US20080139662A1 - Use of Sphingosine-1-Phosphate (S1P) Receptor Agonists For the Treatment of Brain Degenerative Diseases - Google Patents

Use of Sphingosine-1-Phosphate (S1P) Receptor Agonists For the Treatment of Brain Degenerative Diseases Download PDF

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US20080139662A1
US20080139662A1 US10/583,106 US58310604A US2008139662A1 US 20080139662 A1 US20080139662 A1 US 20080139662A1 US 58310604 A US58310604 A US 58310604A US 2008139662 A1 US2008139662 A1 US 2008139662A1
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Volker Brinkmann
Nicole Kaneider
Christian J. Wiedermann
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Priority to US14/093,975 priority patent/US20140162964A1/en
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Definitions

  • the present invention relates to a new use for a sphingosine-1-phosphate (S1P) receptor agonist, particularly in the treatment of progressive dementia or brain degenerative diseases.
  • S1P sphingosine-1-phosphate
  • 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 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, or to internalization/desensitization of the receptors as a result of super-agonism and consequently an antagonism of receptor signaling by the natural ligand S1P.
  • the binding affinity of S1P receptor agonists to individual human S1P receptors may be determined in following assay:
  • S1P receptor agonist activities of compounds are tested on the human S1P receptors S1P 1 , S1P 3 , S1P 2 , 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). EC 50 s are calculated using standard curve fitting software. In this assay, the S1P receptor agonists preferably have a binding affinity to S1P receptor ⁇ 50 nM.
  • S1P receptors Internalization and desensitization of S1P receptors is determined using e.g. Chinese hamster ovary (CHO) cells transfected with a myc-tagged human S1P receptor. Internationalization of the receptor as a results of stimulation by agonists is determined by FACS analysis using fluorescently labeled anti-myc antibodies.
  • CHO Chinese hamster ovary
  • Preferred S1P receptor agonists 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 agonist 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 depletes peripheral blood lymphocytes, e.g. by 50%, when administered at a dose of e.g. ⁇ 20 mg/kg.
  • Preferred S1P receptor agonists are further compounds which in addition to their S1P binding properties internalize/desensitize S1P receptors, thereby antagonizing inflammatory processes driven by lysophospholipids, including i.e.
  • S1P sphingosine 1-phosphate
  • SPC sphingophosphorylcholine
  • LPA lysophosphatidic acid
  • S1P receptor agonists examples include, for example
  • R 1 is a straight- or branched (C 12-22 )carbon chain
  • R′ 2 , R′ 3 , R′ 4 and R′ 5 independently, is H, alkyl or acyl, or a pharmaceutically acceptable salt 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 3-8 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.
  • X a is O, S, NR 1s 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
  • 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 lower 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, cycloalkyl, aryl, heterocycle, cycloalkyl substituted by up to three substituents selected from groups a and b,
  • 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 or ester thereof;
  • X f is O or S
  • R 1f , R 2f , R 3f and n f are as disclosed in WO 03/29184 and O3/29205, each of R 4f and R 5f , independently is H or a residue of formula
  • each of R 8f and R 9f is H or C 1-4 alkyl 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 pharmacological salt 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;
  • 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 halogeno, OH, COOH, C 1-4 alkyl, S(O) 0,1 or2 C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycl
  • R 1j is halogen, trihalomethyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, aralkyl, or optionally substituted phenoxy or aralkyloxy
  • R 2j is H, halogen, trihalomethyl, C 1-4 alkyl, C 1-4 alkoxy, aralkyl or aralkyloxy
  • R 3j is H, halogen, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or benzyloxy
  • R 4j is H, C 1-4 alkyl, phenyl, benzyl optionally substituted, lower aliphatic acyl having 1 to 5 C or benzoyl optionally substituted
  • R 5j is H, monohalomethyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, hydroxyethyl, hydroxypropyl, phenyl, aral
  • a S1P receptor agonist for use in a combination of the invention may also be a selective S1P1 receptor, e.g. a compound which possesses a selectivity for the S1P1 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 S1P1 receptor to the EC 50 for the S1P3 receptor as evaluated in a 35 S-GTP ⁇ S binding assay, said compound having an EC 50 for binding to the S1P1 receptor of 100 nM or less as evaluated by the 35 S-GTP ⁇ S binding assay.
