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US20100093672A1 - Use of s1p receptor modulator - Google Patents

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US20100093672A1
US20100093672A1 US12/598,771 US59877108A US2010093672A1 US 20100093672 A1 US20100093672 A1 US 20100093672A1 US 59877108 A US59877108 A US 59877108A US 2010093672 A1 US2010093672 A1 US 2010093672A1
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alkyl
receptor modulator
compound
bdnf
substituted
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Yves-Alain Barde
Graeme Bilbe
Ruben Deogracias
Rainer R. Kuhn
Tomoya Matsumoto
Anis K. Mir
Anna S. Schubart
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Novartis AG
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Definitions

  • BDNF brain-derived neurotrophic factor
  • S1P receptor modulators can induce BDNF production.
  • BDNF has been known as a therapeutic agent for treatment of neurodegenerative diseases (e.g., ALS) or diabetic peripheral neuropathy. BDNF has also been described to be useful as a therapeutic agent for treatment of diabetic mellitus.
  • neurodegenerative diseases e.g., ALS
  • diabetic peripheral neuropathy e.g., diabetic peripheral neuropathy
  • S1P receptor modulators can be employed to treat such conditions affected by BDNF, i.e. conditions which can be treated, delayed or prevented by the increased expression of BDNF.
  • S1P receptor modulators 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 Y.
  • Sphingosine-1 phosphate is a natural serum lipid.
  • S1P receptor modulators 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 Y
  • Z is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl substituted by OH, C 1-6 alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl, phenyl and phenyl substituted by OH, or CH 2 —R 4z wherein R 4z is OH, acyloxy or a residue of formula (a)
  • Z 1 is a direct bond or O, preferably O; each of R 5 , and R 6z , independently, is H, or C 1-4 alkyl optionally substituted by 1, 2 or 3 halogen atoms; R 1z , is OH, acyloxy or a residue of formula (a); and each of R 2z and R 3z independently, is H, C 1-4 alkyl or acyl.
  • Group of formula Y 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 1z is or comprises a residue of formula (a), signals as an agonist at one of more sphingosine-1-phosphate receptor.
  • S1P receptor modulators are compounds which signal as agonists at one or 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 G ⁇ -GTP and G ⁇ -GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling pathways/kinases.
  • the binding affinity of S1P receptor modulators to individual human S1P receptors may be determined in following assay:
  • S1P receptor modulator activities of compounds are tested on the human S1P receptors S1P 1 , S1P 2 , S1P 3 , S1P 4 and S1P 5 .
  • Functional receptor activation is assessed by quantifying compound induced GTP [ ⁇ - 35 S] 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).
  • DMSO dissolved compounds are serially diluted and added to SPA-bead (Amersham-Pharmacia) immobilised S1P receptor expressing membrane protein (10-20 ⁇ g/well) in the presence of 50 mM Hepes, 100 mM NaCl, 10 mM MgCl 2 , 10 ⁇ M GDP, 0.1% fat free BSA and 0.2 nM GTP [ ⁇ - 35 S] (1200 Ci/mmol). After incubation in 96 well microtiterplates at RT for 120 min, unbound GTP [ ⁇ - 35 S] is separated by a centrifugation step. Luminescence of SPA beads triggered by membrane bound GTP [ ⁇ - 35 S] is quantified with a TOPcount plate reader (Packard).
  • the S1P receptor modulators preferably have a binding affinity to S1P receptor ⁇ 50 nM.
  • Preferred S1P receptor modulators are e.g. compounds which in addition to their S1P binding properties also have accelerating lymphocyte homing properties, e.g. compounds which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, without evoking a generalized immunosuppression.
  • Na ⁇ ve cells are sequestered; CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP).
  • the lymphocyte homing property may be measured in following Blood Lymphocyte Depletion assay:
  • a S1P receptor modulator or the vehicle is administered orally by gavage to rats.
