EP2015746A2 - Utilisation de dérivés de glycérine substitués dans la production d'une préparation pharmaceutique - Google Patents

Utilisation de dérivés de glycérine substitués dans la production d'une préparation pharmaceutique

Info

Publication number
EP2015746A2
EP2015746A2 EP07722324A EP07722324A EP2015746A2 EP 2015746 A2 EP2015746 A2 EP 2015746A2 EP 07722324 A EP07722324 A EP 07722324A EP 07722324 A EP07722324 A EP 07722324A EP 2015746 A2 EP2015746 A2 EP 2015746A2
Authority
EP
European Patent Office
Prior art keywords
sub
radical
use according
alkyl
pharmaceutical preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07722324A
Other languages
German (de)
English (en)
Inventor
Dieter Mueller-Enoch
Thomas Haehner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haehner Thomas
Universitaet Ulm
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP2015746A2 publication Critical patent/EP2015746A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of substituted glycerol derivatives or pharmaceutically acceptable salts of these compounds, for the preparation of a pharmaceutical preparation as well as such preparations themselves, in particular for administration to humans.
  • liver disease the so-called fatty liver, which can develop into liver inflammation or hepatitis, and in the later stages to cirrhosis of the liver.
  • the risk and the extent of the liver damage depends directly on the amount and duration of alcohol consumption, whereby the risk varies individually.
  • Alcohol-induced inflammation of the liver is a possibly life-threatening disease, which may be accompanied by fever, jaundice and an increase in white blood cells.
  • Such alcohol-induced liver inflammation can be cured by complete alcohol abstinence, scarring excluded in cirrhosis.
  • hepatides are also produced in persons who do not engage in alcohol abuse or do not drink any alcohol at all. Such hepatides are induced, for example, by environmental toxins, for example when working in coating plants and / or by medicaments.
  • Alzheimer's disease is a progressive dementia disease that ultimately leads to complete loss of memory and personality. It is caused by protein deposits in nerve cells, the plaques, which are formed from ß-amyloid or so-called ⁇ -proteins. The egg- The true cause is unknown so far, whereby both metabolic disorders, gene mutations, as well as so-called slow virus infections or prions are discussed.
  • Alzheimer's disease it is known that in the brain of transgenic mice, a trigger of plaque formation is lipid oxidation leading to a G-amyloid precursor protein which forms the known plaques.
  • Parkinson's disease is a degeneration of dopaminergic neurons in the substantia nigra of the brain. It is the most common neurological disease in old age. Beginning signs are here in particular trembling movements (tremor), a depressive mood, apathy as well as slowed thinking. Again, it is believed that reactive oxygen species are involved in the development of the disease.
  • cytochromes are a variety of different enzymes whose active center has a heme structure. They catalyze the transfer of electrons to an acceptor in a variety of oxidation and Hydroxil michiganson.
  • cytochromes of the P450 family CYP-450
  • CYP-450 cytochromes of the P450 family
  • monooxygenases which are among the most important enzymes of the metabolism of hydrophobic exogenous substances and the modification of hydrophobic hormones called steroids.
  • Cytochrome P450 enzymes therefore play an important role in detoxification. It is estimated that approximately half of all current drugs are hydroxylated by cytochrome P450 enzymes of the liver. The residence time of many drugs in the body is therefore considerably reduced by the activity of cytochrome P450 enzymes. The vast majority of cytochrome P450 is found in mammals in the liver, as this is the central detoxification organ. Cytochrome P450 is usually present in the form bound to the membrane of the endoplasmic reticulum.
  • Cytochrome P450 enzymes also play a key role in mediating the resistance of insects to insecticides and plants to herbicides.
  • cytochrome P450 has a six-coordinate heme group, which undergoes a reaction in the following scheme
  • the cytochrome P450 itself is present in a variety of different forms, such as 1A1, 2B1, 2C9, 2J2, 2E1, 3A1, etc.
