Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2000-03-22
2002-09-17
Celsa, Bennett (Department: 1627)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S261000
Reexamination Certificate
active
06451918
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to combinatorial library creation requiring the immobilization of amines by employing a novel sulfonyl linker.
2. Description of the Related Art
The creation of combinatorial libraries has become a rapid developing technology and an efficient tool in drug discovery. It allows for the biological screening of many compounds in a relatively short period of time, a goal not attainable by traditional medicinal organic synthetic pathways.
Combinatorial library creation often requires an amine to be attached to a solid phase support. This is usually done by using a linker that covalently binds the amine either as a caroboxamide or as a carbamate. The linkers themselves are insoluble in the reaction solvents and inert to the reagents employed in the synthetic sequence. The linker bond is eventually cleaved and the products are eluted or filtered from the solid support. However, the relatively high reactivity of carboxamides and carbamates limits the chemical scope of library synthesis. Quite often, amides are not orthogonal to the other functional groups present in the synthetic scheme. Also, immobilization of highly functionalized aziridine scaffolds through amide linkers usually yield very poor regioselectivities in nucleophilic opening reactions, giving rise to mixtures of compounds that are difficult to separate. Further, cleavage conditions are quite often harsh (i.e. acidic or basic reaction conditions) and incompatible with functional groups present in the products, thereby limiting the scope of library synthesis.
Recently, polymer bound sulfonamide linkers have been employed because of their chemical stability. Kay, C., Murray, P. J., Sandow, L., Holmes, A.,
Tetrahedron Lett.
1997, 38, 6941-44. The use of this group as a linker for solid phase chemistry allows a wide range of chemistries to be performed. In contrast to common arene sulfonamides, the S—N bond can be readily cleaved under homogenous conditions using PhS
−
. Fukuyama, T., Jow, C., Cheung, M.
Tetrahedron Lett.
1995, 36, 6373. One problem with this method, however, is its lack of versatility, since the sulfonamide is formed before the linker is attached to the solid support. A better approach would be to first attach the linker to the support and then react the sulfonyl chloride with an amine. Further, the aromatic core is highly activated due to the presence of three electron withdrawing groups. This arrangement can lead to undesirable side reactions, such as single electron transfer reactions and aziridine decomposition. Thus, aziridines cannot be immobilized in high yield with this linker due to the very high reactivity of the sulfonyl group.
It is therefore desirable to employ a linker that allows cleavage of the amine from the solid support under mild reaction conditions while still providing the greatest degree of synthetic versatility. Aziridine scaffolds that are immobilized with a carbamate or carboxamide linker usually give poor regioselectivity in nucleophilic opening reactions. It is known that N-sulfonylaziridines give much better regioselectivities, preventing the formation of undesired compound mixtures.
SUMMARY OF THE INVENTION
This invention provides novel compounds of the Formula I which function as a sulfonyl linker between a target molecule and a polymer solid support. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I:
wherein
X and Y are different and represent hydrogen or NO
2
; and
A, B and C are different and represent hydrogen or D where
D is
wherein
SS is a solid support;
Z is O, NH or NR where R is lower alkyl; and
n is 0, 1, 2 or 3.
The invention further encompasses the use of immobilized sulfonyl aziridine scaffold intermediates to optimize the regioselectivity associated with the nucleophilic substitution of these aziridines. The invention also provides a method for making derivatized aziridine. Also, the invention provides for a method for making derivatized amines. For example, known compounds such as the vasodilator Isoxsoprine® (A) can be synthesized with the method of the present invention.
REFERENCES:
1995, Fukuyama, T., et al., Tetrahedron Lett. 36:6373.
1997, Kay, C., et al., Tetrahedron Lett. 38:6941-44.
1986, RajanBabu, T.V., et al., J. Org. Chem. 51:1704-1712.
1997, Siegel, M.G., et al., Tetrahedron Lett. 38:3357-3360.
Kolb Hartmuth C.
McGeehan Gerard
Celsa Bennett
Coelacanth Corporation
McDonnell & Boehnen Hulbert & Berghoff
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