  • Tail blood for hematological monitoring is obtained on day ⁇ 1 to give the baseline individual values, and at 2, 6, 24, 48 and 72 hours after application.
  • the S1P receptor agonist or modulator depletes peripheral blood lymphocytes, e.g. by 50%, when administered at a dose of e.g. ⁇ 20 mg/kg.
  • S1P receptor modulators are, for example:
  • R 1 is halogen, trihalomethyl, OH, C 1-7 alkyl, C 1-4 alkoxy, trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy, cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH 2 —OH, CH 2 —CH 2 —OH, C 1-4 alkylthio, C 1-4 alkylsulfonyl, benzylthio, acetyl, nitro or cyano, or phenyl, phenylC 1-4 alkyl or phenyl-C 1-4 alkoxy each phenyl group thereof being optionally substituted by halogen, CF 3 , C 1-4 alkyl or C 1-4 alkoxy; R 2 is H, halogen, trihalomethyl, C 1-4 alkoxy, phenethyl or benzyloxy; R 3
  • each of R 8 and R 9 independently, is H or C 1-4 alkyl optionally substituted by halogen; and n is an integer from 1 to 4; or a pharmaceutically acceptable salt thereof; or a compound of formula II
  • halogen encompasses fluorine, chlorine, bromine and iodine.
  • trihalomethyl group encompasses trifluoromethyl and trichloromethyl.
  • C 1-7 alkyl encompasses straight-chained or branched alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or heptyl.
  • substituted or unsubstituted phenoxy group encompasses those that have, at any position of its benzene ring, a halogen atom, such as fluorine, chlorine, bromine and iodine, trifluoromethyl, C 1-4 alkyl or C 1-4 alkoxy.
  • aralkyl group as in “aralkyl group” or “aralkyloxy group” encompasses benzyl, diphenylmethyl, phenethyl and phenylpropyl.
  • any alkyl moiety as present in “C 1-4 alkoxy”, “C 1-4 alkylthio”, “C 1-4 alkylsulfinyl” or “C 1-4 alkylsulfonyl encompasses straight-chained or branched C 1-4 alkyl, e.g. methyl, ethyl, propyl, isopropyl or butyl.
  • substituted or unsubstituted aralkyl group encompasses those that have, at any position of its benzene ring, a halogen atom, such as fluorine, chlorine, bromine and iodine, trifluoromethyl, lower alkyl having 1-4 carbon atoms, or lower alkoxy having 1-4 carbon atoms.
  • a halogen atom such as fluorine, chlorine, bromine and iodine, trifluoromethyl, lower alkyl having 1-4 carbon atoms, or lower alkoxy having 1-4 carbon atoms.
  • R 2 , R 3 , R 4 , R 5 and n are as defined above; and R 6 is hydrogen, halogen, C 1-7 alkyl, C 1-4 alkoxy or trifluoromethyl.
  • R 3 is chlorine, e.g., 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-propane-1,3-diol, 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol or 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-propane-diol or a pharmacological salts or hydrates thereof and theirs corresponding phosphate derivatives.
  • phosphoric acid mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]ester is also exemplified.
  • the phosphoric acid mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]ester can be prepared enantiomerically pure by the procedures described in WO 2005/021503.
  • an optically active compound of structural formula (Ia), phosphoric acid mono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]ester can be prepared as described in the scheme below utilizing the procedures of Schuding et al. (2003) supra.
  • R 1 is a straight- or branched (C 12-22 )chain
  • R′ 2 , R′ 3 , R′ 4 and R′ 5 independently, is H, C 1-6 alkyl or acyl, or a pharmaceutically acceptable salt or hydrate thereof;
  • W is H; C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; unsubstituted or by OH substituted phenyl; R′′ 4 —O—(CH 2 ) n ; or C 1-6 alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C 3-5 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.
