Illllllllllllll
`
`US008741963B2
`US008741963B2
`
`llllllllll
`
`(12) United States Patent
`(12) United States Patent
`Hiestand et al.
`Hiestand et al.
`
`(10) Patent No.:
`(io) Patent No.:
`(45) Date of Patent:
`(45) Date of Patent:
`
`US 8,741,963 B2
`US 8,741,963 B2
`Jun. 3, 2014
`Jun. 3, 2014
`
`WO WO 2004/050073
`6/2004
`6/2004
`WO WO 2004/050.073
`12/2004
`WO WO 2004/113330
`12/2004
`WO WO 2004/113330
`WO WO 2005/123104
`12/2005
`12/2005
`WO WO 2005/123104
`5/2006
`WO WO 2006/055809
`5/2006
`WO WO 2006/055.809
`6/2006
`WO WO 2006/058316
`6/2006
`WO WO 2006/058316
`6/2006
`WO WO 2006/066086
`6/2006
`WO WO 2006/066086
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
`Targets
`
`(54) SIP RECEPTOR MODULATORS FOR
`(54) S1P RECEPTORMODULATORS FOR
`TREATING MULTIPLE SCLEROSIS
`TREATING MULTIPLE SCLEROSIS
`
`e
`-
`Inventors: Peter C. Hiestand, Allschwil
`(CH);
`(75)
`(75) Inventors: Peter C. Hiestand, Allschwil (CH):
`Christian Schnell, Hesingue (FR)
`Christian Schnell, Hésingue (FR)
`(73) Assignee: Novartis AG, Basel (CH)
`(73) Assignee: Novartis AG, Basel (CH)
`term
`the
`( * ) Notice:
`Subject to any disclaimer,
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 21 days.
`U.S.C. 154(b) by 21 days.
`(21) Appl.No.: 13/149,468
`(21) Appl. No.: 13/149,468
`May 31, 2011
`(22) Filed:
`(22) Filed:
`May 31, 2011
`Prior Publication Data
`(65)
`(65)
`Prior Publication Data
`US 2011/0237682 Al
`Sep. 29, 2011
`|US 2011/0237682 A1
`Sep. 29, 2011
`
`Brinkmann, Volker et al., “The Immune Modulator FTY720 Targets
`FTY720
`"The al., Immune Modulator
`
`
`Brinkmann, Volker et
`of
`this
`Sphingosine 1-Phosphate Receptors”, The Journal of Biological
`Sphingosine 1-Phosphate Receptors", The Journal of Biological
`Chemistry, vol. 277, No. 24, Issue of Jun. 14, pp. 21453-21457,
`Chemistry, vol. 277, No. 24, Issue of Jun. 14, pp. 21453-21457,
`(2002).
`(2002).
`Miller et al., Neurol, & Neurosci. Reports, (Sep. 2010), 1095), pp.
`(Sep. 2010), 1095), pp.
`Miller et al., Neurol, & Neurosci. Reports,
`397-406.
`397–406.
`6, 20(4), part 1, A20. 2006),
`
`
`(Mar.
`Journal,
`Hla, T., FASEB
`Hla, T., FASEB Journal, (Mar. 6, 2006), 2004), part 1, A20.
`LaMontagne K. ...Antagonism of Sphingosine-1-Phosphate Recep
`LaMontagne K. ,,Antagonism of Sphingosine-1-Phosphate
`Recep­
`tors by FTY720 Inhibits Angiogenesis. Cancer Research, Jan. 2006,
`tors by FTY720 Inhibits Angiogenesis.. Cancer Research,
`Jan.
`2006,
`66, 221-231.
`66, 221-231.
`Hla. T. ...Physiological and pathological actions of sphingosine
`Hla. T. ,,Physiological and pathological actions of sphingosine
`1-phosphate Seminars in Cell & Developmental Biology, Oct. 2004,
`1-phosphate Seminars
`in Cell
`
`& pmental Biology, Oct. Develo
`
`2004,
`15(5), 513-520.
`15(5), 513-520.
`Related U.S. Application Data
`Related U.S. Application Data
`Kappos L et al. ...FTY720 in relapsing MS . . . Jun. 23, 2005 online
`Kappos L et al. ,,FTY720 in relapsing MS . . . Jun. 23, 2005 online
`
`
`(found Jun. 2, 2011) URL:http://www.ms-in-europe.com/printver
`(found Jun. 2, 2011) URL:http://www.ms-in-europe.com/printver-
`(63) Continuation of application No. 12/303,765, filed as
`(63) Continuation of application No. 12/303,765, filed as
`sion/index.php?anr=105&cnr=4/>.
`sion/ index .php? anr= 10 5&cnr=4/>.
`application No. PCT/EP2007/005597 on Jun. 25,
`application No. PCT/EP2007/005597 on Jun. 25,
`Ho J.W et al. ... Effects of a novel immunomodulating agent . . .
`agent . . .
`Ho J.W et al. ,, Effects of a novel immunomodulating
`2007, now abandoned.
`2007, now abandoned.
`Molecular cancer theraputics, 2005 Set, 4(9), 1430-1438.
