FOR
`(54) SIP RECEPTOR MODULATORS
`TREATING RELASPING-REMITTING
`MULTIPLE SCLEROSIS
`
`WO
`WO
`WO
`
`(71) Applicants:Peter C. Hiestand,
`Austria
`Christian Schnell, Hesingue
`(FR)
`
`(72)
`
`Inventors: Peter C. Hiestand, Austria
`Christian Schnell, Hesingue
`
`(CH);
`(FR)
`
`(73) Assignee: Novartis AG, Basel
`
`(CH)
`
`( * ) Notice:
`
`the
`Subject to any disclaimer,
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0
`days.
`
`(21) Appl.No.: 14/257,342
`
`(22) Filed:
`
`Apr. 21, 2014
`
`(65)
`
`Prior Publication Data
`US 2014/0228446 Al Aug. 14, 2014
`
`Related U.S. Application Data
`(60) Division of application No.
`
`13/149,468, on May
`31, 2011, now Pat. No. 8,741,963, which is a
`filed as
`continuation of application No. 12/303,765,
`application No. PCT/EP2007/005597 on Jun. 25,
`2007, now abandoned.
`
`(30)
`
`Foreign Application Priority
`
`Data
`
`Jun. 27, 2006 (GB)
`
`0612721.1
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(CH);
`Agonism Impairs the
`
`Receptor
`Xie et al., "Sphingosine-1-Phosphate
`Efficiency of
`the
`
`Local Immune Response
`by Altering Trafficking of
`Naive and Antigen-Activated CD + T Cells", J Immunol; vol. 170,pp.
`3662-3670, 2003.
`Budde et al., "First Human Trial of FTY720, a Novel
`Immunomodulator, in Stable Renal Transplant Patients". J Am
`Nephrol, vol. 13, pp.
`
`1073-1083, 2002.
`Kataoka et al.,
`Receptor Modu­
`
`'iTTY720, Sphingosine 1-Phosphate
`term
`of
`this
`lator, Ameliorates Experimental Autoimmune Encephalomyelitis
`Inhibition of T Cell Infiltration", Cellular & Molecular
`Immunology,
`vol. 2, No. 6, pp.
`439-448,
`Dec.
`2005.
`Forrest et al., "Immune
`
`Cell Regulation and Cardiovascular
`of Sphingosine 1-Phosphate
`
`Receptor Agonist in Rodents Are Medi­
`ated via Distinct Receptor
`Subtypes",
`The
`Journal
`work not protected
`and experimental
`therapeutics
`(U.S
`Government
`by U.S. copyright),
`vol.
`309,
`pp.
`758-768,
`Suzuki et al., "An
`immunosuppressive
`regimen
`bined with cyclosporin in canine kidney transplantation", Transpl
`Int., vol. 11, No.
`2,
`pp.
`95-101,
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`Webb et al., "Sphingosine
`1-phosphate receptor agonists attenuate
`relapsing-remitting experimental autoimmune encephalitis in SJL
`
`
`153, vol. No. 1, pp. 108-121
`(2004).
`mice", J. Neuroimmun.,
`a€CE The immune modulator
`BrinkmannV.
`
`. . FTY720 . &ۥ Jour-
`
`filed
`nal of Biol. Chemistry, Americ. Society of Biolochem. Biol. vol. 277,
`No. 24. pp. 21453-21457.
`Miller et al., Neurol. & Neurosci. Reports, (Sep. 2010), 10(5), pp.
`397-406.
`Hla, T., FASEB
`6, 20(4), Part 1, A20. 2006),
`
`
`(Mar.
`Journal,
`Maschkowskij M.D. Pharmaceuticals, Moscow, Nowaja Wolna,
`vol.
`1
`p.
`11.
`2001, in 2 volumes,
`LaMontagne K. a€z Antagonism of Sphingosine-l-Phosphate
`Receptors by FTY720 Inhibits Angiogenesis . .
`. a€cE Cancer
`
`66, 221-231. Found on: URL:http://cancerres.
`Research, Jan. 2006,
`aacrjournals.org/content/66/1/221 .till.
`(51) Int. CI.
`Hla. T. Physiological and pathological actions of sphingosine 1-phos-
`A6IK 31/13
`phatea€ Seminars in Cell & Developmental Biology, Oct. 2004,
`C07C 215/08
`15(5), 513-520.
`A6 IK 31/137
`KapposL et al. a€z FTY720 in relapsing MS ... a€(£ Jun. 23,2005
`
`A61K 31/397
`online (found Jun. 2, 2011) URL:http://www.ms-in-europe.com/
`(52) U.S. CI.
`printversion/index .php? anr= 105 &cnr=4/>.
`C07C215/08
`(2013.01); A61K31/137
`CPC
`(Continued)
`(2013.01); A61K31/397
`31/13
`A61K
`(2013.01);
`(2013.01)
`Primary Examiner — Kevin
`E Weddington
`(74) Attorney, Agent, or Firm — Jim
`Lynch
`
`US009187405B2
`
`Illlllllll
`
`(12) United States Patent
`Hiestand et al.
