Polyhydroxy polymers substituted with styryl ether groups...

Details Polyhydroxy polymers substituted with styryl ether groups... Polyhydroxy polymers substituted with styryl ether groups...

1999-05-11

2001-07-03

Nutter, Nathan M. (Department: 1711)

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

Synthetic resins

Ethylenically unsaturated reactant admixed with either...

C525S056000, C526S238200, C526S288000, C526S332000, C526S333000, C526S334000, C527S300000, C527S315000

Reexamination Certificate

active

06255385

ABSTRACT:

This application claims priority to PCT Application Number PCT/SE97/00255, filed Feb. 17, 1997, which, in turn, claims priority to Swedish Patent Application 96 00612-7 filed Feb. 20, 1996.
1. Technical Field
The present invention concerns novel polyhydroxy polymers substituted with alkene group-containing substituents and polymerised forms of such polymers. These polymers comply with the general formula
R—B—P,
where R is an alkene group, B is an organic bridge and P is a polyhydroxy polymer and contains additional groups R—B—. P without any groups R—B— is designated P′. In the invention the alkene group is a styryl ether group. The inventive polymer will further on be called styryl ether polyhydroxy polymers.
R—B—P polymers have earlier been used for the manufacture of separation media for biorganic molecules and as hydrophilization agents etc. Potential fields of use encompass a) supports for the synthesis of oligopeptides and oligonucleotides, b) carriers for cell culture, c) carriers for enzymes, e) amphiphilic polymers etc and novel starting material for these types of supports, carriers, media, polymers etc.
2. Technical Background
The polyhydroxy polymers (P′) used so far for the synthesis of separation media have been based on native polymers, such as dextran, agarose, cellulose, starch etc, or synthetic polymers, such as poly(hydroxy alkyl acrylates) including corresponding poly(methacrylates). These separation media have been used in gel forms, i.e. swelled in the liquid in which they are to be used. In order to achieve the proper rigidity, porosity etc, the degree of cross-linking etc, the type of cross-linker, concentrations of cross-linker and polymer etc have been varied. The liquids used in the context of biotechnological applications have been water and mixtures of water and water miscible liquids, such as methanol, ethanol, isopropanol, acrylonitrile and water-miscible mixtures of liquids.
Polymers R—B—P have earlier been suggested as base constituents for the manufacture of separation media (Söderberg L., U.S. Pat. No. 4,094,832 (dextran) and U.S. Pat. No. 4,094,833 (dextran), and Nochumsson S, EP 87,995 (agarose)). The suggested uses have been as media for electrophoresis, liquid chromatography, such as gel permeation chromatography and various forms of affinity chromatography (ion exchange, hydrophobic, covalent, biospecific affinity etc chromatography).
It has also been suggested to adsorb polyhydroxy polymers substituted with hydrophobic groups onto surfaces in order to hydrophilise hydrophobic surfaces and obtain surface-bound gel layers (Henis et al., U.S. Pat. Nos. 4,794,002 and 5,139,881; and Varady L et al., U.S. Pat. No. 5,030,352). The adsorbed layers have often been stabilised by crosslinking. For hydrophobic groups containing an alkene structure, grafting has been suggested (Allmér K., WO 9529203).
In earlier publications the alkene group (R) has been allyl, such as in allyl glycidyl, and acryl/methacryl. See Allmér K., WO 9529203; Söderberg L., U.S. Pat. Nos. 4,094,832 and 4,094,833; and Nochumsson S, EP 87,995.
The bridge B has been stable against hydrolysis in the pH-range 2-14 and inert in the separation process contemplated.
Drawbacks of Earlier used Polyhydroxy Polymers
There have been certain drawbacks with the prior art separation media. Those based on native polymers have often exhibited a poor rigidity. This has implicated the manufacture of media based on synthetic polymers, such as styrene-divinyl benzene copolymers and the like, which in many cases have had an improved mechanical and chemical stability. However, the resulting polymers often have had a hydrophobic character promoting non-desired protein adsorption.
