S1p receptor modulators for treating multiple sclerosis

Abstract

To provide the use of a compound in the production of a pharmaceutical to prevent, inhibit or treat neo-angiogenesis associated with a demyelinating disease, e.g. multiple sclerosis, a method including the administration of the compound, and a pharmaceutical composition.SOLUTION: The present invention provides the use of e.g. a 2-substituted 2-aminopropane-1,3-diol or 2-amino-propanol derivative with a specific structure.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the treatment or prevention of angiogenesis associated with demyelinating diseases (e.g., multiple sclerosis). The present invention relates to the use of S1P receptor modulators in [Background technology]

[0002] S1P receptor modulators are typically sphingosine analogs, e.g., 2-substituted 2-aminopropane-1,3-diol or 2-aminopropanol derivatives, such as those of the formula It is a compound containing a group X. Summary of the Invention

[0003] Sphingosine-1 phosphate (hereafter referred to as "S1P") is a naturally occurring serum lipid. Currently, eight S1P receptors are known, namely S1P1 to S1P8. The metabolic modulators are typically sphingosine analogs, e.g., 2-substituted 2-amino Propane-1,3-diol or 2-aminopropanol derivatives, such as those of formula X: [ka] [In the formula, Z is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, phenyl (substituted by OH), C 1-6 Alkyl {halogen, C 3-8 Cycloal 1 selected from the group consisting of alkyl, phenyl and phenyl (substituted with OH). or CH2-R 4z {where R 4z teeth , OH, acyloxy or formula (a): [ka] (Wherein, Z1 is a direct bond or O, preferably O; R 5z and R 6z are each independently H or C 1-4 Alkyl (optionally 1 , substituted by 2 or 3 halogen atoms. It is a group of . and; R 1z is OH, acyloxy or a group of formula (a); R 2z and R 3z are independently H, C 1-4 It is alkyl or acyl. ] It is a compound containing the group:

[0004] The group of formula X comprises at least one Z and R 1z is a group of the formula (a) or a group of the formula (a) When the resulting molecule contains one or more sphingosine-1-phosphate receptor agonists, As long as it signals as a target, it may be hydrophilic or lipophilic and may contain one or more lipids. Attached as an end group to a moiety containing an aliphatic group, an alicyclic group, an aromatic group, and / or a heterocyclic group It is a functional group that is

[0005] S1P receptor modulators are those that bind to one or more sphingosine-1 phosphate receptors ( It is a compound that acts as an agonist for S1P1 to S1P8. It binds to S1P receptors. The agonists that bind to the Gα-GTP and Gβγ-GTP are, for example, intracellular heterotrimers. dissociation of mer-G proteins and / or increased phosphorylation of agonist-bound receptors and This can result in activation of downstream signaling pathways / kinases.

[0006] The binding affinity of S1P receptor modulators to individual human S1P receptors was evaluated using the following assay: It can be determined by Say: The S1P receptor modulator activity of the compounds was determined by measuring the S1P receptors S1P1, S1P2, and S The appropriate human S1P receptors are stably expressed and tested for S1P3, S1P4 and S1P5. Membrane proteins prepared from transfected CHO or RH7777 cells expressing Compound-induced GTP[γ- 35 S] binding to determine functional receptor activity. The assay used is SPA (scintillation proximity based) Briefly, compounds dissolved in DMSO were serially diluted and assayed for S1P receptor activation. Presence of membrane proteins was confirmed by buffering with 50 mM Hepes, 100 mM NaCl, 10 mM MgCl 2, 10 μM GDP, 0.1% lipid-free BSA and 0.2 nM GTP[γ- 3 5 S] (1200 Ci / mmol) was added to immobilized SPA beads (Amersham-Pharmacia). (10-20 μg / well) in a 96-well microtiter plate. After incubation for 1 min, unbound GTP[γ- 35 The membrane is separated by centrifugation. bound GTP[γ- 35 The luminescence of SPA beads triggered by [S] was measured using TOPcount Quantitation was performed using a triad (Packard). 50 Using standard curve fitting software In this assay, S1P receptor modulators are Preferably, it has a binding affinity to the S1P receptor of <50 nM.

[0007] Desirable S1P receptor modulators may, for example, have lymphocyte homing properties in addition to S1P binding properties. Compounds that promote the immune-regulating properties of the immune system, e.g., secondary lymphoid tissues, without causing systemic immunosuppression. Induce lymphopenia by redistribution (preferably reversible) of lymphocytes from the circulation to the Compound. Sequesters naive cells; CD4 and CD8 T cells and B cells from blood stimulates the cells to migrate to lymph nodes (LNs) and Peyer's patches (PPs).

