WO2011096941A1 - Méthode de traitement d'une allergie oculaire - Google Patents

Méthode de traitement d'une allergie oculaire Download PDF

Info

Publication number
WO2011096941A1
WO2011096941A1 PCT/US2010/023501 US2010023501W WO2011096941A1 WO 2011096941 A1 WO2011096941 A1 WO 2011096941A1 US 2010023501 W US2010023501 W US 2010023501W WO 2011096941 A1 WO2011096941 A1 WO 2011096941A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
alkyl
cycloalkyl
phenyl
Prior art date
Application number
PCT/US2010/023501
Other languages
English (en)
Inventor
Peter G. Klimko
Clay Beauregard
Original Assignee
Alcon Research, Ltd.
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 Alcon Research, Ltd. filed Critical Alcon Research, Ltd.
Priority to PCT/US2010/023501 priority Critical patent/WO2011096941A1/fr
Publication of WO2011096941A1 publication Critical patent/WO2011096941A1/fr

Links

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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • 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
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61P27/14—Decongestants or antiallergics

Definitions

  • the present invention is directed to the topical treatment of ocular allergic disorders, such as allergic conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis.
  • ocular allergic disorders such as allergic conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis.
  • the present invention is directed toward the topical use of 5,6,7-trihydroxyheptanoic acid and its analogs to treat ocular allergy.
  • the eye particularly the conjunctiva, has a relatively large number of mast cells.
  • allergens When allergens are present they can bind to immunoglobulins on the surface of these mast cells and trigger their degranulation (breakdown). Degranulation releases mast cell components, including histamine, into the environment outside the mast cell. Through a variety of mechanisms these components produce ocular surface inflammation resulting in itching, tearing, lid and conjunctival edema/redness, and photophobia. This is frequently designated as an acute phase response, as is seen with seasonal allergic conjunctivitis and perennial allergic conjunctivitis.
  • histamine receptor antagonists such as olopatidine or mast cell stabilizers such as lodoxamide are frequently used to alleviate these symptoms [for a review, see: Bielory et a/., Drugs 2005, 65(2), 215-228].
  • the acute phase response can progress to a late phase response characterized by an influx of eosinophils and neutrophils into the conjunctiva.
  • a late phase response characterized by an influx of eosinophils and neutrophils into the conjunctiva.
  • vernal keratoconjunctivitis exemplified by vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis
  • eyelid swelling and remodeling of the ocular surface tissues can occur.
  • Lipoxin A 4 is an anti-inflammatory eicosanoid biosynthesized from arachidonic acid, and is produced locally at inflammation sites via the interaction of neutrophils with platelets or of other leukocytes with epithelial cells. Lipoxin A is believed to act endogenously to resolve inflammation by inducing apoptosis and phagocytosis/clearance of activated leukocytes.
  • Lipoxin A 4 binds to at least two receptors with nM affinity.
  • the first is the lipoxin A4 cognate receptor, called ALXR. This is the same as the formyl peptide receptor FPRL-1.
  • the second receptor is that for the cysteinyl leukotriene LTD .
  • Lipoxins are thought to function as ALXR agonists and LTD 4 receptor antagonists [Fronert et al., Am. J. Pathol. 2001 , 758(1 ), 3-8].
  • lipoxin A4 structural analogs inhibit allergen-induced eosinophil infiltration, decrease production of pro-inflammatory allergic mediators like cysteinyl leukotrienes, IL-5, and eotaxin, and reduce tissue edema in several animal models, including: a mouse model of allergic asthma [Levy et al., Nat. Med. 2002, 8(9), 1018-1023]; allergen-induced skin inflammation in mice and guinea pigs [Schottelieus et al., J. Immun. 2002, 769(12), 1029-1036]; and allergen- induced pleurisy in rats [Bandeira-Melo et al., J. Immun. 2000, 764(5), 2267- 2271 ].
  • the present invention is directed to methods for the topical treatment of ocular allergy, including seasonal and perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis.
  • a 5,6,7- trihydroxyheptanoic acid or analog is topically administered to a patient, alone or in combination with a histamine receptor antagonist and/or a mast cell degranulation inhibitor, such as olopatidine and emedastine.
  • the 5,6,7- trihydroxyheptanoic acid or analog is administered in an ophthalmic composition dosed topically to a patient's eye.
  • composition comprising a compound of formula I alone or in combination with a histamine receptor antagonist and/or a mast cell degranulation inhibitor is topically administered to a mammal in need thereof:
  • R is H, C-i-6 straight chain or branched alkyl, C3..6 cycloalkyl, or phenyl, or R is a carboxylate salt of formula CO 2 " R ⁇ where R + is Li + , Na + , K + , or an ammonium moiety of formula + NR 10 R 1 R 12 R 13 ;
  • R 2 , R 3 are independently H, Ci -6 alkyl, C3-6 cycloalkyl, benzyl, phenyl, OH, OCH3, or OC2H5, provided that at most only one of R 2 , R 3 is OH, OCH3, or OC 2 H 5 ;
  • R 4 is H, C(O)R 14 , C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, or phenyl;
  • R 5 , R 6 are independently H, C(O)R 14 , Ci -6 alkyl, C 3-6 cycloalkyl, benzyl, phenyl, OH, OCH 3 , or OC 2 H 5 , provided that at most only one of R 2 , R 3
  • R 10 -R 13 are independently H or C -6 alkyl, each alkyl group optionally bearing an OH or OCH 3 substituent;
  • R 14 is H, Ci-6 alkyl, C 3- 6 cycloalkyl, benzyl, or phenyl;
  • R 15 is Ci -6 alkyl, C3-6 cycloalkyl, benzyl, or phenyl;
  • Preferred compounds of formula I are those wherein:
  • R 1 is C 2 H 5 , CO 2 R, CH 2 OR 4 , or a carboxylate salt of formula CO 2 " R + ;
  • R + is Li + , Na + , K + , or NH 4 + ;
  • R is H, CH 3 , C 2 H 5 , n-C 3 H 7 , or /-C 3 H 7 ;
  • R 4 is H, COCH3, or CH 3 ;
  • R 7 , R 8 , R 9 are independently H, CH 3 , or CH 3 CO;
