(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`17 February 2005 (17.02.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/013892 A3
`
`(51) International Patent Classification7:
`C07F 5/02
`
`A61K 31/69,
`
`(74) Agent: LENTINI, David, P.; Foley & Lardner LLP, 1530
`Page Mill Road, Palo Alto, CA 94304 (US).
`
`(21) International Application Number:
`PCT/US2004/018765
`
`(22) International Filing Date:
`
`15 June 2004 (15.06.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/478,921
`
`16 June 2003 (16.06.2003) US
`
`== -
`
`(71) Applicant (for all designated States except US): ANA(cid:173)
`COR PHARMACEUTICALS, INC. [US/US]; 1060East
`Meadow Circle, Palo Alto, CA 94303 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): LEE, Ving [US/US];
`1335 Carvo Court, Los Altos, CA 94024 (US). PLAT(cid:173)
`TNER, Jacob, J. [US/US]; 1016 Ami to Avenue, Berkeley,
`CA 94705 (US). BENKOVIC, Stephen, J. [US/US]; 771
`Teaberry Lane, State College, PA 16803 (US). BAKER,
`Stephen, J. [GB/GB]; 1568 Begen Avenue, Mountain
`View, CA 94040 (US). MAPLES, Kirk, R. [US/US];
`1195 San Moritz Drive, San Jose, CA 95132 (US).
`BELLINGER-KAWAHARA, Carolyn
`[US/US]; 15
`Landa Lane, Redwood City, CA 94061 (US). AKAMA,
`Tsutomu [JP/US]; 832 Azure Street, Sunnyvale, CA
`94087
`(US). ZHANG, Yong-Kang [US/US]; 5151
`Westmont Avenue, San Jose, CA 95130 (US). SINGH,
`Rajeshwar [CA/CA]; 1435 Loewen Court, Edmonton,
`Alberta T6R 2Yl (CA). SAURO, Vittorio, A. [CA/CA];
`3843 24th Street, Edmonton, Alberta T6T 1K6 (CA).
`
`iiiiiiii --
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(88) Date of publication of the international search report:
`16 June 2005
`
`(15) Information about Correction:
`Previous Correction:
`see PCT Gazette No. 15/2005 of 14 April 2005, Section II
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`M °" QO
`
`~
`,....i
`Q
`..........
`lf) ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`
`g (54) Title: HYDROLYTICALLY-RESISTANT BORON-CONTAINING THERAPEUTICS AND METHODS OF USE
`M 0 (57) Abstract: Compositions and methods of use of borole derivatives, including benzoxaboroles, benzazaboroles and benzthi(cid:173)
`> aboroles, as therapeutic agents for treatment of diseases caused by bacteria or viruses are disclosed, as well as methods for synthesis
`
`~ of said agents and compositions thereof.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 1 of 80
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`PCT/US04/18765
`
`CLASSIFICATION OF SUBJECT MATTER
`A.
`: A61K 31/69; C07F 5102
`IPC(7)
`514/64; 568/6
`:
`USCL
`According: to International Patent Classification <IPC) or to both national classification and IPC
`B.
`FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`U.S. : 514/64; 568/6
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`Please See Continuation Sheet
`
`c.
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Category*
`Citation of document, with indication, where appropriate, of the relevant passages
`x
`Zhdankin et al, Tetrahedron Letters, Symthesis and Structures of Benzoboroxoles: Novel
`Organoboron Heterocycles, 1999, 40, pages 6705-6708, see page 6707 bottom, compond 9.
`Koster et al, Liebigs Annalen der Chemie; Cyclisierung vo Bor-Stickstoff-Verbindungen in
`der Hitze, 1968, 720, pages 23-31, see page 25, top, compound 6cl.
`US 5,880,188 A (AUSTIN et al) 09 March 1999 (09.03.1999), see entire document.
`
`x
`
`A
`
`Relevant to claim No.
