WO2009042444A2 - Methods and compounds for treating retinol-related diseases - Google Patents

Methods and compounds for treating retinol-related diseases Download PDF

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Publication number
WO2009042444A2
WO2009042444A2 PCT/US2008/076499 US2008076499W WO2009042444A2 WO 2009042444 A2 WO2009042444 A2 WO 2009042444A2 US 2008076499 W US2008076499 W US 2008076499W WO 2009042444 A2 WO2009042444 A2 WO 2009042444A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
compound
optionally substituted
butyl
Prior art date
Application number
PCT/US2008/076499
Other languages
English (en)
French (fr)
Other versions
WO2009042444A3 (en
Inventor
Nathan L. Mata
Kim B. Phan
Tam V. Bui
Mustapha Haddach
Original Assignee
Sirion Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sirion Therapeutics, Inc. filed Critical Sirion Therapeutics, Inc.
Priority to JP2010527024A priority Critical patent/JP2010540541A/ja
Priority to AU2008305303A priority patent/AU2008305303A1/en
Priority to CN200880107835A priority patent/CN101873852A/zh
Priority to EP08834564A priority patent/EP2205234A4/en
Priority to CA2699773A priority patent/CA2699773A1/en
Publication of WO2009042444A2 publication Critical patent/WO2009042444A2/en
Publication of WO2009042444A3 publication Critical patent/WO2009042444A3/en
Priority to IL204728A priority patent/IL204728A0/en

