`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`MP
`
`(43) International Publication Date
`1 June 2006 (01.06.2006)
`
`PCT
`
`(10) International Publication Number
`WO 2006/058316 A1
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, EI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, IP, 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, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`
`SK, SL, SM, SY, TI, TM, TN, TR, TT, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(51) International Patent Classification:
`A61K31/135 (2006.01)
`A61P 37/06 (2006.01)
`
`(21) International Application Number:
`PCT/US2005/043044
`
`(22) International Filing Date:
`28 November 2005 (28.11.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/631,483
`
`29 November 2004 (29.11.2004) US
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available)•. ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`TM),
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TI,
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, EI,
`ER, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BE, BI, CE, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant (for all designated States except US): NOVAR-
`TIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel
`
`(CH).
`
`(71) Applicant (for AT only)-. NOVARTIS PHARMA GmbH
`[AT/AT]; Brunner Strasse 59, A-1230 Vienna (AT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KOVARIK, John,
`M. [US/CH]; Kraftstrasse 10, CH-4056 Basel (CH). AP-
`PEL-DINGEMANSE, Silke [DE/CH]; Luetzelbachweg
`28, CH-4123 Allschwil (CH).
`
`Declaration under Rule 4.17:
`— as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17(iii))
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`= (74) Agent: SAVITSKY, Thomas, R.; NOVARTIS, Corporate
`Intellectual Property Department, One Health Plaza, Bldg
`104, East Hanover, NI 07936-1080 (US).
`
`For two-letter codes and other abbreviations, refer to the "Guid­
`ance Notes on Codes and Abbreviations" appearing at the begin­
`ning of each regular issue of the PCT Gazette.
`
`<
`
`m
`00
`IT) o
`^sO o ^ (54) Title: DOSAGE REGIMEN OF AN SIP
`
`RECEPTOR AGONIST
`
`(57) Abstract: SIP receptor modulators or agonists are administered following a
`regimen whereby during the initial 3 to
`dosage
`6 days of treatment the daily dosage is raised so that in total the R-fold (R being the accumulation factor) standard daily dosage is
`
`administered and thereafter continued at the standard daily dosage or at a
`daily dosage
`lower
`than the standard
`daily
`
`£
`
`dosage.
`
`APOTEX - EXHIBIT 1004
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`Dosage Regimen of an S1P Receptor Agonist
`
`The present invention relates to a dosage
`regimen of an S1P receptor modulator
`particularly in the course of the treatment of transplant patients or patients suffering
`autoimmune diseases
`or disorders.
`
`or agonist
`from
`
`S1P receptor modulators or agonists are compounds
`signal as
`which
`agonists
`at
`more sphingosine-1 phosphate receptors, e.g. S1P1 to S1P8. Agonist binding to a S1P
`receptor may e.g. result in dissociation of intracellular heterotrimeric G-proteins
`into Ga-GTP
`and GPY-GTP, and/or increased phosphorylation of the agonist-occupied
`receptor and
`activation of downstream signaling pathways/kinases.
`
`one
`
`or
`
`S1P receptor modulators
`or
`agonists
`valuable compounds
`are
`for
`the
`manufacture
`of
`medication for the
`treatment
`various conditions
`of
`in mammals, especially in human beings.
`For example, efficacy in transplantation has been demonstrated
`in rats (skin, heart, liver,
`small bowel), dogs (kidney), and monkeys (kidney) models. Combination experiments
`with
`cyclosporin A showed
`synergy
`in skin and heart transplantation models
`in rats and in monkey
`renal transplantation. S1P receptor agonists
`or modulators
`with everolimus
`combined
`prolong survival of cardiac (rat) and renal (monkey) allografts. Due to their immune-
`modulating potency, S1P
`receptor modulators or agonists
`are
`useful for the
`also
`treatment
`inflammatory and autoimmune diseases. Further characteristics
`of S1P receptor agonists
`can be found in the following publications:
`
`of
`
`Brinkmann V, Chen S, Feng L, et al (2001) FTY720 alters
`lymphocyte homing and
`protects allografts without
`inducing general immunosuppression. Transplant Proc;
`33:530-531.
`Brinkmann V, Pinschewer D, Feng L, et al (2001) FTY720: altered lymphocyte traffic
`results in allograft protection (review). Transplantation; 72:764-769.
`Pinschewer DD, Ochsenbein AF, Odermatt B, et al (2000) FTY720
`immunosuppression
`impairs effector T-celI peripheral homing without affecting
`induction, expansion, and memory. J Immunol; 164:5761.
