EP0112872A1 - Neue glycerinderivate zur synthese von phospholipiden - Google Patents

Neue glycerinderivate zur synthese von phospholipiden

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Publication number
EP0112872A1
EP0112872A1 EP83902086A EP83902086A EP0112872A1 EP 0112872 A1 EP0112872 A1 EP 0112872A1 EP 83902086 A EP83902086 A EP 83902086A EP 83902086 A EP83902086 A EP 83902086A EP 0112872 A1 EP0112872 A1 EP 0112872A1
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EP
European Patent Office
Prior art keywords
alkyl
carbon atoms
benzyl
group
amino
Prior art date
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Pending
Application number
EP83902086A
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German (de)
English (en)
French (fr)
Inventor
Hansjörg EIBL
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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Publication of EP0112872A1 publication Critical patent/EP0112872A1/de
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Classifications

    • 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 Table
    • 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
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1785—Unsaturated ethers containing hydroxy or O-metal groups having more than one ether bound
    • 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 Table
    • 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
    • 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 Table
    • 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
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • 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 Table
    • 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
    • C07F9/14—Esters of phosphoric acids containing P(=O)-halide groups
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2408—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyalkyl compounds

Definitions

  • the invention relates to new glycerol derivatives for the synthesis of phospholipids, such as diester, monoester, monoether, ether / ester and diether phospholipids and corresponding phosphoric acid amide analogs.
  • Glycerin phosphatides are extremely important biologically and technically. Isolating pure, uniform glycerol phosphatides from natural tissues is extremely difficult and costly. Their synthesis is particularly problematic when glycerol phosphatides are to be produced in which glycerol with very specific radicals should be acylated in a very specific position.
  • Another disadvantage of this method is that during the acy lation step, a migration of the phosphoric acid residue from the 3 to the 2 position takes place to a considerable extent. Rearrangements of both fatty acids and phosphate residues can also occur during the reacylation of monoacylglycerol phosphoric acid esters (cf. A. Plückthun and EA Dennis, Biochemistry (1982), 21, 1743 - 1750; H. Eibl, Chem. Phys. Lipids ( 1980), 26, 405-429; H. Eibl, Liposomes: From Physical Structure to Therapeutic Application: Chapter 2: Phospholipid Synthesis (1981), 19-59; CG Knight, Ed., Elsevier, Amsterdam).
  • the invention is therefore based on the object to provide starting materials and ways of producing glycerol phosphates (phospholipids) in which the problems mentioned do not occur and which have a defined distribution of acyl, alkyl and phosphate residues over positions 1, 2 and 3 of the Allow glycerol molecule. This object is achieved with the present invention.
  • the invention relates to glycerol derivatives of For my I, II and III
  • Z is methyl, optionally a phenyl radical-containing alkyl with a CC multiple bond in the ⁇ -position, benzyl or an equivalent of a physiologically compatible cation, preferably methyl
  • R 1 and R 2 are identical or different and a hydrogen atom
  • R is alkyl having 1 to 24 carbon atoms or halogen, hydroxy or carboxyalkyl having 2 to 24 carbon atoms, where alkyl can be straight-chain or branched and can contain double or triple bonds , and can be substituted by cycloalkyl having 3 to 6 carbon atoms or by aryl radicals, and in which a hydroxyl and / or carboxy group can also contain a protective group
  • An alkyl group can be branched or, preferably, straight chain and can contain double or triple bonds.
  • An alkyl group with a double bond is, for example, the allyl radical serving as a protective group.
  • Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl and preferably cyclohexyl.
  • An aryl radical is in particular one having 6 to 14 carbon atoms, preferably naphthyl- (1) or - (2), and especially phenyl.
  • An alkyl group substituted with a phenyl radical is, for example, the benzyl group serving as a protective group.
  • An acyl group -COR is derived in particular from saturated and unsaturated natural fatty acids, such as, for example, behenic, lauric, stearic, palmitic, myristic, capric or arachidic acid, and oleic, linoleic or arachidonic acid and more unsaturated fatty acids.
  • Halogen can be fluorine, bromine or iodine and is especially chlorine.
  • a physiologically acceptable cation Z is preferably a mono-, di- or trivalent physiologically acceptable cation, such as. As sodium, potassium, calcium and especially lithium. If Z is alkyl with ⁇ -unsaturation, it is preferably alkyl or its homologues.
