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WO2004028544A1 - Utilisation de composes mas pour le traitement des maladies associees au metabolisme des lipides - Google Patents

Utilisation de composes mas pour le traitement des maladies associees au metabolisme des lipides Download PDF

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Publication number
WO2004028544A1
WO2004028544A1 PCT/DK2003/000619 DK0300619W WO2004028544A1 WO 2004028544 A1 WO2004028544 A1 WO 2004028544A1 DK 0300619 W DK0300619 W DK 0300619W WO 2004028544 A1 WO2004028544 A1 WO 2004028544A1
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WIPO (PCT)
Prior art keywords
pregna
methyl
dimethyl
dien
stated above
Prior art date
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Ceased
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PCT/DK2003/000619
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English (en)
Inventor
Christian GRØNDAHL
Bernhard Lindenthal
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.)
Bayer Pharma AG
Novo Nordisk AS
Original Assignee
Schering AG
Novo Nordisk AS
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Priority to AU2003266210A priority Critical patent/AU2003266210A1/en
Publication of WO2004028544A1 publication Critical patent/WO2004028544A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to the use of novel compounds mentioned below for increasing the HDL cholesterol to non-HDL cholesterol ratio, for treatment and/or prevention of artherosclerosis, for treatment and/or prevention of hyperlipidemia, for treatment of diabetic dyslipididemia, for treatment of hyper-cholesterolemia, for treatment of diseases of illness related to metabolic dysfunction, for treatment of obesity or obesitas related diseases, and for treat- ment of neurological diseases, for example, Alzheimer, associated with lipid metabolism.
  • the present invention also embraces pharmaceutical compositions and kits comprising these compounds and methods of using the compounds and their pharmaceutical compositions, for example, to humans.
  • lipoprotein covers any of the lipid-protein complexes in which lipids are transported in the blood.
  • Lipoprotein particles consists of a spherical hydrophobic core of triglycerides or cholesteryl esters surrounded by an amphiphatic monolayer of phospholipids, cholesterol, and apolipoproteins.
  • the expression HDL cholesterol covers high-density lipoprotein and the expression non-HDL cholesterol covers the remaining lipoproteins.
  • Atherosclerosis is an extremely common form of arteriosclerosis in which deposits of yellowish plaques (atheromas) containing cholesterol, lipid material, and lipophages are formed within the intima and inner media of large and medium-sized arteries.
  • Arterosclerosis is a group of diseases characterized in thickening and loss of elasticity of arterial walls.
  • Hyperlipidemia is a general term for elevated concentrations of any or all of the lip- ids in the plasma, including, for example, hypertriglyceridema and hypercholesterolemia.
  • Diabetic dyslipidemia is the typical lipid disorder associated to type II diabetes characterized by low HDC, high LDC, and high small very dense lipid particles.
  • Hyper-cholesterolemia is the presence of an excess of cholesterol in the blood. Metabolic dysfunctions cover the general term describing an inappropriate regula- tion of the glucose and lipid metabolism.
  • Alzheimer's disease is a progressive degenerative disease of the brain of unknown etiology characterized by diffuse atrophy throughout the cerebral cortex with distinctive histo- pathology changes termed "senile plaques" (microscopic lesions composed of fragmented axon terminals and dendrites surrounding a core of amyloidal) and "neurofibrillary tangles" (intracellular knots or clums of neurofibrils).
  • the cholesterol synthesis proceeds via the following compounds: HMG-CoA ⁇ evalonic acid ->• lanosterol - FF-MAS ⁇ T-MAS ⁇ desmosterol ⁇ cholesterol.
  • statins for example, Simvastatin, are known to interact on the HMG-CoA ⁇ evalonic acid step.
  • the desmosterol ⁇ cholesterol is controlled by a sterol ⁇ 24 reductase.
  • One object of this invention is to provide a medicament which can be used for increasing the HDL cholesterol to non-HDL cholesterol ratio.