`l, 2, 5 and 66
`
`1, 4, 5 and 66
`
`20-43
`
`D Further documents are listed in the continuation of Box C. D
`
`Special categories of cited documents:
`
`"T"
`
`·x·
`
`"Y"
`
`See patent family annex.
`later document published after the international filing date or priority
`date and not in conflict with the application but cited to understand the
`principle or theory underlying the invention
`
`document of particular relevance; the claimed invention cannot be
`considered novel or cannot be considered to involve an inventive step
`when the document is taken alone
`
`document of particular relevance; the claimed invention cannot be
`considered to involve an inventive step when the document is
`combined with one or more other such documents, such combination
`being obvious to a person skilled in the art
`
`"&"
`
`document member of the same patent family
`
`Date of mailing of 1J ~rjtt~ s2Ut/5port
`
`~;;"""7 -
`'
`• J
`Authorized officer/// ~,,,.i:-cJ ~
`Paul A. Zucker
`
`':.J
`
`Telephone No. 703-308-1235
`
`*
`"A"
`
`document defining the general state of the art which is not considered to be
`of particular relevance
`
`"E"
`
`earlier application or patent published on or after the international filing date
`
`"L" document which may throw doubts on priority claim(s) or which is cited to
`establish the publication date of another citation or other special reason (as
`specified)
`
`"O" document referring to an oral disclosure, use, exhibition or other means
`
`"P"
`
`document published prior to the international filing date but later than the
`priority date claimed
`
`Date of the actual completion of the international search
`
`09 Februarv 2005 (09.02.2005)
`Name and mailing address of the ISNUS
`Mail Stop PCT, Attn: ISA/US
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`Facsimile No. (703) 305-3230
`Form PCT/ISN210 (second sheet) (January 2004)
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 2 of 80
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT /US04/18765
`
`Continuation of B. FIELDS SEARCHED Item 3:
`CASONLINE
`search terms: structures, ?bact?, ?microb?
`
`Form PCT/ISA/210 (extra sheet) (January 2004)
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 3 of 80
`
`

`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`I CORRECTED VERSION I
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`17 February 2005 (17.02.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/013892 A2
`
`(51) International Patent Classification7:
`
`A61K
`
`(74) Agent: LENTINI, David, P.; Foley & Lardner LLP, 1530
`Page Mill Road, Palo Alto, CA 94304 (US).
`
`(21) International Application Number:
`PCT/US2004/018765
`
`(22) International Filing Date:
`
`15 June 2004 (15.06.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/478,921
`
`16 June 2003 (16.06.2003) US
`
`(71) Applicant (for all designated States except US): ANA(cid:173)
`COR PHARMACEUTICALS, INC. [US/US]; 1060East
`Meadow Circle, Palo Alto, CA 94303 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): LEE, Ving [US/US];
`1335 Carvo Court, Los Altos, CA 94024 (US). PLAT(cid:173)
`TNER, Jacob, J. [US/US]; 1016 Ami to Avenue, Berkeley,
`CA 94705 (US). BENKOVIC, Stephen, J. [US/US]; 771
`Teaberry Lane, State College, PA 16803 (US). BAKER,
`Stephen, J. [GB/GB]; 1568 Begen Avenue, Mountain
`View, CA 94040 (US). MAPLES, Kirk, R. [US/US];
`1195 San Moritz Drive, San Jose, CA 95132 (US).
`BELLINGER-KAWAHARA, Carolyn
`[US/US]; 15
`Landa Lane, Redwood City, CA 94061 (US). AKAMA,
`Tsutomu [JP/US]; 832 Azure Street, Sunnyvale, CA
`94087
`(US). ZHANG, Yong-Kang [US/US]; 5151
`Westmont Avenue, San Jose, CA 95130 (US). SINGH,
`Rajeshwar [CA/CA]; 1435 Loewen Court, Edmonton,
`Alberta T6R 2Yl (CA). SAURO, Vittorio, A. [CA/CA];
`3843 24th Street, Edmonton, Alberta T6T 1K6 (CA).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`(48) Date of publication of this corrected version:
`14 April 2005
`
`(15) Information about Correction:
`see PCT Gazette No. 15/2005 of 14 April 2005, Section II
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`iiiiiiii --
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`M °" QO
`
`~
`,....i
`Q
`..........