`Molecular cancer
`theraputics,
`2005
`Set,
`4(9),
`Virely D.J. “Developing therapeutics for the treatment of multiple
`Virely D.J. "Developing
`therapeutics
`
`for the treatment of multiple
`Foreign Application Priority Data
`(30)
`Foreign Application Priority Data
`(30)
`sclerosis.” Journal of American Society for Experimental Neuro
`sclerosis." Journal of American Society for Experimental Neuro
`Therapeutics. Oct. 2005, 2, 638-649. http://pubget.com/paper/
`Therapeutics. Oct. 2005, 2, 638-649. http://pubget.com/paper/
`(GB)
`Jun. 27, 2006
`0612721.1
`Jun. 27, 2006 (GB) ................................... 0612721.1
`16489371.
`16489371.
`Fujino et al. ‘Amelioration of experimental autoimmune
`'Amelioration of experimental autoimmune
`Fujino et al.
`(51) Int. CI.
`(51) Int. Cl.
`encephalomyelitis . . . . The Journal of Pharmacology and Experi
`encephalomyelitis
`
`. . . ' The Journal of Pharmacology and Experi-
`A61K 31/13
`A6 IK 31/13
`mental Therapeutics, vol. 305, No. 1, pp. 70-77, 2003.
`mental Therapeutics,
`vol.
`305,
`No.
`1,
`pp.
`(52) U.S. CI.
`K. Rammohan et al, Poster on ‘Long-Term Safety of Fingolimod in
`K. Rammohan et
`al,
`
`on Poster 'Long-Term Safety
`
`of
`Fingolimod
`(52) U.S. CI.
`Patients with Relapsing-Remitting Multiple Sclerosis: Results from
`Patients with Relapsing-Remitting
`Multiple
`Sclerosis:
`514/667; 514/903
`USPC
`USPC ........................................... 514/667: 514/903
`Phase 3 FREEDOMS
`II Extension Study' Mar. 16-23, 2013, San
`Phase 3 FREEDOMS II Extension Study’ Mar. 16-23, 2013, San
`(58) Field of Classification Search
`(58) Field of Classification Search
`Diego, US, 65” American Academy of Neurology Annual Meeting.
`Diego, US, 65"' American
`Academy
`of
`Neurology
`514/667, 903
`USPC
`USPC .................................................. 514/667, 903
`search history. Primary Examiner — Kevin E Weddington
`See application file for complete
`See application file for complete search history.
`Primary Examiner – Kevin E Weddington
`(74) Attorney, Agent, or Firm — Andrew Holmes
`(74) Attorney, Agent, or Firm – Andrew Holmes
`References Cited
`References Cited
`ABSTRACT
`(57)
`(57)
`ABSTRACT
`U.S. PATENT DOCUMENTS
`|U.S. PATENT DOCUMENTS
`The present invention relates to the use of the SIP
`The present invention relates to the use of the S1P receptor
`modulator 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3
`modulator 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-
`diol, administered at a daily dosage
`of 0.5 mg,
`diol, administered at a daily dosage of 0.5 mg, for inhibiting
`or treating neo-angiogenesis associated with multiple sclero-
`or treating neo-angiogenesis associated with multiple sclero
`sis.
`S1S.
`
`(2006.01)
`(2006.01)
`
`(56)
`(56)
`
`2006/0046979 Al
`2006/0046979 A1
`
`3/2006 Foster etal.
`3/2006 Foster et al.
`
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`
`WO 03/097028
`WO
`WO
`WO 03/097.028
`WO 03/099192
`WO
`WO 03/099.192
`WO
`WO WO 2004/028521
`WO WO 2004/028521
`
`11/2003
`11/2003
`12/2003
`12/2003
`4/2004
`4/2004
`
`9 Claims, No Drawings
`9 Claims, No Drawings
`
`1430-1438.
`
`70-77,
`in
`Results
`
`2003.
`
`from
`
`Annual
`
`Meeting.
`
`inhibiting
`
`receptor
`
`for
`
`TEVA EX. 1013
`Page 1
`
`

`

`1
`1
`SIP RECEPTOR MODULATORS FOR
`S1P RECEPTOR MODULATORS FOR
`TREATING MULTIPLE SCLEROSIS
`TREATING MULTIPLE SCLEROSIS
`
`US 8,741,963 B2
`US 8,741,963 B2
`
`10
`10
`
`15
`15
`
`(X)
`(X)
`
`(a)
`(a)
`
`45
`45
`
`z
`
`R32R22N + CH2R1.
`
`'CH2R1Z
`
`—Zj— P:
`
`o
`
`•OR-v
`OR5,
`
`ORsz
`
`2
`2
`SIP receptor modulator activities of compounds are tested on
`S1P receptor modulator activities of compounds are tested on
`the human SIP receptors SIPj, S1P2, S1P3, S1P4 and S1P5.
`the human S1P receptors S1P1, S1P2, S1Pa, S1Pa and S1Ps.
`Functional receptor activation is assessed by quantifying
`Functional receptor activation is assessed by quantifying
`compound induced GTPIY-ºS|binding to membrane protein
`This application is a Continuation of U.S. application Ser.
