AU2012202709A1 - Ophthalmic uses of SIP receptor modulators - Google Patents

Abstract

C\NRPonb\DCC\RBR\41j7293_ .DOC.9-52112 The present invention pertains to the use of a S1P receptor agonist in the manufacture of a medicament in the treatment of an ocular disorder.

Description

Australian Patents Act 1990- Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Ophthalmic uses of S I P receptor modulators" The following statement is a full description of this invention, including the best method of performing it known to me/us: C\NRPnrhM\DCC\RBR\4317498 I DOC CANRPorbl\DCC\RBRW 17293_ 1DOC-9/0S12012 Ophthalmic uses of S1 P receptor modulators This application is a divisional application of Australian Application No. 2010202185 the specification and drawings of which as originally filed are incorporated herein in their entirety by reference. The present invention relates to the use of a an S1P receptor agonist in the manufacture of a medicament for the treatment of ocular disorders. Ocular disorders which may be treated according to this invention include typically an ocular disease and disorder which may directly or indirectly involve the degeneration of retinal or corneal cells, in particular by apoptosis. Ocular disorders, as used herein, include ischemic retinopathies in general, anterior ischemic optic neuropathy, all forms of optic neuritis, age- related macular degeneration (AMD), in its dry forms (dry AMD) and wet forms (wet AMD), diabetic retinopathy, diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), cystoid macular edema (CME), retinal detachment, retinitis pigmentosa (RP), Stargardt's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degenerations, pathologic myopia, retinopathy of prematurity, and Leber's hereditary optic neuropathy, the after effects of corneal transplantation or of refractive corneal surgery, keratoconjunctivitis sicca (KCS) or dry eye and herpes keratitis. Preferably, said ocular disorders are selected from: Dry AMD, wet AMD, diabetic retinopathy, diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), retinitis pigmentosa (RP), and keratoconjunctivits sicca (KCS), and even more preferably, said ocular disorders are selected from: Dry AMD, wet AMD, DME and PDR. Also preferably said ocular disorder is PDR. Also preferably said ocular disorder is DME. Also preferably said ocular disorder is keratoconjunctivits sicca (KCS). Highly preferably, said ocular disorders are selected from dry AMD and wet AMD. In the present description the terms "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease-modifying treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.

-2 S1P receptor agonists are compounds which signal as agonists at one or more sphingosine 1 phosphate receptors, e.g. S1P1 to S1P8. Agonist binding to a SIP receptor may e.g. result in dissociation of intracellular heterotrimeric G-proteins into Ga-GTP and Goy-GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling pathways/kinases. S1 P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino propane-1,3-diol or 2-amino-propanol derivatives, e. g. a compound comprising a group of formula X z

R

3 Z R 2 N CH 2 R (X) wherein Z is H, C 1 .Oalkyl, C 2 -ealkenyl, C 2 -ealkynyl, phenyl, phenyl substituted by OH, C 1 .6alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C 3 cycloalkyl, phenyl and phenyl substituted by OH, or CH 2

-R

4 z wherein R 4 1 is OH, acyloxy or a residue of formula (a) 0 R 5 0 wherein Z 1 is a direct bond or 0, preferably 0; each of R 5 z and R 6 z, independently, is H, or C 1 4alkyl optionally substituted by 1, 2 or 3 halogen atoms;

R

1 , is OH, acyloxy or a residue of formula (a); and each of R2z and R 3 1 independently, is H,

C

1 4alkyl 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, aromatic and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one of Z and

R

1 z is or comprises a residue of formula (a), signals as an agonist at one of more sphingosine-1 -phosphate receptor. Examples of preferred S1 P receptor agonists are, for example: -3 - Compounds as disclosed in EP627406A1, e.g. a compound of formula I H2O3 wherein R 1 is a straight- or branched (C 1 2

-

22 )chain - which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, 0, S, NR 6 , wherein R6 is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or - which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or

R

1 is - a phenylalkyl wherein alkyl is a straight- or branched (Cs- 2 o)carbon chain; or - a phenylalkyl wherein alkyl is a straight- or branched (C 1 -o)carbon chain wherein said phenylalkyl is substituted by - a straight- or branched (C 6

-

2 0 )carbon chain optionally substituted by halogen, - a straight- or branched (Cr-20)alkoxy chain optionally substitued by halogen, - a straight- or branched (Co-20)alkenyloxy, - phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, - cycloalkylalkyl substituted by C 6

.

