CA2100228C - Phospholipid derivatives - Google Patents

Phospholipid derivatives Download PDF

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CA2100228C
CA2100228C CA002100228A CA2100228A CA2100228C CA 2100228 C CA2100228 C CA 2100228C CA 002100228 A CA002100228 A CA 002100228A CA 2100228 A CA2100228 A CA 2100228A CA 2100228 C CA2100228 C CA 2100228C
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phosphate
compound
octadecyl
dimethylpiperidinio
pharmaceutically
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CA2100228A1 (en
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Gerhard Nossner
Bernhard Kutscher
Jurgen Engel
Wolfgang Schumacher
Jurij Stekar
Peter Hilgard
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Aeterna Zentaris GmbH
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Zentaris AG
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Abstract

Compounds of the general formula I

(see formula I) in which: R is a straight-chain or branched alkyl radical having 10 to 24 carbon atoms, which also can contain one to three double or triple bonds; R1 and R2, independently of one another, are hydrogen, or each is a straight-chain or branched saturated alkyl radical having 1 to 6 carbon atoms, a straight-chain or branched unsaturated alkyl radical having 2 to 6 carbon atoms, or a cyclic saturated or unsaturated alkyl radical having 3 to 6 carbon atoms, which also can contain a Cl, OH or NH2 group; and where straight-chain or branched alkyl radicals R1 and R2 also can be bonded together to form a ring; A is a single bond or one of the groups having the formulae -CH2-CH2-CH2-O- (II) -CH2-CH2-O- (III) (see formula IV) -s-(CH2)8-O- (V) (see formula VI) wherein: the groups (II) to (VI) are arranged such that the oxygen atom is bonded to the phosphorus atom of the compound (I); X is an oxygen or sulphur atom, or NH if A is a single bond, or is an oxygen or sulphur atom if A is one of the groups (II) to (VI); y is 0 or a natural number between 1 and 3; and m + n independently of one another are 0 or natural numbers, with the proviso that m + n = 2 to 8;
and pharmaceutically-acceptable salts thereof. These novel phospholipid derivatives are useful for treating tumours, protozoal and fungal diseases, autoimmune diseases, skin diseases, bone marrow damage due to treatment with cytostatic and other myelotoxic agents, and viral diseases.
Preparation and purification methods for the compound are also disclosed.

Description

PHOSPHOLIPID DERIVATIVES
The invention relates to new phospholiped derivatives, processes for preparing them, pharmaceutical compositions containing them; and their use in the treatment of tumours, protozoal and fungal diseases, autoimmune diseases, skin diseases, bone marrow damage due to treatment with cytostatic and other myelotoxic agents, and viral diseases.
Published European Patent Application 108,565 describes compounds of the general formula Rl (O) n P OCH2CH2N=R3 i _ \R4 and their pharmaceutically-acceptable salts, in which R1 is an aliphatic hydrocarbon radical having 8-30 carbon atoms and the radicals R2, R3 and R4 are identical or different and are hydrogen or lower alkyl radicals, or in which the group NR2R3R4 is a cyclic ammonium group, and n has the value 0 or 1. Antitumor and antifungal activity are indicated for these compounds.
The present invention relates to alkyl or alkene phosphates in which the choline.radical is part of a heterocyclic ring, to a process f.or the preparation of those compounds, to pharmaceutical compositions containing the compounds as active ingredients, and to processes for the preparation of those drugs.
More specifically, the present invention provides compounds of the general formula I
/(CH2)m \ ~Rl R-X-A-P-O- ( CH2 ) y CH' N.
O_ \(.CHZ) ~ \R

In WhlCh:
R is a straight-chain or branched alkyl radical having 10 to 24 carbon atoms, which also can contain one to three double or triple bonds;
R1 and R2, independently of one another, are hydrogen, ~r each is a straight-chain or branched saturated alkyl radical having 1 to 6 carbon atoms, a straight-chain or branched unsaturated alkyl radical having 2 to 6 carbon atoms, or a cyclic saturated or unsaturated alkyl radical having,3 to 6 carbon atoms, which also can contain a Cl, OH
or NHz group, and where straight-chain or branched alkyl radicals R1 and R2 also can be bonded together to form a ring;
A is a single bond or one of the groups having the formulae -CH2-CH2-CH2-O- (II) -CH2-CH2-O- (III) -CH2-CH-O- (IV) -S-(CH2)g-O- (V) H2 ~ ~ (VI) wherein the groups (II) to (VI) are arranged such that the oxygen atom is bonded to the phosphorus atom of the compound ( I ) ;
X is an oxygen or sulphur atom, or NH if A is a sing~:~
bond, or is an oxygen or sulphur atom if A is one of the groups (II) to (VI);
y is 0 or a natural number between 1 and 3; and m + n independently of one another are 0 or natural numbers, with the proviso that m + n = 2 to 8;
and pharmaceutically-acceptable salts thereof.
Preferably, X is an oxygen atom, A is a single bond and R1 and RZ are each methyl groups.