`
`US 9,187,405 B2
`(10) Patent No.:
`(45) Date of Patent:
`Nov. 17, 2015
`
`2006/055809
`5/2006
`2006/058316
`6/2006
`2006/066086
`6/2006
`OTHER PUBLICATIONS
`
`by
`
`Effects
`
`2004.
`using
`
`of
`
`FTY720
`
`Search
`(58) Field of Classification
`CPC
`A61K 31/13; A61K 31/137
`514/667, 903
`USPC
`search
`See application
`
`file for
`
`complete
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2006/0046979 Al
`2014/0228446 Al
`
`3/2006 Hiestand
`8/2014 Hiestand et al.
`
`FOREIGN PATENT DOCUMENTS
`
`RU
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`
`2199339 C2
`2278687 CI
`03/097028
`03/099192
`2004/028521
`2004/050073
`2004/113330
`2005123104 A2
`
`2/2003
`6/2006
`11/2003
`12/2003
`4/2004
`6/2004
`12/2004
`12/2005
`
`ABSTRACT
`(57)
`history.
`of receptor modu­an
`
`
`uses
`invention
`relates
`The present
`lator such as 2-substituted 2-amino-propane-l,3-diol or
`2-amino-propanol derivatives, e. g. a compound comprising a
`group of formula X
`
`SIP
`
`(X)
`
`'CH2R1Z.
`
`for the treatment or prevention of neo-angiogenesis associ­
`ated with a demyelinating
`disease,
`e.g.
`multiple
`
`sclerosis.
`
`6 Claims, No Drawings
`
`APOTEX - EXHIBIT 1001
`
`

`

`US 9,187,405 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Ho J.W et al. a€z Effects of a novel immunomodulating agent . . .
`a€ce Molecular cancer theraputics, 2005 Set, 4(9), 1430-1438.
`Found: http://mct.aacrjournals.org/content/4/9/1430.full.pdf+html.
`Virely D.J. a€(E Developing therapeutics for the treatment of mul-
`tiple sclerosis. §.€• Journal of American Society for Experimental
`Neuro Therapeutics. Oct. 2005, 2, 638-649. Found on: http://pubget.
`com/paper/16489371.
`Fujino et al. a€ Amelioration of experimental autoimmune
`encephalomyelitis . .
`. a€™ The Journal of Pharmacology and
`Experimental Therapeutics, vol. 305, No. 1, pp. 70-77.
`
`K. Rammohan et al, Poster on a€ Long-Term Safety of Fingolimod
`in Patients with Relapsing-Remitting Multiple Sclerosis: Results
`from Phase 3 FREEDOMS II Extension Studya€™ Mar. 16-23,
`2013, San Diego, US, 65th American Academy ofNeurology Annual
`Meeting.
`Ludwik Kappos et Al: "A place controlled trial of oral Fingolimod in
`relapsing multiple sclerosis", New England Journal of Medecine,
`Boston, MA , USA, vol. 362, No. 5, Feb. 4, 2010, pp. 387-401.
`Thompson A., 'iTTY720 inmultiple sclerosis: the emerging evidence
`ofits therapeutic value", Core Evidence, 2006, No. 1,3, pp. 157-167.
`T.E. Schmidt et al., Multiple Sclerosis, Guide for Physicians, 2nd
`edition—M., MED press-inform 2010, pp. 15-16 (English Transla­
`tion).
`
`

`

`US 9,187,405 B2
`
`1
`SIP RECEPTOR MODULATORS FOR
`TREATING RELASPING-REMITTING
`MULTIPLE SCLEROSIS
`
`The present invention relates to the use of an S1P receptor 5
`modulator in the treatment or prevention of neo-angiogenesis
`associated with a demyelinating disease, e.g. multiple scle­
`rosis.
`SI P receptor modulators are typically sphingosine ana­
`logues, such as 2-substituted 2-amino-propane-l,3-diol or
`2-amino-propanol derivatives, e. g. a compound comprising a
`group of formula X.
`Sphingosine-1 phosphate (hereinafter "SIP") is a natural
`serum lipid. Presently there are eight known SIP receptors,
`namely SI PI to SI P8. SI Preceptor modulators are typically
`sphingosine analogues, such as 2-substituted 2-amino-pro-
`pane-l,3-diol or 2-amino-propanol derivatives, e. g. a com­
`pound comprising a group of formula X
`
`15
`
`2
`bly expressing the appropriate human SIP receptor. The
`assay technology used is SPA (scintillation proximity based
`assay). Briefly, DMSO dissolved compounds are serially
`diluted and added to SPA-bead (Amersham-Pharmacia)
`immobilised SIP receptor expressing membrane protein (10-
`20 (xg/well) in the presence of 50 mM Hepes, 100 mM NaCl,
`10 mM MgCl2, 10 nM GDP, 0.1% fat free BSA and 0.2 nM
`GTP [Y-35S] (1200 Ci/mmol). After incubation in 96 well
`microtiterplates at RT for 120 min, unbound GTP [Y-35S] is
`10 separated by a centrifugation step. Luminescence of SPA
`beads triggered by membrane bound GTP [Y-35S] is quanti­
`fied with a TOPcount plate reader (Packard). EC50s are cal­
`culated using standard curve fitting software. In this assay, the
`SIP receptor modulators preferably have a binding affinity to
`SIP receptor <50 nM.