20 alkyl, - heteroarylalkyl substituted by Ce-2 0 alkyl, - heterocyclic C 6

-

2 oalkyl or - heterocyclic alkyl substituted by C 2

-

2 oalkyl, and wherein the alkyl moiety may have - in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, 0, S, sulfinyl, sulfonyl, or NR 0 , wherein R 6 is as defined above, and - as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R 2 , R 3 , R 4 and R 5 , independently, is H, C 1 .4 alkyl or acyl or a pharmacologically acceptable salt, solvate or hydrate thereof; - Compounds as disclosed in EP 1002792A1, e.g. a compound of formula 1I -4

CH

2 0R' 3 O

R'

4 R',N-C-(CH2) C - (CH2)

CH

2 0R'2 wherein m is 1 to 9 and each of R' 2 , R' 3 , R' 4 and R' 5 , independently, is H, alkyl or acyl, or a pharmacologically acceptable salt, solvate or hydrate thereof; - Compounds as disclosed in EP0778263 Al, e.g. a compound of formula liI N R", R"2 W -C-Z 2

(CH

2 )mO R" 3 wherein W is H; C 1

.

6 alkyl, C 2 .ealkenyl or C 2

.

8 alkynyl; unsubstituted or by OH substituted phenyl; R" 4 0(CH 2 )n; or C 1 .6alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C3- 8 cycloalkyl, 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 I to 3 substitutents selected from the group consisting of C 1 .6 alkyl, OH, C1.0alkoxy, acyloxy, amino, C 1 .6alkylamino, acylamino, oxo, haloC 1

.

6 alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C1.6alkyl, OH, C1.6alkoxy, acyl, acyloxy, amino, C1.0alkylamino, acylamino, haloC 1

.

6 alkyl and halogen; Y is H, C 1 .ealkyl, OH, C 1 .6alkoxy, acyl, acyloxy, amino, C1. 6 alkylamino, acylamino, haloC 1

.

6 alkyl or halogen, Z 2 is a single bond or a straight chain alkylene having a number or carbon atoms of q, each of p and q, independently, is an integer of 1 to 20, with the proviso of 6:p+qS23, m' is 1, 2 or 3, n is 2 or 3, each of R",, R" 2 , R" 3 and R" 4 , independently, is H, C 1

.

4 alkyl or acyl, or a pharmacologically acceptable salt, solvate or hydrate thereof, -Compounds as disclosed in W002/18395, e.g. a compound of formula IVa or lVb -5

CH

2

R

3 b Ria I I

CH

2

R

3 a Ri

(R

2

.)

2 N-C-C H 2 -X-;- P =0 I

(R

2

.)

2 N-C-CH,-X-y-- P =0 I I C H2 R~b

CH

2 Rib I~H 2

CH

2 or

(CH

2

)

7

CH

3 IVa Ya-R 4 a IVb wherein X, is 0, S, NR 1 ., or a group -(CH 2 )na-, which group is unsubstituted or substituted by 1 to 4 halogen; na is 1 or 2, R 1 , is H or (C 1 4)alkyl, which alkyl is unsubstituted or substituted by halogen; Ria is H, OH, (C 1 4)alkyl or O(C 1

.

4 )alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; Rib is H, OH or (C 1 .4)alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R 2 . is independently selected from H or (C 1 4)alkyl, which alkyl is unsubstituted or substitued by halogen; R 3 , is H, OH, halogen or O(C 1 .4)alkyl wherein alkyl is unsubstituted or substituted by halogen; and R3b is H, OH, halogen, (C 1 .)alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C 1 .4)alkyl wherein alkyl is unsubstituted or substituted by halogen; Ya is -CH 2 -, -C(O)-, -CH(OH)-, -C(=NOH)-, 0 or S, and R 4 a is (C 4 . 1 4)alkyl or (C 4

.

1 4)alkenyl; or a pharmacologically acceptable salt, solvate or hydrate thereof; - Compounds as disclosed in WO 02/076995, e.g. a compound of formula V Rc

R

4

.R

3 e (CH2)m.-X.R 2 e V wherein me is 1, 2 or 3; Xe is 0 or a direct bond;

R

1 e is H; C 1

.