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 therefcr.. The pharmaceutical composition also may include pharmaceutically-acceptable excipients, adjuncts, fillers and diluents. The.amount of active ingredient in the pharmaceutical dosage unit the pharmaceutical composition preferably is 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-dimethylhexahydroazepinio-4-yl phosphate, octadecyl (1,1-dimethylpiperidinio-2-yl)methyl phosphate, erucyl 1,1-dimethylpiperidinio-4-yl phosphate, erucyl l,l-dimethylhexahydroazepinio-4-yl phosphate, hexadecyl (1,1-dimethylpyrrolidinio-2-yl)methyl phosphate and octadecyl (1,1-dimethylpyrrolidinio-2-yl)methyl phosphate.
The present invention also provides for treating a tumor, autoimmune disease or skin disease, and for combating protozoal and fungal diseases, using effective amounts of the compounds. They are particularly useful for treating leishmaniasis, multiple sclerosis and psoriasis.
In addition, the invention provides for treating bone marrow damage due to treatment with cytostatic agents and other myelotoxic 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 the invention.
2a s, The invention also provides for treatment of a viral disease by administering to a host having such a disease an effective amount of a compound of the invention.
Surprisingly, the compounds according to the invention have better antitumor activity than the open-chain.
derivatives described in E.P. 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 R-X-A-H (VII) in which R, X and A are as defined above, is reacted with phosphorus oxychloride in the presence of a suitable auxiliary base, and then reacted with a compound of the general formula ~(_CH2jm ~R1 HO- ( CH2 j y CH
(VIII) (CH2j n in which Rl and R2, y, m and n are as defined above and Y-is halide, mesylate or, tosylate, to give a compound of the general formula I (above):
or optionally a compound of the general formula ~(CH2~~~
HO-(CH2)~,-CH N ' R1 \(CH2)n~
(IX) in which R1, y, m and n are 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 R1 and/or R2 are hydrogen, using alkylating agents R2-Y in which R2 is as defined above 2b and Y is chlorine, bromine, iodine, tosyl or mesyl, in a manner known per se.
In another embodiment the invention also provides compounds of the general formula o.
R-X'pi II-o'(~~~y- B
(IA) O_ wherein B is the ring system ~(~~~~+/Ri -CH\ /tJ~
\(CH~n R2 in which:
R is a straight-chain or branched alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds;
R1 and RZ, independently of one another, are selected from the group consisting of hydrogen and straight-chain alkyl radicals having 1 to 3 carbon atoms;
A is a single bond and X is an oxygen atom;
y is 0, l, 2 or 3; and m and n are independently 0 or an integer, with the proviso that m + n = 2 to 8;
or pharmaceutically-acceptable salts thereof.
B may be selected from the group consisting of a pyrrolidinio, piperidinio and hexahydroazepinio rings, and R can be selected from the group consisting of octadecyl, hexadecyl, erucyl, tetradecyl, cis-D9 octadecyl and eicosyl radicals. Preferably, the sum of m + n equals 4.
The present invention also provides a process for the purification of the compounds, in which a solution of the compound, which has 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.
2c ~~ ~h~~J
The first step of process A consists in reacting phosphorus oxychloride with long-chain alcohol in halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 C 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.
l0 Examples of possible halogenated hydrocarbons are' hydrocarbons having 1 to 6 C 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 di,isopropyl ether.
Possible saturated hydrocarbons are unbranched and branched 30. hydrocarbons which consist of 5 to 1.0 carbon atoms and are liquid, possible examples being pentane, hexane, heptane and cyclohexane.
Examples of possible aromatic hydrocarbons are benzene and alkyl-substituted benzeries, the alkyl substituents consisting of 1 to 5 carbon atoms.
~' ' ~ ') ;l hI ~ ~~ ~ nJ ~~l '.J
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 NR1R2R3, R1, R2 and R3 being identical or different and being hydrogen or C1-C6- 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 else before the amino l0 alcohol or ammonium alcohol salt.
A solvent is necessary in every case for this 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 reaction of the phosphorus oxychloride with the long-chain alcohol is carried out in the presence of a basic substance, the amount of the basic substance is for example 1 to 3 mol, based on 1 mol of PoCl3. The amount of basic substance used for the subsequent conversion to the phosphoric acid diester is for example 1 to 5 mol, based on 1 mol.
The temperature of the reaction of phosphorus.oxychloride with the long-chain alcohol is between -30°C and +30°C,~
preferably between -15°C and +5°C and especially between -10°C and -5°C.
The duration of this reaction is for example 0.5 - 5 hours, preferably 1 - 3 hours and especially 1.5 - 2 hours. If it is carried out in the presence of a basic substance, the reaction generally proceeds rapidly (about 30 minutes).
The amino alcohol or the ammonium alcohol salt is then , added in portions or all at once. Possible ammonium alcohol salts are those with mineral acids (for example sulphuric acid, hydrochloric acid) and also those with organic acids, for example acetic acid, paratoluene-sulphonic acid and the like. This reaction step takes place in an inert solvent. Possible solvents here are the same ones as those used for the reaction of the phosphorus oxychloride with the long- chain alcohol, in the case where this reaction is carried out in a solvent.
The basic substance is then added dropwise, either dissolved in one of the indicated solvents or without a solvent. The following are preferably used here as solvents for the basic substance: halogenated hydrocarbons, saturated cyclic ethers, acyclic ethers, saturated hydrocarbons having 5 to 10 carbon atoms, liquid aromatic hydrocarbons or mixtures of the above-mentioned solvents.
These are the same solvents as those which can be used for the reaction of the phosphorus oxychloride with the long-chain alcohol.
The addition of the basic substance raises the temperature.
Care is taken to ensure that the temperature is kept in a range of between 0°C and 40°C, preferably between 10°C
and 30°C and especially between 15°C and 20°C.
The reaction mixture is then stirred at 5°C to 30°C, preferably 15°C to 25°C (for example for 1 hour to 40 hours, preferably 3 hours to 15 hours).
The reaction mixture is hydrolyzed by the addition of water, during which the temperature should be kept at ~,~.p~~~~?
between 10°C and 30°C, preferably between 15°C and 30°C and especially between 15°C and 20°C.
The above-mentioned hydrolyzing liquids can also contain basic substances, such basic substances possibly being' alkali metal and alkaline earth metal carbonates and bicarbonates.
To complete the hydrolysis, stirring is then continued for a further 0.5 hour to 4 hours, preferably 1 to 3 hours and especially 1.5 to 2.5 hours, at 10°C to 30°C, preferably at 15°C to 25°C and especially at 18°C to 22°C.
The reaction solution is then washed with a mixture of water and alcohols (preferably saturated aliphatic alcohols having 1 to 4 carbon atoms) which can optionally also contain a basic substance. The mixing ratio water: alcohol can be for example between 5 and 0.5, preferably l - 3 (v/v).
Examples of possible basic substances for the washing liquid are alkali metal and alkaline earth metal carbonates and bicarbonates, as well as ammonia (for example aqueous ammonia). A 3% solution of sodium carbonate in water is particularly preferred.
The reaction solution can then optionally be washed with an acid solution. The acid washing is advantageous for removing basic components of the reaction solution which have not yet reacted, especially when methylene chloride is used as the solvent.
The washing solution consists of a mixture of water and alcohols. Mixtures of saturated aliphatic alcohols having 1 to 4 carbon atoms are preferred, it optionally being possible for an acid substance to be present as well. The mixing ratio water:alcohol can be for example between 5 and 0_5, preferably 1 - 3 (v/v).
Examples of possible acid substances for the washing liquid are mineral acids and organic acids, for example hydrochloric acid, sulphuric acid, tartaric acid or citric acid. A loo solution of hydrochloric acid in water is particularly preferred.
This is followed by a further washing with a mixture of water and alcohols. Mixtures of saturated aliphatic alcohols having 1 to 4 carbon atoms are preferred, it optionally being possible for a basic substance to be present as well. The mixing ratio water:alcohol can be for example between 5 and 0.5, preferably 1 - 3.
The washed phases are then combined and dried in conventional manner, after which the solvent is removed (preferably under reduced pressure, for example at 5 to-100 mbar), optionally after the addition of 150 - 1000 ml, preferably 300 - 700 ml and especially 450 - 550 ml of an aliphatic alcohol (based on 1 molar part by weight of dry ..
product). Preferred alcohols are saturated aliphatic alcohols with a chain length of 1 to 5 carbon. atoms, particularly preferred alcohols being n-butanoi and isopropanol. The purpose of this alcohol treatment is the complete removal of residual water and the avoidance of foaming .
Further purification of the, product can be effected for example by dissolving the crude product in hot ethanol, filtering off the residue and treating the filtrate with a TM
mixed bed ion exchanger such as, for example, Amberlite MB3 in ethanolic solution. Any commercially available acid and basic ion exchangers can be used, simultaneously or successively, instead of a mixed bed ion exchanger.

