WO2001000189A2 - Combinaison d'inhibiteurs de mtp et principes actifs agissant sur le metabolisme et leur utilisation dans les medicaments - Google Patents

Combinaison d'inhibiteurs de mtp et principes actifs agissant sur le metabolisme et leur utilisation dans les medicaments Download PDF

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Publication number
WO2001000189A2
WO2001000189A2 PCT/EP2000/005575 EP0005575W WO0100189A2 WO 2001000189 A2 WO2001000189 A2 WO 2001000189A2 EP 0005575 W EP0005575 W EP 0005575W WO 0100189 A2 WO0100189 A2 WO 0100189A2
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carbon atoms
chain
straight
branched alkyl
phenyl
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PCT/EP2000/005575
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German (de)
English (en)
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WO2001000189A3 (fr
Inventor
Rudi Grützmann
Ulrich Müller
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Bayer Aktiengesellschaft
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Priority to AU56829/00A priority Critical patent/AU5682900A/en
Publication of WO2001000189A2 publication Critical patent/WO2001000189A2/fr
Publication of WO2001000189A3 publication Critical patent/WO2001000189A3/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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to the use of a combination of at least one selected MTP inhibitor (component A) and metabolism-influencing
  • Active ingredients for combating diseases, medicaments containing this combination and their preparation.
  • the present invention relates to the use of a combination of at least one MTP inhibitor as component A of the general formula (AI)
  • R ° is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R3 and R ⁇ together with the double bond connecting them form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical,
  • Rl / R ⁇ and R- / R4 optionally up to 3 times the same or different by halogen, trifluoromethyl, carboxy, hydroxy, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or are substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn can be substituted by hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms,
  • 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 represents a group of the formula -NR 9 ,
  • R 9 is hydrogen or straight-chain or branched alkyl with up to 6 Carbon atoms, which is optionally substituted by hydroxy or phenyl,
  • 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 are 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 optionally by a group of the formula -OR ⁇ or -NR! 1R12 are substituted,
  • RIO 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
  • Rl3 and Rl4 are the same or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms
  • R represents hydrogen, carboxy or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms
  • Rl5 is 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 denotes hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl with up to 6 carbon atoms,
  • R ' represents 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
  • R- ⁇ R O , R7 and R ° are the same or different and
  • R 9 trifluoromethyl, benzyl or a 5- to 7-membered, optionally benzocondensed heterocycle with up to 3 heter atoms from the
  • Row S, N and / or O means, which is optionally substituted up to 3 times identically or differently by halogen, phenyl, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or a group of the formula -S (O) a -R ⁇ means
  • a represents a number 0, 1 or 2
  • RIO means straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may optionally be replaced by straight-chain or branched acyl having up to 6 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
  • Rl 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, hydroxy, straight-chain or branched alkyl or Alkoxy is each substituted with up to 4 carbon atoms,
  • R ⁇ 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 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,
  • R4 represents hydrogen or a group of the formula -CH2-OH or CH2O-CO- R 1 1 ,
  • RU is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, cyano or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
  • T represents a nitrogen atom or the -CH group
  • R6, R ?, R10 and R11 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,
  • Rl stands for cycloalkyl with 3 to 10 carbon atoms or for straight-chain or branched alkyl with 1 to 10 carbon atoms, or for phenyl, which may optionally be identical or different up to 2 times through halogen, cyano, hydroxy, straight-chain or branched alkyl or alkoxy up to 4 carbon atoms is substituted,
  • R2 for hydrogen or straight-chain or branched alkyl with up to 3
  • R ⁇ 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, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,
  • R ⁇ represents hydrogen or a group of the formula -CH2-OH or CH2O-CO- R 1 ,
  • R12 is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, cyano or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
  • R ⁇ , R ⁇ , R ⁇ and R ⁇ are the same or different and
  • cycloalkyl having 3 to 7 carbon atoms or aryl having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally substituted by halogen, hydroxy or aryl having 6 to 10 carbon atoms.
  • 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
  • Hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally by cycloalkyl having 3 to 8 carbon atoms, or by a 5- to 6-membered, aromatic, optionally benzo-condensed heterocycle are substituted by up to 3 heteroatoms from the series S, N and / or O, or by aryl having 6 to 10 carbon atoms, the cycles in turn being identical or different up to 3 times by a 5- to 6-membered aromatic heterocycle up to 3 heteroatoms from the series S, N and / or O, or by phenyl, benzyl, halogen, hydroxy, carboxyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each having up to 6 carbon atoms, can be substituted, or
  • a number means 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,
  • Rl represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be 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,
  • Rl 1 and Rl2 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 having up to 8 carbon atoms or for the group of the formula
  • R 13 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 14 represents hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O
  • Rl5 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 hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms.
  • R1 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 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 identical 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 Koh is substituted, 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 ⁇ or -NR ⁇ R6,
  • R ⁇ is 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
  • R7 and R 8 are the same or different and
  • Hydrogen or straight-chain or branched acyl with up to 8 carbon atoms mean
  • 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 and
  • R3 stands for phenyl, which is optionally up to 3 times identical 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 ⁇ or -NR ⁇ R ⁇ .
  • R4 is hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms
  • R 7 and R 8 are the same or different and
  • component B optionally in an isomeric form and their salts with active ingredients of component B from the group CETP inhibitors, antidiabetic agents, with the exception of glucosidase and amylase inhibitors, anti-obesity agents, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and thyromimetics, HMG-CoA inhibitors
  • Reductase gene expression Reductase gene expression, squalene synthesis inhibitors, ACAT inhibitors, blood flow-promoting agents, platelet aggregation inhibitors, anticoagulants and angiotensin II receptor antagonists,