`Yanagawa Y, Sugahara K, Kataoka H, et al (1998) FTY720, a novel
`immunosuppressant, induces sequestration
`circulating mature lymphocytes by
`of
`acceleration of lymphocyte homing in rats. II. FTY720 prolongs
`skin allograft survival
`by decreasing T cell
`infiltration into grafts but not cytokine production in vivo. J
`Immunol.; 160(11):5493-9.
`
`It has now surprisingly been found that a specific dosage
`provide further unexpected benefits.
`
`regimen,
`a loading dose, will
`e.g.
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`The binding affinity of S1P receptor agonists or modulators to individual human S1P
`receptors may be determined in following assay:
`S1P receptor agonist or modulator activities of compounds are tested on the human S1P
`receptors SIP -i, SIP2, SIP3, SIP4 and SIP5. Functional receptor activation is assessed by
`quantifying compound induced GTP [Y-35S] binding to membrane protein prepared from
`transfected CHO or RH7777 cells stably expressing the appropriate human S1P 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 S1P receptor expressing membrane protein (10-20|_ig/well) in the presence of
`50 mM Hepes, 100 mM NaCI, 10 mM MgC^, 10 pM 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 separated by a centrifugation step. Luminescence of SPA beads
`triggered by membrane bound GTP [y-35S] is quantified with a TOPcount plate reader
`(Packard). EC50S are calculated using standard curve fitting software. In this assay, the S1P
`receptor <50
`a binding affinity to S1P
`preferably have
`or agonists
`receptor modulators
`
`nM.
`
`compounds which in addition to their
`e.g.
`are
`modulators
`or
`agonists
`receptor
`Preferred S1P
`lymphocyte homing properties, e.g.
`accelerating
`have
`S1P binding properties also
`compounds which elicit a lymphopenia resulting from a re-distribution, preferably reversible,
`tissue, without evoking a generalized
`lymphatic
`from circulation to secondary
`of lymphocytes
`from
`the
`and B-cells
`and CDS T-cells
`immunosuppression. Naive cells are sequestered; CD4
`(PP).
`(LN) and Peyer's patches
`blood are stimulated to migrate into lymph nodes
`
`in following Blood Lymphocyte Depletion
`
`The lymphocyte homing property may be measured
`assay:
`to rats.
`is administered orally by gavage
`vehicle
`modulator or the
`or
`A S1P receptor agonist
`baseline
`individual
`the
`to give
`Tail blood for hematological monitoring is obtained on day -1
`In this assay, the S1P receptor
`application.
`after
`hours
`values, and at 2, 6, 24, 48 and 72
`blood lymphocytes, e.g. by 50%, when
`peripheral
`agonist or modulator depletes
`of e.g. < 20 mg/kg.
`dose
`a
`administered at
`
`2-
`sphingosine
`such as
`typically
`are
`or agonists
`S1 P receptor modulators
`substituted 2-amino- propane-1,3-diol or 2-amino-propanol derivatives, e. g. a compound
`comprising a group of formula X
`
`analogues,
`
`

`

`WO 2006/058316
`
`PCT/U S2005/043044
`
`Z
`
`R3ZR2ZN
`
`CH2R1Z
`
`(X)
`
`wherein Z is H, C^alkyl, C2.6alkenyl, C2.6alkynyl, phenyl, phenyl substituted by OH, Ci^alkyl
`substituted by 1 to 3 substituents
`selected
`from the
`
`group halogen, C3.
`consisting
`scycloalkyl, phenyl and phenyl substituted by OH, or CH2-R4Z wherein R4Z is OH, acyloxy
`or a
`residue of formula (a)
`
`0 R 5 Z
`
`°R6Z
`
`Z?
`
`P
`II
`0
`
`(a)
`
`wherein Zi is a direct bond or O, preferably O;
`
`each of Rsz and Rez, independently, is H, or C^alkyl optionally
`halogen atoms;
`
`
`
`
`
`by substituted 1, 2 or 3
`
`R1z is OH, acyloxy or a residue of
`C^alkyl or acyl.
`
`formula
`
`(a);
`
`
`
`and Rzz and Raz independently, is H each of
`
`
`
`
`
`Group of formula X is a functional group attached as
`group
`terminal
`a
`
`aliphatic, aromatic and/or alicyclic,
`
`be hydrophilic or lipophilic and comprise one
`or more
`heterocyclic residues,
`
`to the extent that the
`resulting molecule wherein
`at
`least
`one Z and
`
`a residue of formula (a), signals as
`R1z is or comprises
`an
`agonist
`at
`one
`sphingosine-1 -phosphate receptor.
`
`to
`
`a
`
`of
`of more
`
`Examples of appropriate S1P
`
`receptor
`
`agonists
`
`or modulators
`
`are,
`
`- Compounds as
`
`
`
`disclosed in EP627406A1,
`
`e.g.