  • Another object of this invention is to provide a medicament which can be used for treatment and/or prevention of artherosclerosis.
  • a further object of this invention is to provide a medicament which can be used for treatment and/or prevention of hyperlipidemia.
  • a still further object of this invention is to provide a medicament which can be used for treatment of diabetic dyslipididemia.
  • a still further object of this invention is to provide a medicament which can be used for treatment of hyper-cholesterolemia.
  • a still further object of this invention is to provide a medicament which can be used for treatment of diseases of illness related to metabolic dysfunction.
  • a still further object of this invention is to provide a medicament which can be used for treatment of obesity or obesitas related diseases.
  • a still further object of this invention is to provide a medicament which can be used for treatment of neurological diseases, e. g. Alzheimer disease.
  • neurological diseases e. g. Alzheimer disease.
  • Other objects of the present invention will become apparent upon reading the present description.
  • FF-MAS is 4,4-dimethyl-5 ⁇ -cholesta-8,14,24-triene-3 ⁇ -ol
  • T-MAS is 4,4-dimethyl-5 ⁇ - cholesta-8,24-diene-3 ⁇ -ol (also designated 4,4-dimethylzymosterol)
  • ZK 255884 is (20S)-20-[(piperidin-1-yl)methyl]-4,4-dimethyl-5 ⁇ -pregna-8,14-dien-3 ⁇ -ol (compound No. 2 in the list below).
  • MAS compound which are defined below can be used for increasing the HDL cholesterol to non- HDL cholesterol ratio, for treatment and/or prevention of artherosclerosis, for treatment and/or prevention of hyperlipidemia, for treatment of diabetic dyslipididemia, for treatment of hyper-cholesterolemia, for treatment of diseases of illness related to metabolic dysfunction, and for treatment of obesity or obesitas related diseases.
  • MAS compounds are all compounds of the general formula I, la, lb, and Ic mentioned in any of the international patent applications having the international publication number WO 96/00235 (our ref.: 4228), WO 97/00884 (our ref.: 4475), WO 98/28323 (our ref.: 5141), WO 99/32506 (earliest priority: 971218), WO 98/52965 (earliest priority: 970516), WO 99/67273 (our ref.: 5558), WO 99/58549 (our ref.: 5509), or WO 2000/47604 (our ref.: 5769), WO 2000/68245 (our ref.: 6238), or WO 2001/62771 (our ref.: 6239), preferably all the specific compounds mentioned specifically in said WO specifications covered by said formula, as well as compounds of the general formula X shown below:
  • Preferred compounds of formula X are such in which at least one double bond is present in the steroid skeleton between carbon atoms C 6 , C 7 , C 8 , C 9 , C 14 and C 15 , respectively.
  • a double bond may be present between C 5 und C 6 in addition to the at least one double bond between C 6 , C 7 , C 8 , C 9 , C 14 and C 15 , respectively. It is especially preferred to have a steroid in which the double bonds are conjugated to each other if more than one double bond is present in the steroid skeleton.
  • C n alkyl, C n fluoroalkyl, C n alkyloxy, C n alkylamino, C n cycloalkyl, C n alkylen, C n alkenyl, C n aryl, C n heteroaryl and the like relate to radicals with n carbon atoms in the moiety, the number of n carbon atoms including all carbon atoms in side chains of for example, branched radicals.
  • an alkyl, alkoxy, alkylen or acyl group has 1 to 10 carbon atoms including side chain carbon atoms if these groups are branched; an alkenyl or alkynyl group has 2 to 10 carbon atoms including side chain carbon atoms if these groups are branched; further a cycloalkyl has 4 to 7 carbon atoms; an aryl has 6 to 10 carbon atoms; and a heterocyclic ring or a heteroaryl have 6 to 10 ring atoms. Further aryl also represents alkylaryl; heteroaryl also represents alkylheteroaryl; and cycloalkyl also represents alkylcycloalkyl.