'2~~~a~~d The solution is then recrystallized from ketones such as, for example, acetone or methyl ethyl ketbne; digestion with the above solvents is sufficient in some cases. It may be convenient to purify the products by column chromatography or flash chromatography on silica gel using mixtures of chloroform, methylene chloride, methanol and 25% ammonia solution, for example, as the eluent.
Process variant B consists in the subsequent alkylation of products which are obtainable by process A using_amino alcohols. Examples of alkylating.agents which can~be used are methyl p-toluenesulphonate or dimethyl sulphate.
Possible solvents are those which have been mentioned above.
Alkali metal carbonates axe examples.of basic substances used. The reaction is carried out at elevated temperature, for example at the boiling point of the solvents.

_ g _ c a n,n'~~~y .~, ai ~~ C-r as Examples:
Example 1: Name (IUPAC nomenclature) 4-(((Octadecyloxy)hydroxyphosphenyl)oxy)-1,1-dimethylpiperidinium hydroxide internal salt Abbreviated name:
Octadecyl 1,1-dimethylpiperidinio-4-yl phosphate C25H52NO4P (461.66) ~ iFi20 Preparation variant A:
10.3 ml (0.11 mol) of phosphorus oxychloride are placed in 100 ml of chloroform and cooled to 5 - 10°C. A solution of 27.0 g (0.10 mol) of 1-octadecanol in 100 ml of chloroform and 35 ml of pyridine is added dropwise over 30 min, with stirring. After subsequent stirring for 30 min at 5 - 10°C, 39.1 g (0.13 mol) of 4-hydroxy-1,1-dimethylpiperidinium tosylate are added in a single portion. After the addition of 40 ml of pyridine and 30 ml of DMF, the mixture is stirred for 24 h at room temperature. It is then hydrolyzed with 15 ml of water and subsequently stirred for 30 min and the organic phase is washed with 200 ml each of water/methanol (1: 1) , 3% Na2C03/methanol (1:1) and finally water/methanol (l:l). The organic phase is concentrated, the residue is dissolved in 300 ml of hot ethanol and the solution is filtered after cooling. The filtrate is stirred with 80 g of Amberlite* MB3 ion exchanger, the mixture is filtered and the filtrate is concentrated. The residue is recrystallized from 300 ml of methyl ethyl ketone, filtered off with suction and dried under vacuum over P205 * Trade-Mark _ g -~:l~J~~~~~' Yield: 4.71 g (10%) Elemental analysis:
C H N
calc.: 65.26% 11.63% 2.62%
found: 64.38% 11.61% .2.73%
65.04a 11.80% 2.78%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.17 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.12 .
Melting point: 270 - 271°C (decomposition) Preparation variant B:
20.1 ml (0.22 mol) of phosphorus oxychloride are placed in 100 ml of methylene chloride and cooled to 5 - 10°C and a solution of 54.1 g (0.20 mol) of octadeca.-:ui in 400 ml of methylene chloride and 70.5 ml of pyridine is added over min, with stirring. After subsequent stirring for one hour, 29.9 g_ (0.26 mol) of 4-hydroxy-1-methylpiperidine in 80 ml of pyridine are added dropwise. After stirring for 3 h at ~0°C, the mixture is hydrolyzed with 30 ml of water 30 while being cooled with ice and is subsequently stirred for one hour. The organic phase is washed with 200.m1 each of water/methanol (1:1), 3 percent hydrochloric acid/ methanol (1:1) and water/methanol (1:1). The organic phase is dried over Na2S04 and concentrated until turbidity appears, and 1 1 of methyl ethyl keton.e is added. The crystals are recrystallized.from l 1 of methyl ethyl ketone, filtered off with suction and dried under vacuum over P2o5.

