EP1913012A2 - Oligomere de cholesterol, sulfate de cholesterol et esters de cholesterol, et medicaments renfermant ces composes - Google Patents

Oligomere de cholesterol, sulfate de cholesterol et esters de cholesterol, et medicaments renfermant ces composes

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Publication number
EP1913012A2
EP1913012A2 EP06762523A EP06762523A EP1913012A2 EP 1913012 A2 EP1913012 A2 EP 1913012A2 EP 06762523 A EP06762523 A EP 06762523A EP 06762523 A EP06762523 A EP 06762523A EP 1913012 A2 EP1913012 A2 EP 1913012A2
Authority
EP
European Patent Office
Prior art keywords
cholesterol
spacer
oligomers
lipid
sulfate
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.)
Ceased
Application number
EP06762523A
Other languages
German (de)
English (en)
Inventor
Hans-Uwe Wolf
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.)
PLT Patent and License Trading Ltd
Original Assignee
PLT Patent and License Trading Ltd
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 PLT Patent and License Trading Ltd filed Critical PLT Patent and License Trading Ltd
Publication of EP1913012A2 publication Critical patent/EP1913012A2/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the invention relates to new substances derived from cholesterol, cholesterol sulfate and cholesterol esters of natural, semi-synthetic or synthetic origin in that they are oligomers with a specific way of linking the cholesterol-based starting materials.
  • lipids and lipid-analogous substances which have structurally different structures, but which are similar in their basic construction.
  • the basic similarity of the structure is that they are composed of a hydrophobic and a hydrophilic portion.
  • the hydrophobic molecular region consists of the ring system of the cyclopentanoperhydrophenanthene with the 1, 5-dimethylhexyl radical in position 17, while the hydrophilic molecule Molecular region is essentially a standing in position 3 hydroxyl group. Cholesterol is thus in the broadest sense of the lipid-analogous substances. The same applies analogously to the compounds derived therefrom cholesterol sulfate and cholesterol esters.
  • the amphiphilic structure of the lipid-analogous substances ie the simultaneous presence of a (strongly) hydrophobic and a hydrophilic, polar portion of the molecular structure, causes the lipid-analogous substances in an aqueous phase together with lipids to spontaneously become a lipid -Doppel für, a so-called "lipid bilayer” arrange, which among other things forms the basis of the structure of biological membranes.
  • the construction principle of this bilayer is the same for all lipids and lipid-analogous substances: they are arranged in two parallel, closely spaced layers, with the hydrophobic residues of the molecules in question directly opposite each other and coming into contact.
  • the structure of the lipid bilayer is spontaneously formed in an organism and has considerable stability, e.g. in the presence of a lipid-metabolic disorder, the possibility that a biological membrane may be part of its lipid
  • Skin changes and skin diseases are based on changes in the lipid composition of the stratum corneum layer in human skin. These changes in the sense of lipid loss lead to a more or less reduced water-binding capacity of the affected skin areas. Skin changes and skin diseases of this kind are, for example:
  • the structure of the present in the organism biological membrane i. e. the lipid bilayers to suitably alter and / or stabilize.
  • biological membranes are very many cells from a lipid bilayer . built, which is an effective barrier to the
  • This skin structure consists of several layers of keratinized corneocytes embedded in a lipid matrix of a highly ordered lamellar structure. These lipid bilayers essentially contain cholesterol as well as ceramides and fatty acids such as palmitic acid.
  • the physiological composition of the membrane lipids of the stratum corneum of human skin is however, for a second reason, the normal structure and function of the skin is of vital importance. The presence of sufficient levels of these lipids assures the unrestricted ability of the skin to bind a physiological amount of water. The loss of part of the stratum corneum lipids therefore leads to a restriction of the water-binding capacity, which manifests itself in the so-called transepidermal water loss of the skin. The consequence of this is the appearance of "dry" and wrinkled skin, which is frequently, but not exclusively, observed in older age.
  • the therapeutic measures outlined here can certainly be regarded as fundamentally correct, since they logically try to compensate for the existing deficiencies of the stratum corneum on lipids and lipid-analogous substances.
  • the experience gained during the past few years with these therapeutic measures shows that despite the fact that the therapeutic approach is in principle correct, the results of these curative treatments are by no means convincing.
  • the success of the measures carried out is uncertain. Even if a nearly acceptable success of the curative treatment sets in, such a curative treatment has at least two serious disadvantages:
