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`
`0601
`
`AGILA ET AL - EXHIBIT 1017 (PART 4 OF 4)
`
`
`
`EAST Search
`
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`
`1071122
`
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`
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`
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`
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`
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`
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`
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`
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`
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`
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`
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`
`
`
`RCEX
`Doc code:
`Doc description:
`
`Request for
`
`Continued
`
`Examination (RCE)
`
`0613
`
`
`
`RCEX
`Doc code:
`Doc description:
`
`Request for
`
`Continued
`
`Examination (RCE)
`
`0614
`
`
`
`Privacy Act
`
`Statement
`
`The Privacy
`
`Act
`
`of
`
`1974 (P.L.
`
`93-579)
`
`0615
`
`
`
`Substitute
`
`for
`
`1449
`
`Complete if
`/PTO
`
`Known
`
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`0616
`
`
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(12) INTERNATIONAL
`APPLICATION
`PUBLISHED
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`22 June 2006 (22.06.2006)
`
`
`
`(10) International Publication Number
`
`WO 2006/065392 A2
`
`(51) International Patent Classification:
`A6IK 31/4184 (2006.01)
`
`(74) Agent: WOODCOCK WASHBURN LLP; One Liberty
`Place, 46th Floor, Philadelphia, PA 19103 (US).
`
`(21) lnternational APP1i°ati0n Number:
`PCT/US2005/040068
`
`(22) '“te"‘3“°"a' “"118 “am
`4NOVCH1bCI 2005
`
`_
`Enghsh
`English
`
`(25) Filing Language‘
`(26) Publication Language:
`(30) Priority Data:
`US
`5 November 2004 (05.11.2004)
`60/625,193
`US
`10 March 2005 (10.03.2005)
`60/660,226
`(for all designated States
`except US):
`(71) Applicant
`CEPHALON, INC.
`[US/US]; 41 Moores Road, 13.0.
`Box 4011, Frazer, PA 19355 (US).
`(72) Inventors; and
`BENDALL,
`(for US only):
`(75) Inventors/Applicants
`Heather, Helene [US/US]; 3082 Portofino Drive, Del
`Published:
`Mar, California 92014 (US). ELLIOTT, Gary, T.
`[US/US]; 12433 Kingspine Avenue, San Diego, California — without international search report and to be republished
`92131 (I IS). LEONI, Lorenzo, M. [CH/CH]; Via Cam—
`upon receipt of that report
`pagna, CH—6527 Lodrino (CH). NIEMEYER, Christina,
`Carol [US/US]; 12439 Holland Road, Poway, California
`92064 (US). MULTANI, Pratik, S.
`[US/US]; 10486
`Hatvest View Way, San Diego, California 92128 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, A7,, BA, BB, BG, BR, BW, BY, B7,, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, H), IL, IN, IS, JP, KE,
`KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, N1,
`’
`UL, VC, VN, YU, LA, [.M, LW.
`_
`.
`.
`.
`(34) ;’F;1g‘f1_‘“°4 stjtes (“"1?” ""’5.;V:7‘]55)"‘/‘\’;:‘{',']:5()‘1»(J];"\;]5‘(’fP"IY
`an 0 regmna. protection avara .e :
`,
`I
`,
`GM: KE: LS: MW: M2: NA: SD: SL: SZ: TZ: UG: ZM:
`ZW). Eurasian (AM. AZ. BY. KG. KZ, MD. RU. TJ. TM).
`1‘E11;r0(§;an(}<]/:TiI1:JE:IgC;:SCI1¥:
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GNs GQ« GW= ML: MR: NE: SN: TD: TG)-
`
`For two—Ietter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes andAbbreviations” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: CANCER TREATMENTS
`
`(57) Abstract: Methods and compositions for treating cancers characterized by death—resistant cancer cells are described. In gen-
`eral, such methods involve administration of a therapeutically effective amount of a compound that induces mitotic catastrophe in
`the some, and preferably most or all, of the cancerous cells. Methods for assessing the efficacy of such treatments are also provided.