  • Compound 1 is commercially available from Biomol Research Laboratories, Plymouth Meeting, PA, and compound 2 can be prepared as detailed in Lee et. al., Biochemical and Biophysical Research Communications 1991 , 180(3), 1416-21 .
  • Compounds 3-6 can be prepared as described in examples 1-4 below.
  • a solution of methyl ester 1 in aqueous MeOH is heated to reflux in the presence of 3 equivalents of lithium hydroxide. After 6 h the reaction is cooled to room temperature and the pH of the solution is adjusted to 6 by the addition of 70-9 mesh sulfonic acid resin MP (commercially available from Novabiochem/EMD Biosciences, 10394 Pacific Center Court, San Diego, CA 92121 ). The solution is filtered through a 0.2 ⁇ poly-terfluoroethylene syringe filter and concentrated to afford the lithium carboxylate 4 as a white solid.
  • 2-deoxy-D-ribose is converted to the acetonide-protected lactol 10 by treatment with 2-methoxypropene and catalytic pyridinium p-toluenesulfonate (PPTS) in ethyl acetate.
  • PPTS catalytic pyridinium p-toluenesulfonate
  • Deprotection of 12 using 0.1 N HCI in ethanol for 5 minutes, followed by quenching with aqueous NaHC0 3 affords 8 after silica gel chromatographic purification.
  • a compound of formula I is administered in a pharmaceutically acceptable carrier for topical ophthalmic administration.
  • the compositions are formulated in accordance with methods known in the art.
  • the compositions may contain more than one compound of formula I. Additionally, the compositions may contain a second drug, other than a compound of formula I.
  • Compound I was evaluated in a mouse model of late-phase allergy as outlined in example 5 below.
  • mice Female BALB/c mice, 6 to 9 months old (Charles River Labs), were given a single intraperitoneal injection of 100 ⁇ g chicken ovalbumin (OVA; Sigma) which had been absorbed to 5 mg of alum (Pierce Chemical) as an adjuvant or 5 mg alum only (unsensitized group). On day 14 after OVA; Sigma, 100 ⁇ g chicken ovalbumin (OVA; Sigma) which had been absorbed to 5 mg of alum (Pierce Chemical) as an adjuvant or 5 mg alum only (unsensitized group). On day 14 after
  • mice were challenged with a single topical drop O.D. of 1 mg OVA dissolved in 5 ⁇ PBS.
  • mice were administered to mice as a single 5 ⁇ drop O.D. at 60 min before challenge and again at 16 hrs after challenge (BID dosing). Mice were euthanized at 24 hrs after challenge.
  • mice were euthanized at 24 hrs after topical challenge and upper and lower eyelids containing palpebral conjunctiva were excised and immediately frozen on dry ice. Samples were weighed frozen and then thawed and homogenized on ice in 2 ml of 50 mM HEPES buffer, pH 6.5. Samples were pelleted at 4000 rpm for 20 min at 4°C and supernatants were discarded. To each pellet, 1 ml of 0.5% cetyltrimethylammonium chloride (CTAC) was added and samples were vortexed vigorously. Samples were then subjected to three freeze-thaw cycles between -80X and 37°C.
  • CTAC cetyltrimethylammonium chloride
  • EPO activity assay was performed on supernatants.
  • 75 ⁇ of each sample were added in triplicate to wells of a 96-well clear flat-bottomed microplate.
  • 75 ⁇ of EPO substrate solution [6 mM o-phenylenediamine (OPD), 8.8 mM H 2 O 2> and 6 mM KBr in 50 mM HEPES, pH 6.5] were then added to each well using a multichannel pipetter. The reaction was allowed to run for 3 min and was stopped by addition of 150 ⁇ of 4M H 2 SO 4 .
  • aS.D. standard deviation, ⁇ unsensitized mouse. °p ⁇ 0.05 compared to vehicle-treated group by Dunnet's t-test. d Not statistically different from dexamethasone-treated group (p > 0.05 compared to dexamethasone-treated group by Dunnet's t-test).
  • compositions of the present invention contain a pharmaceutically effective amount of a compound of formula I.
  • a pharmaceutically effective amount means an amount sufficient to reduce or eliminate allergic conjunctivitis symptoms.
  • the compositions of the present invention will contain from 0.000001 to 1 % of a compound of formula I.
  • the compositions of the present invention will contain from 0.00003 to 0.01 % of a compound of formula I.
  • compositions administered according to the present invention may also include various other ingredients, including but not limited to surfactants, tonicity agents, buffers, preservatives, co-solvents and viscosity building agents.
  • tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity agent will vary, depending on the particular agent to be added.
  • the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150 - 450 mOsm, preferably 250 - 350 mOsm).
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • the particular concentration will vary, depending on the agent employed.
  • the buffer will be chosen to maintain a target pH within the range of pH 5.5 - 8.
  • Topical ophthalmic products are typically packaged in multidose form.
  • Preservatives are typically required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art.
  • Such preservatives are typically employed at a level of from 0.001 to 1 .0% w/v. Unit dose compositions of the present invention will be sterile, but typically will not contain a preservative and will be unpreserved.
  • 1-2 drops of such compositions will be administered from once to many times per day.
  • Example 6 Representative eye drop formulations are provided below in Examples 6 and 7 for treating allergic conjunctivitis.
  • Example 6 Representative eye drop formulations are provided below in Examples 6 and 7 for treating allergic conjunctivitis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a pour objet l'utilisation topique de l'acide 5,6,7-trihydroxyheptanoïque et de ses analogues, seuls ou en association avec des antagonistes histaminiques et/ou des agents stabilisants des mastocytes pour le traitement d'une allergie oculaire.
PCT/US2010/023501 2010-02-08 2010-02-08 Méthode de traitement d'une allergie oculaire WO2011096941A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2010/023501 WO2011096941A1 (fr) 2010-02-08 2010-02-08 Méthode de traitement d'une allergie oculaire