  • Representative S1P1 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
  • the compounds of formulae I to XIV may exist in free or salt form.
  • pharmaceutically acceptable salts of the compounds of the formulae I to XIII 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 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.
  • 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 I 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.
  • a preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol.
  • a particularly preferred S1P receptor agonist of formula I is FTY720, 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 II is the one wherein each of R′ 2 to R′ 5 is H and m is 4, i.e. 2-amino-2- ⁇ 2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl ⁇ propane-1,3-diol, in free form or in pharmaceutically acceptable 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′′ 1 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 IVa 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 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.
  • Preferred compounds of formula XII are those wherein R 1j is CF 3 or benzyloxy and R 6j is H
  • Compounds of formulae I to XIV have, on the basis of observed activity, e.g. as described in EP-A1-627,406, been found to be useful e.g. as immunosuppressants, e.g. in the treatment of acute allograft rejection or autoimmune disorders.
  • Brain degenerative diseases are becoming more common in developed countries as the population includes more and more older persons. There is no known cause for the diseases. It is not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's.
  • Alzheimer disease is a progressive degenerative disease of the brain characterized by the insidious onset of dementia. Impairment of memory, judgment, attention span, and problem solving skills are followed by global loss of cognitive abilities.
  • agents which are effective in the treatment of such diseases and disorders e.g. in reducing or preventing disease progression and/or alleviating the symptoms and/or improving quality of life. It has now been found that S1P receptor agonists have interesting properties which make them useful for treating progressive dementia and brain degeneration.
  • a method for treating progressive dementia or brain degeneration in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a sphingosine-1-phosphate (S1P) receptor agonist, e.g. a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a sphingosine-1-phosphate (S1P) receptor agonist e.g. a compound of formula I or a pharmaceutically acceptable salt thereof.
  • diseases and disorders are e.g. Alzheimer disease, amyloidosis, Lewy Body diseases, Multi-Infarct dementia, Pick's disease or cerebral atherosclerosis.
  • a method for reducing or inhibiting loss of cognitive abilities in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a sphingosine-1-phosphate (S1P) receptor agonist, e.g. a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a sphingosine-1-phosphate (S1P) receptor agonist e.g. a compound of formula I, or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in any method as defined under 1.1 to 1.3 above.
  • a pharmaceutical composition for use in any method as defined under 1.1 to 1.3 above comprising a sphingosine-1-phosphate (S1P) receptor agonist, e.g. a compound of formula I or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable diluents or carriers therefor.
  • the progressive dementia or brain degeneration is other than senile dementia.
  • S1P sphingosine-1-phosphate
  • Peripheral blood mononuclear cells are prepared from peripheral venous blood of healthy volunteers (anticoagulated with EDTA). After Lymphoprep® density gradient centrifugation, peripheral blood mononuclear cells are collected and washed three times with normal saline. Positive selection of monocytes is performed by adding MACS colloidal superparamagnetic microbeads conjugated with monoclonal anti-human CD14 antibodies to cooled, freshly prepared peripheral blood mononuclear cell preparations in MACS buffer (PBS with 5 mM EDTA and 0.5% bovine serum albumin) according to the manufacturer's instructions. Cells and microbeads are incubated for 15 min at 4-6° C.
  • MACS buffer PBS with 5 mM EDTA and 0.5% bovine serum albumin
  • the separation column is positioned in the MACS magnetic field and washed with MACS buffer at room temperature.
  • the cells are washed with MACS buffer, resuspended, and loaded onto the top of the separation column.
  • the eluent containing CD14 cells is withdrawn and after removal of the column from the magnet, trapped monocytes (CD14 + ) are eluted with the sixfold amount of cold MACS buffer, centrifuged, and resuspended in medium containing 0.5% BSA.