`
`0617
`
`
`
`2006/065392A2||||||||||||||||||||||||||||||||||||||||||ll|||||||||||||||||||||||||||||||||||||||||||||||||||
`
`0617
`
`
`
`WO 2006/065392
`
`PCT/US2005/040068
`
`CANCER TREATMENTS
`
`FIELD OF
`This invention
`
`THE INVENTION
`relates
`
`generally
`
`0618
`
`
`
`WO 2006/065392
`
`2
`
`PCT/US2005/040068
`
`Suppressive genes
`
`are
`
`growth
`
`0619
`
`
`
`WO 2006/065392
`
`3
`
`PCT/US2005/040068
`
`[0008]
`
`The adverse
`
`effects
`
`of systemic
`
`chemotherapy
`neoplastic disease
`
`used in
`
`0620
`
`
`
`WO 2006/065392
`
`4
`
`PCT/US2005/040068
`
`In the
`
`context
`
`of
`
`this invention,
`
`a
`
`"chemotherapeutic agent"
`chemical intended
`
`0621
`
`
`
`WO 2006/065392
`
`5
`
`PCT/US2005/040068
`
`[00015]
`
`"Monotherapy"
`
`refers
`
`to
`
`a treatment
`
`regimen
`
`0622
`
`
`
`WO 2006/065392
`
`6
`
`PCT/US2005/040068
`
`claims are
`
`to
`
`be
`
`interpreted
`
`in
`
`0623
`
`
`
`WO 2006/065392
`
`7
`
`PCT/US2005/040068
`
`[00021] The term"anti-CD20
`
`refractory" means prior
`
`treatment
`interacts with
`
`with
`the
`
`0624
`
`
`
`WO 2006/065392
`
`8
`
`PCT/US2005/040068
`
`context of
`
`combination
`
`therapy,
`
`what
`
`constitutes
`
`0625
`
`
`
`WO 2006/065392
`
`9
`
`PCT/US2005/040068
`
`CD20 agent,
`
`e.g.,
`
`rituximab. These methods
`
`comprise
`
`0626
`
`
`
`WO 2006/065392
`
`10
`
`PCT/US2005/040068
`
`agent(s) is(are)
`
`given
`
`within
`
`about
`
`0627
`
`
`
`WO 2006/065392
`
`11
`
`PCT/US2005/040068
`
`business in
`
`the
`
`treatment
`
`of such
`
`cancers,
`
`0628
`
`
`
`WO 2006/065392
`
`12
`
`PCT/US2005/040068
`
`metabolite (50
`
`[xM;
`
`lane
`
`4),
`
`0629
`
`
`
`WO 2006/065392
`
`13
`
`PCT/US2005/040068
`
`BER pathway
`
`in
`
`the cytotoxic
`
`activity
`
`of bendamustine and
`metabolite, phosphoramide
`
`0630
`
`
`
`WO 2006/065392
`
`14
`
`PCT/US2005/040068
`
`90 minutes. After the
`
`timed
`
`drug
`
`incubation,
`
`0631
`
`
`
`WO 2006/065392
`
`15
`
`PCT/US2005/040068
`
`exhibits alklyating
`
`activity, i.e.,
`
`it is
`
`a
`
`DNA-damaging
`humans (typically
`
`agent. When administered
`by bolus
`
`0632
`
`
`
`WO 2006/065392
`
`16
`
`PCT/US2005/040068
`
`[00046] The drugs
`
`used
`
`in
`
`the practice
`
`of the
`
`invention may
`
`0633
`
`
`
`WO 2006/065392
`
`17
`
`PCT/US2005/040068
`
`[00048] The preparation
`
`of
`
`therapeutic compositions
`
`is
`
`0634
`
`
`
`WO 2006/065392
`
`18
`
`PCT/US2005/040068
`
`[00051] The compositions
`
`may
`
`also be
`
`prepared
`
`in
`
`0635
`
`
`
`WO 2006/065392
`
`19
`
`PCT/US2005/040068
`
`the skin
`
`(e.g., liniments,
`
`lotions,
`
`ointments, creams,
`
`or
`
`0636
`
`
`
`WO 2006/065392
`
`20
`
`PCT/US2005/040068
`
`mytomycin, pipobroman,
`
`procarbazine,
`
`streptozocin, thiotepa,
`Preferred anti-metabolites
`
`0637
`
`
`
`WO 2006/065392
`
`21
`
`PCT/US2005/040068
`
`Example 1
`Molecular Analysis
`
`of
`
`the
`
`0638
`
`
`
`WO 2006/065392
`
`22
`
`PCT/US2005/040068
`
`alkylation activity,
`
`as
`
`DNA double-strand
`
`breaks
`
`0639
`
`
`
`WO 2006/065392
`
`23
`
`PCT/US2005/040068
`
`b. Reagents.
`
`[00063] Bendamustine hydrochloride
`
`was
`
`obtained from
`
`0640
`
`
`
`WO 2006/065392
`
`Chemically fragmented
`
`24
`
`IVT
`
`PCT/US2005/040068
`
`RNA (15
`
`fig)
`
`0641
`
`
`
`WO 2006/065392
`
`25
`
`PCT/US2005/040068
`
`f. Quantitative PGR
`
`Analysis.
`
`[00067] The expression
`
`levels
`
`of specific
`
`0642
`
`
`
`WO 2006/065392
`
`26
`
`PCT/US2005/040068
`
`protocol was
`
`used.