  • Y is H, OH, C 1-6 alkoxy, acyl, acyloxy, amino, C 1-6 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
  • X a is O, S, NR is or a group —(CH 2 ) na —, which group is unsubstituted or substituted by 1 to 4 halogen; n a is 1 or 2, R 1s is H or (C 1-4 )alkyl, which alkyl is unsubstituted or substituted by halogen; R 1a is H, OH, (C 1-4 alkyl or O(C 1-4 )alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R 1b is H, OH or (C 1-4 alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R 2a is independently selected from H or (C 1-4 alkyl, which alkyl is unsubstituted or substituted by halogen; R 3a is H, OH, halogen or O(C 1-4 )alkyl wherein alkyl is unsubstituted or substituted
  • R 1d and R 2d independently, is H or an amino-protecting group;
  • R 3d is hydrogen, a hydroxy-protecting group or a residue of formula
  • R 4d is C 1-4 alkyl; n d is an integer of 1 to 6; X d is ethylene, vinylene, ethynylene, a group having a formula -D-CH 2 — (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; Y d 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 1-10 alkylene having O or S in the middle or end of the carbon chain, or C 1-10 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; R 5d is hydrogen, C 3-6 cycloalkyl, aryl, heterocyclic group, C 3-6 cycloalkyl substituted by up to three substituents
  • R 1e , R 2e , R 3e , R 4e , R 5e , R 6e , R 7e , n e , X e and Y e are as disclosed in JP-14316985; or a pharmacologically acceptable salt, ester or hydrate thereof;
  • Ar is phenyl or naphthyl; each of m g and n g independently is 0 or 1; A is selected from COOH, PO 3 H 2 , PO 2 H, SO 3 H, PO(C 1-3 alkyl)OH and 1H-tetrazol-5-yl; each of R 1g and R 2g independently is H, halogen, OH, COOH or C 1-4 alkyl optionally substituted by halogen; R 3g is H or C 1-4 alkyl optionally substituted by halogen or OH; each R 4g independently is halogen, or optionally halogen substituted C 1-4 alkyl or C 1-3 alkoxy; and each of R g and M has one of the significances as indicated for B and C, respectively, in WO03/062252A1; or a pharmacologically acceptable salt, solvate or hydrate thereof;
  • Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH, 1H-tetrazol-5-yl, PO 3 H 2 , PO 2 H 2 , —SO 3 H or PO(R 5h )OH wherein R 5h is selected from C 1-4 alkyl, hydroxyC 1-4 alkyl, phenyl, —CO—C 1-3 alkoxy and —CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionally substituted; each of R 1h and R 2h independently is H, halogen, OH, COOH, or optionally halogeno substituted C 1-6 alkyl or phenyl; R 3h is H or C 1-4 alkyl optionally substituted by halogen and/OH; each R 4h independently is halogen, OH, COOH, C 1-4 alkyl, S(O) 0,1 or 2 C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cyclo
  • a k is COOR 5k , OPO(OR 5k ) 2 , PO(OR 5k ) 2 , SO 2 OR 5k , POR 5k OR 5k or 1H-tetrazol-5-yl, R 5k being H or C 1-6 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 substituted by 1 to 3 radicals selected from halogene, OH, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy;
  • Z k is a heterocyclic group as indicated in WO 04/103306A, e.g.
  • R 1k is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1k may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or —C 1-6 alkoxy; R 2k is H, C 1-6 alkyl, halo substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl: and each of R 3k
  • the compounds of formulae III to XIb may exist in free or salt form.
  • pharmaceutically acceptable salts of the compounds of the formulae III to VIII 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 combination of the present invention encompass hydrate and solvate forms.
  • Acyl as indicated above may be a residue R y —CO— wherein R y is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenyl-C 1-4 alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.
  • Aryl may be phenyl or naphthyl, preferably phenyl.
  • the carbon chain as R 1 is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy.
  • the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted.
  • the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.
