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

a technology which is applied in the field of synthetic compounds and derivatives as modulators of smoking or nicotine ingestion and lung cancer, can solve the problems of reducing the pharmacological activity reducing the success rate of current therapies to reduce smoking (e.g., nicotine patches), and many of the metabolites and constituents of tobacco and tobacco smoke are toxic, so as to reduce the risk of developing cancer

Inactive Publication Date: 2008-08-07
HUMAN BIOMOLECULAR RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides compounds, pharmaceutical compositions, and methods of treatment that can inhibit the activity of cytochrome P450 2A6 and / or 2A13, which are enzymes involved in the metabolism of tobacco and tobacco smoke. By administering these compounds, the invention aims to reduce the harmful effects of tobacco use on health, such as cancer, and to modulate tobacco consumption and use in humans. The compounds can also selectively modulate nicotinic acetylcholine receptors in the CNS, which are involved in nicotine addiction and neurodegenerative diseases."

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.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

Chemical Synthesis of Substituted Tetrahydrofuran Nicotine Analogs

[0197]The synthesis of analogs of nicotine where the pyrrolidine ring was replaced with a substituted tetrahydrofuran ring system to mimic the parent compound were synthesized in a multistep sequence that provided the target compounds in overall acceptable yields. The synthesis is shown in FIG. 1. Generally, the bromide was derivatized with various functional groups to obtain the desired target compounds. The target compounds were fully characterized spectrally and subjected to biological evaluation. Purity was evaluated by HPLC analysis of the compounds.

example 2

Chemical Synthesis of Substituted Heteroaryl Analogs of Nicotine

[0198]The synthesis of analogues of nicotine where the pyrrolidine ring was replaced with a heteroaryl group to mimic the parent compound is shown in FIG. 2. The appropriate aryl bromide was treated with tetrakis(triphenylphosphine)palladium(0), sodium carbonate as the base and appropriate boronic acid for 1 hour at elevated temperature. The products were obtained after workup and column chromatography in yields ranging from 40-95%. The products were characterized by NMR and mass spectrometry and subjected to biological evaluation.

example 3

Chemical Synthesis of Substituted Carbocyclic Analogs of Nicotine

[0199]The synthesis of analogues of nicotine where the pyrrolidine ring was replaced with a substituted cyclopropyl ring system to mimic the parent compound is shown in FIG. 3.

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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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439C07D409/04C07D405/04C07D401/04A61K31/443A61K31/4436A61P35/00C07D407/04C07D409/14
CPCC07D401/04C07D409/14C07D409/04C07D405/04A61P25/34A61P35/00
Inventor CASHMAN, JOHN R.
Owner HUMAN BIOMOLECULAR RES INST
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