Yield: 54:1 g (60%) of octadecyl 1-meth~tlpiperidinio-4-yl phosphate 98.1 8 (0.22 mol) of octadecyl 1-methylpiperidinio-4-yl phosphate are suspended in 500 mi of absolute ethanol and heated to boiling. Under reflux,.a total of 71.8 g (0.39 mol) of methyl p-toluenesulphonate and 26.5 g (0.19 mol) of potassium carbonate are added alternately in eight portions over 2 h. When the addition is complete,- the mixture is refluxed for a further hour: After cooling, it is~
filtered, the filtrate is concentrated to half and 150 g of , TM
moist Amberlite MB3 ion exchanger are added to the solution. After stirring for two hours, the mixture is filtered with suction over kieselguhr/activated charcoal and the filtrate is concentrated and crystallized with acetone. The crystal cake is recrystallized from methyl ethyl ketone and dried under vacuum over P2C5.
Yield: 46.1 g (46%) of octadecyl 1,1-dimethylpiperidinio-4-yl phosphate Elemental analysis:
C H N
calc.: 65.260 11.63% 2.62%
found: 65.18% 11.620 2.68%
65.07% 11.710 2.70%
Melting point: 271 - 272°C (decomposition) Example 2: Hexadecyl piperidinio-4-yl phosphate C21H44N~4P (405.558) .v ~,,.tr~s~
~j ~ I d id 7.1 ml (77 mmol) of phosphorus oxychloride are dissolved in 50 ml of dry tetrahydrofuran and, after-cooling to - 10°C, a solution of 17 g (70 mmol) of hexadecanol and 48 ml of triethylamine in 150 ml of tetrahydrofuran is 5 added dropwise, with stirring. When the addition is complete, the mixture is subsequently stirred for 30 min in an ice bath and then left to warm up to room temperature.
10.1 g (100 mmol) of 4-piperidinol are dissolved in 100 ml of tetrahydrofuran and mixed with 17 ml of triethylamine and the mixture is added dropwise to the reaction solution, with stirring, so that the temperature does not exceed 40°C. When the addition is complete, the mixture is refluxed for one hour. While still hot, the solution is separated from the triethylammonium chloride by filtration , and, after cooling, is poured into an ice/2 M hydrochloric acid mixture, with stirring. The product-obtained on cooling in a refrigerator is taken up in methylene chloride, dried over Mgs04, concentrated and chromato-graphed on silica gel with methylene chloride/methanol/ 25%
ammonia (70:30:5). The product fractions are combined and concentrated. After recrystallization from methanol, the product is dried under vacuum over P205.
Yield: 10.0 g (35%) Elemental analysis:
C H N
calc.: 62.19% 10.94% 3.45a found: 65.15% 11.14% 3.54%
62.41% 11.19% 3.34%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 70:20:10) Rf = 0.42 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.33 Example 3: Hexadecyl 1,1-dimethylpiperidinio-4-yl phosphate C25H52N~4P (461.64) - H20 5.7 g (14 mmol) of hexadecyl piperidinio-4-yl phosphate are dissolved in 100 ml of methanol and mixed with 11.6 g (84 mmol) of_potassium carbonate. 4.0 ml (42 mmol) of dimethyl sulphate are added dropwise over 30 min., with thorough stirring. The mixture is subsequently.stirred for 4 h at~4o°C, cooled, filtered and concentrated. The residue is digested with acetone and, after filtration with suction, is dissolved in 100 ml of 96% ethanol. 15 g of Amberlite MB3 ion exchanger are added and the mixture is stirred for 3 h. After filtration, the filtrate is concentrated and recrystallized twice from methyl ethyl ketone. The crystals are dried under vacuum over P205.
Yield: 3.70 g (61%) Elemental analysis:
C H N _ calc.: 61.17% 11.16% 3.10%
found: 60.83% 11.14% 2.99%
60.92% 11.26% 3.00%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 70:20:10) Rf = 0.28 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.13 Melting point: 230°C (decomposition) Example 4: Erucyl 1,1-dimethylpiperidinio-4-yl phosphate C29H58N~4P (515.765) ~ I-Z20 10.3 ml (o.ll mal) of phosphorus oxychloride are placed in 50 ml of chloroform, and a solution of 32.5 g (0.10 mol) of erucyl alcohol and 32 ml of pyridine in 100 ml of chloroform is- added dropwise at 5 - l0°C. After subsequent stirring for half an hour, 39.1 g (0.13 mol) of 4-hydroxy-1,1-dimethylpiperidinium tosylate are added in a single portion. After the dropwise addition of 40 ml of pyridine, the mixture is left to warm up to room temperature and stirred for 3 h. It is then hydrolyzed with 15 ml of water, subsequently stirred for half an hour and washed with 100 ml each of water/methanol (1:1), 3% sodium carbonate solution/methanol (1:1), 3% citric acid/methanol (1:1) and water/methanol (l: l). The residue obtained after concentration of the organic phase is digested with acetone and then dissolved in 150 ml of 96% ethanol. This solution is stirred for 3 h with 20 g of Amberlite~MB3 ion exchanger and filtered over kieselguhr to give a clear solution.
This is concentrated and chromatographed on silica gel with chloroform/ methanol/25% ammonia 70:40:10. The product fractions are combined and concentrated to dryness under vacuum.