  • By immunocytochemistry, preparations yield a purity of approximately 98%.
  • Leukocyte migration is measured using a modified 48-blindwell microchemotaxis chamber equipped with 5 ⁇ m pore-sized nitrocellulose filters for monocyte chemotaxis.
  • cells are incubated for 20 min with GFX [500 nM], staurosporine [10 ng/mL], tyrphostin-23 [10 ng/mL], wortmannin [10 nM], cholera toxin [1 nM], DMS [20 pg/mL to 20 ⁇ g/mL] or pertussis toxin [1 nM].
  • a ⁇ 's potency to affect monocyte chemotaxis toward fMLP cells with A ⁇ [1 aM to 1 ⁇ M] are incubated for 20 min. After washing twice, 50 ⁇ l of cell suspension [1 ⁇ 10 6 cells/mL] is put into the upper compartment of the chemotaxis chamber and cells are allowed to migrate for 90 min toward fMLP. After these migration periods the filters are dehydrated, fixed and stained with haematoxylin-eosin. Migration depth is quantified by microscopy, the distance from the surface of the filter to the leading front of three cells being measured. Data are expressed as “chemotaxis index”, which is the ratio between the distance of directed and undirected migration.
  • RNA Total RNA is isolated from 8 ⁇ 10 6 cells by phenol-chloroform-isoamylalcohol extraction (RNACleanTM; Hybaid-AGS, Ulm, Germany).
  • Reverse transcriptase reaction is performed on 1 ⁇ g of RNA using random hexamers reverse transcriptase (Gibco BRL, Life Technologies, Vienna, Austria). 10 ⁇ L of the reverse transcriptase reaction mixture is then subjected to 35 cycles of PCR in a 50 ⁇ L reaction mixture containing 1 pmol of sense and anti-sense primer pairs in a Perkin-Elmer thermocycler: 95° C.—30 sec (denaturation), 53° C.—60 sec (annealing), 72° C.—30 sec (extension).
  • Hot Start Taq polymerase is from Qiagen Inc. (Valencia, Calif., USA).
  • Primers (MWG Biotech, Ebersdorf, Germany) are designed to amplify about 400 bp coding sequences of the receptors.
  • Primers are designed as follows: Sphingosine-1-phosphate receptor (S1PR) 1 sense: CTG TGA ACA ATG CAC TGG, anti-sense: CCT ACG TAC TCA ACA TAG CC.
  • S1PR 3 sense: ATC TGC AGC TTC ATC GTC, anti-sense: AGA TTG AGG CAG TTC.
  • S1PR 2 sense: ACC ACG CAC AGC ACA TAA TG, anti-sense: AAA CAG CAA GTT CCA CTC GG.
  • S1PR 4 sense: TGA ACA TCA CGC TGA GTG, anti-sense: ATC ATC AGC ACC GTC TTC.
  • S1PR 5 sense: GAA ATG CAG CCA AAG GTG, anti-sense: TT ATC ACC CAC AAG GTC CTT C.
  • the PCR products are subjected to agarose gel analysis.
  • monocytes are allowed to migrate toward different concentrations of A ⁇ [10 nmol/L to 1 ⁇ mol/L] or A ⁇ -PP [10 nmol/L to 1 ⁇ mol/L] for 90 min.
  • Directed migration of monocytes is measured using a modified 48-blindwell microchemotaxis chamber equipped with 5 ⁇ m pore-sized nitrocellulose filters for monocyte chemotaxis. Migration depth is quantified by microscopy, measuring the distance from the surface of the filter to the leading front of three cells. Data are expressed as “chemotaxis index”, which is the ratio between the distance of directed and undirected migration.
  • neuropeptides e.g. bombesin, CGRP, SP, SN or VIP and chemotaxis toward A ⁇ and A ⁇ -PP is tested as described above. All neuropeptides inhibit chemotaxis concentration-dependently.
  • Monocytes are incubated with several enzyme blockers.