  • the rat cytochrome P450 2B1 and human cytochrome P450 2E1 differ in their amino acid sequence by about 60%, ie that both the structures of the active and catalytic centers as well as the size and shape of the access channels for the substrate differ considerably. This ultimately leads to the fact that both enzymes metabolize completely different classes of substrates.
  • the isoform 2E1 reacts with much smaller molecules, such as ethanol, acetone or p-nitrophenol.
  • chemotherapeutic agents used in cancer therapy are also broken down by cytochrome P450 enzymes.
  • Cytochrome P450 2J2 is an epoxygenase that converts the substrate arachidonic acid into four different isomeric epoxyeicosatrienoid (EET) acids.
  • EET isomeric epoxyeicosatrienoid
  • EETs inhibit angiogenesis, i. H. promote the formation of new blood vessels. This process plays an important role in the growth of tumors (Pozzi A. et al. "Characterization of 5,6- and 8,9-epoxy-eicosatrienoic Acids (5,6- and 8,9-EET as Potent in Vivo Angiogenic Lipids Chem. 280: 27138-27146, 2005). J. Biol. Chem.
  • Müller-Enoch et al. describe in Z. Naturforsch. (2001) 56c, pages 1082-1090, the inhibition of cytochrome P450 2B1 of the rat by means of lysophosphatidyl cholines, lysophosphatidylinositol and arachidonic and oleic acids or by means of monoacylglycerols, monooleylglycerols, and monopalmitoylglycerols.
  • the object of the present invention is to provide compositions for the preparation of a pharmaceutical preparation which can be used for the prevention or treatment of cancers, pathological consequences of alcohol abuse, viral hepatitis, steato-hepatitis, acute and chronic pancreatitis, Alzheimer's disease, Parkinson's disease, toxic kidney diseases , acute renal failure, diabetes mellitus, Wilson's disease, siderosis, ischemia-reperfusion injury, and / or arteriosclerosis, for use as an antidote to environmental toxins and drug intoxication, to prolong the residence time of drugs in the organism, or to combat toxic side effects in the administration of chemotherapeutic agents.
  • ROS reactive oxygen species
  • oxygen radicals such as the superoxide anion (O 2 " " ) and the hydroxyl radical (• OH)
  • O 2 " " oxygen radicals
  • OH hydroxyl radical
  • the compounds of the invention have the formula
  • R1 / R6 / R7 / R8 may in principle take the form RX.
  • R is an aliphatic or aromatic hydrocarbon radical preferably having 6 to 40 carbon atoms, which has a particularly terminal, hydrophilic radical A and X is at least one free carbon atom. or heteroelectron pair and / or Pl-electron-containing radical.
  • the radical R is in particular lipophilic.
  • the radical R is an alkyl radical. Thus, it may be straight-chain or branched, have single, double or triple bonds and be substituted. It usually has an aliphatic backbone with 6 to 26, in particular 8 to 22 carbon atoms. Useful hydrocarbon chains with a backbone of 10 to 15, in particular 10 to 13 carbon atoms. If R is an alicyclic or aromatic hydrocarbon radical which may be condensed and / or lipophilicly substituted, it usually has at least 5 or 6 and at most 40 or at most 25 carbon atoms. Further expedient minimum lengths are 7 or 8 C atoms and further expedient maximum lengths are 22 or 20 C atoms.
  • Suitable radicals X are heterocycles, as well as alkynyl radicals.
  • the heterocycles are in particular nitrogen, oxygen and / or sulfur-containing heterocycles.
  • the heterocycles may be aromatic and / or non-aromatic and usually have 5 or 6 ring atoms.
  • X can also be a condensed heterocycle. Examples of such heterocycles are imidazole, pyrrole, pyrazole, pyridine, pyrazine, indole, isoindole, indazole.
  • Preferred heterocycles are 6 and in particular 5 atoms having rings with one, two or three heteroatoms. Further suitable heterocycles are, for example, thiazoles, triazoles, furans.
  • Preferred alkynes have the structure -C ⁇ C-Ri 2 , wherein Ri 2 is a hydrogen or an optionally substituted Cr to C 15 or maximum C-io-alkyl radical, which in turn may optionally have double or triple bonds. Usually, however, Ri 2 has a maximum of 5, in particular a maximum of 3 C atoms. In a further expedient embodiment of the invention, the radical X is for example
  • radicals X are expediently radicals which coordinate with the prosthetic heme group.
  • Ri which is normally a hydrogen or a C 6 - or C 7 - to C 26 or C 2 o-alkyl chain, in one preferred embodiment has one or more double and / or triple bonds.