  • Protecting groups for the hydroxyl group are, for example, benzyl, allyl, trityl, tetrahydropyranyl, mesyl and tosyl; for the carboxy group, for example, tert-butyl.
  • the precursors of the compounds, of the formulas I, II or III with free hydroxyl groups on the phosphorus can be obtained analogously to a synthetic route known for glycerol derivatives (cf. for example D. Arnold, HU Weltzien and O. Westphal, Liebigs Ann. Chem. 709 (1967 ), 234 to 239; HU Weltzien and O. Westphal, Liebigs Ann. Chem. 709 (1967), 240 to 243; K. Eibl and 0. Westphal, Liebigs Ann. Chem.
  • the compounds of formula I lead to phospholipids of natural configuration (sn-3-phosphates), those of formula II and III to compounds with non-natural configurations (sn-1- or -2-phosphates).
  • glycerol derivatives mentioned above and below can exist both as optically pure stereoisomers and as racemates.
  • the methyl group in formulas I, II and III is superior to corresponding benzyl groups in many respects. It has sufficient stability for the necessary ones Reaction steps, for example the phosphoric acid methyl esters of the formulas I, II and III are stable under catalytic hydrogenolysis, acidic trityl and propenyl elimination under the selected conditions. With lithium bromide, the methyl group can be removed easily and without destroying the phospholipid molecule.
  • the invention therefore also relates to a process for the further processing of the compounds of the formulas I, II or III for the preparation of phospholipids, which is characterized in that
  • Lithium bromide demethylated, or d) for the preparation of mono-ether phospholipids starts from a compound in which R 1 and R 2 are different and R 1 is alkyl, benzyl, allyl or trityl, R 2 is alkyl, benzyl or allyl, one radical R 1 or R 2 is an alkyl group, and demethylated with lithium bromide, or e) for the preparation of ether / ester phospholipids, starts from a compound in which R 1 and R 2 are different and R 1 is alkyl, benzyl, allyl or trityl be means R 2 is alkyl, benzyl or allyl, where a radical R 1 or R 2 is an alkyl group, splits off a benzyl, allyl or trityl group R 1 or R 2, acylates the resulting hydroxyl group, and then demethylates with lithium bromide, or f) for the preparation of diether phospholipids from
  • a compound obtained according to a) to f) cleaves off protective groups which are known per se and / or aminates the phosphorus-containing radical or converts it to another phosphorus-containing radical
  • the cleavage of benzyl, allyl or trityl can also be carried out after the amination or conversion into another phosphorus-containing radical.
  • the processes can also be carried out by starting from a product obtained by one of the process steps and carrying out the remaining process steps. Taking into account all residues present in the molecule, it is also possible, for example, to interchange the order of the individual process steps.
  • acylation of a free hydroxy group can be carried out by Reaction with acid chlorides in the presence of triethylamine or pyridine can be carried out (cf. H. Eibl and 0. Westphal, Liebigs Ann. Chem. 709 (1967), 244).
  • acylation methods known per se for example as described by Gupta et al, Proc. Nat. Acad. Sci. USA 74 (1977), 4315).
  • Acy lation is particularly easy with free fatty acid and dicyclohexylcarbodiimide in the presence of dimethylaminopyridine.
  • the trityl group is cleaved off under weakly acidic conditions, preferably at a pH of 4 to 6, it being easy to determine the most favorable value taking into account the other substituents in the molecule.
  • the allyl and benzyl protective groups are completely stable.
  • the reaction can be carried out in an aqueous or aqueous-organic medium, but also in a purely organic medium, for example in absolute ethanol, in the presence of HCl or H 2 SO 4 .
  • the organic solvent can be a
  • the reaction particularly when working in a two-phase system, advantageously takes place with vigorous stirring.
  • the temperature is generally 20 to 80 ° C.
  • a higher alcohol such as propanol (2), in a small amount.
  • the benzyl group is split off by catalytic hydrogenolysis.
  • the reaction conditions correspond to the usual conditions.
  • the hydrogenolysis is carried out in an inert solvent, such as ethanol, in the presence of a palladium or platinum / palladium catalyst, preferably at room temperature and under normal pressure (cf. H. Eibl et al, Liebigs Ann. Chemie, 738 (1970), 161).
  • the cleavage of the allyl group (rearrangement into propenyl and subsequent cleavage of propenyl) can be carried out by two different methods, namely 1) under alkaline conditions, such as with potassium tert-butoxide in dimethylformamide and subsequent cleavage with bromine in buffered solution at a pH - Value around 5 to 6, or 2) by rearrangement in the presence of a palladium (carbon) catalyst to form the propenyl group which spontaneously cleaves under these conditions, expediently in 80% methanol, which in the aqueous phase is 20% Contains formic acid, is carried out at reflux temperature. In general, variant 1, i.e. H. cleavage with bromine is preferred.
  • Iodine can also be used to split off the propenyl group in the 1 position (Eibl and Lands, Biochemistry 9 (1970), 423). However, while the propenyl group cannot be split off in the 2-position with iodine, such a split-off can surprisingly be carried out completely and in a few minutes using bromine.
