Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same

Abstract

Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by Interleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula: Each X, Y and Z are independently selected from a member of the group consisting of C(R3), N,N(R3) and S. Each R1, R2 and R3 is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraminoalkyl, C(5-15)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(3-8)alkoxyl, C(1-11)alkoxyalkyl, and C(1-20)dialkoxyalkyl.

Description

[0001] This is a continuation-in-part of U.S. application Ser. No. 09 / 008,020, which was filed Jan. 16, 1998, the entire disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention generally relates to novel therapeutic compounds, pharmaceutical compositions containing such compounds, methods for preparing such compounds and methods for using these compounds, alone or in combination with other therapeutic agents, for the treatment and prevention of symptoms or manifestations (e.g., inflammation) associated with disorders affected by Interleukin-12 (“L-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. BACKGROUND OF THE INVENTION [0003] Inflammatory responses are a component of the pathogenesis of many vertebrate disorders / diseases, including those in humans. In its broadest meaning, the term “inflammation” denotes local as well as systemic responses. Increased blood flow, vasodilation, fluid transudation f...

AI Technical Summary

Benefits of technology

[0017] It is another object of the present invention to provide novel therapeutic compounds, pharmaceutical compositions thereof and methods that are capable of limiting the inflammatory response of a subject without adversely affecting the specificity of the immune system deemed necessary for protecting the subject.

Problems solved by technology

In severe cases, shock and death may occur.

Diseases involving inflammation are particularly harmful when they afflict the respiratory system, resulting in obstructed breathing, hypoxemia, hypercapnia and lung tissue damage.

Furthermore, steroid treatment broadly attenuates cytokine production, but it cannot modulate it selectively, e.g., just the Th0, the Th1 or the Th2 pathways.

Although their effect in reversing some of the acute symptoms of autoimmune disease, such as MS, are well known, their side effects have precluded long-term use.

These drugs act like “sledgehammers” in that they suppress the entire immune system and raise problems that attend broad-spectrum immunosuppression therapies.

The same problems also are likely with newer therapies such as cyclosporine, anti-CD4 monoclonal antibodies, and others.

However, antibody based immunotherapy may result in immune complex formation and deposition, thus leading to glomerulonephritis, vasculitis and arthritis.

The use of anti-inflammatory and symptomatic relief reagents is a serious problem because of their side effects or their failure to attack the underlying cause of an inflammatory response.

These agents, however, have serious side effect potential, including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression.

Thus, such drugs have found limited clinical use, for example, in the treatment of most airway hyperresponsiveness lung diseases.

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