  • lipids or lipid-analogous substances are not static but dynamic components of the skin. This means that they balance membrane components with the non-membrane-bound lipid pool of the organism. In this dynamic equilibrium, the individual lipid components can be quickly exchanged.
  • the lipid pool itself, they are intermediates of a reaction sequence in which the lipids required by the skin, e.g. are made available from dietary fats (triglycerides) or other nutritional constituents and are subsequently introduced into the fatty acid metabolism after their function as a membrane component of the stratum corneum. This is also true in principle for the cholesterol.
  • This reaction sequence represents a flow equilibrium in which a certain amount of said components is metabolically altered by the action of certain enzymes from stage to stage. There is thus a certain throughput of substance.
  • the exogenously supplied as Hauttherapeutica lipids are introduced into this reaction sequence. If there is a priori disturbance of such a reaction sequence, which then leads to a pathological lipid composition of the stratum corneum, it is to be expected that the exogenous supply of lipids in the form of a therapeutic agent can fundamentally change nothing or not at all in this pathological condition, since the exogenously supplied lipid component is further processed by the organism in the same way as is the case with the endogenous lipid content provided.
  • the present problem is not easily solved.
  • the rate of uptake of lipids and lipid-analogous substances into the stratum corneum is subject to certain physiological and physico-chemical or biochemical limits, eg. B. in terms of the rate of diffusion of the therapeutic agents supplied as active ingredients. This speed can not, at least according to current knowledge, be increased to the extent necessary for a lasting success in healing.
  • Synthesizing and metabolizing enzymes are involved in the above-mentioned reaction sequences of the lipid assembly and degradation, which function as the function of the
  • the object of the present invention is therefore to provide compounds by which biological membranes present in the organism can be suitably modified or stabilized.
  • the compounds proposed by the invention thus consist of oligomers of cholesterol, cholesterol sulfate and cholesterol esters.
  • Oligomers in the context of the invention are understood to mean the linking of two to twelve monomers. Particularly preferred here are dimers, tetramers, hexamers and octamers.
  • oligomers is used even if these compounds are not only the combination of several molecules, but also if they are connected by molecular bridges in the form of different spacers.
  • the building blocks of the oligomers according to the invention preferably consist of the naturally occurring cholesterol, the cholesterol sulfate and chlorine. lesterolestern.
  • the compounds of the invention must meet the following requirements:
  • Oligomerization must occur with formation of only covalent bonds between the individual cholesterol species.
  • the structure of the lipids or lipid-analogous substances used should be modified so far that they can only function to a lesser extent as substrates of the enzymes present in the skin.
  • Variant 1 ie the tail-to-tail arrangement, Siert on the linkage preferably the respective ⁇ -standing carbon atoms of the fatty acid residues of the two molecules to be joined together, for example by means of a spacer.
  • a spacer can be termed an "intradimeric" spacer because two or more monomers are linked together to form a dimer, since this spacer is arranged inside the membrane when the dimer is incorporated into the biological membrane, but is preferably referred to as an "intramembrane" spacer , The terms intradimeric and intra-membranous are therefore to be equated with their meaning.
  • FIG. 2 shows the type of linkage and the similarity of the dimerization product with the physiological structure of the lipid double membrane using the example of two cholesterol molecules (see FIG. 1).
  • the tail-to-tail arrangement represents the immediate imitation of the stable arrangement of fatty acids naturally present in the biological membranes, as can be seen by comparison with the arrangement of the components in FIG.
  • the tail-to-tail dimer is one of two possible basic structures for the entirety of all others here. to write written cholesterol oligomers.
  • the dimerization of the cholesterol thus leads to molecules which not only fit into the structure of a lipid double membrane without problems, but also by virtue of the presence of a covalent bond between the ⁇ -standing C atoms of 1, 5-dimethylhexyl residues of two opposing cholesterol molecules contribute to a considerable structural stabilization of the lipid double membrane.
  • Variant 2 i.e. the head-to-head dimer has a structure that does not allow integration of the molecule into a single lipid bilayer, because the hydrophilic region of this dimeric molecule would be in the hydrophobic interior of the membrane bilayer, which is a highly unstable structure would therefore not be formed spontaneously.