[0008] Lymphocyte homing properties may be measured in the blood lymphocyte depletion assay described below. S1P receptor modulators or vehicle were administered orally by gavage to rats. Tail blood was taken on day -1 to monitor blood levels and baseline individual values. and tail blood was collected at 2, 6, 24, 48 and 72 hours after application. In this assay, an S1P receptor agonist or modulator may be used, for example Reduces peripheral blood lymphocytes by 50% when administered at <20mg / kg.

[0009] Examples of suitable S1P receptor modulators are, for example, those described below. Compounds disclosed in EP 627406A1, such as those of formula I: [ka] [In the formula, R1 is (C 12-22 ) straight or branched chain; In the chain, double bonds, triple bonds, O, S, NR6 (wherein R6 is H, C 1-4 Alki Aryl, aryl-C 1-4 Alkyl, acyl or (C 1-4 alkoxy)carbonyl . ), and carbonyl, and / or As a substituent, C 1-4 Alkoxy, C 2-4 Alkenyloxy, C 2-4 Alkynyl Oxy, Aryl C 1-4 Alkyl-oxy, acyl, C 1-4 Alkylamino, C 1- 4Alkylthio, acylamino, (C 1-4 alkoxy)carbonyl, (C 1-4 Alcoki (C)-carbonylamino, acyloxy, 1-4 Alkyl)carbamoyl, nitro, ha may have halogen, amino, hydroxyimino, hydroxy or carboxy; or R1 is, Phenylalkyl (wherein alkyl is a straight or branched (C 6-20 ) carbon chain .) or Phenylalkyl (wherein alkyl is a straight or branched (C 1-30 ) Carbon chain wherein the phenylalkyl is Linear or branched (C 6-20 ) Carbon chain , Linear or branched (C 6-20 ) Arco Xylic chain, Linear or branched (C 6-20 ) alkenyloxy, Phenyl-C 1-14 Alkoxy, halophenyl-C 1-4 Alkoxy, phenyl- C 1-14 Alkoxy-C 1-14 Alkyl, Phenoxy-C 1-4 Alkoxy or F Phenoxy-C 1-4 Alkyl, C6-20 cycloalkylalkyl substituted by alkyl; C 6-20 heteroarylalkyl substituted by alkyl; Heterocycle C 6-20 Alkyl, or C 2-20 Heterocyclic alkyl substituted with alkyl wherein the alkyl moiety is In the carbon chain, a double bond, a triple bond, O, S, sulfinyl, sulfonyl or NR6 (wherein R6 is as defined above) It is okay to As a substituent, C 1-4 Alkoxy, C 2-4 Alkenyloxy, C 2-4 Alkini ruoxy, aryl C 1-4 Alkyloxy, Acyl, C 1-4 Alkyl-amino, C1 -4 Alkylthio, acylamino, (C 1-4 alkoxy)carbonyl, (C 1-4 Arco oxy)carbonylamino, acyloxy, (C 1-4 Alkyl)carbamoyl, nitro, ha It may have halogen, amino, hydroxy or carboxy. has been replaced by; R2, R3, R4 and R5 are each independently H, C 1-4 Alkyl or Acyl It is.] a compound of formula (I) or a pharma- ceutically acceptable salt or hydrate thereof;

[0010] Compounds disclosed in EP 1002792A1, such as those of formula II: [ka] [In the formula, m is 1 to 9, and R'2, R'3, R'4 and R'5 are each independently , H, C 1-6 It is alkyl or acyl. a compound of formula (I) or a pharma- ceutically acceptable salt or hydrate thereof;

[0011] Compounds disclosed in EP0778263 A1, such as those of formula III: [ka] [Wherein, W is H; C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Non Phenyl substituted or substituted by OH; R''4O(CH2) n ; or C 1-6 Alkyl (halogen, C 3-8 Cycloalkyl, phenyl and phenyl(OH substituted by 1 to 3 substituents selected from the group consisting of (That is; X is H or an unsubstituted or substituted linear alkyl having p carbon atoms, or or unsubstituted or substituted straight-chain alkoxy having (p-1) carbon atoms; , for example C 1-6 Alkyl, OH, C 1-6 Alkoxy, acyloxy, amino, C 1- 6 alkylamino, acylamino, oxo, haloC 1-6 Alkyl, halogen, unsubstituted Phenyl and Phenyl(C 1-6 Alkyl, OH, C 1-6 Alkoxy, acyl, acyl Oxy, Amino, C 1-6 Alkylamino, Acylamino, HaloC 1-6 Alkyl and and substituted with 1 to 3 substituents selected from the group consisting of halogen. and Y is substituted by 1 to 3 substituents selected from the group consisting of H, C 1-6 Alkyl, OH, C 1-6 Alkoxy, acyl, acyloxy, amino, C 1-6 Alki Amino, Acylamino, HaloC 1-6 alkyl or halogen; Z2 is a single bond. is a straight chain alkylene having q or 10 carbon atoms; p and q are each independently an integer from 1 to 20, provided that < p+q < twenty three m' is 1, 2 or 3, and n is 2 or 3; R″1, R″2, R″3 and R″4 are each independently H, C 1-4 Alkyl or is an acyl. a compound of formula (I) or a pharma- ceutically acceptable salt or hydrate thereof;

