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
1999-11-10
2002-03-12
Nutter, Nathan M. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S054200, C525S054300, C530S812000, C530S815000, C436S008000, C436S528000, C436S531000, C436S532000
Reexamination Certificate
active
06355726
ABSTRACT:
The invention relates to a process for the preparation of polymers having nucleobases as side groups by means of multicomponent reactions, especially the Ugi reaction.
The present invention relates also to multifunctional isonitriles, to a process for their preparation and to their use in multicomponent reactions. Such isonitriles can be used in the process according to the invention for the preparation of polymers having nucleobases as side groups.
Multicomponent reactions (MCRs) are valuable processes in organic synthesis. They are used, for example, in synthesising antibiotics, peptides, etc., that is to say complex molecules having a high degree of diversity. In the case of customary MCRs, such as, for example, a four-component reaction (4-CC), an isonitrile, an aldehyde, a carboxylic acid and an amine are reacted to form a defined product. The isonitriles used hitherto have been monofunctional compounds, with the result that the variety of products of such multicomponent reactions has been limited (see Isonitrile Chemistry; I. Ugi (Ed.), Academic Press, New York, London 1971) and the reaction in question has been complete as soon as the individual components have finished reacting with one another.
Regulatory action on gene expression by means of polymeric peptide nucleic acids (PNA) was first described in the sixties by Svachkin et al. (R. A. Paégle, M. G. Plata, M. Yu. Lidak, S. A. Giller, Yu. P. Shvachkin, in: Present State of the Chemotherapy of Malignant Tumors [in Russian], Riga (1968), 103 ff.; Review: Yu. P. Shavachkin, G. P. Mishin, G. A. Korshunova, Russian Chemical Reviews, 51, 1982, 178-188). In 1978 Zamecnik and Stephenson introduced the terms “antisense” and “antigen”: those terms describe mechanisms by which it is possible to intervene therapeutically in the translation and transcription of genes (Proc. Natl. Acad. Sci. U.S.A., 1978, 75, 280 and 285).
In the antisense strategy, an antisense molecule binds to mRNA and thus prevents its translation to a protein. In the antigen strategy, a triple helix of the antigen molecule with the double-stranded DNA is formed, thus modifying transcription into mRNA (E. Uhlmann, A. Peyman, Chem. Rev., 90, 1990, 544-584). In this context, various substances are potential therapeutic agents for the treatment of viral diseases, cancer, etc., in various clinical phases.
A good antisense molecule should inter alia satisfy the following requirements:
1. It should have good accessibility to the cell and cell nucleus without the assistance of so-called transfection reagents or liposomes;
2. It should have nuclease and peptidase resistance in order to obtain sufficient bioavailability; and
3. It should recognise precisely the sequence of the natural sense strand.
The PNA described by Nielsen et al. (Science 1991, 254, 1497-1500; WO 92/20702) has proved to be a highly promising antisense and antigen polymer, and has also been used in a variety of ways as a tool in molecular biology. This is attributable primarily to the high affinity of the PNA for the sense strand (DNA, RNA) combined with very good sequence specificity. PNA is able to identify mismatches in sequences substantially better than do natural DNA and RNA. Moreover, pyrimidine-rich PNA strands are able to wind up the DNA double helix and form a (PNA)
2
DNA triple helix. Such structures are potential translation and replication complex mimetics and it might be possible to use them to turn specific genes on and off. Various properties of PNA still need to be improved and optimised for in vivo use, however. For example, PNA does not have cell-accessibility. The (PNA)
2
DNA triple helix formation mentioned occurs only in the case of pyrimidine-fich PNA strands and only at non-physiological salt concentrations. PNAs aggregate and have poor solubility in water. PNA—itself a polar polymer—binds to the DNA or RNA target structure in both parallel and anti-parallel manner with similar binding constants. There have also been reports of PNA having strong cytotoxic effects (EP 0 672 677 A2).