  • the novel steroid compounds of formula X have a number of chiral centers such that these compounds exist in several isomeric forms. All these isomeric forms are within the scope of the present invention unless otherwise described herein.
  • a steroid compound with the general formula below is preferred:
  • ⁇ 5 -pregenene derivatives preferably ⁇ 8,14 -pregnadien derivatives, the ⁇ 8 -pregnene derivatives and the ⁇ 5,7 -pregnadiene derivatives are useful as pharmaceutically active steroid compounds, i.e. compounds having the general formulae shown below:
  • the outstanding properties of the novel compounds may be attributed to the amino group in the side chain linked to the C 17 carbon atom in the steroid skeleton via a C 2 - C 3 alkylen spacer (including the C 20 -R 20 group).
  • R 3 is CH-OH, in particu- lar a 3 ⁇ -hydroxy radical bonded to the C 3 atom of the steroid skeleton.
  • R 3 may be an ester radical of a monocarboxylic acid, of a dicarboxylic acid, of an inorganic acid or of any other acid, bonded to the C 3 atom of the steroid skeleton.
  • R 3 being an ester radical of a dicarboxylic acid
  • the ester radical may also be formed from an inorganic acid such as phosphoric acid, sulfuric acid and sulphamic acid, further from a monocarboxylic acid such as acetic acid, propionic acid, n-butanoic acid, pivalic acid, benzoic acid, nicotinic acid and isonicotinic acid.
  • the ester radical may be formed from a dicarboxylic acid, such as from succinic acid and glutaric acid.
  • Further steroid compounds according to the present invention may also include derivatives, in which C-O-R 3 represents a cyclic ether including the C 3 atom of the steroid skeleton.
  • R 3 may also form a cyclic ring structure together with the C 3 atom, R 3 being unsubstituted or substituted, linear or branched C 2 - C 10 alkylen.
  • C 3 R 3 may be a cyclopropylen, cyclobutylen, cyclopentylen or cyclohexylen radical. It may also represent an unsaturated cyclic ring structure such as cyclopropenylen, cyclobutenylen, cyclopentenylen and cyclohexenylen.
  • the ring structure may also be substituted by any of halogen, hydroxy, alkoxy, aryloxy and the like.
  • steroid compound R 3' may be hemi succinoyl.
  • novel steroid compounds R 4 and R 4' are preferably hydrogen or a linear or branched C-i - C alkyl group, i.e. methyl, ethyl, propyl and butyl, and especially methyl.
  • R 4 and R 4' may also be C ⁇ - C alkyl, substituted by halogen, hydroxy, alkoxy or aryloxy.
  • R 20 is preferably hydrogen or linear or branched Ci - C 4 alkyl, i.e. methyl, ethyl, pro- pyl and butyl. R 20 is especially methyl.
  • R 23 and R 23' may specifically be hydrogen or a C 1 - C 8 alkyl group, such as methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, ferf-butyl, n-pentyl, /so-pentyl, ferf-pentyl, neo-pentyl, further hexyl and cyclohexyl and the like.
  • R 23 and R 23 ' independently, may also be a C 2 - C 8 alkenyl group, i.e.
  • an unsaturated alkyl group for example, vinyl, allyl, /so-propenyl and prenyl, further C 6 - C 10 aryl, such as phenyl and 1-naphthyl, this group also comprising alkylaryl, being bonded via the aryl moiety or via the alkyl moiety to the nitrogen atom, for example, benzyl and tolyl.
  • R 23 and R 23' may preferably be alkyl and alkenyl, being substituted by at least one radical, selected from the group, comprising linear or branched C-i - C 4 alkyl and d - C 4 alkoxy.
  • the phenyl and 1-naphthyl radical may also be substituted by halogen, Ci - C 4 alkoxy, hydroxy or C 1 - C 4 alkyl, including the fluoroalkoxy and fluoroalkyl derivatives.