`lf) ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`
`g (54) Title: HYDROLYTICALLY-RESISTANT BORON-CONTAINING THERAPEUTICS AND METHODS OF USE
`M 0 (57) Abstract: Compositions and methods of use of borole derivatives, including benzoxaboroles, benzazaboroles and benzthi(cid:173)
`> aboroles, as therapeutic agents for treatment of diseases caused by bacteria or viruses are disclosed, as well as methods for synthesis
`
`~ of said agents and compositions thereof.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 4 of 80
`
`

`
`WO 2005/013892
`
`PCT/US2004/018765
`
`HYDROLYTICALLY-RESISTANT BORON(cid:173)
`CONTAINING THERAPEUTICS AND METHODS
`
`5
`
`OF USE
`
`This application claims priority of U.S. Provisional Application Serial
`10 No. 60/478,921, filed 16 June 2003, the disclosure of which is hereby
`incorporated by reference in its entirety.
`
`15
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel compounds and compositions
`which have selective therapeutic activities, processes for making such
`compounds, synthetic intermediates employed in these processes and a
`20 method for treating human or other mammal in need of medical treatments.
`
`BACKGROUND OF THE INVENTION
`
`25
`
`Many advances in medicine in the 20th century have been due to the
`
`discovery of new classes of small molecular weight effectors for various
`therapeutic needs. Herein we disclose
`the diverse, but selective
`pharmacologically active boron-containing entities.
`
`30
`
`One hallmark of the modern era of medicine has been the decline in
`morbidity and mortality associated with bacterial and fungal
`infections.
`
`1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 5 of 80
`
`

`
`WO 2005/013892
`
`PCT/US2004/018765
`
`However, misuse· of conventional antibiotics and natural selection of the
`
`infectious bacterial population has resulted in the development of varying
`degrees of drug resistance by most bacterial infectious agents to most
`antibiotic agents.
`In severe cases, such as MRSA (Multidrug-Resistant
`5 StaphA), one or only a few antibiotics are currently effective. In addition, the
`existence of immunodeficiency syndromes results in additional incidences of
`opportunistic infections requiring intensive antibiotic treatment.
`
`Viruses are implicated in a variety of animal and human disease.
`1 O Numerous approaches have been proposed to combat these pathogens which
`include, but are not limited to herpesviruses 1 and 2 (HSV-1 and HSV-2),
`influenza viruses A, B and C, parainfluenza viruses 1-4, syncytial virus, Epstein(cid:173)
`Barr virus, rhinoviruses, human immunodeficiency viruses (HIV), polioviruses,
`
`coxsackieviruses, echoviruses, rubella virus, varicella-zoster virus, neuroderma-
`tropic virus, variola virus, cytomegalovirus, hepatitis A, B and C viruses,
`
`15
`
`papoviruses, rabies virus, yellow fever virus, dengue virus, West Nile virus and
`SARS virus.
`
`20
`
`One approach in the development of antiviral compounds has been to
`identify compounds which interfere with the normal viral metabolism and
`replication in infected host cells. During the screening of new borinic ester
`
`compounds, we have found that certain of these compounds show antiviral
`activity in cell culture assay systems. Many existing compounds currently in
`
`use for treating viral diseases are subject to resistance mechanisms, are
`
`25
`
`expensive to make, do not adequately treat patients or have adverse side
`
`effects. Therefore, there is a continuing need for new compounds which act to
`kill viruses, to inhibit viral replication or to block.the pathogenic action of viruses.