  • the hydrocarbon backbone can be formed with alicyclic and / or aromatic hydrocarbon, which may be necessary because of the ring structures up to 40 carbon atoms.
  • Ri has an ⁇ -double bond and an ⁇ -permanent triple bond such.
  • a ⁇ -acetylenic sphingosine it is also possible to arrange the triple bond in a long molecule in the middle, and that it coordinates with the heme, such.
  • the terminal triple bond may be substituted by a heterocycle or other heme coordinating group.
  • Ri may have one or more substituents. If R 1 contains a terminal heterocycle, then this heterocycle can have one of the definitions given for R 6 to Rs.
  • the radicals R 2 to R 5 may be identical or different and are usually a C 1 to C 5 alkyl radical or hydrogen.
  • the alkyl radicals may optionally be substituted and, for example, an alkanol, alkylamine or aikylthiol radical be. Particular preference is given to hydrogen, methyl, ethyl and propyl radicals or derivatives thereof.
  • Re to Rs are connected via the bond B 6 , B 7 and B 8 with the respective glycerol C atom and may be identical or different and hydrogen, a CQ or C 7 to C 26 or C 20 , in particular Cs or C 9 to C22 or Ci 8 be alkyl radical.
  • These alkyl radicals can be both substituted and unsubstituted, preference being given to those substituents which have one or more triple bonds between the C 4 or Cg to C 15 or Cu C atoms.
  • the hydrocarbon backbone can be formed with alicyclic and / or aromatic hydrocarbons, in which case up to 40 or up to 25 carbon atoms may be necessary because of the ring structures.
  • the length of the aliphatic backbone comprises 6 or 9-26 or 13 carbon atoms, if R1 is an imidazole radical.
  • R1 is an imidazole radical.
  • a representative of this preferred group is, for example, 12-imidazolyl-dodecanol or 1-imidazolyl-dodecane.
  • the length of the aliphatic backbone comprises 6 or 14-26 or 18 carbon atoms if R1 is an ethynyl radical.
  • R1 is an ethynyl radical.
  • Representative of this preferred group is e.g. 17-Octadecinyl-1 acid.
  • the length of the aliphatic backbone comprises 9-13 carbon atoms when R1 is ethynyl.
  • Representatives of this preferred group are e.g. 2,2-dimethyl-11-dodecynoic acid, 10-undecynyl sulfate, 10-undecynoic acid or 10-undecinol.
  • At least one of the radicals R ⁇ to Rs is a glycoside, in particular a monosaccharide, which is optionally substituted, for example by means of a sulfate or an amino radical.
  • di- or oligosaccharides are quite suitable for the purpose of the invention.
  • Preferred saccharides are pentoses and hexoses and mixed saccharides.
  • the glycosides can also be thiosugars.
  • At least one of R ⁇ to R 8 is a positively or negatively charged amino acid residue, particularly an amino acid having an additional amino group, wherein amino acid groups of the structure - (CH 2 ) H -N + (Rg-Rn) is a convenient alternative embodiment represent.
  • n is usually an integer between 1 and 5, with 1 to 3, in particular 2 being preferred.
  • the radicals Rg to Rn are usually hydrogen or a methyl, ethyl or propyl group.
  • R 9 to Rn may be the same or different.
  • one of the X with one of the Re to R 8 radicals together form a phosphocholine group or other phosphate esters, such as. B.
  • the heme-coordinating group is a bonded via a nitrogen atom imidazole or ethynyl (-C ⁇ CRi 2 ), wherein R 12 is hydrogen or a substituted or unsubstituted aliphatic Ci to C 12 hydrocarbon radical.
  • the use according to the invention makes it possible to reduce the formation of such reactive oxygen species and to treat the abovementioned diseases.
  • these compounds offer the possibility of inhibiting the formation and proliferation of tumor tissue, since the application of the compounds used according to the invention avoids the conversion of arachidonic acid into the proliferation-promoting and apoptosis-inhibiting epoxyeicosatrienoid acids.
  • the compounds according to the invention further develop such that the functional groups of the hydrocarbon radicals R 1 , R 6 , R 7 , Rs, ie the terminal hydrocarbon radicals, the alcoholic OH group, the sulfate or the Co-A group or the organic acid group are modified by addition of another, hydrophilic residue.