`compound induced GTP [y-35 S] binding to membrane protein
`This application is a Continuation of U.S. application Ser.
`No. 12/303,765 filed Dec. 8, 2008 which is a 371 of PCX/ 5 prepared from transfected CHO or RH7777 cells stably
`prepared from transfected CHO or RH7777 cells stably
`No. 12/303,765 filed Dec. 8, 2008 which is a 371 of PCT/
`expressing the appropriate human S1P receptor. The assay
`EP2007/005597 filed on Jun. 25, 2007, which claims benefit
`expressing the appropriate human SIP receptor. The assay
`EP2007/005597 filed on Jun. 25, 2007, which claims benefit
`of Great Britain Application No. 0612721.1 filed on Jun. 27,
`technology used is SPA (scintillation proximity based assay).
`technology used is SPA (scintillation proximity based assay).
`of Great Britain Application No. 0612721.1 filed on Jun. 27,
`Briefly, DMSO dissolved compounds are serially diluted and
`2006, which in their entirety are herein incorporated by ref­
`Briefly, DMSO dissolved compounds are serially diluted and
`2006, which in their entirety are herein incorporated by ref
`added to SPA-bead (Amersham-Pharmacia) immobilised
`erence.
`added to SPA-bead (Amersham-Pharmacia) immobilised
`erence.
`S1P receptor expressing membrane protein (10-20 pg/well)
`SIP receptor expressing membrane protein (10-20 (xg/well)
`The present invention relates to the use of an SIP receptor
`The present invention relates to the use of an S1P receptor
`in the presence of 50 mM Hepes, 100 mM NaCl, 10 mM
`modulator in the treatment or prevention of neo-angiogenesis
`modulator in the treatment or prevention of neo-angiogenesis
`in the presence of 50 mM Hepes, 100 mM NaCl, 10 mM
`associated with a demyelinating disease, e.g. multiple scle- MgCl2, 10 jxM GDP, 0.1% fat free BSA and 0.2 nM GTP
`associated with a demyelinating disease, e.g. multiple scle
`MgCl2, 10 puM GDP, 0.1% fat free BSA and 0.2 nM GTP
`[y-º’S] (1200 Ci/mmol). After incubation in 96 well microti
`rosis.
`[Y-35S] (1200 Ci/mmol). After incubation in 96 well microti-
`rosis.
`terplates at RT for 120 min, unbound GTP?y-ºS] is separated
`SIP receptor modulators are typically sphingosine ana­
`terplates at RT for 120 min, unbound GTP [Y-35S] is separated
`S1P receptor modulators are typically sphingosine ana
`logues, such as 2-substituted 2-amino-propane-1,3-diol or
`logues, such as 2-substituted 2-amino-propane-l,3-diol or
`by a centrifugation step. Luminescence of SPA beads trig­
`by a centrifugation step. Luminescence of SPA beads trig
`gered by membrane bound GTP ?y-'S] is quantified with a
`2-amino-propanol derivatives, e.g. a compound comprising a
`2-amino-propanol derivatives, e.g. a compound comprising a
`gered by membrane bound GTP [Y-35S] is quantified with a
`group of formula X.
`TOPcount plate reader (Packard). EC50s are calculated using
`group of formula X.
`TOPcount plate reader (Packard). ECsos are calculated using
`Sphingosine-1 phosphate (hereinafter "SIP") is a natural
`Sphingosine-1 phosphate (hereinafter “S1P’) is a natural
`standard curve fitting software. In this assay, the SIP receptor
`standard curve fitting software. In this assay, the S1P receptor
`serum lipid. Presently there are eight known S1P receptors,
`serum lipid. Presently there are eight known SIP receptors, 20 modulators preferably have a binding affinity to SIPreceptor
`modulators preferably have a binding affinity to S1P receptor
`20
`namely SI PI to S1P8. SIP receptor modulators are typically
`namely S1P1 to S1P8. S1P receptor modulators are typically
`<50 nM.
`<50 nM.
`sphingosine analogues, such as 2-substituted 2-amino-pro
`sphingosine analogues, such as 2-substituted 2-amino-pro-
`Preferred SIP receptor modulators are e.g. compounds
`Preferred S1P receptor modulators are e.g. compounds
`pane-1,3-diol or 2-amino-propanol derivatives, e.g. a com
`pane-l,3-diol or 2-amino-propanol derivatives, e.g. a com­
`which in addition to their SIP binding properties also have
`which in addition to their S1P binding properties also have
`pound comprising a group of formula X
`pound comprising a group of formula X
`accelerating lymphocyte homing properties, e.g. compounds
`accelerating lymphocyte homing properties, e.g. compounds
`25
`25 which elicit a lymphopenia resulting from a re-distribution,
`which elicit a lymphopenia resulting from a re-distribution,
`preferably reversible, of lymphocytes from circulation to sec­
`preferably reversible, of lymphocytes from circulation to sec
`ondary lymphatic tissue, without evoking a generalized
`ondary lymphatic tissue, without evoking a generalized
`immunosuppression. Naïve cells are sequestered: CD4 and
`immunosuppression. Naive cells are sequestered; CD4 and
`30 CDS T-cells and B-cells from the blood are stimulated to
`CD8 T-cells and B-cells from the blood are stimulated to
`30
`migrate into lymph nodes (LN) and Peyer's patches (PP).