`Preferred SIP receptor modulators are e.g. compounds
`which in addition to their SIP binding properties also have
`accelerating lymphocyte homing properties, e.g. compounds
`which elicit a lymphopenia resulting from a re-distribution,
`preferably reversible, of lymphocytes from circulation to sec­
`ondary lymphatic tissue, without evoking a generalized
`immunosuppression. Nave cells are sequestered; CD4 and
`CDS T-cells and B-cells from the blood are stimulated to
`25 migrate into lymph nodes (LN) and Peyer's patches (PP).
`The lymphocyte homing property may be measured in
`following Blood Lymphocyte Depletion assay:
`wherein Z is H, C1.6alkyl, C2_6alkenyl, C2_6alkynyl, phenyl,
`A SIP receptor modulator or the vehicle is administered
`phenyl substituted by OH, C^alkyl substituted by 1 to 3
`orally by gavage to rats. Tail blood for hematological moni-
`substituents selected from the group consisting of halogen, 30 toring is obtained on day -1 to give the baseline individual
`values, and at 2, 6, 24, 48 and 72 hours after application. In
`C3_8cycloalkyl, phenyl and phenyl substituted by OH, or
`is OH, acyloxy or a residue of
`CH2—wherein
`this assay, the SIP receptor agonist or modulator depletes
`formula (a)
`peripheral blood lymphocytes, e.g. by 50%, when adminis­
`tered at a dose of e.g. <20 mg/kg.
`Examples of appropriate SIP receptor modulators are, for
`example:
`Compounds as disclosed in EP627406A1, e.g. a compound
`of formula I
`
`20
`
`(X)
`
`35
`
`(a)
`
`R3ZR2ZN'
`
`'CH2R1Z
`
`•ORsz
`
`'ORsz
`
`z,—p;
`
`o
`
`40
`
`45
`
`wherein Z1 is a direct bond or O, preferably O;
`each of R5z, and R6Z, independently, is H, or C^alkyl option­
`ally substituted by 1, 2 or 3 halogen atoms;
`RLZ is OH, acyloxy or a residue of formula (a); and each of R
`2z
`and R3z independently, is H, C^alkyl or acyl.
`Group of formula X is a functional group attached as a
`terminal group to a moiety which may be hydrophilic or
`lipophilic and comprise one or more aliphatic, alicyclic, aro­
`matic and/or heterocyclic residues, to the extent that the
`resulting molecule wherein at least one of Z and Rlz is or 50
`comprises a residue of formula (a), signals as an agonist at one
`of more sphingosine-1-phosphate receptor.
`SIP receptor modulators are compounds which signal as
`agonists at one or more sphingosine-1 phosphate receptors,
`e.g. SI PI to S1P8. Agonist binding to a SIP receptor may e.g. 55
`result in dissociation of intracellular heterotrimeric G-pro-
`teins into Ga-GTP and GfSy-GTP, and/or increased phospho­
`rylation of the agonist-occupied receptor and activation of
`downstream signaling pathways/kinases.
`The binding affinity of SIP receptor modulators to indi- 60
`vidual human SIP receptors may be determined in following
`assay:
`SIP receptor modulator activities of compounds are tested
`on the human SIP receptors SIP^ S1P2, S1P3, SIP4 and
`S1P5. Functional receptor activation is assessed by quantify- 65
`ing compound induced GTP [Y-35S] binding to membrane
`protein prepared from transfected CHO or RH7777 cells sta-
`
`CH2OR3
`
`R4R5N
`
`'CH2OR2
`
`Ri
`
`I
`
`wherein Rj is a straight- or branched (C
`2) chain
`12-2
`which may have in the chain a bond or a hetero atom
`selected from a double bond, a triple bond, O, S, NR6,
`wherein R6 is H, C^alkyl, aryl-C^alkyl, acyl or (C
`1-4
`alkoxy)carbonyl, and carbonyl, and/or
`whichmay have as a substituent C^alkoxy, C^alkeny-
`acyl,
`loxy, C2_4alkynyloxy, arylC^alkyl-oxy,
`C^alkylamino, acylamino, (C1_4alkoxy)carbonyl,
`(C1_4alkoxy)-carbonylamino, acyloxy, (C^alkyl)
`carbamoyl, nitro, halogen, amino, hydroxyimino,
`hydroxy or carboxy; or
`
`R! is
`a phenylalkyl wherein alkyl is a straight- or branched
`(C6_2o)carbon chain; or
`a phenylalkyl wherein alkyl is a straight- or branched
`(Ci_3o)carbon chain wherein said phenylalkyl is substi­
`tuted by
`a straight- or branched (C6_20)carbon chain optionally sub­
`stituted by halogen,
`a straight- or branched (C6_20)alkoxy chain optionally sub-
`stitued by halogen,
`
`

`