`
`a
`
`
`
`compound of formula I
`
`QH2OR3
`
`R4R5N
`
`CH2OR2
`
`R1
`
`I
`
`wherein R1 is a straight- or branched (Ci2-22)chain
`from a double bond, a triple
`- which may have in the chain a bond or a hetero atom selected
`bond, O, S, NR6, wherein Re is H, Chalky!, aryl-C^alkyl, acyl or (C1.4alkoxy)carbonyl, and
`carbonyl, and/or
`C^alkoxy, C2^alkenyloxy, C^alkynyloxy, arylC^alkyl-
`
`- which may have as a substituent
`oxy, acyl, C^alkylamino, C^alkylthio, acylamino, (Ci^alkoxyjcarbonyl, (C^alkoxy)-
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`~ 4"
`
`carbonylamino, acyloxy, (C^alkyOcarbamoyl, nitro, halogen, amino, hydroxyimino,
`hydroxy or carboxy; or
`
`RT 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 substituted by
`- a straight- or branched
`(C6.2o)carbon chain optionally substituted by halogen,
`- a straight- or branched (C6.2o)alkoxy chain optionally substitued by halogen,
`- a straight- or branched (C6-2o)alkenyloxy,
`- phenyl-C-i.^alkoxy, halophenyl-C^alkoxy, phenyl-C^ualkoxy-Cv^alkyl, phenoxy-C^alkoxy
`or phenoxy-Ci^alkyl,
`- cycloalkylalkyl substituted by Ce-aoalkyl,
`- heteroarylalkyl substituted by C6.2oalkyl,
`- heterocyclic Ce^oalkyl or
`- heterocyclic alkyl substituted by C2.2oalkyl,
`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 NRe, wherein Re is as defined above,
`and
`- as a
`substituent C^alkoxy,
`C2-4alkenyloxy,
`C^alkynyloxy, arylC-ualkyloxy, acyl, C^alkyl-
`amino, C^alkylthio, acylamino, (C1^alkoxy)carbonyl, (C1^alkoxy)carbonylaminol acyloxy,
`(C^alkyOcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and
`each of R2, R3, R4 and R5, independently, is H, C-1.4 alkyl or acyl
`or a pharmaceutically acceptable
`or hydrate thereof;
`salt
`- Compounds as
`in EP 1002792A1,
`disclosed
`e.g. a compound of formula II
`
`C H 2 O R ,3
`
`R' 4R' 5H-C-(CH 2) 2-
`
`C H 2 O R ' 2
`
`^ //
`
`0
`c
`
`(CH2)m-
`
`%
`
`//
`
`II
`
`wherein m is 1 to 9 and each
`R'2, R's, R'4 and R'5, independently,
`of
`or a pharmaceutically acceptable
`or hydrate thereof;
`salt
`- Compounds as
`disclosed
`EP0778263 A1, e.g. a compound of formula III
`in
`
`is H, C^ealkyl or acyl
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`N R'1! R"2
`w-c-z2—
`
`(CH 2) m.OR"3
`
`Y
`
`X
`
`I I !
`
`wherein W is H; Ci^alkyl, C2-6alkenyl or C^alkynyl; unsubstituted or by OH substituted
`phenyl; R"40(CH2)n; or C^ealkyl substituted by 1 to 3 substituents
`selected
`
`from the group
`consisting of halogen, Cs-scycloalkyl, phenyl 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
`selected
`from the group consisting of C^alkyl, OH,
`
`Ci.ealkoxy, acyloxy, amino, C-^alkylamino, acylamino, oxo, haloCi-ealkyl, halogen,
`unsubstituted phenyl and phenyl substituted by 1 to 3 substituents
`
`selected
`from the group
`consisting of C^ealkyl, OH, C-i-ealkoxy, acyl, acyloxy, amino, C^alkylamino, acylamino,
`haloC^ealkyl and halogen; Y is H, C^ealkyl, OH, C^alkoxy, acyl, acyloxy, amino, Ci.
`ealkylamino, acylamino, haloCi-ealkyl or halogen, Z2 is a single
`
`bond or a straight chain
`alkylene having a number or carbon atoms
`of q,
`
`1, 2 or 3, n is 2 or 3,
`each of R'*!, R'a, R"3 and R'U, independently, is H, C^alkyl or acyl,
`thereof,
`or a pharmaceutically acceptable
`salt
`or
`hydrate
`- Compounds as disclosed
`in WO02/18395, e.g.
`a
`
`compound formula IVa or IVb of
`
`
`each of p and q, independently, is an integer of 1 to 20, with the proviso of 6<p+q<23, m' is
`
`CH2R
`%
`3 a
`(R2a)2N1C-CH2-XR- P=0
`
`CH2
`CH2
`
`ftb
`
`or
`
`CH2R3b
`
`ft.
