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US20100168078A1 - S1p receptor modulators for treating multiple sclerosis - Google Patents

S1p receptor modulators for treating multiple sclerosis Download PDF

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US20100168078A1
US20100168078A1 US12/303,765 US30376507A US2010168078A1 US 20100168078 A1 US20100168078 A1 US 20100168078A1 US 30376507 A US30376507 A US 30376507A US 2010168078 A1 US2010168078 A1 US 2010168078A1
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Peter C. Hiestand
Christian Schnell
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the use of an S1P receptor modulator in the treatment or prevention of neo-angiogenesis associated with a demyelinating disease, e.g. multiple sclerosis.
  • S1 P 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 X.
  • 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 X
  • 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 5z 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 X is a functional group attached as a terminal group to a moiety which may be hydrophilic or lipophilic and comprise one or more aliphatic, alicyclic, aromatic and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one of Z and R 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 5 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 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 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
  • Ar is phenyl or naphthyl; each of m g and n 9 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;
  • 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 I to IXb may exist in free or salt form.
  • pharmaceutically acceptable salts of the compounds of the formulae I to VI 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 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.
  • 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 heteocyclic
  • 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 salt, 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 VI is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbutan-1-ol.
  • a preferred compound of formula IXa is e.g. 1- ⁇ 4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl ⁇ -azetidine-3-carboxylic acid, or a prodrug thereof.
  • S1P receptor agonists or modulators are known as having immunosuppressive properties or anti-angiogenic properties in the treatment of tumors, e.g. as disclosed in EP627406A1, WO 04/103306, WO 05/000833, WO 05/103309, WO 05/113330 or WO 03/097028.
  • MS Multiple sclerosis
  • demyelinating diseases e.g. multiple sclerosis or Guillain-Barré syndrome
  • Characteristic pathological features of demyelinating diseases include inflammation, demyelination and axonal and oligodendrocyte loss. In addition lesions can also have a significant vascular component. A firm link has recently been established between chronic inflammation and angiogenesis and neovascularization seems to have a significant role in the progression of disease.
  • S1P receptor modulators have an inhibitory effect on neo-angiogenesis associated with demyelinating diseases, e.g. MS.
  • the present invention provides:
  • the S1P receptor modulators may be useful in the treatment of one or more of Relapsing-remitting (RR-MS), Secondary-progressive (SP-MS), Primary-progressive (PP-MS) and Progressive-relapsing (PR-MS).
  • RR-MS Relapsing-remitting
  • SP-MS Secondary-progressive
  • PP-MS Primary-progressive
  • PR-MS Progressive-relapsing
  • the S1P receptor modulators as described herein e.g. FTY720, i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-dio, are useful for treating PP-MS.
  • FTY720 i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-dio
  • S1P receptor modulators e.g. the S1P receptor modulators comprising a group of formula X
  • Utility of the S1P receptor modulators in preventing or treating neo-angiogenesis associated with a demyelinating disease as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.
  • the left ventricle is punctured with a 19 gauge needle from a winged infusion set (SV-19BLK; Termudo, Elkton, Md.), which is connected to an airtight pressurized syringe containing the rinsing solution (NaCl 0.9% with 250,000 U/I heparin at 35° C.).
  • the right atrium is punctured to provide outflow, and the perfusate is infused under a precise controlled pressure of 120 mm Hg.
  • the perfusion is continued for 5 min (at a constant rate of 20 ml/min) followed by a pre-fixation solution (2% performaldehyde in PBS at 35° C.).
  • polyurethane resin (PUII4; Vasqtec, Z ⁇ rich, Switzerland) is infused at the same rate.
  • PII4 polyurethane resin
  • the resin-filled brain and spinal cord are excised from the animal and the soft tissue removed by maceration in 7.5% KOH during 24 hr at 50° C.
  • the casts are then thoroughly cleaned with and stored in distilled water before drying by lyophilization.
  • These vascular casts are quantitated using micro computer tomography.
  • a S1P1 receptor modulator e.g. Compound A significantly blocks disease-associated neo-angiogenesis when administered to the animals at a dose of from 0.1 to 20 mg/kg p.o.
  • Compound A, in the hydrochloride salt form fully blocks disease-associated angiogenesis and completely inhibits the relapse phases when administered daily at a dose of 0.3 mg/kg p.o.
  • the same effect is obtained when Compound A, in the hydrochloride salt form, is administered p.o. at 0.3 mg/kg every 2 nd or 3 rd day or once a week.
  • S1P receptor modulator Daily dosages required in practicing the method of the present invention when a S1P receptor modulator alone 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 modulator 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 modulator, together with one or more pharmaceutically acceptable diluents or carriers therefore.
  • the S1Preceptor modulator e.g. Compound A
  • the S1P receptor modulator may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, a VEGF-receptor antagonist.
  • VEGF-receptor antagonist examples include e.g. compounds, proteins or antibodies which inhibit the VEGF receptor tyrosine kinase, inhibit a VEGF receptor or bind to VEGF, and are e.g. in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 98/35958, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, in WO 00/27820, e.g. a N-aryl(thio) anthranilic acid amide derivative e.g.
  • 4-Pyridylmethyl-phthalazine derivatives are e.g. preferred inhibitors of VEGF receptor tyrosine kinase.
  • Such derivatives and their preparation, pharmaceutical formulations thereof and methods of making such compounds are described in WO00/59509, EP02/04892, WO01/10859 and, in particular, in U.S. Pat. No. 6,258,812, which are here incorporated by reference.
  • VEGF-receptor antagonist where the S1P receptor modulator is administered in conjunction with a VEGF-receptor antagonist, dosages of the co-administered VEGF-receptor agonist will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
  • the present invention provides in a yet further aspect:
  • 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.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a S1P receptor modulator and a VEGF-receptor antagonist, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a S1P receptor modulator and a VEGF-receptor antagonist, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.

