WO2001000183A2 - COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS - Google Patents

COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS Download PDF

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WO2001000183A2
WO2001000183A2 PCT/EP2000/005410 EP0005410W WO0100183A2 WO 2001000183 A2 WO2001000183 A2 WO 2001000183A2 EP 0005410 W EP0005410 W EP 0005410W WO 0100183 A2 WO0100183 A2 WO 0100183A2
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carbon atoms
chain
straight
branched alkyl
phenyl
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PCT/EP2000/005410
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German (de)
English (en)
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WO2001000183A3 (fr
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Rudi Grützmann
Ulrich Müller
Hilmar Bischoff
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Bayer Aktiengesellschaft
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Priority to EP00942056A priority Critical patent/EP1196194A2/fr
Priority to AU56809/00A priority patent/AU5680900A/en
Priority to CA002376881A priority patent/CA2376881A1/fr
Priority to JP2001505893A priority patent/JP2003503342A/ja
Publication of WO2001000183A2 publication Critical patent/WO2001000183A2/fr
Publication of WO2001000183A3 publication Critical patent/WO2001000183A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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

  • the invention relates to the use of a combination of at least one selected MTP inhibitor (component A) and an HMG-CoA reductase inhibitor (component B) for combating cardiovascular diseases, medicaments containing this combination and their preparation.
  • HMG-CoA reductase inhibitors are a class of lipid-lowering agents well known to the person skilled in the art.
  • Statins preferred as HMG-CoA reductase inhibitors in the context of this invention are e.g. described in EP 325 130 or US 5,177,080.
  • the present invention relates to the use of a combination of at least one MTP inhibitor as component A of the general formula (AI)
  • R8 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R ⁇ and R ⁇ together with the double bond connecting them form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical,
  • D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms or straight-chain or branched alkyl having up to 12 carbon atoms,
  • E represents the -CO or -CS group
  • L represents an oxygen or sulfur atom or a group of the formula
  • R is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which may be by hydroxy or
  • R5 represents phenyl or a 5- to 7-membered saturated or unsaturated heterocycle with up to 3 heteroatoms from the series S, N and / or O,
  • cycles are optionally up to 3 times the same or different by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted is substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or the cycles are optionally substituted by a group of the formula -OR ⁇ or -NR 1 R 12 ,
  • R ⁇ O is hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms
  • RU or Rl2 are the same or different and are phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms
  • acyl with up to 8 carbon mean atoms which is optionally substituted by a group of the formula -NR 13 R 14 ,
  • Rl3 and Rl4 are the same or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,
  • R 1 denotes phenyl which is optionally substituted up to 3 times identically or differently by halogen, hydroxyl or by straight-chain or branched alkyl having up to 5 carbon atoms,
  • Rl6 is hydrogen, benzyl, tr ⁇ phenylmethyl or straight-chain or branched acyl having up to 6 carbon atoms, R ⁇ stands for hydrogen or
  • Q represents a nitrogen atom or the -CH group
  • T represents a group of the formula -SO2 or -CO or an oxygen or sulfur atom
  • V represents an oxygen or sulfur atom
  • R5, R6, R7 and R8 are the same or different and
  • R 9 is trifluoromethyl, benzyl or a 5- to 7-membered, optionally benzocondensed heterocycle with up to 3 heteratoms from the series S, N and / or O, which may be up to 3 times the same or different by halogen, phenyl, hydroxy or by straight-chain or branched alkyl or alkoxy, each with up to 4
  • Is substituted carbon atoms or denotes a group of the formula -S (O) a -R ⁇ ,
  • RIO means straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be by straight-chain or branched acyl having up to 6 carbon atoms or by aryl or aroyl each having up to 10
  • Carbon atoms are substituted, which in turn may be substituted up to 2 times the same or different by halogen, trifluoromethyl or by straight-chain or branched acyl having up to 5 carbon atoms, or aryl having 6 to 10 carbon atoms, optionally by halogen, hydroxy, trifluoromethyl or straight-chain or branched alkyl or alkoxy, each having up to 5 carbon atoms,
  • D and E are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
  • Z represents an oxygen or sulfur atom
  • R 1 stands for cycloalkyl with 3 to 10 carbon atoms or for straight-chain or branched alkyl with 1 to 10 carbon atoms, or stands for phenyl which may optionally be identical or different up to 2 times through halogen, nitro, cyano, hydroxyl, straight-chain or branched alkyl or alkoxy is substituted in each case with up to 4 carbon atoms,
  • R 2 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
  • R-3 represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the series S , N and / or O, which are optionally substituted up to 3 times identically or differently by halogen, nitro, phenyl, hydroxy or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,
  • R 4 represents hydrogen or a group of the formula -CH2-OH or CH2O-CO-
  • R 1 1 stands.
  • R 1 1 is hydrogen, straight-chain or branched alkyl with up to 8
  • T represents a nitrogen atom or the -CH group
  • R ", R ⁇ , R 1 ⁇ and R 1 are the same or different and
  • R- ⁇ R8 and R 9 are the same or different and
  • R ⁇ can also mean benzyl.
  • E and L are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