6 alkyl optionally substituted by OH, acyl, halogen, C3.1 0 cycloalkyl, phenyl or hydroxy-phenylene; C 2 -salkenyl; C 2 -6alkynyl; or phenyl optionally substituted by OH;

R

2 1 is ORr --- PCORc

O

-6 wherein R 5 c is H or C 1

.

4 alkyl optionally substituted by 1, 2 or 3 halogen atoms, and R 6 1 is H or C 1 .4alkyl optionally substituted by halogen; each of R 3 , and R 4 c, independently, is H, C 1 4alkyl optionally substituted by halogen, or acyl, and Re is C 13 2 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) Ryc -(CH2)2-4- o R8 (a) Be wherein R 7 e is H, C 1 -alkyl or Clualkoxy, and R 8 , is substituted C 1

.

20 alkanoyl, phenylC 1

.

14 alkyl wherein the C 1 14 alkyl is optionally substituted by halogen or OH, cycloalkylCl 1

.

4 alkoxy or phenylC 1

.

4 alkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C 1 -alkyl and/or C 1 4alkoxy, phenylCs 1 4 alkoxy

C

1 .i 4 alkyl, phenoxyC 1 14 alkoxy or phenoxyC 1

..

4 alkyl, Re being also a residue of formula (a) wherein R 8 c is C 1

.

14 alkoxy when R 1 e is C 1 -alkyl,

C

2 -ealkenyl or C 2

.

6 alkynyl, or a compound of formula VI R R R N CH 2 )nx VI CH2-OR R wherein nx is2,3or4

R

1 x is H; C 1

.

6 alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene;

C

2 .alkenyl; C 2 -salkynyl; or phenyl optionally substituted by OH; R2x is H, C 1

.

4 alkyl or acyl each of R 3 x and R 4 ., independently is H, C 1 .4alkyl optionally substituted by halogen or acyl, Rix is H, C1,alkyl or C1-4alkoxy, and -7 Re] is C 1

.

20 alkanoyl substituted by cycloalkyl; cyloalkylCl.

1 4 alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, C1.4alkyl and/or C 1 .4alkoxy; phenylC 1

.

1 4 alkoxy wherein the phenyl ring is optionally substituted by halogen, C 1 .4alkyl and/or C 1 4alkoxy, Rex being also C 4

.

1 4 alkoxy when R 1 x is C 2 4 alkyl substituted by OH, or pentyloxy or hexyloxy when R 1 x is C 1 4akyl, provided that R 6 1 is other than phenyl-butylenoxy when either R 5 x is H or R 1 is methyl, or a pharmacologically acceptable salt, solvate or hydrate thereof; - Compounds as disclosed in W002/06268Al, e.g. a compound of formula VII NR dR 2 d R 6 d R 7 d

R

4 d (CH 2 )" Xd--Y--Rd VII RUO wherein each of Rid and R2d, independently, is H or an amino-protecting group; R3 is hydrogen, a hydroxy-protecting group or a residue of formula ORed OR8 d 0 R4d is lower alkyl; nd is an integer of 1 to 6; Xd is ethylene, vinylene, ethynylene, a group having a formula - D-CH 2 - (wherein D is carbonyl, - CH(OH)-, 0, S or N), aryl or aryl substituted by up to three substitutents selected from group a as defined hereinafter; Yd is single bond, C 1

.

10 alkylene, C 1

.

10 alkylene which is substituted by up to three substitutents selected from groups a and b, C 1 1 oalkylene having 0 or S in the middle or end of the carbon chain, or C 1

.

10 alkylene having 0 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; R5d is hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl 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 heterocycle substituted by up to three substituents selected from groups a and b; each of Red and R7d, independently, is H or a substituent selected from group a; each of Red and Red, independently, is H or C 1

.

4 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-lower alkylamino, lower aliphatic acylamino, cyano or nitro; and <group b > is cycloalkyl, aryl, heterocycle, each being optionally substituted by up to three substituents selected from group a; with the proviso that when R5d is hydrogen, Yd is a either a single bond or linear C 1

.

0 alkylene, or a pharmacologically acceptable salt or ester thereof; -Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a compound of formula Vill NR eR 2e R 6

.