  • the compounds according to the invention which contain the heme-coordinating hydrocarbon radical already described comprise compounds having the basic structure of sphingosines, mono-, di- and triglycerides, as well as imidazolated or ethinylated phosphoglycerides, glycolipids, sphingolipids, gangliosides and cerebrosides, in particular their imidazolated or ethinylated forms.
  • hydrophilic moiety does not interfere with the binding of the molecule to the active site of cytochrome P450. This can be precisely controlled by choosing the length of the carbon backbone.
  • one of R 1, R 6 , R 7 , Re is a choline or ethanolamine, an ⁇ -, ⁇ - or ⁇ -hydroxyamino acid, such as, for example, serine, threonine, inositol or else galactose.
  • B 6 , B 7 and Bs may be the same or different and represent O, S, NH, PO 4 , Se, SO 4.
  • the bond B 6 , 7i8 which represents the respective carbon atom of the glycerol or polyol moiety R 6 , 7 , s is usually an ether, and / or an ester bond between an alcoholic polyol or glycerol and an or- ganic and / or inorganic acid group of R ⁇ j, a, such as.
  • Examples of such compounds are e.g. 12-imidazolyl-dodecanol-i-phosphatidylcholine, 10-imidazolyl-decanol-i-phosphatidylcholine or 17-octadecynyl-1-phosphatidylcholine.
  • the compounds used in the invention include in particular mono-, di- or triglycerides, phospholipids and glycolipids.
  • the use according to the invention has the advantage that the compounds are not directly accessible to enzymes of the ⁇ -oxidation metabolism and therefore are not metabolized immediately.
  • heme-coordinating monoglycerides are produced, which are also referred to as lysolipids, and which serve with the help of lipoproteins, ie non-covalent aggregates of lipids and proteins that form micelle-like particles and the transport of water-insoluble lipids in the blood ,
  • heme-coordinating monoglycerides such as. B. ethinylated or imidazoliere monoglycerides according to the above definition, which have already been administered as such. Since certain pathogenic tissues, such as tumors, have a high energy conversion, and promote the self-vascularization by release of growth factors (VEGF, PDGF), loaded with said heme-coordinating monoglycerides lipoproteins migrate with the blood stream preferably in these tissues. The "packaging" of the heme-coordinating hydrocarbon radicals in the form of lysolipids thus allows targeted transport of the same into the said target organs.
  • VEGF growth factors
  • the heme-coordinating compounds have the property of interacting with the active site of cytochrome P450 to inhibit its activity.
  • the compounds have a potential role in cancer therapy. It is hoped that its delivery will inhibit cytochrome P450-mediated conversion of arachidonic acid to epoxyeicosatrienoid acid. The latter, as already mentioned, promote cell division and proliferation and inhibit apoptosis. It is also to be hoped that the administration of such a compound inhibits the hydroxylation of chemotherapeutic agents, which ultimately leads to their excretion. Such a compound could thus be used for both direct and adjuvant tumor therapy. For this reason, the above-mentioned preferred embodiment, which enables a targeted transport into solid organs and tumors, is particularly promising.
  • hydrophilic radical R 2 does not impair the binding of the molecule to the active site of the cytochrome P450. This can be precisely controlled by choosing the length of the carbon backbone.
  • the invention further provides a pharmaceutical preparation comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • a pharmaceutical preparation comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • inflammations or pancreatitis in addition to alcohol abuse, can also be caused by toxic substances. These include, in particular, environmental toxins, such as occupational chemicals or even medicines. Also, viral infections or metabolic endocrine factors can cause such pancreatitis, with reactive oxygen species in all cases involved in disease development and disease progression.
  • the pharmaceutical according to the invention has been found to be suitable. It has been shown that ⁇ -islet cells of the islets of Langerhans are particularly sensitive to oxidative processes and that they rapidly decrease with increased oxidative stress. This oxidative stress can be avoided with the pharmaceutical according to the invention, but at least reduce massively.