`
`30
`
`2
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 6 of 80
`
`

`
`WO 2005/013892
`
`PCT/US2004/018765
`
`Virus Category
`
`Picornaviridae
`
`Togaviridae and F/aviviridae
`
`Coronaviridae
`
`Rhabdoviridae
`
`Paramyxoviridae
`
`Orthomyxoviridae
`
`Bunyaviridae
`
`Arenaviridae
`
`Reoviridae
`
`Retroviridae
`
`Papovaviridae
`Adenoviridae
`
`Pertinent Human Infections
`RNA Viruses
`
`Polio
`Human hepatitis A
`Human rhinovirus
`Rubella - German measles
`Yellow fever
`Human respiratory coronavirus (HGV)
`Severe acute respiratory syndrome (SAR)
`Lyssavirus - Rabies
`
`Paramyxovirus - Mumps
`Morbillvirus - measles
`Pneumo virus - respiratory syncytial virus
`Influenza A-C
`Bunyavirus - Bunyamwera (BUN)
`Hantavirus - Hantaan (HTN)
`Nairevirus - Crimean-Congo hemorrhagic fever (CCHF)
`Phlebovirus - Sandfly fever (SFN)
`Uukuvirus - Uukuniemi (UUK)
`Rift Valley Fever (RVFN)
`Junin - Argentine hemorrhagic fever
`Machupo - Bolivian hemorrhagic fever
`Lassa - Lassa fever
`LCM- aseptic lymphocyctic choriomeningitis
`Rotovirus
`Reovirus
`Orbivirus
`Human immunodeficiency virus 1 (HIV-1)
`Human immunodeficiency virus 2 (HIV-2)
`Simian immunodeficiency virus (SIV)
`DNA Viruses
`Pediatric viruses that reside in kidney
`Human respiratory distress and some deep-seated eye infections
`
`Parvoviridae
`
`Human gastro-intestinal distress (Norwalk Virus)
`
`Herpesviridae
`
`Poxviridae
`Hepadnaviridae
`
`Herpes simplex virus 1 (HSV-1)
`Herpes simplex virus 2 (HSV-2)
`Human cytomegalovirus (HCMV)
`Varicella zoster virus (VZV)
`Epstein-Barr virus (EBV)
`Human herpes virus 6 (HHV6)
`Orthopoxvirus is sub-genus for smallpox
`Hepatitis B virus (HBV)
`Hepatitis C virus (HGV)
`
`Boron containing compounds have received increasing attention as
`therapeutic agents over the past few years as technology in organic synthesis
`has expanded to include this atom. [Boron Therapeutics on the horizon,
`
`5
`
`3
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 7 of 80
`
`

`
`WO 2005/013892
`
`PCT/US2004/018765
`
`5
`
`Groziak, M.P.; American Journal of Therapeutics (2001) 8, 321-328] The most
`notable boron containing therapeutic is the boronic acid bortezomib which
`was
`recently
`launched
`for
`the
`treatment of multiple myeloma. This
`breakthrough demonstrates
`the
`feasibility of using boron containing
`compounds as pharmaceutical agents. Boron containing compounds have
`been shown to have various biological activities including herbicides [Organic
`boron compounds as herbicides. Barnsley, G.E.; Eaton, J.K.; Airs, R.S.;
`(1957), DE 1016978 19571003], boron neutron capture therapy [Molecular
`Design and Synthesis of B-10 Carriers for Neutron Capture Therapy.