  • cycloalkyl having 3 to 10 carbon atoms or straight-chain or branched alkyl having 1 to 10 carbon atoms, or represents phenyl which is optionally substituted up to 2 times identically or differently by halogen, cyano, hydroxy, straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
  • R 2 represents hydrogen or straight-chain or branched alkyl with up to 3
  • R3 represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which are optionally substituted up to 3 times identically or differently by halogen, nitro, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,
  • R 4 represents hydrogen or a group of the formula -CH2-OH or CH2O-CO- R 1 ,
  • Rl2 is hydrogen, straight-chain or branched alkyl with up to 8
  • Carbon atoms or phenyl means that optionally up to 3 times the same or different by halogen, hydroxy, cyano or straight-chain or branched alkyl or alkoxy, each with up to 4
  • R 3 , R 4 , R6 and R ⁇ are the same or different and
  • T, V, X and Y are the same or different and represent an oxygen or sulfur atom
  • R5 and R8 are the same or different and
  • a represents a number 0 or 1
  • R 9 and RIO are the same or different and
  • D and E are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,
  • R 1 represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, optionally by cycloalkyl having 3 to 6 carbon atoms, phenyl or by a 5- to 6-membered aromatic Heterocycle are substituted with up to 3 heteroatoms from the series S, N and / or O, or represents phenyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where the ring systems optionally up to 3 times the same or different by halogen, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms, hydroxy or by one
  • Rl 1 and R 12 have the meaning given above of R 9 and R ⁇ and are the same or different with this,
  • L represents an oxygen or sulfur atom
  • R 2 for mercapto, hydroxy, straight-chain or branched alkoxy with up to 8
  • R13 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R * 4 denotes hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O,
  • R! 5 is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxy,
  • A, D, E, G, L and M are the same or different and represent hydrogen, halogen, trifluoromethyl, carboxy, hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms which in turn can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms
  • Rl and R 2 are the same or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represent phenyl, which is optionally substituted by Halogen or trifluoromethyl is substituted, or
  • Rl and R 2 together with the carbon atom form a 4-8 membered cycloalkyl ring
  • R3 represents phenyl, which is optionally up to 3 times the same or different by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or is optionally substituted by a group of the formula -OR 4 or -NR ⁇ R ",
  • R 4 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms
  • R5 or R6 are the same or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula - NR 7 R 8 ,
  • R? and R8 are the same or different and
  • A, D, E, G, L and M are the same or different and represent hydrogen, halogen, trifluoromethyl, carboxy, hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms which in turn can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,
  • R 1 and R 2 are identical or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represents phenyl which is optionally substituted by halogen or trifluoromethyl, or
  • Rl and R 2 together with the carbon atom form a 4-8 membered cycloalkyl ring
  • R 3 represents phenyl, which is optionally up to 3 times identical or different through nitro, carboxy, halogen, cyano or through straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or through straight-chain or branched alkyl with up to 6 Carbon atoms, which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and or is optionally substituted by a group of the formula -OR 4 or -NR ⁇ Ro,
  • R 4 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms
  • R5 or R6 are identical or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or mean straight-chain or branched acyl having up to 8 carbon atoms, which is optionally replaced by a group of the formula -
  • NR 7 R 8 is substituted, embedded image in which
  • R 7 and R 8 are identical or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms
  • HMG-CoA reductase inhibitors as component B in prophylaxis
  • cardiovascular diseases preferably those cardiovascular diseases associated with metabolic diseases or deficits, e.g. Disorders of fat metabolism or carbohydrate metabolism, e.g. Diabetes.
  • the invention further relates to pharmaceutical preparations containing these combinations of components A and B and their preparation.
  • the compounds of the general formula (AI) are of great interest as combination partners of component A, and the compounds of examples 1 to 119 below, in particular the compounds of examples 92 to 119, very particularly the compounds of the examples, are also of particular importance 48 and 80, (2S) -2-cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2- (IR) -hydroxy-l-phenyl-ethyl) -acetamide (Example 48) and (2S) -2-cyclo ⁇ entyl-2- [4- (2,4-dimethyl-pyrimido [1,2-a] indol-10-ylmethyl) phenyl] -
  • physiologically acceptable salts of the MTP inhibitors listed above is also claimed.
  • physiologically acceptable salts of the compounds according to the invention are e.g.
  • Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids are particularly preferred. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically acceptable salts of the MTP inhibitors listed above can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • Sodium, potassium, magnesium or calcium salts and also ammonium salts derived from ammonia, or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.
  • the MTP inhibitors and HMG-CoA reductase inhibitors according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers and also diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
  • HMG-CoA reductase inhibitors are generally within the scope of the invention for all classes of substances listed in the prior art under this term.
  • the abbreviation "HMG-CoA” stands for "3-hydroxy-3-methylglutaryl-coenzyme A”.