  • the pharmaceutical of the invention has been found to be effective. It has been found, for example, that with the substances according to the invention the concentration of dopamine can be increased by reduced degradation.
  • toxic kidney diseases as well as other diseases, such as. B. by side effects in the administration of chemotherapeutic agents, in particular cell toxins, such as metal complexes such as cisplatin, carboplatin, titanocene dichloride or gold complexes are caused to be treated with the medicament of the invention.
  • chemotherapeutic agents in particular cell toxins, such as metal complexes such as cisplatin, carboplatin, titanocene dichloride or gold complexes are caused to be treated with the medicament of the invention.
  • the organotoxicity of metal complexes or other toxic agents such as halogenated hydrocarbons, both mono- and also polihalogenated hydrocarbons including halohydrothane type vapor anesthetics, and corresponding aromatic hydrocarbons, nitrosamines, Acrylamide or medicinal products such as paracetamol, methotrexate, isoniazid or aminoglycoride antibiotics or x-ray contrast agents.
  • the medicament according to the invention is thus also suitable for the treatment of the organotoxicity of environmental poisons, in particular as an antidote for this to organs such as liver, kidney, central nervous system, pancreas, etc.
  • cytotoxic drugs in cancer treatment, and may increase against this background as adjuvant therapy, the prospects of success of chemotherapy.
  • the pharmaceutical preparation according to the invention for the treatment of acute renal failure, in particular those renal failure caused by drug intoxication, hemolytic diseases, hemolytic uremic syndrome (Gasser syndrome), rhabdomyolysis gangue of striated skeletal muscle), caused by circulatory ischemic processes and / or a viral infection.
  • acute renal failure in particular those renal failure caused by drug intoxication, hemolytic diseases, hemolytic uremic syndrome (Gasser syndrome), rhabdomyolysis gangue of striated skeletal muscle), caused by circulatory ischemic processes and / or a viral infection.
  • the agent according to the invention is thus also particularly suitable for the prevention of reperfusion damage in transplanted organs.
  • transplanted organs Such organs are kept in a cooled nutrient solution until their transplantation into the body of a new recipient. After transplantation, these are then re-perfused with body fluids after connection to the circulatory system of the recipient, which leads to reperfusion damage.
  • the substances according to the invention have proved to be especially inhibitors of the human isoforms of gene family 2 of cytochrome P450, in particular of isoforms 2E1 and 2J2 and diseases caused by them.
  • the pharmaceutical preparation is incorporated in liposomes.
  • the compounds forming the basis of the preparation have long hydrocarbon radicals makes their incorporation into liposomes a very suitable form of administration.
  • Such liposomes are suitable for intravenous, intramuscular, intraperitoneal, percutaneous or even oral administration.
  • an administration as an aerosol is suitable.
  • the compounds according to the invention can also be administered directly as such. Also in this case, the above administration modes are suitable.
  • a) 12-imidazolyl-1-dodecanoic acid is synthesized according to a method described in Alterman et al. ("Fatty acid discrimination and omega-hydroxylation by cytochrome P4504A1 and a cytochrome P4504A1 / NADPH-P450 reducase fusion protein", Archives of Biochemistry and Biophysics 1995, 320: 289-296).
  • 12-bromo-1-dodecanol is oxidized with Jones' reagent to 12-bromo-1-dodecanoic acid.
  • the white solid acid is then esterified with diazomethane to the corresponding methyl ester.
  • the methyl ester is added directly with imidazole and reacted at 8O 0 C for five hours to 12-imidazolyl-1-dodecanoic acid methyl ester.
  • the resulting thick mass is partitioned between water and dichloromethane, the organic phase is dried over Na 2 SO 4 and evaporated.
  • the oily residue is purified by chromatography on salicagel and then dissolved in a mixture of methanol and tetrahydrofuran (3: 4), mixed with LiOHeH 2 O and the mixture is refluxed for two hours. warms. After evaporation of the solvents, the white residue is redissolved in water, extracted with dichloromethane, acidified to pH 5-6 and extracted again with ethyl acetate. The ethyl acetate extract is dried over Na 2 SO 4 , filtered and evaporated. The white solid residue is recrystallized from methanol / ether to give 12-imidazolyl-1-dodecanoic acid.