X-Y-R 8

R

4 , (CHN)nR Vill

R

3

,

0

R

7 , wherein Rle,R2e,R3e,R4e,R5e,R6e,,R7e, ne, Xe and Y, are as disclosed in JP-14316985; or a pharmacologically acceptable salt, solvate or hydrate or ester thereof; -Compounds as disclosed in WO 03/29184 and WO 03/29205, e.g. compounds of formula IX R x R 3 f NH 2 R IX

R

21

(CH

2 ),f CH 2 0Rf wherein Xf is 0 or S, and Rjf, RV, Ra 1 and nf are as disclosed in WO 03/29184 and WO 03/29205, each of R4, and R 5 ,, independently is H or a residue of formula OR f 11 OR,, 0 wherein each of Rat and Rqf, independently, is H or C 1 .4alkyl optionally substituted by halogen; e.g. 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 pharmacologically acceptable salt, solvate or hydrate thereof; -Compounds as disclosed in W003/062252A1, e.g. a compound of formula X' -9 Rg (R4g)o A (CH( H2)ArRM wherein Ar is phenyl or naphthyl; each of mg and ng independently is 0 or 1; A is selected from COOH, P0 3

H

2 , PO 2 H, SO 3 H, PO(C 1

.

3 alkyl)OH and 1 H-tetrazol-5-yl; each of Rig and R 2 g independently is H, halogen, OH, COOH or C 1 ,alkyl optionally substituted by halogen; R 3 g is H or C 1 -alkyl optionally substituted by halogen or OH; each R4g independently is halogen, or optionally halogen substituted C 1

.

4 alkyl or C 1

.

3 alkoxy; and each of Rg and M has one of the significances as indicated for B and C, respectively, in W003/062252A1; or a pharmacologically acceptable salt, salvate or hydrate thereof; -Compounds as disclosed in WO 03/062248A2, e.g. a compound of formula XI R Rl

/(R

4 1)0.4 A IN A RM- XM

R

2 h wherein Ar is phenyl or naphthyl; n is 2,3 or 4; A is COOH, 1H-tetrazol-5-yi, P0 3

H

2 , P0 2

H

2 , SO 3 H or PO(R 5 h)OH wherein Rsh is selected from C 1 _alkyl, hydroxyC 1 ,alkyl, phenyl, -CO-C 1 .. 3 alkoxy and -CH(OH)-phenyl wherein said phenyl or phenyl moiety is opitonally substituted; each of Rlh and R2h independently is H, halogen, OH, COOH, or optionally halogeno substituted C 1

.

6 alkyl or phenyl; R3h is H or C 1 4alkyl optionally substituted by halogen and/ OH; each R 4 h independently is halogeno, OH, COOH, C,,alkyl, S(O) 0

,

1 0

C

1

-

3 alkyl, C 1 . 3 alkoxy, Cmcycloalkoxy, aryl or aralkoxy, wherein the alkyl portions may optionally be substituted by 1-3 halogens; and each of Rg and M has one of the significances as indicated for B and C, respectively, in W003/062248A2; - Compounds as disclosed in WO 04/026817A, e.g. compounds of formula XII -10 R

XNHR

4 J R 6 j XII

R

2

(CH

2 )nj R 51

OR

7 j wherein R1j is halogen, trihalomethyl, C14alkyl, C 1 4alkoxy, C 1

.

4 alkylthio, C 1

.

4 alkylsulifinyl, C14alkyl sulfonyl, aralkyl, optionally substituted phenoxy or aralkyloxy, R 2 j is H, halogen, trihalo methyl, C 1

.

4 alkyl, C 1 4alkoxy, aralkyl or aralkyloxy, R3i is H, halogen, CF 3 , C 1

.

4 alkyl, C 1 4alkoxy,

C

1 4alkylthio or benzyloxy, R 4 1 is H, C14alkyl, phenyl, optionally substituted benzyl or benzoyl, or lower aliphatic C 1

.

