EP1646627A1 - Compositions chimiques contenant du tocopherol et au moins une autre substance pharmaceutique active - Google Patents

Compositions chimiques contenant du tocopherol et au moins une autre substance pharmaceutique active

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Publication number
EP1646627A1
EP1646627A1 EP04737365A EP04737365A EP1646627A1 EP 1646627 A1 EP1646627 A1 EP 1646627A1 EP 04737365 A EP04737365 A EP 04737365A EP 04737365 A EP04737365 A EP 04737365A EP 1646627 A1 EP1646627 A1 EP 1646627A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
radical
aryl
spacer
het
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
EP04737365A
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German (de)
English (en)
Inventor
Manfred Windisch
Barbara Matuszczak
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.)
JSW-Research Forschungslabor GmbH
JSW Research Forschungslabor GmbH
Original Assignee
JSW-Research Forschungslabor GmbH
JSW Research Forschungslabor GmbH
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 JSW-Research Forschungslabor GmbH, JSW Research Forschungslabor GmbH filed Critical JSW-Research Forschungslabor GmbH
Publication of EP1646627A1 publication Critical patent/EP1646627A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • the invention relates to chemical compounds containing tocopherol and at least one other pharmaceutical
  • Medicament or prodrug tocopherol has the effect of an antioxidant, whereas the other pharmaceutical active ingredient is preferably a non-steroidal anti-inflammatory drug (NSAID) which is linked to tocopherol directly or via a spacer.
  • NSAID non-steroidal anti-inflammatory drug
  • This "chemically fixed combination of two active pharmaceutical ingredients” leads to more effective and better contractual derivatives.
  • the compounds claimed here are released by metabolic processes such as enzymatically catalyzed ester hydrolysis, the pharmaceutical active ingredient and tocopherol, which can then develop their known effects.
  • the increase in efficacy results from the optimization of the physicochemical parameters and the resulting improved absorption and absorption of the active substances by the central nervous system (CNS).
  • the improved tolerability is mainly due to the reduction of possible local toxic effects, such as the reduction of locally caused toxic effects of the NSAID component in the gastrointestinal tract by masking the carboxylic acid function, as well as the reduction of the active ingredient concentration in the periphery by increased absorption of the compounds in the CNS attributed.
  • the invention further relates to a method for producing the aforementioned chemical compounds and their use as drugs or prodrugs for the treatment or prophylaxis of degenerative diseases of the central nervous system, such as Alzheimer's disease, Lewy body dementia, Parkinson's disease, Huntington's disease (chorea).
  • the digestive system the blood vessel system, such as leukemia, hamoglinopathy, the connective tissue, such as
  • Rheumatism the eyes, as with lens opacification, are the subject of the invention.
  • the chemical compounds according to the invention are expressly suitable for the production of medicaments for the
  • Inflammatory processes play an important role in the neurodegenerative diseases mentioned in several respects. In previous work it was postulated that inflammatory processes in the brain only occur if the blood-brain barrier is damaged. However, it was later demonstrated that the brain can initiate and maintain its own inflammatory processes. It is now known that inflammation processes, particularly in the case of Alzheimer's disease, are very significantly involved in the beginning and progress of the disease. This has been proven by a number of epidemiological studies (McGeer, 1992, Akiyama 2000).
  • ß-amyloid plaques are necessary but not sufficient to trigger and advance Alzheimer's disease. Inflammation reactions are a highly probable complementary factor that is also necessary for the development of the clinical picture (Rogers et al. 1995). It is interesting that the toxicity of ß-amyloid increases up to a thousandfold after activation of complement proteins found in the brain (Shalit et al. 1994). Aggregated ß-amyloid is much more toxic than - more easily soluble - non-aggregated. It could be demonstrated in vitro that the complement protein Clq increases the aggregation of ⁇ -amyloid (Webster et al. 1994).
  • ß-amyloid activates Clq (Jiang et al. 1994).
  • Tau pathology which plays an essential role in addition to ß-amyloid in neurodegeneration, is closely related to inflammatory processes and the activation of the complement system (Shen et al. 2001).
  • pro-inflammatory cytokines such as interleukin 1, tumor necrosis factor alpha, are released from various cell types in response to appropriate stimuli (which include lipopolysaccharide, as well as various forms of cell stress).