`
`A Sulforhodamine B protein assay estimated cell
`The COMPARE
`method
`
`0643
`
`
`
`WO 2006/065392
`
`27
`
`PCT/US2005/040068
`
`evaluated by
`
`the
`
`MTT
`
`assay (13)
`
`and an
`
`IC50 was
`
`0644
`
`
`
`WO 2006/065392
`
`28
`
`PCT/US2005/040068
`
`AxioPlan 2e
`
`imaging microscope
`
`with
`
`DIG
`
`0645
`
`
`
`WO 2006/065392
`
`29
`
`PCT/US2005/040068
`
`compare the
`
`expression
`
`levels
`
`of over
`
`12,000 genes
`
`0646
`
`
`
`WO 2006/065392
`
`30
`
`PCT/US2005/040068
`
`regulated in
`
`bendamustine-treated
`
`cells
`
`0647
`
`
`
`WO 2006/065392
`
`31
`
`PCT/US2005/040068
`
`[00080] Two examples
`
`of
`
`"canonical" p53-dependent genes
`
`0648
`
`
`
`WO 2006/065392
`
`32
`
`PCT/US2005/040068
`
`[00084]
`
`In parallel
`
`with
`
`the induction
`
`of
`
`phosphorylated
`
`0649
`
`
`
`WO 2006/065392
`
`33
`
`PCT/US2005/040068
`
`d. Inhibition of
`
`base excision
`
`repair,
`
`but
`
`0650
`
`
`
`WO 2006/065392
`
`34
`
`PCT/US2005/040068
`
`H2AX occurred
`
`earlier
`
`other 2-chloroethylamino
`than with
`cyclophosphamide. Cell-cycle analysis
`
`DNA alkylators
`
`0651
`
`
`
`WO 2006/065392
`
`35
`
`PCT/US2005/040068
`
`when compared
`
`to other
`
`clinically used
`
`compounds
`
`that
`
`0652
`
`
`
`WO 2006/065392
`
`36
`
`PCT/US2005/040068
`
`between the
`
`ability of
`
`the three
`
`drugs
`
`to
`
`cause PARP
`
`0653
`
`
`
`WO 2006/065392
`
`37
`
`PCT/US2005/040068
`
`repair genes
`
`differentially
`
`regulated by
`
`bendamustine
`
`0654
`
`
`
`WO 2006/065392
`
`38
`
`PCT/US2005/040068
`
`have a
`
`high
`
`correlation coefficient
`
`between
`
`0655
`
`
`
`WO 2006/065392
`
`39
`
`PCT/US2005/040068
`
`Bendamustine Activity
`
`in
`
`NHL Cells
`
`Example 2
`
`0656
`
`
`
`WO 2006/065392
`
`40
`
`PCT/US2005/040068
`
`unique mechanism
`
`of
`
`action
`
`when
`
`0657
`
`
`
`WO 2006/065392
`
`41
`
`PCT/US2005/040068
`
`[00104] An adenylate
`
`kinase
`
`(ADK)
`
`assay
`
`0658
`
`
`
`WO 2006/065392
`
`42
`
`PCT/US2005/040068
`
`in the
`
`"wash-out" experiments, plates
`
`were
`
`0659
`
`
`
`WO 2006/065392
`
`43
`
`PCT/US2005/040068
`
`Stage III/TV
`
`disease.
`
`Patients
`
`received
`
`0660
`
`
`
`WO 2006/065392
`
`44
`
`PCT/US2005/040068
`
`[00115]
`
`All patents,
`
`patent
`
`applications,
`
`and publications
`specification are
`
`0661
`
`
`
`WO 2006/065392
`
`45
`
`PCT/US2005/040068
`
`What it
`
`claimed is:
`
`1.
`
`A method of treating
`
`cancer,
`
`comprising
`
`0662
`
`
`
`WO 2006/065392
`
`46
`
`PCT/US2005/040068
`
`10. A method according to
`
`claim 5,
`
`wherein
`
`the
`
`0663
`
`
`
`WO 2006/065392
`
`16.
`
`A method
`
`according
`
`47
`
`to
`
`PCT/US2005/040068
`
`claim 15
`
`wherein
`
`0664
`
`
`
`WO 2006/065392
`
`26.
`
`Use of
`
`bendamustine
`
`48
`
`in
`
`PCT/US2005/040068
`
`the
`
`0665
`
`
`
`clustering:
`
`expression profile
`
`Bendamustine gene
`
`Figure 1A
`
`0666
`
`
`
`four and
`
`CQ CQ o 0.
`® ss
`y"
`
`c* C ^ "
`
`, P o
`
`o o y
`
`2
`_ o 0
`
`up-regulated by the three
`
`genes
`
`Top
`
`Figure 1B:
`
`0667
`
`
`
`selected
`
`of
`
`validation
`
`Q-PCR
`
`Figure 2A'.
`
`0668
`
`
`
`of
`
`validation
`
`Q-PCR
`
`Figure 2B:
`
`0669
`
`
`
`4-
`
`i
`
`'j
`
`of
`
`validation
`
`Q-PCR
`
`Figure 2C:
`
`0670
`
`
`
`WO 2006/065392
`
`PCT/US2005/040068
`
`Q.
`on
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`0.
