CA2511753C - Phospholipid derivatives - Google Patents
Phospholipid derivatives Download PDFInfo
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- CA2511753C CA2511753C CA002511753A CA2511753A CA2511753C CA 2511753 C CA2511753 C CA 2511753C CA 002511753 A CA002511753 A CA 002511753A CA 2511753 A CA2511753 A CA 2511753A CA 2511753 C CA2511753 C CA 2511753C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
- C07F9/106—Adducts, complexes, salts of phosphatides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/5532—Seven-(or more) membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
Abstract
Compounds of the general formula See formula 1 wherein: B is a quinuclidinio ring system linked via a carbon atom of the quinuclidinio ring and in which the nitrogen atom optionally is substituted by a methyl group, or a tropanio ring system linked via a carbon atom of the tropanio ring and in which the nitrogen atom optionally is substituted by one or two methyl groups. R is a straight--chain or branched-chain alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds; and y is 0, 1, 2 or 3; and pharmaceutically--acceptable salts thereof. These phospholiped derivatives are useful for treating tumours, and protozoal and fungal diseases.
Description
PHOSPHOLIPID DERIVATIVES
The invention relates to new phospholiped derivatives, pharmaceutical compositions containing them, and their use in the treatment of tumours, and protozoal and fungal diseases.
This patent application is divided from and comprises the disclosure of Canadian Patent Application 2,100,228, filed July 9, 1993. Consequently, the language "the invention"
and the like as used herein, and the description and examples given, are not restricted to the subject matter claimed in this divided application, but may include subject matter not specifically claimed.
Published European Patent Application 108,565 describes compounds of the general formula 11 +
R1(O)n P OCH2CH2N -R3 and their pharmaceutically-acceptable salts, in which R' 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 for the preparation of those compounds, to pharmaceutical compositions containing the compounds as active ingredients, and to processes for the preparation of those drugs.
In a broad aspect the compounds have the general formula R-X-A- I-0-(cH,2)y- .B
o-wherein:
B is the ring system (CH2)m\ R, -CH\(CEiz)n / R2 or B is a tropanio or quinuclidinio ring system, which is linked via a carbon-carbon bond and optionally is substituted by one or more methyl groups;
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;
R' 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 the straight-chain or branched alkyl radical R' 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)8-O- (V) IH3' I ~ (VI) H2C j \CH2 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, 1, 2 or 3; and m and n are independently 0 or an integer, with the proviso that m + n = 2 to 8;
and pharmaceutically-acceptable salts thereof.
In a specific embodiment, the present invention provides compounds of the general formula R O P O (CH,)y B
O-wherein:
B is a quinuclidinio ring system linked via a carbon atom of the quinuclidinio ring and in which the nitrogen atom optionally is substituted by a methyl group, or a tropanio ring system linked via a carbon atom of the tropanio ring and in which the nitrogen atom optionally is substituted by one or two methyl groups;
R is a straight-chain or branched-chain alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds; and y is 0, 1, 2 or 3;
or a pharmaceutically-acceptable salt thereof.
Preferably, y is zero, and R is an octadecyl or hexadecyl group. Also B advantageously is a 1-methylquinuclidinio-3-yl or 1,1-dimethyltropanio-4-yl ring.
The present invention also provides a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the invention, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier therefor. 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.
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.
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 provides processes for the preparation and processes for the purification of the novel compounds.
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.
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 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-chairi 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 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 POC13. 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 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 C to 25 C and especially at 18 C to 22 C.
The reaction solution is then washed with a mixture of 15 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 1 - 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 10% 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 l 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-butanol 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.
The solution is then recrystallized from ketones such as, for example, acetone or methyl ethyl ketone; 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 are examples of basic substances used. The reaction is carried out at elevated temperature, for example at the boiling point of the solvents.
The following examples comprise some which are included herein for illustrative and comparative purposes, and as such may enhance an understanding of the invention, although not all of the compounds prepared are specifically claimed herein.
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) - ZH2O
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-l,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% Na2CO3/methanol (1:1) and finally water/methanol (1:1). 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 Yield: 4.71 g (10%) Elemental analysis:
C H N
calc.: 65.26% 11.63% 2.620 found: 64.38% 11.61% -.2.730 65.04% 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 octadecanol 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-l-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 ml each of water/methanol (1:1), 3 percent hydrochloric acid/ methanol (1:1) and water/methanol (1:1). The organic phase is dried over Na2SO4 and concentrated until turbidity appears, and 1 1 of methyl ethyl ketone is added. The crystals are recrystallized from 1 1 of methyl ethyl ketone, filtered off with suction and dried under vacuum over P205.
Yield: 54.1 g(600) of octadecyl 1-methylpiperidinio-4-yl phosphate 98.1 g (0.22 mol) of octadecyl 1-methylpiperidinio-4-yl phosphate are suspended in 500 ml 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 P205.