  • the invention therefore also relates to the use of the chemical compounds according to the invention for the production of
  • Oxidative stress is a particularly important one in neurodegenerative diseases, both in the initial stage and later
  • Central nervous system appear to be particularly at risk in terms of damage caused by radicals:
  • the brain uses a lot of oxygen compared to other body regions. Expressed in numbers, this means a share of 20% of the total 0 2 requirement with only a 2% share of body weight.
  • the result is a particularly large potential for the formation of radicals.
  • proteins Markesbery and Carney 1999
  • lipids Stemcells e.g., IL-12, IL-12
  • Mc Kracken et al. 2001 nuclear and mitochondrial DNA
  • RNA Nunomura et al.
  • ROS radical oxygen compounds
  • Oxidative stress therefore plays an important role in the damage caused by stroke, both in the first few hours and over longer-lasting reaction products even days later. Measurements of the 8-hydroxyguanosine (80HG) content have shown that increased oxidative stress is very early A characteristic of Alzheimer's disease is (Nunomura et al. 2001).
  • ⁇ -Synuclein which is also a protein that tends to aggregate and is at the heart of the pathology of Parkinson's disease, also increases oxidative stress. Even in vivo and in vitro studies, some of which are not directly related to ⁇ -synuclein, show that oxidative stress is an early and very striking, detectable parameter in the development of Parkinson's disease (Migliore et al. 2002, Munch et al. 2000, Roghani and Behzadi 2001).
  • oxidative stress can lead to arrhythmias, myocardial infarction, arteriosclerosis, pneumonia, cerebral edema, hamorrhagic and non-hamorrhagic infarcts, such as stroke, diseases of the gastric mucosa, pancreas, cirrhosis, leukemia, sepsis, hemoglobinopathy, various forms Diabetes, stress reactions, diseases of the excretory system, such as inflammation of the kidneys, kidney failure, diseases of the supporting apparatus, such as rheumatism, of the sensory organs, such as lens clouding, lead, or make a significant contribution to the development of the disease or influence the course of recovery.
  • NSAIDs non steroidal anti-inflammatory drugs
  • Duodenal ulcers are NSAIDs.
  • the bleeding that occurs can be life-threatening. This fact is a major problem since in the case of neurodegenerative
  • NSAIDs such as ibuprofen
  • ibuprofen occupy prominent positions in drug side effects statistics. According to a report in the New England Journal of Medicme, 16,000 people die each year from the side effects of NSAIDs in the United States (Wolfe et al. 1999). As can be proven by literature, the toxicity of some ibuprofen derivatives is significantly lower than that of ibuprofen (Lolli et al. 2001).
  • the use of NSAIDs is a very interesting and realistic possibility for the treatment of degenerative diseases of the central nervous system. As already mentioned, antioxidant substances such as vitamin E and others also represent a promising approach.
  • derivatives according to the invention were also shown with a spacer between the active ingredient groups and thus a three-component prodrug.
  • the spacer cannot only absorption and CNS movement, but also the extent and speed of hydrolysis are modified.
  • the invention relates to chemical compounds of general structure I as racemates, enantiomers and diastereomers and in the form of their physiologically acceptable
  • Salts and solvates in particular hydrates and addition compounds with alcohols. These compounds are characterized in that they contain an active pharmaceutical ingredient “R-A” and
  • the radical R denotes the unchanged part of the variable pharmaceutical active substance molecule.
  • R symbolizes in particular the acyl residues of the NSAID, such as acetylsalicylic acid, diclofenacid, ibuprofen, indomethacin, ketoprofen, mefenammic acid, naproxen and derivatives thereof, in particular reduction products of indomethacm, the CON substructure being formally replaced by -CH 2 Noprofen and Ketoprofen the keto-carbonyl group is formally replaced by -CH (OH) - or by -CH 2 -.
  • the abbreviation Toc denotes a tocopheryl radical, in which R ', R''andR''' mean H or methyl.
  • Toc denotes a tocopheryl radical, in which R ', R''andR''' mean H or methyl.
  • the invention comprises the chemical compounds of the general formula I with regard to all possible racemates, enantiomers and diastereomers. If an acidic or basic partial structure is present in the compounds of the formula I (for example derivatives of mefenamic acid or diclofenic acid), their physiologically acceptable salts are also the subject of this invention. Furthermore, the invention also includes solvates, in particular hydrates and alcohol addition compounds, of the compounds I and their physiologically acceptable salts.
