl, SO,H, SCP,, CN, halogen, CF,, NO,, (CH,),
`NR._R23 (wherein R 20 and R 21 are independently selected
`fro111 hydrogen, alh.-yl, and alkanoyl)(t=O to 2), S02NH2,
`OCH2CH2NH,, OCH,CH,NHalk')'l, OCH2CH2N(alkyl),,
`oxuzolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
`In a preferred c1nbodiment ofFonnula 1, R* is a substi(cid:173)
`tuted or unsubstin1ted aralkyl. In a further preferred e1nbodi-
`111ent thereof the substituted aralkyl has the structure
`
`As used herein, the following terms have the stated 1neaning:
`By "alk.-yl", "lower alk')'I", and "C 1-C6 alkyl" in the present
`invention is n1canl slmight or branched chain alkyl groups
`having 1-6 carbon <1to1ns, such as, tncthyl, ethyl, propyl,
`isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, iso-
`pentyl, ncopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-inethylpen(cid:173)
`tyl.
`By "alkanoyl" in the present invention is n1eunl slrdight or
`30 branched chain <llkanoyl groups having 1-6 carbon ato1ns,
`such as, acetyl, propanoyl, butanoyL pentanoyl, hexanoyl,
`isobutanoyL 3-inethylbutanoyl, and 4-inethylpentanoyl.
`By "alkoxy", "lower alkoxy", and "C 1-Cr. alkoxy" in the
`present invention is 1neant straight or bninched chain alkoxy
`35 groups having 1-6 c<Jrbon ato1ns, such as, for cxan1ple, n1cth(cid:173)
`oxy. ethoX:y, propoxy, isopropoxy, n-butoxy, sec-bu1oxy, tert- ·
`butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy,
`2-hexoxy, 3-hexoxy, and 3-1nethylpen1oxy.
`By the tenn "halogen" in the present invention is n1eant
`40 fluorine, bro1ninc, chlorine, and iodine.
`I3y "cycloalk-yl", e.g .• C 3-C7 cycloalk-yl, in the present
`invention is tneant cycloalk')'l groups having 3-7 ato1ns such
`as, for exmnple cyclopropyl, cyclobutyl, cyclopentyl, cyclo(cid:173)
`hexyl, and cycloheptyl. In the CrC7 cycloalk.-yl groups, pref-
`45 erably in the C5-C7 cyeloalkyl groups, one or two of the
`carbon aton1s fanning the ring can optionally be replaced
`with a hetero ato1n, such as sulfur. oxygen or nitrogen.
`Exmnples of such groups are piperidinyl, piperazinyl. n1or(cid:173)
`pholinyl, pyrrolidinyl, in1idazolidinyl, oxazolidinyl, perhy-
`50 dronzepinyl, pcrhydrooxaz.1pinyl, oxepanyl, pcrhydrooxepa(cid:173)
`nyl. tctrahydrofuranyl, and tetrahydropyranyl. C 3 and C 4
`cycloalkyl groups having a 1ncmber replaced by nitrogen or
`oxygen include uziri<linyl. azetidinyl, nxetanyl, und oxiranyl.
`By "aryl" is 1nean1 an aro1natic carbocyclic group having a
`55 single ring (e.g., phenyl), n1uhiplc rings (e.g., biphenyl), or
`1nultiple condensed rings in which at least one is aro1natic,
`(e.g., J ,2,3,4-tetrahydronaphthyl, naphthyl, antliryl, or
`phenanthryl), \Vhich is optionally mono-, di-, or 1risubstituted
`with, e.g., halogen, lo\ver alk')'l, lower alkoxy, lower alk-y-
`60 lthi.o, trifluoro1nethyl, lower acyloxy, aryl, heteroaryl, and
`hydroxy. Preferred <Jryl groups include phenyl and naphthyl,
`each of which is optionally substin1tcd as defined herein.
`By "heteroaryl" is 1neant one or n1ore aron1atic ring sys(cid:173)
`te1ns of 5-, 6-, or 7-1ne1nbered rings containing at lenst one
`65 and up to four heteroaton1s selected fron1 nitrogen, oxygen, or
`sulfur. Such heteronryl groups include, for exmnple, thienyl,
`fi.1ranyl, thiazolyl, i1nidazolyL (is)oxazolyl, pyridyl, pyri1n-
`
`, R 13 and R14 are defined as before.
