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-11590118-B2
Publication Date
2023-02-28
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 invention relates to improving visual acuity in a subject diagnosed with a retina-associated disease. The method comprises orally administering to the subject a therapeutically effective amount of a compound that is a co-crystal of Formula 2. The co-crystal is defined by substituent variables, an anion X, an integer j, and a co-crystal former selected from a listed group.
In Formula 2, R1 is specified to be C1-6-alkyl, C1-6-haloalkyl, O—C1-6-haloalkyl, or halogen, and m is 1, 2 or 3. R2a and R2b are each independently selected from H, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, COO—C1-6-alkyl, O—C1-6-alkyl, CONR2b.1R2b.2, or halogen, with further constraints defining R2b.1 and R2b.2. R3 is H or C1-6-alkyl.
The co-crystal includes an anion X selected from chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate and p-toluenesulphonate. The integer j is 0, 0.5, 1, 1.5 or 2. The co-crystal former is selected from orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, 3-hydroxy-2-naphtoic acid, mucic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine.
Claims Coverage
The independent claim is directed to improving visual acuity by orally administering a therapeutically effective amount of a co-crystal of Formula 2 in a subject diagnosed with a retina-associated disease. The claims set out three main inventive features: the method of oral administration for visual acuity improvement, the defined Formula 2 co-crystal structure including substituent and anion constraints, and the selection of a co-crystal former from a listed group.
Oral visual acuity improvement with defined Formula 2 co-crystal
A method of improving visual acuity in a subject diagnosed with a retina-associated disease by orally administering a therapeutically effective amount of a compound that is a co-crystal of Formula 2, wherein R1, m, R2a, R2b, R2b.1, R2b.2, and R3 are defined by the stated selections.
Anion X and integer j specification in the co-crystal
The co-crystal specifies X as an anion selected from the stated group and specifies j as 0, 0.5, 1, 1.5 or 2.
Defined co-crystal former selection
The co-crystal is formed with a co-crystal former selected from a defined group including orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, 3-hydroxy-2-naphtoic acid, mucic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine.
The claim coverage is centered on orally administering a therapeutically effective amount of a Formula 2 co-crystal with defined substituent, anion, integer, and co-crystal former constraints to improve visual acuity in a subject diagnosed with a retina-associated disease.
Stated Advantages
Improves visual acuity in a subject diagnosed with a retina-associated disease.
Provides a non–anti-VEGF therapeutic approach framework by using CCR3 antagonism without altering VEGF-A levels or broadly suppressing the immune system.
Documented Applications
Treatment of retina-associated diseases including retinopathy of prematurity (ROP), age-related macular degeneration (AMD), central retinal vein occlusion (CRVO), and diabetic retinopathy by improving visual acuity outcomes.
Use in connection with visual acuity endpoints such as ETDRS BCVA (before and after administering the compound).
Potential combination context with standard-of-care anti-VEGF therapies (ranibizumab, aflibercept, bevacizumab).
Improving visual acuity in a subject diagnosed with a retina-associated disease.
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