Yield: 46.1 g(46%) of octadecyl 1,1-dimethylpiperidinio-4-yl phosphate Elemental analysis:
C H N
calc.: 65.26% 11.63% 2.62%
found: 65.18% 11.62% 2.68%
65.070 11.710 2.700 Melting point: 271 - 272 C (decomposition) Example 2: Hexadecyl piperidinio-4-yl phosphate C21H44N04P (405.558) 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 MgSO4, 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% 3.45%
found: 65.15% 11.14% 3.54%
62.41% 11.19% 3.34%
Thin layer chromatogram:
(chloroform/methanol/25o 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 -C25H52NO4P ( 4 61. 64 )- H2O
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 40 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
ca1c.: 61.17% 11.16% 3.10%
found: 60.83% 11.14% 2.99%
60.920. 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 C29HS8NO4P (515.765) - H20 10.3 ml (0.11 mol) 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 - 10 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 (1:1). 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
caic.: 65.26% 11.63% 2.62%
found: 64.380 11.610 2.73%
65.04% 11.80% 2.78%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:20:10) Rf = 0.30 Example 5: Hexadecyl 1,1-dimethylpiperidinio-3-yl phosphate C23H48NO4P (433.616) = H20 10.3 ml (0.11 mol) of phosphorus oxychioride 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 ml 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 15ml of water, 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 (1:1).
The organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in 150-ml of 96%
ethanol, the solution is filtered and the filtrate is stirred with Amberlite*MB3 ion exchanger. After the ion * Trade-Mark 18 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.: 61.170 11.16% 3.10%
found: 60.780 11.410 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 Example 6: Octadecyl 1,1-dimethylpiperidinio-3-yl phosphate C2SH52NO4P (461.670) = zH20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychioride, 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 Example 7: Hexadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C24H50N04P (447.643) = zH20 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-l,1-dimethylpiperidinium tosylate.
Yield: 22.9 g (51%) 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 Example 8: Octadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C26H54NO4P (475.697) - 2H2O
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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.47 Example 9: Hexadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C24H50NO4P (447.643) = 1H2O
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-l,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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.29 Example 10: Octadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C26H54NO4P (475.697) = H2O
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%) Elemental analysis:
C H N
calc.: 63.25% 11.43% 2.84%
found: 62.98% 12.210 2.760 63.67% 12.47% 2.80%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 Example 11: Tetradecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C22H46N04P (419.54) = HZO -This is prepared analogously to Example 5 from 9.6 g (45 mmol) of tetradecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10_+ 20 ml of pyridine and 21.3 g (67.5 mmol) of hydroxy-l,l-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: 60.470 11.29% 3.63%
60.78% 11.52% 3.68%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.08 Example 12: Hexadecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C24H48NO4P (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-l,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) Rf = 0.10 Melting point: >250 C (decomposition) Example 13: Octadecyl 1,1-dimethylhexahydroazep'inio-4-yl phosphate - -C26H54NO4P (475.695) - 2H20 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-l,l-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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.22 Melting point: >250 C (decomposition) Example 14: Cis-A 9-octadecenyl 1,1-dimethylhexahydro azepinio-4-yl phosphate C26H52NO4P (473.679) - H2O
This is prepared analogously to Example 5 from 12.1 g (45 mmol) of cis-O9-octadecenol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-l,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography on silica gel with methylene chloride/ methanol/25% ammonia 70:30:10.
Yield: 4.5 g (21%) Elemental analysis:
C H N
calc.: 63.51% 11.070 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 <
Example 15: Eicosyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C28H58NO4P (503.754) = H2O
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-l,l-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 Example 16: Erucyl 1,1-dimethylhexahydroazepinio-4-yl phosphate - -C30H6oN04P (529.789) = H2O
This is prepared analogously to Example 5 from 16.2 g (50 mmol) of erucyl alcohol, 5.1 ml (55 mmol) of phosphorus oxychloride, 18 + 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 methylene chloride/methanol/ 25% ammonia 70:30:10.
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/l M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 Example 17: Octadecyl 1,1-dimethylpyrrolidinio-3-yl phosphate C24HS0N04P (447.643) - ZH2O
This is prepared analogously to Example 5 from 3.25 g (12 mmol) of octadecanol, 1.21 ml (13 mmol) of phosphorus oxychloride, 3.7 + 4.8 ml of pyridine and 4.31 g(15 mmol) of hydroxy-1,1-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: 62.990 11.28a 2.80%
62.74% 11.27% 2.89%
Thin layer chromatogram:
(chloroform/methanol/i 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 C24H50NO4P (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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.38 * Trade-Mark Example 19: Octadecyl 2-(1,1-dimethylpyrrolidinio-2-yl)ethyl phosphate C26H54NO4P (475.697) - ZH2O
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%) Elemental analysis:
C H N
caic.: 64.43% 11.440 2.89%
found: 64.69% 11.77% 2.64%
64.84% 11.880 2.690 Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.35 * Trade-Mark Example 20: Hexadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate C23H48NO4P (433.616) = 2H2O
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 purified by dissolution in 96% ethanol and treatment with Amberlite*MB3 ion exchan_ger_ Yield: 8.3 g (51%) Elemental analysis:
C H N
ca1c.: 62.410 11_16% 3_160 found: 62.09% 11.48% 3.01%
62.25% 11.66% 3.09%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.33 * Trade-Mark Example 21: Octadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate C25H52NO4P ( 4 61. 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 inmol) of 2-hydroxymethyl-1,1-dimethylpyrrolidinium tosylate. It is purified by dissolution in 96% ethanol and treatment with Amberlite MB3 ion exchanger.