  • the head-to-head dimers have a biological or medicinal significance in that the two cholesterol molecules linked in this way can be anchored in two parallel lipid bilayers, each of the two cholesterol monomers each half of the two parallel lipid bilayers is located. Such closely spaced lipid bilayers come e.g. in the medullary sheath of nerve cells.
  • the principle of the same structure results from linking the two cholesterol-derived molecule variants cholesterol sulfate and cholesterol ester.
  • cholesterol sulfate e.g. each esterified the free acid function of the sulfate with an alcoholic OH group provided on the spacer.
  • covalent attachment to the alkyl group of the ester is achieved by e.g. the ⁇ -standing OH groups of the ester alkyl groups are linked by water leakage to an ether bond.
  • the two dimers are each of the monomers in the tail-to-tail arrangement by linking with HiI Fe constructed of the above-mentioned intramembrane spacer.
  • the linking of the two dimers takes place in the head-to-head arrangement via a further spacer, which can be referred to as an interdimeric spacer, because it is arranged between two preformed dimers.
  • an extramembrane spacer since it is outside the two membranes after integration of the whole molecule, it is more advantageously referred to as an extramembrane spacer.
  • the two terms interdimer and extramembrane therefore have in their sense a practically identical meaning.
  • the extramembrane spacer must have a hydrophilic structure because of its location outside the membrane, that is, in the hydrophilic extramembrane region of the cell.
  • the linking of the cholesterol molecules can take place in the "tail-to-tail” arrangement in each case via the hydrophobic 1, 5-dimethylhexyl radical, preferably via its ⁇ -containing carbon atom, wherein the compound is produced by a covalent bond becomes.
  • a second possibility is that instead of a covalent bond an intramembrane spacer with freely selectable molecular chain length is used.
  • the intramembrane spacer consists of at least one carbon atom and / or at least one heteroatom such. As oxygen or nitrogen.
  • Preferred chain lengths of the intramembrane spacer are 1-4 atoms. Even when linking the cholesterol molecules via the "head-to-head” arrangement, this can take place via the hydrophilic structural portion through a covalent bond.
  • the "head-to-head” linkage it is provided according to the invention as an alternative to use an extramembrane spacer with a freely selectable molecular chain length and composition.
  • an extramembrane spacer it is preferred that this is predominantly hydrophilic.
  • Suitable structural components for such a hydrophilic spacer are glycerol, amino acids and / or carbohydrate components such as monosaccharides, disaccharides, oligosaccharides, etc.
  • Variant 3 of the lipid dimerization has virtually no biological or medical significance, since a molecule of this structure can not be integrated in any way into one or two biological lipid bilayers arranged in parallel. In all cases, at least partially hydrophilic structural components would have to be integrated into hydrophobic regions of the membranes, which would be known to lead to very unstable structures, which for this reason can not spontaneously form.
  • the invention furthermore comprises the possibility of preparing hybrid dimers of cholesterol + cholesterol sulfate, cholesterol + cholesterol esters or cholesterol sulfate + cholesterol esters according to claims 1 and 2 and to use them for therapeutic purposes in the manner described below.
  • dimerization, and in particular especially the oligomerization of the cholesterol molecule and the cholesterol compounds results in such a dimer or oligomer being degraded or rebuilt much more slowly by the enzymes of the cholesterol metabolism present in the skin, as this is true for the monomeric Cholesterolstayn.
  • the enlargement of the molecule associated with the dimerization leads to a marked reduction in the enzymatically controlled metabolization because, given the well-known substrate specificity of most enzymes, the size change of a substrate by a factor of at least 2 significantly reduces the rate of substrate turnover.
  • the resulting degradation products of their general structure are so similar to the naturally occurring cholesterol variants that it is possible to introduce these compounds into the corresponding reaction sequences without problems.
  • a certain degree of physiological degradability of the cholesterol dimers and oligomers which, however, is considered to be significantly lower than that of the monomeric cholesterol molecules, is thus desirable for pharmacokinetic and pharmacological reasons Property of the molecule according to the invention, because in this way the controllability of the therapy is better ensured than if no further metabolic degradation would be possible.
  • this spacer of at least one heteroatom such.
  • oxygen or nitrogen optionally in combination with a few carbon atoms exist.
  • Preferred chain lengths of the intramembrane spacer are 1-4 atoms.
  • the carbon atoms in the immediate vicinity of the bridge oxygen atom are now particularly sensitive to hydroxylation, for example by the cytochrome P 450- dependent mixed-functional monooxygenases.
  • hydroxylation occurring in the immediate vicinity of the O atom results in the formation of unstable compounds having a hemiacetal structure which decompose into the corresponding reaction products.
