Purine and Pyrimidine Cdk Inhitbitors and Their use for The Treatment of Autoimmune Diseases

Abstract

The present invention relates to the use of an inhibitor of CDK2 and / or CDK7 and / or CDK9, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with antinuclear antibodies, wherein the inhibitor of CDK2 and / or CDK7 and / or CDK9 or pharmaceutically acceptable salt thereof is administered in an amount sufficient to down-regulate the levels of antinuclear antibodies. A further aspect of the invention relates to a combination comprising an inhibitor of CDK2 and / or CDK7 and / or CDK9, or a pharmaceutically acceptable salt thereof, and methylprednisolone, and its use in the treatment of diseases associated with antinuclear antibodies, such as SLE.

Description

[0001]The present invention relates to a method of treating diseases associated with antinuclear antibodies. More specifically, but not exclusively, the invention relates to methods of treating autoimmune rheumatic diseases such as human systemic lupus erythematosus (SLE), and pharmaceutical compositions and combinations therefor.BACKGROUND TO THE INVENTION[0002]The purpose of the immune system is to protect the body from potentially harmful substances (antigens) such as microorganisms, toxins, cancer cells, and foreign blood or tissues from another person or species. Antigens are destroyed by the immune response, which includes production of antibodies (molecules that attach to the antigen and make it more susceptible to destruction) and sensitized lymphocytes (specialized white blood cells that recognize and destroy particular antigens).[0003]Immune system disorders occur when the immune response is inappropriate, excessive, or lacking. Autoimmune disorders refers to any disease c...

AI Technical Summary

Benefits of technology

[0055]In vitro assays for T cell function are appropriate screening tools to identify compounds that may have the ability to modulate the immune response in the complex situation of autoimmune disease. One such assay is a T cell proliferation assay, further details of which are set forth in the accompanying Examples. In autoimmune diseases involving anti-nuclear antibody production normal T cell function is required to stimulate autoantibody production by B cells. Accordingly, compounds affecting T cell function (one measure of T cell function is the ability to proliferate in response to an immune stimulus) should also prevent the formation of autoantibodies, by controlling the ability of T cells to communicate with B cells and in addition by preventing T cells from migrating to the site of auto-immune damage.

[0135]The present invention also includes the use of all suitable isotopic variations of the agent or pharmaceutically acceptable salt thereof. An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.Solvates

Problems solved by technology

Immune system disorders occur when the immune response is inappropriate, excessive, or lacking.

Autoimmune disorders typically result in destruction of one or more types of body tissues, abnormal growth of an organ, or changes in organ function.

However, autoimmune diseases are often associated with non-specific symptoms such as fatigue, dizziness, malaise (non-specific feeling of not being well), fever, and low-grade temperature elevations.

However, many of treatments available to date are associated with severe adverse side effects.

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