  • statins as described, for example, in EP 247 633, US 5 006 530, EP 33 538, US 4346 227, EP 22 478 or EP 114 027.
  • Atorvastatin (commercially available under the name Lipitor® from Parke-
  • fluvastatin commercially available under the name Lescol® from Novartis
  • Lovastatin commercially available under the name Mevacor® from Merck
  • Pravastatin commercially available under the name Lipostat® from Bristol-Myers Squibb
  • Itavastatin also called "Nisvastatin”; NK-104; systematic name: [S- [R *, S * - (E)]] - 7- [2-Cyclopro ⁇ yl-4- (4-fluo henyl) -3- quinolinyl] -3,5-dihydroxy-6-heptenoic acid);
  • Statins are usually used as lactones (see, for example, lovastatin), esters or as carboxylic acids or as salts of the carboxylic acid (see, for example, cerivastatin sodium).
  • the statins can be used in all suitable forms, ie in the form of the respective salts, hydrates, alcoholates, esters, lactones and tautomers.
  • Atorvastatin cerivastatin, fluvastatin, lovastatin, pravastatin, itavastatin, simvastatin and (+) - (3R, 5S) -Bis- (7- (4- (4-fluo ⁇ henyl) -6-isopropyl-2 - (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl) -3,5-dihydroxy-6 (E) -heptenoic acid and their respective salts, hydrates, alcoholates, esters, lactones and tautomers.
  • atorvastatin and in particular cerivastatin and their respective salts, hydrates, alcoholates, esters, lactones and tautomers are very particularly preferred.
  • salt means in the
  • physiologically acceptable salts of the compounds in question Salts with mineral acids, carboxylic acids or sulfonic acids, in particular with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid,
  • Lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid or mixed salts thereof can also be salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmo ⁇ holin, dihydro-abietylamine, 1-ephenamine or methyl-piperidine and mixed salts thereof.
  • customary bases such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, e
  • statin salts which can be used according to the invention are fluindostatin (the monosodium salt of fluvastatin); the monopotassium salt and the calcium salt of itavastatin; as well as the calcium salt of (+) - (3R, 5S) -Bis- (7- (4- (4-fluo ⁇ henyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine) 5-yl) -3,5-dihydroxy-6 (E) - heptenoic acid ("ZD 4522" or "S 4522” from Shionogi or AstraZeneca).
  • fluindostatin the monosodium salt of fluvastatin
  • statin salts which can be used according to the invention are the monosodium and the Monopotassium salts and the calcium salts of cerivastatin, atorvastatin and pravastatin
  • the monosodium salt of cerivastatin (“cerivastatin sodium") is very particularly preferably used.
  • EP-A-0 325 130 relates to substituted pyridines
  • EP-A-0-491 226 describes substituted pyridyl-dihydroxyheptenoic acid derivatives and their salts, including in particular the cerivastatin particularly preferred according to the invention (claim 6 of EP-A-0 491 226).
  • HMG-CoA reductase inhibitors which are described in Bioorganic & Medicinal Chemistry, Vol. 2, pages 437-444 (1997), the disclosure of which is hereby fully incorporated by reference.
  • HMG-CoA reductase inhibitors can be found in pharmacy in our time, 28th year, No. 3, pages 147-152 (1999).
  • Preferred MTP inhibitors are the compounds listed in the following table:
  • MTP inhibitors are the compounds listed in the table below.
  • Phytosterolaemia high blood pressure, osteoporosis, obesity, syndrome X, thrombosis, pancreatitis, constipation (constipation), brain dysfunction, cerebrovascular insufficiency, cerebral circulatory disorders, apoplexy, transient ischemic attacks (TLA) and fainting.
  • the combinations according to the invention are suitable for the treatment of secondary hypercholesterolemias and secondary hypertriglyceridemias which, for example are associated with apolipoprotein E-polymorphism (e.g. apolipoprotein phenotype E 4/4 or E 3/4), obesity, chylomicronemia and chylomicronemia syndrome, renal failure, chronic renal failure, nephrotic syndrome, diabetes mellitus type II and with hepatomas and plasmacytomas.
  • apolipoprotein E-polymorphism e.g. apolipoprotein phenotype E 4/4 or E 3/4
  • obesity chylomicronemia and chylomicronemia syndrome
  • renal failure chronic renal failure
  • nephrotic syndrome nephrotic syndrome
  • diabetes mellitus type II hepatomas and plasmacytomas.
  • Circulatory disorders and disorders of fat metabolism An example is dyslipidemia, which occurs in diabetics but also in patients who do not suffer from diabetes.
  • an unexpected synergistic effect is observed, for example when lowering the LDL (low density lipoprotein) level.
  • the amounts of components A and B used can thus be reduced in comparison to monotherapy.
  • Vitamins preferably all fat-soluble ones, in particular vitamins A and E, may be mentioned as an example. These vitamins or other components can be added individually or together.
  • Another example of an additional component is acetylsalicylic acid.
  • “Dyslipidemia” here means either hypertriglyceridemia or hypercholesterolemia, but especially mixed hyperlipidemia, ie a disease state with an elevated cholesterol level (LDL and total cholesterol) and an increased triglyceride level. This may be associated with a decrease in plasma HDL (high density lipoprotein) cholesterol or a disturbed HDL-C / LDL-C ratio.
  • the combinations according to the invention are also particularly suitable for the treatment of dyslipidemia in diabetics or insulin resistance and IGT (impaired glucose tolerance).
  • the combinations according to the invention are furthermore particularly suitable for the prophylaxis and treatment of arteriosclerosis.
  • the combinations according to the invention are preferably used in human medicine, but are also suitable for veterinary medicine, in particular for the treatment of mammals.
  • the combinations according to the invention can be administered parenterally or, preferably, orally.
  • components A and B can be converted into the customary formulations in a known manner, which can be liquid or solid formulations. Examples are tablets, dragees, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices.
