Prodrugs of carbamate inhibitors of IMPDH

Abstract

The present invention relates to novel compounds, methods of preparing these compounds, and pharmaceutical compositions comprising these compounds. These compounds are carbamate prodrugs that convert to active inhibitors of the IMPDH enzyme in vivo. The compounds and pharmaceutical compositions of this invention are particularly well suited for activation and subsequent inhibition of the IMPDH enzyme activity. Consequently, these prodrugs may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds and compositions of this invention.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to novel compounds, methods of preparing these compounds, and pharmaceutical compositions comprising these compounds. These compounds are carbamate prodrugs that convert to active inhibitors of the IMPDH enzyme in vivo. The compounds and pharmaceutical compositions of this invention are particularly well suited for activation and subsequent inhibition of the IMPDH enzyme activity. Consequently, these prodrugs may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds and compositions of this invention. BACKGROUND OF THE INVENTION [0002] IMPDH (EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanosine nucleotides. The synthesis of nucleotides in organisms, in general, is required for the cells in those organisms to divide and replicate. Nucleotide synthesis in mammals may be achieved t...

AI Technical Summary

Benefits of technology

[0014] The present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that are prodrugs of carbamate derivatives, described in U.S. Pat. No. 5,807,876, and in co-pending continuation application Ser. Nos. 08 / 801,780 and 08 / 832,165, that function as inhibitors of IMPDH. The invention further provides a method for preparing pH-triggered, cyclizing prodrugs of drug substances comprising secondary carbamates. The carbamate prodrugs described herein can be selectively activated to produce an active compound and a non-toxic by-product. The release of the active compounds can modulated as a function of pH and rate of liberation, which in turn allows absorption to be more carefully controlled. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antibiotics, and immunosuppressants for the treatment or prophylaxis of transplant rejection and autoimmune disease. Additionally, these compounds are useful, alone or in combination with other agents, as therapeutic and prophylactic agents for antiviral, anti-tumor, anti-cancer, immunosuppressive chemotherapy and restenosis therapy regimens.

[0056] The compounds of this invention, as well as those used in the methods of this invention demonstrate a different metabolic profile than MPA and its derivatives. Because of this difference, methods of this invention and the compounds used therein may offer advantages as therapeutics for IMPDH mediated disease. These advantages include increased overall therapeutic benefit and reduction in deleterious side effects.

Problems solved by technology

MPA is characterized by undesirable pharmacological properties, however, such as gastrointestinal toxicity and poor bioavailability.

Several clinical observations, however, limit the therapeutic potential of this drug.

This effectively lowers the drug's in vivo potency, while increasing its undesirable gastrointestinal side effects.

In addition, MMF has inherent drawbacks as a prodrug.

Therefore, it is difficult to control the time and location of activation of the drug.

But the aqueous solubility of these compounds is less than optimum.

For example, the oral administration of a highly hydrophobic compound can very easily result in poor absorption due to precipitation in the gastrointestinal tract.

Formulation of such hydrophobic compounds with surfactants and complexing agents can improve the aqueous solubility of these compounds, but this method becomes more impractical as the aqueous solubility decreases.

However, chemical modification of a drug into a bio- or chemically-reversible prodrug can confer temporary aqueous solubility to the drug substance that allows absorption following oral administration.

These methods, however, are inadequate for the formation of prodrugs of drugs lacking alcohols, phenols, or primary and secondary amines.

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