Topical phosphoinositide 3-kinase inhibitors
Inventors
Abdel-Magid, Ahmed F. • Kydonieus, Agis • Rossi, Thomas • Tan, Hock S.
Assignees
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Publication Number
US-11661429-B2
Publication Date
2023-05-30
Expiration Date
Abstract
The present invention provides compounds and topical formulations including the compounds for the treatment of vascular malformations, wherein the compounds are according to formula (I): wherein subscript m, L1, R1, and L1-R1 are as described herein.
Core Innovation
The disclosed subject matter relates to a compound of formula (I), including a hydrate, solvate, and/or a pharmaceutically acceptable salt thereof. The compound is defined by variable structural elements, including subscript m from 0 to 2, linkage group L1 selected from specified carbonyl-linked forms, and substituent R1 selected from aliphatic, hydroxyalkyl, haloalkyl, alkenyl, aryl, and aryl-alkyl variants within defined carbon ranges. The scaffold further includes an L1-R1 linkage portion where R3, R4, R5, R6, and R7, and combined groups form a 3-6 membered heterocycle optionally containing additional heteroatoms selected from O, S, and N as ring vertices.
In an alternative embodiment, L1 is —C(O)— and R1 is an aliphatic chain of a saturated fatty acid having 8-18 carbon atoms or an unsaturated fatty acid having 10-18 carbon atoms. The disclosed chemical space therefore includes both general aromatic and aryl-containing substituent options and a fatty-acid chain embodiment restricted to defined carbon counts and saturation states. The document additionally addresses pharmaceutically acceptable salts, solvates, hydrates, tautomers, geometric isomers, and isotopic variants.
The invention further discloses a topical formulation comprising a compound of formula (I) and topical excipients for treating vascular malformations. It states that topical administration is used to inhibit PI3K, and that after topical delivery the formula (I) compounds are substantially converted to corresponding PI3K-inhibiting compounds of formula (IV). The document also describes enhanced skin permeation relative to formula (IV) and hydrolysis limits over time or conditions.
Claims Coverage
The independent claim covers a broad Markush family of compounds of formula (I) including hydrates, solvates, and pharmaceutically acceptable salts. It defines two structural embodiment paths with multiple variable features, including a heterocycle-forming linkage framework and an alternative fatty-acid chain embodiment.
Formula (I) compound forms
A compound having formula (I), including a hydrate, solvate, and/or a pharmaceutically acceptable salt thereof.
Variable scaffold with defined L1 and R1
Subscript m is an integer from 0 to 2, L1 is selected as —C(O)—, —C(O)O—, —C(O)S—, or —C(O)NH—, and R1 is selected as C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, C6-10 aryl, C6-10 aryl-C1-6 alkyl, or C6-10 aryl-C2-6 alkenyl.
Heterocycle-forming linkage with R3-R7 definitions
L1-R1 has the indicated linkage framework, t is an integer from 0 to 1, p and q are independently an integer from 0 to 2, and R3, R4, R5, R6, and R7 are defined so that R6 and R7 are combined to form a 3-6 membered heterocycle optionally having additional 1-2 heteroatoms selected from O, S, and N as ring vertices.
Fatty-acid chain embodiment
Alternatively, L1 is —C(O)— and R1 is an aliphatic chain of a saturated fatty acid having 8-18 carbon atoms or an unsaturated fatty acid having 10-18 carbon atoms.
The protection centers on compounds defined by formula (I) with pharmaceutically acceptable forms, using a variable scaffold defined by L1 and R1 selections and a heterocycle-forming linkage framework, together with an alternative embodiment where L1 is —C(O)— and R1 is a constrained saturated or unsaturated fatty-acid chain.
Stated Advantages
Hydrolysis of the compound of formula (I) to the corresponding compound of formula (IV) is limited under described conditions.
Enhanced skin permeation versus the compound of formula (IV), with skin flux increased by about 2-5 fold in animal skin models.
Topical administration results in conversion of the compound of formula (I) to the compound of formula (IV).
Topical administration to inhibit PI3K for treatment of vascular malformations.
Documented Applications
Topical treatment of vascular malformations by inhibiting PI3K using the compound of formula (I) that is converted to formula (IV).
Topical formulation for treating vascular malformations using a compound of formula (I) with topical excipients.
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