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US12/303,765 2006-06-27 2007-06-25 S1p receptor modulators for treating multiple sclerosis Abandoned US20100168078A1 (en)

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GB0612721.1 2006-06-27
GBGB0612721.1A GB0612721D0 (en) 2006-06-27 2006-06-27 Organic compounds
PCT/EP2007/005597 WO2008000419A1 (en) 2006-06-27 2007-06-25 S1p receptor modulators for treating multiple sclerosis

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10022340B2 (en) 2013-10-11 2018-07-17 Teikoku Pharma Usa, Inc. Topical sphingosine-1-phosphate receptor agonist formulations and methods of using the same
US10675254B2 (en) 2013-10-11 2020-06-09 Teikoku Seiyaku Co., Ltd. Sphingosine-1-phosphate receptor agonist iontophoretic devices and methods of using the same

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0612721D0 (en) 2006-06-27 2006-08-09 Novartis Ag Organic compounds
CN101674819A (zh) * 2007-05-04 2010-03-17 诺瓦提斯公司 S1p受体调节剂的用途
KR20180017232A (ko) * 2008-06-20 2018-02-20 노파르티스 아게 다발성 경화증을 치료하기 위한 소아용 조성물
KR101618906B1 (ko) 2008-08-18 2016-05-09 노파르티스 아게 말초 신경병증의 치료를 위한 화합물
EP2177521A1 (en) 2008-10-14 2010-04-21 Almirall, S.A. New 2-Amidothiadiazole Derivatives
CN102256941A (zh) * 2008-12-18 2011-11-23 诺瓦提斯公司 新的盐
JP5627597B2 (ja) * 2008-12-18 2014-11-19 ノバルティス アーゲー １−［４−［１−（４−シクロヘキシル−３−トリフルオロメチル−ベンジルオキシイミノ）−エチル］−２−エチル−ベンジル］−アゼチジン−３−カルボン酸ヘミフマル酸塩
KR20110112352A (ko) * 2008-12-18 2011-10-12 노파르티스 아게 1-（4-｛ｌ-［（ｅ）-4-시클로헥실-3-트리플루오로메틸-벤질옥시이미노］-에틸｝-2-에틸-벤질）-아제티딘-3-카르복실산의 신규한 다형체 형태
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
EP2305660A1 (en) 2009-09-25 2011-04-06 Almirall, S.A. New thiadiazole derivatives
US20110124605A1 (en) * 2009-11-20 2011-05-26 Shreeram Aradhye Use of an S1P Receptor Agonist
CN102712618B (zh) * 2009-11-24 2014-11-26 阿勒根公司 作为具有治疗效用的受体调节剂的新型化合物
EP2343287A1 (en) 2009-12-10 2011-07-13 Almirall, S.A. New 2-aminothiadiazole derivatives
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
JO3619B1 (ar) 2011-01-07 2020-08-27 Novartis Ag صياغات مثبطة للمناعة
CN102120720B (zh) * 2011-01-25 2013-05-22 上海华升生物科技有限公司 盐酸芬戈莫德的合成新方法
WO2013057212A1 (en) * 2011-10-21 2013-04-25 Novartis Ag Dosage regimen for an s1p receptor modulator or agonist
JP6222081B2 (ja) * 2012-03-23 2017-11-01 日本電気株式会社 加入者サーバ、監視サーバ、移動端末、これらに関する方法、及びプログラム
RU2506949C1 (ru) * 2012-06-13 2014-02-20 Открытое акционерное общество "Новосибхимфарм" Фармацевтическая композиция агониста рецептора s1p для лечения демиелинизационных заболеваний
CN102887829B (zh) * 2012-09-05 2014-07-02 中国科学院上海药物研究所 芬戈莫德粘酸盐及其晶体的制备方法和用途
US20180042895A1 (en) 2015-02-26 2018-02-15 Novartis Ag Treatment of autoimmune disease in a patient receiving additionally a beta-blocker
WO2017120124A1 (en) 2016-01-04 2017-07-13 Auspex Pharmaceuticals, Inc. Azetidine modulators of the sphingosine 1-phosphate receptor
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
US11629124B2 (en) 2017-03-09 2023-04-18 Novartis Ag Solid forms comprising an oxime ether compound, compositions and methods of use thereof
