Rapafucin derivative compounds and methods of use thereof
Inventors
Liu, Jun • Hong, Sam • Ullman, Brett R. • Semple, Joseph E. • YAMAMOTO, Kana • Kumar, Puneet • Sadagopan, Magesh • Schmitt, Jennifer C.
Assignees
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Publication Number
US-11945827-B2
Publication Date
2024-04-02
Expiration Date
Abstract
The present disclosure provides macrocyclic compounds inspired by the immunophilin ligand family of natural products FK506 and rapamycin. The generation of a Rapafucin library of macrocyles that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.
Core Innovation
The disclosure relates to compounds of Formula (V), or optically pure stereoisomers or pharmaceutically acceptable salts thereof. The structural definition specifies L as optionally substituted (CH2)nNR20C1-6 alkylene, A as NH, NMe, O, S(O)2 or S, each X as O, E as CH or N, and R1 as H.
The structural definition further specifies R2 as C1-20 alkoxy, R3 as C1-20 alkyl, and R4 as H or forming a cyclic structure with R3, where the cyclic structure is C2-10 heterocyclyl. The fixed values n = 0, m = 2, p = 2, and q = 4 are repeatedly stated, and dependent scope narrows R2 to methoxy and E to CH.
The disclosure also describes stereochemically defined compounds with carboxylic acid and amino functionality, together with example structures that vary in ring systems, heteroatom content, and stereochemistry. The examples and schematic descriptions are presented as members of the broader Formula (V) compound family and related stereoisomer and salt scope.
Claims Coverage
The claim coverage centers on one independent Formula (V) compound claim, with dependent claims that narrow specific substituent choices and one dependent claim that extends to a pharmaceutical composition. The inventive features focus on the defined linker, heteroatom, and substituent selections, together with the fixed parameter values n = 0, m = 2, p = 2, and q = 4.
Formula (V) compound with optically pure stereoisomer or pharmaceutically acceptable salt
A compound of Formula (V), or an optically pure stereoisomer or pharmaceutically acceptable salt thereof, wherein L is optionally substituted (CH2)nNR20C1-6alkylene; A is NH, NMe, O, S(O)2 or S; each X is O; E is CH or N; R1 is H; R2 is C1-20 alkoxy; R3 is C1-20 alkyl; R4 is H or forms a cyclic structure with R3, where the cyclic structure is C2-10 heterocyclyl; R20 is H; n is 0; m is 2; p is 2; and q is 4.
Methoxy selection for R2
The compound of Formula (V) is specified such that R2 is methoxy.
CH selection for E
The compound of Formula (V) is specified such that E is CH.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound of Formula (V), or an optically pure stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claims cover a Formula (V) compound defined by specific linker, heteroatom, and substituent constraints with fixed parameter values, extend to optically pure stereoisomers and pharmaceutically acceptable salts, and include dependent narrowing to R2 as methoxy and E as CH, plus a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Broad chemical diversity through extensive substituent and ring-identity options, supporting library generation and identification of leads for treating diseases.
Documented Applications
Leads for treating diseases.
Cancer and autoimmune disease.
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