Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
2000-08-18
2002-07-02
Ponnaluri, Padmashri (Department: 1627)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C548S317100, C530S334000, C530S335000
Reexamination Certificate
active
06413785
ABSTRACT:
TECHNICAL FIELD
The subject invention relates to methods for synthesizing 1-aminohydantoin compounds, using a solid-support resin to facilitate purification of intermediates.
BACKGROUND OF THE INVENTION
Resin based chemistry methods have blossomed the past decade, and have proved to be highly useful for multi-step syntheses.
Interest in compounds having the 1-amino variant of the hydantoin nucleus (1-below) stems from the demonstrated commercial significance as anti-infective (e.g., nitrofurantoin (2)), skeletal smooth muscle relaxant (e.g., dantrium (3)), anti-arrhythmic (e.g., azimilide (4)), and other interesting pharmacological diversity (e.g., prostaglandin D receptor agonist (5)) of different species.
Furthermore, the 1-aminohydantoins contain the aza surrogate of amino acids (i.e. hydrazino acids), and aza amino acid replacements have pharmacological significance in many therapeutic areas. This aza replacement adds significantly different chemical and physical properties to the hydantoin ring system; one example of this is stable imine formation at the 1-amino position (semicarbazone-like).
Currently known solid phase based hydantoin routes that utilize cyclizative cleavage are disclosed in: (a) Dewitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Reynolds Cody, D. M.; Pavia, M. R.;
Proc. Natl. Acad. Sci.,
, vol. 90 (1993), pp. 6909-6913; (b) Dressman, B. A.; Spangle, L. A. Kaldor, S. W.;
Tetrahedron Lett.
, vol. 37 (1996), pp. 937-940; (c) Hanessian, S.; Yang, R.-Y.;
Tetrahedron Lett.
, vol. 37 (1996), pp. 5835-5838; (d) Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y.;
Tetrahedron Lett,
vol. 38 (1997), pp. 4603-4606; (e) Matthews, J.; Rivero, R. A.;
J. Org. Chem.
, vol. 62 (1997), pp. 6090-6092. For an example of amine displacements on &agr;-bromo resin esters, see: Scott, B. O.; Siegmund, A. C.; Marlowe, C. K.; Pei, Y.; Spear, K. L.;
Molecular Diversity,
vol. 1 (1995), pp. 125-134.
Solution based chemist methods for making 1-aminohydantoins are disclosed, for example, in European Patent Application No. 0 126 849 of the Wellcome Foundation, inventor Caldwell, published Dec. 5, 1984.
SUMMARY OF THE INVENTION
The subject invention involves processes for making 1-aminohydantoin compounds:
using a solid-support resin having a linking moiety capable of reacting with carboxylic acids and attaching them to the resin, comprising the following steps:
(a) preparing resin-bound, protected &agr;-hydrazinyl esters;
(1) by reacting the resin with &agr;-bromo carboxylic acids; then with a protected hydrazine; or
(2) by reacting the resin with protected &agr;-hydrazinyl carboxylic acids;
(b) preparing resin-bound imines by removing the blocking group from the hydrazinyl moiety of the &agr;-hydrazinyl esters, then reacting the unprotected hydrazinyl moiety with aldehydes or ketones;
(c) preparing resin-bound secondary ureas;
(1) by reacting the resin-bound imines with p-nitrophenylchloroformate or triphosgene, then with primary amines; or
(2) by reacting the resin-bound imines with isocyanates; and
(d) preparing the 1-aminohydantoin compounds by removing the resin-bound secondary ureas from the resin and cyclizing them.
REFERENCES:
patent: 4363916 (1982-12-01), Fukui et al.
patent: 5324483 (1994-06-01), Cody et al.
patent: 5462940 (1995-10-01), Yu et al.
patent: 0126849 (1984-12-01), None
patent: 0284202 (1988-09-01), None
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Matthews et al., “Base-Promoted Solid-Phase Synthesis of Substituted Hydantoins and Thiohydantoins”,J. Org. Chem.,vol. 62, pp. 6090-6092 (1997).
Dressman et al., “Solid Phase Synthesis of Hydantoins Using a Carbamate Linker and a Novel Cyclization/Cleavage Step”,Tetrahedron Letters,vol. 37, No. 7, pp. 937-940 (1996).
Short et al., “The Synthesis of Hydantoin 4-Imides on Solid Support”,Tetrahedron Letters,vol. 37, No. 42, pp. 7489-7492 (1996).
Kim et al., “Solid Phase Synthesis of Hydantoin Library Using a Novel Cyclization and Traceless Cleavage Step”,Tetrahedron Letters,vol. 38, No. 26, pp. 4603-4606 (1997).
Hoffman et al., “The Preparation of 2-Hydrazinyl Esters in High Optical Purity From 2-Sulfonyloxy Esters”,Tetrahedron Letters, vol. 31, No. 21, pp. 2953-2956 (1990).
DeWitt et al., “Diversomers: An Approach to Nonpeptide, Nonoligmeric Chemical Diversity”,Proc. Natl. Acad. Sci.,vol. 90, pp. 6909-6913 (1993).
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Li Min
Portlock David Edward
Wilson Lawrence Joseph
Echler Sr. Richard S.
Graff Milton B.
Ponnaluri Padmashri
Roof Carl J.
The Procter & Gamble Co.
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