Resin derivatization method and uses thereof

Details Resin derivatization method and uses thereof Resin derivatization method and uses thereof

1998-07-24

2004-09-07

Celsa, Bennett (Department: 1639)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S329900, C525S330500, C525S333600, C525S376000

Reexamination Certificate

active

06787612

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention provides processes and methods for making derivatized resins useful in the arts of solid-phase peptide synthesis, combinatorial chemistry, peptide or protein purification and separation, and other arts. Resins prepared according to the method of this invention are solid support reagents suitable for use in conventional automated, semi-automated or manual peptide synthesis using protected amino acids or amino acid analogs, to give a protected peptide (or peptide analog) aldehyde or ketoamide, attached to the support reagent. The product peptide aldehyde or ketoamide peptide or peptide analog is cleaved from the support and deprotected to give the desired peptide or peptide analog in good yield. As opposed to known methods for peptide aldehyde or peptide ketoamide synthesis, the process of the present invention provides, among other benefits, a method for solid-phase peptide or peptide analog synthesis that minimizes the amount of solution-phase synthetic steps required.
2. Background
In the field of protease inhibition, a number of peptide and peptide analog inhibitors have been developed, as have methods for their synthesis (see U.S. Pat. Nos. 5,283,293; 5,367,072; 5,371,072; 5,492,895; 5,514,777; 5,597,804; 5,637,599; 5,646,165; 5,656,600; 5,656,645; 5,681,844; 5,696,231; 5,703,208; 5,714,580; 5,731,413; 5,739,112; all of which are herein incorporated by reference. Accordingly, there have been significant developments in the field of protease inhibition and the development of structure-activity profiles for a number of classes of protease inhibitors.
Of particular significance to the field of protease inhibition is the development of synthetic methods of ever increasing efficiency. Accordingly, there is a continued need in the art for efficient processes for solid-phase production of protease inhibitors and other peptidyl and peptidomimetic compounds. The present invention provides processes that are an improvement on existing solid-phase synthetic methods and resins.
In the art of protease inhibition, compounds including peptides, peptide analogs, and peptidomimetic compounds having an aldehyde group on the C-terminus of the peptide have been found to be good transition-state inhibitors, many of which show marked selectivity for specific proteolytic enzymes. However, significant difficulty has been encountered in the synthetic production of such molecules. Several methods for solution-phase synthesis of such compounds have been reported (see, for Example, U.S. Pat. No. 5,514,777 and references cited therein).
Methods for the solution-phase synthesis of peptide aldehydes have been reported. (McConnell, R. M. et al., J. Med. Chem. 33:86-93, 1990, and references cited therein; see also Kawamura et al., Chem. Pharm. Bull. 17:1902, 1969; Someno et al., Chem. Pharm. Bull. 34, 1748, 1986). The use of semicarbazides as aldehyde protecting reagents for the solution synthesis of peptide aldehydes has also been reported. (Westerik and Wolfinden, J. Biol. Chem., 247, 8195 (1972); Ito et al., Chem. Pharm. Bull. 23, 3081 (1975)). The use of soluble semicarbazide functionalized polymer has been reported for the manual preparation of some peptide aldehydes. (Galpin, et al., Pept. Struct. Funct. Proc. Am. Pept. Symp., 9th, 799-802, 1985, Edited by: Deber, C. M., Hruby, V. J., Kopple, K. D., Pierce Chem. Co., Rockford, Ill.). However such supports were reported not to be suitable for the automatic synthesis of peptide aldehydes, since they dissolve in the solvents used for the coupling steps.
The use of semicarbazone intermediates has been reported in the synthesis of peptidyl argininals. The unsubstituted semicarbazone, N
g
-nitro-L-argininal semicarbazone was used as an intermediate in the synthesis of peptidyl argininals. McConnell, R. M., et al., J. Med. Chem., 33:86 (1990); R. M. McConnel, J. L. York, D. Frissell, C, Ezell, J. Med. Chem. 36:1084-1089 (1993). N