`migrate into lymph nodes (LN) and Peyer’s patches (PP).
`The lymphocyte homing property may be measured in
`The lymphocyte homing property may be measured in
`wherein Z is H, C1-galkyl, C2-calkenyl, C2-calkynyl, phenyl,
`wherein Z is H, C1.6alkyl, C2_6alkenyl, C
`alkynyl, phenyl,
`following Blood Lymphocyte Depletion assay:
`following Blood Lymphocyte Depletion assay:
`2-6
`phenyl substituted by OH, C^alkyl substituted by 1 to 3
`phenyl substituted by OH, C-calkyl substituted by 1 to 3
`substituents selected from the group consisting of halogen, 35 A SIP receptor modulator or the vehicle is administered
`A S1P receptor modulator or the vehicle is administered
`substituents selected from the group consisting of halogen,
`35
`orally by gavage to rats. Tail blood for hematological moni
`orally by gavage to rats. Tail blood for hematological moni-
`C3_8cycloalkyl, phenyl and phenyl substituted by OH, or
`Cs-scycloalkyl, phenyl and phenyl substituted by OH, or
`toring is obtained on day -1 to give the baseline individual
`CH2—wherein R^ is OH, acyloxy or a residue of formula
`toring is obtained on day –1 to give the baseline individual
`CH2–Raº wherein R4 is OH, acyloxy or a residue offormula
`values, and at 2, 6, 24, 48 and 72 hours after application. In
`(a)
`values, and at 2, 6, 24, 48 and 72 hours after application. In
`(a)
`this assay, the SIP receptor agonist or modulator depletes
`this assay, the S1P receptor agonist or modulator depletes
`4Q peripheral blood lymphocytes, e.g. by 50%, when adminis­
`peripheral blood lymphocytes, e.g. by 50%, when adminis
`40
`tered at a dose of e.g. <20 mg/kg.
`tered at a dose of e.g. <20 mg/kg.
`Examples of appropriate SIP receptor modulators are, for
`Examples of appropriate S1P receptor modulators are, for
`example:
`example:
`Compounds as disclosed in EP627406A1, e.g. a compound
`Compounds as disclosed in EP627406A1, e.g. a compound
`of formula I
`of formula I
`
`wherein Z1 is a direct bond or O, preferably O;
`wherein Z is a direct bond or O, preferably O,
`each of R5z and R6Z, independently, is H, or C^alkyl option­
`each of Rs, and Raº, independently, is H, or Claalkyl option
`ally substituted by 1, 2 or 3 halogen atoms;
`ally substituted by 1, 2 or 3 halogen atoms;
`RLZ is OH, acyloxy or a residue of formula (a); and each of R
`R1 is OH, acyloxy or a residue of formula (a); and each of R2.
`2z
`and R3z independently, is H, C^alkyl or acyl.
`and Rs, independently, is H. Claalkyl or acyl.
`Group of formula X is a functional group attached as a
`Group of formula X is a functional group attached as a
`terminal group to a moiety which may be hydrophilic or
`terminal group to a moiety which may be hydrophilic or
`lipophilic and comprise one or more aliphatic, alicyclic, aro­
`lipophilic and comprise one or more aliphatic, alicyclic, aro
`matic and/or heterocyclic residues, to the extent that the
`matic and/or heterocyclic residues, to the extent that the
`resulting molecule wherein at least one of Z and RLZ is or 55
`resulting molecule wherein at least one of Z and RL is or
`55
`comprises a residue of formula (a), signals as an agonist at one
`comprises a residue offormula (a), signals as an agonist at one
`of more sphingosine-1-phosphate receptor.
`of more sphingosine-1-phosphate receptor.
`SIP receptor modulators are compounds which signal as
`S1P receptor modulators are compounds which signal as
`agonists at one or more sphingosine-1 phosphate receptors,
`agonists at one or more sphingosine-1 phosphate receptors,
`e.g. SI PI to S1P8. Agonist binding to a SIP receptor may e.g. 60
`e.g. S1P1 to S1P8. Agonist binding to a S1P receptor may e.g.
`60
`result in dissociation of intracellular heterotrimeric G-pro-
`result in dissociation of intracellular heterotrimeric G-pro
`teins into Ga-GTP and GfSy-GTP, and/or increased phospho­
`teins into Go-GTP and Gfèy-GTP, and/or increased phospho
`rylation of the agonist-occupied receptor and activation of
`rylation of the agonist-occupied receptor and activation of
`downstream signaling pathways/kinases.
`downstream signaling pathways/kinases.
