Substituted imidazo[l,2-a]pyrazines and pyrazino[l,2-a] pyrimidines as topical agents for dermatological applications
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Publication Number
US-12168665-B2
Publication Date
2024-12-17
Expiration Date
Abstract
Provided are compounds of formula (I): or a cosmeceutically acceptable or pharmaceutically acceptable salts thereof. Additionally provided are pharmaceutical and/or cosmeceutical compositions and formulations comprising the compounds and/or the cosmeceutically acceptable or pharmaceutically acceptable salts thereof, therapeutic and/or cosmetic methods using same for modulating (e.g., inhibiting) CREB binding protein (CBP)/β-catenin mediated signaling in treating skin related diseases, conditions or disorders (e.g., dermatitis, psoriasis, scarring, alopecia, etc.) mediated by aberrant CBP/β-catenin signaling, and cosmetic methods for treating skin conditions (e.g., aging, etc.) mediated by aberrant CBP/β-catenin signaling.
Core Innovation
Substituted imidazo[l,2-a]pyrazines and pyrazino[l,2-a]pyrimidines are provided as compounds of formula (I), including related (Ia)/(Ib)/(Ic) forms and embodiments in which L, X, Y, R, R1-R3, Q, and n satisfy the defined structural constraints. The compounds are provided as cosmeceutically acceptable or pharmaceutically acceptable salts, with optional substitution on benzyl and phenyl and with Q as benzyl, phenyl, or an 8- to 11-membered bicyclic aryl optionally containing nitrogen, oxygen, or sulfur.
The invention describes the compounds as potent Wnt/β-catenin modulators that inhibit CBP/β-catenin-mediated signaling and interacts with CBP/CREB-binding protein signaling in the context of skin diseases and cosmetic or aging conditions. The approach is focused on topical dermatological use and topical pharmaceutical/cosmeceutical use in a mammalian subject in need thereof, with cosmeceutically effective amount as the treatment basis.
The disclosure further includes an esterified prodrug strategy linked to improved stratum corneum penetration, and presents prodrugs and isotopically labeled analogs. It also references in vitro reporter assays such as HEK293 Wnt/TCF/LEF reporter (Luc) and SuperTOPFLASH, and prodrug stability by HPLC as part of the characterization narrative.
Claims Coverage
The consolidated claim set includes four independent claims: one directed to the compound of formula (I) and three directed to topical cosmetic or cosmeceutical treatment, including compositions and methods. Across the independent claims, the core inventive features are the defined structural formula (I) with multiple substituent constraints, topical administration of a cosmeceutically effective amount, and CBP/β-catenin-mediated signaling as the mechanistic basis.
Compound of formula (I) with defined structural constraints
A compound of formula (I) or a cosmeceutically acceptable or pharmaceutically acceptable salt thereof, wherein L is —C(O)— or —S(O)2—; X is —C(O)— or —CH2C(O)—; Y is H or C(O)R; R is C1-30 alkyl or C2-30 alkenyl; R1 is H or CH3; R2 is H or CH3; R3 is H or D; Q is benzyl, phenyl, or an 8- to 11-membered bicyclic aryl optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; and n is 1 or 2, with optional substitution on benzyl and phenyl as specified.
Topical cosmeceutical treating method using a compound of formula (I)
A method for cosmetically treating a skin condition in a mammalian subject, comprising topically administering a cosmeceutically effective amount of a compound of formula (I) or a cosmeceutically acceptable salt thereof with the same structural constraints for L, X, Y, R, R1, R2, R3, Q, and n.
Topical cosmeceutical composition-based treating method using formula (I) compound
A method for cosmetically treating a skin condition in a mammalian subject, comprising topically administering a cosmeceutically effective amount of a cosmeceutical composition comprising a cosmeceutically acceptable excipient and a compound of formula (I) or a cosmeceutically acceptable salt thereof with the same structural constraints.
Overall, the claims cover structurally defined formula (I) Wnt/β-catenin modulator compounds and topical cosmetic or cosmeceutical treatment of a skin condition in a mammalian subject using those compounds and compositions.
Stated Advantages
Improved stratum corneum penetration.
Potent Wnt/β-catenin modulation and inhibition of CBP/β-catenin-mediated signaling.
Topical dermatological application for skin conditions and cosmetic/aging conditions.
Documented Applications
Topical dermatological use for treating skin diseases and cosmetic/aging conditions, including dermatitis, psoriasis, scarring, alopecia, wrinkles, hyperpigmentation, redness, rosacea, dryness, acne, cracking, hair loss, loss of elasticity, loss of hair coloration, loss of vibrance, reduced cuticle growth, reduced eyebrow growth, reduced eyelash growth, reduced nail growth, sun damage, thinning, and ultraviolet damage.
Cosmetic treatment of aging skin conditions in a mammalian subject by topical administration of a cosmeceutically effective amount of a compound of formula (I) or a cosmeceutical composition comprising the compound.
Cosmetic evaluation involving an 8-week human cosmetic study reporting improvement in wrinkle and redness.
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