`(R2a)2N-|C-CH 2-X I— P = 0
`
`CH2
`
`CH2
`
`^Ib
`
`(CH2)7CH3
`
`IVa
`
`Ya-R4a
`
`IVb
`
`wherein X a is O, S, NR1s or a group -(C^ W , which group
`is unsubstituted or substituted by
`
`1 to 4 halogen; na is 1 or 2, R1s is H or (C^Jalkyl, which alkyl is unsubstituted or substituted
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`0
`
`by halogen; Ria is H, OH, (Ci^alkyl or 0(C1^)alkyl wherein alkyl is unsubstituted or
`substituted by 1 to 3 halogen;
`is H, OH or (C^alkyl,
`wherein alkyl is unsubstituted or
`substituted by halogen; each R2a is independently selected
`H or (ClJ,)alkyl, which alkyl
`from
`is unsubstituted or substitued by halogen; Rsa is H, OH, halogen or 0(Ci.4)alkyl wherein alkyl
`is unsubstituted or substituted by halogen; and R3b is H, OH, halogen, (C^alkyl wherein
`alkyl is unsubstituted or substituted by hydroxy, or 0(Ci_4)alkyl wherein alkyl is unsubstituted
`or substituted by halogen; Ya is -CH2-,
`-C(O)-, -CH(OH)-, -C(=NOH)-, O or S, and R4a is
`(C^^alkyl or ^.^alkenyl;
`or a pharmaceutically acceptable
`salt
`or hydrate
`thereof;
`- Compounds as
`disclosed
`WO 02/076995,
`in
`e.g.
`compound of formula V
`a
`
`^40^30^
`
`Ric
`
`Rc
`
`(CH2)mc-XcR2c V
`
`wherein
`mc
`is 1, 2 or 3;
`Xc
`is O or a direct bond;
`R1c
`is H;
`alkyl optionally substituted by OH, acyl, halogen, Cs-iocycloalkyl, phenyl or
`hydroxy-phenylene; C2-6alkenyl; C2-6alkynyl; or phenyl optionally substituted by OH;
`is
`
`Rzc
`
`0R5C
`— p<
`ORac
`o
`wherein Rgc is H or Ci^alkyl optionally substituted by 1, 2 or 3 halogen
`is H or C^alkyl optionally
`substituted by halogen;
`each of Rsc and R4C, independently, is H, Ci^alkyl optionally substituted by halogen, or acyl,
`and
`Rc
`
`is C^oalkyl which may optionally have in the chain an oxygen atom and which may
`optionally be
`substituted by nitro, halogen, amino, hydroxy or carboxy; or a
`residue
`of
`formula (a)
`
`atoms,
`and R6c
`
`-(CH2)2.4--
`
`?7C
`
`(a)
`
`Rgc
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`wherein Rye is H, C^alkyl or Ci^alkoxy, and Rac
`is substituted Ci.2oalkanoyl,
`phenylC^^alkyl wherein the C^^alkyl is optionally substituted by halogen or OH,
`cycloalkylC -i
`.-nalkoxy or phenyiC^nalkoxy wherein the cycloalkyl or phenyl ring is
`optionally substituted by halogen, C-j^alkyl and/or C^alkoxy, phenylC-i.^alkoxy-
`C^^alkyl, phenoxyCi.^alkoxy or phenoxyCi.^alkyl,
`being also a residue
`formula (a) wherein R8c is C^-ualkoxy when R1c is C^alkyl,
`of
`Cz-ealkenyl or Ca-ealkynyl,
`or a compound of formula VI
`
`Rc
`
`R4XR3XN
`
`Rix
`
`(CH2)n-
`CH2-OR2X
`
`Rsx 4^
`
`VI
`
`R6X
`
`R1x
`
`wherein
`nx
`is 2, 3 or 4
`is H; C^eaikyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or
`hydroxy-phenylene; C2-6alkenyl; Ca-ealkynyl; or phenyl optionally substituted by OH;
`Rax
`is H, C1.4 alkyl or acyl
`each of Rsx and R4X, independently
`is H, C^alkyl optionally substituted by halogen or acyl,
`Rsx
`is H, C^alkyl or C^alkoxy, and
`is
`alkanoyl substituted by cycloalkyl; cyloalkylCv^alkoxy wherein the cycloalkyl
`ring is optionally substituted by halogen, C-Malkyl and/or C^alkoxy;
`phenylC^ualkoxy
`wherein the phenyl ring is optionally substituted by halogen, C-Malkyl and/or C-Malkoxy,
`Rex being also C^alkoxy
`when
`is Ca^alkyl substituted by OH, or pentyloxy or hexyloxy
`R-,*
`when R1x is C^akyl,
`provided that Rex is other
`than phenyl-butylenoxy
`either Rsx is H or R1x is methyl,
`when
`or a pharmaceutically acceptable salt
`or hydrate
`thereof;
`- Compounds as
`disclosed
`W002/06268A1,
`in
`e.g.
