Chemistry: analytical and immunological testing – Involving producing or treating antigen or hapten – Producing labeled antigens
Reexamination Certificate
1998-06-11
2004-01-13
Ceperley, Mary E. (Department: 1641)
Chemistry: analytical and immunological testing
Involving producing or treating antigen or hapten
Producing labeled antigens
C424S093700, C424S179100, C435S006120, C435S007200, C435S007210, C435S007500, C435S007950, C436S501000, C436S533000, C436S534000, C436S827000, C436S909000, C530S391100, C530S391900, C530S402000, C530S404000
Reexamination Certificate
active
06677164
ABSTRACT:
The present invention relates to biologically degradable polypeptides which possess active halogen atoms which are covalently bound to side chains; to such polypeptides which possess recognition molecules and/or water-soluble groups which are bound in the side chains; and also to processes for their preparation by reacting polyamides which contain functional groups with halomethylcarbonylating agents or reacting the polypeptides which contain active halogen atoms with this group-containing recognition molecules or water-soluble groups; and to the use of these polymers in therapeutic compositions or in the active layer of diagnostic agents.
Receptor-ligand interactions are of great importance in intracellular communication and in intercellular recognition processes. The initiation of diseases, for example bacterial diseases [J. C. Paulson, The receptors, Vol. II, Ed.: P. M. Conn, Academic Press, 1985, 131], viral Infections [Strömberg et al. EMBO J. 1990, (9), 2001] and inflammatory diseases [Dasgupta, F., Rao, B. N. N., Exp. Opin. Invest. Drugs 3:709-724 (1994)] takes place by way of ligand-receptor interactions. In specified examples, the ligands are oligosaccharides. It is not possible to use free oligosaccharides, which are to bind to receptors in place of natural ligands, for the therapy of these diseases because of the very high quantities of oligosaccharides which have to be administered since the affinity between the receptors and the ligands is too low.
It is known that an increased interaction between receptor and ligand is achieved by coupling several ligands on a surface. The example of the viral protein haemagglutinine, binding to neuramic acid on the cell surface and their interaction has been used to show how this polyvalent effect obtained by using a polymer affects such an interaction [A. Spaltenstein et al.
J. Am. Chem. Soc
. 1991 (113) 686].
Polymeric compounds which present ligands in multivalent form can lead, in ligand-receptor recognition processes, to increased interactions with receptors and be used therapeutically, for example as receptor blockers [W. J. Lees et.al.,
J. Med. Chem
. 1994, 37, 3419; EP 601417 A2] or multivalent enzyme inhibitors [WO 90/02558].
Other applications have also been reported for polymers which are functionalized by defined quantities of active molecules. For targeting active substances, use can be made of more complex polymers which, in addition to active compounds, also carry substances which are selectively recognized by particular cell-surface receptors so that these active compounds are preferentially transported to these types of cells [J. Kopecjek, R. Duncan, J. Controlled Release 1987, 6, 315].
In addition, active compounds which are coupled covalently to polymers by way of labile bonds can be selectively released in the organism at sights where these bonds are cleaved by particular physiological conditions [B. Zorc et. al., Acta Pharm. 1994, 44,103; B.Zorc et. al., Int. J. Pharmaceutics 1993, 99, 135; G. Giammona et. al., Eur. J. Pharm. Biopharm. 1992, 38, 159; G. Giammona et. al., Eur. J. Pharm Biopharm. 1992, 38, 159; G. Giammona et. al. Int J. Pharmaceutics 1989, 57, 55].
Polymers which are functionalized by receptor molecules or ligands can be widely used in diagnostics. Immobilized marker molecules, for example biotin, can be used when carrying out biological tests [N. E. Nifant'ev et. al., in “Synthetic Oligosaccharides”, Ed.: P. Kovac, ACS Symposium Series 560, Washington, D.C. 1994)]. Compounds of this nature can be present as recognition elements in the active layers of sensors [Janata, Principles of Chemical Sensors, Plenum Press, New York 1989].
Immobilized active molecules can also be antigens which can be employed as vaccines [Conjugate Vaccines, Eds.: J. M. Cruse, R. E. Lewis, Jr; Karger, Basel 1989; Towards Better Carbohydrate Vaccines, Eds.: R. Bell, G. Torrigiani, John Wiley & Sons, Chichester 1987].