Yield: 9.0 g (520) Elemental analysis:
C H N
caic.: 63.80% 11.35% 2.98%
found: 63.13% 11.57% 2.84%
63.55% 11.66% 2.82%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.35 * Trade-Mark Example 22: Hexadecyl 1-methylquinuclidinio-3-yl phosphate C24H48NO4P (445.64) = 1.5 H20 2.7 ml (30 mmol) of phosphorus oxychloride are dissolved in 25 ml of chloroform and cooled to 5 - 10 C and a solution of 6.4 g (26 mmol) of hexadecanol and 10 ml of pyridine in 50 ml of chloroform is added dropwise over one hour. After subsequent stirring for half an hour at room temperature, a solution of 4.5 g (35 mmol) of 3-hydroxyquinuclidine and 5 ml of pyridine in 10 ml of chloroform is added. After stirring for 5 h at room temperature, the mixture is hydrolyzed with 15 ml of water and subsequently stirred for half an hour. It is then washed twice with 100 ml of water/methanol (1:1) and the organic phase is dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on silica gel with methylene chloride/methanol 80:25 and then methylene chloride/
methanol/25% ammonia 80:25:5. The product fractions are purified, evaporated to dryness and crystallized with acetone. The crystals are dried under vacuum over P205.
Yield: 4.95 g (44%) of hexadecyl quinuclidinio-3-yl phosphate 4.95 g (11.5 mmol) of hexadecyl quinuclidinio-3-yl phosphate are dissolved in 30 ml of inethariol, 13.7 g (69 mmol) of potassium carbonate and 8.5 ml of water are added and a solution of 3.3 ml (35 mmol) of dimethyl sulphate in 5 ml of methanol is added dropwise, with thorough stirring. After stirring for 14 h at room temperature, the inorganic salts are filtered off, the filtrate is concentrated to dryness and the residue is taken up in methylene chloride. After filtration, the filtrate is chromatographed on silica gel with methylene chloride/methanol/25% ammonia 70:30:5. The product fractions are combined, evaporated to dryness and stirred with acetone until crystallization occurs. The crystals are dried under vacuum over P205.
Yield: 2.7 g (49%) Elemental analysis:
C H N
calc.: 60.99% 10.88% 2.96%
found: 61.38% 11.04% 3.29%
61.46% 11.22% 3.25%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 70:40:10) Rf = 0.44 =Example 23: Octadecyl 1-methylquinuclidinio-3-yl phosphate C26H52NO4P (473.68) = 2H2O
This is prepared analogously to Example 5 from 18.3 g (67.5=mmol) of octadecanol, 7.0 ml (75 mmol) of phosphorus oxychloride, 18 + 20 ml of pyridine and 28.3 g(90 mmol) of 3-hydroxy-l-methylquinuclidinium tosylate_ It is purified by dissolution in 96% ethanol and treatment with Amberlite*
MB3 ion exchanger.
Yield: 18.4 g (57%) Elemental analysis:
C H N
calc.: 61.27% 11.07% 2.75%
found: 61.27% 10.91% 2.45%
61.95% 11.23% 2.51%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.37 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.13 *
Trade-Mark Example 24: Hexadecyl 1,1-dimethyltropanio-4-yl phosphate C25H50N04P (459.654) - H20 This is prepared analogously to Example 5 from 12.1 g (50 mmol) of hexadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 40 ml of pyridine and 21.3 g (65 mmol) of 4-hydroxy-l,l-dimethyltropanium tosylate. It is purified *
by dissolution in 96% ethanol, treatment with Amberlite MB3 ion exchanger and recrystallization from acetone._ Yield: 11.3 g (49%) Elemental analysis:
C H N
calc.: 62.86% 10.97% 2.93%
found: 62.45g 11.52% 2.82%
62.58% 11.52% 2.75%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.28 * Trade-Mark Example 25: Octadecyl 1,1-dimethyltropanio-4-yl phosphate C27H54NO4P (487.708) This is prepared-analogously to Example 5 from 13.5 g (50 mmol) of octadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 20 ml of pyridine and 21.3 g (65 mmol) of 4-hydroxy-1,l-dimethyltropanium tosylate. It is purified by dissolution in 96% ethanol and treatment with Amberlite*
MB3 ion exchanger_ Yield: 10.7 g (44%) Elemental analysis:
C H N
calc.: 66.49% 11.16% 2.87%
found: 65.720 11.48% 2.64%
66.27% 11.78% 2.65%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.22 * Trade-Mark
The invention relates to new phospholiped derivatives, pharmaceutical compositions containing them, and their use in the treatment of tumours, and protozoal and fungal diseases.
This patent application is divided from and comprises the disclosure of Canadian Patent Application 2,100,228, filed July 9, 1993. Consequently, the language "the invention"
and the like as used herein, and the description and examples given, are not restricted to the subject matter claimed in this divided application, but may include subject matter not specifically claimed.
Published European Patent Application 108,565 describes compounds of the general formula 11 +
R1(O)n P OCH2CH2N -R3 and their pharmaceutically-acceptable salts, in which R' 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 for the preparation of those compounds, to pharmaceutical compositions containing the compounds as active ingredients, and to processes for the preparation of those drugs.
