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Publication Number
US-11897885-B2
Publication Date
2024-02-13
Expiration Date
Abstract
The purinone derivative 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one hydrochloride has Btk-selective inhibitory activity and, in addition to having excellent metabolic stability, it is a compound that exhibits a high level of solubility and absorption with respect to the free base and can be crystallized, hence it can serve as a therapeutic agent for diseases involving B cells and mast cells.
Core Innovation
The invention provides a purinone derivative hydrochloride, 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one hydrochloride, described as a Btk-selective inhibitor. The hydrochloride form is characterized with improved metabolic stability, higher solubility and absorption versus the free base, and is further described as being able to form crystals.
The document provides solid-state identification for the hydrochloride crystal, including powder X-ray diffraction using 2θ peak lists and DSC melting behavior. The description also addresses isomer/mixture scope and compares the hydrochloride form to suspensions of Compound A, the free base.
Biological and pharmacokinetic results are reported for very potent Btk inhibition with selectivity over Lck, Fyn, and LynA, improved oral bioavailability in dogs for the hydrochloride form, higher solubility across multiple dissolution media, and enhanced metabolic stability in rat and human liver microsomes. The intended therapeutic context is stated as disease areas involving B cells and mast cells, including allergic, autoimmune, inflammatory, thromboembolic, and cancer indications, including non-Hodgkin’s lymphoma, and example pharmaceutical composition and formulation types are also described.
Claims Coverage
The document includes one independent claim directed to treating a Btk-related disease by administering the specified hydrochloride to a mammal, with dependent claims narrowing the disease scope to autoimmune diseases and further to a specified list of autoimmune conditions. Across the claims, there are three inventive-feature levels.
Administering a specific Btk-selective hydrochloride for treatment
A method of treating a Btk-related disease by administering to a mammal in need thereof an effective amount of 6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one hydrochloride.
Treating an autoimmune Btk-related disease
The method wherein the Btk-related disease is an autoimmune disease.
Selecting from a list of autoimmune diseases
The method wherein the autoimmune disease is selected from a specified list of autoimmune conditions.
The claim set centers on treatment of Btk-related disease using the specified purinone derivative hydrochloride, and narrows the target pathology to autoimmune diseases, then to a defined enumerable set of autoimmune conditions.
Stated Advantages
Improved metabolic stability (hydrochloride versus free base).
Higher solubility and absorption (hydrochloride versus free base).
Crystalline hydrochloride form (ability to form crystals).
Very potent Btk inhibition with selectivity over Lck/Fyn/LynA.
Improved oral bioavailability in dogs for the hydrochloride form compared to suspensions of Compound A.
Higher solubility across multiple dissolution media.
Enhanced metabolic stability in rat and human liver microsomes.
Documented Applications
Treating a Btk-related disease in a mammal by administering an effective amount of the specified hydrochloride.
Treating an autoimmune disease as a Btk-related disease (with autoimmune disease selected from a specified list of autoimmune conditions).
Therapeutic disease areas involving B cells and mast cells, including allergic, autoimmune, inflammatory, thromboembolic, and cancer indications, including non-Hodgkin’s lymphoma.
Example pharmaceutical composition/formulation types are described for the therapeutic use.
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