[0012] Compounds disclosed in WO 02 / 18395, such as compounds of formula IVa or IVb: [ka] [In the formula, X a are O, S, and NR 1s , or the group -(CH2) na - (wherein the group is a non-substituted or substituted with 1 to 4 halogens; a teeth, 1 or 2; R 1s is H or (C 1-4 ) alkyl (wherein alkyl is an unsubstituted or substituted by halogen; R 1a H, OH, ( C 1-4 ) alkyl, or O(C1-4 ) alkyl (wherein alkyl is unsubstituted or substituted by 1 to 3 halogens; R 1b H, O H, or (C 1-4 ) alkyl, where alkyl is unsubstituted or halogen ) and each R 2a is H or (C 1-4 ) Alki where alkyl is unsubstituted or substituted by halogen. are independently selected from; R 3a is H, OH, halogen or O(C 1-4 ) Alkyl ( wherein the alkyl is unsubstituted or substituted by halogen. ;R 3b is H, OH, halogen, (C 1-4 ) alkyl (wherein alkyl is unsubstituted ), or O(C 1-4 )Alkyl ( wherein the alkyl is unsubstituted or substituted by halogen. R;Y a is -CH2-, -C(O)-, -CH(OH)-, -C(=NOH)-, O or S and R 4a (C 4-14 ) alkyl or (C 4-14 ) alkenyl. a compound of formula (I), a pharma- ceutically acceptable salt thereof, or a hydrate thereof;

[0013] Compounds disclosed in WO 02 / 06268AI, such as compounds of formula V: [ka] [In the formula, R 1d and R 2dare each independently H or an amino protecting group; R 3d is hydrogen, a hydroxy protecting group or a group of the formula: [ka] is the basis of; R 4d is C 1-4 is alkyl; n d is an integer from 1 to 6; X d is ethylene, vinylene, ethynylene, formula: -D-CH2- (where D is carbo aryl, -CH(OH)-, O, S or N. substituted with up to three substituents selected from group a defined below) can be; Y d is a single bond, C 1-10 Alkylene, C 1-10 Alkylene (from groups a and b) and at the middle or end of the carbon chain, or C with S 1-10 Alkylene or O or S in the middle or end of the carbon chain C 1-10 Alkylene (up to three substituents selected from groups a and b) (substituted by ); R 5d is hydrogen, C 3-6 Cycloalkyl, aryl, heterocyclic groups, C 3-6 Cycloal alkyl (substituted with up to three substituents selected from groups a and b); aryl (substituted by up to three substituents selected from groups a and b); or a heterocyclic group (substituted with up to three substituents selected from groups a and b) (which is being considered); R6d and R 7d are each independently H or a substituent selected from group a It is a base; R 8d and R 9d are each independently H or C 1-4 Alkyl (optionally halo) (replaced by Gen); <Group a> is a halogen, a lower alkyl, a halogeno lower alkyl, a lower alkoxy, Lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic Acyl, amino, mono-lower alkylamino, di-C 1-4 Alkylamino, acylamin no, cyano or nitro; <Group b> is C 3-6 cycloalkyl, aryl or heterocyclic group, which is optionally substituted with up to three substituents selected from group a; However, R 5d When is hydrogen, Y d is a single bond or linear C 1-10 Alkylene .] a compound of the formula (I) or a pharmacologically acceptable salt, ester, or hydrate thereof;

[0014] Compounds disclosed in JP-14316985 (JP2002316985), such as compounds of formula VI: [ka] [In the formula, R 1e , R 2e , R 3e , R 4e , R 5e , R 6e , R 7e , n e , X e and Y e as disclosed in JP-14316985.] or a pharmacologically acceptable salt, ester or hydrate thereof;

[0015] Compounds disclosed in WO 03 / 062252A1, such as compounds of formula VII: [ka] [In the formula, Ar is phenyl or naphthyl; g and n g are each independently 0 or is 1; A is COOH, PO3H2, PO2H, SO3H, PO(C 1-3 Alki R is selected from 1H-tetrazol-5-yl; 1g and R 2g Yes, that Each independently represents H, halogen, OH, COOH or C 1-4 Alkyl (optionally ha substituted by halogen); R 3g is H or C 1-4 Alkyl (optional) each R is substituted by halogen or OH; 4g is independent and C which is halogen or optionally halogen-substituted. 1-4 Alkyl or is C 1-3 Alkoxy; R g and M are the same as B and M, respectively, described in WO 03 / 062252A1. Each C has one of the meanings given. a compound of formula (I), a pharmacologically acceptable salt thereof, a solvate or a hydrate thereof;