In a broad aspect the compounds have the general formula R-X-A- I-0-(cH,2)y- .B
o-wherein:
B is the ring system (CH2)m\ R, -CH\(CEiz)n / R2 or B is a tropanio or quinuclidinio ring system, which is linked via a carbon-carbon bond and optionally is substituted by one or more methyl groups;
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;
R' 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 the straight-chain or branched alkyl radical R' 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)8-O- (V) IH3' I ~ (VI) H2C j \CH2 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, 1, 2 or 3; and m and n are independently 0 or an integer, with the proviso that m + n = 2 to 8;
and pharmaceutically-acceptable salts thereof.
In a specific embodiment, the present invention provides compounds of the general formula R O P O (CH,)y B
O-wherein:
B is a quinuclidinio ring system linked via a carbon atom of the quinuclidinio ring and in which the nitrogen atom optionally is substituted by a methyl group, or a tropanio ring system linked via a carbon atom of the tropanio ring and in which the nitrogen atom optionally is substituted by one or two methyl groups;
R is a straight-chain or branched-chain alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds; and y is 0, 1, 2 or 3;
or a pharmaceutically-acceptable salt thereof.
Preferably, y is zero, and R is an octadecyl or hexadecyl group. Also B advantageously is a 1-methylquinuclidinio-3-yl or 1,1-dimethyltropanio-4-yl ring.
The present invention also provides a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the invention, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier therefor. 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.
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.
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 provides processes for the preparation and processes for the purification of the novel compounds.
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.
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 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-chairi 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 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 POC13. 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 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 C to 25 C and especially at 18 C to 22 C.
The reaction solution is then washed with a mixture of 15 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 1 - 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 10% 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 l 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-butanol 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.
The solution is then recrystallized from ketones such as, for example, acetone or methyl ethyl ketone; 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 are examples of basic substances used. The reaction is carried out at elevated temperature, for example at the boiling point of the solvents.
The following examples comprise some which are included herein for illustrative and comparative purposes, and as such may enhance an understanding of the invention, although not all of the compounds prepared are specifically claimed herein.
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) - ZH2O
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-l,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% Na2CO3/methanol (1:1) and finally water/methanol (1:1). 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 Yield: 4.71 g (10%) Elemental analysis:
C H N
calc.: 65.26% 11.63% 2.620 found: 64.38% 11.61% -.2.730 65.04% 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 octadecanol 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-l-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 ml each of water/methanol (1:1), 3 percent hydrochloric acid/ methanol (1:1) and water/methanol (1:1). The organic phase is dried over Na2SO4 and concentrated until turbidity appears, and 1 1 of methyl ethyl ketone is added. The crystals are recrystallized from 1 1 of methyl ethyl ketone, filtered off with suction and dried under vacuum over P205.
Yield: 54.1 g(600) of octadecyl 1-methylpiperidinio-4-yl phosphate 98.1 g (0.22 mol) of octadecyl 1-methylpiperidinio-4-yl phosphate are suspended in 500 ml 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 P205.
Yield: 46.1 g(46%) of octadecyl 1,1-dimethylpiperidinio-4-yl phosphate Elemental analysis:
C H N
calc.: 65.26% 11.63% 2.62%
found: 65.18% 11.62% 2.68%
65.070 11.710 2.700 Melting point: 271 - 272 C (decomposition) Example 2: Hexadecyl piperidinio-4-yl phosphate C21H44N04P (405.558) 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 MgSO4, 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% 3.45%
found: 65.15% 11.14% 3.54%
62.41% 11.19% 3.34%
Thin layer chromatogram:
(chloroform/methanol/25o 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 -C25H52NO4P ( 4 61. 64 )- H2O
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 40 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
ca1c.: 61.17% 11.16% 3.10%
found: 60.83% 11.14% 2.99%
60.920. 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 C29HS8NO4P (515.765) - H20 10.3 ml (0.11 mol) 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 - 10 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 (1:1). 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
caic.: 65.26% 11.63% 2.62%
found: 64.380 11.610 2.73%
65.04% 11.80% 2.78%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:20:10) Rf = 0.30 Example 5: Hexadecyl 1,1-dimethylpiperidinio-3-yl phosphate C23H48NO4P (433.616) = H20 10.3 ml (0.11 mol) of phosphorus oxychioride 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 ml 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 15ml of water, 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 (1:1).
The organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in 150-ml of 96%
ethanol, the solution is filtered and the filtrate is stirred with Amberlite*MB3 ion exchanger. After the ion * Trade-Mark 18 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.: 61.170 11.16% 3.10%
found: 60.780 11.410 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 Example 6: Octadecyl 1,1-dimethylpiperidinio-3-yl phosphate C2SH52NO4P (461.670) = zH20 This is prepared analogously to Example 5 from 10.3 ml (0.11 mol) of phosphorus oxychioride, 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 Example 7: Hexadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C24H50N04P (447.643) = zH20 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-l,1-dimethylpiperidinium tosylate.