  • the protein kinase C inhibitor GFX, the tyrosine kinase inhibitor tyrphostin-23, and the phospholipase-3 inhibitor WTN are used first for blocking signaling enzymes; involvement of G proteins is then tested with PTX which is known to induce Gi proteins, and CTX which induces Gs proteins.
  • chemotaxis experiments toward A ⁇ (1 pmol/l) and A ⁇ -PP (1 pmol/l) are performed. Data are expressed as chemotaxis index, which is the ratio between directed and random migration. Mean distance of random migration is 54 ⁇ 3.2 ⁇ m.
  • DMS selective sphingosine kinase inhibitor
  • S1P Receptor Agonist Deactivates Migration of Human Monocytes Toward A ⁇ and Chemokines
  • Monocytes are incubated with DMS, Compound A or medium for 20 min. After washing, chemotaxis experiments toward A ⁇ [1 pmol/L] are performed. Data are expressed as chemotaxis index, which is the ratio between directed and random migration. Mean distance of random migration is 56 ⁇ 5.6 ⁇ m. DMS and a S1P receptor agonist alone inhibit the migration of the cells, whereas co-treatment with both restores the chemotactic effect of A ⁇ and A ⁇ -PP. Results with Compound A are as follows:
  • chemotaxis index which is the ratio between directed and undirected migration of cells.
  • RT-PCR is performed and equal amounts of cDNA are subjected to agarose gel electrophoresis. Induction of S1PR 2 and S1PR 5 mRNA in A ⁇ -treated cells is observed.
  • the trial is carried out employing groups comprising 6 to 10 subjects identified as exhibiting mild to moderate Alzheimer dementia in accordance with parameters defined in DSM-III (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition) and excluding subjects exhibiting severe cardiovascular disease, hypotension, severe endocrine disease, severe liver disease, renal insufficiency.
  • the trial commences with an EEG and psychometric test at time 0. Subjects then receive placebo, or test medication administered as described below, and the EEG and psychometric tests are repeated 60, 120 and 180 minutes subsequent to administration.
  • Psychometric tests employed include:
  • subjects receive either a placebo or a S1P receptor agonist, e.g. Compound A, at dosages of from ca. 0.25 to ca. 10 mg/p.o. administered once or in divided dosages 2 or 3 ⁇ .
  • a S1P receptor agonist e.g. Compound A
  • a S1P receptor agonist e.g. Compound A
  • S1P receptor agonist Daily dosages required in practicing the method of the present invention when S1P receptor agonist is used will vary depending upon, for example, the compound used, the host, the mode of administration and the severity of the condition to be treated.
  • a preferred daily dosage range is about from 0.1 to 100 mg as a single dose or in divided doses.
  • Suitable daily dosages for patients are on the order of from e.g. 0.1 to 50 mg p.o.
  • the S1P receptor agonist may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.
  • Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 30 mg, usually 0.25 to 30 mg S1P receptor agonist, e.g. Compound A, together with one or more pharmaceutically acceptable diluents or carriers therefor.
  • the S1P receptor agonist may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions, or topically.
  • Pharmaceutical compositions comprising a S1P receptor agonist, e.g. a compound of formula I may be manufactured in conventional manner, e.g. as described in EP-A1-627,406 or in EP-A1-1,002,792.
  • the S1P receptor agonists may be administered as the sole ingredient or together with other drugs useful in the alleviation or treatment of brain degenerative diseases or progressive dementia, e.g. an AMPA receptor agonist, a noortropic agent, a painkiller or an anti-inflammatory agent.
  • other drugs useful in the alleviation or treatment of brain degenerative diseases or progressive dementia e.g. an AMPA receptor agonist, a noortropic agent, a painkiller or an anti-inflammatory agent.