`10 Yamamoto, Y.; Pure Appl. Chem., (1991) 63, 423-426], serine protease
`inhibition [Borinic acid inhibitors as probes of the factors involved in binding at
`
`the active sites of subtilisin Carlsberg and a-chymotrypsin. Simpelkamp, J.;
`
`15
`
`Jones, J.B.; Bioorganic & Medicinal Chemistry Letters, (1992), 2(11), 1391-4],
`[Design, Synthesis and Biological Evaluation of Selective Boron-containing
`Thrombin Inhibitors. Weinand, A.; Ehrhardt, C.; Metternich, R.; Tapparelli, C.;
`Bioorganic
`and Medicinal Chemistry,
`(1999),
`7,
`1295-1307],
`acetylcholinesterase inhibition [New, specific and reversible bifunctional
`alkylborinic acid inhibitor of acetylcholinesterase. Koehler, K.A.; Hess, G.P.;
`Biochemistry (1974), 13, 5345-50] and as antibacterial agents [Boron-
`20 Containing Antibacterial Agents: Effects on Growth and Morphology of
`Bacteria Under Various Culture Conditions. Bailey, P.J.; Cousins, G.; Snow,
`G.A.; and White, A.J.; Antimicrobial Agents and Chemotherapy, (1980), 17,
`549-553]. The boron containing compounds with antibacterial activity can be
`sub-divided into two main classes, the diazaborinines, which have been
`known since the 1960's, and dithienylborinic acid complexes. This latter class
`has been expanded to include many different diarylborinic acid complexes
`with potent antibacterial activity [Preparation of diarylborinic acid esters as
`DNA methyl transferase inhibitors. Benkovic, S.J.; Shapiro, L.; Baker, S.J.;
`Wahnon, D.C.; Wall, M.; Shier, V.K.; Scott, C.P.; Baboval, J.; PCT Int. Appl.
`(2002), WO 2002044184]. Synthetic developments described
`in Benkovic et
`al.
`enabled creation of a much more diverse class of unsymmetrical di-
`substituted borinic acid complexes not possible before.
`
`25
`
`30
`
`4
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 8 of 80
`
`

`
`WO 2005/013892
`
`PCT /US2004/018765
`
`Thus, there continues to be a need in the medical arts for novel, more
`effective, antibiotic compounds, especially for treating infectious diseases,
`that are resistant to currently available therapies.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`BRIEF SUMMARY OF THE INVENTION
`
`In one aspect, the present invention relates to therapeutic compounds,
`which are boron-containing. These compounds
`include structures
`that
`encompass benzoxaboroles, benzazaboroles, benzthiaboroles and related
`analogs.
`
`These compounds are also provided as pharmaceutical compositions
`that can be administered to an animal, most preferably a human, for treatment
`of a disease having either bacterial, fungal or viral etiology, most preferably a
`human, in an immunologically compromised or debilitated state of health.
`
`In preferred embodiments, the compounds of the invention are those
`having the structures given by Formula 1, with preferred substituents as
`disclosed herein.
`
`The invention also provides methods for preparing these therapeutic
`compounds and pharmaceutical compositions thereof, and methods of using
`said compounds therapeutically. Kits and packaged embodiments of these
`invention are also
`compounds and pharmaceutical compositions of the
`contemplated.
`
`30
`
`The invention also relates to methods of treating various medical
`conditions, using the compounds disclosed herein.
`
`5
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1062 - Page 9 of 80
`
`

`
`WO 2005/013892
`
`PCT /US2004/018765
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`This
`
`invention provides
`
`therapeutic agents, and
`
`specifically
`
`antibacterial, antifungal, or antiviral compounds, useful in treating and/or
`
`5
`
`preventing conditions due to these pathogens.