`The binding affinity of SIP receptor modulators to indi- 65
`The binding affinity of S1P receptor modulators to indi
`65
`vidual human SIP receptors may be determined in following
`vidual human S1P receptors may be determined in following
`assay:
`assay:
`
`50
`50
`
`I
`
`CH2OR3
`CH2OR3
`
`R4R5N
`
`'CH2OR2
`
`RI
`Ri
`
`wherein R! is a straight- or branched (C12_22) chain
`wherein R1 is a straight- or branched (C12-22) chain
`which may have in the chain a bond or a hetero atom
`which may have in the chain a bond or a hetero atom
`selected from a double bond, a triple bond, O, S, NR6,
`selected from a double bond, a triple bond, O, S, NRa,
`wherein R6 is H, C^alkyl, aryl-C^alkyl, acyl or
`wherein Ra is H. Claalkyl, aryl-Cu-aalkyl, acyl or
`(C1-aalkoxy)carbonyl, and carbonyl, and/or
`(C1_4alkoxy)carbonyl, and carbonyl, and/or
`whichmay have as a substituent C^alkoxy, C^alkeny-
`which may have as a substituent Claalkoxy, C2-aalkeny
`loxy,
`C2-aalkynyloxy,
`acyl,
`Claalkylamino,
`acyl, C^alkylamino,
`loxy, C2_4alkynyloxy,
`Claalkylthio, acylamino, (C-4alkoxy)carbonyl,
`C^alkylthio,
`acylamino,
`(C1_4alkoxy)carbonyl,
`(C1-aalkoxy)-carbonylamino, acyloxy, (C-4alkyl)
`(C1_4alkoxy)-carbonylamino, acyloxy, (C^alkyl)
`carbamoyl, nitro, halogen, amino, hydroxyimino,
`carbamoyl, nitro, halogen, amino, hydroxyimino,
`hydroxy or carboxy; or
`hydroxy or carboxy; or
`
`TEVA EX. 1013
`Page 2
`
`

`

`R-! is
`R1 is
`a phenylalkyl wherein alkyl is a straight- or branched
`a phenylalkyl wherein alkyl is a straight- or branched
`(C6_2o)carbon chain; or
`(CG-20)carbon chain; or
`a phenylalkyl wherein alkyl is a straight- or branched
`a phenylalkyl wherein alkyl is a straight- or branched
`(Ci_3o)carbon chain wherein said phenylalkyl is substi­
`(C1 so)carbon chain wherein said phenylalkyl is substi
`tuted by
`tuted by
`a straight- or branched (C6_20)carbon chain optionally sub­
`a straight- or branched (Co-20)carbon chain optionally sub
`stituted by halogen,
`stituted by halogen,
`a straight- or branched (C6_20)alkoxy chain optionally sub­
`a straight- or branched (CG-20)alkoxy chain optionally sub
`stituted by halogen,
`stituted by halogen,
`a straight- or branched (CG-20)alkenyloxy,
`a straight- or branched (C6_20)alkenyloxy,
`phenyl-C-1aalkoxy, halophenyl-Claalkoxy, phenyl
`phenyl-C^^alkoxy, halophenyl-C^alkoxy,
`phenyl-
`C1-14alkoxy-C1-14alkyl, phenoxy-C1-4alkoxy or phe
`C1.14alkoxy-C1.14alkyl, phenoxy-C^alkoxy or phe-
`noxy-Claalkyl,
`noxy-C^alkyl,
`cycloalkylalkyl substituted by Ca.30alkyl,
`cycloalkylalkyl substituted by C6_20alkyl,
`heteroarylalkyl substituted by Ca.30alkyl,
`heteroarylalkyl substituted by C6_20alkyl,
`heterocyclic Co.20alkyl or
`heterocyclic C6_20alkyl or
`heterocyclic alkyl substituted by C2.20alkyl,
`heterocyclic alkyl substituted by C2_20alkyl,
`and wherein
`and wherein
`the alkyl moiety may have
`the alkyl moiety may have
`in the carbon chain, a bond or a heteroatom selected from
`in the carbon chain, a bond or a heteroatom selected from
`a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or
`a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or
`NR6, wherein R6 is as defined above, and
`NRa, wherein Ra is as defined above, and
`as a substituent C1-aalkoxy, C2-aalkenyloxy, C2-aalkyny
`as a substituent C^alkoxy, C^alkenyloxy, C^alkyny- 25
`25
`loxy, arylC1-4alkyloxy, acyl, C1-4alkylamino, C1-4alky
`loxy, arylC^alkyloxy, acyl, C^alkylamino, C^alky-
`lthio, acylamino, (C1-aalkoxy)carbonyl, (C1-aalkoxy)
`Ithio, acylamino, (C1_4alkoxy)carbonyl, (C1_4alkoxy)
`carbonylamino, acyloxy, (C-4alkyl)carbamoyl, nitro,
`carbonylamino, acyloxy, (C1_4alkyl)carbamoyl, nitro,
`halogen, amino, hydroxy or carboxy, and
`halogen, amino, hydroxy or carboxy, and
`alkyl or 30
`each of R2, R3, R4 and R5, independently, is H,
`each of R2, Rs. Ra and Rs, independently, is H, Cia alkyl or
`30
`acyl or a pharmaceutically acceptable salt or hydrate thereof;
`acyl or a pharmaceutically acceptable salt or hydrate thereof;
`Compounds as disclosed in EP 1002792A1, e.g. a com­
`Compounds as disclosed in EP 1002792A1, e.g. a com
