Synthetic Compounds and Derivatives as Modulators of Smoking or Nicotine Ingestion and Lung Cancer

Abstract

Disclosed are nicotine-related compounds that selectively inhibit cytochrome P-450 2A6 (CYP2A6), selectively inhibit cytochrome P-450 2A13 (CYP2A13), and / or selectively modulate a nicotinic acetylcholine receptor (nAChR). Also disclosed are pharmaceutical compositions comprising a compound of the invention, as well as methods of using the pharmaceutical compositions for treating or preventing a disease or disorder associated with nicotine-ingestion, or a disease or disorder amenable to treatment by selective modulation of nAChRs.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]The present application claims benefit to U.S. Provisional Application No. 60 / 531,696, filed Dec. 23, 2003, the entire disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention provides pharmaceutical compositions and compounds useful in methods of inhibiting cytochrome P450 2A6 and / or 2A13, reducing the use of tobacco products, reducing the exposure to nicotine and the harmful by-products associated with the use of tobacco products, and reducing the harmful health and addictive effects associated with the use of such products. The pharmaceutical compositions and compounds are also useful in treating central nervous system (CNS) diseases and disorders.BACKGROUND OF THE INVENTION[0003]Even though over 1.1 billion persons worldwide smoke tobacco, current therapies to reduce smoking (e.g., the nicotine patch) have a low success rate after one year. There is an urgent need to develop a specific medica...

AI Technical Summary

Benefits of technology

[0009]In another aspect, the present invention provides methods of ameliorating the harmful effects (e.g., cancer) of tobacco use (e.g., smoking tobacco in cigarettes, cigars, or pipes; chewing tobacco) on health by administering a compound of Formula I or, more preferably, a compound of Formula XI, XII, or XIII, to a tobacco user. In one embodiment, the administered compound interferes with the metabolism of constituents of tobacco or tobacco smoke (e.g., nicotine, nitrosamines) so as to reduce the formation of carcinogenic metabolites.

[0063]The term “therapeutically effective regime” means that a pharmaceutical composition or combination thereof is administered in sufficient amount and frequency and by an appropriate route to at least detectably prevent, delay, inhibit, or reverse development of at least one symptom or biochemical marker of a nicotine-related disorder. In certain embodiments, the “therapeutically effective regime” predisposes a subject to ingest lower amounts of nicotine and / or inhibits mutagenic activation of N-nitrosamines to in turn decrease the risk of developing cancer.

Problems solved by technology

Even though over 1.1 billion persons worldwide smoke tobacco, current therapies to reduce smoking (e.g., the nicotine patch) have a low success rate after one year.

After administration to humans, nicotine undergoes extensive metabolism which reduces its pharmacological activity.

Many of the metabolites and constituents of tobacco and tobacco smoke are toxic, for instance, the highly carcinogenic tobacco-specific N-nitrosamines.

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