5 acyl, R 5 1 is H, monohalomethyl, C 14 alkyl, C1.4alkoxymethyl, C 1 4alkyl thiomethyl, hydroxyethyl, hydroxypropyl, phenyl, aralkyl, C 2 4alkenyl or -alkynyl, each of R6j and Ryj, independently, is H or C 1 .4alkyl, or R 7 j being also a residue of formula OR -- P <(ORB OR 0 wherein each of Raj and R 9 ;, independently, is H or C1.4alkyl optionally substituted by halogen Xi is 0, S, SO or SO 2 and n; is an integer of 1 to 4, e.g. 2-amino-4-[4-(3 benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutane-1-ol or 2-amino-4-[4-(3 benzyloxyphenylthio)-2-chlorophenyl]-2-ethylbutane-1-ol; - Compounds as disclosed in WO 041103306A, WO 05/000833, WO 05/103309 or WO 05/113330, e.g. compounds of formula XIla or Xillb R . R R1k AW-- Z, Ya N A,-- Z, y N Rk N H aaxin NO-- Rik X11la Xilib wherein Ak is COORsk, OPO(OR 5 k) 2 , PO(OR 5

)

2 . SO2OR5k, PORskORk or 1H-tetrazol-5-y, Rek being H or C 1

.

6 alkyl; Wk is a bond, C 1

.

3 alkylene or C 2

.

3 alkenylene; Yk is C 6

.

1 0aryl or C 3 -gheteroaryl, optionally substituted by 1 to 3 radicals selected from halogene, OH, NO 2 , C 1

.

6 alkyl, C 1 .6alkoxy; halo-substituted C 1 .salkyl and halo-substituted

C

1

.

6 alkoxy; - 11 Zk is a heterocyclic group as indicated in WO 04/103306A, e.g. azetidine; R1k is C.

1 oaryl or C 3 a 9 heteroaryl, optionally substituted by C 1

.

6 alkyl, C0.1oaryl, C 8

.

10 arylC 14 alkyl,

C

3

.

9 heteroaryl, C 3 .gheteroarylC.

4 alkyl, C 3

.

8 cycloalkyl, C3-acycloalkylCl-4alkyl,

C

3

.

8 heterocycloalkyl or C 3

.

8 heterocycloalkylC4alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of Rik may be substituted by I to 5 groups selected from halogen, C 1 . Galkyl, C 1

.

6 alkoxy and halo substituted-C 1 .salkyl or -C 1 .-alkoxy; R2k is H, C 1 .- alkyl, halo substituted C 1

.

4 alkyl, C 2 -salkenyl or C 2 .alkynyl: and each of R3k or R4k, independently, is H, halogen, OH, C 1

.

6 alkyl, C 1

.

6 alkoxy or halo substituted

C

1

.

6 alkyl or C 1

.

6 alkoxy; and the N-oxide derivatives thereof or prodrugs thereof, or a pharmacologically acceptable salt, solvate or hydrate thereof. According to a further embodiment of the invention, a S1P receptor agonist for use in the invention may also be a selective S1P1 receptor, e.g. a compound which possesses a selectivity for the S1 P1 receptor over the S1P3 receptor of at least 20 fold, e.g. 100, 500, 1000 or 2000 fold, as measured by the ratio of EC 50 for the S1 P1 receptor to the EC6 0 for the S1P3 receptor as evaluated in a 35 S-GTPyS binding assay, said compound having an ECSO for binding to the S1 P1 receptor of 100 nM or less as evaluated by the 35 S-GTPyS binding assay. Representative S1 P1 receptor agonists are e.g. the compounds listed in WO 03/061567, the contents of which being incorporated herein by reference, for instance a compound of formula XIV or XV OH OH OH C,~H) XiV or XV When the compounds of formulae I to XV have one or more asymmetric centers in the molecule, the present invention is to be understood as embracing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof are embraced. Compounds of formula Ill or IVb, when the carbon atom bearing the amino group is asymmetric, have preferably the R-configuration at this carbon atom.

- 12 The compounds of above formulae may exist in free or salt form. Examples of pharmaceutically acceptable salts of the compounds of the above formulae 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 with dibasic amino acids, such as lysine. The compounds and salts of the present invention encompass hydrate and solvate forms. Acyl as indicated above may be a residue Ry-CO- wherein Ry is C 1 .salkyl, C 3

.

0 cycloalkyl, phenyl or phenyl-C 1 .alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched. When in the compounds of formula I the carbon chain as R 1 is substituted, it is preferably 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. Preferred compounds of formula I are those wherein R 1 is C 1 3 20 alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R 1 is phenylalkyl substituted by C6.

1 4 -alkyl chain optionally substituted by halogen and the alkyl moiety is a C 1 .5alkyl optionally substituted by hydroxy. More preferably, R 1 is phenyl-C 1 .ealkyl substituted on the phenyl by a straight or branched, preferably straight, C 6

.