`
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`
`tss
`
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`
`6/14
`
`0671
`
`
`
`S o
`
`inhibitor)
`
`(Ape-1
`
`of MX
`
`Effect
`
`Figure 4A:
`
`0672
`
`
`
`cyclophosphamide, and
`
`3 o
`
`of 06-Benzylguanine on
`
`Effect
`
`Figure 4B:
`
`0673
`
`
`
`apoptosis
`Activation of
`
`repair Exoi.Fem
`Inefficient DNA
`
`damage \
`
`Checkpoint Control / PLK-1, Aurora
`
`Extensive DNA
`
`kinases
`
`—
`
`Inhibition of
`
`Bendamustine
`
`s
`
`Figure 5
`
`0674
`
`
`
`K 5000-
`
`« 6000-
`«
`
`9000-
`
`10000-
`
`Wash
`
`•U
`
`©
`
`11000-1
`
`Fresh Media for
`
`Grow in
`
`for Indicated Time,
`
`3 o
`
`ts)
`
`Cells to
`Indicated Drug
`
`Out, and Allow
`
`Treat with
`
`Assay -
`
`Adenylate Kinase
`
`Figure 6
`
`0675
`
`
`
`4-
`
`h-k
`
`Time, Wash
`
`Fresh Media
`
`for Indicated
`
`Grow in
`
`22500n
`Cells to
`Indicated Drug
`
`Out, and Allow
`with
`
`Assay »Treat
`
`Adenylate Kinase
`
`3 o
`
`ts)
`
`Figure 7
`
`0676
`
`
`
`21.3
`
`3.4
`33.2
`
`(jiM)
`
`Mustard
`Phosporamide
`Chlorambucil
`Bendamustine
`
`Ave IC50
`
`Drug
`
`SU-DHL-1
`
`Cell Line
`
`bJ
`
`SU-DHL-1 cells
`
`3 o
`
`0>
`O
`O
`ts)
`
`in
`
`PM, Chlorambucil,
`
`Bendamustine,
`
`IC50s of
`
`Table 1:
`
`0677
`
`
`
`GO Description:
`
`Groups
`Functional
`
`2C)
`gene
`
`cells (see Figure
`from bendamustine-indced
`
`analysis
`
`from GO-clustering
`
`Table 2: Results
`
`0678
`
`
`
`bendamustine
`
`compounds to
`
`Closest
`
`Table 3:
`
`0679
`
`
`
`Electronic Patent
`
`Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`11330868
`
`12-Jan-2006
`
`Title of
`
`Invention:
`
`BENDAMUSTINE PHARMACEUTICAL
`
`First Named
`
`Inventor/Applicant
`
`0680
`
`
`
`Description
`
`Fee Code
`
`Quantity
`
`Sub-Total
`Amount
`
`in
`
`USD($)
`
`Miscellaneous:
`
`Request
`
`for
`
`continued
`
`examination
`
`0681
`
`
`
`Electronic Acknowledgement
`
`Receipt
`
`EFSID:
`
`14234022
`
`Application Number:
`
`11330868
`
`International Application
`
`Number:
`
`Confirmation Number:
`
`Title of
`
`0682
`
`
`
`Charge any
`
`Additional
`
`Fees
`
`required
`
`0683
`
`
`
`Substitute
`
`for
`
`1449
`
`/PTO
`
`Complete if
`
`Known
`
`INFORMATION DISCLOSURE
`STATEMENT BY
`
`0684
`
`
`
`£) EuropSisches Patentamt
`
`European Patent
`
`Office
`
`(19)
`
`Office europeen
`
`des
`
`brevets
`
`0685
`
`
`
`EP 0
`
`780 386
`
`heteroaralkyl, heteroalkyl
`
`A1
`
`or
`
`lower
`
`alkoxy;
`hydrogen,
`cycloalkylalkyl; or
`
`0686
`
`
`
`EP 0
`
`780 386
`
`A1
`
`Description
`
`The present
`
`invention
`
`relates
`
`to
`
`0687
`
`
`
`EP 0
`
`780 386
`
`A1
`
`release of
`
`other
`
`biologically
`
`active
`
`molecules
`
`0688
`
`
`
`EP 0
`
`780 386
`
`A1
`
`resorption disease (such as osteoporosis), the enhanced collagen destruction associated with diabetes, chronic
`obstructive pulmonary
`disease,
`cerebral
`
`0689
`
`
`
`EP 0
`
`780 386
`
`A1
`
`2-{1-cyclopropylmethyl-4-[4-(4-fluorophenoxy)-phenylsulfonyl]-piperidin-4-yl}-A/-hydroxyacetamide;
`A/-hydroxy-2-[4-(4-phenoxyphenylsulfinyl)-tetrahydropyran-4-yl]-acetamide;
`2-{4-[4-(4-chlorophenoxy)-phenylsulfinyl]-tetrahydropyran-4-yl}-A/-hydroxyacetamide;
`2-{4-[4-(4-fluorophenoxy)-phenylsulfinyl]-tetrahydropyran-4-yl}-A/-hydroxyacetamide;
`A/-hydroxy-2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]-acetamide;
`2-{4-[4-(4-chlorophenoxy)-phenylthio]-tetrahydropyran-4-yl}-A/-hydroxyacetamide;
`2-{4-[4-(4-fluorophenoxy)-phenylthio]-1etrahydropyran-4-yl}-/\/-hydroxyacetamide;
`4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`4-[4-(4-bromophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(/V-hydroxycarboxamide);
`4-[4-(4-fluorophenoxy)-phenylsulfonylmethyl]-tetrahydropyran-4-(/V-hydroxycarboxamide);
`3-[4-(4-chlorophenoxy)phenylsulfonyl]-2,2-dimethyl-/V-hydroxypropionamide;