Yield: 22.9 g (51%) 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 Example 8: Octadecyl (1,1-dimethylpiperidinio-2-yl) methyl phosphate C26H54NO4P (475.697) - 2H2O
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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.47 Example 9: Hexadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C24H50NO4P (447.643) = 1H2O
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-l,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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.29 Example 10: Octadecyl (1,1-dimethylpiperidinio-3-yl) methyl phosphate C26H54NO4P (475.697) = H2O
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%) Elemental analysis:
C H N
calc.: 63.25% 11.43% 2.84%
found: 62.98% 12.210 2.760 63.67% 12.47% 2.80%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 Example 11: Tetradecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C22H46N04P (419.54) = HZO -This is prepared analogously to Example 5 from 9.6 g (45 mmol) of tetradecanol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10_+ 20 ml of pyridine and 21.3 g (67.5 mmol) of hydroxy-l,l-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: 60.470 11.29% 3.63%
60.78% 11.52% 3.68%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.08 Example 12: Hexadecyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C24H48NO4P (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-l,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) Rf = 0.10 Melting point: >250 C (decomposition) Example 13: Octadecyl 1,1-dimethylhexahydroazep'inio-4-yl phosphate - -C26H54NO4P (475.695) - 2H20 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-l,l-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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.22 Melting point: >250 C (decomposition) Example 14: Cis-A 9-octadecenyl 1,1-dimethylhexahydro azepinio-4-yl phosphate C26H52NO4P (473.679) - H2O
This is prepared analogously to Example 5 from 12.1 g (45 mmol) of cis-O9-octadecenol, 4.6 ml (50 mmol) of phosphorus oxychloride, 10 + 20 ml of pyridine and 21.3 g (67.5 mmol) of 4-hydroxy-l,1-dimethylhexahydroazepinium tosylate. It is purified by flash chromatography on silica gel with methylene chloride/ methanol/25% ammonia 70:30:10.
Yield: 4.5 g (21%) Elemental analysis:
C H N
calc.: 63.51% 11.070 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 <
Example 15: Eicosyl 1,1-dimethylhexahydroazepinio-4-yl phosphate C28H58NO4P (503.754) = H2O
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-l,l-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 Example 16: Erucyl 1,1-dimethylhexahydroazepinio-4-yl phosphate - -C30H6oN04P (529.789) = H2O
This is prepared analogously to Example 5 from 16.2 g (50 mmol) of erucyl alcohol, 5.1 ml (55 mmol) of phosphorus oxychloride, 18 + 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 methylene chloride/methanol/ 25% ammonia 70:30:10.
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/l M sodium acetate in 25% ammonia 70:40:10) Rf = 0.30 Example 17: Octadecyl 1,1-dimethylpyrrolidinio-3-yl phosphate C24HS0N04P (447.643) - ZH2O
This is prepared analogously to Example 5 from 3.25 g (12 mmol) of octadecanol, 1.21 ml (13 mmol) of phosphorus oxychloride, 3.7 + 4.8 ml of pyridine and 4.31 g(15 mmol) of hydroxy-1,1-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: 62.990 11.28a 2.80%
62.74% 11.27% 2.89%
Thin layer chromatogram:
(chloroform/methanol/i 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 C24H50NO4P (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/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.38 * Trade-Mark Example 19: Octadecyl 2-(1,1-dimethylpyrrolidinio-2-yl)ethyl phosphate C26H54NO4P (475.697) - ZH2O
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%) Elemental analysis:
C H N
caic.: 64.43% 11.440 2.89%
found: 64.69% 11.77% 2.64%
64.84% 11.880 2.690 Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.35 * Trade-Mark Example 20: Hexadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate C23H48NO4P (433.616) = 2H2O
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 purified by dissolution in 96% ethanol and treatment with Amberlite*MB3 ion exchan_ger_ Yield: 8.3 g (51%) Elemental analysis:
C H N
ca1c.: 62.410 11_16% 3_160 found: 62.09% 11.48% 3.01%
62.25% 11.66% 3.09%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.33 * Trade-Mark Example 21: Octadecyl (1,1-dimethylpyrrolidinio-2-yl) methyl phosphate C25H52NO4P ( 4 61. 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 inmol) of 2-hydroxymethyl-1,1-dimethylpyrrolidinium tosylate. It is purified by dissolution in 96% ethanol and treatment with Amberlite MB3 ion exchanger.
Yield: 9.0 g (520) Elemental analysis:
C H N
caic.: 63.80% 11.35% 2.98%
found: 63.13% 11.57% 2.84%
63.55% 11.66% 2.82%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.35 * Trade-Mark Example 22: Hexadecyl 1-methylquinuclidinio-3-yl phosphate C24H48NO4P (445.64) = 1.5 H20 2.7 ml (30 mmol) of phosphorus oxychloride are dissolved in 25 ml of chloroform and cooled to 5 - 10 C and a solution of 6.4 g (26 mmol) of hexadecanol and 10 ml of pyridine in 50 ml of chloroform is added dropwise over one hour. After subsequent stirring for half an hour at room temperature, a solution of 4.5 g (35 mmol) of 3-hydroxyquinuclidine and 5 ml of pyridine in 10 ml of chloroform is added. After stirring for 5 h at room temperature, the mixture is hydrolyzed with 15 ml of water and subsequently stirred for half an hour. It is then washed twice with 100 ml of water/methanol (1:1) and the organic phase is dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on silica gel with methylene chloride/methanol 80:25 and then methylene chloride/
methanol/25% ammonia 80:25:5. The product fractions are purified, evaporated to dryness and crystallized with acetone. The crystals are dried under vacuum over P205.