  • AMPA receptor antagonist includes, but is not limited to an quinoxaline-dione aminoalkylphosphonate, e.g. as disclosed in WO 98/17672, or to further compounds such as EGIS 8332 (7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 4-(7-chloro-2-methyl-4H-3,10,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BIIR 561; N,N-dimethyl-2-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4-[[[[(4-carboxyphenyl)-amino]carbonyl]oxy
  • YM90K (6-imidazol-1-yl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione), S-34730 (7-chloro-6-sulfamoyl-2-(1H)-quinolinone-3-phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl)-acetic acid), GYKI-52466 (4-(8-methyl-9H-1,3-dioxa-6,7-diaza-cyclohepta[f]inden-5-yl)-phenylamine), ZK-200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H-quinoxalin-1-ylmethyl)-phosphonic acid), CP-465022
  • nootropics as used herein includes, but is not limited to nootropical plant extracts, calcium antagonists, cholinesterase inhibitors, dihydroergotoxin, nicergoline, piracetame, purine derivates, pyritinol, vincamine and vinpocetine.
  • nootropical plant extracts as used herein includes, but is not limited to extracts from Ginkgo leafs.
  • calcium antagonists as used herein includes, but is not limited to cinnarizine and nimodipine.
  • cholinesterase inhibitors as used herein includes, but is not limited to donepezil hydrochloride, rivastigmine and galantamine hydrobromide.
  • purine derivates as used herein includes, but is not limited, to pentifyllin.
  • a suitable anti-inflammatory agent is e.g. a NSAIDs, e.g. naproxen.
  • Extracts from Ginkgo leafs can be administered, e.g., in the form as marketed, e.g. under the trademark GinkodilatTM according to the information provided by the package insert.
  • Cinnarizine can be administered, e.g., in the form as marketed, e.g. under the trademark Cinnarizin Forte-RatiopharmTM.
  • Nimodipine can be administered, e.g., in the form as marketed, e.g. under the trademark NimotopTM.
  • Donepezil hydrochloride can be administered, e.g., in the form as marketed, e.g. under the trademark AriceptTM.
  • Rivastigmine can be prepared as disclosed in U.S. Pat. No. 5,602,176.
  • Galantamine hydrobromide can be administered, e.g., in the form as marketed, e.g. under the trademark ReminylTM.
  • Dihydroergotoxin can be administered, e.g., in the form as marketed, e.g. under the trademark HyderginTM.
  • Nicergoline can be administered, e.g., in the form as marketed, e.g. under the trademark SermionTM.
  • Piracetam can be administered, e.g., in the form as marketed, e.g. under the trademark Cerebrofortem.
  • Pentifyllin can be administered, e.g., in the form as marketed, e.g. under the trademark CosaldonTM.
  • Pyritinol can be administered, e.g., in the form as marketed, e.g. under the trademark EncephabolTM.
  • Vinpocetin can be administered, e.g., in the form as marketed, e.g. under the trademark CavintonTM.
  • co-administered compound will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition to be treated, and so forth.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • S1P receptor agonists are well tolerated at dosages required for use in accordance with the present invention.
  • Compound A has an acute LD 50 >10 mg/kg p.o. in rats and monkeys.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265458B2 (en) 2012-12-04 2016-02-23 Sync-Think, Inc. Application of smooth pursuit cognitive testing paradigms to clinical drug development
US9380976B2 (en) 2013-03-11 2016-07-05 Sync-Think, Inc. Optical neuroinformatics
US10329534B2 (en) 2010-03-01 2019-06-25 Janssen Biotech, Inc. Methods for purifying cells derived from pluripotent stem cells
US10344264B2 (en) 2012-12-31 2019-07-09 Janssen Biotech, Inc. Culturing of human embryonic stem cells at the air-liquid interface for differentiation into pancreatic endocrine cells
US10358628B2 (en) 2011-12-22 2019-07-23 Janssen Biotech, Inc. Differentiation of human embryonic stem cells into single hormonal insulin positive cells
US10377989B2 (en) 2012-12-31 2019-08-13 Janssen Biotech, Inc. Methods for suspension cultures of human pluripotent stem cells

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1905434A1 (en) * 2006-09-26 2008-04-02 Novartis AG Organic compounds comprising an S1P receptor agonist and their therapeutic use
LT3103448T (lt) * 2006-09-26 2019-10-10 Novartis Ag Farmacinės kompozicijos, apimančios s1p moduliatorių
CN104311472B9 (zh) 2008-07-23 2020-03-17 艾尼纳制药公司 经取代的1,2,3,4-四氢环戊并[b]吲哚-3-基乙酸衍生物
MX2011002199A (es) 2008-08-27 2011-05-10 Arena Pharm Inc Derivados de acidos triciclicos substituidos como agonistas del receptor s1p1 utiles en el tratamiento de trastornos autoinmunes e inflamatorios.
