Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-09-29
2002-11-12
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C546S022000, C546S016000
Reexamination Certificate
active
06479472
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to Published European Patent Application 108 565 relates to compounds of the General Formula:
and their pharmaceutically acceptable salts, in which R
1
is an aliphatic hydrocarbon radical having 8-30 carbon atoms and the radicals R
2
, R
3
and R
4
are identical or different and are hydrogen or lower alkyl radicals, or in which the group NR
2
R
3
R
4
is a cyclic ammonium group, and n has the value 0 or 1. Antitumor and antifungal activity are indicated for these compounds.
SUMMARY OF THE INVENTION
The present invention relates to alkyl or alkene phosphates in which the choline radical is part of a heterocyclic ring, to a process for the preparation of the class of compounds, to pharmaceutical compositions containing the compounds as active ingredients and to processes for the preparation of said drugs.
More specifically, the present invention provides compounds of the General Formula I:
in which
R is a linear or branched alkyl radical having 10 to 24 carbon atoms, which can also contain one to three double or triple bonds, R
1
and R
2
independently of one another are hydrogen or in each case a linear, branched or cyclic saturated or unsaturated alkyl radical having 1 to 6 carbon atoms, which can also contain a Cl, OH or NH
2
group, it also being possible for two of these radicals to be bonded together to form a ring,
A is a single bond or one of the groups of the formulae
—CH
2
—CH
2
—CH
2
—O— (II),
—CH
2
—CH
2
—O— (III),
the groups (II) to (VI) being orientated in such a way that the oxygen atom is bonded to the phosphorus atom of compound (I), X is an oxygen or sulphur atom or NH when A is a single bond, or an oxygen or sulphur atom when A is one of the groups (II) to (VI),
y is equal to 0 or a natural number between 1 and 3, and
m and n independently of one another are 0 or natural numbers, with the proviso that m+n=2 to 8.
The present invention also provides a pharmaceutical composition comprising, as the active ingredient, at least one compound according to General Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor. The pharmaceutical composition may also include pharmaceutically acceptable excipients, adjuncts, fillers and diluents. The amount of active ingredient in the pharmaceutical dosage unit the pharmaceutical composition is preferably between 50 mg and 250 mg. Preferred compounds for the pharmaceutical composition are selected from the group consisting of octadecyl 1,1-dimethylpiperidinio-4-yl phosphate, octadecyl 1,1-dimethylperhydroazepinio-4-yl phosphate, octaecyl 1,1-dimethylperhydroazepinio-4-yl phosphate, erucyl 1,1-dimethylpiperidinio-4-yl phosphate and erucyl 1,1-dimethylperhydroazepinio-4-yl phosphate.
The present invention also provides methods of treating a tumor, autoimmune disease or skin disease or skin disease, and of combating protozoal and fungal diseases, which comprises administering to a host in need o such treatment an effective amount of a compound of General Formula (I). Such methods are particularly useful for treating leishmaniasis, multiple sclerosis, and psoriasis.
In addition, the invention provides a method of treating bone marrow damage due to treatment with cytostatic agents and other myeloxtoxic active ingredients which comprises administering, to a host having bone marrow damage due to treatment with cytostatic agents or other myelotoxic active ingredients, an effective amount of a compound of General Formula (I).
The invention also provides a method of treating a viral disease which comprises administering to a host having such a disease an effective amount of a compound of General Formula (I). This method should be particularly useful in treating AIDS.
Surprisingly, the compounds according to the invention have better antitumor activity than the open-chain derivatives described in EP-A 108 565. The invention further relates to processes for the preparation and processes for the purification of the novel compounds.
More specifically, the present invention relates to a procedure for the preparation of compounds of general formula I—further referred to as process A—in which a compound of the general formula VII.
R—X—A—H (VII)
in which R, X and A are as defined above, is reacted with phosphorus oxytrichloride in the presence of a suitable auxiliary base, with or without a solvent, and then reacted with a compound of the general formula:
in which R
1
, R
2
, y, m and n are as defined above and Y
−
is halide, mesylate or tosylate, to give compounds of the general formula I, or optionally compounds of the General Formula IX:
in which R
1
, y, m and n as defined above can be used instead of compounds of the general formula VIII during the process mentioned above. Process B consists in the subsequent alkylation of compounds of general formula I obtained by process A, in which R
1
and/or R
2
are hydrogen, using alkylating agents R
2
—Y in which R
2
is as defined above and Y is chlorine, bromine, iodine, tosyl or mesyl, in a manner known per se.
The present invention also provides a process for the purification of the compounds of General Formula I in which a solution of the compounds of General Formula I, which have been prepared by means of known processes or by a process as described above, in an organic solvent is treated with a mixed bed ion exchanger or successively or simultaneously with an acid or basic ion exchanger.
The first step of process A consists in reacting phosphorus oxytrichloride with a compound of Formula VII in halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 carbon atoms or liquid aromatic hydrocarbons which can also be substituted by halogen (especially chlorine), or in mixtures of the above-mentioned solvents, or without a solvent, optionally in the presence of a basic substance conventionally used for this purpose.
Examples of possible halogenated hydrocarbons are hydrocarbons having 1 to 6 carbon atoms, one or more or all of the hydrogen atoms being replaced with chlorine atoms. Methylene chloride, chloroform, ethylene chloride, chlorobenzene and dichlorobenzene, for example, can be used. In the case of halogen-substituted aromatic hydrocarbons, these are preferably substituted by one or two halogen atoms.
Examples of saturated cyclic ethers which can be used are ethers with a ring size of 5-6 which consist of carbon atoms and one or 2 oxygen atoms, examples of such ethers being tetrahydrofuran and dioxane.
The acyclic ethers consist of 2 to 8 carbon atoms and are liquid, possible examples being diethyl ether, diisobutyl ether, methyl tert-butyl ether and diisopropyl ether.
Possible saturated hydrocarbons are unbranched and branched hydrocarbons which consist of 5 to 10 carbon atoms and are liquid, possible examples being pentane, hexane, heptane and cyclohexane.
Examples of possible aromatic hydrocarbons are benzene and alkyl-substituted benzenes, the alkyl substituents consisting of 1 to 5 carbon atoms.
Possible basic substances both for the reaction of the phosphorus oxychloride with the long-chain alcohol and for the subsequent conversion to the phosphoric acid diester are amines, for example aliphatic amines of the formula NR
1
R
2
R
3
, R
1
, R
2
and R
3
being identical or different and being hydrogen or C
1
-C
6
-alkyl, or else aromatic amines such as pyridine, picoline and quinoline. The basic substance required for the conversion to the phosphoric acid diester can be added simultaneously with or before the amino alcohol or ammonium alcohol salt.
A solvent is necessary in every case for the second reaction, i.e., if the first reaction step is carried out without a particular solvent, one must now be added. The molar ratio of phosphorus oxychloride to the long-chain alcohol is for example between 1.5:1 and 0.8:1.
The amino alcohol or the ammonium alcohol salt is for example used in excess, based on the long-chain alcohol (about 1.1-1.5 molar excess).
If the reactio
Engel Jürgen
Hilgard Peter
Kutscher Bernhard
Nössner Gerhard
Schumacher Wolfgang
Asta Medica Aktiengesellschaft
McKenzie Thomas C.
Shah Mukund J.
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