`, R 12
`, R 11
`wherein R 10
`In a preferred e1nbodin1ent of Fonnula 1, R* is a substi(cid:173)
`nited or unsubstituted heteroaryl. In a further preferred
`e1nbodi1nent thereof the heteroaryl has the stn1cn1re
`
`wherein X=CH=CH, N=CH, NR 17 (wherein R17-H,
`alkyl, <iryl or bcnzyl), 0, or S
`and wherein Y=CH or N
`and \Vhcrcin R 15 and R 16 arc each independently selected
`the group consisting of hydrogen, alkyl,
`fro1n
`cycloalkyl, haloalJ:. .. ")·l, aryl, substituted aryl, aralkyl, sub(cid:173)
`stituted aralkyl, (CH2)~0H (where u== 1, 2 or 3), (CH2),,
`NR 24 R25 ('vhert!in R 4 und R25 ure independently
`selected fro1n hydrogen, alk')'l and alkanoyl)(v=O to 3),
`C02H, C02alk')'l, CONH2 , S-alk-yl, S-aryl, S02alk')'l,
`S03l-L SCF3 • CN, halogen, CF3 and N0 2.
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`idinyl, (iso)quinolinyl, napthyridinyl, benzi1nidazolyl_. and
`benzoxazolyl. Preferred heteroaryls are thiazolyl, pyri111idi(cid:173)
`nyl, preferably pyriinidin-2-yl, and pyridyl. Other preferred
`heleroaryl groups include l -i1nidazolyl, 2-thienyl, 1-(or
`2-)quinolinyl, 1-(or 2-)isoquinolinyl, 1-(or 2-)tctrahydroiso(cid:173)
`quinolinyl, and 2-(or 3-)furanyl.
`TI1e invention <1lso provides e1nbodi1nents of the con1-
`pounds disclosed herein as phannaceutical con1positions.
`The plmnnaceutical co1npositions of the present invention
`can be nianufoctured in a manner that is itself known, e.g., by 10
`ineans of a conventional 1nixing, dissolving. granulating. dm(cid:173)
`gee-1naking, levigating, e1nulsifying, encapsulating, entrap(cid:173)
`ping or lyophilizing processes.
`Phannaceutical co1npositions for use in accordance with
`- the present invention thus can be fonnulated in conventional 15
`111anner using one or n1ore physiologically acceptable carriers
`con1prising excipients and auxiliaries that facilitate process(cid:173)
`ing of the active con1pounds into preparations that cru1 be used
`pharmaceutically. Proper fom1ulation is dependent upon Lhe
`route of ad1nin.istration chosen.
`Non-toxic phannaceutical salts include salts of acids such
`as hydrochloric, phosphoric, hydrobromic, sulfi.Jric, sulfinic,
`fonnic, toluenesulfonic, 1nethanesulfonic, hydroxyethane- ·
`sulfonic, nitric, henzok:, citric, tarturic, 1naleic, hy<lroiodic,
`alkanoic such as acetic, 1-IOOC-(CH2),,-CH3 where n is 25
`0-4, and the like. Non-toxic phannaceu1ieal base addition
`salts include salts of bases such as sodiu1n, potassi1nn, cal(cid:173)
`chun, anunoniu111, and functional equivalents. Those skilled
`in the art will recogni:t.e a wide variety of non-toxic phun1K1-
`ceutically acceptable addition salts.
`For injection, the co1npounds of the invention can be for(cid:173)
`nndated in appropriate aqueous solutions. such as physiologi(cid:173)
`cally cotnpatible buffers such as Hanks's solution, Ringer's
`solution, or physiological saline bufler. Fortrans1nucosnl rind
`transcutancous ad111inistration, penctmnts cippropriate to the JS
`barrier io be pennecited are used in the fonnulation. Such
`penetrants are generally known in the art.
`For oral adininistration, the co1npounds can be fonnulated
`readily byco1nbin.ing theactivecon1pounds with phannnceu(cid:173)
`tically cicceptable carriers well known in the art. Such carriers 40
`enable the cmnpounds of the invention to be fonnulated as
`tablets, pills, capsules, liquids. gels. syn1ps, slurries. suspen(cid:173)
`sions and the like, for oral ingestion by a patient to be trecited.
`Phannaceutical preparations t<.1roral use can beobtnined with
`solid cxcipient. optionally grinding a resulting 1nixturc, and 45
`processing the n1ixture of granules, <tiler cidding suitable aux(cid:173)
`iliaries, if desired, to obtain tablets. Suitable excipients are, in
`particular, fillers such as sugars, including lactose, sucrose,
`nu1nnitol, or sorbitol~ cellulose preparations such as, for
`cxainplc, 1naize starch, wheat starch, rice starch. potCllo 50
`starch, gelatin, gu111 tragacanth, 111cthyl cellulose, hydrox(cid:173)
`ypropyln1ethyl-cellulosc, sodiun1 carboxy1nethylcellulose,
`and/or polyvinylpyrrolidone (PVP). If desired, disintegrating
`agents can be ndded, such as the cross-linked polyvinyl pyr(cid:173)
`rolidone, agar, or alginic acid or 8 salt thereof such as sodiu111 55
`alginate.