Yield: 4.95 g (44%) of hexadecyl quinuclidinio-3-yl phosphate 4.95 g (11.5 mmol) of hexadecyl quinuclidinio-3-yl phosphate are dissolved in 30 ml of inethariol, 13.7 g (69 mmol) of potassium carbonate and 8.5 ml of water are added and a solution of 3.3 ml (35 mmol) of dimethyl sulphate in 5 ml of methanol is added dropwise, with thorough stirring. After stirring for 14 h at room temperature, the inorganic salts are filtered off, the filtrate is concentrated to dryness and the residue is taken up in methylene chloride. After filtration, the filtrate is chromatographed on silica gel with methylene chloride/methanol/25% ammonia 70:30:5. The product fractions are combined, evaporated to dryness and stirred with acetone until crystallization occurs. The crystals are dried under vacuum over P205.
Yield: 2.7 g (49%) Elemental analysis:
C H N
calc.: 60.99% 10.88% 2.96%
found: 61.38% 11.04% 3.29%
61.46% 11.22% 3.25%
Thin layer chromatogram:
(chloroform/methanol/25% ammonia 70:40:10) Rf = 0.44 =Example 23: Octadecyl 1-methylquinuclidinio-3-yl phosphate C26H52NO4P (473.68) = 2H2O
This is prepared analogously to Example 5 from 18.3 g (67.5=mmol) of octadecanol, 7.0 ml (75 mmol) of phosphorus oxychloride, 18 + 20 ml of pyridine and 28.3 g(90 mmol) of 3-hydroxy-l-methylquinuclidinium tosylate_ It is purified by dissolution in 96% ethanol and treatment with Amberlite*
MB3 ion exchanger.
Yield: 18.4 g (57%) Elemental analysis:
C H N
calc.: 61.27% 11.07% 2.75%
found: 61.27% 10.91% 2.45%
61.95% 11.23% 2.51%
Thin layer chromatogram:
(chloroform/methanol/1 M sodium acetate in 25% ammonia 70:40:10) Rf = 0.37 (1-butanol/glacial acetic acid/water 40:10:10) Rf = 0.13 *
Trade-Mark Example 24: Hexadecyl 1,1-dimethyltropanio-4-yl phosphate C25H50N04P (459.654) - H20 This is prepared analogously to Example 5 from 12.1 g (50 mmol) of hexadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 40 ml of pyridine and 21.3 g (65 mmol) of 4-hydroxy-l,l-dimethyltropanium tosylate. It is purified *
by dissolution in 96% ethanol, treatment with Amberlite MB3 ion exchanger and recrystallization from acetone._ Yield: 11.3 g (49%) Elemental analysis:
C H N
calc.: 62.86% 10.97% 2.93%
found: 62.45g 11.52% 2.82%
62.58% 11.52% 2.75%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.28 * Trade-Mark Example 25: Octadecyl 1,1-dimethyltropanio-4-yl phosphate C27H54NO4P (487.708) This is prepared-analogously to Example 5 from 13.5 g (50 mmol) of octadecanol, 5.1 ml (55 mmol) of phosphorus oxychloride, 17 + 20 ml of pyridine and 21.3 g (65 mmol) of 4-hydroxy-1,l-dimethyltropanium tosylate. It is purified by dissolution in 96% ethanol and treatment with Amberlite*
MB3 ion exchanger_ Yield: 10.7 g (44%) Elemental analysis:
C H N
calc.: 66.49% 11.16% 2.87%
found: 65.720 11.48% 2.64%
66.27% 11.78% 2.65%
Thin layer chromatogram:
(chloroform/methanol/i M sodium acetate in 25% ammonia 70:40:10) Rf = 0.22 * Trade-Mark
Claims (17)
1. A compound of the general formula wherein:
B is a quinuclidinio ring system linked via a carbon atom of the quinuclidinio ring and in which the nitrogen atom optionally is substituted by a methyl group, or a tropanio ring system linked via a carbon atom of the tropanio ring and in which the nitrogen atom optionally is substituted by one or two methyl groups;
R is a straight-chain or branched-chain alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds; and y is 0, 1, 2 or 3;
or a pharmaceutically-acceptable salt thereof.
B is a quinuclidinio ring system linked via a carbon atom of the quinuclidinio ring and in which the nitrogen atom optionally is substituted by a methyl group, or a tropanio ring system linked via a carbon atom of the tropanio ring and in which the nitrogen atom optionally is substituted by one or two methyl groups;
R is a straight-chain or branched-chain alkyl radical having 10 to 24 carbon atoms, which also can contain one or more double or triple bonds; and y is 0, 1, 2 or 3;
or a pharmaceutically-acceptable salt thereof.
2. A compound as defined in claim 1, wherein y is zero.
3. A compound as defined in claim 1 or 2, wherein R is an octadecyl or hexadecyl group.
4. A compound as defined in claim 1, 2 or 3, wherein B is a 1-methylquinuclidinio-3-yl or 1,1-dimethyltropanio-4-yl ring.
5. A compound which is:
hexadecyl 1-methylquinuclidinio-3-yl-phosphate, octadecyl 1-methylquinuclidinio-3-yl phosphate, hexadecyl 1,1-dimethyltropanio-4-yl phosphate, or octadecyl 1,1-dimethyltropanio-4-yl phosphate;
or a pharmaceutically-acceptable salt thereof.
hexadecyl 1-methylquinuclidinio-3-yl-phosphate, octadecyl 1-methylquinuclidinio-3-yl phosphate, hexadecyl 1,1-dimethyltropanio-4-yl phosphate, or octadecyl 1,1-dimethyltropanio-4-yl phosphate;
or a pharmaceutically-acceptable salt thereof.