`compound of formula VII
`a
`
`Rex
`
`N R 1 d R 2 d
`R 6d
`/R7d
`—(CH 2) n f f^yx
`d—Y —R5d
`s
`
`V I I
`
`*4?
`
`RadO
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`wherein each
`of R1d and R2d, independently, is H or an amino-protecting group;
`Rsd is hydrogen, a hydroxy-protecting group or a residue of formula
`
`OR 9d
`P<
`OR 8d
`o
`
`R4d is C-i^alkyl;
`nd is an integer of 1 to 6;
`Xd is ethylene, vinylene, ethynylene, a group having a formula - D-CHa- (wherein D is
`carbonyl, - CH(OH)-, O, S or N), aryl or aryl substituted by up to three substitutents selected
`from group a
`as
`
`defined hereinafter;
`Yd is single bond, C^oalkylene, C-Moalkylene which is substituted by up to three substitutents
`selected
`from groups
`
`
`and a b, C^^alkylene having O or S
`in the middle or end of the carbon
`chain, or C^^alkylene 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;
`
`Rsd is hydrogen, Cs-ecycloalkyl, aryl, heterocyclic group, Ca-ecycloalkyl substituted by up to
`three substituents
`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 b;
`and
`from group a;
`
`each of Red and Rya, independently, is H or a substituent selected
`each of R8d and Rgd, independently, is H or C^alkyl optionally substituted by halogen;
`<group a > is halogen, lower alkyl, halogeno
`lower alkyl, lower alkoxy, lower alkylthio,
`carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-lower alkylamino,
`di-Ci^alkylamino, acylamino, cyano or nitro; and
`-<group- b > is Cg-ecycloalkylraryl orheterocyclic
`group, each being-optionally substituted by
`up to three
`substituents
`
`selected group a; from
`
`single bond or linear C
`
`with the proviso that when Rsd is hydrogen, Yd is a either a
`1-10
`alkylene, or a pharmacologically acceptable
`
`salt, ester or hydrate
`thereof;
`
`-Compounds as
`
`
`
`in disclosed JP-14316985
`
`
`
`(JP2002316985),
`
`
`
`e.g. a compound of formula VIII
`
`R
`6e'
`NR1eR2e
`< C H 2)nr4
`
`Rye'
`
`S
`
`*43-
`
`R a e O
`
`X - Y — R 5 e
`
`V I I I
`
`wherein Rie.Rae.Rse.F^e.Rse.Ree.Rre, rie, Xe and Ye are as disclosed
`in
`JP-14316985;
`or a pharmacologically acceptable
`
`salt, ester or hydrate thereof;
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`• 9
`
`-Compounds as disclosed in WO 03/29184
`IX
`
`and WO 03/29205, e.g. compounds of formula
`
`R l f -
`
`x , .
`
`n h 2
`
`R g f
`
`(CH2)nf
`
`c h 2 o r 5 f
`
`c h 2 o r 4 f
`
`IX
`
`wherein Xf is O, S, SO or SO2
`
`is halogen, trihalomethyl, OH, C^alkyl, C^alkoxy, trifluoromethoxy, phenoxy,
`
`Rn
`cyclohexylmethyloxy, pyridylmethoxy, cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH2-
`C1.4alkylsulfinyl, C-Malkylsulfonyl, benzylthio, acetyl, nitro or
`
`C^alkylthio,
`OH, CHa-CHa-OH,
`cyano, or phenyl, phenylC^alkyl or phenyl-C^alkoxy each
`phenyl
`
`group being
`thereof
`optionally substituted by halogen, CF3, C^alkyl or C1.4alkoxy;
`Rar is H, halogen,
`trihalomethyl, C^alkoxy,
`Ci-yalkyl, phenethyl or benzyloxy;
`Rsf H, halogen, CF3, OH, C^yalkyl, C^alkoxy, benzyloxy
`or C^alkoxymethyl;
`is
`
`H or a residue of formula
`each of R4fand R5f, independently
`
`OR 8f
`P<
`0R9f
`
`O
`
`of Rsf and Rgf, independently, is H or C^alkyl optionally substituted by
`
`wherein each
`halogen;and
`• nf is an integer
`from 1 to 4;
`e.g. 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]ethyl-1,3-propane-diol, 2-amino-2-
`[4-(benzyloxyphenylthio)-2-
`chlorophenyl]ethyl-1,3-propane-diol, 2-amino-2-[4-(3-
`benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol
`or
`2-amino-2-[4-
`(benzyloxyphenylthio)-2-
`chlorophenyl]propyl-1,3-propane-diol,
`or a pharmacological salt, solvate or hydrate
`thereof;
`
`-Compounds as
`
`wherein
`
`
`
`
`
`in disclosed WO03/062252A1,
`
`
`
`e.g. compound of formula X a
`
`
`
`("49)0-4
`
`— M
`
`(CH^
`
`(CH2)ng
`A /
`
`*11'
`
`X
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`- 1 0 -
`
`Ar is phenyl or naphthyl; each of rrig and n g independently
`from
`or 0 1; A is selected
`
`
`is
`COOH, PO3H2, PO2H SO3H, PO(Ci.3alkyl)OH and 1 H-tetrazol-S-yl; each
`of and Rsg
`independently
`is H, halogen, OH, COOH or C-Malkyl optionally substituted by halogen; Rsg is
`H or Ci^alkyl optionally substituted by halogen or OH; each R4g independently
`is
`
`halogen, or
`optionally halogen
`substituted C^alkyl or C^salkoxy; and each of Rg and M has one of the
`significances as
`
`for indicated B and C, respectively, in WO03/062252A1;
`
`or a pharmacologically acceptable
`salt, solvate or hydrate thereof;
`
`
`-Compounds as
`
`
`
`disclosed WO 03/062248A2, e.g. a compound of formula XI in
`
`
`
`^1h
`
`A
`
`L
`
`Jn H
`
`Fah
`
`(^4h)o-4
`
`Rh-M
`
`XI
`
`wherein Ar is phenyl or naphthyl; n is 2,3 or 4; A is COOH, 1/V-tetrazol-5-yl, PO3H2, PO2H2, -
`SO3H or PO(R5h)OH wherein Rsn is selected
`from Ci^alkyl, hydroxyCi^alkyl, phenyl, -CO-C1.
`salkoxy and -CH(OH)-phenyl wherein said phenyl or phenyl moiety is opitonally substituted;
`each of R-ih and R2h independently
`is H, halogen, OH, COOH, or optionally halogeno
`substituted C^alkyl or phenyl; Rsh is H or C^alkyl optionally substituted by halogen and/
`OH; each R^
`independently
`is halogeno, OH, COOH, C^alkyl, 8(0)0,!
`o^C^alkyl,
`salkoxy, Cs^cycloalkoxy, aryl or aralkoxy, wherein the alkyl portions may optionally be
`substituted by 1-3 halogens;
`and each of Rh and M has one of the significances
`as
`for B and C, respectively, in WO03/062248A2;
`or a pharmacologically acceptable
`
`salt, solvate or hydrate
`
`thereof;
`
`disclosed in WO 04/103306A, WO 05/000833, WO 05/103309
`
`- Compounds as
`05/113330,
`e.g. compounds of formula Xlla orXllb
`
`or WO
`
`C^
`
`indicated
`
`Ar
`
`z*
`
`•Fak r
`
`Yk
`
`N
`\
`o—w
`
`S
`
`J*,.
`
`Ak
`
`^ 1 k
`
`X l l a
`
`X l l b
`
`wherein
`Ak is COORSK, OPO(OR5k)2, PO(OR5k)2, SOaORsk, PORskORsk or 1H-tetrazol-5-yl, R5k being
`H or C-i-ealkyl;
`Wk is a bond, Ci^alkylene or C2-3alkenylene;
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`- 1 1 -
`
`Yk is Ce-ioaryl or Cs-gheteroaryl, optionally substituted by 1 to 3 radicals selected from
`halogene, OH, NOa, C1.6alkyl, C^ealkoxy; halo-substituted C^alkyl and halo-substituted
`Ci-ealkoxy;
`WO 04/103306A, e.g. azetidine;
`in
`indicated
`Zk is a heterocyclic group as
`R1k is Ce-ioaryl or Ca^heteroaryl, optionally substituted by C^alkyl, Ce-ioaryl,
`Cs-gheteroaryl, C3.9heteroarylC1.4alkyl, Cs-acycloalkyl, Cs-scycloalkylCi^alkyl,
`Cs-sheterocycloalkyl or Cs-gheterocycloalkylCi^alkyl; wherein any aryl, heteroaryl, cycloalkyl
`from
`halogen, Ci_
`selected
`groups
`or heterocycloalkyl of Rik may be substituted by 1 to 5
`6alkyl, C^alkoxy and halo substituted-Ci-ealkyl or -Ci.6alkoxy;
`RSK is H, Ci_6alkyl, halo substituted Ci-ealkyl, Ca-ealkenyl or C2-6alkynyl: and
`each of RSK or R^, independently, is H, halogen, OH, C^ealkyl, Ci.6alkoxy
`Ci.6alkyl or C^ealkoxy;
`and the N-oxide derivatives thereof or prodrugs thereof,
`solvate or hydrate
`salt,
`or a pharmacologically acceptable
`
`or halo
`
`substituted
`
`thereof.