* Trade-Mark Yield: 4.4 g (9%) Elemental analysis:
C ~ H N
calc.: 65.26% 11.63% 2.62%
found: 64.38% 11.61% 2.73%
65.04% 11.80% 2.78%
Thin layer chromatogram: .
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:20:10) Rf = 0.30 Example 5: Hexadecyl 1,1-dimethylpiperidinio-3-yl phosphate C23H48N04P (433.616) - H20 10.3 ml (0.11 mol) of phosphorus oxychloride are placed in 50 ml of chloroform and cooled to 0 - 10°C. 24.2 g (0.10 mol) of n-hexadecanol are dissolved in 100 m1 of chloroform, 32 ml of pyridine are added and the mixture is added dropwise to the phosphorus oxychloride solution over one hour, with ice cooling. After subsequent stirring for half an hour, 39.2 g (0.13 mol) of 3-hydroxy-1,1-dimethyl-piperidinium tosylate are added in a single portion and 40 ml of pyridine are added dropwise over 15 min at room temperature. After stirring for 16 h at room temperature, the mixture is hydrolyzed with 15.m1 of water, stirred for half an hour and washed with 10o ml each of water/ methanol (1:1), 3% sodium carbonate solution/ methanol (1:1), 3% citric acid/methanol (1:1) and water/ methanol (1:1)..
The organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in 150~m1 of 96%
ethanol, the solution is filtered and the filtrate is stirred with Amberlite* MB3 ion exchanger. After the ion * Trade-Mark ~~ .r }
~',~Uw:ri!
exchanger has been filtered off, the filtrate is concentrated and the residue is crystallized with acetone, filtered off with suction and dried under vacuum over P205.
Yield: 13.5 g (31%) Elemental analysis:
C H N
calc.: 61.17% 11.16% 3.10%
found: 60.78% 11.41% 2.87%
60.85% 11.31% 2.86%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.37 2~ ~~~,~
Example 6: Octadecyl 1,1-dimethylpiperidinio-3-yl phosphate C25H52NO4P (461.670) ~ ZH20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 39.2 g (0.13 mol) of 3-hydroxy-1,1-dimethylpiperidinium tosylate.
Yield: 18.7 g (40%) Elemental analysis:
C H N
calc.: 63.80% 11.35% 2.98%
found: 63.38% 11.72% 2.63%
63.61% 11.98% 2.61%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.35 .7 ~a fit y~ ~ !:
~~ . L ~'.) tt i d d ', ) Example 7: Hexadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C24H5oN~4P (447.643) ~ ?H20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 24.2 g (0.10 mol) of hexadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol) of 2-hydroxymethyl-1,1-dimethylpiperidinium tosylate.
l0 Yield: 22.9 g (51%) i Elemental analysis:
C H N
calc.: 63.13% 11.26% 3.07%
found: 63.69% 11.73% 3.04%
63.75% 11.71% 3.04%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10 Rf = 0.47 2~~~~
Example 8: Octadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C26H54N04P (475.697) ~ ZH20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol) of 2-hydroxymethyl-1,1-dimethylpiperidinium tosylate.
Yield: 23.9 g (50%) Elemental analysis:
C , H N
calc.: 64.43% 11.44% 2.89%
found: 64.50% 11.61% 2.67%
64.11% 11.49% 2.77%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.47 ~~ !~
Example 9: Hexadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C24HSON~4P (447.643) ~ 1H20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 24.2 g (0.10 mol) of hexadecano1,,32 + 40 ml of pyridine and 41.0 g (0.13 mol) , of 3-hydroxymethyl-1,1-dimethylpiperidinium tosylate.
Yield: 17.2 g (39%) Elemental analysis:
C H N
calc.: 61.91% 11.26% 3.01%
found: 62.32% 12.21% 2.86%
61.79% 11.96% 2.98%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.29 Example l0: Octadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C26H54NO4P (475.697) - H20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychloride, 27.0 g (0.10 mol) of octadecanol, 32 + 40 ml of pyridine and 41.0 g (0.13 mol) of 3-hydroxymethyl-1,1-dimethylpiperidinium tosylate.
Yield: 16.7 g (35%) i Elemental analysis:
C H N
calc.: 63.25% 11.43% 2.84%
found: 62.98% 12.21% 2.76%
63.67% 12.47% 2.80%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 2~.~~j'~' Example 11: Tetradecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C22H46N~4P ( 419 . 54 ) ~ H20 This is prepared analogously to Example 5 from 9.6 g (45 mmol) of tetradecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, l0 + 20 ml of pyridine and"21.3 g (67.5 mmol) of hydroxy-1,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography on silica gel with methylene chloride/methanol/ 25% ammonia 70:40:10,.
Yield: 2.70 g (15%) Elemental analysis:
C H N
calc.: 60.40% 11.05% 3.20%
found: 60.47% 11.29% 3.63%
60.78% 11.52% 3.68%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.08 ~~~~~~1~
Example 12: Hexadecyl 1,1-dimethy:lhexahydroazepinio-4-yl phosphate C24H4gN04P (445.62) This is prepared analogously to Example 5 from 10.8 g (45 mmol) of hexadecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography on silica gel with methylene chloride/methanol/ 25% ammonia 70:30:10 Yield: 5.0 g (25%) Elemental analysis:
C H N
calc.: 64.69% 10.86% 3.14%
