Compounds having S1P5 receptor agonistic activity
Inventors
Watanabe, Toshihide • Kusumi, Kensuke • IMAIDE, SATOMI • ENDO, TOSHIMITSU • Komiya, Takaki • Tsuburaya, Naomi
Assignees
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Publication Number
US-12049445-B2
Publication Date
2024-07-30
Expiration Date
Abstract
A compound represented by the general formula (V) wherein all the symbols are as defined in the specification, has an improved balance of the agonist activity against the S1P5 receptor relative to the S1P1 receptor, and can thus serve as a therapeutic agent for S1P5-mediated diseases such as schizophrenia and Binswanger's disease and other neurodegenerative diseases.
Core Innovation
The invention relates to S1P5 receptor agonist dihydronaphthalene compounds and substituted azetidine-3-carboxylic acid derivatives that incorporate a 3,4-dihydronaphthalene core. The compounds are defined by general formula (V), related formula sets including (V-1), (V-2), (I), and (I-1), and include stereoisomers and isotopic variants such as deuterium and tritium isotopes, together with pharmaceutically acceptable forms including salts, solvates, hydrates, cocrystals, salt-solvates, N-oxides, and prodrugs.
The disclosure includes 1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid and the corresponding (3R) stereoisomer, as well as additional substituted methyl azetidine-3-carboxylate derivatives converted into the corresponding carboxylic acids. It also describes optical resolution to obtain enantiomerically enriched products and characterization by 1H-NMR, LCMS retention times, and SFC retention times.
The invention addresses improved S1P5 agonist activity balance and selectivity over S1P1 (EDG-1), and states that the compounds exhibit S1P5 (EDG-8) receptor agonist activity. The disclosed compounds are linked to treating S1P5-mediated diseases, including neurodegenerative diseases such as schizophrenia, Alzheimer-type dementia, Parkinson’s disease, Lewy body dementia, and Binswanger’s disease, as well as autoimmune diseases, infections, cancer, and therapeutic effectiveness in a mouse experimental autoimmune encephalomyelitis (EAE) model.
Claims Coverage
The independent claims cover three related method-for-treatment claim sets that share the common therapeutic target, S1P5-mediated disease, and differ by the administered entity: a specific compound, a compound of a specified structure, or a pharmaceutically acceptable salt. Across the claims, the main inventive features are administration of defined dihydronaphthalene-based azetidine-3-carboxylic acid compounds or salts in the S1P5 treatment context.
Treating an S1P5-mediated disease with a (3S) azetidine-3-carboxylic acid
A method for treating an S1P5-mediated disease in a subject in need thereof by administering an effective amount of 1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof to the subject.
Treating an S1P5-mediated disease with an azetidine-3-carboxylic acid of a specified structure
A method for treating an S1P5-mediated disease in a subject in need thereof by administering an effective amount of a compound of the following structure to the subject.
Treating an S1P5-mediated disease with a pharmaceutically acceptable salt of a specified compound
A method for treating an S1P5-mediated disease in a subject in need thereof by administering an effective amount of a pharmaceutically acceptable salt of the compound of the following structure to the subject.
Overall, the claim coverage is directed to administering defined dihydronaphthalene-based azetidine-3-carboxylic acid compounds, or pharmaceutically acceptable salts, for treating an S1P5-mediated disease in a subject. Dependent claim refinements narrow the disease scope to specified categories and named neurodegenerative disorders, including schizophrenia, Alzheimer-type dementia, Parkinson’s disease, Lewy body dementia, and Binswanger’s disease.
Stated Advantages
Selective S1P5 receptor agonist activity versus S1P1 (EDG-1) with some compounds showing improved S1P5/S1P1 activity balance.
Qualitative statements on low clearance and high bioavailability.
Therapeutic effectiveness in a mouse experimental autoimmune encephalomyelitis (EAE) model.
Improved agonist activity balance/selectivity for S1P5 over S1P1.
High S1P5 selectivity.
Documented Applications
Treatment of an S1P5-mediated disease in a subject, including neurodegenerative disease.
Use in a mouse experimental autoimmune encephalomyelitis (EAE) model to describe therapeutic effectiveness.
Preventing and/or treating S1P5-mediated diseases using compounds with S1P5 (EDG-8) receptor agonist activity.
Treating non-limiting categories of S1P5-mediated diseases including neurodegenerative, autoimmune, infections, and cancer.
Treating neurodegenerative disease subsets such as schizophrenia, Alzheimer-type dementia, Parkinson’s disease, Lewy body dementia, and Binswanger’s disease, in a mammal via prophylactic and/or therapeutic use.
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