  • n 0, 1, 2, 3, 4, 5 or 6 and is preferably 0,1, 2 or 3
  • m is 1 or 2 (preferably)
  • R 1 is H, C ⁇ -C ⁇ 0 alkyl (preferably C 1 -C 6 alkyl), aryl, Het or an aryl or Het radical bonded via a C 6 spacer (preferably C1-C 3 ).
  • R 2 stands for an alkylene, arylene or het spacer or combinations thereof, these either directly or via the function previously defined as A or via the
  • Grouping X 0 -AX p are linked together.
  • the spacers are to be defined in analogy to the "alkyl", “aryl” and “het” radicals. o and p stand for 0, 1 or 2; they can be the same or different.
  • R 3 and R 4 are H, C ⁇ -C ⁇ 0 alkyl (preferably C ⁇ -C 6 - alkyl), aryl, Het or a C 1 -C 6 spacer (preferably C ⁇ -C 3) bound aryl or Het residue.
  • Alkyl radicals include unbranched, branched or cyclic, saturated or with double and / or Triple bond (s) partially unsaturated, unsubstituted or at least single, preferably with F, Cl, Br, CN, N0 2 , NR 6 R 7 ,
  • alkyl radical contains more than one substituent, these can be the same or different.
  • alkyl radicals are preferably methyl, ethyl, propyl, isopropyl,
  • Aryl radical represents an unsubstituted or at least simple, preferably with F, Cl, Br, CN, alkyl, CF 3 , N0 2 , NR 6 R 7 , CHO, SO m alkyl, OH, OR 6 , COR 6 , COOR 6 , COCOR 6 , CONR 6 R 7 , CSNR 6 R 7 , aryl, or Het-substituted phenyl radical.
  • the phenyl radical can be condensed with other cycles.
  • the rest Het denotes a saturated, unsaturated or aromatic mono- or bicyclic heterocycle with 5 to 10 ring members, with at least one heteroatom, preferably nitrogen, oxygen and / or sulfur and which is optionally provided with a fused-on carbo- or heterocycle.
  • R 6 and R 7 represent H, -C 10 alkyl, preferably C 6 alkyl, an aryl, heteroaryl or an aryl bonded via a C 6 spacer, preferably ⁇ -C 3 - or heteroaryl residue.
  • the invention further relates to a method for producing the chemical compounds of the general formula (I).
  • suitable condensing agents are dicyclohexylcarbodimide (DCC), carbonyldumidazole (CDI), thionyldumidazole (ThDI) and l-hydroxy-l ⁇ - benzotriazole (HBT);
  • an inorganic condensation agent for example an inorganic anhydride, such as phosphorus pentoxide or an inorganic acid halide, such as phosphorus oxychloride.
  • the reaction takes place as an acid-catalyzed condensation reaction.
  • a non-oxidizing, strong acid is suitable for this.
  • This can be both inorganic (e.g. concentrated sulfuric acid) and organic (e.g. benzene or toluenesulfonic acid).
  • inorganic e.g. concentrated sulfuric acid
  • organic e.g. benzene or toluenesulfonic acid
  • the procedure can be carried out either in an inert solvent or solvent mixture, but also in the absence of a solvent.
  • the reaction takes place at -10 to 250 ° C, the reaction according to A) or usually already at low temperature (generally at room temperature), the esterification according to B) or C) usually requires relatively drastic conditions: This applies above all to variant C), since continuous distillation of the water is necessary here.
  • carboxylic acid derivatives are usually used in acylation reactions.
  • the bean below ⁇ cast-methods are characterized in that a derivative of the carboxylic acid is used with higher reactivity.
  • This activated compound can also be formed in situ in that the derivative is not isolated from the reaction mixture, but instead is reacted directly with the nucleophile tocopherol to give the claimed structure I compounds.
  • oxalyl chloride or 2, 4, 6-trichloro-1, 3, 5- triazine are used in nature, the activation by means of 2, 4, 6-trichloro-l, 3, 5-triazine in particular also being very good for the synthesis of the esters in a one-pot process, in which the acid chloride is primarily prepared and then directly on is implemented.
  • the target compounds can be prepared by acylation of tocopherol using an acid anhydride. This reaction is optionally carried out with the addition of a base, for example pyridine.
  • Suitable acylation reagents according to this method are both pure anhydrides of the drug and mixed anhydrides, preferably anhydrides from the drug and carbonic acid monoester.