  • the reaction product with ⁇ -containing OH group is identical to the starting product 27-hydroxycholesterol.
  • 27-hydroxycholesterol is suspected of having an atherogenic effect.
  • such an undesirable effect will be of practically no importance since, due to the low metabolic degradation of the cholesterol oligomers, only such an amount of 27-hydroxycholesterol is liberated which is negligibly small compared to the total amount present in the organism.
  • the other reaction product is a cholesterol with ⁇ -standing aldehyde function, which is further oxidized to the carboxylic acid group.
  • the resulting dimeric cholesterol molecule should have a longer chain than that If the sum of the chain lengths of the monomeric molecules is equal, a longer intramembrane spacer can be incorporated between the two cholesterol molecules. This is e.g. achieved by the use of glycols, in the simplest case of ethylene glycol, for the bridging of 27-hydroxy-cholesterol. In this case, a reaction product containing two oxygen atoms in the total chain is formed:
  • the total molecule is thus compared to the sum of the two monomeric molecules practically the length of the grown intramembrane spacer -0-CH 2 -CH 2 -O-.
  • the two oxygen atoms present in this chain owing to the oxidizability of the carbon atoms adjacent to the O atoms, a readily controllable rate of degradation of the total molecule can be achieved.
  • Dimers can be linked. This can again take place analogously to the reactions described above, by forming a bridge oxygen atom or by inserting an intradimimer spacer described above.
  • An essential aspect of the pathogenesis of the abovementioned skin lesions or skin diseases is the reduced water-binding capacity of the skin tissue, in particular in the region of the stratum corneum.
  • the water is not incorporated within, but, since there are several lipid layers arranged in parallel, between the individual lipid bilayers. This is due to the fact that the interior of the lipid bilayer is composed of highly hydrophobic molecular fractions, for example of fatty acid residues and the predominant portion of the cholesterol molecule (or the cholesterol analogs) incl. the 1, 5-dimethylhexyl radical, while the medium outside the lipid bilayer hydrophilic nature. Storage of water in the hydrophobic inner regions of the lipid double membrane is practically impossible.
  • the skin changes and diseases mentioned above are ultimately due to the loss of a portion of the parallel lipid bilayers and the hydrophilic interlayers sandwiched between these bilayers, leading in particular to a loss of water binding capability.
  • the aim of the therapeutic measures in these diseases is thus not only the reconstruction and stabilization of the lipid bilayers themselves, as is done with the help of the above-described dimer of cholesterol and its analogs, but also the structure and stabilization of the multilamellar lipid structures with the intermediate hydrophilic intermediate layers, the ultimately of crucial importance to the water-binding capacity of the skin.
  • This goal is achieved by covalently linking at least two of the aforementioned dimers of cholesterol or its analogs.
  • dimeric cholesterol molecules by creating a covalent bond in the hydrophobic region of the cholesterol, i. e.
  • the covalent bonding of two dimers of the cholesterol or its analogues takes place according to another principle:
  • Acid function of the sulfuric acid coupled to the cholesterol is the sulfuric acid coupled to the cholesterol.
  • Dimeric cholesterol esters can also be built up by esterification of two cholesterol molecules with a dicarboxylic acid.
  • urea derivative as a structural element of the extramembrane d spacer. This is e.g. by the use of two molecules of an amino dicarboxylic acid, e.g. Glutamic acid possible. This results in a relatively long spacer with a strong hydrophilic nature, the u. a. given by the presence of the two negatively charged carboxyl groups:
  • urea-analogous structure is therefore of particular interest because urea has a very high water binding capacity, which is already used today in the form of urea-containing ointments for the treatment of such skin diseases in which drying out of the skin is an essential Disease feature (eg in dyshidrotic eczema).
  • spacer structures and the length of the usable extramembrane spacers are virtually unlimited.
  • the structure as well as the chain length can be adapted to the special therapy requirements in wide ranges as needed. It is possible u. a. also the incorporation of certain monosaccharides such as e.g. glucose, which in turn leads to derivatives of physiological substances.
  • the oligomeric molecules with 4-12 monomers (or 2-6 dimers), especially tetramers, hexamers or octamers have a greater ability to alter the structure of the parallel lipid
  • These compounds lead to the formation of 2 parallel bilayers in the case of tetramers, of 3 parallel bilayers in the case of hexameric groups, and of 4 parallel bilayers in the case of octamers , etc., with an increased tendency to embed water and hydrophilic molecules of various sizes in the spaces between the parallel lipid bilayers.