`
`The invention comprises a compound having the following structures
`
`R*
`I
`E .... GXB'M
`II
`I
`D~ 'J,..W
`
`Formula 1
`
`10
`
`wherein Bis boron, Mis selected from oxygen, sulfur and NR**
`wherein R* is selected from substituted or unsubstituted alkyl (C1 - C4),
`substituted or unsubstituted cycloalkyl (C3 - C7), substituted or unsubstituted
`alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
`
`15
`
`aralkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`heteroaryl,
`
`wherein R**
`
`is H, alkyl, alkyloxy, alkoxyalkyl, substituted or
`
`unsubstituted aryl, substituted or unsubstituted heteroaryl,
`and wherein A is CH, CR 1
`, or N
`and wherein D is CH, CR2
`
`, or N
`
`and wherein E is CH, CR3
`
`, or N
`
`and wherein G is CH, CR4, or N
`and the combination of nitrogens (A + D + E + G) is 0-3
`and wherein J is (CH2)n (n = 0 to 2) or CHR5
`and wherein Wis (CH2)m (m = 0 to 1), C=O (carbonyl) or CHR6
`
`20
`
`25
`
`, R3 and R4 are each independently selected from the
`, R2
`wherein R1
`group consisting of hydrogen, haloalkyl, alkyl, cycloalkyl, (CH 2)POH {p =
`
`6
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`1 to 3),, halogen, CHO, CH= NOH, C0 2H, C0 2-alkyl, S-alkyl, S0 2-alkyl, S(cid:173)
`ary!, (CH 2)qNR 18R19 (wherein R18 and R19 are independently selected from
`hydrogen, alkyl, and alkanoyl)(q = 0 to 2), alkoxy, CF3 , SCF3 , N0 2, S03H,
`OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,
`
`5
`
`substituted or unsubstituted heteroaryl, fused substituted or unsubstituted
`
`aryl, fused substituted or unsubstituted heteroaryl,
`wherein R5 is selected from substituted or unsubstituted alkyl (C1 - C4),
`substituted or unsubstituted cycloalkyl (C3 - C7), substituted or unsubstituted
`alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
`aralkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`heteroaryl,
`wherein R6 is selected from substituted or unsubstituted alkyl (C1 - C4),
`substituted or unsubstituted cycloalkyl (C3 - C7), substituted or unsubstituted
`alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
`aralkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`heteroaryl,
`
`10
`
`15
`
`including salts thereof, especially all pharmaceutically acceptable salts.
`
`20
`
`In preferred embodiments of Formula 1, M is oxygen, or M is sulfur, or
`Mis NR**. Further preferred embodiments of any of these three are any of the
`following.
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`unsubstituted alkyl (C1 - C4).
`
`25
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`unsubstituted cycloalkyl (C3 - C7).
`
`30
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`In a further preferred embodiment thereof, the
`unsubstituted alkenyl.
`substituted alkenyl has the structure
`
`7
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`5
`
`, R8
`wherein R7
`, and R9 are each independently selected from the group
`consisting of hydrogen, alkyl, haloalkyl, aryl, substituted aryl, aralkyl,
`substituted aralkyl, (CH2)rOH (where r = 1 to 3), CH2NR20R21 (wherein R20 and
`R21 are independently selected from hydrogen and alkyl), C02H, C02alkyl,
`CONH2, S-alkyl, S-aryl, S02alkyl, S03H, SCF3, CN, halogen, CF3 and N02.
`
`10
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`
`unsubstituted alkynyl.
`
`In a
`
`further preferred embodiment
`
`thereof
`
`the
`
`substituted alkynyl has the structure
`
`[ - R7
`
`15
`
`wherein R7 is defined as before.
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`
`unsubstituted aryl. In a further preferred embodiment thereof the substituted
`
`20
`
`aryl has the structure
`
`25
`
`wherein R10, R11 , R12, R13 and R14 are each i1,1dependently selected
`from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl,
`substituted aralkyl, (CH2)sOH (where s = 1 to 3), C02H, C02alkyl, CONH2,
`CONHalkyl, CON(alkyl)2, OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, S02alkyl,
`S03H, SCF3, CN, halogen, CF3, N02, (CH2)tNR22R23 (wherein R20 and R21 are
`
`independently selected from hydrogen, alkyl, and alkanoyl)(t = 0 to 2),
`
`8
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`S02NH2, OCH2CH2NH2, OCH2CH2NHalkyl, OCH2CH2N(alkyl)2, oxazolidin-2-
`yl, or alkyl substituted oxazolidin-2-yl.