[0016] Compounds disclosed in WO 03 / 062248A2, such as compounds of formula VIII: [ka] wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH, 1H-tetrazol-5-yl, PO3H2, PO2H2, -SO3H or PO(R 5h )OH, where R 5h is C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, phenyl, -CO-C 1-3 Alkoxy and -CH(OH)-phenyl (wherein wherein the phenyl or phenyl moiety is optionally substituted; R 1h and R 2h each independently represents H, halogen, OH, COOH, or optionally C substituted with halogen 1-6 alkyl or phenyl; R 3h H, also is C 1-4 Alkyl (optionally substituted with halogen and / or OH) Yes; each R 4h are independently halogeno, OH, COOH, C 1-4 Alkyl, S(O) 0、1または2 C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkoxy aryl or aralkoxy, wherein the alkyl moiety optionally has 1 to 3 may be substituted by halogens; R h and M are the same as those described in WO 03 / 062248 B and C have the meanings given in A2.] a compound of formula (I), a pharmacologically acceptable salt thereof, a solvate or a hydrate thereof;

[0017] Compounds disclosed in WO 04 / 103306A, WO 05 / 000833, WO 05 / 103309 or WO 05 / 113330 For example, formula IXa or IXb: [ka] [In the formula, A k COOR 5k , OPO(OR 5k )2, PO(OR 5k )2, SO2OR 5k , P.O. R 5k OR 5k or 1H-tetrazol-5-yl, where R 5k is H or C 1-6 is alkyl; W k is a bond, C 1-3 Alkylene, or C 2-3 alkenylene; Y k is C 6-10 Aryl or C 3-9 Heteroaryl, optionally halogen , OH, NO2, C 1-6 Alkyl, C 1-6 Alkoxy;Halo-substituted C 1-6 Alkyl, and halo-substituted C 1-6 alkoxy; the law of nature; Z k is a heterocyclic group as shown in WO 04 / 103306A, such as azetidine; R 1k is C 6-10 Aryl or C 3-9 Heteroaryl (optionally C 1-6 Al Kill, C. 6-10 Aryl, C 6-10 Aryl C 1-4 Alkyl, C 3-9 Hetero ant Ru, C 3-9 Heteroaryl C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 S Chloroalkyl C 1-4 Alkyl, C 3-8 Heterocycloalkyl or C 3-8 Heterosi Chloroalkyl C 1-4 substituted by alkyl; 1k All of The aryl, heteroaryl, cycloalkyl or heterocycloalkyl of , C 1-6 Alkyl, C 1-6 Alkoxy and halo substituted -C 1-6 Alkyl or - C 1-6 Optionally substituted with 1 to 5 groups selected from alkoxy; R 2k , H, C 1-6 Alkyl, halo substituted C 1-6 Alkyl, C 2-6 Alkenyl or is C 2-6 Alkynyl is: R 3k or R 4k are each independently H, halogen, OH, or C 1-6 Alkyl, C 1-6 Alkoxy or halo substituted C 1-6 Alkyl or C 1-6 Alkoxy .] and N-oxide derivatives or prodrugs thereof, or a pharmacologically acceptable salt thereof, a solvate or a hydrate thereof.

[0018] The compounds of formulae I to IXb may exist in free form or in salt form. Examples of pharma- ceutically acceptable salts of the compound include those with inorganic acids, such as hydrochloric acid, hydrobromic acid, and sulfuric acid. Salts, organic acids (e.g., acetic acid, fumaric acid, maleic acid, benzoic acid, citric acid, malic acid, or, where appropriate, with Metal salts (e.g., sodium, potassium, calcium and aluminum salts), amines (e.g. triethylamine) and salts with dibasic amino acids (e.g. lysine). The combinations of compounds and salts of the present invention include hydrate and solvate forms.

[0019] The acyl described above is a group R y -CO- (where R y is C 1-6 Alkyl, C 3- 6 Cycloalkyl, phenyl or phenyl-C 1-4 It may be alkyl. Unless otherwise specified, alkyl, alkoxy, alkenyl, or alkynyl are straight chain. It may be a molecular chain. Aryl may be phenyl or naphthyl, preferably phenyl. .

[0020] In the compounds of formula I, when the carbon chain as R1 is substituted, it is preferably is substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is separated by an optionally substituted phenylene, the carbon chain is It is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably Substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy There are.