As has been shown, new improved PNAs are found most effectively by screening a large number of variants (S. Jordan et al., Bioorganic & Medicinal Chemistry Letters, 1997, 7, 681 and 687). The methods of PNA synthesis described hitherto, which are based on sequential two-component reactions of monomers which themselves must be synthesised from suitable commercial precursors via many steps, do not appear to be optimally suited to the systematic and rapid production of a large number of analogues (M. Egholm et al., Journal of the American Chemical Society, (1992) 114, 1895).
The problem underlying the present invention is accordingly to provide a process by which complex monomers, oligomers and polymers having nucleobases as side groups, and especially PNAs having a large capacity for variation, can be produced.
A further problem of the present invention is to provide a component with which the diversity of MCRs and especially of processes for the preparation of polymers having nucleobases as side groups can be considerably increased and complex molecules can be synthesised, that is to say a component that can be reacted in an MCR-type reaction. Such components must satisfy the following preconditions:
1. They must be easy and inexpensive to produce;
2. The protecting groups used therein must be readily removable, that is to say under mild conditions;
3. The protecting groups used therein must be stable under customary reaction conditions for the reaction of other functional groups;
4. The components must be so synthesised that, after the removal of a protecting group, functional groups suitable for an MCR are freed without other groups, for example functional groups of the components or of the reactants, being modified.
According to the invention, there is disclosed a process for the preparation of compounds of formula (I)
characterised in that compounds of formulae
are reacted with one another, optionally simultaneously, in a first step,
as appropriate one or more protecting groups are removed,
and the reaction is repeated m times,
wherein, after the first step, the product of each preceding step is used instead of the compound of formula II,
wherein
m is 0 or an integer from 1 to 1000, preferably from 1 to 300, more especially from 1 to 100, especially from 1 to 50, from 1 to 30, from 1 to 10 or from 1 to 5,
A is a radical of the amino component being a radical customary in the Ugi reaction, such as a hydrogen atom, a substituent, (cyclo)alkyl, (cyclo)alkenyl, (cyclo)alkynyl, aroyl, heteroaroyl, a heterocycle, a fluorescent label, an intercalator, an antibiotic, a minor groove binder, a major groove binder, a biotinyl radical, an intercalating radical, an alkylating radical, a steroid, a lipid, a polyamine, an agent that facilitates cell uptake, a saccharide or oligosaccharide, an antisense polymer, a peptide, an antibody conjugate, a synthetic polymer or an appropriately modified surface,
B is a hydrogen atom, a substituent, (cyclo)alkyl, (cyclo)alkenyl, (cyclo)alkynyl, aroyl, heteroaroyl, a heterocycle, a fluorescent label, an intercalator, an antibiotic, a minor groove binder, a major groove binder, a biotinyl radical, an intercalating radical, an alkylating radical, a steroid, a lipid, a polyamine, an agent that facilitates cell uptake, a saccharide or oligosaccharide, an antisense polymer, a peptide, an antibody conjugate, a synthetic polymer or an appropriately modified surface, or a radical X--NPG of compound V,
R
1
-G is selected from structures of the following formulae:
wherein the group R
1
-G can be linked to the compound of formula IV by way of a molecular spacer via R
1
or R or R
4
;
R
1
and R each independently of the other is a radical of the acid component being a radical customary in the Ugi reaction, such as H, a substituent, (cyclo)alkyl, (cyclo)alkenyl, (cyclo)alkynyl, aroyl, heteroaroyl, a heterocycle, a fluorescent label, an intercalator, an antibiotic, a minor groove binder, a major groove binder, a biotinyl radical, an intercalating radical, an alkyl
Doemling Alexander
Richter Wolfgang
Frommer & Lawrence & Haug LLP
Morphochem AG
Nutter Nathan M.
LandOfFree
Method for producing polymers having nucleo-bases as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing polymers having nucleo-bases as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing polymers having nucleo-bases as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2854833