`Phannaceutical preparations that can be used orally
`include push-111 capsules 1n;:1de of gelatin, us well as soft,
`sea.led capsules 111a.de of gelatin and a plasticizer, such as
`glycerol or sorbitol. The push-fit capsules can contain the 60
`active ingredients in ad1nixture with filler such as lactose,
`binders such as starches, and/or lubricants such as talc or
`111agnesiu1n stearate and, optionally. stabilizers. In soft cap(cid:173)
`sules, the active compounds can be dissolved or suspended in
`suitable liquids, such as fany oils, liquid paraffin. or liquid 65
`polyethylene glycols. In addition, stabilizers can be added.
`All fonnulations for oral ad1ninistration should be in dosages
`
`8
`suitable for such administration. For buccal adininistration,
`the co1npositions can take the fonn of tablets or lozenges
`fonnulated in conventional n1anner.
`For administration by inhalation, the compounds for use
`according to the present invention are conveniently delivered
`in the f onn of an aerosol spray presentation fron1 pressurized
`packs or a nebuliser, with the use of a suitable propellant. e.g.,
`dichlorodifl.uoron1ethane,
`trichlorofl.uoro1nethane, dichlo-
`rotetra-fl.uoroethane, carbon dioxide or other suitable gas. In
`the case of a pressurized aerosol the dosage unit can be
`determined by providing a valve to deliver a n1etered mnount.
`Capsules and cartridges of e.g., gelatin for use in an inhaler,
`can be fonnulated containing a powder 1nix of the co1npound
`and a suitable powder base such us lactose or starch.
`The co1npounds can be fonnulatcd for parenteral ad1ninis-
`tration by injection, e.g., by bolus injection or continuous
`infusion. Fonnulations for injection can be presented in unit
`dosage fonn, e.g., in a1npoules or in multi-dose containers,
`with an added preservative. The compositions can Lake such
`20 fonns as suspensions, solutions or cnndsions in oily or aque(cid:173)
`ous vehicles, and can contain formulatory agents such as
`suspending, stabilizing and/or dispersing agents.
`Pharn1aceutical fonnulations for parenteral adininistration
`include aqueous solutions of the active compounds in watcr(cid:173)
`solublc fonn. Additionally, suspensions of the <1ctive co111-
`pounds can be prepared as appropriate oily injection suspen-
`sions. Suitable lipophilic solvents or vehicles include fany
`oils such as sesmne oil, or synthetic fatty acid esters, such as
`ethyl olel:lte or trig\y(.-erides, or liposo1nes. Aqll(."1.1US i1~jecLion
`JO suspensions can contain substances that increase the viscosity
`of the suspension, such as sodium carboxy111ethyl cellulose,
`sorbitol, or dextran. Optionally, the suspension can also con(cid:173)
`tain suitable stabilizers or agents that increase the solubility
`of the con1pounds to allow tOr the preparation of highly
`conce1~tratcd sol.titions. Alten1atiyely, the active ingredient
`can be in powder form forconstinnion with a suitable vehicle,
`e.g., sterile pyrogen-free water, before use. The con1pounds
`can also be fonnulated in rectal compositions such as sup(cid:173)
`positories or retention enen1as, e.g., con1<1ining conventional
`suppository bases such as cocoa butter or other glyccridcs.
`In addition to the fonnulations described previously, the
`con1pounds can also be fonnulated as a depot preparation.
`Such long acting fonnulations can be adininistered by
`itnplantation (fOr exmnple subcutaneously or intra1nuscu(cid:173)
`larly) or by intramuscular injection. Thus, for cxan1plc, the
`co1npounds cai1 be fonnulated with suitable polyn1eric or
`hydrophobic materials (for exan1ple as an en1ulsion in an
`acceptable oil) or ion exchange resins, or as sparingly soluble
`derivatives, for exainple, as a sparingly soluble salt.