1 4 alkyl chain. The

C

6

.

14 alkyl chain may be in ortho, meta or para, preferably in para. Preferably each of R 2 to R 5 is H. A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred SIP receptor agonist of formula I is FTY720, ie. 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 A), e.g. the hydrochloride, as shown: N

HCI

-13 A preferred compound of formula 11 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]ethyllpropane-1,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound B), e.g. the hydrochloride. A preferred compound of formula III is the one wherein W is CH 3 , each of R", to R" 3 is H, Z 2 is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride. The R-enantiomer is particularly preferred. A preferred compound of formula IVa is the FTY720-phosphate (R 2 a is H, R 3 a is OH, Xa is 0, R1, and Rib are OH). A preferred compound of formula IVb is the Compound C-phosphate

(R

2 . is H, R3b is OH, Xa is 0, R1a and Rib are OH, Ya is 0 and R 4 a is heptyl). A preferred 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 IX is a compound wherein Xf is S or 0, Rif is benzyloxy,

R

2 , R 4 f and Rsr are each H, R 3 is Cl and nf is 2. A preferred compound of formula XII is a compound wherein Xj is S or 0, R1; is benzyloxy,

R

2 5, R 4 , Rej and R 7 ; are each H, R 31 is Cl, R5j is hydroxyethyl or hydroxypropyl and nj is 2. Binding affinity of S1P receptor agonists to individual human S1P receptors may be determined in following assays: Transient transfection of human S1P receptors into HEK293 cells EDG receptors and Gi proteins are cloned, and equal amounts of 4 cDNAs for the EDG receptor, G-a, G-p and G-y are mixed and used to transfect monolayers of HEK293 cells using the calcium phosphate precipitate method (M. Wigler et al., Cell. 1977;11;223 and DS. Im et al., Mol. Pharmacol. 2000;57;753). Briefly, a DNA mixture containing 25 pg of DNA and 0.25 M CaCI is added to HEPES-buffered 2 mM Na 2

HPO

4 . Subconfluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and refed media (90% 1:1 Dulbecco's modified essential media (DMEM):F-12 + 10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer -14 (in mM: 20 HEPES, 5 MgC 2 , 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer. After centrifugation at 800xg, the supernatant is diluted with HME without sucrose and centrifuged at 100,000xg for 1h. The resulting pellet is rehomogenized and centrifuged a second hour at 100,000xg. This crude membrane pellet is resuspended in HME with sucrose, aliquoted, and snap-frozen by immersion in liquid nitrogen. The membranes are stored at 70 0 C. Protein concentration is determined spectroscopically by Bradford protein assay. GTPyS binding assay using SIP receptor/HEK293 membrane preparations GTPyS binding experiments are performed as described by DS. Im et al., Mol. Pharmacol. 2000; 57:753. Ligand-mediated GTPyS binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl 2 , pH 7.5) using 25 pg of a membrane preparation from transiently transfected HEK293 cells. Ligand is added to membranes in the presence of 10 pM GDP and 0.1 nM [ 3 S]GTPyS (1200 Ci/mmol) and incubated at 30 0 C for 30 min. Bound GTPyS is separated from unbound using the Brandel harvester (Gaithersburg, MD) and counted with a liquid scintillation counter. Compounds of formula A are disclosed e.g. in WO 94/09010, WO 95/16691, WO 96/41807, USP 5,362,718 or WO 99/15530 which are incorporated herein by reference. They may be prepared as disclosed or by analogy to the procedures described in these references. In a series of further specific or alternative embodiments, the present invention also provides: 1.1. A method for treating an ocular disorder, said method comprising administering to an affected individual a therapeutically effective amount of a SIP receptor agonist. Preferred S1P receptor agonist is Compound A, B or C, (2R)-2-amino-4-[3-(4 cyclohexyloxybutyl)-benzo[b]thien-6-y]-2-methylbutan-1-ol, or a compound of formula IX wherein Xf is S or 0, Rif is.benzyloxy, R2, R 4 r and R 5 r are each H, R 3 t is Cl and nr is 2. As used herein, administration is preferably pertaining to oral, rectal, parenteral and topical administration. An even more preferred administration pertains to topical administration.