  • cardiovascular diseases especially cardiovascular diseases, preferably those cardiovascular diseases that are associated with metabolic diseases or deficits, such as Disorders of fat metabolism or carbohydrate metabolism, e.g. Diabetes.
  • the invention further relates to pharmaceutical preparations containing them
  • the compounds of the general formula (AI) are of great interest as combination partners of component A, and the compounds of Examples 1 to 11 below, in particular those, are also of particular importance
  • physiologically acceptable salts of the MTP inhibitors listed above are, for example, salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • salts with hydrochloric acid, hydrobromic acid are particularly preferred.
  • seric 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, ethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.
  • the MTP inhibitors and active ingredients of component B 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 diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
  • CETP-In ibitoren are mentioned for example in EP-A 818 197, EP 818 448, WO 98/34 895, WO 99/14 215, WO 99/14 174 or in WO 99/15 504, the content of which is hereby incorporated by reference .
  • the other active ingredients of component B according to the invention are also known from the literature. Examples include:
  • Antidiabetics that do not inhibit glucosidase or amylase are in particular sulfonylureas, such as glibenclamide, repaglinide or glimepiride, insulin, insulin-sensitizing agents, such as thiazolidinediones, troglitazones, rosiglitazones, pioglitazones, metformin and proglycosyn.
  • sulfonylureas such as glibenclamide, repaglinide or glimepiride
  • insulin insulin-sensitizing agents, such as thiazolidinediones, troglitazones, rosiglitazones, pioglitazones, metformin and proglycosyn.
  • Antioxidants are to be understood in particular as probucol.
  • Nitrogen mustard derivatives such as Cyclophosphamides, trofosfamides, ifosfamides, melphalan, chlorambucil, dacarbazines; N-nitrosourea derivatives such as e.g. Cannustin, lomustine, nimustine; aziridines; cisplatin; busulfan; Antimetabolites, preferably folic acid antagonists such as e.g. Methotrexate and aminopterin, pyrimidine analogs such as e.g. Fluorouracil, purine analogues such as e.g. Azathioprine, mercaptopurine;
  • Mitosis inhibitors such as Colchicine, podophyllotoxin, vinblastine, vincristine, vindesine and cytostatic antibiotics such as actinomycin, anthracycline, aclarubicin, daunorubicin, doxorubicin, epirubicin, bleomycin, as well as hormones and hormone antagonists that inhibit the growth of cancer cells.
  • Calcium antagonists are to be understood in particular to mean: nifedipine, nitrendipine, nimodipine, nisoldipine, nicardipine, barnidipine, felodipine, lacidipine, nilvadipine, flunarizine, isradipine, amlodipine, lercanidipine, verapamil, gallopamil, filtinil, diltiazem,.
  • ACE angiotensin converting enzyme
  • Beta blockers such as
  • Dextrothyroxine is an example of thyroid hormones or thyroid mimetics.
  • Pentoxifylline, naftidrofuryl and buflomedil may be mentioned as examples of agents which promote circulation.
  • Platelet aggregation inhibitors may be mentioned in particular: ticlopidine, cilostazol, xemilofiban, PGI2 analogs, aspirin, xemilofiban, tirofiban, roxifiban, sibrafiban, lamifiban, xemilofiban, fradafiban, sibrafiban, lefradafiban.
  • Heparin is an example of an anticoagulant.
  • angiotensin II receptor antagonists saralasin, valsartan and losartan.
  • Preferred MTP inhibitors are the compounds listed in the following table:
  • MTP inhibitors are the compounds listed in the table below.
  • the combinations according to the invention show a broad and varied spectrum of action.
  • tumors such as hematological tumors, solid tumors, metastatic tumors, leukaemias such as acute and chronic myolic leukemia, acute and chronic lymphatic leukemia, lymphogranulomatosis (Hodgkin's disease) and non-Hodgkin lymphomas.
  • leukaemias such as acute and chronic myolic leukemia, acute and chronic lymphatic leukemia, lymphogranulomatosis (Hodgkin's disease) and non-Hodgkin lymphomas.
  • diseases which are influenced or caused by more than one risk factor, such as, for example, arteriosclerosis, diseases of the coronary arteries, in particular the arterial coronary arteries, elevated semipipids, hypercholesterolemia, hypertriglyceridemia, and an increase in semicholesterol as well as the serum triglycerides combined with increased VLDL (very low density lipoprotein) or LDL (low density lipoprotein) and / or increase in chylomicrons, eg chylomicronemia in plasma and syndrome X.
  • VLDL very low density lipoprotein
  • LDL low density lipoprotein
  • the combinations according to the invention are furthermore suitable for the treatment of secondary hypercholesterolemias and secondary hypertriglyceridemias, which e.g. are associated with apolipoprotein E polymorphism (e.g. apolipoprotein phenotype
  • E 4/4 or E 3/4 obesity, chylomicronemia and chylomicronemia syndrome, renal insufficiency, chronic renal insufficiency, nephrotic syndrome, type II diabetes mellitus and with hepatomas and plasma cytomas.
  • dyslipidemia which occurs in diabetics but also in patients who do not suffer from diabetes.
  • LDL low density lipoprotein
  • 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.
  • Hypercholesterolemia but especially a mixed hyperlipidemia understood become, that is, a disease state with increased cholesterol (LDL and total cholesterol) and increased triglyceride levels. This may be associated with a decrease in plasma HDL (high density lipoprotein) cholesterol or a disturbed HDL-C / LDL-C ratio.
  • LDL low density lipoprotein
  • the combinations according to the invention are also particularly suitable for the treatment of dyslipidemia in diabetics or insulin resistance and IGT.
  • the combinations according to the invention are furthermore particularly suitable for the prophylaxis and treatment of
  • the combinations according to the invention are surprisingly well tolerated, although there are indications of adverse effects in the literature, such as e.g. Warnings about combinations with lipid-lowering drugs.
  • 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.
  • the active ingredients of 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, coated tablets, pills, capsules, granules, aerosols, simpe, emulsions, suspensions, juices.
  • 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 when administered orally.
  • 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.
  • Combinations therefore offer the highest possible patient compliance and thus 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 are physiologically harmless, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugar (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders ( For example, polyvinylpyrrolidone, gelatin, starch and cellulose derivatives), and all other auxiliaries which are used for the production of pharmaceutical formulations of the desired Properties are required, e.g. lubricants (magnesium stearate), e.g. 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 by 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 triglcerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium lauryl sulfate) ), as well as other auxiliary substances that are required for the production of pharmaceutical formulations of the desired properties, eg viscosity increasing agents, e.g. pH corrections, e.g. Sweeteners and flavors, e.g. Antioxidants, e.g. Stabilizers, e.g. Preservative.
  • solvents e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglcerides
  • the main components of the capsule formulations are, for example, gelatin or hydroxypropylmethyl cellulose.