`pound of formula II
`pound of formula II
`
`3
`3
`
`US 8,741,963 B2
`US 8,741,963 B2
`
`4
`4
`OH, C1-galkoxy, acyl, acyloxy, amino, C1-calkylamino, acy
`OH, C^galkoxy, acyl, acyloxy, amino, Q.galkylamino, acy-
`lamino, haloC1-calkyl and halogen; Y is H, C1-calkyl, OH,
`lamino, haloC^galkyl and halogen; Y is H, C^alkyl, OH,
`C1-galkoxy, acyl, acyloxy, amino, C1-calkylamino, acy
`C^galkoxy, acyl, acyloxy, amino, C^galkylamino, acy-
`lamino, haloC^galkyl or halogen, Z2 is a single bond or a
`lamino, haloC1-calkyl or halogen, Z2 is a single bond or a
`straight chain alkylene having a number or carbon atoms of q,
`straight chain alkylene having a number or carbon atoms of q,
`5 each of p and q, independently, is an integer of 1 to 20, with
`5
`each of p and q, independently, is an integer of 1 to 20, with
`the proviso of 6<p+q<23, m' is 1, 2 or 3, n is 2 or 3,
`the proviso of 6sp+q=23, m' is 1, 2 or 3, n is 2 or 3,
`eachofR"!, R"2, R"3 and R"4, independently, is H, C^alkyl
`each of R", R", R"s and R"a, independently, is H, Claalkyl
`or acyl,
`or acyl,
`or a pharmaceutically acceptable salt or hydrate thereof,
`or a pharmaceutically acceptable salt or hydrate thereof,
`Compounds as disclosed in WO02/18395, e.g. a compound
`Compounds as disclosed in WOO2/18395, e.g. a compound
`of formula IVa or IVb
`of formula IVa or IVb
`
`10
`10
`
`IVa
`IV a
`
`IVb
`IVb
`
`CH2R3a
`CH2R3a
`R1a
`Rio
`|
`I
`ºs------
`(R2A)2N—C—CH2-XA-P=0
`CH2
`º
`R1b.
`CH2
`CH2
`
`Ru
`
`or
`Or
`
`(CH2)7CH3
`(CH3)3CH3
`
`CH2R3>
`CH2R35
`R1a
`Rla
`I
`(R2.)2N—C—CH2-X0-P=O
`
`CH2
`CH2
`CH2
`CH2
`
`R15
`Rli
`
`15
`15
`
`20
`20
`
`35
`35
`
`II
`II
`
`NR" R"
`NR" IR"2
`Y
`|IN 2
`,Y
`,
`W | Z
`/)
`w—c—z2
`— — 22
`\ }{x
`|
`(CH2V0R"3
`(CH2), OR"3
`55
`wherein W is H; C^alkyl, C2_6alkenyl or C2_6alkynyl; 55
`wherein W is H; C1-calkyl, C2-calkenyl or C2-galkynyl;
`unsubstituted or by OH substituted phenyl; R"40(CH2)n; or
`unsubstituted or by OH substituted phenyl; R",0(CH2), or
`C^galkyl substituted by 1 to 3 substituents selected from the
`C1-calkyl substituted by 1 to 3 substituents selected from the
`group consisting of halogen, Cs scycloalkyl, phenyl and phe
`group consisting of halogen, C3_8cycloalkyl, phenyl and phe­
`nyl substituted by OH;
`nyl substituted by OH:
`X is H or unsubstituted or substituted straight chain alkyl
`X is H or unsubstituted or substituted straight chain alkyl
`having a number p of carbon atoms or unsubstituted or sub­
`having a number p of carbon atoms or unsubstituted or sub
`stituted straight chain alkoxy having a number (p-1) of car­
`stituted straight chain alkoxy having a number (p-1) of car
`bon atoms, e.g. substituted by 1 to 3 substitutents selected
`bon atoms, e.g. substituted by 1 to 3 substitutents selected
`from the group consisting of C1-galkyl, OH, C1-galkoxy, acy
`from the group consisting of C^alkyl, OH, C^alkoxy, acy­
`loxy, amino, C1-calkylamino, acylamino, oxo, haloC1-galkyl,
`loxy, amino, C^galkylamino, acylamino, oxo, haloC^galkyl, 65
`65
`halogen, unsubstituted phenyl and phenyl substituted by 1 to
`halogen, unsubstituted phenyl and phenyl substituted by 1 to
`3 substituents selected from the group consisting of C^alkyl,
`3 substituents selected from the group consisting of C1-calkyl,
`
`CH20R'3
`CH2OR's
`
`RUR'sN —C
`
`(CH2)2-
`
`CH2OR2
`
`o
`O
`•c
`
`(CH2)OT'
`
`\ /
`
`\ / 40 wherein X, is O, S, NR^ or a group —(CH2)„a—, which
`
`40
`
`Ya-R4,
`R40
`wherein X, is O, S, NRIs or a group –(CH2), , which
`group is unsubstituted or substituted by 1 to 4 halogen; na is 1
`group is unsubstituted or substituted by 1 to 4 halogen; n., is 1
`or 2, R^ is H or (C^alkyl, which alkyl is unsubstituted or
`or 2, R1, is H or (Cla)alkyl, which alkyl is unsubstituted or
`whereinmis 1 to 9 andeachofR'2, R^andR'j, independently,
`wherein m is 1 to 9 and each of R'2, R'a and R's, independently,
`substituted by halogen; Rla is H, OH, (C^alkyl or 0(C1_4)
`substituted by halogen; Ria is H, OH, (C-4)alkyl or O(C-4)
`is H, Cj^alkyl or acyl,
`is H, C, calkyl or acyl,