  • Oligomeric cholesterol molecules with an odd number of monomers in the simplest case a trimeric molecule of cholesterol or cholesterol analogs with an intramembrane and an extra-membranous spacer, can also be used for the purposes mentioned here, although they are not have the optimal properties for integration into the existing lipid bilayers.
  • the two molecules linked via an intramembrane spacer would optimally integrate into a lipid bilayer, while the additional molecule connected via an extramembrane spacer would only project into one half of the next lipid bilayer.
  • a special case is a dimeric molecule of cholesterol or cholesterol analogs, which is connected via an extramembrane spacer (according to the above-mentioned variant 2 of the linkage in the Dirne- rization). It is also true for this molecule that it can be used for the purposes mentioned here, even if it has less of the optimal properties for integration into the existing lipid bilayer. In this case, both existing molecules of cholesterol or cholesterol analogues protrude into only one half of the respective adjacent lipid bilayers.
  • hybrid forms are also possible when the dimeric and oligomeric molecules are built up.
  • a dimer for example, this is a molecule composed of a cholesterol monomer and a cholesterol sulfate monomer.
  • Further possible combinations are: cholesterol monomer + cholesterol ester monomer and cholesterol sulfate monomer + cholesterol ester monomer.
  • hybrid oligomers This combination of all three cholesterol components makes it possible to produce preparations for the treatment of skin diseases, the optimal desired proportions or relations of the three components cholesterol
  • a composition can be based, for example, on the physiological composition of the healthy skin on the three monomers mentioned (Hatfeld RM and Fung LW (1999): Biochemistry 38 (2): 784-791)).
  • FIGS. These are not intended to limit the present invention to the embodiments shown herein.
  • Fig. 1 shows the arrangement of cholesterol molecules in a typical stable structure of the lipid bilayer of biological membranes. The one in position 17 of the
  • Cholesterol molecule standing, highly hydrophobic 1, 5-dimethylhexyl radical is directed into the interior of the double layer, while the hydrophilic, in position 3 standing hydroxyl group is directed to the outside.
  • FIG. 2 shows a coupling according to the invention of two cholesterol molecules to form a dimer with formation of a covalent bond (FIG. 2a) and by linking with an intra-membranal spacer, represented by a rectangle with diagonals (FIG. 2b).
  • FIG. 3 shows a schematic representation of the structure of a "head-to-head” cholesterol dimer according to the invention by linking with an extramembrane spacer, represented by a long, empty rectangle.
  • the dimer is anchored with one monomer in each half of two parallel lipid bilayers. Only one half of each is shown two adjacent double membranes.
  • FIG. 4 shows, in a schematic representation, the arrangement of tetrameric cholesterol molecules according to the invention which are used as connecting
  • Dimers located inside the membrane contain an intramembrane spacer (rectangle with diagonals). The two dimers are themselves linked via an extramembrane spacer (open rectangle), which is located in the hydrophilic • space between the two membranes.
  • hexamers according to the invention can likewise be incorporated into three mutually separate, parallel-arranged lipid membranes, octamers in four lipid membranes, etc.
  • Cholesterol oligomers of the type described can be used in medicine for therapeutic purposes wherever the natural structure of biological membranes is disturbed by pathological processes and by the use of these oligomeric compounds a stabilization of the membrane structure and / or a change in membrane properties in terms of a therapeutic goal (eg to increase the membrane stability, increase the water binding capacity, etc.) to be achieved.
  • a change in the lipid composition of nerve cells occurs in a large number of different pathological lesions of nerve cells. These include u. a. neuronopathy, axonopathy and myelinopathy.
  • membranes of the myelin sheaths are preferably dimers of cholesterol with relatively short hydrophobic intramembrane spacers between the monomers and oligomers with relatively short hydrophilic extramembrane spacers.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne de nouvelles substances dérivant du cholestérol, du sulfate de cholestérol et d'esters de cholestérol d'origine naturelle, semi-synthétique ou synthétique, de sorte qu'elles représentent des oligomères d'un type spécifique de liaison des substances de départ à base de cholestérol.
EP06762523A 2005-07-11 2006-07-11 Oligomere de cholesterol, sulfate de cholesterol et esters de cholesterol, et medicaments renfermant ces composes Ceased EP1913012A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005032268A DE102005032268A1 (de) 2005-07-11 2005-07-11 Oligomere von Cholesterol und dessen Derivaten sowie diese enthaltende Arzneimittel
PCT/EP2006/006772 WO2007006549A2 (fr) 2005-07-11 2006-07-11 Oligomere de cholesterol, sulfate de cholesterol et esters de cholesterol, et medicaments renfermant ces composes