  • 12-imidazolyl-1-dodecanol and 1-imidazolyldodecane are synthesized according to a method described in Lu et al. ("Heme-coordinating analogs of lauric acid as inhibitors of fatty acid ⁇ -hydroxylation", Archives of Biochemistry and Biophysics 1997, 337: 1-7).
  • 12-bromo-1-dodecanol and imidazole are heated in a molar ratio of 1: 3 at 80 0 C for five hours.
  • the crude product is partitioned between water and dichloromethane.
  • the organic phase is dried over Na 2 SO 4 and evaporated.
  • the 12-imidazolyl-1-dodecanol is recrystallized from benzene / n-hexane.
  • 1-imidazolyldodecane is prepared from 1-bromododecane and imidazole in the molar ratio 1: 3 with stirring and heating at 85 ° C.
  • the crude product is dissolved in dichloromethane and shaken out three times with water.
  • the organic phase is dried over Na 2 SO 4 , filtered and evaporated.
  • the oily evaporation residue is crystallized from n-hexane to yield 1-imidazolyldodecane.
  • Phosphatidylcholine is reacted under acidic conditions in the presence of dicyclohexylcarbodiimide to form an O-phosphorylthiourea.
  • dicyclohexylcarbodiimide to form an O-phosphorylthiourea.
  • 12-imidazolyl-1-dodecanol which nucleophilically attacks on the phosphoryl group and forms an ester linkage therewith to form 12-imidazolyl-1-phosphatidylcholine.
  • Dicyclohexylurea precipitates.
  • 4-diethylamino-pyridine 4-diethylamino-pyridine.
  • the reaction mechanism is similar to that of Steglich esterification in which dicyclohexylcarbodiimide is used to esterify an organic acid with an alcohol.
  • the purified 3-benzyl-sn-glycerol is treated with a fatty acid, e.g. Palmitate, dissolved in carbon tetrachloride.
  • a fatty acid e.g. Palmitate
  • 4-diethylaminopyridine and dicyclohexylcarbodiimide gives rise to ester bonds between the alcohol groups of 3-benzyl-sn-glycerol and the carboxyl groups of the fatty acids, whereby dicyclohexylurea precipitates.
  • This reaction mechanism is also called "Steglich esterification".
  • 1,2-Dipalmitoyl-3-benzyl-sn-glyceride is dissolved in tetrahydrofuran and hydrogenolysed in the presence of a catalyst (10% Pd / C) with elemental hydrogen.
  • a catalyst (10% Pd / C) with elemental hydrogen.
  • the benzyl radical is substituted by a hydrogen atom, and there is 1, 2-dipalmitoyl-sn-glyceride.
  • Phosphoryl trichloride is treated with triethylamine dissolved in tetrahydrofuran and stirred in ice. Subsequently, 1, 2-dipalmitoyl-sn-glyceride dissolved in tetrahydrofuran is added dropwise. This initially produces 1, 2-dipalmi- toyl-sn-glyceride-3-phosphoryl dichloride.
  • the mixture is purified, cooled, treated with sodium carbonate and hexane and shaken.
  • the bond between the phosphate radical and the chloride is hydrolyzed.
  • the product formed is the sodium salt of 1,2-dipalmitoyl-sn-glyceride-3-phosphoryl bromoethyl ester.
  • 1-Di-dipalmitoyl-sn-glyceride-S-phosphoryl-bromoethyl ester is dissolved in a mixture of diethyl ether and distilled water containing CaCl 2 "2H 2 O.
  • the pH is adjusted to 7.5 by adding Palitzsch buffer. Subsequently, the enzyme phospholipase IK 2 is added and stirred at 35 ° C for 60 min. In this case, the ester bond is hydrolyzed at position 2 of the glycerol, and there is the corresponding 1-PalmitoyI-sn-glyceride-3-PhosphoaIkylester carrying an OH group at position 2, and a free fatty acid.
  • the resulting molecule can now be selectively esterified at position 2 of the glycerol residue with a labeled fatty acid, e.g. an imidazolated or ethinylated fatty acid.
  • a labeled fatty acid e.g. an imidazolated or ethinylated fatty acid.
  • the phosphoalkyl ester at position 3 can be reacted with a suitable alcohol, e.g. Choline, serine, ethanolamine or inositol, to be transesterified.
  • the obtained 1-palmitoyl-sn-glyceride-3-phosphoalkyl ester is dissolved in carbon tetrachloride, an imidazolated or ethynylated fatty acid is added, and the mixture is stirred.
  • the added fatty acid may be e.g. 17-octadecic acid available from Sigma Aldrich. It may also be 12-imidazolyl-1-dodecanoic acid, which can be synthesized as described under 1..