`alkyl wherein alkyl is unsubstituted or substituted by 1 to 3
`alkyl wherein alkyl is unsubstituted or substituted by 1 to 3
`or a pharmaceutically acceptable salt or hydrate thereof;
`45 halogen; R16 is H, OH or (C^alkyl, wherein alkyl is unsub­
`or a pharmaceutically acceptable salt or hydrate thereof;
`halogen; R1, is H, OH or (Cla)alkyl, wherein alkyl is unsub
`45
`stituted or substituted by halogen; each R29 is independently
`stituted or substituted by halogen; each R2, is independently
`Compounds as disclosed in EP0778263 Al, e.g. a com­
`Compounds as disclosed in EP0778.263 A1, e.g. a com
`selected from H or (C^alkyl, which alkyl is unsubstituted or
`selected from Hor(Cla)alkyl, which alkyl is unsubstituted or
`pound of formula III
`pound of formula III
`substituted by halogen; R3a is H, OH, halogen or 0(C1_4)alkyl
`substituted by halogen; Rs, is H, OH, halogen or O(C-4)alkyl
`wherein alkyl is unsubstituted or substituted by halogen; and
`wherein alkyl is unsubstituted or substituted by halogen; and
`Rs, is H, OH, halogen, (Cla)alkyl wherein alkyl is unsubsti
`® ' halogen, (C^^lkyl wherein alkyl is unsubsti­
`tuted or substituted by hydroxy, or 0(C1 _4)alkyl wherein alkyl
`tuted or substituted by hydroxy, or O(Cla)alkyl wherein alkyl
`is unsubstituted or substituted by halogen; Ya is —CH2—,
`is unsubstituted or substituted by halogen; Y, is –CH2—,
`is
`—C(O)—, —CH(OH)—, —C(=NOH)—, O or S, and R
`—C(O)—, -CH(OH)—, -C(=NOH)—, O or S, and Ra, is
`4a
`(C4-1a)alkyl or (C4-1a)alkenyl;
`(C4_14)alkyl or (^.^alkenyl;
`or a pharmaceutically acceptable salt or hydrate thereof;
`or a pharmaceutically acceptable salt or hydrate thereof;
`Compounds as disclosed in W002/06268A1, e.g. a com­
`Compounds as disclosed in WOO2/06268A1, e.g. a com
`pound of formula V
`pound of formula V
`
`III 50
`50
`III
`
`<
`
`/
`
`60
`60
`
`V
`
`NRjAtf
`
`(CH2)„D
`
`n \
`\-/
`
`j!
`
`'S
`
`Yd — R5d
`
`R«
`
`R3dO
`
`wherein each of R! d and R2rf, independently, is H or an amino-
`wherein each of R1a and R2, independently, is Horanamino
`protecting group;
`protecting group;
`
`TEVA EX. 1013
`Page 3
`
`

`

`5
`5
`Rs, is hydrogen, a hydroxy-protecting group or a residue of
`R3rf is hydrogen, a hydroxy-protecting group or a residue of
`formula
`formula
`
`US 8,741,963 B2
`US 8,741,963 B2
`
`6
`6
`
`ORM
`— P 2ORya
`P^"
`|NOR,
`ORsd
`o
`O
`
`5
`
`wherein
`wherein
`Aris phenyl or naphthyl; each of m, and n, independently is
`Ar is phenyl or naphthyl; each of mg and ng independently is
`0 or 1; A is selected from COOH, P03H2, P02H, S03H,
`0 or 1: A is selected from COOH, POAH2, PO,H, SOAH,
`PO(C-3alkyl)0H and 1H-tetrazol-5-yl; each of R, and R2,
`PO(C1_3alkyl)OH and lH-tetrazol-5-yl; each of Rlg and R2g
`independently is H, halogen, OH, COOH or Claalkyl option
`independently is H, halogen, OH, COOH or C^alkyl option­
`ally substituted by halogen; Rae is H or C-alkyl optionally
`ally substituted by halogen; R3g is H or C^alkyl optionally
`substituted by halogen or OH: each Raº independently is
`substituted by halogen or OH; each R^ independently is
`halogen, or optionally halogen substituted Claalkyl or
`halogen, or optionally halogen substituted C^alkyl or
`C1_3alkoxy; and each of Rg and M has one of the significances
`C, salkoxy; and each of R, and Mhas one of the significances
`as indicated for B and C, respectively, in WO03/062252A1;
`as indicated for B and C, respectively, in WOO3/062252A1;
`or a pharmacologically acceptable salt, solvate or hydrate
`or a pharmacologically acceptable salt, solvate or hydrate
`thereof;
`thereof;
`Compounds as disclosed in WO 03/062248A2, e.g. a com­
`Compounds as disclosed in WO 03/062248A2, e.g. a com
`pound of formula VIII
`pound of formula VIII
`
`Raº is C1-4alkyl;
`R^isC^alkyl;
`VLd is an integer of 1 to 6;
`nº is an integer of 1 to 6;
`X, is ethylene, vinylene, ethynylene, a group having a for
`is ethylene, vinylene, ethynylene, a group having a for- J Q
`10
`mula -D-CH2— (wherein D is carbonyl, —CH(OH)—, O, S
`mula -D-CH2—(wherein D is carbonyl, -CH(OH)—, O, S
`or N), aryl or aryl substituted by up to three substitutents