Abstract

L'invention concerne l'utilisation d'une combinaison contenant au moins un inhibiteur de MTP (composante A) sélectionné et des principes actifs agissant sur le métabolisme (composante B) destiné à lutter contre des maladies. L'invention concerne également des médicaments contenant cette combinaison et leur production.
PCT/EP2000/005575 1999-06-25 2000-06-16 Combinaison d'inhibiteurs de mtp et principes actifs agissant sur le metabolisme et leur utilisation dans les medicaments WO2001000189A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56829/00A AU5682900A (en) 1999-06-25 2000-06-16 Combination of mtp inhibitors and active agents that influence the metabolism and use thereof in medicaments

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Application Number Priority Date Filing Date Title
DE19929012A DE19929012A1 (de) 1999-06-25 1999-06-25 Kombination von MTP-Inhibitoren und stoffwechselbeeinflussenden Wirkstoffen und ihre Verwendung in Arzneimitteln
DE19929012.1 1999-06-25

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WO2003072532A1 (fr) * 2002-02-28 2003-09-04 Japan Tobacco Inc. Compose d'esters et ses utilisation en medecine
EP1367058A1 (fr) * 2002-05-31 2003-12-03 Yamanouchi Pharmaceutical Co. Ltd. Dérivés de tetrahydropyrane
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

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WO2007143164A1 (fr) * 2006-06-02 2007-12-13 San Diego State University Research Foundation Compositions et procédés pour améliorer l'hyperlipidémie

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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

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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 (9)

* 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
EP1367058A1 (fr) * 2002-05-31 2003-12-03 Yamanouchi Pharmaceutical Co. Ltd. Dérivés de tetrahydropyrane
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

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