[0021] Preferred compounds of formula I are those in which R1 is C 13-20 Alkyl (optionally nitro, halogen , substituted by amino, hydroxy or carboxy; More preferably, R1 is phenylalkyl (C 6-14 Alkyl chain (optionally halogenated) and wherein the alkyl moiety is optionally substituted by C is more hydroxy substituted 1-6 More preferred are compounds in which the aryl group is an alkyl group. Or, R1 is phenyl-C 1-6 Alkyl (straight or branched on the phenyl) Preferably linear C 6-14 The C is substituted with an alkyl chain. 6-14 The alkyl chain may be in the ortho, meta or para position, preferably in the para position. . Preferably, R2 to R5 are each H.

[0022] In the above formula V, the "heterocyclic group" is a heterocyclic group having 1 to 3 heterocyclic rings selected from S, O and N. The heterocyclic group is a 5- to 7-membered heterocyclic group having a heteroatom. Examples of the heterocyclic group are as described above. Heteroaryl groups, and the corresponding partially or fully hydrogenated heteroaryl groups. Heterocyclic compounds such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imino Dazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- Oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl , pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyranyl, morpholinyl, thi Omorpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl or Preferred heterocyclic groups are 5- or 6-membered heteroaryl groups. and the most preferred heterocyclic groups are morpholinyl, thiomorpholinyl, or piperidinyl. It is based on

[0023] A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. Particularly preferred S1P receptor agonists of formula I are FTY720, That is As shown below 2-Amino-2-[2-(4-octyl)amino]phenylacetamide, in free form or in pharma- ceutically acceptable salt form (e.g., hydrochloride salt) The compound is (phenyl)ethyl]propane-1,3-diol (hereinafter referred to as compound A). [ka]

[0024] Preferred compounds of formula II include those having R The compound in which R'2 to R'5 are each H and m is 4, i.e., 2-amino-2-{2 -[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-di The compound was then reacted with the compound B.

[0025] Preferred compounds of formula III are those in free form or in pharma- ceutically acceptable salt form (e.g., the hydrochloride salt): W is CH3, R''1 to R''3 are each H, Z2 is ethylene, and X is The compound where Y is H, i.e., 2-amino-4-(4-heptyloxy) The R-oxyphenyl)-2-methyl-butanol (hereinafter referred to as compound C). The antiomers are particularly preferred.

[0026] The compound may be in phosphorylated form. A preferred compound of formula IVa is FTY720- Phosphate (R 2a is H and R 3a is OH and X a is O and R 1a and R 1bA preferred compound of formula IVb is the compound C-phosphate (R a is H and R 3b is OH and X a is O and R 1a and R 1b is OH , Y a is O and R 4a is heptyl). A preferred compound of formula V is the compound B-phosphate.

[0027] A preferred compound of formula VI is (2R)-2-amino-4-[3-(4-cyclohexyloxy) butyl)-benzo[b]thien-6-yl]-2-methylbutan-1-ol.

[0028] A preferred compound of formula IXa is, for example, 1-{4-[1-(4-cyclohexyl-3- Fluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidin The compound is benzoquinone-3-carboxylic acid, or a prodrug thereof.

[0029] S1P receptor agonists or modulators are described, for example, in EP 627406A1, WO 04 / 103306 , as disclosed in WO 05 / 000833, WO 05 / 103309, WO 05 / 113330 or WO 03 / 097028, In the treatment of tumors, it is known to have immunosuppressive or antiangiogenic properties.

[0030] Multiple sclerosis (MS) causes progressive decline and persistent disability of motor and sensory functions. Multiple sclerosis is an immune-mediated disease of the central nervous system that is associated with chronic inflammation and demyelination. In most cases, the disease is only partially effective and continues to worsen despite anti-inflammatory and immunosuppressive treatments. It does not have any therapeutic effect, but only delays the progression of the disease for a short period of time. reducing, stabilizing, or alleviating a demyelinating disease (e.g., multiple sclerosis or Guillain-Barré syndrome) There is a need for agents that are effective in inhibiting or treating the syndrome.

[0031] The characteristic pathological features of demyelinating diseases are inflammation, demyelination, and axonal and oligodendrocyte proliferation. In addition, the lesions may also have a significant vascular component. A strong link between inflammation and angiogenesis has been established, with angiogenesis being important in disease progression. is seen to have a role.

[0032] Currently, S1P receptor modulators are being investigated for their potential to inhibit angiogenesis associated with demyelinating diseases (e.g., MS). It has been found to have an inhibitory effect on