  • Step 2 a "Steglich esterification” is carried out in which 4-diethylaminopyridine and dicyclohexylcarbodiimide are added to the mixture, whereby an ester bond is formed between the remaining OH group on the glycerine residue and the carboxyl group of the labeled fatty acid.
  • the precipitated dicyclohexylurea is removed and the solvent evaporated.
  • the product obtained is a 1-palmitoyi-2-acyl-sn-glyceride-3-phosphoalkyl ester.
  • i-Palmitoyl-acyl-sn-glyceride-S-phosphoryl-bromoethyl ester is dissolved in chloroform. Subsequently, 2-propanol-trimethylamine is added. The reaction vessel is incubated at 50 0 C, then the solvent is evaporated with nitrogen. The reaction product is purified to yield a gelatinized 1-palmitoyl-acyl-sn-glyceride-S-phosphatidylcholine.
  • the labeled 1-palmitoyl-2-acyl-sn-glyceride-3-phosphatidylserine represented by the above-mentioned is incorporated into Dissolved CH 2 Cl 2 and added trifluoroacetic acid and perchloric acid. The mixture is then stirred in the cold and washed with water and methanol. After phase separation, the lower phase is extracted with Na 2 CO 3 and evaporated. Upon addition of methanol, crystals are formed which are labeled 1-palmitoyl-2-acyl-sn-glyceride-3-phosphatidylethanolamine.
  • the attached tables list some exemplary compounds of the invention. It is immediately apparent to the person skilled in the art that a multiplicity of further compounds can be subsumed under the cited claims.
  • the aliphatic radicals may be straight-chain or branched, have single, double or triple bonds and be substituted, and have an aliphatic backbone with 6 or 9 to 26 or 19 carbon atoms.
  • the hydrocarbon backbone can be formed with alicyclic and / or aromatic hydrocarbons, which may be necessary because of the ring structures up to 40 carbon atoms.
  • hydrophilic radicals are other alcohols such as inositol or ethanolamine or their glycerides.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé de formule (I) ou des sels pharmaceutiquement acceptables dudit composé, qui peuvent être utilisés pour produire une préparation pharmaceutique destinée à prévenir ou à traiter des maladies cancéreuses, des suites pathologiques de l'abus d'alcool, l'hépatite virale, la stéatohépatite, la pancréatite aiguë et chronique, les maladies rénales toxiques, l'insulinorésistance hépatique en cas de diabète sucré, les lésions hépatiques de la maladie de Wilson et/ou les sidéroses et les lésions d'ischémie-reperfusion, à servir d'antidotes contre des produits nocifs pour l'environnement et contre l'intoxication médicamenteuse, à prolonger le temps de rétention de médicaments dans l'organisme et/ou à lutter contre des effets secondaires toxiques lors de l'administration d'agents chimiothérapeutiques. Dans ladite formule, B<SUB>6</SUB>, B<SUB>7</SUB> et B<SUB>8</SUB> sont identiques ou différents et signifient O, S, NH, PO<SUB>4</SUB>, Se, SO<SUB>4</SUB>. R<SUB>1</SUB> = H ou une chaîne alkyle en C<SUB>6</SUB> ou C<SUB>7</SUB> à C<SUB>26</SUB> ou C<SUB>20</SUB> et R<SUB>2</SUB>, R<SUB>3</SUB>, R<SUB>4</SUB> et R<SUB>5</SUB> peuvent être identiques ou différents et désigner H ou un groupe alkyle en C<SUB>1</SUB>-C<SUB>3</SUB>, alcanol, alkylamine et/ou alkylthiol. R<SUB>6</SUB>, R<SUB>7</SUB> et R<SUB>8</SUB> peuvent être identiques ou différents et représenter H, un résidu alkyle en C<SUB>6</SUB> ou C<SUB>7</SUB> à C<SUB>26</SUB> substitué ou non substitué, un résidu glycoside, un résidu aminoacide chargé positivement ou négativement ou (CH<SUB>2</SUB>)<SUB>n</SUB>-N<SUP>+</SUP>(R<SUB>9</SUB>, R<SUB>10</SUB>, R<SUB>11</SUB>), R<SUB>9</SUB>, R<SUB>10</SUB>, R<SUB>11</SUB> représentant H, un résidu méthyle, éthyle et/ou propyle et au moins deux des éléments R<SUB>2</SUB>, R<SUB>3</SUB>, R<SUB>4</SUB> et R<SUB>5</SUB> pouvant former ensemble un résidu polyol et n représentant un nombre entier de 1 à 5.
EP07722324A 2006-04-28 2007-04-27 Utilisation de dérivés de glycérine substitués dans la production d'une préparation pharmaceutique Withdrawn EP2015746A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006019907A DE102006019907A1 (de) 2006-04-28 2006-04-28 Verwendung von substituierten Glycerinderivaten zur Herstellung einer pharmazeutischen Zubereitung
PCT/DE2007/000767 WO2007124733A2 (fr) 2006-04-28 2007-04-27 Utilisation de dérivés de glycérine substitués dans la production d'une préparation pharmaceutique

