Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-12-31
2000-11-14
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514183, 514410, C07D48722, A61K 3140
Patent
active
061472077
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of polyether-including chlorins and bacteriochlorins, compounds as such and their use.
It is known to use polyether-including chlorins and bacteriochlorins for treating tumors in the photodynamic therapy. They are prepared by initially synthesizing chlorins and bacteriochlorins from porphyrins. Following isolation and purification, polyethers are bound to the chlorins and bacteriochlorins. The resulting polyether-including chlorins and bacteriochlorins are then isolated and purified. The multiple isolation and purification steps render the process very complicated and expensive. In addition, the polyether-including chlorins and bacteriochlorins may only be prepared in small amounts and poor yield.
Therefore, it is the object of the present invention to provide a process by which polyether-including chlorins and bacteriochlorins can be prepared with the above drawbacks.
According to the invention this is achieved by the subject matters defined in the claims.
Thus, the subject matter of the present invention relates to a process for the preparation of polyether-including chlorins and/or bacteriochlorins, which comprises the following steps:
The expression "porphyrin" comprises compounds of any kind having the macrocyclic tetrapyrrole skeleton. Representatives of these compounds are porphyrins which have one or more, preferably 4, functional groups, e.g. acid groups such as carboxylic acid and/or sulfonic acid groups. Examples thereof are o-, m- and/or p-tetracarboxyphenylporphin (TCCP) and o-, m- and/or p-tetrasulfophenylporphin. It is favorable for the porphyrin to be activated with the polyether prior to its reaction. Such an activation may be e.g. the conversion of the above acid groups into a more reactive derivative, e.g. acid halide such as acid chloride or bromide.
In step (a) of the process according to the invention, a polyether is bound to the porphyrin so as to obtain a polyether-including porphyrin. The bond may be covalent. For example, the polyether may be bound to functional groups of the porphyrin. The polyether preferably has a molecular weight of 100 to 20,000 daltons, more preferably 2,000 to 5,000 daltons and most preferably about 5,000 daltons. In addition, the polyether may be etherified or esterified at the terminal hydroxyl group with a C.sub.1 -C.sub.12 alkyl group, particularly methyl group. Representatives of the polyethers are polyethylene glycols such as methoxypolyethylene glycol and amino-.OMEGA.-methoxypolyethylene glycol (aminoPEG). Several polyethers, preferably four, may be bound to the porphyrin. The polyethers may be identical or differ from one another. If several polyethers are bound to the porphyrin, the sum of the molecular weight of the polyethers is preferably from 8,000 to 50,000 daltons.
In step (b) of the process according to the invention, the polyether-including porphyrin of step (a) is reacted by means of a reducing agent. For this purpose, the porphyrin needs not be either isolated or purified. Therefore, steps (a) and (b) can be carried out in a one-pot reaction. Every agent which can effect a reduction of the porphyrin to form a chlorin, i.e. dihydroporphyrin, particularly 7,8-dihydroporphyrin, and/or bacteriochlorin, i.e. tetra-hydroporphyrin, particularly 7,8,17,18-tetrahydroporphyrin, is suitable as reducing agent. Examples of such reducing agents are hydrazides such as toluenesulfonic acid hydrazide.
Steps (a) and (b) of the process according to the invention are preferably carried out in an organic, polar solvent miscible with water, e.g. dioxan or a mixture of dioxan and ethylene triamine. The advantage of this is e.g. that water or aqueous solutions may be added and an ultrafiltration may be carried out for separating undesired accompanying substances.
Following step (b) of the process according to the invention, the reaction batch has polyether-including chlorins and/or bacteriochlorins. The composition of the reaction batch depends on the reducing agent, its amount and reaction time. Th
REFERENCES:
patent: 5238940 (1993-08-01), Liu et al.
patent: 5284831 (1994-02-01), Kahl et al.
Whitlock, Jr. et al. "Diimide Reduction of Porphyrins," Journal of the American Chemical Society. XP-002053835. Dec. 17, 1969, pp. 7485-7489.
Kaus Michael
Maier-Borst Wolfgang
Schrenk Hans-Hermann
Sinn Hannsjorg
Stehle Gerd
Barrett William A.
Deutsches Krebsforschungszentrum Stiftung des Offentlichen
Hultquist Steven J.
Shah Mukund J.
Sripada Pavanaram K
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