  • Preferred compounds of formula III are those wherein R 1 is C 13-20 alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R 1 is phenylalkyl substituted by C 6-14 -alkyl chain optionally substituted by halogen and the alkyl moiety is a C 1-6 alkyl optionally substituted by hydroxy. More preferably, R 1 is phenyl-C 1-6 alkyl substituted on the phenyl by a straight or branched, preferably straight, C 6-14 alkyl chain. The C 6-14 alkyl chain may be in ortho, meta or para, preferably in para.
  • each of R 2 to R 5 is H.
  • heterocyclic group represents a 5- to 7 membered heterocyclic group having 1 to 3 heteroatoms selected from S, O and N.
  • heterocyclic groups include the heteroaryl groups indicated above, and heterocyclic compounds corresponding to partially or completely hydrogenated heteroaryl groups, e.g.
  • heterocyclic groups are 5- or 6-membered heteroaryl groups and the most preferred heterocyclic group is a
  • a preferred compound of formula III is 2-amino-2-tetradecyl-1,3-propanediol.
  • a particularly preferred S1P receptor agonist of formula I is FTY720, i.e. 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:
  • a preferred compound of formula IV 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 salt form (referred to hereinafter as Compound B), e.g the hydrochloride.
  • a preferred compound of formula V 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.
  • Compound C e.g. the hydrochloride.
  • the R-enantiomer is particularly preferred.
  • a preferred compound of formula VIa is the FTY720-phosphate (R 2a is H, R 3a is OH, X a is O, R 1a and R 1b are OH).
  • a preferred compound of formula IVb is the Compound C-phosphate (R 2a is H, R 3b is OH, X a is O, R 1a and R 1b are OH, Y a is O and R 4a is heptyl).
  • a preferred compound of formula V is Compound B-phosphate.
  • 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 XIa is e.g. 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, or a prodrug thereof.
  • the compounds as described herein may be the direct active substances, or may be prodrugs.
  • the compounds may be phosphorylated forms.
  • S1P receptor modulators have an inhibitory, preventative or delaying effect on conditions associated with or dependent on or affected by levels of BDNF.
  • the compounds as described herein representing the genus of S1P receptor modulators, increase the levels of BDNF, for example, the compounds as described herein stimulate BDNF production.
  • a compound which induces brain-derived neurotrophic factor (BDNF) expression can be used as a therapeutic agent for treatment of nervous system disorders and diseases, or treatment of diabetes mellitus.
  • BDNF brain-derived neurotrophic factor
  • it can be used in the treatment of conditions wherein sensory neurons or retinal ganglion cells are injured.
  • the compounds can be used in the treatment of congenital conditions or neurodegenerative diseases, for example, Alzheimer's disease, Parkinson's disease (the symptoms of Parkinson's disease may be caused by the degeneration of dopaminergic neuron), Parkinson-Plus syndromes (e.g., progressive spranuclear palsy (Steele-Richardson-Olszewski syndromes), olivopontocerebellar atrophy (OPCA), Shy-Drager syndromes (Multiple Systems Atrophy), and Parkinson dementia complex of Guam), Huntington's disease (Huntington's chorea), and Rett Syndrome, but are not limited thereto.
  • Parkinson-Plus syndromes e.g., progressive spranuclear palsy (Steele-Richardson-Olszewski syndromes), olivopontocerebellar atrophy (OPCA), Shy-Drager syndromes (Multiple Systems Atrophy), and Parkinson dementia complex of Guam
  • OPCA olivopontocerebellar atrophy
  • the compounds can be used in the treatment of sensory nerve dysfunction and congenital diseases or neurodegenerative diseases being associated with degenerative of retina.
  • the compounds can be used in the treatment of inherited convulsive paraplegia associated with retina degeneration (Kjellin and Barnard-Scholz syndromes), retinitis pigmentosa, Stargardt disease, Usher syndromes (retinitis pigmentosa accompanied by congenital hearing loss) and Refsum syndrome (retinitis pigmentosa, congenital hearing loss, and polyneuropathy).
