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 lnterleukin-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)tetraaminoalkyl, 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

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This patent application is a (1) continuation-in-part of U.S. application Ser. No. 09 / 288,556, which was filed Apr. 9, 1999, which in turn is a continuation-in-part of U.S. application Ser. No. 09 / 008,020, which was filed Jan. 16, 1998; (2) continuation-in-part of allowed U.S. application Ser. No. 08 / 486,264, which was filed Jun. 7, 1995, which in turn is a continuation-in-part of abandoned U.S. application Ser. No. 08 / 217,051, which was filed Mar. 24, 1994; and (3) continuation-in-part of allowed U.S. application Ser. No. 08 / 483,871, which was filed Jun. 7, 1995, which in turn is a continuation-in-part of abandoned U.S. application Ser. No. 08 / 199,368, which was filed Feb. 18, 1994. The entire disclosures of the above-identified patent applications are incorporated herein by reference and the benefit of each is hereby claimed.FIELD OF THE INVENTION [0002] The present invention generally relates to novel therapeutic compounds, pharmaceu...

AI Technical Summary

Benefits of technology

"The present invention provides novel compounds, pharmaceutical compositions, and methods for inhibiting the inflammatory response in a mammal. These compounds are designed to inhibit the IL-12 signaling pathway, which is involved in the immune system's response to inflammation. The compounds have a unique structure that allows them to selectively target the IL-12 pathway without affecting other parts of the immune system. This makes the compounds effective in treating inflammatory responses without causing harmful side effects. The compounds can be used as therapeutic agents or in the development of new treatments for inflammatory diseases."

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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