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2010/023501 WO2011096941A1 (fr) 2010-02-08 2010-02-08 Méthode de traitement d'une allergie oculaire

Publications (1)

Publication Number Publication Date
WO2011096941A1 true WO2011096941A1 (fr) 2011-08-11

Family

ID=42102821

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/023501 WO2011096941A1 (fr) 2010-02-08 2010-02-08 Méthode de traitement d'une allergie oculaire

Country Status (1)

Country Link
WO (1) WO2011096941A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005112905A1 (fr) * 2004-05-14 2005-12-01 Alcon, Inc. Procede de traitement des problemes des yeux secs et de l’uveite
WO2006052950A1 (fr) * 2004-11-09 2006-05-18 Alcon, Inc. Acide 5,6,7-trihydroxyheptanoique et analogues dudit acide dans le traitement de maladies oculaires ou associees a des reactions de type hyperproliferantes et angiogeniques
US20060154981A1 (en) * 2005-01-12 2006-07-13 Alcon, Inc. Method of reducing intraocular pressure and treating glaucoma
US20080108695A1 (en) * 2006-11-07 2008-05-08 Alcon Manufacturing Ltd. Method of Treating Asthma, Allergic Rhinitis, and Skin Disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005112905A1 (fr) * 2004-05-14 2005-12-01 Alcon, Inc. Procede de traitement des problemes des yeux secs et de l’uveite
WO2006052950A1 (fr) * 2004-11-09 2006-05-18 Alcon, Inc. Acide 5,6,7-trihydroxyheptanoique et analogues dudit acide dans le traitement de maladies oculaires ou associees a des reactions de type hyperproliferantes et angiogeniques
US20060154981A1 (en) * 2005-01-12 2006-07-13 Alcon, Inc. Method of reducing intraocular pressure and treating glaucoma
US20080108695A1 (en) * 2006-11-07 2008-05-08 Alcon Manufacturing Ltd. Method of Treating Asthma, Allergic Rhinitis, and Skin Disorders