  • the methyl phosphoric acid is demethylated with lithium bromide by boiling in a suitable organic solvent, preferably in methyl ethyl ketone.
  • the amination of the residue containing phosphorus can be carried out in a manner known per se (cf., for example, BH Eibl and A. Nicksch, Chem. Phys. Lipids, 22 (1978), 1; W. Diembeck and H. Eibl, Chem. Phys Lipids, 24 (1979), 237), as well as the subsequent alkylation of a free amino group.
  • Compounds of the formula I and II according to the invention are also of great importance because of their particular effectiveness in the growth of tumors.
  • R 1 denotes the radical - (CH 2 ) m -CH 3 , where m is 13-19
  • R 3 is alkyl with 1 to 12 carbon atoms, alkyl with 2 to 11 carbon atoms substituted by hydroxy or trityloxy, alkyl substituted with carboxy or tert-butyloxycarbonyl to 1 to 11 carbon atoms, 2- (amino- or tert-butyloxycarbonylamino) -2-tert-butyloxycarbonylethyl, 1,2-dihydroxy- or 1,2-isopropylidenedioxy-propyl, pentahydroxy- or pentabenzyloxy-cyclohexyl, or by bromine, amino, methylamino, dimethylamino, trimethylammonio, tert.- Butyl
  • Lyso compounds (1-alkyl-2-OH) according to the invention are based in part on a completely new active principle. They are not detoxified by acyltransferases or only very slowly. This is based on some of the lyso compounds according to the invention in which the radical R 3 z. B. one by
  • acyltransferases no longer attack; Phosphorus lipases A 2 are still attacking, but the acyltransferases can no longer reactylate.
  • Residue - (CH 2 ) m -CH 3 in which m is 13 to 19 and R 2 denotes an acyl residue COR, act as a precursor of the above-mentioned tumor-active substances in natural form. With phospholipase A 2 they go into the active substances in vivo.
  • the 1-alkyl-2-acylglycerol derivatives are not hemolytic; they can therefore be dosed higher without any problems. It is advantageous to use matrix molecules with stable ether structures that are not cleaved by phospholipase A 2 , such as in particular, for. B. 1-octadecyl-2-oleyl compounds.
  • the effectiveness of compounds on the growth of tumors is expedient on tumors in experimental animals proven.
  • Various experimental tumors are used for this, for example the Ehrlich-Ascites tumor, a methylcholanthrene-induced tumor and a myeloma tumor in mice, and also a chemically induced rat tumor.
  • the anti-tumor substances are administered parenterally into the tumor-bearing test animals. Intravenous and intra- or subcutaneous administration is preferred. Oral applicability is with a correspondingly higher dosage of the anti-tumor agent and with a physiologically compatible preparation, for. B. in capsules, not excluded.
  • the invention therefore also relates to medicaments which contain one or more of the abovementioned tumor growth-inhibiting compounds of the formula I or II as active ingredient.
  • these medicaments may also contain, in addition to the compounds of the formulas I and II, to assist therapy, if appropriate, provided that these, together with the compounds according to the invention, do not show any undesirable side effects.
  • the dosage and application essentially correspond to the conditions given for the anti-tumor agents of DE-OS 2 619 686, but due to the higher effectiveness, lower doses and / or less frequent administration can also be considered. In the case of parenteral administration, it has proven expedient to use about 0.05 to 5 mg / kg of body weight as the dosage.
  • One which has proven to be a particularly favorable pharmaceutical composition is one in which the active ingredient component according to the invention consists of a mixture of about 80-95% by weight of 1-alkyl-2-acyl compound and about 20-5% by weight of 1-alkyl -2-OH connection exists. Such a composition is not hemolytic due to the higher content of 1-alkyl-2-anyl compound.
  • the process according to the invention is a very selective, simple and economical method for the production of phospholipids, which is particularly important for the stereo- and position-specific preparation of glycerol phosphatides with two or three different radicals.
  • the following examples illustrate the invention without restricting it.
  • the starting product is 3,4-isopropylidene-D-mannitol (CF Wiggins, J. Chem. Soc. 13, 1946).
  • a solution of 0.1 mol in 1 l of toluene is mixed with 0.5 mol of K-tert-butoxide and boiled under reflux.
  • 0.5 mol of benzyl chloride is added dropwise with stirring.
  • TLC control After completion of the reaction (TLC control), the reaction mixture is extracted with water and the toluene phase is spun in. The residue is taken up in 1 l of methanol / 2-propanol 1: 1 (v / v) for deacetonation, 50 ml of 2N-H 2 SO 4 are added and the mixture is boiled under reflux.
  • 1, 2,5,6-tetrabenzyl-D-mannitol (0.1 mol) is dissolved in 500 ml of benzene, and lead tetraacetate (approx. 0.1 mol) is added in portions until the starting product is completely converted (TLC control) . It is washed twice with 500 ml of water each time, the benzene phase is rotated in and the residue is taken up in 500 ml of methanol. The solution of the aldehydes in methanol is added in portions NaBH 4 (approx. 0.1 mol) was added. After the reaction has ended, 500 ml of diisopropyl ether are added and the mixture is washed with water. The diisopropyl ether phase is spun in and the residue is chromatographed on silica gel. The yield of 1,2-dibenzyl-sn-glycerol is 95%; Rotation value (in substance).