`4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-1-(cyclopropylmethyl)piperidine-4-(A/-hydroxycarboxamide);
`4-[4-(4-chlorophenoxy)phenylsulfonylme1hyl]-1 -(nicotinoyl)piperidine-4-(A/-hydroxycarboxamide);
`4-[4-(phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(N-hydroxycarboxamide);
`4-[4-(4-(thiophen-2-yl)-phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`4-[4-(4-(thiophen-3-yl)-phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(/V-hydroxycarboxamide);
`4-[4-(4-(furan-2-yl)-phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(/V-hydroxycarboxamide);
`4-[4-(4-(benzofuran-2-yl)-phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(/V-hydroxycarboxamide);
`4-[4-(4-(thiazol-2-yl)-phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`4-[4-(4-(thiazol-4-yl)-phenoxy)phenylsulfonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`4-[4-(4-(thiazol-5-yl)-phenox/)phenylsulfonylmethyl]-tetrahydropyran-4-(A/-hydrox/carboxamide);
`4-[4-(4-(imidazol-1-yl)-phenoxy)phenylsuHonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`4-[4-(4-(imidazol-2-yl)-phenoxy)phenylsuHonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`4-[4-(5-chloro-2-pyridyloxy)phenylsulfonylmethyl]-tetrahydropyran-4-(A/-hydroxycarboxamide);
`3-[4-(5-chloro-2-pyridyloxy)phenylsulfonyl]-2,2-dimethyl-A/-hydroxypropionamide;
`(R)-2-(CBZ-valinamido)-N-hydroxy-3-(4-phenoxyphenylsulfonyl)propionamide;
`(R)-N-hydroxy-2-valinamido-3-(4-phenoxyphenylsulfonyl)-propionamide;
`(R)-2-dime1hylamino-N-hydroxy-3-(4-phenoxyphenylsulfonyl)-propionamide;
`(R)-2-dime1hylaminosulfonamido-N-hydroxy-3-(4-phenoxyphenylsulfonyl)-propionamide
`
`and pharmaceutically
`
`acceptable salts
`
`thereot.
`
`Definitions
`
`The following
`
`definitions
`
`are
`
`5
`
`10
`
`IS
`
`20
`
`25
`
`30
`
`0690
`
`
`
`EP 0 780 386 A1
`EP 0
`780
`
`386
`
`A1
`
`(imidazol-2-yl), phenyl-(thiazol-2-yl),
`phenyl-(morpholin-2-yl), and
`(imidazol-2-yl), phenyl-(thiazol-2-yl), phenyl-(morpholin-2-yl), and phenyl-(oxazol-2-yl), (the ring(s) represented by Ra
`being optionally mono-or disubstituted by hydroxy, carboxy, lower alkyl, lower alkoxy, halo, trifluoromethyl and/or cyano).
`Examples of aryl substituted by R“-Z- are benzoyl, diphenylmethane, biphenyl, 6-methoxybiphenyl, 4-(4-methylphe-
`noxy)pheny|, 4-phenoxyphenyl, 2-thiophenoxyphenyl, 4-pyridethenylphenyl, 4-(thiophen-2-y|)phenoxypheny|, 4-(thi-
`ophen-3-y|)phenoxypheny|, 4-(2-pyridy|oxy)pheny|, 4-(5-chloro-2-pyridy|oxy)pheny|, 4-(thiazol-5-y|)phenoxypheny|, 4-
`(imidazol-2-y|)phenoxypheny|, and the like.
`"Heteroary|" refers to a monovalent aromatic carbocyclic radical having one or two rings incorporating one, two or
`three heteroatoms (chosen from N, O or S) within the ring(s), such as thiazole, oxazole, imidazole, thiophene, quinolyl,
`benzofuranyl, pyridyl, and indolyl, which can optionally be mono—, di— or tri—substituted, independently, with OH, COOH,
`lower alkyl, lower alkoxy, halo, trifluoromethyl and/or cyano.
`"Aralkyl" refers to a radical of the formula Rb-R°-, wherein R” is aryl as defined above and R° is alkylene as defined
`above, for example benzyl, phenylethylene, 3-phenylpropyl, biphenylpropyl.
`"Benzyloxycarbonyl" refers to a radical of the formula RdCH2OC(O)-, where Rd is phenyl. "Benzy|oxycarbo-
`nylamino" refers to a radical of the formula RdCH2OC(O)NH-, where Rd is phenyl.
`"Cycloa|ky|" means a saturated monovalent monocyclic hydrocarbon radical containing 3-8 carbon atoms, such as
`cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
`"Cycloalkyla|ky|" means cycloalkyl as defined above attached to an alkylene radical as defined above.
`"Halo" refers to bromo, chloro or fluoro.
`"Heteroaralkyl" refers to a radical of the formula R°R°-, where R9 is heteroaryl as defined above and R° is alkylene
`as defined above.