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
BANDEIRA-MELO ET AL., J. IMMUN., vol. 164, no. 5, 2000, pages 2267 - 2271
BIELORY ET AL., DRUGS, vol. 65, no. 2, 2005, pages 215 - 228
FRONERT ET AL., AM. J. PATHOL., vol. 158, no. 1, 2001, pages 3 - 8
GRONERT ET AL., AM. J. PATH., vol. 158, no. 1, 2000, pages 3 - 9
J. EXP. MED., vol. 180, no. 1, 1994, pages 253 - 260
JOZSEF ET AL., PROC. NATL. ACAD. SCI. USA, vol. 99, no. 20, 2002, pages 13266 - 13271
LEE T H ET AL: "INHIBITION OF LEUKOTRIENE B4-INDUCED NEUTROPHIL MIGRATION BY LIPOXIN A4: STRUCTURE-FUNCTION RELATIONSHIPS", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US LNKD- DOI:10.1016/S0006-291X(05)81354-3, vol. 180, no. 3, 14 November 1991 (1991-11-14), pages 1416 - 1421, XP008042397, ISSN: 0006-291X *
LEE, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 180, no. 3, 1991, pages 1416 - 21
LEVY ET AL., NAT. MED., vol. 8, no. 9, 2002, pages 1018 - 1023
MITCHELL H. FRIEDLAENDER: "Conjunctivitis", June 2008 (2008-06-01), XP002578839, Retrieved from the Internet <URL:http://www.merck.com/mmpe/sec09/ch101/ch101c.html> [retrieved on 20100421] *
ONO; ABELSON, J. ALLERGY CLIN. LMMUNOL., vol. 1 15, no. 1, 2005, pages 118 - 122
PETASIS ET AL., PROSTAGLANDINS LEUKOT. ESSENT. FATTY ACIDS, vol. 73, no. 3-4, 2005, pages 301 - 321
SCHOTTELIEUS ET AL., J. IMMUN., vol. 169, no. 12, 2002, pages 1029 - 1036

Similar Documents

Publication Publication Date Title
AU711482B2 (en) Compositions for treatment of diabetic complications
KR20080005957A (ko) 피부 결합조직질환 치료용 베타-2 아드레노리셉터 작용제
JP6343000B2 (ja) オイゲノールを有効成分として含有するアトピー性皮膚炎の予防又は治療用組成物
US8034839B2 (en) Method of treating ocular allergy
AU2013271836B2 (en) Method for treating skin inflammatory diseases
WO2017111069A1 (fr) Agent antiprurigineux
WO2008058098A2 (fr) Procédé de traitement de l&#39;asthme, de la rhinite allergique et de troubles cutanés
BR112015014367B1 (pt) Composição inibidora de lfa-1, método para estabilizar a dita composição e uso da mesma para tratar uma doença ocular
WO2011096941A1 (fr) Méthode de traitement d&#39;une allergie oculaire
RU2543326C2 (ru) Фармацевтическая композиция для лечения зуда кожи
EP0532512B1 (fr) Emploi d&#39;antagonistes de facteur d&#39;activation plaquettaire comme agents antipruritiques
CA2540859A1 (fr) Compositions et procedes pour le traitement topique ou la prevention topique d&#39;etats pathologiques de la peau
JP5021155B2 (ja) エピナスチンと１種以上のさらなる抗−ｈ１−ヒスタミン類との組合せを含む皮膚疾患治療用製薬組成物
US6277846B1 (en) Use of platelet activating factor antagonists as anti-pruritic agents
JP7257091B2 (ja) 認知症の治療及び予防薬
US20100069490A1 (en) Composition for a pharmaceutical treatment based on triethyl citrate and adapalene
CA3159633A1 (fr) Antagonists de mrgprx2 et leurs utilisations
EP2083824B1 (fr) Procédés de traitement d&#39;états inflammatoires
PT96703A (pt) Processo de preparacao de composicoes farmaceuticas a base de derivados de acido 6-n-butil-1,4,7,1o-tetra-hidro-4,1o-dioxo-1,7-fenantrolina-2,8-dicarboxilico
MXPA00004525A (en) Treatment of t-helper cell type 2 mediated immune diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10704288

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10704288

Country of ref document: EP

Kind code of ref document: A1