Antitumor benzoylsulfonamides

In recent years fundamental advances have been made in the development of chemical agents and regimens of therapy to combat neoplastic diseases. Despite these continuing advances, cancers continue to exact intolerable levels of human pain and suffering. The need for new and better methods of treating malignant neoplasms and leukemias continues to fuel efforts to create new classes of compounds, especially in the area of inoperable or metastatic solid tumors. The recent avalanche of information regarding the basic biological processes involved in neoplasms has led to a deeper understanding of the heterogeneity of tumors. It is because of this extreme heterogeneity among populations of neoplastic cells that new chemotherapeutic agents should have a wide spectrum of activity and an acceptable therapeutic index. In addition, such agents must be chemically stable and compatible with other agents. It is also important that any chemotherapeutic regimen be as convenient and painless as possible to the patient.

Chemotherapy and radiation are frequently used in the treatment of cancer and, although they often produce some response in the malignant disease, they are rarely curative. Most solid tumors increase in mass through the proliferation of malignant cells and stromal cells, including endothelial cells. In order for a tumor to grow larger than 2-3 millimeters in diameter, it must form a vasculature, a process known as angiogenesis. Suppression of tumor-induced angiogenesis by angiostatin and endostatin has been reported to result in antitumor activity (O\'Reilly, et al., Cell, 88, 277-285 (1997)). Because angiogenesis is a critical component of the mass expansion of most solid tumors, the development of new agents for the inhibition of tins process represents a promising approach for antitumor therapy. This approach to antitumor therapy may lack the toxic side effects or drug resistance-inducing properties of conventional chemotherapy (Judah Folkman, Endogenous Inhibitors of Angiogenesis, The Harvey Lectures, Series 92, pages 65-82, Wiley-Liss Inc., (1998)).

The present invention provides novel N-[benzoyl]-bicyclylsulfonamide compounds useful in the treatment of susceptible neoplasms.

The present invention provides a compound of Formula I:

where;

• Ar is

or a heterocyclic selected from the group consisting of 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrohenzofur-5-yl, benzo[1,3]dioxol-5-yl, 1-(C₁-C₆ alkyl)indolin-6-yl, benzothien-2-yl, benzothien-5-yl, 5-(C₁-C₆ alkyl)benzothien-2-yl, 6-(C₁-C₆ alkyl)benzothien-2-yl, benzothiazol-6-yl, benzofur-2-yl, benzofur-6-yl, thieno[3,2-b]pyridin-2-yl, and 1-(C₁-C₆ alkyl)indol-2-yl;

• A is phenyl, benzofuryl, cyclopentadienyl, cyclobutyl, or a cyclopentyl that is optionally substituted at one of the two carbons adjacent to the ring fusion of the cyclopentyl with an oxo moiety;
• R₁ and R₂ are either both halo, both trifluoromethyl, or one is halo and the other is C₁-C₆ alkyl; or a pharmaceutically acceptable base addition salt thereof.