`US 9,187,405 B2
`
`5
`
`10
`
`alkyl or
`
`20
`
`3
`a straight- or branched (C6_20)alkenyloxy,
`phenyl-Cj^alkoxy, halophenyl-C^alkoxy, phenyl-C
`1-14
`alkoxy-C^^alkyl, phenoxy-C1_4alkoxy or phenoxy-
`Ci.4 alkyl,
`cycloalkylalkyl substituted by C6_20alkyl,
`heteroarylalkyl substituted by C6_20alkyl,
`heterocyclic C6_20alkyl or
`heterocyclic alkyl substituted by C2_20alkyl,
`and wherein
`the alkyl moiety may have
`in the carbon chain, a bond or a heteroatom selected from
`a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or
`NR6, wherein R6 is as defined above, and
`as a substituent C^alkoxy, C^alkenyloxy, C^alkyny-
`loxy, arylC^alkyloxy, acyl, C^alkylamino, Chalky- 15
`Ithio, acylamino, (C1_4alkoxy)carbonyl, (C1_4alkoxy)
`carbonylamino, acyloxy, (C^alky^carbamoyl, nitro,
`halogen, amino, hydroxy or carboxy, and
`each of R2, R3, R4 and R5, independently, is H,
`acyl
`or a pharmaceutically acceptable salt or hydrate thereof;
`Compounds as disclosed in EP 1002792A1, e.g. a com­
`pound of formula II
`
`25
`
`II
`
`R^R'sN
`
`CH2OR3
`I
`C
`I CH2OR2
`
`(CH2)2
`
`\ /
`
`o
`
`•C
`
`(CH2)OT'
`
`\ / 30
`
`wherein m is 1 to 9 and each of R'2, R'3, R'4 and R'5, indepen­
`dently, is H, Cj^alkyl or acyl,
`or a pharmaceutically acceptable salt or hydrate thereof;
`Compounds as disclosed in EP0778263 Al, e.g. a com-
`pound of formula III
`
`35
`
`W — C — Z2' v r-x
`
`NR'^R'^
`
`(CH2)M.OR"3
`
`m
`
`,Y
`/)
`
`wherein W is H; C^alkyl, C2_6alkenyl or C
`alkynyl;
`2-6
`unsubstituted or by OH substituted phenyl; R"40(CH2)„;
`orC^galkyl substituted by 1 to 3 substituents selected from
`the group consisting of halogen, C3_8cycloalkyl, phenyl 50
`and phenyl substituted by OH;
`X is H or unsubstituted or substituted straight chain alkyl
`having a number p of carbon atoms or unsubstituted or
`substituted straight chain alkoxy having a number (p-1) of
`carbon atoms, e.g. substituted by 1 to 3 substitutents 55
`selected from the group consisting of C^alkyl, OH,
`Q.galkoxy, acyloxy, amino, C^galkylamino, acylamino,
`oxo, haloC^galkyl, halogen, unsubstituted phenyl and phe­
`nyl substituted by 1 to 3 substituents selected from the
`group consisting of C1.6alkyl, OH, C^alkoxy, acyl, acy- 60
`loxy, amino, C^galkylamino, acylamino, haloC^galkyl
`and halogen; Y is H, OH, C^alkoxy, acyl, acyloxy, amino,
`C^galkylamino, acylamino, haloC^galkyl or halogen, Z2
`is a single bond or a straight chain alkylene having a num­
`ber or carbon atoms of q,
`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,
`
`65
`
`4
`each ofR'1!, R"2, R"3 and R"4, independently, is H, C1_4alkyl
`or acyl,
`or a pharmaceutically acceptable salt or hydrate thereof,
`Compounds as disclosed in WO02/18395, e.g. a compound
`of formula IVa or IVb
`
`IVa
`
`IVb
`
`CH2R3A
`Rio
`I
`(R2J2N—C—CH2—X,,—P=0
`CH2
`CH2
`
`Ru
`
`or
`
`(CH2)7CH3
`
`CH2R3,,
`(R2O)2N — C — CH2—XA
`CH2
`CH2
`
`Rio
`I
`P = 0
`
`Ru
`
`Yo R40
`
`wherein Xa is O, S, NRla or a group —(CH2)„a—, which
`group is unsubstituted or substituted by 1 to 4 halogen; na
`is 1 or 2, Rla is H or (C^alkyl, which alkyl is unsubsti­
`tuted or substituted by halogen; Rla is H, OH, (C^alkyl
`or 0(C1_4)alkyl wherein alkyl is unsubstituted or substi­
`tuted by 1 to 3 halogen; R16 is H, OH or (C^alkyl,
`wherein alkyl is unsubstituted or substituted by halogen;
`each R2a is independently selected from H or (C^alkyl,
`which alkyl is unsubstituted or substituted by halogen; R3a
`is H, OH, halogen or 0(C1_4)alkyl wherein alkyl is unsub­
`stituted or substituted by halogen; and R36 is H, OH, halo­
`gen, (C1_4)alkyl wherein alkyl is unsubstituted or substi­
`tuted by hydroxy, or 0(C1_4)alkyl wherein alkyl is
`unsubstituted or substituted by halogen; Ya is —CH2—,
`—C(0)—, — CH(OH)—, —C(=NOH)—, O or S, and
`R4* is (C4_14)alkyl or (Q^^alkenyl;
`or a pharmaceutically acceptable salt or hydrate thereof;
`Compounds as disclosed in W002/06268AI, e.g. a com­
`pound of formula V
`
`Red
`
`-x-X
`NRiArf
`B
`\\
`(CH2)„D—jj-
`"u—XD — YD—R5D
`
`R-Td
`
`s
`
`Rtd
`
`R3DO'
`
`V
`