g
-nitro-L-argininal semicarbazonyl-4-methylcyclohexane carboxylic acid was reported as an intermediate in the preparation of peptide aldehydes by a solid phase method. Murphy, A. M. et al., J. Am. Chem. Soc., 114:3156 (1992); and Webb, T. R., U.S. Pat. No. 5,283,293 (Feb. 1, 1994), and U.S. Pat. No. 5,367,072 (Nov. 22, 1994). N
g
-nitro-L-argininal semicarbazonyl-4-diphenylmethane was reported as an intermediate for the solution-phase synthesis of peptidyl argininals. Brunck, T. K. et al., WO 93/14779 (1993). Solution and solid phase syntheses of peptidyl argininals was disclosed in U.S. Pat. No. 5,731,413 (Mar. 24, 1998). The disclosed methods implicated the use of an intermediate arginine cyclol N- or O-linked to a polymeric support.
The present invention provides a new method for the efficient production of argininal and other peptide or peptidomimetic aldehydes and ketoamides by solid phase synthesis, wherein a linkage between the aldehyde or ketoamide and a solid support provides for simplified chemistry with high yields of the desired product aldehyde or ketoamide. As opposed to known methods for peptide aldehyde synthesis, the process of the present invention provides a method for solid-phase peptide or peptide analog synthesis which provides the option of reduced reliance on solution-phase synthetic manipulation to produce desired aldehyde product. Accordingly, those skilled in the art will appreciate that the method of this invention represents a substantial contribution to the art in that solution-phase reactions, which may result in reduced product yield and which may require days if not weeks to accomplish, are accomplished according to the method of this invention within hours, due to reduced solution-phase synthetic chemistry heretofore required. By substantially reducing the product development cycle, true solid-phase combinatorial chemistry is enabled, including for heretofore difficult to synthesize, pharmacologically significant, aldehyde and ketoamide protease inhibitors.
SUMMARY OF THE INVENTION
Methods for synthesizing a derivatized solid support, the prototypical example of which is hydrazyl-carbonyl-amino methylated polystyrene (also referred to herein as “HCAM” resin or solid support), are provided by this invention. The processes according to this invention are used for preparing a functionalized solid support having the formula (I): la (I):
R4-NH—(C═X)—Y—Z—SS wherein:  (I)
R4 is —NH—R3, —NH
2
, —OH, or —O—R3, wherein R3 is a protecting group, provided that when R4 is —NH—R3 or —O—R3, then the protecting group is removed and replaced by —H in the final product (I);
X is O, S, or NR7;
R7 is H, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or heterocycle;
Y is absent, —NH—, or —CH
2
—;
Z is absent or is a substituent selected from the group consisting of —NH—, —O—, —(C═O)—, —S—, SO
2
—, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocycle, and combinations thereof, provided that when Y is absent and X is O or S, Z does not comprise —(C═O)— immediately adjacent to —(C═X)—, and when Y is —NH— and Z comprises an —NH— or an —S—, at least one carbon atom separates Y and the —NH— or —S— of Z, wherein, under conditions for peptide synthesis, functional groups of Z are protected; and
SS is a solid support.
The derivatized solid support (I) is available for reaction at R4 with appropriately protected aldehyde or ketoamide moieties, extension of a peptide or peptide analog chain thereon, and subsequent cleavage thereof from the resin to yield free aldehyde or ketoamide product.
The product produced according to the methods of this invention is useful as a solid support for solid-phase peptide synthesis, combinatorial chemistry, the purification or isolation of peptides or proteins, and other uses.
Accordingly, it is one object of the present invention to provide a method whereby solid-phase peptide or peptidomimetic compounds comprising an aldehyde or ketoamide at the P1 position (i.e. the carboxy-terminal end) of the peptide or peptidomimetic compound is achieved, with reduced need for solution-phase synthetic manipulat

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