-15 Efficacy in the described ocular disorders might be established for example in the following animal models: 1) Genetic animal models for retinal degeneration, e.g. rd mouse (as described in Li et al., Invest. Ophthalmol. Vis. Sci. 2001 ; 42: 2981-2989), Rpe65-deficient mouse (Van Hooser et al., PNAS 2000. ; 97: 8623-8628), RCS rat (Faktorovich et al., Nature 1990; 347:83-86), rds mouse (Ali et al., Nature Genetics 2000, 25 : 306-310), rcdl dog (Suber et al., PNAS 1993; 90: 3968-3972) 2) Experimental retinal degeneration induced by - light exposure in mice (as described in Wenzel et al., Invest. Ophthalmol. Vis. Sci. 2001; 42: 1653-1659) or rats (Faktorovich et al., J. Neurosci: 1992; 12: 3554-3567) - administration of N-methyl-N-nitrosourea (Kiuchi et al., Exp. Eye Res. 2002; 74: 383-392) or sodium iodate (Sorsby & Harding, Vision Res. 1962; 2: 139-148). 3) Experimental model for the injury of the optic nerve (ON) - by ON crush in mice (Levkovitch-Verbin et al., Invest. Ophthalmol. Vis. Sci. 2000; 41: 4169 4174) and rats (Yoles and Schwartz, Exp. Neurol. 1998; 153:1-7) - by ON transection in rats (as described in Martin et al., Invest. Ophthalmol. Vis. Sci. 2002; 43: 2236-2243, Solomon et al. J. Neurosci. Methods 1996; 70:21-25) - by experimental transient (acute) retinal ischemia in rats after ophthalmic vessel ligature (as described in Lafuente et al., Invest. Ophthalmol. Vis. Sci. 2001; 42:2074-2084) or cannulation of the anterior chamber (Buchi et al., Ophthalmologica 1991; 203:138-147) - by intraocular endothelin-1 injection in rats (Stokely at al., Invest. Ophthalmol. Vis. Sci. 2002; 43: 3223-3230) or rabbits (Takei et al., Graefes Arch. Clin. Exp. Ophthalmol 1993; 231:476-481) The pharmaceutical compositions of this invention comprise, for example, enteral or parenteral administration forms from approximately 5 % to approximately 90 %, preferably from approximately 10 % to approximately 80 %, active ingredient. Pharmaceutical compositions according to the invention for enteral or parenteral administration are, for example, in unit dose form, such as in the form of dragies, tablets, capsules or suppositories, and also ampoules. They are prepared in a manner known per so, for example by means of conventional mixing, granulating, confectioning, dissolving or - 16 lyophilising processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, after the addition of appropriate excipients, into tablets or dragee cores. Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and/or polyvinylpyrrolidone, if desired disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow agents, flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Drag~e cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient. Other orally administrable pharmaceutical compositions are hard gelatin capsules and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The hard gelatin capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible for stabilisers to be added. Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules that -17 comprise a combination of the active ingredient with a base material may also be used. Suitable base materials include, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons. There are suitable for parenteral administration by infusion and/or injection especially aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilisers. The compounds may also be administered topically in or around the eye, for example as eyedrops, ophthalmic suspensions or ointments, subconjunctival, peribulbar, retrobulbar or intravitreal injections, possibly with the use of slow-release devices, such as conjunctival inserts, microspheres or other periocular or intraocular depot devices. The dosage of the active ingredient depends on the species of warm-blooded animal, the age and the individual condition and also on the mode of administration. Normally the estimated approximate daily dose in the case of oral administration to a patient weighing approximately 75 kg is from approximately 10 mg to approximately 500 mg. In the case of topical administration, the approximate estimated daily dosage may vary from 0.001 to 10 mg, depending on the mode of administration. The amount of active ingredient in a topical formulation is typically much lower than in oral or parenteral formulations. Typically the active in a topical formulation would range from 0.01% - 10% by weight of total weight.

Claims (5)

1. Use of an SIP receptor agonist ii) the manufacture of a predicament for the treatment of an ocular disorder.

2. Method to treat an ocular disorder which is treatable by an SiP receptor agonist, said method comprising the administration of an effective amount of an SIP receptor agonist to a subject suffering from said ocular disorder.