`wherein each of R! d and R2rf, independently, is H or an amino-
`protecting group;
`
`

`

`5
`R3rf is hydrogen, a hydroxy-protecting group or a residue of
`formula
`
`US 9,187,405 B2
`
`ORM
`
`'0R8d
`
`O
`
`5
`
`^(CH2)„g
`
`6
`
`R3g
`
`N'
`
`(CH2)MG
`
`Rig
`
`VII
`
`(R4g)o-4
`/
`'AT
`
`•RG-M
`
`10
`
`20
`
`30
`
`35
`
`40
`
`R^isC^^lkyl;
`VLd is an integer of 1 to 6;
`is ethylene, vinylene, ethynylene, a group having a for­
`mula -D-CH2— (wherein D is carbonyl, —CH(OH)—, O,
`S or N), aryl or aryl substituted by up to three substitutents 15
`selected from group a as defined hereinafter;
`Yd is single bond, C1.10alkylene, C1.10alkylene which is sub­
`stituted by up to three substitutents selected from groups a
`and b, C1.10alkylene having O or S in the middle or end of
`the carbon chain, or C1.10alkylene having O or S in the
`middle or end of the carbon chain which is substituted by
`up to three substituents selected from groups a and b;
`R5rf is hydrogen, C3_6cycloalkyl, aryl, heterocyclic group,
`C3_6cycloalkyl substituted by up to three substituents 25
`selected from groups a and b, aryl substituted by up to three
`substituents selected from groups a and b, or heterocyclic
`group substituted by up to three substituents selected from
`groups a and b;
`each of R6rf and R7rf, independently, is H or a substituent
`selected from group a;
`each of R8rfandR9rf, independently, is H or Chalky 1 option­
`ally substituted by halogen;
`<group a> is halogen, lower alkyl, halogeno lower alkyl,
`lower alkoxy, lower alkylthio, carboxyl, lower alkoxycar-
`bonyl, hydroxy, lower aliphatic acyl, amino, mono-lower
`alkylamino, di-Chalkylamino, acylamino, cyano ornitro;
`and
`<group b> is C3_6cycloalkyl, aryl or heterocyclic group, each
`being optionally substituted by up to three substituents
`selected from group a;
`with the proviso that when R5rf is hydrogen, Yd is a either a 45
`single bond or linear C^Q alkylene, or a pharmacologi­
`cally acceptable salt, ester or hydrate thereof;
`Compounds
`as
`disclosed
`in
`JP-14316985
`(JP2002316985), e.g. a compound of formula VI
`
`Xg Yg
`
`VI
`
`R5<
`
`NRLER2( rvs
`
`R6«
`
`(CH2)„e-n-
`
`I
`
`R7<
`
`Rt,
`
`RseO'
`
`s
`
`wherein Rle, R2e, R3e, R4e, R5e, R6e, R7e, ne, Xe andYe are as
`disclosed in JP-14316985;
`or a pharmacologically acceptable salt, ester or hydrate
`thereof;
`Compounds as disclosed in WO03/062252A1, e.g. a com­
`pound of formula VII
`
`50
`
`55
`
`60
`
`65
`
`wherein
`Ar is phenyl or naphthyl; each of mg and ng independently is
`0 or 1; A is selected from COOH, P03H2, P02H, S03H,
`PO(C1_3alkyl)OH and lH-tetrazol-5-yl; each of Rlg and
`R^„ independently is H, halogen, OH, COOH or C^alkyl
`2g
`optionally substituted by halogen; R3g is H or C^alkyl
`optionally substituted by halogen or OH; each R4g inde­
`pendently is halogen, or optionally halogen substituted
`C^alkyl or C1_3alkoxy; and each of Rg and M has one of
`the significances as indicated for B and C, respectively, in
`WO03/062252A1;
`or a pharmacologically acceptable salt, solvate or hydrate
`thereof;
`Compounds as disclosed in WO 03/062248A2, e.g. a com­
`pound of formula VIII
`
`VIII
`
`R34
`
`(R4A)o-4
`/
`'AT
`
`RJ—M
`
`Rli
`
`A—
`
`R24
`
`wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH,
`lH-tetrazol-5-yl, P03H2, P02H2, —S03H or PO(R5/I)OH
`wherein R5/i is selected from C^alkyl, hydroxyC^alkyl,
`phenyl, —CO—C1_3alkoxy and —CH(OH)-phenyl
`wherein said phenyl or phenyl moiety is optionally substi­
`tuted; each of R1A and R2/i independently is H, halogen,
`OH, COOH, or optionally halogeno substituted C^alkyl
`or phenyl; R3/i is H or C^alkyl optionally substituted by
`halogen and/OH; each R^ independently is halogeno, OH,
`COOH, S(O)0j ! or 2C1_3alkyl, C^alkoxy, C3_6cy-
`cloalkoxy, aryl or aralkoxy, wherein the alkyl portions may
`optionally be substituted by 1-3 halogens; and each of RA
`and M has one of the significances as indicated for B and C,
`respectively, in WO03/062248A2
`or a pharmacologically acceptable salt, solvate or hydrate
`thereof.