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`
`5
`
`unsubstituted aralkyl.
`
`In a
`
`further preferred embodiment
`
`thereof
`
`the
`
`substituted aralkyl has the structure
`
`10
`
`15
`
`20
`
`25
`
`wherein R10, R11 , R12, R13 and R14 are defined as before.
`
`In a preferred embodiment of Formula 1, R* is a substituted or
`
`unsubstituted heteroaryl.
`
`In a further preferred embodiment thereof the
`
`heteroaryl has the structure
`
`R16
`
`x:::Jv
`R15~
`
`or
`
`wherein X = CH=CH, N=CH, NR17 (wherein R17 = H, alkyl, aryl or
`benzyl), 0, or S
`
`and wherein Y = CH or N
`and wherein R15 and R16 are each independently selected from the
`group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, substituted aryl,
`aralkyl, substituted aralkyl, (CH2)uOH (where u = 1, 2 or 3), (CH2)vNR24R25
`(wherein R24 and R25 are independently selected from hydrogen, alkyl and
`alkanoyl)(v = 0 to 3), C02H, C02alkyl, CONH2, S-alkyl, S-aryl, S02alkyl,
`S03H, SCF3, CN, halogen, CF3 and N02.
`
`The structures of the invention also permit solvent interactions that may
`afford structures (Formula 18) that include atoms derived from the solvent
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`9
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`invention during synthetic
`the
`the compounds of
`encountered by
`manipulations and therapeutic uses. Structures 1 B arise from formation of a
`dative bond between the solvent(s) with the Lewis acidic boron center. Thus,
`such solvent complexes 1 B could be stable entities with comparative
`bioactivities. Such structures are expressly contemplated by the present
`invention where R*** is H or alkyl.
`
`5
`
`G
`
`E ... X'M
`
`R***
`R* I
`,O.._
`I
`'H
`B''
`II
`I
`D~ :J"W
`Formula 18
`
`10
`
`15
`
`As used herein, the following terms have the stated meaning:
`By "alkyl", "lower alkyl", and "C1-Cs alkyl" in the present invention is
`meant straight or branched chain alkyl groups having 1-6 carbon atoms, such
`as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, ten-butyl, pentyl, 2-
`pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
`
`By "alkanoyl" in the present invention is meant straight or branched
`chain alkanoyl groups having 1-6 carbon atoms, such as, acetyl, propanoyl,
`butanoyl, pentanoyl, hexanoyl,
`isobutanoyl, 3-methylbutanoyl, and 4-
`methylpentanoyl.
`
`20
`
`By "alkoxy", "lower alkoxy", and "C1-C6 alkoxy" in the present invention
`is meant straight or branched chain alkoxy groups having 1-6 carbon atoms,
`
`such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec(cid:173)
`butoxy, terl-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-
`hexoxy, 3-hexoxy, and 3-methylpentoxy.
`
`25
`
`By the term "halogen" in the present invention is meant fluorine,
`bromine, chlorine, and iodine.
`
`10
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`By "cycloalkyl", e.g., C3-C7 cycloalkyl, in the present invention is meant
`cycloalkyl groups having 3-7 atoms such as,
`for example cyclopropyl,
`
`In the C3-C1 cycloalkyl
`cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
`groups, preferably in the C5-C7 cycloalkyl groups, one or two of the carbon
`atoms forming the ring can optionally be replaced with a hetero atom, such as
`
`5
`
`sulfur, oxygen or nitrogen. Examples of such groups are piperidinyl,
`
`piperazinyl,
`
`morpholinyl,
`
`pyrrolidinyl,
`
`imidazolidinyl,
`
`oxazolidinyl,
`
`perhydroazepinyl,
`
`perhydrooxazapinyl,
`
`oxepanyl,
`
`perhydrooxepanyl,
`
`tetrahydrofuranyl, and tetrahydropyranyl. C3 and C4 cycloalkyl groups having
`a member replaced by nitrogen or oxygen include aziridinyl, azetidinyl,
`
`10
`
`oxetanyl, and oxiranyl.
