Compositions and methods comprising 2-(acylamino)imidazoles
Inventors
Looper, Ryan E. • Vaden, Rachel M. • Gibbons, Joseph B. • Salvant, Justin M. • Edwards, Anne V. • Sigman, Matthew S. • Welm, Bryan E.
Assignees
CURZA GLOBAL LLC • Utag, University of, Research Foundation of • University of Utah Research Foundation Inc
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Publication Number
US-10493061-B2
Publication Date
2019-12-03
Expiration Date
Abstract
The present invention presents 2-(acylamino)imidazoles with therapeutic activity, including selective activity against cancer cells, and compositions comprising them. Methods of using and preparing the 2-(acylamino)imidazoles are also presented.
Core Innovation
The invention relates to therapeutic compositions comprising a pharmaceutically acceptable excipient and a 2-(acylamino)imidazole compound selected from a structurally defined group, and salts thereof. The disclosed 2-(acylamino)imidazole structure includes defined substituent classes for R1, X, Y, R2, R3, R4a, R4b, R5a, R5b, A1-A10, and R7, with specific linkage constraints in the partial content. The composition is characterized by impurity constraints, including less than 2% (w/w) N2,N2-diacylation and less than 2% (w/w) of acyl regioisomers.
A further aspect of the invention describes a method of selectively preparing a 2-acylamino imidazole. The method cyclizes an N-monoprotected α-guanidinyl alkyne reactant to form a 3-N-protected imidazolidin-2-imine product with a 4-exocyclic olefin, and then selectively acylates at the 2-amino position to form a 2-acylamino product. The 2-acylamino product is characterized as substantially free from 1-acyl and 3-acyl regioisomers.
Claims Coverage
The independent claims cover two core inventive aspects: a therapeutic composition comprising a pharmaceutically acceptable excipient and a structurally defined 2-(acylamino)imidazole compound with impurity constraints, and a method for selectively preparing a 2-acylamino imidazole with regioisomer control.
Therapeutic composition with defined 2-(acylamino)imidazole structure and impurity limits
A composition for therapeutic use comprising a pharmaceutically acceptable excipient and a 2-(acylamino)imidazole compound selected from the structurally defined group or salts thereof, with extensive substituent definitions for R1, X, Y, R2, R3, R4a/R4b, R5a/R5b, A1-A10, and R7, and impurity/regioisomer constraints including less than 2% (w/w) N2,N2-diacylation and less than 2% (w/w) acyl regioisomers.
Selective preparation of 2-acylamino imidazole via cyclization and selective acylation with regioisomer control
A method of selectively preparing a 2-acylamino imidazole comprising cyclizing an N-monoprotected α-guanidinyl alkyne reactant to form a 3-N-protected imidazolidin-2-imine product with a 4-exocyclic olefin, then selectively acylating at the 2-amino position to form a 2-acylamino product, wherein the product is substantially free from 1-acyl and 3-acyl regioisomers.
Overall, the independent claims cover both a therapeutic composition and a selective preparation method. The composition claim emphasizes a broadly defined 2-(acylamino)imidazole structure with explicitly constrained N2,N2-diacylation and acyl regioisomers, while the method claim emphasizes cyclization to a 3-N-protected imidazolidin-2-imine intermediate followed by selective acylation to yield a 2-acylamino product substantially free from 1-acyl and 3-acyl regioisomers.
Stated Advantages
Less than 2% (w/w) N2,N2-diacylation.
Less than 2% (w/w) of acyl regioisomers.
The 2-acylamino product is substantially free from 1-acyl and 3-acyl regioisomers.
Documented Applications
Therapeutic use of a composition comprising a pharmaceutically acceptable excipient and a 2-(acylamino)imidazole compound (or a salt thereof).
Cancer treatment by administering the composition.
Cancer-cell viability assays using ZNA and related compounds.
Metal-transport biology, including Zn2+ flux.
Transcriptome/RT-PCR evaluation, including metallothionein genes (MT1F/MT1X/MT2A) and Zn2+ transport-related genes (SLC30A1, SLC30A2).
In vivo mouse tumor studies, including a ZNA in vivo mouse mammary tumor model.
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