[0033] In further specific or other aspects, the present invention provides: 1.1 Preventing or inhibiting angiogenesis associated with demyelinating diseases (e.g., MS) in a subject in need thereof or a method of treating, comprising administering to the subject a therapeutically effective amount of an S1P receptor modulator (e.g. for example, a compound of formula I to IXb; 1.2 In a subject in need thereof, a demyelinating disease (e.g., multiple sclerosis or Guillain-Barré syndrome) is A method for alleviating symptoms or slowing progression of a disease, comprising administering to said patient angiogenesis inhibitors associated with said disease. and administering to the subject a therapeutically effective amount of an S1P receptor molecule, the growth of which is prevented or inhibited. a method comprising administering to the subject a modulator (e.g., a compound of Formula I-IXb); 1.3 In a subject in need thereof, a demyelinating disease (e.g., multiple sclerosis or Guillain-Barré syndrome) is ) in a method for reducing, preventing or ameliorating recurrence of the disease, angiogenesis is prevented or inhibited, wherein the subject is administered a therapeutically effective amount of an S1P receptor antagonist. a method comprising administering a modulator (e.g., a compound of Formulas I-IXb); 1.4 In subjects who are in the relapsing-remitting phase of the disease, demyelinating diseases (e.g. multiple sclerosis or A method for slowing the progression of Guillain-Barre syndrome, comprising administering to the patient angiogenesis associated with the disease and (c) administering to the subject a therapeutically effective amount of an S1P receptor module, a method comprising administering to said patient a compound of formula I-IXb; 1.5 The method as set forth above, wherein the S1P receptor modulator is administered intermittently, For example, methods in which the S1P receptor is administered once every 2 or 3 days or once a week; 2. An S1P receptor modulator, together with one or more pharma- ceutically acceptable diluents or carriers. Any one of methods 1.1 to 1.5, comprising a tertiary amine (e.g., a compound of formula I to IXb as defined above). a pharmaceutical composition for use in 3. An S1P receptor modulator for use in any one of methods 1.1 to 1.5. For example compounds of formulae I to IXb as defined above; 4. An S1P receptor for use in the manufacture of a medicament for use in any one of methods 1.1 to 1.5. Receptor modulators (eg compounds of formulae I to IXb as defined above).

[0034] Clinicians typically categorize patients with MS into four types of disease patterns: Relapsing-remitting MS (RR-MS): Occurs over 1-2 weeks and often lasts for 1-2 months Discrete motor, sensory, cerebellar or visual seizures with recovery after each episode. Some patients remain clinically stable until relapse. Approximately 85% of patients initially Although most experience the RR form of S, approximately half progress to secondary progressive disease within 10 years; Secondary Progressive (SP-MS): Initial RR followed by gradual progression with or without relapses Major irreversible disability often occurs during SP. be; Primary Progressive MS (PP-MS): Disease progression occurs from the beginning without any relapses or remissions. Approximately 15% of people with MS are affected; Progressive-relapsing MS (PR-MS): Progressive disease with clear acute relapses from the beginning; It is characterized by a continuation of progression over a period of time.

[0035] Thus, S1P receptor modulators, such as the compounds of formulae I to IXb defined above, Relapsing-remitting MS (RR-MS), secondary progressive MS (SP-MS), primary progressive MS (PP-MS) and progressive The therapeutic agents may be useful in the treatment of one or more of the following:

[0036] In particular, the S1P receptor modulators described herein, such as FTY720, That is 2- Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol is a PP - Useful for treating MS.

[0037] S1P receptor modulators, for example S1P receptor modulators comprising a group of formula X, The utility of the compounds in preventing or treating angiogenesis associated with the above-mentioned demyelinating diseases is demonstrated by animal test methods. and in clinical trials, for example according to the methods described below.

[0038] In vivo: Relapsing experimental autoimmune encephalomyelitis (EAE) The disease was induced in female Lewis rats by injecting mofetil emulsified in complete Freund's adjuvant. The disease was induced by immunization with rat spinal cord tissue, which produced an acute disease by day 11. This is followed by a near-complete remission around day 16, followed by a relapse around day 26. On the sixth day, the rats were deeply anesthetized with isoflurane (3%, 20 L / min), and the thorax was excised and the heart was The left ventricle of the liver was perfused with rinsing solution (NaCl 0.9%, 250,000 A winged infusion set was attached to an airtight pressurized syringe containing 0.0 U / l heparin, 35°C. The right atrium was perforated with a 19-gauge needle from a thoracic ventricle catheter (SV-19BLK; Termudo, Elkton, MD). A hole is drilled to inject irrigation fluid under a precisely controlled pressure of 120 mmHg. This was continued for 5 min (at a constant rate of 20 ml / min) followed by the addition of pre-fixation solution (P Add 2% performaldehyde in BS (35°C). Finally, add up to 30 ml of polyurethane. Polypropylene resin (PUII4; Vasqtec, Zuerich, Switzerland) was injected at the same rate. After 48 h, the Lipid-filled brains and spinal cords were removed from the animals and dissociated in 7.5% KOH at 50°C for 24 hours. The casts were then washed thoroughly with distilled water and After storage in water, they are dried by freeze-drying. These vascular casts are then The results will be quantified using computed tomography.