Publications (1)

Publication Number Publication Date
EP2015746A2 true EP2015746A2 (fr) 2009-01-21

Family

ID=38542358

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07722324A Withdrawn EP2015746A2 (fr) 2006-04-28 2007-04-27 Utilisation de dérivés de glycérine substitués dans la production d'une préparation pharmaceutique

Country Status (4)

Country Link
US (1) US20100028417A1 (fr)
EP (1) EP2015746A2 (fr)
DE (2) DE102006019907A1 (fr)
WO (1) WO2007124733A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007051338A1 (de) 2007-10-26 2009-04-30 Müller-Enoch, Dieter, Prof. Dr. Verwendung von substituierten Glycerinderivaten zur Herstellung einer pharmazeutischen Zubereitung zur Behandlung und zur Vorbeugung von Dyslipidämien
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
CN105541727B (zh) * 2016-01-15 2018-01-30 徐州医学院 一种具放疗增敏功能的脂质分子、其制备方法及其在肿瘤放射治疗药物中的应用

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL84387A0 (en) * 1987-11-06 1990-02-09 Rapaport Erich Pharmaceutical compositions containing a substituted phosphatide
DE4408011C1 (de) * 1994-03-10 1995-11-02 Max Delbrueck Centrum Pharmazeutisches Mittel zur Tumortherapie
US5534499A (en) * 1994-05-19 1996-07-09 The University Of British Columbia Lipophilic drug derivatives for use in liposomes
ES2153053T3 (es) * 1994-10-14 2001-02-16 Liposome Co Inc Liposomas de eter-lipido y su uso terapeutico.
US6121245A (en) * 1997-01-29 2000-09-19 Firshein; Richard N. Method of treating cancer using alkylglycerols in conjunction with chemotherapy
DE19822509A1 (de) * 1998-05-19 1999-11-25 Medmark Pharma Gmbh Edelfosin zur Behandlung von Hirntumoren
DE19829448A1 (de) * 1998-07-01 2000-10-12 Medmark Pharma Gmbh 1-Octadecyl-2-methyl-sn-glycero-3-phosphocholin (ET180CH3) zur Behandlung von humanen Mammakarzinomen
IL127143A0 (en) * 1998-11-19 1999-09-22 Dpharm Ltd Phospholipid terivatives of non-steroidal anti inflammatory drugs
IL131887A0 (en) * 1999-09-14 2001-03-19 Dpharm Ltd Phospholipid prodrugs of anti-proliferative drugs
FR2828487B1 (fr) * 2001-08-09 2005-05-27 Genfit S A Nouveaux composes derives d'acides gras, preparation et utilisations
WO2004062593A2 (fr) * 2003-01-09 2004-07-29 Zeneus Pharma Limited Composes d'ether lipidique antineoplasiques presentant des modifications au niveau du groupe carbone sn-2
WO2004062595A2 (fr) * 2003-01-09 2004-07-29 Zeneus Pharma Limited Composes d'ether lipidique antineoplasiques presentant des modifications au niveau du groupe carbone sn-1
FR2850650B1 (fr) * 2003-01-31 2005-03-25 Genfit S A Utilisation therapeutique d'acylglycerols et de leurs analogues azotes et sulfures
DE102004052697A1 (de) * 2004-10-29 2006-05-04 Haehner, Thomas, Dr. Pharmazeutische Zubereitungen zur Behandlung von Folgen des Alkoholmissbrauchs, Hepatitis, Pankreatitis, Alzheimererkrankung, Morbus Parkinson, Diabetes, toxischen Nierenerkrankungen, Reperfusionsschäden, der Arteriosklerose sowie als Antidote gegen Umweltgifte und Medikamentenintoxikation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007124733A2 *

Also Published As

Publication number Publication date
US20100028417A1 (en) 2010-02-04
DE102006019907A1 (de) 2007-10-31
WO2007124733A2 (fr) 2007-11-08
WO2007124733A3 (fr) 2008-01-24
DE112007001613A5 (de) 2009-04-09

Similar Documents

Publication Publication Date Title
EP2023911A2 (fr) Utilisation de composés de formule a-r-x ou de sels pharmaceutiquement acceptables desdits composés dans la production d&#39;une préparation pharmaceutique
EP2205072A1 (fr) Procédés de traitement de différentes maladies et affections, et composés utilisés
DE60118198T2 (de) Fettsäure-analoge zur behandlung von krebs
JP5640019B2 (ja) 糖尿病及び肥満症を治療するためのプテロシン化合物の使用
DE60224276T2 (de) Krebsmetastasen-hemmer mit carbacyclischen phosphatidinsäurederivaten
JP2025071293A (ja) ミトコンドリア障害を処置するための方法
CA2896073C (fr) Stimulation et augmentation de la regeneration de tissus
EP2015746A2 (fr) Utilisation de dérivés de glycérine substitués dans la production d&#39;une préparation pharmaceutique
DE69907720T2 (de) Phospholipid-derivate von nichtsteroiden entzündungshemmenden medikamenten
EP1814533A2 (fr) Traitement des consequences de l&#39;abus d&#39;alcool, de l&#39;hepatite, de la pancreatite
EP1909800B1 (fr) Acylglycerophospholipides pour traiter des troubles associes au cancer
RU2528898C1 (ru) Гепатопротекторное средство из морских водорослей
DE102007051338A1 (de) Verwendung von substituierten Glycerinderivaten zur Herstellung einer pharmazeutischen Zubereitung zur Behandlung und zur Vorbeugung von Dyslipidämien
DE19547827A1 (de) Verfahren zur Herstellung glykosidierter Phospholipide, besonders glucosidiertes Lecithin, und dessen proliferationshemmende Wirkung epithelialer Zellen, besonders der Keratinocyten
HK1134902B (zh) 用於制备药物制剂的化合物a-r-x

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20081128

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: HAEHNER, THOMAS

Owner name: UNIVERSITAET ULM

RIN1 Information on inventor provided before grant (corrected)

Inventor name: HAEHNER, THOMAS

Inventor name: MUELLER-ENOCH, DIETER

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20100525