EP2177521A1 (en) 2008-10-14 2010-04-21 Almirall, S.A. New 2-Amidothiadiazole Derivatives
EP2202232A1 (en) 2008-12-26 2010-06-30 Laboratorios Almirall, S.A. 1,2,4-oxadiazole derivatives and their therapeutic use
EP2210890A1 (en) 2009-01-19 2010-07-28 Almirall, S.A. Oxadiazole derivatives as S1P1 receptor agonists
US20120128666A1 (en) * 2009-06-24 2012-05-24 Lpath, Inc. Methods of increasing neuronal differentiation using antibodies to lysophosphatidic acid
UY32858A (es) 2009-08-31 2011-03-31 Abbott Healthcare Products Bv Derivados de (tio)morfolina como moduladores de sip
EP2305660A1 (en) 2009-09-25 2011-04-06 Almirall, S.A. New thiadiazole derivatives
EP2343287A1 (en) 2009-12-10 2011-07-13 Almirall, S.A. New 2-aminothiadiazole derivatives
CN103221391B (zh) 2010-01-27 2018-07-06 艾尼纳制药公司 (R)-2-(7-(4-环戊基-3-(三氟甲基)苄基氧基)-1,2,3,4-四氢环戊二烯并[b]吲哚-3-基)乙酸及其盐的制备方法
CA2789480A1 (en) 2010-03-03 2011-09-09 Arena Pharmaceuticals, Inc. Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof
EP2366702A1 (en) 2010-03-18 2011-09-21 Almirall, S.A. New oxadiazole derivatives
EP2390252A1 (en) 2010-05-19 2011-11-30 Almirall, S.A. New pyrazole derivatives
TW201643169A (zh) 2010-07-09 2016-12-16 艾伯維股份有限公司 作為s1p調節劑的螺-哌啶衍生物
TWI522361B (zh) 2010-07-09 2016-02-21 艾伯維公司 作為s1p調節劑的稠合雜環衍生物
TW201206893A (en) 2010-07-09 2012-02-16 Abbott Healthcare Products Bv Bisaryl (thio) morpholine derivatives as S1P modulators
RU2482842C1 (ru) * 2012-04-26 2013-05-27 Открытое акционерное общество "Новосибхимфарм" Фармацевтическая композиция агониста рецептора s1p для лечения демиелинизационных заболеваний (варианты) и способ ее получения
EP2878339A1 (en) * 2013-12-02 2015-06-03 Siena Biotech S.p.A. SIP3 antagonists
AU2016205361C1 (en) 2015-01-06 2021-04-08 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
KR102603199B1 (ko) 2015-06-22 2023-11-16 아레나 파마슈티칼스, 인크. Ｓ1ｐ1 수용체-관련 장애에서의 사용을 위한 (ｒ)-2-(7-(4-시클로펜틸-3-(트리플루오로메틸)벤질옥시)-1,2,3,4-테트라히드로시클로-펜타[ｂ]인돌-3-일)아세트산 (화합물 1)의 결정성 ｌ-아르기닌 염
KR20190113955A (ko) 2017-02-16 2019-10-08 아레나 파마슈티칼스, 인크. 장-외 증상을 갖는 염증성 장질환의 치료를 위한 화합물 및 방법
MX2019009841A (es) 2017-02-16 2020-01-30 Arena Pharm Inc Compuestos y metodos para el tratamiento de la colangitis biliar primaria.