  • R 23 and R 23' may further be for example, 4-hydroxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dichlorophenyl, 4- fluorophenyl, 4-trifluoromethylphenyl and 2-pentafluoroethylphenyl.
  • R 23 and R 23' may also represent alkyl and alkenyl, at least one of the alkyl and alkenyl carbon atoms, respectively, being replaced by any of O, N and S, for example, methoxymethylen, methoxyethylen, methoxypropylen, ethoxypropylen and the like.
  • R 23 and R 23' together may also form a heterocyclic ring structure bonded to the side chain via the nitrogen atom in the side chain, the nitrogen atom being linked to the C 20 carbon atom of the steroid skeleton via the spacer group A.
  • This heterocyclic ring structure formed by N(R 23 )(R 23' ), may especially be a moiety being selected from the group, comprising piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, pyrrolidin-1-yl, pyrrol-1-yl, indol-1-yl, pyrazol- - yl, imidazol-1-yl, thiazolidin-1-yl and oxazolidin-3-yl ring structures and substituted derivatives thereof.
  • Especially preferred heterocyclic ring structures are the saturated radicals, namely piperidin-1-yl, morpholin-4-yl, piperazin-1-yl and pyrrolidin-1-yl.
  • the heterocyclic ring structures may be substituted with hydroxy, carboxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, aryl, alkylaryl, hydroxy, alkoxy, alkyl- cycloalkyloxy, alkyloxycycloalkyl, alkylaryloxy, alkyloxyaryl, halogen and acyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy and acyl have a number of carbon atoms as indicated above.
  • the heterocyclic ring structure may also be substituted with heterocyclic radicals, such as the heterocyclic ring structures to which they may be bonded and in addition to these as the further radicals, for example, pyridinyl, chinolinyl, isochinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, chinoxalinyl, thiazolyl and oxazolyl, further including all other isomers of these radicals, for example, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. Further if N(R 23 )(R 23' ) is a heterocyclic ring structure this ring structure may also include an oxo group in the ring.
  • heterocyclic radicals such as the heterocyclic ring structures to which they may be bonded and in addition to these as the further radicals, for example, pyridinyl, chinolinyl, isochinolinyl,
  • N(R 23 )(R 23' ) is piperazin-1-yl this moiety may be especially substituted by pyridin-2- yl, pyridin-3-yl and pyridin-4-yl, to preferably give the respective N(R 23 )(R 23' ) groups in which the piperazin-1-yl group is substituted in para-position, for example, 4-(pyridin-3-yl)piperazin- 1-yl.
  • N(R 3 )(R 23' ) may also be any moiety shown of the following formula:
  • R 24 is alkyl, alkenyl, alkynyl, aryl, the number of carbon atoms of which is defined as above. Further R 24 may be a heterocyclic ring structure, wherein the number of ring atoms is as defined above.
  • N(R 23 )(R 23' ) is not bonded directly but via A to the C 20 atom, wherein A is an unsubstituted or substituted methylen or ethylen spacer group, such as for example, (unsubstituted) methylen and (unsubstituted) ethylen and further / ' so-propylen, tert- butylen and the like.
  • A is methylen and ethylen.
  • R 3 is hydroxy or hemi succinate ester
  • R 4 , R 4' and R 20 are each methyl and in which the heterocyclic ring structure N(R 23 )R 23' ) including the amino nitrogen atom is an unsubstituted or substituted morpholin-4- yl, piperidin-1-yl, piperazin-1- or pyrrolidin-1-yl.