`Compounds as disclosed in WO 04/103306A, WO
`05/000833, WO 05/103309 or WO 05/113330, e.g. com-
`pounds of formula IXa or IXb
`
`Rlir X
`
`Aj:
`
`Zj-
`
`RSJ:
`
`Y*
`
`Rlir Y
`
`IXa
`
`Rlir
`
`NH
`\
`O—W
`
`

`

`Rlir
`
`A
`
`.OH
`"^NHj
`
`K-it
`
`US 9,187,405 B2
`
`IXb
`
`15
`
`QH
`
`HQ
`
`H2N
`
`•HC1
`
`7
`-continued
`
`R-Sir
`
`A/f
`
`Z*
`
`wt
`
`R4J: X
`
`8
`Preferably each of R2 to R5 is H.
`In the above formula of V "heterocyclic group" represents
`a 5 - to 7 membered heterocyclic group having 1 to 3 heteroa-
`toms selected from S, O and N. Examples of such heterocy-
`5 clic groups include the heteroaryl groups indicated above,
`and heterocyclic compounds corresponding to partially or
`completely hydrogenated heteroaryl groups, e.g. furyl, thie-
`wherein
`nyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isox-
`azolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl,
`Ai is COOR5i, OPO(OR5i)2, PO(OR5i)2, S020R5i,
`tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrim-
`POR5i;OR5i;or lH-tetrazol-5-yl, R5i;being H orC^galkyl; JQ
`idinyl, pyrazinyl, tetrahydropyranyl, morpholinyl, thiomor-
`WJ. is a bond, Cj^alkylene or C2_3alkenylene;
`pholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidi-
`Yk is C6_10aryl or C3_9heteroaryl, optionally substituted by 1
`nyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,
`to 3 radicals selected from halogen, OH, N02, C^galkoxy;
`thiazolidinyl or pyrazolidinyl. Preferred heterocyclic groups
`halo-substituted C^alkyl
`and
`halo-substituted
`are 5- or 6-membered heteroaryl groups and the most pre­
`C^galkoxy;
`ferred heterocyclic group is a morpholinyl, thiomorpholinyl
`Zk is a heterocyclic group as indicated in WO 04/103306A,
`or piperidinyl group.
`e.g. azetidine;
`A preferred compound of formula I is 2-amino-2-tetrade-
`cyl-l,3-propanediol. A particularly preferred SIP receptor
`Rli; is C6_10aryl or C3_9heteroaryl, optionally substituted by
`agonist of formula I is FTY720, i.e. 2-amino-2-[2-(4-oc-
`C^galkyl, C6_10aryl, Cg.^aiylC^^lkyl, C3_9heteroaryl,
`C3 8cy- 20 tylphenyl)ethyl]propane-l,3-diolinfreeformorinapharma-
`C3_9heteroarylC1_4alkyl,
`C3_8cycloalkyl,
`ceutically acceptable salt form (referred to hereinafter as
`cloalkylC1_4alkyl, C3_8heterocycloalkyl or C3_8heterocy-
`Compound A), e.g. the hydrochloride salt, as shown:
`cloalkylCj^alkyl; wherein any aryl, heteroaryl, cycloalkyl
`or heterocycloalkyl of Rli; may be substituted by 1 to 5
`groups selected from halogen, C1.6alkyl, C^galkoxy and
`halo substituted-C^galkyl or -C^alkoxy;
`R2i; is H, C1.6alkyl, halo substituted C1.6alkyl, C2_6alkenyl or
`C2_6alkynyl: and
`each of R3i; or R4i;, independently, is H, halogen, OH,
`C^.galkyl, C^galkoxy or halo substituted C^galkyl or 30
`C^galkoxy;
`A preferred compound of formula II is the one wherein
`and the N-oxide derivatives thereof or prodrugs thereof,
`each of R'2 to R'5 is H and m is 4, i.e. 2-amino-2-{2-[4-(l-
`or a pharmacologically acceptable salt, solvate or hydrate
`oxo-5-phenylpentyl)phenyl]ethyl}propane-l,3-diol, in free
`thereof.