  • the compound R-CH 2 OH can, for example, represent a reduced form of a biologically active carboxylic acid.
  • the compounds of structure I with n-1 according to the invention are formally made up of the components active ingredient (in structure I the unchanged part is identified by R), spacers (B) and
  • Tocopherol These components can be linked in different ways and in different orders.
  • reaction steps include the processes of oxidation, reduction, ether cleavage, acylation, alkylation, etc. which are familiar to the person skilled in the art.
  • protective groups in particular common hydroxyl and ammo protective groups, may be necessary;
  • the following diagram shows some variants for the preparation of the compounds I. However, these variants are only for illustration and do not limit the scope of the invention to these. In general, it should be noted that bifunctional derivatives are often used in the reactions.
  • reaction can also be carried out in such a way that the two-component intermediates are only formed in situ and then reacted further, without isolation from the reaction mixture.
  • the required starting materials are generally known or commercially available; unknown starting materials can be prepared analogously to the known compounds.
  • the claimed compounds can also be synthesized directly from the three components, although this generally results in lower yields of the desired compound.
  • a compound of glycolic acid is present as a spacer in compounds 1-2, and this component can correspond to that previously discussed
  • a protective group must be selected which can be split off under very mild reaction conditions.
  • This A suitable benzyl ester fulfills the requirement, since experience has shown that such esters can be selectively cleaved.
  • a solution of the respective active ingredient for example the corresponding NSAID, is mixed with an auxiliary base, and the carboxylate anion formed is then converted into the corresponding c_> acylated glycolic acid ester by reaction with benzyl bromoacetate.
  • the crude product obtained after the reaction is complete can be used either directly or after purification (preferably by distillation) to acylate the corresponding nucleophile (e.g. ⁇ -tocopherol).
  • the activated carboxylic acid and the nucleophile are mixed in approximately equivalent amounts in an inert solvent (e.g. dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile or the like) in the presence of an auxiliary base (preferably triethylamine or pyride) - if necessary after adding an acylation catalyst (preferably 4 -D ⁇ methylammopyridin) - brought to reaction.
  • an inert solvent e.g. dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile or the like
  • an auxiliary base preferably triethylamine or pyride
  • NSAID dexibuprofen antioxidant: ⁇ -tocopherol reaction time 43 h
  • NSAID Naproxen antioxidant: ⁇ -tocopherol reaction time 40 h Appearance: yellow, tough 01
  • NSAID indomethacin antioxidant: ⁇ -tocopherol reaction time 40 h Appearance: light yellow, tough 01
  • NSAID ketoprofen antioxidant: ⁇ -tocopherol reaction time 15 h
  • the mixture is hydrogenated at room temperature under constant rubble (reaction time: 2.5-24 hours, the reaction is controlled by means of TLC). After the reaction has ended, the solution is again covered with nitrogen, the catalyst is filtered off and the solvent is distilled off in vacuo.
  • the crude product obtained is purified either by recrystallization from a suitable solvent (for example diisopropyl ether) or by column chromatography.
  • the solvent is distilled off in vacuo, the residue is taken up in ethyl acetate.
  • the organic phase is washed with 2M hydrochloric acid and saturated sodium hydrogen carbonate solution, neutralized with water and predried with saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is completely distilled off and the crude product thus obtained is purified by means of column chromatography.
  • NSAID naproxen spacer: glycolic acid antioxidant: ⁇ -tocopherol reaction time 17 h
  • NSAID indomethacin spacer: glycolic acid antioxidant: ⁇ -tocopherol reaction time 24 h
  • Appearance light yellow foam resin
  • Purification column chromatography stationary phase: silica gel, mobile phase: dichloromethane / petroleum ether (ratio: 10/1)
  • NSAID dexibuprofen spacer: glycolic acid antioxidant: ⁇ -tocopherol reaction time 47 h
  • NSAID spacer diclofenate: antioxidant glycolic acid: ⁇ -tocopherol reaction time 34 h
  • Appearance white-yellowish resin
  • NSAID mefenamic acid spacer: glycolic acid antioxidant: ⁇ -tocopherol reaction time 66 h
  • the keto function is reduced as part of the splitting off of the benzyl protective group by reaction with hydrogen at 50 psi in the presence of a suitable catalyst; after the required amount of hydrogen has been taken up, the reaction is stopped. The corresponding O-acylated glycolic acid is then activated and reacted with tocopherol.