  • the combinations according to the invention are well tolerated and are effective even in low doses, a wide variety of formulation variants can be implemented.
  • the two individual components A and B do not necessarily have to be taken at the same time; staggered intake may be beneficial to achieve optimal effects.
  • Fixed combinations are also suitable as a further formulation variant for the combinations according to the invention.
  • “Fixed combination” is to be understood here to mean medicinal forms in which the two components are present together in a fixed quantitative ratio.
  • Such fixed combinations can be implemented, for example, as oral solutions, but are preferably solid oral medicinal preparations, for example capsules or tablets.
  • the combinations according to the invention are dosed up to 3 times a day; preference is given to those combinations which permit one daily application.
  • the combinations according to the invention preferably contain 0.01 to 20 mg / kg, in particular 0.1 to 5 mg / kg of active ingredient of component A and 0.001 to 30 mg / kg, in particular 0.005 to 10 mg / kg of active ingredient of component B, in each case based on kg Body weight of the patient with oral application.
  • the active ingredients of components A and B are particularly suitable for being formulated in a fixed combination in the form of a fixed oral dosage form. It is generally known that the reliability of compliance (compliance) in patients depends to a large extent on the factors number of dosage forms per time of intake and size and weight of the (fixed oral)
  • Drug form is dependent. Therefore, the number of different medicinal products to be taken separately should be as small as possible (advantage of a fixed combination), and the size and weight of a fixed oral dosage form should be as small as possible with full therapeutic potency in order to ensure that the patient can take the medicinal product to be as comfortable as possible.
  • This enables fixed combinations in the form of solid oral pharmaceutical formulations to be implemented with a minimal size and minimal weight.
  • the fixed combinations according to the invention accordingly offer the highest possible patient compliance and thereby decisively improve the safety and reliability of a therapy.
  • the drug release can be controlled by combining the two components A and B and modifying the composition or functionality. For example, by delaying the release of active ingredient (retardation) of a component, the above-mentioned temporal decoupling of the onset of action can also be achieved in fixed combinations.
  • the solid oral dosage forms listed here are manufactured according to the general standard procedures. Ingredients are those that are pharmaceutically accepted and physiologically harmless, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugar (e.g. lactose), sugar alcohols
  • lubricants magnesium stearate
  • Disintegrants e.g. cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose
  • wetting agents e.g. sodium lauryl sulfate
  • retardants e.g. cellulose derivatives, polyacrylic acid derivatives
  • stabilizers e.g. flavors, e.g. Color pigments.
  • Liquid formulations are also produced using standard methods with pharmaceutically customary auxiliaries and contain the active ingredient or the two active ingredients either dissolved or suspended. Typical application volumes of these pharmaceutical preparations are 1 to 10 ml.
  • auxiliaries in these liquid formulations are: solvents (e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglycerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium lauryl sulfate) ), and others
  • Excipients required for the preparation of pharmaceutical formulations with the desired properties e.g. viscosity increasing agents, e.g. pH corrections, e.g. Sweeteners and flavors, e.g. Antioxidants, e.g. Stabilizers, e.g. Preservative.
  • viscosity increasing agents e.g. pH corrections, e.g. Sweeteners and flavors, e.g. Antioxidants, e.g. Stabilizers, e.g. Preservative.
  • the main components of the capsule formulations are, for example, gelatin or hydroxypropylmethyl cellulose.
  • the serum triglyceride-lowering effect of the substances was tested in dogs of both sexes (Beagle, breeder: Marshall Farms, Inc. North Rose NY, USA). The dogs (9 female and 9 male) were randomly assigned to the groups, taking care to assign the genders evenly to the groups.
  • Control group 3 male and 2 female dogs
  • Example 48 group 2 male and 2 female dogs
  • Combination group (Cerivastatin + Ex. 48): 3 female and 2 male dogs
  • the body weights of the dogs were 8.3 to 12.7 kg at the start of the experiment.
  • the substances were mixed with canned food (Top Dog, Sniff, Soest, Germany) in an application volume of 10 g / kg body weight. 1)
  • the control animals (n 5) received the corresponding amount of canned food without substances
  • cerivastatin was dissolved in an application volume of 0.1 ml water / kg body weight and the corresponding amount was mixed with the canned food.
  • both substances corresponding to a dose of 0.03 mg cerivastatin / kg body weight and 4 mg, for example, 48 / kg body weight were mixed into the canned feed and administered to the animals.
  • Blood was taken from the jugular vein to determine the triglyceride.
  • the blood samples were taken immediately before the first substance application at 9:00 a.m. (morning), on day 6 after the start of treatment 23 hours after the substance application and on day 10 after the start of treatment 23 hours after the last treatment.
  • the blood was taken up in heparinized Monovettes LH and centrifuged.
  • the triglycerides in the plasma were determined enzymatically using a commercially available test kit (Boehringer Mannheim, Germany) on an EPOS analyzer (Eppendorf Adjustbau, Netheler and Hinz, Hamburg, Germany). The individual differences between the plasma triglyceride concentrations after treatment and the corresponding pre-values before the first were calculated