`form or in pharmaceutically acceptable salt form (referred to
`The compounds of formulae I to IXb may exist in free or 35 hereinafter as Compound B), e.g. the hydrochloride,
`A preferred compound of formula III is the one wherein W
`salt form. Examples of pharmaceutically acceptable salts of
`the compounds of the formulae I to VI include salts with
`is CH3, each of R" l to R"3 is H, Z2 is ethylene, X is heptyloxy
`and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-
`inorganic acids, such as hydrochloride, hydrobromide and
`butanol, in free form or in pharmaceutically acceptable salt
`sulfate, salts with organic acids, such as acetate, fumarate,
`maleate, benzoate, citrate, malate, methanesulfonate andben- 40 form (referred to hereinafter as Compound C), e.g. the hydro-
`chloride. The R-enantiomer is particularly preferred.
`zenesulfonate salts, or, when appropriate, salts with metals
`Compounds may be in phosphorylated form. A preferred
`such as sodium, potassium, calcium and aluminium, salts
`compound of formula IVa is the FTY720-phosphate (R2a is
`with amines, such as triethylamine and salts with dibasic
`H, R3a is OH, Xa is O, Rla and R16 are OH). A preferred
`amino acids, such as lysine. The compounds and salts of the
`combination of the present invention encompass hydrate and 45 compound of formula IVb is the Compound C-phosphate
`(R2a is H, R36 is OH, Xa is O, Rla andR16 areOH,Ya is O and
`solvate forms.
`Acyl as indicated above may be a residue —CO—
`R^ is heptyl). A preferred compound of formula V is Com­
`pound B-phosphate.
`wherein Rj, is C^alkyl, C3_6cycloalkyl, phenyl or phenyl-
`A preferred compound of formula VI is (2R)-2-amino-4-
`Cj^ alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or
`alkynyl may be straight or branched.
`50 [3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbu-
`Aryl may be phenyl or naphthyl, preferably phenyl.
`tan-l-ol.
`A preferred compound of formula IXa is e.g. l-{4-[l-(4-
`When in the compounds of formula I the carbon chain as R!
`cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl] -2-
`is substituted, it is preferably substituted by halogen, nitro,
`ethyl-benzyl}-azetidine-3-carboxylic acid, or a prodrug
`amino, hydroxy or carboxy. When the carbon chain is inter­
`rupted by an optionally substituted phenylene, the carbon 55 thereof,
`SIP receptor agonists or modulators are known as having
`chain is preferably unsubstituted. When the phenylene moi­
`immunosuppressive properties or anti-angiogenic properties
`ety is substituted, it is preferably substituted by halogen,
`in the treatment of tumors, e.g. as disclosed in EP627406A1,
`nitro, amino, methoxy, hydroxy or carboxy.
`Preferred compounds of formula I are those wherein R! is
`WO 04/103306, WO 05/000833, WO 05/103309, WO
`alkyl, optionally substituted by nitro, halogen, amino, 60 05/113330 or WO 03/097028.
`Ci 3-20
`hydroxy or carboxy, and, more preferably those wherein Rj is
`Multiple sclerosis (MS) is an immune-mediated disease of
`phenylalkyl substituted by Cg.^-alkyl chain optionally sub­
`the central nervous system with chronic inflammatory demy-
`stituted by halogen and the alkyl moiety is a C^alkyl option­
`elination leading to progressive decline of motor and sensory
`ally substituted by hydroxy. More preferably, R! is phenyl-
`functions and permanent disability. The therapy of multiple
`C^galkyl substituted on the phenyl by a straight or branched, 65 sclerosis is only partially effective, and in most cases only
`preferably straight, Cg.^alkyl chain. The Cg.^alkyl chain
`offers a short delay in disease progression despite anti-in­
`may be in ortho, meta or para, preferably in para.
`flammatory and immunosuppressive treatment. Accordingly,
`
`

`

`5
`
`15
`
`US 9,187,405 B2
`
`10
`9
`and often resolve over 1 -2 months. Some patients accrue
`there is a need for agents which are effective in the inhibition
`ortreatment of demyelinating diseases, e.g. multiple sclerosis
`disability with each episode, yet remain clinically stable
`or Guillain-Barre syndrome, including reduction of, allevia­
`between relapses. About 85% of patients initially expe­
`tion of, stabilization of or relief from the symptoms which
`rience the RR form of MS, but within 10 years about half
`affect the oiganism.
`will develop the secondary progressive form.
`Characteristic pathological features of demyelinating dis­
`Secondary-progressive (SP-MS): Initially RR followed by
`eases include inflammation, demyelination and axonal and
`gradually increasing disability, with or without relapses.
`oligodendrocyte loss. In addition lesions can also have a
`Major irreversible disabilities appear most often during
`significant vascular component. A firm link has recently been
`SP.
`established between chronic inflammation and angiogenesis 10
`Primary-progressive (PP-MS): Progression disease course
`and neovascularization seems to have a significant role in the
`from onset without any relapses or remissions, affecting
`progression of disease.