  • 1,2-dibenzyl-sn-glycerol (C 14 H 20 O 3 ; 272.35) calcd. C 74.97 H 7.40 found. C 74.91 H 7.40.
  • 1,2-Dibenzyl-sn-glycero-3-phosphomethyl-N-BOC-serine tert-butyl ester (0.1 mol) are dissolved in 400 ml THF and with 10 g Pd / C (10% Pd on activated carbon ) and 1 g of palladium black. The mixture is left under stirring under a H 2 atmosphere until the H 2 uptake is complete. The reaction is quantitative. The catalyst is filtered off and the solvent is removed in vacuo. The oily residue is directly implemented further.
  • the intermediates with two free hydroxyl groups in the sn-1 and sn-2 positions of the glycerol can now be used with the desired fatty acids are implemented, for example with palmitic acid or with oleic acid.
  • 0.1 mol are dissolved in 300 ml of methylene chloride, the fatty acids (0.25 mol) in 200 ml of methylene chloride, with dicyclohexylcarbodiimide (0.25 mol) and 4-dimethylaminopyridine (0.05 mol) are added.
  • the precipitated urea is filtered off with stirring at 20 ° C., washed with water and the methylene chloride phase is spun in. The residue is purified on silica gel by chromatography. The yield of acylated product is 95%.
  • the residue mainly 1-trityl-2-benzyl-sn-glycero-3-phosphodichloride, is taken up in 500 ml of THF and triethylamine (0.3 mol) is added.
  • triethylamine 0.3 mol
  • bromoalkanols 0.2 mol
  • methanol 1 mol
  • the methanolysis is quickly completed at 30 ° C (approx. 2 hours).
  • 500 ml of diisopropyl ether are added and the organic phase is extracted with water.
  • the diisopropyl ether phase is spun in.
  • the oily residue (0.1 mol) from a) is concentrated in 500 ml CH 3 OH, the 5 ml. Contain H 2 SO 4 , taken up and heated to 50 ° C. The reaction is complete after 10 minutes, the mixture is cooled to 0 ° C. and the crystal is filtered linen trityl methyl ether. After the addition of chloroform, 500 ml, the mixture is washed with 500 ml of 1M NaHCO 3 (pH of the aqueous phase should be at least 5). The chloroform phase is dried over Na 2 SO 4 and evaporated.
  • the residue from a) is taken up in 500 ml of methylene chloride and mixed with palmitic acid (0.25 mol). After addition of dicyclohexylcarbodiimide (0.25 mol) and 4-dimethylaminopyridine (0.05 mol), the mixture is stirred at 20 ° C. for 3 hours. The precipitated urea is filtered off, the filtrate is washed with water and the methylene chloride is removed in vacuo. The residue is chromatographed on silica gel. The yield is 75% based on 1-trityl-2-benzyl-sn-glycerol.
  • the amination of the bromoalkyl esters can be carried out in a manner known per se (cf., for example, BH Eibl and A. Nicksch, Chem. Phys. Lipids 22 (1978) 1; W. Diembeck and H. Eibl, Chem. Phys. Lipids 24 (1979) 237).
  • the reaction with the amine e.g. B. trimethylamine, z. B. in chloroform / propanol (2) (1/1) as a solvent.
  • the phosphoric acid triesters (0.1 mol) from e) are dissolved in 500 ml of chloroform and mixed with 500 ml of 2-propanol which contains trimethylamine (1 mol). After 24 hours at 50 ° C the reaction is complete. The solvent is removed and 500 ml of chloroform, methanol and water are added. The chloroform phase contains 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-N, N, N-trimethylalkanolamine ester. The solvent is removed and the mixture is purified by chromatography. The yields are more than 90%. Monoester phospholipids a) Demethylation
  • the products of the first acylation are demethylated with LiBr; for example, 1-palmitoyl-2-benzyl-sn-glycero-3-phosphomethyl-bromoalkyl ester (0.1 mol) is boiled under reflux with LiBr (0.5 mol) in 500 ml of ethyl methyl ketone. After 60 minutes, the implementation is quantitative.
  • the amination can be carried out as described above under g).
  • 1-Palmitoyl-2-benzyl-sn-glycero-3-phospho-N, N, N-trimethylalkanolamine ester (0.1 mol) are dissolved in alcohol, 1 l, and with 10 g Pd / C catalyst (10% palladium on activated carbon) and 1 g of palladium black. The mixture is stirred until the hydrogen uptake has ended. Debenzylation is quantitative. The catalyst is filtered off and the solvent is removed in vacuo. The residue is taken up in 100 ml of CHCl 3 and precipitated with 400 ml of acetone. The precipitate is filtered off and dried.
  • Mono-ether phospholipids can be prepared in exactly the same way as the mono-ester phospholipids.
  • 1-octadecyl-2-benzyl-sn-glycerol for example, is used as the starting product.
  • Ether / ester phospholipids are obtained if, for example, 1-octadecyl-2-benzyl-sn-glycerol is used as the starting product and the procedure for diester phospholipids, mixed-chain, is used. After phosphorylation a), however, the catalytic debenzylation d) and the second acylation e) take place immediately. Then proceed as described there.
  • 1, 2-diether-sn-glycerols like the 1,2-diester-sn-glycerols, can be converted into the corresponding phospholipids if the same chain procedure is used as for diester phospholipids and process steps b), phosphorylation, e), Demethylation and f), splitting off the protective groups, applies.