[0039] In this assay, an S1P1 receptor modulator, e.g., Compound A, is administered to an animal: When administered orally at 0.1 to 20 mg / kg, it significantly blocks disease-associated angiogenesis. The hydrochloride salt of Compound A completely blocked disease-associated angiogenesis and was administered orally at 0.3 mg / kg. Compound A hydrochloride was administered at 0.3 mg / kg once every 2 or 3 days. Similar effects are obtained when administered orally once or once weekly.

[0040] C. Clinical Trials Clinical Benefit Testing of S1P Receptor Agonists, E.g. Compounds of Formula I, E.g. Compound A Twenty patients with relapsing-remitting MS were administered the compound at doses of 0.5, 1.25 or 2.5 mg. The patient's general clinical condition was monitored weekly by a physician and laboratory. Changes in disease status and progression will be monitored by radiological examination (MRI) and Initially, patients are treated for 2-6 months. Treatment is continued as long as there is no progression and the drug is satisfactorily tolerated. Primary variables to evaluate: safety (adverse events), standard serum chemistry and hematology, magnetic resonance imaging Imaging (MRI).

[0041] When an S1P receptor modulator is used alone, the amount of S1P receptor modulator required to carry out the method of the present invention is The daily dosage will vary depending, for example, on the compound used, the host, the method of administration and the severity of the condition being treated. The preferred daily dose range is 0.5 to 20 mg / day, either as a single dose or in divided doses. 1 to 100 mg. Suitable daily doses for patients are, for example, of the order of 0.1 to 50 mg. The S1P receptor modulators may be administered orally by any conventional route. It may be administered enterally, in particular orally, e.g., by tablets, capsules, drinking solutions, nasally, They may be administered pulmonary (by inhalation) or parenterally, for example in the form of an injectable solution or suspension. Suitable unit dosage forms for oral administration may be prepared by administering the composition in a dosage form containing one or more pharma- ceutically acceptable diluents or carriers. Approximately 0.1 to 30 mg, usually 0.25 to 30 mg, of an S1P receptor modulator is administered to the body. As already mentioned, the S1P receptor modulator (e.g., compound A) may alternatively be For example, doses of 0.5 to 30 mg may be administered intermittently, such as every other day or once a week.

[0042] According to another embodiment of the invention, the S1P receptor modulator is or in combination with a VEGF receptor antagonist, e.g., as an adjuvant. It can be done.

[0043] Examples of suitable VEGF receptor antagonists include, for example, VEGF receptor tyrosine kinase inhibitors. Compounds and proteins that inhibit VEGF enzymes, inhibit VEGF receptors, or bind to VEGF and the like, for example, the compounds generally and specifically disclosed in the following documents: Proteins or monoclonal antibodies, in particular those disclosed in WO 98 / 35958, e.g. -(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutical acceptable salt thereof salts such as succinates, as disclosed in WO 00 / 27820, such as N-aryl(thio) ) anthranilic acid amide derivatives, such as 2-[(4-pyridyl)methyl]amino-N-[3-methyl 2-[(1-oxy-5-(trifluoromethyl)phenyl]benzamide or 2-[(1-oxy- 4-pyridyl)methyl]amino-N-[3-trifluoromethylphenyl]benzamide, or WO 00 / 09495, WO 00 / 59509, WO 98 / 11223, WO 00 / 27819, WO 01 / 55114, WO 01 / 58899 and those disclosed in EP 0 769 947; M. Prewett et al, Cancer Research 59 (1999) 5209-5218, F. Yuan et al., Proc. Natl. Acad. Sci. USA, vol. 93, p. p. 14765-14770, Dec. 1996; Z. Zhu et al, Cancer Res. 58, 1998, 3 209-3214, and J. Mordenti et al, Toxicologic Pathology, Vol. 7, no. 1, pp 14-21, 1999; those described in WO 00 / 37502 and WO 94 / 10202 Angiostatin (trade name) described in MS O'Reilly et al, Cell 79, 1994, 315-328 Endostatin™, described in MS O'Reilly et al, Cell 88, 1997, 277-285; Anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or is an anti-VEGF receptor antibody, e.g., RhuMab.

[0044] 4-pyridylmethyl-phthalazine derivatives are useful for inhibiting, for example, VEGF receptor tyrosine kinases. The derivatives and their preparation, pharmaceutical formulations, and methods for preparing the compounds are also disclosed. The method is described in WO 00 / 59509, EP 02 / 04892, WO 01 / 10859, and in particular in U.S. Pat. No. 6,258,812. No. 6,399,433, which are incorporated herein by reference.

[0045] When an S1P receptor modulator is administered with a VEGF receptor antagonist, The dose of VEGF receptor agonist administered depends on the type of concomitant medication used (e.g. the specific drug used (whether the drug is a steroid or a calcineurin inhibitor); The dosage will of course vary depending on the condition being treated, etc.