  • N(R 23 )(R 23' ) is in particular 3-hydroxypiperidin- 1-yl, 4-hydroxy-piperidin-1-yl, 3-ketopiperidin-1-yl, 4-ketopiperidin-1-yl, 4-dimethylamino- piperidin-1-yl, 3,3-dimethylpiperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 3-carboxypiperidin-1-yl, 4-carboxy-piperidin, 4-phenylpiperidin-1-yl, 4-benzoyl-piperidin-1-yl, 4-(piperidin-1-yl)- piperidin-1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-phenylpiperazin-1-yl, 4- benzylpiperazin-1 -yl, 4-benzoylpiperazin-1 -yl, 4-(pyridin-2-yl)piperazin-1 -yl, 4-(pyridin-4
  • Hydrogen atoms may be bonded to all other skeleton C atoms of the steroid compounds, i.e. to C ⁇ C 2 , C 6 , C 7 , C 8 , C 9 , C 11 , C 12 , C 14 , C 15 and C 16 .
  • pharmaceutically acceptable compounds of the present invention are salts of steroid compounds of general formula X. Examples of these salts are listed in Journal of Pharmaceutical Science, 66, 2 et seq. (1977), which are hereby incorporated by reference.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, methane sulphonic acid and the like.
  • Suitable inorganic acids to form pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.
  • a further object of the present invention is pharmaceutical compositions comprising at least one MAS compound and at least one pharmaceutically acceptable excipient well known in the art, for example, at least one carrier, diluent, absorption enhancer, preservative, buffer, agent for adjusting the osmotic pressure and rheology of the medicament if it will be liquid, surfactant, solvent, tablet disintegrating agent, micro capsules, filler, slip additive, colorant, flavour and other ingredient. These substances are conventionally used in the art.
  • the steroid compounds used according to the present invention i.e. the MAS compounds
  • solid carriers examples include magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talkum, gelatin, pectin, starch, silica gel, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes and cacao butter.
  • Liquid compositions include sterile solutions, suspensions and emulsions, which may be administered for example, orally by nasal administration or as an ointment. Such liq- uid compositions may also be suitable for injection or for use in connection with ex vivo or in vivo application.
  • the liquid may contain a pharmaceutically acceptable oil and/or lipophilic, surfactant and/or solvent which is miscible with water.
  • WO 97/21440 A1 which is hereby incorporated by reference.
  • compositions may also contain other ingredients, which are conventionally used in the art, some of which are mentioned in the list above.
  • a composition for transdermal administration of a compound of the present invention may be provided in the form of a patch.
  • a composition for nasal administration may be provided in the form of a nasal spray in liquid or in powder form.
  • these compounds may also be formulated as cyclodextrin chlatrates.
  • the compounds are compounded with ⁇ -, ⁇ - or ⁇ -cyclodextrin or derivatives thereof.
  • the medica- ment contains excipients for regulating the rheology of the medicament, surfactants, pre- servatives, solvents, diluents, substances for enhancing skin permeation ability, further flavours and protective skin substances such as conditioners and moisture regulators.
  • the medicament may also contain further active agents to enhance or regulate the effectiveness of the steroid compounds or to produce other desired effects of the medica- ment.
  • the steroid compounds i.e., the MAS compounds
  • a pharmaceutically acceptable diluent Oils are very often used in combination with solvents, surfactants, suspension or emulsion agents, for example, olive oil, peanut oil, soybean oil, caster oil and the like.
  • solvents for example, olive oil, peanut oil, soybean oil, caster oil and the like.
  • surfactants for example, olive oil, peanut oil, soybean oil, caster oil and the like.
  • suspension or emulsion agents for example, olive oil, peanut oil, soybean oil, caster oil and the like.
  • any liquid carrier may be employed. These liquids often also contain agents for the regulation of the viscosity thereof as well as agents for regulating isotonicity of the liquid.
  • the steroid compound according to the present invention may further be administered as an injectable depot or as an implantate, which may for example, be administered subcutanely, such that delayed release of the steroid compounds is made possible.
  • an injectable depot or as an implantate which may for example, be administered subcutanely, such that delayed release of the steroid compounds is made possible.
  • various techniques may be employed, for example, administration of depots, which include a membrane containing the active compound, or of slowly dissolving depots.