AU2020372647A1 (en) 2019-10-31 2022-06-16 Idorsia Pharmaceuticals Ltd Combination of a CXCR7 antagonist with an S1P1 receptor modulator
WO2023019320A1 (en) * 2021-08-20 2023-02-23 Carnegie Venture Capital Pty Ltd Combinatorial therapies including implantable damping devices and therapeutic agents for treating a condition and associated systems and methods of use
EP4212156A1 (en) 2022-01-13 2023-07-19 Abivax Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB612721A (en) 1946-02-11 1948-11-17 Richard William Bailey Improvements in combustion product power plant
DK0627406T3 (da) 1992-10-21 1999-07-12 Taito Co 2-Amino-1,3-propandiolforbindelser og immunundertrykkende midler
EP1167384B1 (en) 1992-10-28 2006-12-13 Genentech, Inc. HVEGF Receptor as Vascular endothelial cell growth factor antagonists
DE69524962T4 (de) 1994-08-22 2003-08-28 Mitsubishi Pharma Corp., Osaka Benzolderivate und deren medizinische verwendung
US5880141A (en) 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
DE19638745C2 (de) 1996-09-11 2001-05-10 Schering Ag Monoklonale Antikörper gegen die extrazelluläre Domäne des menschlichen VEGF - Rezeptorproteins (KDR)
CO4950519A1 (es) 1997-02-13 2000-09-01 Novartis Ag Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion
USRE39072E1 (en) 1997-04-04 2006-04-18 Mitsubishi Pharma Corporation 2-aminopropane-1,3-diol compounds, medicinal use thereof, and intermediates in synthesizing the same
CA2339961C (en) 1998-08-11 2009-01-20 Novartis Ag Isoquinoline derivatives with angiogenesis inhibiting activity
UA71587C2 (uk) 1998-11-10 2004-12-15 Шерінг Акцієнгезелльшафт Аміди антранілової кислоти та їхнє застосування як лікарських засобів
GB9824579D0 (en) 1998-11-10 1999-01-06 Novartis Ag Organic compounds
EP1140173B2 (en) 1998-12-22 2013-04-03 Genentech, Inc. Vascular endothelial cell growth factor antagonists and uses thereof
AU766081B2 (en) 1999-03-30 2003-10-09 Novartis Ag Phthalazine derivatives for treating inflammatory diseases
AR025068A1 (es) 1999-08-10 2002-11-06 Bayer Corp Pirazinas sustituidas y piridazinas fusionadas, composicion farmaceutica que las comprenden, uso de dichos compuestos para la manufactura de un medicamentocon actividad inhibidora de angiogenesis
GB0001930D0 (en) 2000-01-27 2000-03-22 Novartis Ag Organic compounds
PT1254138E (pt) 2000-02-09 2005-09-30 Novartis Ag Derivados de piridina que inibem a angiogenese e/ou o receptor de tirosina cinase do vegf
DE10033541C2 (de) 2000-07-11 2003-05-15 Litef Gmbh Lichtleitfaserspule für ein faseroptisches Sagnac-Interferometer und Verfahren zu ihrer Herstellung
CN1267429C (zh) 2000-07-13 2006-08-02 三共株式会社 氨基醇衍生物
AU2001285331B2 (en) 2000-08-31 2006-04-06 Merck & Co., Inc. Phosphate derivatives as immunoregulatory agents
RU2199339C2 (ru) 2001-02-23 2003-02-27 Общество с ограниченной ответственностью "Биотех" Способ лечения рассеянного склероза
JP2002316985A (ja) 2001-04-20 2002-10-31 Sankyo Co Ltd ベンゾチオフェン誘導体
WO2003062252A1 (en) 2002-01-18 2003-07-31 Merck & Co., Inc. Edg receptor agonists
CA2472713C (en) 2002-01-18 2011-07-19 Merck & Co., Inc. N-(benzyl)aminoalkylcarboxylates, phosphinates, phosphonates and tetrazoles as edg receptor agonists