`A phannaecutical carrier for the hydrophobic co1npounds
`of the invention is a cosolvent systen1 co1nprising benzyl
`alcohol, a nonpolar surfactant, a water-n1iscible organic poly(cid:173)
`tner, and an aqueous phi:ise. The cosolvent system can be the
`\.'PD co-solvent syste1n. VPD is a solution of3% vdv benzyl
`alcohol, 8% w/v of the nonpolar surfactant polysorbate 80,
`and 65% w/v polyethylene glycol 300, 111ade up to volun1c in
`absolute ethanol. ll1e VPD co-solvent syste111 (VPD:5W)
`consists of VPD diluted 1: 1 with a 5°/o dextrose in water
`solution. This co-solvent syste111 dissolves hydrophobic co1n(cid:173)
`pounds well, and itself produces low toxicity llpon syste1nic
`ad1nin.istration. Naturally, the proportions of a co-solvent sys-
`ten1 can be varied considerably without destroying its solu(cid:173)
`bility andtoxicitycharacteristics. Furthennore, the identity of
`the co-solvent con1ponents can be varied: fOr exmnple, other
`low·-toxicity nonpolar s1irfactants can be used instead of
`polysorbatc 80; the fraction size of polyethylene glycol can be
`varied: other biocon1patible polyn1ers can replace polyethyl-
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`ene glycol, e.g. polyvinyl pyrrolidone; and other sugars or
`polysaccharides can substitute for dextrose.
`Ahen1atively, other delivery systen1s for hydrophobic
`phannaceutical con1pounds can be e1nployed. Liposo1nesand
`e1nulsions are well known examples of delivery vehicles or,
`carriers for hydrophobic dn1gs. Certain organic solvents such
`as din1cthyl sulfoxidc also can be c1nploycd, although usually
`at the cost of greater toxicity. Additionally, the compounds
`c<m be delivered using a sustained-release system, such as
`sen1ipenneable 1natrices of solid hydrophobic polyn1ers con- 10
`taining the therapeutic agent. Various sustained-release mate(cid:173)
`rials have been established and are well known by those
`skilled in the art. Sustained-release capsules can, depending
`on their chemical nature, release the compounds for a few
`weeks up to over 100 days. Depending on the che1nical nature
`and the biological stability of the therapeutic reagent, addi- 15
`tional strategics for protein and nucleic acid stabilization can
`be en1ployed.
`'Jl1e pharmaceutical compositions also can con1prise suit(cid:173)
`able solid or gel phase carriers or excipients. Exa1uples of
`such carriers or excipients include but are not lin1ited to 2()
`calciun1 carbonate, calchun phosphate, various sugars,
`starches, cellulose derivatives, gelatin, and poly1ners such as
`polyethylene glycols.
`1lie co1npounds of the invention can be provided as salts
`with phannaceutically compatible countcrions. Pham1accu-
`tically co1npacible salts can be fOrmed with inany acids,
`including hut not limited to hydrochloric, sulfuric, acetic,
`lactic, tartaric, n1alic, succinic, phosphoric, hydrobro1nic,
`sulfinic, fom1ic, toluenesulfonic, 1nethanesulfonic, nitic, ben(cid:173)
`zoic, citric, tartaric, inaleic, hydroiodic, alkanoic such as ace(cid:173)
`tic, I--IOOC-(CI-1 2),,--Cl·J3 where n is 0-4, and the like. Salts 30
`tend to be 1nore soluble in aqueous or other proton.ic solvents
`that are the corresponding free base fonns. Non-toxic phar(cid:173)
`n1aceutical base addition salts include salts of bases such as
`sodiu1n, potasshnn, calciu1n, am1noniu1n, and the like. Those
`skilled in the art \Viii recognize a wide variety of non-toxic 35
`-pharn1aceuticaUy-acceptable addition salts.
`Phannaceutical con1positions of the con1pounds of the
`present
`invention can be fornndated and adn1inistered
`through a variety of1neans, including syste1nic, localized, or
`topical ad1ninistration. Techniques for fonnulation and 40
`adininistration can be found in "Re1nington 's Phannaceutical
`Sciences," Mack Publishing Co., Easton, Pa. The n1odc of
`adininistration c<1n be selected to n1axi1nize delivery to a
`desired target site in the body. Suitable routes of administrd·
`ti on can, forexainple, include oral, rectal, transn1ucosal, tran(cid:173)
`scutaneous, or intestinal adn1inistration; parenteral delivery, 45
`including intramuscular, subcutaneous, intra111edullary injec(cid:173)
`tions, as well as intrathecal, direct intraventricular. intrave(cid:173)
`nous, intraperitoneal, intranasal, or intraocular iizjeCtions.
`Alten1ativcly, one can ad1ninister the con1pound in a local
`rather than systemic nuumcr, for cxan1plc, via injection of the 5ll
`co1npou11d directly into a specific tissue, often in a depot or
`sustnined release fOnnulntion.
`Phannaceutical compositions suitable for use in the
`present invention include con1positions wherein the active
`ingredients are contained in an effective atnount to achieve its 55
`intended purpose. More specifically, a therapeutically effec(cid:173)
`tive an1ount n1eans an an1ount effective to prevent develop-
`1nent of or to alleviate the existing syn1pto1ns of the subject
`being treated. Detennination of the effective mnounts is v...-cll
`within the cr