`
`"Heterocyclo" refers to a monovalent saturated carbocyclic radical, consisting of either a 5 to 7 membered mono-
`cyclic ring or a 9 to 14 membered bicyclic ring, substituted by one, two or three heteroatoms chosen from N, O, or S,
`optionally fused to a substituted or unsubstituted benzene ring. Examples of heterocyclo radicals are morpholino, pip-
`erazinyl, piperidinyl, pyrrolidinyl, tetrahydrothiopyranyl,
`tetrahydrothiopyranyl-1,1—dioxide, tetrahydropyranyl, and the
`like, which can be optionally substituted by one or more substituents independently selected from lower alkyl, lower
`alkoxy, alkylamino, alkylaminoalkyl, acyl valyl, alkylsulfonyl, dialkylamino, heteroaroyl, alkoxycarbonylalkyl, and an
`amino protecting group where appropriate (e.g. CBZ, for example, 1-CBZ-piperidin-4-yl). However, the definition "R6
`and R7 together with the nitrogen to which they are attached represent a heterocyclo group" clearly can refer only to a
`heterocyclo group containing at least one nitrogen atom.
`"Hydroxy|amino" refers to the group -NHOH.
`"BOC" refers to ferf—butoxycarbony|.
`"CBZ" refers to benzyloxycarbonyl.
`"DCC" refers to 1,3-dicyclohexylcarbodiimide.
`"Va|ine amide" refers to the radical (CH3)2CHCH(NH2)C(O)NH-.
`"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and
`that the description includes instances where said event or circumstance occurs and instances in which it does not. For
`example, "optionally substituted phenyl or ary|" means that the phenyl or aryl moiety may or may not be substituted and
`that the description includes both substituted and unsubstituted phenyl. The phrase "optional pharmaceutical excipi—
`ents" indicates that a composition or dosage form so described may or may not include pharmaceutical excipients other
`than those specifically stated to be present, and that the formulation or dosage form so described includes instances in
`which optional excipients are present and instances in which they are not.
`"Amino-protecting group" as used herein refers to those organic groups intended to protect nitrogen atoms against
`undesirable reactions during synthetic procedures, and includes, but is not limited to, benzyl, acyl, benzyloxycarbonyl
`(carbobenzyloxy), p-methoxybenzyloxy-carbonyl, p-nitrobenzyloxycarbonyl,
`ferf-butoxycarbonyl, trifluoroacetyl, and
`the like.
`
`"Base" as used here includes both strong inorganic bases such as sodium hydroxide, lithium hydroxide, ammonium
`hydroxide, potassium carbonate and the like, and organic bases such as pyridine, diisopropylethylamine, 4-methylmor-
`pholine, triethylamine, dimethylaminopyridine and the like.
`"Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of
`the free bases or free acids and which are not biologically or othenivise undesirable. If the compound exists as a free
`base, the desired acid salt may be prepared by methods known to those of ordinary skill in the art, such as treatment
`of the compound with an inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phos-
`phoric acid and the like; or with an organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
`acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, man-
`delic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
`If the com-
`pound exists as a free acid, the desired base salt may also be prepared by methods known to those of ordinary skill in
`the art, such as the treatment of the compound with an inorganic base or an organic base. Salts derived from inorganic
`bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, cop-
`per, manganese, aluminum salts and the like. Salts derived from organic bases include. but are not limited to. salts of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`0691
`
`0691
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`primary, secondary, and tertiary
`
`amines,
`amines and basic
`
`occurring substituted
`substituted amines including naturally
`such as
`ion
`exchange resins,
`pylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine,
`arginine, histidine,
`caffeine,
`
`0692
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`R1
`
`R2 v^s<o)n
`
`Y
`O R3 R4
`
`5
`
`10
`
`A compound of
`
`Formula
`
`I
`
`wherein
`
`0693
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`5
`
`R2
`
`R1
`
`Y
`
`SR5
`
`O R3
`
`R4
`
`io with an
`
`oxidizing
`
`agent.
`
`Suitable
`
`oxidation
`
`0694
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`under basic
`
`conditions,
`
`for
`
`example
`
`sodium
`
`0695
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`from about
`
`0
`
`o
`
`C
`
`to
`
`40o C,
`
`preferably
`
`at
`
`0696
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`5
`
`R1
`
`R2
`
`EtO
`
`OEt
`
`R1
`step 1
`
`10
`
`O O
`(7)
`
`(9)
`
`15
`
`20
`
`25
`
`step 2
`OH
`
`TV
`
`R2
`EtO.
`
`O
`
`(8)
`
`step 3
`
`Step 1
`
`-
`
`Preparation
`
`of
`
`Compounds
`
`0697
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`Preparation of
`
`Compounds
`
`of Formula
`
`(10)
`
`where
`
`R
`
`0698
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`VI
`
`5
`
`10
`
`R1
`EtO
`
`OEt
`
`R2 vv
`
`O O
`(7)
`
`IS
`
`(n) +
`
`O
`
`R
`
`R
`
`20
`
`25
`
`30
`
`(9b)
`
`Step 1
`
`-
`
`Preparation
`
`0699
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`rahydropyran or
`
`an
`
`ester
`
`thereof,
`
`for
`
`0700
`
`
`
`EP 0
`
`780
`
`386
`
`(1924) for
`
`acids
`
`where R
`
`A1
`
`3
`
`and
`
`R
`
`4
`
`0701
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`VIII
`
`5
`
`la +
`
`f-BuONH2
`
`step 1
`*HCI
`
`R1
`f-BuOHN
`
`10
`
`15
`
`20
`
`0702
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`Step 3
`
`-
`
`Preparation
`
`of
`
`Compounds
`
`0703
`
`
`
`EP 0
`780
`386
`EP 0 780 386 A1
`
`A1
`
`REACTION SCHEME
`REACTION SCHEME IX
`
`IX
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`R‘
`
`R2
`
`Ho\n>$<sn5
`
`OR3R“'
`
`la
`
`step 1
`
`R‘
`
`R2
`
`5
`
`sn5
`
`Cl
`
`(12)
`
`step 2
`————»
`
`(12)
`
`R1
`
`R2
`
`HOHN
`
`SR5
`
`o R3
`
`R4
`
`lba
`
`R‘
`
`R2
`
`R] R2
`HO.