`
`Ce-ioarylCi^alkyl,
`
`the invention, a S1P receptor agonist
`of
`further embodiment
`According to a
`receptor, e.g. a
`S1P1
`use in a combination of the invention may also be a selective
`S1P3
`the
`SI
`P1 receptor over
`the
`for
`selectivity
`a
`compound which possesses
`the ratio of EC50 for the
`fold, as measured by
`fold, e.g. 100, 500, 1000 or 2000
`least 20
`a 35S-GTPyS binding assay,
`evaluated
`as
`receptor
`S1P1 receptor to the EC50 for the S1P3
`100 nM or less as
`of
`receptor
`said compound having an EC50 for binding to the S1P1
`or
`evaluated by the 35S-GTPyS binding assay. Representative S1P1 receptor agonists
`of which being
`listed in WO 03/061567, the contents
`compounds
`the
`modulators are e.g.
`incorporated herein by reference, for instance a compound of formula XIII or XIV
`
`or
`
`modulator
`
`receptor
`at
`
`in
`
`for
`
`of
`
`%
`
`CF?
`
`0-\j>
`
`NH
`
`XIII
`
`OH
`
`or
`
`CH3-(CH2)8'
`
`XIV
`
`OH
`
`OH
`OH
`
`centers
`in the
`formulae I to XIV have one or more asymmetric
`of
`When the compounds
`optical
`various
`molecule, the present invention is to be understood as embracing the
`embraced.
`mixtures thereof are
`and
`diastereoisomers
`as racemates,
`well
`isomers, as
`is
`Compounds of formula III or IVb, when the carbon atom bearing the amino group
`carbon atom.
`this
`asymmetric, have preferably the R-configuration at
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`- 1 2 -
`
`The compounds of formulae I to XIV may exist
`in free or salt form. Examples of
`pharmaceutically acceptable
`
`salts the compounds of
`
`of the formulae I to XIV include salts
`
`with inorganic acids, such as
`
`hydrochloride, hydrobromide and sulfate, salts with organic
`acids, such as acetate,
`
`fumarate, maleate, benzoate, citrate, malate, methanesulfonate and
`benzenesulfonate
`salts, or, when appropriate, salts
`with metals such as
`
`sodium, potassium,
`
`calcium and aluminium, salts with amines, such as
`triethylamine and
`
`salts dibasic amino with
`acids, such as lysine. The
`compounds and salts
`of the combination of the present invention
`
`encompass hydrate and solvate forms.
`
`indicated above may be a residue Ry-CO- wherein Ry is C^alkyl, Cs-ecycloalkyl,
`Acyl as
`phenyl or phenyl-C^alkyl. Unless otherwise
`stated, alkyl, alkoxy, alkenyl or alkynyl may be
`straight or branched.
`
`Aryl may be phenyl or naphthyl, preferably phenyl.
`
`of formula I the carbon chain as Ri is substituted, it is preferably
`
`When in the compounds
`substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon
`
`chain is
`interrupted by an optionally substituted phenylene,
`the
`
`carbon chain is preferably
`unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by
`halogen, nitro, amino, methoxy, hydroxy or carboxy.
`
`formula I are those wherein Ri is Cis-aoalkyl, optionally substituted
`of
`Preferred compounds
`by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those
`wherein R! is
`phenylalkyl substituted by Ce^-alkyl chain optionally substituted by halogen and the alkyl
`moiety is a C^alkyl optionally substituted by hydroxy. More preferably, R-, is phenyl-C^ealkyl
`substituted on
`the phenyl by a straight or branched, preferably straight, Ce-ualkyl chain. The
`Ce-^alkyl chain may be in ortho, meta or para, preferably in para.
`
`Preferably each
`
`of R2 to R5 is H.
`
`5- membered heterocyclic to 7
`
`
`
`formula of VII "heterocyclic group" represents a
`In the above
`group having 1 to 3 heteroatoms
`selected
`
`S, from O and N. Examples of such heterocyclic
`
`groups include the
`
`heteroaryl groups indicated above, and heterocyclic compounds
`corresponding to partially or completely hydrogenated heteroaryl groups, e.g. furyl, thienyl,
`pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-
`oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,
`pyrazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl,
`pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl or pyrazolidinyl.
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`- 13-
`
`6-membered heteroaryl groups and the most
`
`5-or
`Preferred heterocyclic groups are
`preferred heteocyclic group
`is a morpholinyl, thiomorpholinyl or piperidinyl group.