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'une combinaison d'au moins un inhibiteur de MTP (constituant A) sélectionné et d'un inhibiteur de HMG-CoA-réductase (constituant B) pour lutter contre des maladies cardio-vasculaires. L'invention concerne également des médicaments contenant ladite combinaison et leur préparation.
PCT/EP2000/005410 1999-06-25 2000-06-13 COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS WO2001000183A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00942056A EP1196194A2 (fr) 1999-06-25 2000-06-13 COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS
AU56809/00A AU5680900A (en) 1999-06-25 2000-06-13 Combination of mtp inhibitors and hmg-coa reductase inhibitors and the use thereof in medicaments
CA002376881A CA2376881A1 (fr) 1999-06-25 2000-06-13 Combinaison d'inhibiteurs de mtp (proteine de transfert microsomale) et inhibiteurs de hmg-coa-reductase et leur utilisation dans des medicaments
JP2001505893A JP2003503342A (ja) 1999-06-25 2000-06-13 ＭＴＰ阻害剤とＨＭＧ−ＣｏＡ還元酵素阻害剤との組み合わせ並びに薬剤におけるその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19929065A DE19929065A1 (de) 1999-06-25 1999-06-25 Kombination von MTP-Inhibitoren und HMG-CoA-Reduktase-Inhibitoren und ihre Verwendung in Arzneimitteln
DE19929065.2 1999-06-25