`
`10
`
`SR5
`
`OR 3
`
`15
`
`20
`
`lba
`
`step 3
`————»
`
`HOHN
`
`s(0),.R5
`
`o R3
`
`R4
`
`Id
`
`25
`
`Step 1
`
`- Preparation of Compounds of Formula lba
`
`In general, an acid halide of a compound of Formula la, designated as compounds of Formula (12), is prepared by
`reacting a compound of Formula la with a halogenating agent.
`The compound of Formula la is reacted with an excess of a halogenating agent, for example oxalyl chloride, oxalyl
`bromide, phosphorous oxychoride, phosphorous trichloride, phosphorous pentachloride, thionyl chloride, preferably
`oxalyl chloride in the presence of a small amount of N, N-dimethylformamide as a catalyst. The reaction is carried out
`in an inert solvent, preferably methylene chloride, in the temperature range from about 0°C to 40°C, preferably at about
`25°C, for about 10 to 30 hours, preferably about 18 hours. The acid halide reaction product, a compound of Formula
`(12), is isolated by conventional means.
`
`Step 2 - Preparation of Compounds of Formula lba
`
`Compounds of Formula I where n is 0 and Y is HONH—, designated as compounds of Formula lba, may be prepared
`by reacting a compound of Formula (12) with about 1-5 molar equivalents, preferably about 3.5 molar equivalents, of N,
`O-bis(trimethylsilyl)-hydroxylamine, or more preferably aqueous hydroxylamine dissolved in a suitable solvent, for
`example a mixture of tert-butanol/1etra-hydrofuran. The reaction is carried out in an inert solvent, preferably methylene
`chloride, in the temperature range from about 0°C to 25°C, preferably at about 25°C, for about 1-10 hours, preferably
`about 3 hours for N, O-bis(trimethylsilyl)hydroxylamine, or about 1.5 hours for aqueous hydroxylamine. The N-
`hydroxamic acid product, a compound of Formula lba, is isolated and purified by conventional means.
`
`Step 3 - Preparation of Compounds of Formula Id
`
`The compound of Formula lba is converted to a compound of Formula Id where n is 1 or 2 in the same manner as
`shown in Reaction Scheme Vlll, steps 2 or 3, above.
`
`20
`
`0704
`
`0704
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`Alternative Preparation
`
`of
`
`Compounds
`
`0705
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`The reaction
`
`is
`
`carried
`
`out
`
`in a
`
`protic
`
`0706
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`reaction is
`
`carried
`
`out
`
`in
`
`a polar solvent,
`
`0707
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`XTT
`
`5
`
`10
`
`step 1
`
`le
`
`15
`
`R] R2
`HO.
`
`so2
`OR 3
`
`I
`
`R4
`
`Ik
`
`20 Step 1
`
`-
`
`Preparation
`
`of
`
`Compounds
`
`0708
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`XIII
`
`5
`
`i
`R
`
`R2
`
`S(0)n
`
`R
`
`f-BuOHN
`5
`
`step 1
`
`10
`
`IS
`
`O
`
`N
`i
`H
`
`II
`
`20
`
`25
`
`30 Step 1
`
`-
`
`0709
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`Preparation of
`
`Compounds
`
`of
`
`Formula
`
`0710
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`XV
`
`lab
`
`step 1
`
`10
`
`IS
`
`20
`
`lo
`
`step 2
`
`IP
`
`25
`
`30
`
`Step 1
`
`-
`
`Preparation of
`
`0711
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`XVT
`
`5
`
`10
`
`IP
`
`step 1
`
`15
`
`20
`
`Step 1
`
`- Preparation of
`
`0712
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`REACTION SCHEME
`
`XVTT
`
`5
`
`10
`
`IS
`
`20
`
`Ir
`
`25
`
`0713
`
`
`
`EP 0
`
`780
`
`and ethanol,
`
`in
`
`A1
`
`386
`
`the
`
`temperature
`
`range
`
`0714
`
`
`
`EP 0
`780
`EP 0 780 386 A1
`
`386
`
`A1
`
`R2
`
`R3
`
`5
`
`H020
`
`R‘
`
`R2
`
`Ft3
`M
`HO2 C
`R"
`
`(4)
`
`where R
`, R
`3
`2
`where R2, R3 and R4 are as defined in the compounds of formula I, except that R2 cannot be -NR5R7;
`
`and R
`
`4
`
`are
`
`with a compound of the formula R5SH, where R5 is as defined in the compounds of formula I, in the presence of a
`secondary base.