`or N), aryl or aryl substituted by up to three substitutents
`selected from group a as defined hereinafter;
`selected from group a as defined hereinafter;
`Y., is single bond, C1-ioalkylene, C1-ioalkylene which is sub
`Yd is single bond, C^Qalkylene, C^Qalkylene which is sub­
`stituted by up to three substitutents selected from groups a and 15
`stituted by up to three substitutents selected from groupsa and
`15
`b, C^^alkylene having O or S in the middle or end of the
`b, Cl-loalkylene having O or S in the middle or end of the
`carbon chain, or C^^alkylene having O or S in the middle or
`carbon chain, or C1-ioalkylene having O or S in the middle or
`end of the carbon chain which is substituted by up to three
`end of the carbon chain which is substituted by up to three
`substituents selected from groups a and b;
`substituents selected from groups a and b;
`Rs, is hydrogen, C3-acycloalkyl, aryl, heterocyclic group,
`R5rf is hydrogen, C3_6cycloalkyl, aryl, heterocyclic group, 20
`20
`C3_6cycloalkyl substituted by up to three substituents selected
`Cs-acycloalkylsubstituted by up to three substituents selected
`from groups a and b, aryl substituted by up to three substitu­
`from groups a and b, aryl substituted by up to three substitu
`ents selected from groups a and b, or heterocyclic group
`ents selected from groups a and b, or heterocyclic group
`substituted by up to three substituents selected from groups a
`substituted by up to three substituents selected from groups a
`25 wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH,
`wherein Ar is phenyl or naphthyl; n is 2, 3 or 4: A is COOH,
`and b;
`and b;
`25
`lH-tetrazol-5-yl, P03H2, P02H
`S03H or PO(R5/I)OH
`1H-tetrazol-5-yl, POAH2, PO2H2, —SOAH or PO(Rs.)OH
`each of R6rf and R7rf, independently, is H or a substituent
`each of Raº and R2, independently, is H or a substituent
`wherein R5/i is selected from C^alkyl, hydroxyC^alkyl,
`wherein Rs, is selected from Claalkyl, hydroxyCi-aalkyl,
`selected from group a;
`selected from group a?
`phenyl, -CO-C, salkoxy and —CH(OH)-phenyl wherein
`phenyl, —CO—C^alkoxy and —CH(OH)-phenyl wherein
`each of R8rfandR9rf, independently, is H or C^alkyl option-
`each of Rs., and Roº, independently, is H or Claalkyl option
`said phenyl or phenyl moiety is optionally substituted; each of
`said phenyl orphenyl moiety is optionally substituted; each of
`ally substituted by halogen;
`ally substituted by halogen;
`<group a> is halogen, lower alkyl, halogeno lower alkyl, 30 R1A and R2/i independently is H, halogen, OH, COOH, or
`<group a- is halogen, lower alkyl, halogeno lower alkyl,
`R1, and R2, independently is H, halogen, OH, COOH, or
`30
`lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbo
`optionally halogeno substituted C1-calkyl or phenyl; Rs, is H
`lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbo-
`optionally halogeno substituted C^alkyl or phenyl; R3/i is H
`nyl, hydroxy, lower aliphatic acyl, amino, mono-lower alky
`nyl, hydroxy, lower aliphatic acyl, amino, mono-lower alky-
`or C^alkyl optionally substituted by halogen and/OH; each
`or Claalkyl optionally substituted by halogen and/OH; each
`lamino, di-Chalkylamino, acylamino, cyano ornitro; and
`lamino, di-Claalkylamino, acylamino, cyano or nitro; and
`K4h independently is halogeno, OH, COOH, C1 4alkyl,
`Ra?, independently is halogeno, OH, COOH, Claalkyl,
`<group b> is C3_6cycloalkyl, aryl or heterocyclic group, each
`<group b- is C3-acycloalkyl, aryl or heterocyclic group, each
`S(0)o
`S(O)on 2,2C-3alkyl, C-3alkoxy, C3-acycloalkoxy, aryl or
`C1_3alkyl, C1_3alkoxy, C3_6cycloalkoxy, aryl or
`, 1 or2
`being optionally substituted by up to three substituents
`being optionally substituted by up to three substituents 35 gj-gikoxy, wherein the alkyl portions may optionally be sub-
`aralkoxy, wherein the alkyl portions may optionally be sub
`35
`selected from group a;
`selected from group a?
`stituted by 1 -3 halogens; and each of RA and M has one of the
`stituted by 1-3 halogens; and each of R, and M has one of the
`with the