Publications (2)

Publication Number Publication Date
WO2001000183A2 true WO2001000183A2 (fr) 2001-01-04
WO2001000183A3 WO2001000183A3 (fr) 2001-05-10

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PCT/EP2000/005410 WO2001000183A2 (fr) 1999-06-25 2000-06-13 COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS

Country Status (12)

Country Link
EP (1) EP1196194A2 (fr)
JP (1) JP2003503342A (fr)
AR (1) AR028996A1 (fr)
AU (1) AU5680900A (fr)
CA (1) CA2376881A1 (fr)
DE (1) DE19929065A1 (fr)
DO (1) DOP2000000022A (fr)
GT (1) GT200000099A (fr)
PE (1) PE20010302A1 (fr)
SV (1) SV2004000109A (fr)
UY (1) UY26218A1 (fr)
WO (1) WO2001000183A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072532A1 (fr) * 2002-02-28 2003-09-04 Japan Tobacco Inc. Compose d'esters et ses utilisation en medecine
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
US10023528B2 (en) 2011-04-13 2018-07-17 Bayer Pharma Aktiengesellschaft Branched 3-phenylpropionic acid derivatives and their use
US11344519B2 (en) 2018-07-24 2022-05-31 Bayer Pharma Aktiengesellschaft Orally administrable modified-release pharmaceutical dosage form