[0046] In accordance with the foregoing, the present invention also provides in further aspects: 5. A non-toxic therapeutically effective amount of an S1P receptor modulator and a VEGF receptor antagonist and / or a VEGF receptor antagonist, such as those described above, either simultaneously or sequentially. A method as defined above, comprising: 6. a) The S1P receptor molecule disclosed herein, in free form or in pharma- ceutically acceptable salt form. a first drug which is an injector; and b) VEGF receptor antagonists, such as those described above. A pharmaceutical combination, e.g., a kit, comprising: That's fine.

[0047] The terms "co-administration" and "concomitant administration," as used herein, refer to multiple It involves administering a selected therapeutic agent to a patient, and the agent is not necessarily administered in the same The term "treatment regimen" is intended to include treatment regimes in which the two or more agents are administered simultaneously or by different routes of administration.

[0048] The term "pharmaceutical combination" as used herein refers to a combination of one or more active ingredients. It means a product obtained by mixing or combining, a fixed combination of active ingredients The term "fixed combination" includes both active and non-active combinations. The active ingredient (e.g., an S1P receptor modulator and a VEGF receptor antagonist) is This means that both are administered in one dosage form to a single patient at the same time. The term "combination" refers to the combination of active ingredients (e.g., an S1P receptor modulator and a VEGF receptor modulator). GF receptor antagonists) in separate dosage forms simultaneously in one patient Both may be administered simultaneously or consecutively, without any specific time limit. This means that the administration provides a therapeutically effective amount of the two compounds in the patient's body.

Claims

1. Preventing, inhibiting or treating angiogenesis associated with demyelinating diseases, such as multiple sclerosis and the like. Use of compounds IXb to IXc.

2. The present invention relates to a method for the prevention, inhibition, or treatment of PP-MS, comprising administering to a patient a therapeutically effective amount of an S1P receptor molecule. The use of a medicament such as a compound of formula I to IXb as defined herein.

3. The S1P receptor modulator has the formula X: 【Chemistry 1】 [In the formula, Z is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, phenyl, phenyl (substituted by OH), C １－６ Alkyl (halogen, C ３－８ Cycloal one selected from the group consisting of alkyl, phenyl, and phenyl (substituted with OH); substituted by three substituents from ２ -R ４ｚ {where R ４ｚ teeth , OH, acyloxy or formula (a): 【Chemistry 2】 (In the formula, Z １ is a direct bond or O, preferably O; R ５ｚ and R ６ｚ are each independently H or C １－４ Alkyl (optionally 1 , substituted by 2 or 3 halogen atoms. It is a group of . and R １ｚ is OH, acyloxy or a group of formula (a); R ２ｚ and R ３ｚ are each independently H, C １－４ It is alkyl or acyl. ] 3. The use according to claim 1 or 2, which comprises the group

4. The medicament is a VEGF receptor antagonist, e.g. a VEGF receptor antagonist as defined herein.

4. The method of claim 1, wherein the compound is co-administered, for example simultaneously or sequentially, with an antagonist.

1. Use as described in paragraph 1.

5. The S1P receptor modulator, e.g., the present invention, is administered together with a pharma- ceutically acceptable diluent or carrier. The use according to any one of claims 1 to 4, comprising the compounds of formulae I to IXb as defined in the specification. A pharmaceutical composition for use.

6. a) an S1P receptor modulator, e.g. as defined herein, in free or pharma- ceutically acceptable form; a first drug which is a compound of Formula I through XIb in an acceptable salt form; and b) a VEGF receptor antagonist, such as a VEGF receptor antagonist as defined herein; Nist A pharmaceutical combination, e.g. a kit, comprising:

7. Preventing angiogenesis associated with demyelinating diseases, such as multiple sclerosis, in a subject in need thereof. The present invention relates to a method for treating, inhibiting or inhibiting a subject's immune system, comprising administering to the subject a therapeutically effective amount of an S1P receptor modulator. The method comprises administering to the patient a compound of formula I to IXb as defined herein.

8. 1. A method of preventing, inhibiting or treating PP-MS in a subject in need thereof, comprising: The subject is administered a therapeutically effective amount of an S1P receptor modulator, such as one having formula I as defined herein. The method comprises administering a compound of formula (IXb) to a patient of the present invention.

9. 9. The method of claim 8, wherein the S1P receptor modulator is administered intermittently.

10. The S1P receptor modulator or agonist may be in free or pharma- ceutically acceptable form. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diamine in salt form 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]ether 1-(4-cyclohexyl-3- Trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetate The method, use or medicine according to any one of claims 1 to 9, wherein the compound is thiocyanate-3-carboxylate. A composition, or a pharmaceutical combination.

11. The S1P receptor modulator is a 2-amino - 2-[2-(4-octylphenyl)ethyl]propane-1,3-diol.

11. A method, use, pharmaceutical composition or pharmaceutical combination according to any one of claims 1 to 10.

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