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  • Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP83902086A 1982-07-06 1983-07-06 Neue glycerinderivate zur synthese von phospholipiden Pending EP0112872A1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE3225213 1982-07-06
DE3225213 1982-07-06
DE19823239817 DE3239817A1 (de) 1982-07-06 1982-10-27 Neue glycerinderivate zur synthese von phospholipiden
DE3239817 1982-10-27

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EP83902086A Pending EP0112872A1 (de) 1982-07-06 1983-07-06 Neue glycerinderivate zur synthese von phospholipiden
EP83106626A Expired EP0099068B1 (de) 1982-07-06 1983-07-06 Neue Glycerinderivate zur Synthese von Phospholipiden

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EP (2) EP0112872A1 (enrdf_load_stackoverflow)
JP (1) JPS59501211A (enrdf_load_stackoverflow)
AT (1) ATE30030T1 (enrdf_load_stackoverflow)
DE (2) DE3239817A1 (enrdf_load_stackoverflow)
WO (1) WO1984000367A1 (enrdf_load_stackoverflow)

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CA1260393A (en) * 1984-10-16 1989-09-26 Lajos Tarcsay Liposomes of synthetic lipids
DE3663522D1 (en) * 1985-11-29 1989-06-29 Takeda Chemical Industries Ltd Phospholipid derivatives, their production and use
JPH01203330A (ja) * 1988-02-05 1989-08-16 Rikagaku Kenkyusho 制癌剤
JPH01203331A (ja) * 1988-02-05 1989-08-16 Rikagaku Kenkyusho 制癌剤
IT1239474B (it) * 1989-10-27 1993-11-02 Depha Team Srl Composizioni farmaceutiche a base di l-alfa-glicerofosforil-d-myo- inositolo o suoi sali alcalini o alcalino-terrosi per la terapia delleneuropatie periferiche di origine dismetabolica o tossica, e delle cerebropatie su base organica e funzionale
IT1244546B (it) * 1991-02-01 1994-07-15 Mediolanum Farmaceutici Spa Analoghi del fosfatidilinositolo inibitori della fosfolipasi c fosfatidilinositolo-specifica
DE4208527A1 (de) * 1992-03-17 1993-09-23 Max Planck Gesellschaft Liposomen mit negativer ueberschussladung
US5651981A (en) * 1994-03-29 1997-07-29 Northwestern University Cationic phospholipids for transfection
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Also Published As

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EP0099068B1 (de) 1987-09-30
DE3373906D1 (en) 1987-11-05
WO1984000367A1 (en) 1984-02-02
JPS59501211A (ja) 1984-07-12
ATE30030T1 (de) 1987-10-15
DE3239817A1 (de) 1984-01-12
EP0099068A1 (de) 1984-01-25
JPH041759B2 (enrdf_load_stackoverflow) 1992-01-14

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