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10030375A1 (de) * 2000-06-21 2002-01-03 Bayer Ag Verwendung von MTP-Inhibitoren zur Senkung von ppTRL
FR2884831B1 (fr) * 2005-04-22 2007-08-10 Merck Sante Soc Par Actions Si Methode de criblage de composes inhibiteurs de la mtp
CN109053927A (zh) * 2018-08-08 2018-12-21 中山大学 一种含维生素b12基团的两亲性海藻酸钠衍生物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023593A1 (fr) * 1996-11-27 1998-06-04 Pfizer Inc. AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
WO1998050028A1 (fr) * 1997-05-01 1998-11-12 Bristol-Myers Squibb Company Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4435477A1 (de) * 1994-10-04 1996-04-11 Bayer Ag Cycloalkano-indol- und -azaindol-derivate
DE19546918A1 (de) * 1995-12-15 1997-06-19 Bayer Ag Bicyclische Heterocyclen
DE19546919A1 (de) * 1995-12-15 1997-06-19 Bayer Ag N-Heterocyclisch substituierte Phenylessigsäure-Derivate
DE19615265A1 (de) * 1996-04-18 1997-12-04 Bayer Ag Neue Pyridazino-, Pyrimido-, Pyrazino- und Triazino-indole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023593A1 (fr) * 1996-11-27 1998-06-04 Pfizer Inc. AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
WO1998050028A1 (fr) * 1997-05-01 1998-11-12 Bristol-Myers Squibb Company Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072532A1 (fr) * 2002-02-28 2003-09-04 Japan Tobacco Inc. Compose d'esters et ses utilisation en medecine
AU2003211617B2 (en) * 2002-02-28 2006-02-02 Japan Tobacco Inc. Ester compound and medicinal use thereof
KR100717098B1 (ko) * 2002-02-28 2007-05-10 니뽄 다바코 산교 가부시키가이샤 에스테르 화합물 및 그 의약 용도
AU2003211617C1 (en) * 2002-02-28 2008-03-06 Japan Tobacco Inc. Ester compound and medicinal use thereof
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
SG165154A1 (en) * 2002-02-28 2010-10-28 Japan Tobacco Inc Ester compound and medical use thereof
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
US10023528B2 (en) 2011-04-13 2018-07-17 Bayer Pharma Aktiengesellschaft Branched 3-phenylpropionic acid derivatives and their use
US10259776B2 (en) 2011-04-13 2019-04-16 Bayer Intellectual Property Gmbh Branched 3-phenylpropionic acid derivatives and their use
US11377417B2 (en) 2011-04-13 2022-07-05 Bayer Intellectual Property Gmbh Branched 3-phenylpropionic acid derivatives and their use
US11344519B2 (en) 2018-07-24 2022-05-31 Bayer Pharma Aktiengesellschaft Orally administrable modified-release pharmaceutical dosage form

Also Published As

Publication number Publication date
UY26218A1 (es) 2001-01-31
JP2003503342A (ja) 2003-01-28
EP1196194A2 (fr) 2002-04-17
SV2004000109A (es) 2004-05-07
PE20010302A1 (es) 2001-04-12
AR028996A1 (es) 2003-06-04
DOP2000000022A (es) 2008-08-15
AU5680900A (en) 2001-01-31
DE19929065A1 (de) 2000-12-28
GT200000099A (es) 2001-12-13
WO2001000183A3 (fr) 2001-05-10
CA2376881A1 (fr) 2001-01-04

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