DK1505959T3 (da) * 2002-05-16 2009-02-23 Novartis Ag Anvendelse af EDG-receptorbindingsmidler ved cancer
BR0311347A (pt) * 2002-05-27 2005-02-22 Novartis Ag Alcanóis bis-aromáticos
EP1575576A2 (en) * 2002-09-24 2005-09-21 Novartis AG Organic compounds
KR20040048231A (ko) * 2002-12-02 2004-06-07 주식회사 두산 신생혈관생성 억제제 및 그를 포함한 암 치료용 키트
FR2848495B1 (fr) * 2002-12-12 2006-11-17 Sidel Sa Four pour chauffer au defile des ebauches de recipients en materiau thermoplastique
PE20090743A1 (es) 2003-04-08 2009-07-17 Novartis Ag Composicion farmaceutica que contiene un agonista del receptor s1p y un alcohol de azucar
BRPI0410746A (pt) * 2003-05-19 2006-06-27 Irm Llc compostos e composições imunossupressoras
EP2644195A1 (en) 2003-05-19 2013-10-02 Irm Llc Immunosuppressant Compounds and Compositions
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
UA74941C2 (en) 2004-04-26 2006-02-15 Fos Internat S A A metal-thermal process for producing magnesium and vacuum induction furnace for realizing the same
WO2005113330A1 (en) 2004-05-05 2005-12-01 Adler, Richard, S. Systems and methods for protecting ship from attack on the surface or under water
MXPA06014421A (es) * 2004-06-10 2007-05-04 Regeneron Pharma Uso de inhibidores de vegf para el tratamiento de cancer humano.
CN102397542B (zh) * 2004-11-18 2014-05-07 英克隆有限责任公司 抗血管内皮生长因子受体-1的抗体
SG187468A1 (en) * 2004-11-29 2013-02-28 Novartis Ag Dosage regimen of an s1p receptor agonist
BRPI0518105A (pt) * 2004-12-17 2008-11-04 Genentech Inc uso de antagonista da angiogênese e uso de anticorpo anti-vegf
RU2278687C1 (ru) 2005-06-16 2006-06-27 Государственное образовательное учреждение высшего профессионального образования "БАШКИРСКИЙ ГОСУДАРСТВЕННЫЙ МЕДИЦИНСКИЙ УНИВЕРСИТЕТ ФЕДЕРАЛЬНОГО АГЕНТСТВА ПО ЗДРАВООХРАНЕНИЮ И СОЦИАЛЬНОМУ РАЗВИТИЮ" (ГОУ ВПО БГМУ РОСЗДРАВА РОССИИ) Способ лечения ремиттирующего рассеянного склероза
MY149159A (en) 2005-11-15 2013-07-31 Hoffmann La Roche Method for treating joint damage
GB0612721D0 (en) 2006-06-27 2006-08-09 Novartis Ag Organic compounds
EP2633864A1 (en) 2008-07-25 2013-09-04 The Regents of the University of Colorado Clip inhibitors and methods of modulating immune function
GB2527550B (en) 2014-06-25 2016-09-21 Cook Medical Technologies Llc Implantable medical device with lumen constriction

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10022340B2 (en) 2013-10-11 2018-07-17 Teikoku Pharma Usa, Inc. Topical sphingosine-1-phosphate receptor agonist formulations and methods of using the same
US10188616B2 (en) 2013-10-11 2019-01-29 Teikoku Pharma Usa, Inc. Topical sphingosine-1-phosphate receptor agonist formulations and methods of using the same
US10617655B2 (en) 2013-10-11 2020-04-14 Teikoku Pharma Usa, Inc. Topical sphingosine-1-phosphate receptor agonist formulations and methods of using the same
US10675254B2 (en) 2013-10-11 2020-06-09 Teikoku Seiyaku Co., Ltd. Sphingosine-1-phosphate receptor agonist iontophoretic devices and methods of using the same

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