3. A method, or use according to any preceding claims, wherein said -cular disorder is selected from the group of ischemic retinopathies in general, anterior ischemic optic neuropathy, all forms of optic neuritis, age-related macular degeneration (AMD), in its dry forms (dry AMD) and wet forms (wet AMD)i diabetic retinopathy, diabetic macular edema (DME). proliferative diabetic retinopathy (PDR), cystold maculeir edema (CME), retinal detachment, retinitis pigmentosa (RP), Stargardt's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degenerations. pathologic myopia, retinopathy of prematuritg,and Leber's hereditary optic neuropathy, the after effects of corneal transplantation or of refractive corneal surgery, keratoconjunotivitis sicca (KCS) or dry eye and herpes keratitis.

4. A method, or use according to any preceding claims, wherein the S1 P receptor agonist is or comprises a group of formula X R 3 ,RaN CHaRa (X) wherein Z is H, C 1 .palkyl, Ca. 1 alkenyl, Casalkynyi, phenyl, phenyl substituted by OH, CGralkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, Ca..cycloalkyl, phenyl and phenyl substituted by OH, or CH 2 -R 4 wherein Re is OH, acyloxy or a residue of formula (a) OR

5 Z Z, P (a) OReZ 0 wherelh 2, is a direct bond or 0, preferably 0; SUBSTITUTE SHEET (RULE 26) - 19 each of Rs, and R&, independently, is H, or C- 4 alkyl optionally substituted by 1, 2 or 3 halogen atoms; Rj is OH, acyloxy or a residue of formula (a); and each of Rzz and R independently, is H, Oealkyl or acyl, and wherein the 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, aromatic and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one of Z and R 1 , is or comprises a residue of formula (a), signals as an agonist at one of more sphingosine-1 -phosphate re ceptor; in free form or in a pharmaceutically acceptable salt form, as solvate or hydrate thereof. A method, or a use according to claimffwherein the S1P receptcr agonist is 2 amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol, Compound B or C, (2R)-2-amino 4-[3-(4-cyclohexyloxybutyl)-benzo[blthen-$-yl-2-rnethylbutn-1 -al, or a compound of formula IX as defined hereinbefore wherein Xt is S or 0, Rif is benzyloxy, Rah R 4 f and Rsr are each H, Rer is C1 and nr is 2, in free form or in a pharmaceutically acceptable salt form. .A method, or a use according to according to any of the preceding claims, wherein the S1P receptor agonist Is 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol (compound A) in free form or In a pharmaceutically acceptable salt form. A method, or a use according to according to any of the precedir.g claims, wherein said S1P receptor agonist Is administered topically in or around the eye. A method, or a use according to according to any of the preceding claims, wherein said 81 P receptor agonist Is or comprises a group of formula (1): R 4 R s N- C2OR 2 R, wherein R1 is a straight- or branched (Cj 2 .4)chain which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, 0. S. NRs, wherein R 6 is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or SUBSTITUTE SHEET (RULE 26) -20 which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or R, is a phenylalkyl wherein alkyl is a straight- or branched (C 6 ,. 2 0)carbon chain; or a phenylalkyl wherein alkyl is a straight- or branched (C 1 .c)carbon chain wherein said phenylalkyl is substituted by a straight- or branched (Ca. 2 u)carbon chain optionally substituted by halogen, a straight- or branched (Csa 0 )alkoxy chain optionally substitued by halogen, a straight- or branched (C 2 oo)aIkenyloxy, phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkylalkyl substituted by Cs,20alkyl, heteroarylalkyl substituted by Co-20alkyl, heterocyclic C. 2 galkyl or heterocyclic alkyl substituted by Ca.2alkyl, and wherein the alkyl moiety may have In the carbon chain, a bond or a heteroatcm selected from a double bond, a triple bond, 0, S, sulfinyl, suifonyl, or NRe, wherein R 6 is as defined above, and as a substituent alkoxy, alkenylaxy, alkynyloxy, aralkylox acyl, alkylamino, alkylthia, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy, and each of R 2 , R3, R 4 and R$, independently, is H, C1. 4 alkyl or acyl; or a pharmacologically acceptable salt, solvate or hydrate thereof, } FA method, or use according to any preceding claims, wherein said otcular disorder is age-related macular degeneration (AMD), In its dry forms (dry AMD) and wet forms (wet AMD). SUBSTITUTE SHEET (RULE 26)