found: 63.90% 11.54% 3.22%
64.08% 11.59% 3.24%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 80:25:5) Rf = 0.10 (1-butanol/glacial acetic acid/water 40:10:10) s 25 Rf = 0.10 Melting point: >250°C (decomposition) ~ .~ pr..:;, ~. 3_ L1 i.a' as ~~ ;:3 Example 13: Octadecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C26H54N04P (475.695) - iH20 This is prepared analogously to Example 5 from 12.1 g (45 mmol) of octadecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography on silica gel with methylene chloride/methanol/ 25% ammonia 70:30:10 Yield: 5.5 g (26%) Elemental analysis:
C H N
calc.: 64.43% 11.44% 2.89%
found: 64.54% 11.64% 2.82%
64.66% 11.58% 2.64%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.22 Melting point: >250°C (decomposition) Example 14: Cis-o9-octadecenyl 1,1-dimethylhexahydro azepinio-4-yl phosphate ' C26H52NC4P (473.679) - H20 This is prepared analogously to Example 5 from 12.1 g (45 mmol) of cis-e9-octadecenol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography,on silica gel with methylene chloride/ methanol/25% ammonia~70:30:10.
r Yield: 4.5 g (21%) Elemental analysis:
C H N
calc.: 63.51% 11.07% 2.85%
found: 64.05% 11.21% 3.10%
63.80% 11.06% 3.06%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 70:40:10) Rf = 0.28 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.10 ,~ r~~~ n ~~r~~~;3 Example 15: Eicosyl 1,1-dimethylhexahydroazepinio-4-yl ' phosphate CZgH5gN04P (503.754) ~ H20 This is prepared analogously to Example 5 from 13.4 g (45 mmol) of eicosanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography on silica gel, with methylene chloride/methanol/ 25% ammonia 70:30:10 Yield: 5.7 g (25%) Elemental analysis:
C H N
calc.: 64.46% 11.59% 2.68%
found: 63.51% 11.48% 2.95%
. 64.00% 11.79% 2.91%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 70:40:10) Rf = 0.12 2~~~~,:?
Example 16: Erucyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C3oH6oN~4P (529.789) ~ H20 This is prepared analogously to Example 5 from 16.2 g (50 mmol) of erucyl alcohol, 5.1 ml (55 mmol) of phosphorus oxychloride,.l8 + 30 ml of pyridine and 20.5 g (65 mmol) of 4-hydroxy-1,1-dimethylhexahydroazepinium tosylate. It is.
purified by flash chromatography on silica gel with methylerie chloride/methanol/ 25% ammonia 70:3os10.~
Yield: 4.1 g (15%) Elemental analysis:
C H N , calc.: 65.78% 11.41% 2.56%
found: 65.76% 12.01% 2.97%
65.82% 11.63% 2.96%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = U.30 i,J
Example 17: Octadecyl 1,1-dimethylpyrrolidinio-3-yl phosphate C24H5oN04~' (447.643) - iH20 This is prepared analogously to Example 5 from 3.25 g (12 mmol) of octade,:anol, 1.21 ml (13 mmol) of phosphorus oxychloride, 3.7 + 4.8 ml of pyridine and 4.31 g (15 mmol) of hydroxy-l,l-dimethylpyrrolidinium tosylate. The crude product is purified by dissolution in 96% ethanol. and treatment with Amberlite*MB3 ion exchanger.
Yield: 1.31 g (25%) Elemental analysis:
C H N ' calc.: 63.13% 11.26% 3.07%
found: 62.99% 11.28% 2.80%
62.74% 11.27% 2.89%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.25 * Trade-Mark Example 18: Hexadecyl 2-(1,1-dimethylpyrrolidinio-2-yl)ethyl phosphate C24H5oN~4p (447.643) ~ H20 This is prepared analogously to Example 5 from 9.21 g (38 mmol) of hexadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.8 g (50 mmol) of 2-(2-hydroxyethyl)-1,1-dimethylpyrrolidinium tosylate. It is purified by dissolution in 96% ethanol and treatment with Amberlite*MB3 ion exchanger. -Yield: 6.0 g (35%) Elemental analysis:
C H N
calc.: 61.91% 11.26% 3.01%
found: 61.82% 11.69% 3.21%
61.93% 11.86% 3.28%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.38 * Trade-Mark ~ ' ~1~~~~
Example 19: Octadecyl 2-(1,1-dimethylpyrrolidinio-2-yl)ethyl phosphate C26H54N~4P (475.697) - '-~H20 . _ This is prepared analogously to Example 5 from 10.3 g (38 mmol) of octadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.8 g (50 mmol) of 2-(2-hydroxyethyl)-1,1-dimethylpyrrolidinium tosylate. It is purified by dissolution in 96% ethanol and treatment with Amberlite*MB3 ion exchanger.
Yield: 7.8 g (43%) Eleraental analysis:
C H N
calc.: 64.43% 11.44% 2.89%
found: 64.69% 11.77% 2.64%
64.84% 11.88% 2.69%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rp = 0.35 * Trade-Mark ~ ~;. ~J ~,1 ~~ E:,~ J
Example 20: Hexadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate C23H48N04P (433.616) ~ 2H20 . _ This is prepared analogously to Example 5 from 9.21 g (38 mmol) of hexadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.1 g (50 mmol) of 2-hydroxymethyl-1,1-dimethylpyrrolidinium tosylate. It is l0 purified by dissolution in 96% ethanol and treatment with Amberlite*MB3 ion exchanger.
Xield: 8.3 g (51%) 15 Elemental analysis:
C H N
calc.: 62.41% 11.16% 3.16%
found: 62.09% 11.48% 3.01%
20 62.25% 11.66% 3.09%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) 25 Rf = 0.33 * Trade-Mark .