US11555015B2 (en) 2018-09-06 2023-01-17 Arena Pharmaceuticals, Inc. Compounds useful in the treatment of autoimmune and inflammatory disorders
US20220296620A1 (en) * 2019-08-07 2022-09-22 National University Corporation Tokyo Medical And Dental University Agent for preventing or treating mild cognitive impairment
TW202132311A (zh) 2019-10-31 2021-09-01 美商Ｅ 斯蓋普生物股份有限公司 S1p受體調節劑之固體形式

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6004565A (en) * 1997-09-02 1999-12-21 Yoshitomi Pharmaceutical Industries, Ltd. Compositions and methods of using compositions with accelerated lymphocyte homing immunosuppressive properties
US6960692B2 (en) * 2001-09-27 2005-11-01 Kyorin Pharmaceutical Co., Ltd. Diaryl sulfide derivative, addition salt thereof, and immunosuppressant
US6963012B2 (en) * 2001-09-27 2005-11-08 Kyorin Pharmaceutical Co., Ltd. Diaryl ether derivative, addition salt thereof, and immunosuppressant
US20070088002A1 (en) * 2003-11-03 2007-04-19 Lynch Kevin R Orally available sphingosine 1-phosphate receptor agonists and antagonists

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3154742B2 (ja) * 1991-04-30 2001-04-09 日本石油化学株式会社 哺乳類の動脈硬化症治療剤
ATE172711T1 (de) 1992-10-21 1998-11-15 Yoshitomi Pharmaceutical 2-amino-1, 3- propandiolverbindung und immunosuppressium
ES2171191T3 (es) 1994-08-22 2002-09-01 Mitsubishi Pharma Corp Compuesto de benceno y uso medicinal del mismo.
ES2171646T3 (es) * 1995-02-15 2002-09-16 Richter Gedeon Vegyeszet Uso de derivados de vinpocetina para la inhibicion o produccion de beta-proteina amiloide.
DE19513630A1 (de) * 1995-04-05 1996-10-10 Schering Ag Neue Verwendung von AMPA-Agonisten
AU705320B2 (en) * 1995-12-28 1999-05-20 Welfide Corporation 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof for use in the preparation of a non-oral medicament, and for treatment of diseases and disorders
AU3641597A (en) * 1996-06-21 1998-01-07 Advanced Research And Technology Institute, Inc. Methods and compositions comprising r-ibuprofen
ITMI962356A1 (it) * 1996-11-13 1998-05-13 Uni Degli Studi Di Brescia D I Uso di composti derivati da molecole ad attivita' antinfiammatoria di tipo non steroideo per la prevenzione e il trattamento di
AU735406B2 (en) * 1997-02-27 2001-07-05 Novartis Ag Pharmaceutical composition
DE69825056T2 (de) 1997-04-04 2005-08-25 Mitsubishi Pharma Corp. 2-aminopropan-1,3-diol-verbindungen, ihre medizinische anwendung und zwischenprodukte zu ihrer synthese
CA2330329C (en) * 1999-02-26 2009-08-25 Marcus Keep Cerebrospinal and vascular pharmaceutical composition and process for preparing the same
US6420369B1 (en) * 1999-05-24 2002-07-16 Ortho-Mcneil Pharmaceutical, Inc. Anticonvulsant derivatives useful in treating dementia
CA2310990A1 (en) * 2000-04-03 2000-10-09 Michael Pontecorvo A use of galantamine for the treatment of alzheimer's disease; targeting the underlying cause of the disease
PL359411A1 (pl) 2000-07-13 2004-08-23 Sankyo Company, Limited Pochodne aminoalkoholowe
EP1315735A4 (en) * 2000-08-31 2005-04-06 Merck & Co Inc Phosphate derivatives as immunoregulatory compounds
US20030013692A1 (en) * 2001-01-19 2003-01-16 Gullans Steven R. Methods of treating neurological disorders