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • retinol-related diseases are macular degenerations, macular dystrophies and retinal dystrophies, including dry- form macular degenerations, geographic atrophy, and/or photoreceptor degeneration.
  • methods, compounds, and compositions for the treatment of hyperretinolemia excess serum retinol levels
  • methods, compounds and compositions for lowering levels of serum retinol, a serum RBP (retinol binding protein), and/or a serum TTR (transthyretin) in a human subject or patient are also presented herein.
  • vitreoretinal diseases such that the level of serum retinol in the body of a patient is lowered.
  • the vitreoretinal diseases are macular degenerations, macular dystrophies and retinal dystrophies.
  • the vitreoretinal diseases are dry form macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophies, diabetic retinopathy, wet form of macular degeneration, retinopathy of prematurity, and/or retinitis pigmentosa.
  • a pharmaceutical composition comprising a compound of Formula (I):
  • a method of treating a vitreoretinal disease comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I) or (II) wherein the retinol binding protein is RBP4.
  • a method of treating a vitreoretinal disease comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I) or (II) wherein the vitreoretinal disease is dry form macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophies, diabetic retinopathy, wet form of macular degeneration, retinopathy of prematurity, and retinitis pigmentosa.
  • D is isopropyl, isobutyl, sec -butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;
  • R is H, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.
  • the therapeutically effective amount of a compound of Formula (II) is provided in the form of an oral pharmaeutical composition for systemic administration of the compound.
  • a method for treating hyperretinolemia comprising administering to a mammal a compound of Formula (I) or (II) wherein hyperretinolemia is associated with a vitreoretinal disease.
  • B is a bond ,-(C 2 -C 7 )alkyl, -(C 2 -C 7 )alkenyl, -(C 3 -C 8 )cycloalkyl, -(C 2 -C 7 )heteroalkyl, - (C 3 -C 8 )heterocycloalkyl, -(C 3 -C 8 )cycloalkenyl, -(C 3 -C 8 )heterocycloalkenyl;
  • R is H, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
  • A is O, NH, or S
  • D is isopropyl, isobutyl, sec -butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;
  • Figure 10 Effect of test compound on reducing total fluorophore levels in ABCA4-/- mice. Mice were treated as described in Figure 1 (above). At the end of the study, one eye from each animal was used to measure total fluorophore levels. Briefly, one whole eye was homogenized in 1 ml phosphate buffer saline (50 mM Na 2 HPOz I , 150 mM NaCl, pH 7.8). Following homogenization, 1 ml methanol was added and the samples were mixed thoroughly. The mixtures were incubated at room temperature for 5 min and extracted twice with 2 ml hexane. The extracts were concentrated to ⁇ 400 ⁇ l for fluorescence measurements.
  • phosphate buffer saline 50 mM Na 2 HPOz I , 150 mM NaCl, pH 7.8
  • 1 ml methanol was added and the samples were mixed thoroughly. The mixtures were incubated at room temperature for 5 min and extracted twice with 2 ml hexane.
  • A is O, NH, or S;
  • B is a bond, -(C 2 -C 7 )alkyl, -(C 2 -C 7 )alkenyl, -(C 3 -C 8 )cycloalkyl, -(C 2 -C 7 )heteroalkyl,
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the term "treating" is used to refer to either prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease, condition or disorder, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition. Amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
  • the administration of the compounds is given continuously or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both are reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • Purified TTR polypeptides comprising a glutathione-S-transferase protein and adsorbed onto glutathione-derivatized wells of 96-well microtiter plates are contacted with test compounds from a small molecule library at pH 7.0 in a physiological buffer solution.
  • Purified TTR polypeptides have been described in the art. See U.S. Patent App. No. 20020160394, herein incorporated by reference.
  • the test compounds in some embodiments, comprise a fluorescent tag. The samples are incubated for 5 minutes to one hour. Control samples are incubated in the absence of a test compound.
  • the buffer solution containing the test compounds is washed from the wells.
  • ETDRS (LogMAR) chart and a standardized refraction and visual acuity protocol. Evaluation of the mean ETDRS (LogMAR) best corrected visual acuity (BCVA) from baseline through the available post-treatment interval visits aids in determining statistical visual improvement. [00352] To assess the ANOVA (analysis of variance between groups) between the control and experimental group, the mean changes in ETDRS (LogMAR) visual acuity from baseline through the available post-treatment interval visits are compared using two-group ANOVA with repeated measures analysis with unstructured covariance using SAS/STAT Software (SAS Institutes Inc, Cary, North Carolina).
  • the serum retinol levels are assessed as follows: after acetonitrile precipitation of serum proteins, the concentrations of retinol are determined from the soluble phase by LC/MS. Alternatively, the serum retinol levels are assessed as described in Driskell et al., J Chromatogr, 1982, 231, 439-444 or Futterman et al., Invest. Ophthalmol Vis Sd, 1975, 14, 125. [00354] Toxicity evaluation after the commencement of the study includes check ups every three months during the subsequent year, every four months the year after and subsequently every six months. Plasma levels of the test compound and its metabolite, serum retinol and/or RBP are also assessed during these visits. The toxicity evaluation includes patients using a compound of Formula (I) or (II) as well as the patients in the control group.
  • Example 25 Activity of non-retinoid modulators on RBP-TTR and CYP 450
  • Example 30c Sublingual (Hard Lozenge) Composition

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/US2008/076499 2007-09-27 2008-09-16 Methods and compounds for treating retinol-related diseases WO2009042444A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2010527024A JP2010540541A (ja) 2007-09-27 2008-09-16 レチノール関連疾患を治療するための方法及び化合物
AU2008305303A AU2008305303A1 (en) 2007-09-27 2008-09-16 Methods and compounds for treating retinol-related diseases
CN200880107835A CN101873852A (zh) 2007-09-27 2008-09-16 治疗视黄醇相关性疾病的方法和化合物
EP08834564A EP2205234A4 (en) 2007-09-27 2008-09-16 METHODS AND COMPOUNDS FOR THE TREATMENT OF RETINOL RELATED DISEASES
CA2699773A CA2699773A1 (en) 2007-09-27 2008-09-16 Methods and compounds for treating retinol-related diseases
IL204728A IL204728A0 (en) 2007-09-27 2010-03-25 Methods and compounds for treating retinol-related diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US97576507P 2007-09-27 2007-09-27
US60/975,765 2007-09-27
US98132207P 2007-10-19 2007-10-19
US60/981,322 2007-10-19

Publications (2)

Publication Number Publication Date
WO2009042444A2 true WO2009042444A2 (en) 2009-04-02
WO2009042444A3 WO2009042444A3 (en) 2009-05-14

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Country Status (8)