  • inherited convulsive paraplegia associated with retina degeneration Kerjellin and Barnard-Scholz syndromes
  • retinitis pigmentosa Stargardt disease
  • Usher syndromes retinitis pigmentosa accompanied by congenital hearing loss
  • Refsum syndrome retinitis pigmentosa, congenital hearing loss, and polyneuropathy
  • the compounds can be used to treat obesity.
  • the compounds may also be used to treat cognitive impairment and/or attention deficit disorder, for example deficits and abnormalities in attention and vigilance, executive functions and memory (for instance working memory and episodic memory).
  • Other disorders relating to cognitive dysfunction include sleep related breathing disorders (SRBD), behavioral impairments, information processing deficits and age-related disorders, Attention-deficit hyperactivity disorder (ADHD), childhood ADHD, adult ADHD, excess daytime somnolence, sleep apnea, traumatic brain injury, neurodegenerative disorders with associated memory and cognitive problems (such as Alzheimer's disease, Lewy body dementia, senile dementia, vascular dementia, Parkinson's disease), chronic fatigue syndrome, fatigue associated with sleep deprivation or prolonged wakefulness, age-related decline in memory and cognitive function (such as mild cognitive impairment), cognitive impairment associated with mood disorders (such as depression) and anxiety, schizophrenia, day time sleepiness associated with narcolepsy.
  • SRBD sleep related breathing disorders
  • ADHD Attention-deficit hyperactivity disorder
  • childhood ADHD childhood ADHD
  • adult ADHD excess daytime somnol
  • the compounds can be used to treat sleep disorders, e.g. narcolepsy, primary insomnia, sleep-awake rhythm disorders (e.g., work-shift syndrome, time-zone syndrome (jet-lag)).
  • sleep disorders e.g. narcolepsy, primary insomnia, sleep-awake rhythm disorders (e.g., work-shift syndrome, time-zone syndrome (jet-lag)).
  • the compounds can be used to treat depressive disorder, e.g. manic-depressive psychosis.
  • the compounds can be useful in making patients feel better.
  • the present invention provides:
  • S1P receptor modulators e.g. the S1P receptor modulators comprising a group of formula Y, in preventing or treating a disease associated with BDNF as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.
  • Female DA rats were treated for 9 days (5 days, 2 day pause, 4 days) with FTY720 p.o.
  • Female DA rats were treated for 9 days (5 days, 2 day pause, 4 days) with FTY720 p.o. 0.1; 0.3 or 1 mg/kg/d vs vehicle
  • Y axis indicates levels of BDNF normalized to control.
  • FTY720 FTY720 (FTY-p) (0.01, 0.1, 1 and 10 nM) for the last 6 days.
  • Y axis indicates levels of BDNF normalized to control.
  • the BDI-II was administered at baseline, and at 3 and 6 months during the core study and at 12 and 24 months during the extension phase (i.e. 6 and 18 months after the start of the extension phase).
  • This is a 21-item self-report scale measuring various symptoms and attitudes associated with depression. Respondents rate depressive symptoms experienced during the past two-weeks on a 4-point scale, coded 0 to 3 by increasing order of severity. A total score across all 21 items can be generated, with lower total scores indicating lower overall severity of depressive symptoms.
  • BDI-II total scores of 14 or above are indicative of clinical depression. Ny reduction in the BDI-II score indicated an improvement in depression.
  • BDI-II scores during the core study are shown in FIG. 5 , and changes in these scores from baseline during the core study are shown in FIG. 6 .
  • BDI-II scores decreased from baseline in patients receiving FTY720 1.25 mg/day, remained consistent in patients receiving FTY720 5.0 mg/day, and increased in patients on placebo.
  • the change in BDI-II scores from baseline in FTY720 1.25 mg/day treated patients was significantly greater than in placebo-treated patients.
  • the difference in changes in BDI-II scores between the two doses of FTY720 was not significant at the 5% level.

