Methods and compositions for treating retina-associated disease using CCR3-inhibitors
Inventors
Corradini, Laura • JACKSON, Sam • Nikolich, Karoly
Assignees
Boehringer Ingelheim International GmbH • Boehringer Ingelheim Pharma GmbH and Co KG • Alkahest Inc
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Publication Number
US-11951102-B2
Publication Date
2024-04-09
Expiration Date
Abstract
Methods of improving visual endpoints related to retina-associated disease with CCR3 modulating agents are provided. An example of such an endpoint is visual acuity. Retina-associated diseases upon which visual acuity and other visual endpoints may be improved include retinopathy of prematurity, age-related macular degeneration, central retinal vein occlusion, and diabetic retinopathy.
Core Innovation
The patent describes orally administrable compounds of Formula 2 for improving visual acuity in a subject diagnosed with a retina-associated disease. The method comprises administering a therapeutically effective amount of a compound of Formula 2, with structural substituents defined by variables including A, R1, R2a, R2b, R3, X, and j. The disclosure further includes ring-forming options, heterocyclic ring formation, stereochemical form options, crystalline salt form options, and counterion options.
The compound definitions specify substituent classes and ranges that include halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, together with COO-C1-6-alkyl, O-C1-6-alkyl, and CONR2b.1R2b.2 options. The anion X is selected from an enumerated group including chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, and p-toluenesulphonate. The allowed values of m and j are 1, 2 or 3 and 0, 0.5, 1, 1.5 or 2, respectively.
The disclosed context connects the Formula 2 compound approach to retina-associated disease indications and visual acuity endpoints. The patent also describes combination therapy with anti-VEGF agents such as ranibizumab, bevacizumab, aflibercept, and brolucizumab. Exploratory anatomical endpoints described as CRT and leakage are also mentioned.
Claims Coverage
The claims coverage centers on one independent method claim for improving visual acuity by oral administration of a therapeutically effective amount of a Formula 2 compound in a subject diagnosed with a retina-associated disease. Dependent claims further refine the compound and method scope by specifying structural substituent ranges, anion selection, crystalline salt form, stereochemical forms, target disease subset, and optional combination therapy.
Oral administration of a Formula 2 compound to improve visual acuity
A method of improving visual acuity in a subject diagnosed with a retina-associated disease, comprising orally administering to the subject a therapeutically effective amount of a compound of Formula 2.
Defined substituent framework for Formula 2
Formula 2 includes defined selections for A, R1, R2a, R2b, R3, m, X, and j, including heterocycle-forming options and the specified substituent classes and ranges.
Specified anion and parameter j associated with Formula 2
X is an anion selected from chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, or p-toluenesulphonate, and j is 0, 0.5, 1, 1.5 or 2.
Crystalline salt form of the Formula 2 compound
The method specifies that the compound of Formula 2 is a crystalline salt of the specified formula.
Stereochemical form options for the Formula 2 compound
The method includes administering the Formula 2 compound as individual optical isomers, a mixture of enantiomers, a racemate, or enantiomerically pure forms.
Specified retina-associated disease set for visual acuity improvement
The method is applied to dry age-related macular degeneration, wet age-related macular degeneration, central retinal vein occlusion, retinopathy of prematurity, or diabetic retinopathy.
Combination therapy with anti-VEGF agents
The method includes combination therapy with anti-VEGF agents such as ranibizumab, bevacizumab, aflibercept, and brolucizumab.
The claims coverage centers on oral administration of a therapeutically effective amount of a Formula 2 compound with defined substituent and anion parameters to improve visual acuity in retina-associated disease, with dependent claims further specifying crystalline salt form, stereochemical form, disease selection, and combination therapy with anti-VEGF agents.
Stated Advantages
Improves visual acuity in a subject diagnosed with a retina-associated disease.
Provides improvement in other visual endpoints in retina-associated diseases.
Oral CCR3 antagonists are presented as not broadly altering VEGF-A levels.
Combination therapy with anti-VEGF-A is described as possible.
Documented Applications
Therapeutic use for retina-associated diseases including retinopathy of prematurity, age-related macular degeneration, central retinal vein occlusion, and diabetic retinopathy.
A method for improving visual acuity in a subject diagnosed with a retina-associated disease by orally administering a therapeutically effective amount of a compound of Formula 2.
Application to dry age-related macular degeneration, wet age-related macular degeneration, central retinal vein occlusion, retinopathy of prematurity, or diabetic retinopathy.
Combination therapy with anti-VEGF therapy for retina-associated diseases, with anti-VEGF agents including ranibizumab, bevacizumab, aflibercept, and brolucizumab.
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