6. A pharmaceutical composition comprising a compound as defined in one of claims 1 to 5, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier or excipient.
7. A pharmaceutical composition as defined in claim 6, comprising 50 to 250 mg of said compound.
8. 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 5, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier or excipient.
9. A pharmaceutical composition as defined in claim 8, for the treatment of leishmaniasis.
10. A pharmaceutical composition as defined in claim 8 or 9, comprising 50 to 250 mg of said compound.
11. Use of a pharmaceutical composition as defined in claim 6 or 7 in the treatment of tumours, protozoal diseases or fungal diseases.
12. Use of a pharmaceutical composition as defined in claim 6 or 7 in the treatment of leishmaniasis.
13. Use of a compound as defined in one of claims 1 to 5 for the production of a medicament for the control of tumours.
14. Use of a compound as defined in one of claims 1 to 5 for the production of a medicament for the control of protozoal diseases or fungal diseases.
15. Use of a compound as defined in one of claims 1 to 5 for the production of medicaments for the control of leishmaniasis.
16. Use of a compound as defined in one of claims 1 to 5 or a pharmaceutically-acceptable salt thereof, for treating tumours, protozoal diseases or fungal diseases.
17. Use of a compound as defined in one of claims 1 to 5 or a pharmaceutically-acceptable salt thereof, for treating leishmaniasis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4222910A DE4222910A1 (en) | 1992-07-11 | 1992-07-11 | New phospholipid derivatives |
| DEP4222910.3 | 1992-07-11 | ||
| CA002100228A CA2100228C (en) | 1992-07-11 | 1993-07-09 | Phospholipid derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002100228A Division CA2100228C (en) | 1992-07-11 | 1993-07-09 | Phospholipid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2511753A1 CA2511753A1 (en) | 1994-01-12 |
| CA2511753C true CA2511753C (en) | 2007-09-25 |
Family
ID=6463031
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002511753A Expired - Lifetime CA2511753C (en) | 1992-07-11 | 1993-07-09 | Phospholipid derivatives |
| CA002100228A Expired - Lifetime CA2100228C (en) | 1992-07-11 | 1993-07-09 | Phospholipid derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002100228A Expired - Lifetime CA2100228C (en) | 1992-07-11 | 1993-07-09 | Phospholipid derivatives |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0579939B1 (en) |
| JP (1) | JP3311431B2 (en) |
| KR (1) | KR100297180B1 (en) |
| CN (1) | CN1039012C (en) |
| AT (1) | ATE176477T1 (en) |
| AU (1) | AU664101B2 (en) |
| BR (1) | BR9302809A (en) |
| CA (2) | CA2511753C (en) |
| CZ (1) | CZ290863B6 (en) |
| DE (2) | DE4222910A1 (en) |
| DK (1) | DK0579939T3 (en) |
| EE (1) | EE03140B1 (en) |
| ES (1) | ES2129053T3 (en) |
| FI (1) | FI111262B (en) |
| GR (1) | GR3029602T3 (en) |
| HR (1) | HRP931046B1 (en) |
| HU (1) | HU218783B (en) |
| IL (1) | IL106289A (en) |
| LT (1) | LT3113B (en) |
| LV (1) | LV10870B (en) |
| MX (1) | MX9304133A (en) |
| NO (1) | NO306468B1 (en) |
| PL (3) | PL177811B1 (en) |
| RU (1) | RU2108336C1 (en) |
| SG (1) | SG46249A1 (en) |
| SI (1) | SI9300365B (en) |
| SK (1) | SK283827B6 (en) |
| TW (1) | TW304956B (en) |
| UA (1) | UA40567C2 (en) |
| YU (1) | YU49079B (en) |
| ZA (1) | ZA934971B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101345002B1 (en) | 2005-01-21 | 2013-12-31 | 아스텍스 테라퓨틱스 리미티드 | Pharmaceutical compounds |
| EP1800684A1 (en) * | 2005-12-20 | 2007-06-27 | Zentaris GmbH | Novel alkyl phospholipid derivatives and uses thereof |
| CA2632449A1 (en) | 2005-12-19 | 2007-06-28 | Aeterna Zentaris Gmbh | Alkyl phospholipid derivatives with reduced cytotoxicity and uses thereof |
| EP1869981A1 (en) * | 2006-06-21 | 2007-12-26 | Staatliches Weinbauinstitut Freiburg | Alkylphospholipids and lysophospholipids for controlling plant pathogens |
| US8883790B2 (en) | 2006-10-12 | 2014-11-11 | Astex Therapeutics Limited | Pharmaceutical combinations |