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Families Citing this family (11)

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Publication number Priority date Publication date Assignee Title
WO2008135522A1 (fr) * 2007-05-04 2008-11-13 Novartis Ag Utilisation d'un modulateur des récepteurs s1p
CN101973898B (zh) * 2010-09-09 2013-06-19 南京明生医药技术有限公司 2-对辛基苯乙基-2-氨基丙二醇衍生物及其应用
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BR112014005626A2 (pt) * 2011-09-13 2017-03-28 Novartis Ag combinações compreendendo um modulador do receptor de s1p
US8946301B2 (en) * 2011-11-29 2015-02-03 Als Therapy Development Institute Targeting of T-lymphocytes to treat amyotrophic lateral sclerosis
US20180042895A1 (en) 2015-02-26 2018-02-15 Novartis Ag Treatment of autoimmune disease in a patient receiving additionally a beta-blocker
CN106466479A (zh) * 2015-08-18 2017-03-01 周意 脑源性神经营养因子前体蛋白用作治疗情感障碍的靶点
US11629124B2 (en) 2017-03-09 2023-04-18 Novartis Ag Solid forms comprising an oxime ether compound, compositions and methods of use thereof
US11434200B2 (en) 2017-03-09 2022-09-06 Novartis Ag Solid forms comprising an oxime ether compound and a coformer, compositions and methods of use thereof
US20230055568A1 (en) * 2020-02-06 2023-02-23 Mitsubishi Tanabe Pharma Corporation Therapeutic agent for myalgic encephalomyelitis/chronic fatigue syndrome

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064616A2 (fr) * 2001-01-30 2002-08-22 University Of Virgina Patent Foundation Agonistes et antagonistes de recepteurs de sphingosine-1-phosphate
AU2002320470A1 (en) * 2001-07-11 2003-01-29 Musc Foundation For Research Development Modulators of ceramidase and methods of use based thereon
CA2461212C (fr) 2001-09-27 2010-08-17 Kyorin Pharmaceutical Co., Ltd. Derive de sulfure de diaryle, sels correspondant et agents immunosuppresseur utilisant ces derives
WO2003062252A1 (fr) 2002-01-18 2003-07-31 Merck & Co., Inc. Agonistes du recepteur edg
MY150088A (en) * 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
CA2539033C (fr) * 2003-09-12 2013-03-05 Neuronova Ab Traitement d'une maladie ou d'une lesion du systeme nerveux au moyen de fty720
WO2005041899A2 (fr) 2003-11-03 2005-05-12 University Of Virginia Patent Foundation Agonistes et antagonistes du recepteur de la sphingosine-1-phosphate pouvant etre pris par voie orale
AU2005237254B2 (en) 2004-05-03 2010-02-04 Novartis Ag Combinations comprising a S1P receptor agonist and a JAK3 kinase inhibitor
AU2005309378B2 (en) * 2004-11-29 2010-02-11 Novartis Ag Dosage regimen of an S1P receptor agonist
WO2006064616A1 (fr) 2004-12-16 2006-06-22 Matsushita Electric Industrial Co., Ltd. Appareil d’elimination de dechets bruts
GB0504544D0 (en) 2005-03-04 2005-04-13 Novartis Ag Organic compounds
GB0612721D0 (en) * 2006-06-27 2006-08-09 Novartis Ag Organic compounds
KR20090104041A (ko) * 2006-12-19 2009-10-05 메리맥 파마슈티컬즈, 인크. 다발성 경화증을 치료하기 위한 α페토프로테인 및 면역조절제의 병용투여
WO2008135522A1 (fr) * 2007-05-04 2008-11-13 Novartis Ag Utilisation d'un modulateur des récepteurs s1p

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Diem, 2007. Journal of Neuroimmunology, 184: 27-36. *
Multiple Sclerosis from NIH, pp. 1-4, Accessed 3/14/2010. Electronic Resource. [http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm]. *
Whitlock & Siskind. Depression as a major symptom of multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry, 1980, 43, 861-865. *

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