Publications (1)

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EP1913012A2 true EP1913012A2 (fr) 2008-04-23

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EP06762523A Ceased EP1913012A2 (fr) 2005-07-11 2006-07-11 Oligomere de cholesterol, sulfate de cholesterol et esters de cholesterol, et medicaments renfermant ces composes

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US (1) US8318961B2 (fr)
EP (1) EP1913012A2 (fr)
DE (1) DE102005032268A1 (fr)
WO (1) WO2007006549A2 (fr)

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Publication number Priority date Publication date Assignee Title
EP2292588A1 (fr) * 2009-06-23 2011-03-09 Hans Uwe Wolf Dimères céramides et leur utilisation en tant que médicament ou préparation cosmétique
EP2266950A1 (fr) 2009-06-23 2010-12-29 Hans Uwe Wolf Dimères céramides et leur utilisation en tant que médicament ou préparation cosmétique

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US2520980A (en) * 1945-10-30 1950-09-05 Nat Chemical Products Pty Ltd Cosmetic creams
JP2831800B2 (ja) * 1990-02-23 1998-12-02 日本エマルジョン株式會社 油溶性ｎ―長鎖アシル酸性アミノ酸エステル、その混合物及びこれらを含む香粧品
JPH05286844A (ja) * 1992-04-09 1993-11-02 Ajinomoto Co Inc 油性基剤組成物およびそれを含有する皮膚外用剤
JPH05320188A (ja) * 1992-05-21 1993-12-03 Kao Corp 新規ステリン誘導体
JP3010968B2 (ja) * 1993-03-31 2000-02-21 サンスター株式会社 保湿用乳化化粧料
JPH07238009A (ja) * 1994-02-24 1995-09-12 Kao Corp 皮膚保護化粧料
US6323191B1 (en) * 1998-06-19 2001-11-27 Genzyme Corporation Small molecule chloride transport
JP3802288B2 (ja) * 1999-04-16 2006-07-26 味の素株式会社 油性原料組成物
CN100436475C (zh) * 2005-12-31 2008-11-26 中山大学 胆甾-5-烯-3β-羟基-24-酮及其衍生物的合成方法

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Title
See references of WO2007006549A2 *

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US20090105199A1 (en) 2009-04-23
WO2007006549A3 (fr) 2007-03-29
DE102005032268A1 (de) 2007-01-18
WO2007006549A2 (fr) 2007-01-18
US8318961B2 (en) 2012-11-27

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