`2. Alternatively, a process for preparing compounds of Formula I comprises:
`
`reacting a compound of the formula:
`
`R1
`
`R2
`
`t-BuOHNWSR5
`
`C)R3
`
`R4
`
`where R‘, R2, R3, R4 and R5 are as defined in the compounds of formula I,
`
`with a mild oxidizing agent, for example, sodium periodate.
`3. Alternatively, a process for preparing compounds of Formula I comprises:
`
`reacting a compound of the formula:
`
`R‘
`
`R2
`
`t-BuOHN NR5
`
`CJR3
`
`R4
`
`where R‘, R2, R3, R4 and R5 are as defined in the compounds of formula I,
`
`with a strong oxidizing agent, for example, OXONE or m-chloroperbenzoic acid.
`4. Alternatively, a process for preparing compounds of Formula I where n is 2 comprises:
`
`reacting a compound of the formula:
`
`093 R4
`
`where R‘, R2, R3, R4 and R5 are as defined in the compounds of formula I,
`
`with a strong oxidizing agent, for example, OXONE or m-chloroperbenzoic acid.
`5. Alternatively, a process for preparing compounds of Formula I comprises:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`31
`
`0715
`
`0715
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`reacting a
`
`compound
`
`of
`
`the formula:
`
`5
`
`10
`
`R1
`
`where n,
`
`Ft
`
`0716
`
`
`
`EP 0
`
`780
`
`with a
`
`compound
`
`A1
`
`386
`
`of
`
`the formula
`picolyl, -S02R
`
`RX, where
`a
`
`R is
`
`lower alkyl, cycloalkylalkyl,
`,
`
`0717
`
`
`
`EP 0
`780
`EP 0 780 386 A1
`
`386
`
`A1
`
`5
`
`1
`
`R
`O
`
`R2
`
`O
`
`R3
`R4
`
`where R
`, R
`,
`2
`1
`where R‘, R2, R3 and R4 are as defined in the compounds of formula I, except that R2 cannot be -NRSR7;
`
`R3 and R4 are
`
`as
`
`with a compound of the formula R5 SH, where R5 is as defined in the compounds of formula I, in the presence of a
`secondary base.
`13. Alternatively, a process for preparing compounds of Formula I comprises:
`
`reacting a compound of the formula:
`
`R1
`
`R2
`
`Ro\">§<
`
`X
`
`0R3
`
`R4
`
`with an anion of a compound of the formula R5SH, where R5 is as defined in the compounds of formula I.
`
`14. Alternatively, a process for preparing compounds of Formula I comprises:
`
`reacting a compound of the formula:
`
`R1
`
`R2
`
`FtOfi_?</SO2R5
`
`O
`
`with an alkyl or aralkyl halide in the presence of a hindered base.
`
`15. Alternatively, a process for preparing compounds of Formula I comprises:
`
`reacting a compound of the formula:
`
`Br
`
`R1
`
`R2
`
`“°m>§<S°2
`
`OR3
`
`R4
`
`with a compound of the formula Ft“B(OH)2 or Ft”SnMe3, where R” is aryl or heteroaryl, in the presence of
`tetrakis(triphenylphosphine)-pal|adium(O).
`
`34
`
`0718
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`0718
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`The compounds
`
`of
`
`Formula I inhibit mammalian matrix
`matrilysin and
`
`metalloproteases, such
`collagenases,
`
`0719
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`sorbitan monolaurate,
`
`triethanolamine
`
`oleate,
`
`0720
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`formaldehyde;
`acetone;
`propionaldehyde;
`cyclopentanone;
`cyclohexanone;
`1,4-cyclohexanedione mono-ethylene
`
`5
`
`ketal;
`4-methylcyclohexanone;
`phenylacetaldehyde;
`4-(biphen-4-yl)butyraldehyde;
`cyclopentylacetaldehyde;
`10
`tetrahydropyranone; and
`tetrahydrothiopyran;
`
`and optionally
`
`0721
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`(20 ml),
`
`keeping
`
`the temperature
`
`below
`
`30o C.
`
`After
`
`the
`
`0722
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`solid was
`
`further
`
`purified through
`
`trituration
`
`with
`
`0723
`
`
`
`EP 0
`
`780
`
`386
`
`ylic acid
`
`ethyl
`
`ester (11.5
`
`A1
`
`g,
`
`97%), which
`
`was taken into the
`
`next reaction
`
`0724
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`higher than
`
`45
`
`0
`
`C.
`
`The
`
`aqueous
`
`0725
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`additional 50
`
`minutes,
`
`and
`
`diiodomethane
`
`0726
`
`
`
`EP 0
`
`780
`
`386
`
`A1
`
`2. A solution of
`
`2-[4-(4-phenoxyphenylthio)-A
`
`/-CBZ-piperidin-4-yl)]-acetic
`dichloroethane (3
`
`0727
`
`
`
`EP 0
`780
`386
`EP 0 780 386 A1
`
`A1
`
`(d), 120.63 (dd,
`45.49 (s),
`64.12
`(t), 116.53
`(dd, JC-F
`= 23.2 Hz), 118.71
`45.49 (3), 64.12 (t), 116.53 (dd, JC_,: = 23.2 Hz), 118.71 ((1), 120.63 (dd, JC_F =