| EP2073803B1 (en) | 2006-10-12 | 2018-09-19 | Astex Therapeutics Limited | Pharmaceutical combinations |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0050327B1 (en) * | 1980-10-21 | 1984-06-20 | Roche Diagnostics GmbH | Phospholipids that contain sulphur, process for their preparation and medicines containing these compounds |
| JPS5984824A (en) * | 1982-11-08 | 1984-05-16 | Takeda Chem Ind Ltd | Antitumor agent |
| DE3530767A1 (en) * | 1985-08-28 | 1987-03-12 | Max Planck Gesellschaft | AGENT AGAINST MULTIPLE Sclerosis |
| IE59778B1 (en) * | 1985-12-04 | 1994-04-06 | Max Planck Gesellschaft | Medicament with anti-tumour action containing hexadecylphosphocholine |
| ES2036210T3 (en) * | 1986-07-14 | 1993-05-16 | Nippon Chemiphar Co., Ltd. | A PROCEDURE FOR THE PREPARATION OF A GLYCEROL DERIVATIVE. |
| US4962096A (en) * | 1987-03-24 | 1990-10-09 | Nippon Chemiphar Co., Ltd. | Heterocyclic glycerol derivatives and their use as anti-hypertensive agents |
| DE3906952A1 (en) * | 1989-03-04 | 1990-09-06 | Boehringer Mannheim Gmbh | (3- (C (DOWN ARROW)) (DOWN ARROW) (DOWN ARROW) 6 (DOWN ARROW) -C (DOWN ARROW) 1 (DOWN ARROW) (DOWN ARROW) 8 (DOWN ARROW)) ALKANSULFINYL AND 2 SULPHONE -METHOXYMETHYL-PROPYL) - (2-TRIMETHYLAMMONIO-ETHYL) PHOSPHATES, METHOD FOR PRODUCING THE MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DE3942933A1 (en) * | 1989-12-23 | 1991-06-27 | Boehringer Mannheim Gmbh | USE OF ALKYLPHOSPHOLIPIDES AS ANTIVIRAL MEDICINAL PRODUCTS AND NEW PHOSPHOLIPID DERIVATIVES |
| DE4114586A1 (en) * | 1991-05-04 | 1992-11-05 | Boehringer Mannheim Gmbh | MEDICINAL PRODUCTS CONTAINING AZACYCLODIPHOSPHONIC ACID DERIVATIVES, NEW AZACYCLODIPHOSPHONIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
-
1992
- 1992-07-11 DE DE4222910A patent/DE4222910A1/en not_active Ceased
-
1993
- 1993-06-01 TW TW082104345A patent/TW304956B/zh not_active IP Right Cessation
- 1993-06-03 SG SG1996001626A patent/SG46249A1/en unknown
- 1993-06-03 AT AT93108904T patent/ATE176477T1/en active
- 1993-06-03 DE DE59309355T patent/DE59309355D1/en not_active Expired - Lifetime
- 1993-06-03 DK DK93108904T patent/DK0579939T3/en active
- 1993-06-03 EP EP93108904A patent/EP0579939B1/en not_active Expired - Lifetime
- 1993-06-03 ES ES93108904T patent/ES2129053T3/en not_active Expired - Lifetime
- 1993-06-04 LT LTIP620A patent/LT3113B/en not_active IP Right Cessation
- 1993-06-23 CZ CZ19931249A patent/CZ290863B6/en not_active IP Right Cessation
- 1993-06-28 SK SK670-93A patent/SK283827B6/en not_active IP Right Cessation
- 1993-07-06 YU YU47393A patent/YU49079B/en unknown
- 1993-07-08 PL PL93318679A patent/PL177811B1/en unknown
- 1993-07-08 PL PL93318680A patent/PL175607B1/en unknown
- 1993-07-08 PL PL93299624A patent/PL173388B1/en unknown
- 1993-07-08 NO NO932502A patent/NO306468B1/en not_active IP Right Cessation
- 1993-07-08 JP JP16911493A patent/JP3311431B2/en not_active Expired - Lifetime
- 1993-07-09 AU AU41864/93A patent/AU664101B2/en not_active Expired
- 1993-07-09 UA UA93002052A patent/UA40567C2/en unknown
- 1993-07-09 CA CA002511753A patent/CA2511753C/en not_active Expired - Lifetime
- 1993-07-09 BR BR9302809A patent/BR9302809A/en not_active Application Discontinuation
- 1993-07-09 RU RU93047049A patent/RU2108336C1/en active
- 1993-07-09 ZA ZA934971A patent/ZA934971B/en unknown
- 1993-07-09 FI FI933165A patent/FI111262B/en not_active IP Right Cessation
- 1993-07-09 CA CA002100228A patent/CA2100228C/en not_active Expired - Lifetime
- 1993-07-09 SI SI9300365A patent/SI9300365B/en unknown
- 1993-07-09 MX MX9304133A patent/MX9304133A/en active IP Right Grant
- 1993-07-09 IL IL10628993A patent/IL106289A/en not_active IP Right Cessation
- 1993-07-09 HR HR931046A patent/HRP931046B1/en not_active IP Right Cessation
- 1993-07-09 HU HU9301992A patent/HU218783B/en unknown
- 1993-07-10 CN CN93108564A patent/CN1039012C/en not_active Expired - Lifetime
- 1993-07-10 KR KR1019930012980A patent/KR100297180B1/en not_active IP Right Cessation
- 1993-07-12 LV LVP-93-988A patent/LV10870B/en unknown
-
1994
- 1994-10-25 EE EE9400199A patent/EE03140B1/en unknown
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1999
- 1999-03-08 GR GR990400689T patent/GR3029602T3/en unknown
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