PL367348A1 (pl) * 2001-03-26 2005-02-21 Novartis Ag Pochodne 2-amino-propanolu
JP2002316985A (ja) 2001-04-20 2002-10-31 Sankyo Co Ltd ベンゾチオフェン誘導体
WO2003011270A1 (de) * 2001-07-31 2003-02-13 Lothar Saiger Mittel zur behandlung von depressionen enthaltend ein lokalanästhetikum
GB0129260D0 (en) * 2001-12-06 2002-01-23 Eisai London Res Lab Ltd Pharmaceutical compositions and their uses
TWI252111B (en) * 2001-12-14 2006-04-01 Solvay Pharm Gmbh Matrix film tablet with controlled release of a natural mixture of conjugated estrogens
JP4430941B2 (ja) * 2002-01-18 2010-03-10 メルク エンド カムパニー インコーポレーテッド Ｅｄｇ受容体作動薬
AU2003216054B2 (en) 2002-01-18 2007-01-04 Merck & Co., Inc. Selective S1P1/Edg1 receptor agonists
WO2003094965A2 (en) * 2002-05-08 2003-11-20 Neuronova Ab Modulation of neural stem cells with s1p or lpa receptor agonists
GB0217152D0 (en) * 2002-07-24 2002-09-04 Novartis Ag Organic compounds
CN100516024C (zh) * 2002-09-13 2009-07-22 诺瓦提斯公司 氨基-丙醇衍生物
US6776328B2 (en) 2002-09-17 2004-08-17 The Boeing Company Radiation assisted friction welding
CN1708293A (zh) * 2002-09-24 2005-12-14 诺瓦提斯公司 治疗脱髓鞘疾病的鞘氨醇－1－磷酸受体激动剂
JP4603531B2 (ja) * 2003-04-30 2010-12-22 ノバルティス アーゲー スフィンゴシン−１−ホスフェートレセプターモジュレーターとしての、アミノプロパノール誘導体
PT1643983E (pt) * 2003-06-24 2010-06-18 Univ Connecticut Métodos de inibir a permeabilidade vascular e apoptose
JP4861177B2 (ja) * 2003-09-12 2012-01-25 ニューロノバ エービー 神経系の障害の処置

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6004565A (en) * 1997-09-02 1999-12-21 Yoshitomi Pharmaceutical Industries, Ltd. Compositions and methods of using compositions with accelerated lymphocyte homing immunosuppressive properties
US6960692B2 (en) * 2001-09-27 2005-11-01 Kyorin Pharmaceutical Co., Ltd. Diaryl sulfide derivative, addition salt thereof, and immunosuppressant
US6963012B2 (en) * 2001-09-27 2005-11-08 Kyorin Pharmaceutical Co., Ltd. Diaryl ether derivative, addition salt thereof, and immunosuppressant
US20070088002A1 (en) * 2003-11-03 2007-04-19 Lynch Kevin R Orally available sphingosine 1-phosphate receptor agonists and antagonists

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10329534B2 (en) 2010-03-01 2019-06-25 Janssen Biotech, Inc. Methods for purifying cells derived from pluripotent stem cells
US10358628B2 (en) 2011-12-22 2019-07-23 Janssen Biotech, Inc. Differentiation of human embryonic stem cells into single hormonal insulin positive cells
US11377640B2 (en) 2011-12-22 2022-07-05 Janssen Biotech, Inc. Differentiation of human embryonic stem cells into single hormonal insulin positive cells
US9265458B2 (en) 2012-12-04 2016-02-23 Sync-Think, Inc. Application of smooth pursuit cognitive testing paradigms to clinical drug development
US10344264B2 (en) 2012-12-31 2019-07-09 Janssen Biotech, Inc. Culturing of human embryonic stem cells at the air-liquid interface for differentiation into pancreatic endocrine cells
US10377989B2 (en) 2012-12-31 2019-08-13 Janssen Biotech, Inc. Methods for suspension cultures of human pluripotent stem cells
US9380976B2 (en) 2013-03-11 2016-07-05 Sync-Think, Inc. Optical neuroinformatics

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