With respect to hydrophilisation, the prior art polymers often give poor adsorption steps. The stabilisation step (grafting/cross-linking) has often meant a reduction of the adsorbed layer.
Objectives of the Present Invention
The main objectives of the present invention is to provide alternative separation media and other supports/carriers that are favourable with respect to hydrophilic/hydrophobic balance, chemical and mechanical stability (including rigidity), methods of manufacture etc.
Other objectives are to provide alternative hydrophilisation processes that result in favourable properties as given for the media and supports/carriers.
Still other objectives are to provide alternative a) supports for the synthesis of oligopeptides and oligonucleotides, b) carriers for cell culture, c) carriers for enzymes, e) amphiphilic polymers etc and novel starting material for these types of supports, carriers, media, polymers etc.
The Invention
We have now found that styryl ether polyhydroxy polymers can be used for the manufacture of separation media and carriers/supports as described above. The higher reactivity of the styryl ether group compared to e.g. an allyl group gives an advantageous situation as far as the polymerisation is concerned. The main aspect of the present invention thus is an alkene group-containing polyhydroxy polymer as defined in the introductory part, the characteristic feature being that the alkene group (R) is a styryl ether group (CH
2
═CHC
6
H
4
O—), where the —O— grouping preferably is orto or para to the alkene group, without exclusion of the meta position. The aromatic ring may be substituted by, for example, one or more lower alkyl groups (C
1-6
), one or more lower alkoxy groups (C
1-6
), one or more halogens (such as chlorine) etc. The alkene group may be substituted with a lower alkyl (C
1-3
) and/or a lower alkoxy group (C
1-3
) or any other group not destroying the reactivity of the alkene group. If not otherwise specified, the expression “styryl ether group” includes substituted forms.
Other aspects of the invention are polymerised forms of styryl ether polyhydroxy polymers and their use as described under the headings Technical Field and Technical Background.
The polyhydroxy polymer (P′) may be a biopolymer, preferably with carbohydrate structure, such as in dextran, cellulose, agarose, starch and other water-soluble or water-insoluble polysaccharides. P′ may also be selected among synthetic polymers, such as polyvinyl alcohols, polymers based on vinyl hydroxyalkyl ethers, polymers based on hydroxyalkyl acrylates or methacrylates. Preferred polymers are water-soluble. Polymers that inherently are water-insoluble can be derivatised to become water-soluble. Among the specific polymers mentioned the preference is for dextran. P′ exhibit may groups other than R—B— as known in the field of chromatography. See below.
The bridge B is selected according to the rules mentioned under the heading Technical Background. Typically B contains one or more straight, branched or cyclic hydrocarbon chains that may be substituted with one or more hydroxy groups or broken by one or more ether oxygens. In order to secure a high stability against hydrolysis, it is preferred to have no more than one oxygen atom bound to each carbon atom of the hydrocarbon chain. Compared to ether groups, thioether (—S—) and sulphonamide (—SO
2
NH—) groups have a comparable or higher hydrolytic stability. They can thus also be present or equivalently replace ether oxygens in the hydrocarbon chain. Similarly, hydroxy groups and hydrogens may be replaced by lower alkoxies (C
1-6
) that in turn may contain ether or hydroxy groups. The structure of the bridge B depends on this coupling techniques employed to provide the polymer with styryl ether groups. The R—B— group is normally attached to the polymer via an ether linkage utilizing a hydroxy oxygen of the polymer.
The styrene derivatised polymer may be synthesised by reacting a polyhydroxy polymer with a styryl alkylene ether derivative CH
2
═CHC
6
H
4
OR′L, where R′ is a hydrocarbon chain of the type mentioned for B, and L is a group reacting with nucleophiles, such as hydroxy groups. L may be halo, epoxy etc. Compounds CH
2
═CHC
6
H
4
OR′L may be obtained by reacting:
where X is a nucleophile that is displaced by the h

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