`about 15% of MS patients.
`It has now been found that SIP receptor modulators have
`Progressive-relapsing (PR-MS): Progressive disease from
`an inhibitory effect on neo-angiogenesis associated with
`onset with clear acute relapses; periods between relapses
`demyelinating diseases, e.g. MS.
`characterized by continuing progression.
`In a series of further specific or alternative embodiments,
`Accordingly, the SIP receptor modulators, e.g. a com­
`the present invention provides:
`pound of formulae I to IXb as defined hereinabove, may be
`1.1. A method for preventing, inhibiting or treating neo-
`useful in the treatment of one or more of Relapsing-remitting
`angiogenesis associated with a demyelinating disease,
`e.g. MS, in a subject in need thereof, comprising admin- 20 (RR-MS), Secondary-progressive (SP-MS), Primary-pro­
`gressive (PP-MS) and Progressive-relapsing (PR-MS).
`istering to said subject a therapeutically effective
`amount of an SIP receptor modulator, e.g. a compound
`In particular, the SIP receptor modulators as described
`of formulae I to IXb.
`herein, e.g. FTY720, i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]
`1.2. A method for alleviating or delaying progression of the
`propane-l,3-dio, are useful for treating PP-MS.
`symptoms of a demyelinating disease, e.g. multiple scle- 25
`Utility of the SIP receptor modulators, e.g. the SIP recep­
`rosis or Guillain-Barre syndrome, in a subject in need
`tor modulators comprising a group of formula X, in prevent­
`thereof, in which method neo-angiogenesis associated
`ing or treating neo-angiogenesis associated with a demyeli­
`with said disease is prevented or inhibited, comprising
`nating disease as hereinabove specified, may be demonstrated
`administering to said subject a therapeutically effective
`in animal test methods as well as in clinic, for example in
`amount of an SIP receptor modulator, e.g. a compound 30
`accordance with the methods hereinafter described.
`of formulae I to IXb.
`1.3. A method for reducing or preventing or alleviating
`relapses in a demyelinating disease, e.g. multiple scle­
`rosis or Guillain-Barre syndrome, in a subject in need
`thereof, in which method neo-angiogenesis associated 35
`Disease is induced in female Lewis rats by immunization
`with said disease is prevented or inhibited, comprising
`with guinea pig spinal cord tissue emulsified in complete
`administering to said subject a therapeutically effective
`Freund's adjuvant. This results in an acute disease within 11
`amount of an SIP receptor modulator, e.g. a compound
`days, followed by an almost complete remission around day
`of formulae I to IXb.
`1.4. A method for slowing progression of a demyelinating 40 ^
`a relaPse at around days 26.
`On day 26 rats are thoracectomized after having been
`disease, e.g. multiple sclerosis or Guillain-Barre syn­
`deeply anesthetized with Isoflurane (3%, 20 L/min) and per­
`drome, in a subject being in a relapsing-remitting phase
`fused through the left ventricle of the heart. The left ventricle
`of the disease, in which method neo-angiogenesis asso­
`is punctured with a 19 gauge needle from a winged infusion
`ciated with said disease is prevented or inhibited, com­
`prising administering to said subject a therapeutically 45 set (SV-19BLK; Termudo, Elkton, Md.), which is connected
`to an airtight pressurized syringe containing the rinsing solu­
`effective amount of an SIP receptor modulator, e.g. a
`compound of formulae I to Xlb.
`tion (NaCl 0.9% with 250,000 U/I heparin at 35° C.). The
`1.5. A method as indicated above, wherein the SIP receptor
`right atrium is punctured to provide outflow, and the perfusate
`modulator is administered intermittently.
`is infused under a precise controlled pressure of 120 mm Hg.
`For example, the SIP receptor modulator may be admin- 50 The perfusion is continued for 5 min (at a constant rate of 20
`istered to the subject every 2"^ or JT* day or once a week.
`ml/min) followed by a pre-fixation solution (2% performal-
`2. A pharmaceutical composition for use in any one of the
`dehyde in PBS at 35° C.). Finally, up to 30 ml of polyurethane
`methods 1.1 to 1.5, comprising an SIP receptor modu­
`resin (PUII4; Vasqtec, Zurich, Switzerland) is infused at the
`lator, e.g. a compound of formulae I to IXb as defined
`same rate. After 48 h, the resin-filled brain and spinal cord are
`hereinabove, together with one or more pharmaceuti- 55
`excised from the animal and the soft tissue removed by mac­
`cally acceptable diluents or carriers therefor.
`eration in 7.5% KOH during 24 hr at 50° C. The casts are then
`3. An SIP receptor modulator, e.g. a compound of formula
`thoroughly cleaned with and stored in distilled water before
`I to IXb as defined herein above, for use in any one of the
`drying by lyophilization. These vascular casts are quantitated
`methods 1.1 to 1.5.
`using micro computer tomography.
`4. An SIP receptor modulator, e.g. a compound of formu- 60
`In this assay, a S1P1 receptor modulator, e.g. Compound A
`lae I to IXb