~1~
Example 21: Octadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate C25Hs2NO4p (461.67) - ZH20 This is prepared analogously to Example 5 from 10.3 g (38 mmol) of octadecanol, 3.9 ml (42 mmol) of phosphorus oxychloride, 13 + 16 ml of pyridine and 15.1 g (50 mmol) of 2-hydroxymethyl-1,1-dimethylpyrrolidinium tosylate. It is l0 purified by dissolution in 96% ethanol and treatment with Amberlite* M83 ion exchanger. _ ~ ' Yield: 9.0 g (52%) Elemental analysis:
C Ii N

calc.: 63.80% 11.35% 2.98%

found: 63.13% 11.57% 2.84%

63.55% 11.66% 2.82%

Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.35 * Trade-Mark

Claims (25)

1. Compounds of the general formula (I) in which:
R is a straight-chain or branched alkyl radical having 10 to 24 carbon atoms, which also can contain one to three double or triple bonds;
R1 and R2; independently of one another, are hydrogen, or each is a straight-chain or branched saturated alkyl radical having 1 to 6 carbon atoms, a straight-chain or branched unsaturated alkyl radical having 2 to 6 carbon atoms, or a cyclic saturated or unsaturated alkyl radical having 3 to 6 carbon atoms, which also can contain a Cl, OH
or NH2 group, and where two of the straight-chain or branched alkyl radicals R1 and R2 also can be bonded together to form a ring structure;
A is a single bond, or one of the groups having the formulae wherein the groups (II) to (VI) are arranged such that the oxygen atom is bonded to the phosphorus atom of the compound (I);
X is an oxygen or sulphur atom, or is NH if A is a single bond, or is an oxygen or sulphur atom if A is one of the groups (II) to (VI);
y is 0 or a natural number between 1 and 3; and m + n independently of one another are 0 or natural numbers, with the proviso that m + n = 2 to 8;
or pharmaceutically-acceptable salts thereof.
2. Compounds according to claim 1, wherein X is an oxygen atom.
3. Compounds according to claim 1 or 2, wherein A is a single bond.
4. Compounds of the general formula wherein B is the ring system in which:
R is a straight-chain or branched alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds;
R1 and R2, independently of one another, are selected from the group consisting of hydrogen and straight-chain alkyl radicals having 1 to 3 carbon atoms;
A is a single bond and X is an oxygen atom;
y is 0, 1, 2 or 3; and m and n are independently 0 or an integer, with the proviso that m + n = 2 to 8;
or pharmaceutically-acceptable salts thereof.
5. Compounds according to claim 9, wherein B is selected from the group consisting of a pyrrolidinio, piperidinio and hexahydroazepinio rings.
6. Compounds according to any one of claims 1 to 4, wherein R1 and R2 each are methyl groups.
7. Compounds according to any one of claims 1 to 6, wherein R is selected from the group consisting of octadecyl, hexadecyl, erucyl, tetradecyl, cis-.DELTA.9 octadecyl and eicosyl radicals.
8. Compounds according to any one of claims 1 to 7, in which the sum of m + n equals 4.
9. A compound selected from the group comprising:
octadecyl 1,1-dimethylpiperidinio-4-yl phosphate, hexadecyl piperidinio-4-yl phosphate, hexadecyl 1,1-dimethylpiperidinio-4-yl phosphate, erucyl 1,1-dimethylpiperidinio-4-yl phosphate, hexadecyl 1,1-dimethylpiperidinio-3-yl phosphate, octadecyl 1,1-dimethylpiperidinio-3-yl phosphate, hexadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate, octadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate, hexadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate, octadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate, tetradecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, hexadecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, octadecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, cis-.DELTA.9-octadecenyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, eicosyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, erucyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, octadecyl 1,1-dimethylpyrrolidinio-3-yl phosphate, hexadecyl 2-(l,l-dimethylpyrrolidinio-2-yl) ethyl phosphate, octadecyl 2-(1,1-dimethylpyrrolidinio-2-yl) ethyl phosphate, hexadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate, octadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate;
or a pharmaceutically-acceptable salt thereof.
10. A compound selected from the group comprising:
octadecyl 1,1-dimethylpiperidinio-4-yl phosphate, octadecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, octadecyl (1,1-dimethylpiperidinio-2-yl)methyl phosphate, erucyl 1,1-dimethylpiperidinio-4-yl phosphate, erucyl 1,1-dimethylhexahydroazepinio-4-yl phosphate, hexadecyl (1,1-dimethylpyrrolidinio-2-yl)methyl phosphate, octadecyl (1,1-dimethylpyrrolidinio-2-yl)methyl phosphate;
or a pharmaceutically-acceptable salt thereof.
11. The compound octadecyl 1,1-dimethylpiperidinio-4-yl phosphate, or a pharmaceutically-acceptable salt thereof.
12. A process for the preparation of a compound as defined in one of claims 1 to 11, wherein a compound of the general formula R-X-A-H (VII) in which R, X and A, respectively as required, are as defined in the said one of claims 1 to 11, is reacted with phosphorus oxychloride in the presence of a suitable auxiliary base, and then is reacted with:
(a) a compound of the general formula in which R1 and R2, y, m and n are as defined in the said one of claims 1 to 11, respectively as required, and Y- is halide, mesylate or tosylate, to give a compound of the general formula (I) or (IA) as defined in the said one of claims 1 to 11, respectively:
or (b) a compound of the general formula in which R1, y, m and n, respectively as required, are as defined in the said one of claims 1 to 11, to give a compound of the general formula (I) or (IA) as defined above wherein R1 and/or R2 axe hydrogen, and optionally subsequent alkylation is carried out with an alkylating agent R2-Y, in which R2 has a meaning as defined in the said one of claims 1 to 11, respectively as required, and Y is chlorine, bromine, iodine, tosyl or mesyl.
13. A process for the purification of a compound prepared by a process defined in claim 12, wherein a solution of the prepared compound in an organic solvent is treated with a mixed-bed ion exchanger, or successively or simultaneously with an acidic or basic ion exchanger.
14. A pharmaceutical composition comprising a compound as defined in one of claims 1 to 11, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier or excipient.
15. A pharmaceutical composition as defined in claim 14, comprising 50 to 250 mg of said compound.
16. A pharmaceutical composition for the treatment of tumours, protozoal diseases or fungal diseases, comprising a pharmaceutically-effective amount of a compound as defined in one of claims 1 to 11, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier or excipient.
17. A pharmaceutical composition as defined in claim 16, for the treatment of leishmaniasis.
18. A pharmaceutical composition as defined in claim 16 or 17, comprising 50 to 250 mg of said compound.
19. Use of a pharmaceutical composition as defined in claim 14 or 15, in the treatment of tumours, protozoal diseases or fungal diseases.
20. Use of a pharmaceutical composition as defined in claim 19 in the treatment of leishmaniasis.
21. Use of a compound as defined in one of claims 1 to 11, for the production of medicaments for the control of tumours.
22. Use of a compound as defined in one of claims 1 to 11, for the production of medicaments for the control of protozoal diseases or fungal diseases.
23. Use of a compound as defined in one of claims 1 to 11, for the production of medicaments for the control of leishmaniasis.
24. Use of a compound as defined in one of claims 1 to 11, or a pharmaceutically-acceptable salt thereof, for treating tumours, protozoal diseases or fungal diseases.
25. Use of a compound as defined in one of claims 1 to 11, or a pharmaceutically-acceptable salt thereof, for treating leishmaniasis.
CA002100228A 1992-07-11 1993-07-09 Phospholipid derivatives Expired - Lifetime CA2100228C (en)

