Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Compositions to be polymerized by wave energy wherein said...
Reexamination Certificate
2000-06-15
2003-02-04
Seidleck, James J. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Compositions to be polymerized by wave energy wherein said...
C522S113000, C522S115000, C522S116000, C522S117000, C522S118000, C522S119000, C522S120000, C522S121000, C522S122000, C522S123000, C522S124000, C522S125000, C522S129000, C522S130000, C522S064000, C522S084000, C522S086000, C522S088000, C522S087000, C522S089000
Reexamination Certificate
active
06515039
ABSTRACT:
The invention concerns a method for the production of continuous polymeric solid phase supporting materials for simultaneous combinatory synthesis of organic compounds by means of SPOT synthesis technology, comprised of a polyolefin supporting matrix and individual chains of a graft copolymer, which are synthesized by heterogeneous photoinitiated graft copolymerization of acrylate, vinyl and allyl monomers on the entire surface of the supporting polymer and contain reactive hydroxyl, carboxyl, amino, mercapto, aldehyde or halogen groups, which can be utilized for additional derivatizing.
DESCRIPTION OF THE PRIOR ART
The chemical synthesis of compounds with the use of the concept of combinatory libraries has an important influence on the process of developing potential candidates for new therapeutic and diagnostic agents. Combinatory chemistry is a technique in which a large number of structurally different compounds are produced under comparable reaction conditions in a cost-favorable and time-efficient manner and can be subsequently introduced into biological testing by high-performance screening assays. The further development of Merrifield's solid phase synthesis strategy [Merrifield, R. B.: J. Am. Chem. Soc. 1963, 85, 2149], originally introduced for the synthesis of peptides, occupies a key position here. Since the use of excess reagents makes possible nearly complete reactions, and since the methodology can be easily automated and biological test systems can be applied directly onto polymeric surfaces, combinatory chemistry is preferably conducted in the solid phase.
The modification and further development of the original polystyrene supporting systems and the later-used polyamide systems [Atherton, E.; Clive, D. L. J.; Sheppard, R. C.; J. Am. Chem. Soc. 1975, 97, 6584] led to new polymers, such as, e.g., Tentagel and PEGA resins [Rapp, W.; Zhang, L.; Häbich, R.; Bayer, E. In Peptides 1988, (G. Jung & E. Bayer, Eds.) Walter de Gruyter, Berlin, New York, p.199; Meldal, M.; Tetrahedron Lett. 1992, 33, 3077]. These systems were increasingly utilized also for solid phase syntheses of non-peptide substances. Although spherical resin beads of various materials are broadly used, other physical forms such as small rods (polyethylene) or continuous surfaces (cellulose, cotton, glass, polyolefins) have led to new synthesis techniques.
The method of Spatially Addressable Combinatorial Libraries [Review: Pirrung, M. C.; Chem. Rev. 1997,97,473] is such a synthesis concept. A decisive advantage of these substance libraries consists of the fact that the position at which a synthesized molecule is found on the polymer describes its composition. Thus, with the use of supporting materials that are suitable in format and structure, the application of compatible biological test systems can lead directly to information relative to the biological activity of the synthesized substances.
The form of appearance, the chemical and physical properties and the surface functionalization of the supporting materials thus act decisively on both the quality and efficiency of the synthesis as well as on compatibility with biological test systems.
The SPOT technology developed by Frank [Frank, R.; Tetrahedron, 1992, 48, 9217] for constructing peptides on planar cellulose surfaces makes particularly possible the efficient parallel construction of large numbers of peptide sequences. The method in which the reagents are pipetted to local addresses on the continuous support is further characterized by applicability of conventional screening assays, since the readout geometries of high-performance test systems are compatible with the planar supporting materials. Thus, for example, SPOT arrays could be utilized, in addition to classical epitope mapping, in order to discover optimal binding sequences of protein kinases or metal-binding peptides [Tegge, W.; Frank, R.; Hoffman, F., Dostmann, W. R. G.: Biochemistry 1995, 34,10569; Malin R.; Steinbrecher, R., Jannsen, J.; Semmler, W.; Noll, B.; Johannsen B.; Frömmel, C.; Höhne, W.; Schenider-Mergener, J.: J. Am. Chem. Soc. 1995, 117,11821].
Based on the limited chemical and mechanical stability of the cellulose membranes, however, the technology has been previously limited, to the production of peptide sequences that are produced under relatively mild synthesis conditions.
Due to the structure of the chemically homogeneous support and the utilization of hydroxy groups as reactive groups, the permanent excess of hydroxy functions on the cellulose surface leads to the fact that selective or complete reactions cannot be achieved. This is a particular disadvantage for the generation of different linker constructs, which decisively limits the variety of possible reactions.
Several developments in the field of planar supporting materials could overcome the disadvantages of cellulose under certain conditions for SPOT synthesis, but have previously not been applied to the SPOT synthesis technique.
Thus, the patents of Berg et al. (WO 90/02749, WO 91/13098) and Batsberg et al. (WO 95/00533) describe the use of polyolefin films (preferably polyethylene). These were modified by gamma irradiation or by means of chemically initiated graft polymerization and homopolymerization of styrene from alcoholic solutions. Another chemical derivatization for introducing reactive groups followed. The supports produced in this way were used in reactors for peptide and oligonucleotide synthesis. In addition, solid-phase assay (ELISA) could be conducted.
Although the grafting of polystyrene chains is a logical further development of the classic Merrifield resin for a planar support, while maintaining conventional peptide synthesis conditions, the selection of this polymer in this context is not compelling. In contrast, it even introduces disadvantages, such as, e.g., the greatly different salvation of the chains in different solvents. In addition, polyethylene is less mechanically stable than the preferred base polymer and the described films or other molded bodies that have been are generally not porous. Possible functionalizing is thus limited to the external surface (i.e., thick or thin grafted layer), which leads to a smaller charge capacity. A surface-selective functionalization is not assured. In fact, additional reactions (e.g., graft polymerization and homopolymerization) are triggered in the polyolefin film by the selection of &ggr;-irradiation for initiating, particularly in the monomer/solvent system, but these reactions only reinforce the mechanical instability and cause a turbidity, which prevents application in assays.
Further, polypropylene membranes also functionalized with amino groups were described by Hudson et al. (WO 94/05394) in addition to the use of porous sintered plates, and a hydrophilic polymer (dextran, partially hydrolyzed chitin) is covalently coupled to these membranes by means of a spacer (PEG). The hydrophilic support materials used in small reactors (grid plates with holes) possess a uniform reactivity and are well suitable for screening purposes. Of course, the harsh primary modification via chromium oxidation is a particular disadvantage with respect to the use of porous supporting materials (with large specific surface and thus more sensitive morphology). Thus the membranes obviously can be handled only when they are fixed in the grid plates, i.e., as discontinuous supporting materials. In addition, the relatively expensive construction of the synthesis device leads to a strictly limited capacity and limited variability of the individual synthesis areas.
The patent of Koster et al. (EP 0 305,929) describes the synthesis of peptides and oligonucleotides on porous membrane polymers, on which reactive groups were produced on the surface by irradiation-initiated generation of radicals. The functionalization by means of very different (due to the selection of initiator and monomers) and strongly crosslinked polymer layers, however, may lead to nonuniform accessibility of the functional groups. Th
Germeroth Lothar
Ulbricht Mathias
Volkmer-Engert Rudolf
Wenschuh Holger
Kriegsman & Kriegsman
McClendon Sanza K
Poly-An GmbH
Seidleck James J.
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