  • Example 10
  • the chemical compounds according to the invention containing tocopherol and at least one further pharmaceutical active substance are, due to their different pharmaceutical active substance groups, suitable for the healing or prophylaxis of, in particular, inflammatory diseases, since the pharmaceutical active substance preferably selected from the group of non-steroidal anti-inflammatories reduces the inflammatory process or even interrupts, whereas the tocopherol residue acts as an antioxidant.
  • the active pharmaceutical ingredient and the tocopherol used are linked to one another either directly or via a spacer. This chemically fixed combination of two active pharmaceutical ingredients when used as

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés chimiques se présentant sous la forme de racémates, d'énantiomères ou de diastéréomères de formule générale (I) dans laquelle: R représente une partie non modifiée d'une molécule de substance pharmaceutique active variable; B est un espaceur; Toc correspond à la formule (II); R', R'' et R''' sont H ou méthyle pour le tocophérol; et A est C=X, SOm, X ou CH2, formule dans laquelle X représente O, S ou NR<1> (pour n = 1), ou S ou NR<1> (pour n = 0) et B est un groupe X-R <2> Y, formule dans laquelle Y représente C=X, SOm ou C (XR<3>) R<4> et n vaut de 0 à 6, de préférence de 0 à 3, et m vaut 1 ou 2, R<1> représentant H, alkyle en C1-C10, de préférence alkyle en C1-C6, ou aryle, Het ou un radical aryle ou Het lié par un espaceur en C1-C6, de préférence en C1-C3, et R<2> étant choisi dans le groupe qui comprend les espaceurs d'alkylène, d'arylène ou de Het, ainsi que des combinaisons de ceux-ci, ceux-ci étant reliés ensemble soit directement, soit par l'intermédiaire du radical A ou du groupe XO-A-Xp dans lequel o et p sont identiques ou différents et valent 0, 1 ou 2, R<3> et R<4> représentant H, alkyle en C1 à C10, de préférence alkyle en C1-C6, ou aryle, Het ou un radical aryle ou Het lié par un espaceur en C1 à C6, de préférence en C1 à C3.
EP04737365A 2003-07-17 2004-07-01 Compositions chimiques contenant du tocopherol et au moins une autre substance pharmaceutique active Ceased EP1646627A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0112703A AT500404A1 (de) 2003-07-17 2003-07-17 Chemische verbindungen enthaltend tocopherol sowie zumindest einen weiteren pharmazeutischen wirkstoff
PCT/AT2004/000234 WO2005007650A1 (fr) 2003-07-17 2004-07-01 Compositions chimiques contenant du tocopherol et au moins une autre substance pharmaceutique active

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EP1646627A1 true EP1646627A1 (fr) 2006-04-19

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US (1) US20060135489A1 (fr)
EP (1) EP1646627A1 (fr)
JP (1) JP2007537979A (fr)
AT (1) AT500404A1 (fr)
AU (1) AU2004257887A1 (fr)
CA (1) CA2496130A1 (fr)
NZ (1) NZ538241A (fr)
WO (1) WO2005007650A1 (fr)

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CA2755069A1 (fr) * 2009-03-16 2010-09-23 Genmedica Therapeutics Sl Conjugues anti-inflammatoires et anti-oxydants utiles pour traiter des troubles metaboliques
CN102421424A (zh) * 2009-03-16 2012-04-18 根梅迪卡治疗公司 用于治疗代谢性疾病的组合疗法
WO2010113939A1 (fr) * 2009-03-30 2010-10-07 味の素株式会社 Composé diphénylméthane
US8466197B2 (en) 2010-12-14 2013-06-18 Genmedica Therapeutics Sl Thiocarbonates as anti-inflammatory and antioxidant compounds useful for treating metabolic disorders
CN114716400B (zh) * 2022-03-15 2023-10-03 上海克琴科技有限公司 化妆品活性物生育酚酯及其绿色合成方法

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AT500404A1 (de) 2005-12-15
AU2004257887A1 (en) 2005-01-27
NZ538241A (en) 2008-04-30
JP2007537979A (ja) 2007-12-27
CA2496130A1 (fr) 2005-01-27
US20060135489A1 (en) 2006-06-22
WO2005007650A1 (fr) 2005-01-27

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