Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-06-13
2004-02-03
Baker, Maurie Garcia (Department: 1639)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C435S007100, C435S091500, C435S091500, C546S192000, C546S194000, C546S245000, C546S279700, C546S281700, C546S185000, C564S152000, C564S169000, C564S193000, C564S194000, C564S199000, C564S200000
Reexamination Certificate
active
06686503
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to a method of synthesizing libraries of diverse and complex highly substituted 2,4-dioxopiperidine and novel intermediate compounds. More particularly, the invention relates to a method of solid phase synthesis of (E)-N-substituted-acetyl-N-(2-methoxycarbonyl-3-(Aryl)-prop-2-enyl)amino acids and condensation of the intermediate esters using commercially available Fmoc-protected amino acids on Wang Resins. The invention is further directed to methods for synthesizing the libraries on solid supports. The invention is also directed to methods for identifying and isolating the highly substituted 2,4-dioxopiperidine and novel intermediate compounds with useful and diverse activities from such libraries.
BACKGROUND OF THE INVENTION
Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through molecular biology techniques or synthetic chemical techniques.
The generation of chemical libraries on and off solid resins have proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTPS) techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available.
Such screening methods include methods wherein each member of the library is tagged with a unique identifier tag to facilitate identification of compounds having biological activity or where the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid substrate wherein a receptor is appropriately labeled to identify binding to the compound, e.g., fluorescent or radioactive labels. Correlation of the labeled receptor bound to the substrate with its location on the substrate identifies the binding compound. Using these techniques, the development of efficient high throughput screening has greatly enhanced the pharmaceutical industry's ability to screen large numbers of compounds for biological activity.
Central to these methods is the screening of a multiplicity of compounds in the library and the ability to identify the structures of the compounds that have a requisite biological activity. Preferably, in order to facilitate synthesis and identification, the compounds in the library are typically formed on solid supports wherein the compound is covalently attached to the support via a cleavable or non-cleavable linking arm. In this regard, libraries of diverse compounds are prepared and then screened to identify “lead compounds” having good binding affinity to the receptor.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity.
Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound.
Recently various 2,4-Dioxopiperidines were found to be potent as therapeutic or prophylactic agents for hepatic disease, for bacterial and viral infections and for diseases, including AIDS. Eur. Pat. No. 149534; WO 95/14012.
Since 2,4-dioxopiperidines have been shown to possess diverse pharmacological and chemical properties and biological activity in a number of therapeutic areas, the generation of a 2,4-dioxopiperidine compound library would be useful as a screening tool.
Accordingly, in order to develop new pharmaceutical drugs to treat various disease conditions, it would be highly desirable to be able to generate such libraries of substituted 2,4-dioxopiperidine and novel intermediate compounds optionally attached to a solid support. Thus, there is a need for a facile in situ method for the generation of a multiplicity of highly substituted 2,4-dioxopiperidine and novel intermediate compounds.
SUMMARY OF THE INVENTION
The present invention is directed to a process that allows for the assembly of diverse, highly substituted 2,4-dioxopiperidine and novel intermediate compounds using commercially available Fmoc-protected amino acids on solid resins. The rapid synthesis of such highly complex drug like molecules with or without defined stereochemistry is unexpected and surprising.
Accordingly, the invention is directed to a method of synthesizing highly substituted 2,4-dioxopiperidine compounds having the general Formula 1:
wherein:
R
1
is selected from the group consisting of a standard natural amino acid side chain, CH
3
, CH(CH
3
)CH
2
CH
3
and CH
2
Phenyl;
R
2
is selected from the group consisting of alkyl, substituted alkyl, aralkyl, phenyl and substituted aryl;
R
3
is selected from the group consisting of COOalkyl, CN, COloweralkyl, COaralkyl (benzyl and substituted benzyl) and COaryl; where aryl is phenyl, substituted phenyl, thienyl, furyl and napthyl; which method comprises,
(a) preparing a compound of the formula:
wherein R
1
to R
3
are as described above, on a solid resin support;
(b) cleaving the compound from the solid resin support and methylating to yield an intermediate methyl ester compound of the formula:
and,
(c) condensing the intermediate methyl ester compound to provide the substituted 2,4-dioxopiperidine compounds of Formula 1.
This invention is also directed to highly substituted novel intermediate compounds assembled by the methods of the present invention having the general formula:
wherein R
1
to R
3
are as recited above.
In one embodiment of this invention, the amino acid derived novel intermediate precursors are covalently attached to a solid support. Solid supports containing such amino acid derived intermediate precursors may comprise a linking arm which links the solid support to the intermediate precursor. The linking arm can be either cleavable or non-cleavable. The novel intermediate precursors attached to the solid support can be used to prepare a library of solid phase 2,4-dioxopiperidine derivatives.
The methods described above can be used to create a library of diverse dioxopiperidine derivatives. Accordingly, in one of its composition aspects, this invention is directed to a library of diverse (E)-N-substituted-acetyl-N-(2-methoxycarbonyl-3-(Aryl)-prop-2-enyl)amino acid derivatives comprising a plurality of solid supports having a plurality of covalently bound (E)-N-substituted-acetyl-N-(2-methoxycarbonyl-3-(Aryl)-prop-2-enyl)amino acid derivatives, wherein the derivatives bound to each of said supports is substantially homogeneous and further wherein the derivatives bound on one support is different from the derivatives bound on the other supports. The library is screened to isolate individual compounds that bind to a receptor or possess some desired property.
DETAILED DESCRIPTION OF THE INVENTION
Relative to the above generic description, certain compounds of the general formulae are preferred.
Particularly preferred embodiments are those compounds in which:
R
1
is selected from the group consisting of a standard natural amino acid side chain, CH
3
, CH(CH
3
)CH
2
CH
3
and CH
2
Phenyl;
R
2
is selected from the group consisting of alkyl, aralkyl, phenyl and substituted phenyl; where the substituents on the substituted phenyl group are selected from lower alkyl, halo, alkoxy, nitrile, cyano, alkoxycarbonyl, aryloxycarbonyl, nitro, furyl and substituted furyl; where the substituents on the substituted furyl group are selected from alkyl, halo, alkoxy, alkoxycarbonyl, nitrile, aryloxycarbonyl, nitro, thienyl and substituted thienyl; where the substituents on the sub
Chai Wenying
Murray William V.
Baker Maurie Garcia
Ortho-McNeil Pharmaceutical , Inc.
LandOfFree
Methods for the synthesis of highly substituted... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for the synthesis of highly substituted..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for the synthesis of highly substituted... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3347070