EP 0601417 A2 already discloses a mixture in which physiologically tolerated and physiologically degradable polymer-based carbohydrate receptor blockers are prepared. These blockers consist of a carbohydrate moiety, a bifunctional spacer, a hydrophilic polymer and an effect enhancer. However, it is not possible to incorporate all or some of the carbohydrate ligands in a specific manner or even to incorporate different ligands in a specific manner.
For the purpose of constructing complex polymers in a controlled manner, small quantities of an active substance can be coupled to a preformed polymer which carries an excess of activated side chains. This principle was exploited for synthesizing polymeric, water-soluble neoglycoconjugates which are based on nitrogen-substituted polyacrylamides [WO 94/11005-A1; N. V. Bovin et. al.,
Glycoconjugate J
. 1993, 10, 142; N. E. Nifant'ev et al., in “Synthetic Oligosaccharides”, Ed.: P. Kovac, ACS Symposium Series 560, Washington, D.C. 1994]. However, the scope for using such compounds is limited by the fact that the polymer backbone is not necessarily biodegradable.
It has now been found, surprisingly, that biodegradable polymers which possess side chains which are functionalized identically or differently can be specifically obtained with a precisely defined, predictable composition when polypeptides which possess activated halogen atoms in the side chains are used as the starting material and are reacted with substituents which contain a mercapto group. In addition, these polypeptides can be prepared in a simple manner and in high yields and purities. Water-soluble, gelatinous or water-insoluble potypeptides can be obtained depending on the hydrophilicity of the substituents. It is particularly worth mentioning that precisely defined active compound densities can be set and it is possible, concomitently to carry out further modification which is controlled in accordance with the desired application. The polypeptides which contain activated halogen atoms are also surprisingly easy to obtain, very stable and readily soluble in various organic solvents.
The invention relates to polypeptides which possess identical or different structural elements of the formula (I),
in which
A is a trivalent, aliphatic hydrocarbon radical having from 1 to 12 C atoms which is unsubstituted or substituted by one or more substituents selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, benzyl and benzyloxy,
R
1
is a direct bond or C
1
-C
6
alkylene,
X
1
is —C(O)O—,—C(O)NR—, —NR—, —S— or —O—;
R
2
is a bivalent bridging group,
X
2
is O or NR, or R
2
and X
2
are together a direct bond,
X
3
is a halogen, and
R is H or C
1
-C
6
alkyl;
with the proviso that X
1
is not —NR—, —S— or —O— when R
1
is a direct bond.
As halogen, X
3
is preferably Cl, Br or I, and particularly preferably Cl or Br.
The trivalent radical A preferably contains from 1 to 8, more preferably from 1 to 6, particularly preferably from 1 to 4 and, in particular, 1 or 2, C atoms. Examples are 1,1,6-, 1,2,6-, 1,3,6-, 1,4,6-, 1,5,6- or 1,6,6-hexanetriyl, 1,1,5-, 1,2,5-, 1,3,5-, 1,4,5- or 1,5,5-pentanetriyl, 1,1,4-, 1,2,4-, 1,3,4- or 1,4,4-butanetriyl, 1,1,3-, 1,2,3- or 1,3,3-propanetriyl, 1,1,2- or 1,2,2-ethanetriyl and methanetriyl. Methanetriyl and 1,1,2- and 1,2,2-ethanetriyl are particularly preferred.
As alkylene, R
1
preferably contains from 1 to 6 C atoms, more preferably 1-4 C atoms, which can be linear or branched. Examples are 1,6-, 1,5-, 1,4-, 1,3-, 1,2-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-hexylene, 1,5-, 1,4-, 1,3-, 1,2-, 2,3-, 2,4-, 2,5-, 3,4- or 3,5-pentylene, 1,4-, 1,3-, 1,2-, 2,3-, 2,4- or 3,4-butylene, 1,3-, 1,2- or 2,3- propylene, 1,2-ethylene and methylene. R
1
is particularly preferably linear and is especially preferably methylene, ethylene, 1,3 propylene or 1,4-butylene.
Within the scope of the present invention, X
1
is preferably NR or —C(O)—NR—, with R particularly preferably being H.
The bridging group can contain fro
Duthaler Rudolf
Ernst Beat
Magnani John Louis
Patton, Jr. John Tinsman
Thoma Gebhard
Ceperley Mary E.
Novartis AG
Wildman David E.
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