Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-06-30
2002-07-09
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S133000
Reexamination Certificate
active
06417397
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to chemical species that are useful in protecting amino functional groups. The present invention relates particularly to amino-protecting species comprising a defined class of acyl compounds that can form an amide bond with an amino group.
BACKGROUND OF THE INVENTION
The amino functional group is found in many biologically important molecules such as amino acids, peptides, polypeptides, proteins, nucleosides, nucleotides, nucleic acids, glycosides, carbohydrate derivatives, alkaloids, and natural products. For most synthetic strategies amino groups must be protected. The utility of any protecting group depends on three considerations: (1) the ease of attaching the protecting group; (2) the ease of removing the protecting group; and (3) the compatibility of the protecting group with synthetic manipulations carried out on the molecule during the synthetic program.
Protection of an amino group is generally carried out by either acylation or alkylation. Both protection methods have advantages and disadvantages. Typically, alkylation is not the first choice for a protection strategy because overalkylation is difficult to control. Acylation of amino groups produces amides, which are easily formed under mild conditions. However, most amides are difficult to hydrolyze. Typically, unmasking an amino group from an amide is accomplished using harsh reaction conditions, e.g. boiling 6N HCl, which is incompatible with most complex synthetic programs. The trifluoroalkylamide is an exception since it can be removed by relatively mild alkaline conditions. Problems associated with the amide-based amino protection strategy may be circumvented using a carbamate protecting group (a special class of acylation-based amino protection). Examples of carbamates utilized in synthetic programs are benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc) and 9-fluoronylmethyl (Fmoc) carbamates. Carbamates are considered state of the art in protection of the amino functional group. However, appropriate amide-based amino protecting groups which can be easily removed under a variety of reaction conditions are still needed in modem synthetic organic chemistry.
Protecting groups may also be used in biological applications for use as prodrugs. The prodrug approach is viewed as one strategy for efficient delivery of lead compounds to the therapeutic site. The design of prodrugs is disclosed, for example, by Shan, D., et al. 1997 J Pharm Sci 765-767; Gangwar, S. et al. 1997 J Org Chem 1356-1362; and Amsberry, K., et al. 1990 J Org Chem 5867-5877, which are incorporated herein by reference. This approach has been particularly effective when prodrugs involve the conversion of a carboxylic acid to an ester, which can be readily hydrolyzed in vivo to release the parent drug. Application of the approach becomes problematic when applied to drugs containing amino groups. First, the chemical and enzymatic stabilities of amide bonds are much higher than those of ester bonds. Secondly, regeneration of an amine drug from the arnide prodrug is difficult. The prodrugs of the present invention address both of these problems.
SUMMARY OF THE INVENTION
In accordance with the invention, there are provided acylated amino protecting groups that can be cleaved under a prescribed set of acidic conditions ranging from highly acidic to very mildly acidic. Substituents on the acyl moiety of the invention protecting group can be widely varied to facilitate removal of the protecting group under a wide range of acidic reaction conditions. Accordingly, this family of amino-protecting groups can be used in conjunction with a variety of applications ranging from complex chemical syntheses to biological applications such as drug delivery.
In accordance with another aspect of the invention, there are provided prodrug compositions useful for improving the bioavailability of pharmaceutically active agents.
In accordance with yet another aspect of the invention, there are provided methods for improving the bioavailability of pharmaceutically active agents.
In accordance with still another aspect of the invention, there are provided pre-prodrug compositions useful for delivering acid-activated prodrugs to acidic environments in vivo.
In accordance with a further aspect of the invention, there are provided methods for delivering acid-activated prodrugs to acidic environments in vivo.
In accordance with a still further aspect of the invention, there are provided methods for protecting an amino group during a chemical synthesis.
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Amsberry and Borchardt, “The Lactonization of 2′-Hydroxyhydrocinnamic Acid Amides: A Potential Prodrug for Amines,”J. Org. Chem.,55:5867-5877 (1990).
Gangwar et al., “Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety,”J. Org. Chem.,62:1356-1362 (1997).
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Creighton Christopher J.
Goodman Murray
Gary, Cary, Ware & Friedrich LLP
Haile Lisa A.
Reyes Hector M
The Regents of the University of California, San Diego
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