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EP (1) EP2205234A4 (enrdf_load_stackoverflow)
JP (1) JP2010540541A (enrdf_load_stackoverflow)
KR (1) KR20100097098A (enrdf_load_stackoverflow)
CN (1) CN101873852A (enrdf_load_stackoverflow)
AU (1) AU2008305303A1 (enrdf_load_stackoverflow)
CA (1) CA2699773A1 (enrdf_load_stackoverflow)
IL (1) IL204728A0 (enrdf_load_stackoverflow)
WO (1) WO2009042444A2 (enrdf_load_stackoverflow)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010119992A1 (en) 2009-04-16 2010-10-21 Takeda Pharmaceutical Company Limited Derivatives of n-acyl-n'-phenylpiperazine useful (inter alia) for the prophylaxis or treatment of diabetes
EP2202223A4 (en) * 2007-10-18 2011-08-10 Takeda Pharmaceutical Heterocyclic compound
WO2012071369A3 (en) * 2010-11-24 2012-08-02 The Trustees Of Columbia University In The City Of New York A non-retinoid rbp4 antagonist for treatment of age-related macular degeneration and stargardt disease
EP2647713A4 (en) * 2010-12-02 2015-11-25 Daiichi Sankyo Co Ltd MODIFIED SINGLE-STRIP POLYNUCLEOTIDE
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
KR20170067791A (ko) 2014-10-24 2017-06-16 다케다 야쿠힌 고교 가부시키가이샤 헤테로시클릭 화합물
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use

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US9944596B2 (en) * 2014-10-24 2018-04-17 Takeda Pharmaceutical Company Limited Heterocyclic compound
EP4142796A4 (en) * 2020-04-29 2024-06-26 Saliogen Therapeutics, Inc. COMPOSITIONS AND METHODS FOR TREATMENT OF HEREDITARY MACULAR DEGENERATION

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US7510710B2 (en) * 2004-01-08 2009-03-31 The Regents Of The University Of Colorado Compositions of UCP inhibitors, Fas antibody, a fatty acid metabolism inhibitor and/or a glucose metabolism inhibitor
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9487509B2 (en) 2007-10-18 2016-11-08 Takeda Pharmaceutical Company Limited Heterocyclic compound
EP2202223A4 (en) * 2007-10-18 2011-08-10 Takeda Pharmaceutical Heterocyclic compound
US8586571B2 (en) 2007-10-18 2013-11-19 Takeda Pharmaceutical Company Limited Heterocyclic compound
US8853215B2 (en) 2009-04-16 2014-10-07 Takeda Pharmaceutical Company Limited Derivatives of N-acyl-N′-phenylpiperazine useful (inter alia) for the prophylaxis or treatment of diabetes
WO2010119992A1 (en) 2009-04-16 2010-10-21 Takeda Pharmaceutical Company Limited Derivatives of n-acyl-n'-phenylpiperazine useful (inter alia) for the prophylaxis or treatment of diabetes
WO2012071369A3 (en) * 2010-11-24 2012-08-02 The Trustees Of Columbia University In The City Of New York A non-retinoid rbp4 antagonist for treatment of age-related macular degeneration and stargardt disease
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
EP2647713A4 (en) * 2010-12-02 2015-11-25 Daiichi Sankyo Co Ltd MODIFIED SINGLE-STRIP POLYNUCLEOTIDE
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US12404277B2 (en) 2014-04-30 2025-09-02 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
EP3848353A1 (en) 2014-10-24 2021-07-14 Takeda Pharmaceutical Company Limited Medicaments for the treatment of ophthalmic diseases
KR20170067791A (ko) 2014-10-24 2017-06-16 다케다 야쿠힌 고교 가부시키가이샤 헤테로시클릭 화합물

Also Published As

Publication number Publication date
KR20100097098A (ko) 2010-09-02
IL204728A0 (en) 2010-11-30
EP2205234A4 (en) 2010-12-22
AU2008305303A1 (en) 2009-04-02
CN101873852A (zh) 2010-10-27
JP2010540541A (ja) 2010-12-24
WO2009042444A3 (en) 2009-05-14
EP2205234A2 (en) 2010-07-14
CA2699773A1 (en) 2009-04-02

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