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CN101146532B (en) 2005-01-21 2012-05-09 阿斯泰克斯治疗有限公司 Pharmaceutical compounds
EP1800684A1 (en) * 2005-12-20 2007-06-27 Zentaris GmbH Novel alkyl phospholipid derivatives and uses thereof
PL1962862T3 (en) * 2005-12-19 2014-01-31 Aeterna Zentaris Gmbh Alkyl phospholipid derivatives with reduced cytotoxicity and uses therof
EP1869981A1 (en) * 2006-06-21 2007-12-26 Staatliches Weinbauinstitut Freiburg Alkylphospholipids and lysophospholipids for controlling plant pathogens
EP2073807A1 (en) 2006-10-12 2009-07-01 Astex Therapeutics Limited Pharmaceutical combinations
US8916552B2 (en) 2006-10-12 2014-12-23 Astex Therapeutics Limited Pharmaceutical combinations

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DE3530767A1 (en) * 1985-08-28 1987-03-12 Max Planck Gesellschaft AGENT AGAINST MULTIPLE Sclerosis
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JP3311431B2 (en) 2002-08-05
YU47393A (en) 1997-08-22
EP0579939B1 (en) 1999-02-03
CZ290863B6 (en) 2002-11-13
CA2100228A1 (en) 1994-01-12
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ZA934971B (en) 1994-02-01
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SG46249A1 (en) 1998-02-20
DE4222910A1 (en) 1994-01-13
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BR9302809A (en) 1994-03-15
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NO306468B1 (en) 1999-11-08
GR3029602T3 (en) 1999-06-30
MX9304133A (en) 1994-04-29
FI933165A0 (en) 1993-07-09
YU49079B (en) 2003-08-29
DE59309355D1 (en) 1999-03-18
EP0579939A1 (en) 1994-01-26
DK0579939T3 (en) 1999-09-20
SI9300365A (en) 1994-03-31
LV10870B (en) 1996-06-20
CN1039012C (en) 1998-07-08
AU4186493A (en) 1994-01-13
ES2129053T3 (en) 1999-06-01
PL175607B1 (en) 1999-01-29
JPH0733791A (en) 1995-02-03
CA2511753A1 (en) 1994-01-12
NO932502L (en) 1994-01-12
EE03140B1 (en) 1998-12-15
CN1084175A (en) 1994-03-23
SK283827B6 (en) 2004-02-03
KR940002265A (en) 1994-02-17
HU218783B (en) 2000-12-28
LT3113B (en) 1994-12-27
IL106289A0 (en) 1994-04-12
KR100297180B1 (en) 2001-11-30
ATE176477T1 (en) 1999-02-15
FI111262B (en) 2003-06-30
SK67093A3 (en) 1995-03-08
HU9301992D0 (en) 1993-09-28
TW304956B (en) 1997-05-11
AU664101B2 (en) 1995-11-02
HRP931046B1 (en) 2000-06-30
LV10870A (en) 1995-10-20
NO932502D0 (en) 1993-07-08
PL299624A1 (en) 1994-02-21
CZ124993A3 (en) 1995-03-15
HUT64548A (en) 1994-01-28
IL106289A (en) 2000-06-01

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