`
`By "aryl" is meant an aromatic carbocyclic group having a single ring
`
`(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in
`
`15 which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl,
`
`anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with,
`
`e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower
`
`acyloxy, aryl, heteroaryl, and hydroxy. Preferred aryl groups include phenyl
`
`and naphthyl, each of which is optionally substituted as defined herein.
`
`20
`
`By "heteroaryl" is meant one or more aromatic ring systems of 5-, 6-, or
`
`?-membered rings containing at least one and up to four heteroatoms selected
`
`from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example,
`
`thienyl,
`
`furanyl,
`
`thiazolyl,
`
`imidazolyl,
`
`(is)oxazolyl, pyridyl, pyrimidinyl,
`
`25
`
`(iso)quinolinyl, napthyridinyl, benzimidazolyl, and benzoxazolyl.
`
`Preferred
`
`heteroaryls are thiazolyl, pyrimidinyl, preferably pyrimidin-2-yl, and pyridyl.
`
`Other preferred heteroaryl groups include 1-imidazolyl, 2-thienyl, 1-(or 2-
`
`)quinolinyl, 1-( or 2-) isoquinolinyl, 1-( or 2-)tetrahydroisoquinolinyl, and 2-( or 3-
`
`)furanyl.
`
`30
`
`The invention also provides embodiments of the compounds disclosed
`
`herein as pharmaceutical compositions. The pharmaceutical compositions of
`
`11
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`the present invention can be manufactured in a manner that is itself known,
`
`e.g., by means of a conventional mixing, dissolving, granulating, dragee(cid:173)
`
`making,
`
`levigating, emulsifying, encapsulating, entrapping or lyophilizing
`
`processes.
`
`5
`
`Pharmaceutical compositions for use in accordance with the present
`
`invention thus can be formulated in conventional manner using one or more
`
`physiologically acceptable carriers comprising excipients and auxiliaries that
`
`facilitate processing of the active compounds into preparations that can be
`
`10
`
`used pharmaceutically. Proper formulation is dependent upon the route of
`
`administration chosen.
`
`Non-toxic pharmaceutical salts
`
`include salts of acids such as
`
`hydrochloric,
`
`phosphoric,
`
`hydrobromic,
`
`sulfuric,
`
`sulfinic,
`
`formic,
`
`15
`
`toluenesulfonic, methanesulfonic, hydroxyethanesulfonic, nitric, benzoic, citric,
`tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-CH3 where
`n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include
`
`salts of bases such as sodium, potassium, calcium, ammonium, and
`
`functional equivalents. Those skilled in the art will recognize a wide variety of
`
`20
`
`non-toxic pharmaceutically acceptable addition salts.
`
`For injection, the compounds of the invention can be formulated in
`
`appropriate aqueous solutions, such as physiologically compatible buffers
`
`such as Hanks's solution, Ringer's solution, or physiological saline buffer. For
`
`25
`
`transmucosal and transcutaneous administration, penetrants appropriate to
`
`the barrier to be permeated are used in the formulation. Such penetrants are
`
`generally known in the art.
`
`For oral administration, the compounds can be formulated readily by
`
`30
`
`combining the active compounds with pharmaceutically acceptable carriers
`
`well known in the art. Such carriers enable the compounds of the invention to
`
`be formulated as tablets, pills, capsules,
`
`liquids, gels, syrups, slurries,
`
`12
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`suspensions and the like, for oral ingestion by a patient to be treated.
`Pharmaceutical preparations for oral use can be obtained with solid excipient,
`optionally grinding a resulting mixture, and processing the mixture of granules,
`after adding suitable auxiliaries, if desired, to obtain tablets. Suitable
`excipients are, in particular