  • Implan- tates may, for example, contain biologically degradable polymers or synthetic silicones as inert material.
  • compositions of the present invention are prepared by intimately bringing into association the active compound with the liquid or solid auxiliary ingredients and then, if necessary, shaping the product into the desired formulation.
  • Usually not more than 3000 mg, preferably not more than 350 mg, and in some preferred instances not more than 30 mg of the steroid compounds are to be administered to mammals, for example, to humans, per day.
  • the present invention also relates to the use of the steroid compounds for the preparation of a composition useful according to this invention.
  • this composition is applicable as a medicament.
  • compositions containing a compound of the present invention may be any route, which effectively transports the active steroid compound to its site of action.
  • the steroid compounds when they are to be administered to a mammal, they are conveniently provided in the form of a pharmaceutical composition, which comprises at least one steroid compound according to the present invention in connection with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for oral use, such compositions are preferably in the form of tablets or capsules.
  • steroid compounds can be synthesised analogously with the preparation of known compounds, vide, for example, WO 02/079220.
  • TMS Trimethylsilyl
  • HepG2 cells were incubated with different concentra- tions of ZK 255884 for 24 hours. After extraction and an alkaline hydrolysis, neutral sterols were converted to their TMS-derivatives and measured by gas-chromatography/mass- spectrometry.
  • Fig. 2 with the heading "Influence on ZK 255884 on serum sterols in rats" shows than by administering once 80 mg/kg of ZK 255884, after 4 days, the cholesterol level is decreased from about 65 to about 10, whereas the control is only decreased to about 40 (left figure).
  • the right figure shows that for both the control and for ZK 255884, the amount of total sterol (defined as cholesterol + desmosterol) is approximately the same at the various times.
  • Figs. 4a, 4b, 4c, and 4d with the heading "Influence on ZK 255884 on sterols in Hep G2 cells" shows a dose response curve to increase desmosterol and the appearance of another sterol at the highest concentrations of 10 ⁇ Min this human liver cell line.
  • Fig. 5 shows a dose response curve in increasing the ratio of desmosterol to cholesterol.
  • the de- ine of the ratio of desmosterol to cholesterol at the highest concentration (10 ⁇ M) is probably due to the additional appearance of another sterol, probably another cholesterol precursor (for example, zymosterol).

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Abstract

Certains stérols peuvent être utilisés pour accroître le rapport entre le cholestérol HDL et le cholestérol non-HDL, pour le traitement et/ou la prévention de l'artériosclérose, pour le traitement et/ou la prévention de l'hyperlipidémie, pour le traitement de la dyslipidémie diabétique, pour le traitement de l'hypercholestérolémie, pour le traitement des maladies liées à un dysfonctionnement du métabolisme, pour le traitement de l'obésité ou des maladies liées à l'obésité, et pour le traitement des troubles neurologiques.
PCT/DK2003/000619 2002-09-25 2003-09-23 Utilisation de composes mas pour le traitement des maladies associees au metabolisme des lipides Ceased WO2004028544A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932268B2 (en) 2004-03-05 2011-04-26 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
CN116509877A (zh) * 2023-04-26 2023-08-01 复旦大学附属肿瘤医院 一种化合物t-mas在制备治疗乳腺癌药物中的应用
US12472172B2 (en) 2020-07-29 2025-11-18 Amryt Pharmaceuticals Inc. Lomitapide for use in methods of treating hyperlipidemia and hypercholesterolemia in pediatric patients

Citations (3)

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US8618135B2 (en) 2004-03-05 2013-12-31 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9364470B2 (en) 2004-03-05 2016-06-14 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9433617B1 (en) 2004-03-05 2016-09-06 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9861622B2 (en) 2004-03-05 2018-01-09 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US10016404B2 (en) 2004-03-05 2018-07-10 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US10555938B2 (en) 2004-03-05 2020-02-11 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US11554113B2 (en) 2004-03-05 2023-01-17 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
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