`
`A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. A particularly
`preferred S1P receptor agonist of formula I is FTY720, La 2-amino-2-[2-(4-octylphenyl)
`ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable
`salt
`
`form (referred to
`hereinafter as
`Compound
`e.g. the hydrochloride, as shown:
`
`A),
`
`HO— OH
`H2N
`
`• HCI
`
`A preferred compound of formula II is the one wherein each of R'2 to R'5 is H and m is 4, i.e.
`2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol, in free form or in
`pharmaceutically acceptable
`
`
`form salt (referred to hereinafter as
`Compound B), e.g the
`
`hydrochloride.
`
`A preferred compound of formula III is the one wherein W is CH3, each of R"! to R"3 is H, Z2
`is ethylene, X is heptyloxy and Y is H, i.e. 2-arinino-4-(4-heptyloxyphenyl)-2-methy!-butanol,
`in free form or in pharmaceutically acceptable
`
`form salt (referred to hereinafter as
`
`Compound C), e.g. the hydrochloride. The R-enantiomer
`particularly preferred.
`is
`
`A preferred compound of formula IVa is the FTY720-phosphate (R2a is H, Raa is OH, Xa is O,
`Ria and R^
`
`are OH). preferred compound of formula IVb is the Compound C-phosphate
`A
`(Rag is H, Rat, is OH, Xa is 0,
`and are OH, Ya is O
`
`and R4a is heptyl). A preferred
`
`R^ R1b
`compound of formula V is Compound B-phosphate.
`
`A preferred compound of formula V is phosphoric acid mono-[(R)-2~amino-2-methyl-4-(4-
`pentyloxy-phenyl)-butyl]ester.
`
`A preferred compound of formula VIII is (2R)~2-amino-4-[3-(4-cyclohexyloxybutyl)-
`benzo[b]thien-6-yl]-2-methylbutan-1-ol.
`
`A preferred compound of formula Xlla is e.g. 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-
`benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic
`
`acid, a prodrug thereof. or
`
`
`in the
`of the invention, it provides the use an S1P receptor modulator or agonist
`
`
`
`According to
`
`
`manufacture of a medication, whereby said medication is administered in such a way that
`during the initial 3 to 6 days, preferably 4
`5 or most preferred 4 days, of treatment days,
`
`
`
`
`the
`
`

`

`WO 2006/058316
`
`PCT/US2005/043044
`
`-14-
`
`receptor modulator or agonist is raised so that in total the R-fold (R
`dosage of said S1P
`receptor modulator or
`of said S1P
`standard daily dosage
`being the accumulation factor)
`is continued with the standard or a
`treatment
`the
`agonist is administered and thereafter
`agonist.
`SIP receptor modulator or
`of said
`lower daily dosage
`
`patients providing prolonged
`transplant
`for
`Preferred medications comprise medication
`for renal, heart, lung
`survival rates, in particular prolonged allograft survival rates especially
`multiple
`e.g.
`autoimmune diseases,
`from
`suffering
`or liver transplants, or for patients
`or psoriasis.
`sclerosis, lupus nephritis, rheumatoid arthritis, inflammatory bowel diseases
`
`In view of the normally prolonged taking of the medication, the standard daily dosage (also
`or agonist
`receptor modulator
`of
`an S1P
`dose) refers to the dosage
`called maintenance
`blood level of the medication or its active metabolite(s)
`trough
`steady-state
`for a
`necessary
`factor (R). By
`accumulation
`the
`is dependent on
`treatment. Said dosage
`providing effective
`time. Trough blood level
`blood level is meant the concentration of a drug in blood at any
`trough
`blood level
`the
`whether
`blood level. Steady-state means
`pre-dose
`a
`to
`corresponds
`for example,
`by
`trough blood levels may be assessed,
`time. Steady-state
`is stable over
`anytime after month 3. The accumulation factor (R) is
`obtaining a pre-dose blood sample
`just before the second dose.
`trough
`calculated on the ratio of the steady-state trough to the
`
`or
`
`or agonist during the initial 3 to 6
`modulator
`receptor
`Preferably, the dosage of the S1P
`is continued with the
`treatment
`the
`Thereafter
`days, of treatment is increased stepwise.
`the standard daily dosage or with a lower daily dosage. When the
`therapy with
`maintenance
`it may be e.g. about 1/50 to Vz, preferably
`treatment is continued at a lower daily dosage,
`agonist.
`of the SIP receptor modulator or
`1/50 to 1/10, of the standard daily dosage
`
`during
`the initial 3 to
`or agonist
`receptor modulator
`said S1P
`of
`Preferably, the total dosage
`of treatment is increased
`days,
`most preferred 4
`days,
`or 5
`6 days, preferably 4
`to 12-fold, particularly