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  • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
  • C07H5/06—Aminosugars
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  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
  • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
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  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• • A—HUMAN NECESSITIES
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  • 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
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • 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
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • 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
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • A—HUMAN NECESSITIES
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
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  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
  • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
• • C—CHEMISTRY; METALLURGY
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  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/02—Acyclic radicals
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  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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  • C07H7/02—Acyclic radicals
  • C07H7/027—Keto-aldonic acids

Definitions

• Novel benzyl radical-substituted 1,4-benzothiepin-1,1-dioxide derivatives processes for their preparation, pharmaceutical compositions containing them and their use
• the invention relates to benzyl residues substituted 1, 4-benzothiepin-1, 1-dioxide derivatives and their physiologically acceptable salts.
• the object of the invention was to provide further compounds which have a hypolipidemic effect.
• the invention therefore relates to the compound of the formula I.
• R1 (dC 6) alkyl
• R2, R2 ⁇ R3, R3 ⁇ R4 R4 1 R5, R5 1 are each independently H, Cl, Br, I, OH, - (CH 2) - OH, CF 3, NO 2, N 3, CN, S ( O) P -R6, OS (O) P -R6, COOH, COO (C 1 -C 6) AIKyI, CONH 2, CONH (C r C6) alkyl, CON [(CrC 6) alkyl] 2, (CrC 6) alkyl, (C 2 -C 6) alkenyl , (C 2 -C 6) alkynyl, O- (Ci-C 6) -alkyl, where in the alkyl radicals, more than one or all hydrogen (s) may be replaced by fluorine;
• R 6 is H, OH, (C 1 -C 6) -alkyl, NH 2 , NH (C 1 -Ce) -AlkVl, N ((C 1 -C 6 ) -alkyl) 2 ;
• R 1 (C 1 -C 6 ) -alkyl
• R 2 , R 2 , R 3 , R 3 , R 4 , R 4 , R 5, R 5 independently of one another are H, Cl, Br, I, OH, - (CH 2 )
• R6 H OH, (d-CeJ-alkyl, NH2, NH ⁇ -CeJ-alkyl, N ((C 1 -C 6) alkyl) 2;
• R1 (C 1 -Ce) -alkyl
• R1 (C 1 -Ce) -alkyl
• R3, R3 ', R4, R4 1 , R5, R5 1 independently of one another are H 1 Cl 1 Br 1 I 1 OH 1 - (CH 2 ) OH, CF 3 , NO 2 , N 3 , CN 1 S (O) p- R6, OS (O) P -R 6, (C r C6) alkylene-S (O) p-R6, (C 1 -C 6) - alkylene-OS (O) p -R6, COOH 1 COO (C 1 -C 6) -alkyl, CONH 2, CONH (C 1 - C 6) alkyl, CONKC 1 -C 6) -alkyl] 2, (C r C6) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6 ) - alkynyl, 0- (C 1 -Ce) -AIkYl 1 wherein in the alkyl radicals one, several, or all
• Hydrogen (e) may be replaced by fluorine; Phenyl, - (CH 2 ) -phenyl, - (CH 2 ) n -phenyl, O-phenyl, O- (CH 2 ) m -phenyl, - (CH 2 ) -O- (CH 2 ) m -phenyl, wherein the phenyl ring may be monosubstituted to trisubstituted with F, Cl, Br 1 I 1 OH 1 CF 3 , NO 2 , CN, OCF 3 , 0- (C 1 -Ce) -Alkyl 1 (C 1 -C 6 ) -Alkyl, NH 2 , NH (C r C 6 ) -alkyl, Nt (C 1 -Ce) -alkyl) 2 , SO 2 -CH 3 , COOH,
• R6 H OH, (Ci-C 6) -alkyl, NH 2, NH (Ci-C 6) -alkyl, N ((C r C6) alkyl) 2;
• R 1 (C 1 -C 6 ) alkyl
• R5 1 (C ⁇ ) alkylene-OS (O) 2 -R 6;
• R3, R3 1 R4, R4 1, R 5 independently of one another H, Cl, Br, I 1 1 OH - (CH 2) -OH, CF 3, NO 2, N 3, CN, S (O) P -R 6 , OS (O) P -R6, (C 1 -C 6 ) -alkylene-S (O) p -R 6, (C 1 -C 6 ) -alkylene-OS (O) p -R 6, COOH, COO (C 1 -C 6 ) C 6 ) alkyl, CONH 2 , CONH (C 1 - C 6) alkyl, CON [(Ci-C 6) alkyl] 2, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, O- (Ci -C 6 ) -alkyl, wherein in the alkyl radicals one, more, or all hydrogen (s) may be replaced by flu
• R 6 is H, OH, (C r C 6 ) alkyl, NH 2 , NH (C r C 6 ) alkyl, N ((C r C 6 ) alkyl) 2 ;
• compounds of the formula I are preferred in which the radical X is equal to O.
• compounds of the formula I are preferred in which the radical X is NH. In one embodiment, compounds of the formula I are preferred in which the radical X is CH 2 .
• compounds of the formula I are those in which the radical at least one of the radicals R2, R2 ', R3, R3 1 R4, R4 ⁇ R5 or R5 1 is equal to -O- benzyl.
• compounds of formula I are preferred in which R3 is -O-benzyl.
• compounds of the formula I are preferred in which the radical R4 is OH or OSO 2 OH.
• compounds of the formula I are preferred in which the radical R4 is OH.
• compounds of formula I are preferred in which at least one of the radicals R2, R2 1, R3, R3 1 R4, R4 1, R 5 or R 5 1 is CH 2 OSO 2 OH.
• compounds of formula I are preferred in which R5 is CH 2 OSO 2 OH.
• compounds of formula I are preferred in which R5 is equal to CH 2 OSO 2 OH and R5 is H 1.
• compounds of formula I are preferred in which R1 is ethyl and R5 is CH 2 OSO 2 OH.
• radicals or substituents can occur several times in the compounds of the formula I, they may all independently of one another have the stated meaning and be identical or different.
• the alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals in the radicals R1, R2, R2 1, R3, R3 1 R4, R4 ⁇ R5, R5 1 and R6 may be straight-chain or branched.
• the invention relates to compounds of the formula I, in the form of their tautomers, racemates, racemic mixtures, stereoisomer mixtures, pure stereoisomers, mixtures of diastereoisomers, pure diastereoisomers. The separation of the mixtures takes place, for example, by chromatographic means.
• Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric and organic acids, e.g.
• Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.
• Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
• the compounds of the invention may also be in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
• alkyl radical a straight or branched chain hydrocarbon chain of one to eight carbons, e.g. Methyl, ethyl, isopropyl, tert -butyl, hexyl, heptyl, octyl.
• the alkyl radicals may be monosubstituted or polysubstituted as described above.
• the compound (s) of the formula I can also be administered in combination with other active substances.
• the amount of a compound of Formula I required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient.
• the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day.
• an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
• Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
• Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
• the compounds according to formula I can themselves be used as compound, but they are preferably present with a compatible carrier in the form of a pharmaceutical composition.
• the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
• the carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet containing from 0.05% to 95% by weight of the active ingredient can.
• Other pharmaceutically active substances may likewise be present, including further compounds of the formula I.
• the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and / or excipients ,
• compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is of the type and severity of the treatment to be treated State and on the nature of the particular compound used in accordance with formula I is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets,
• Lozenges or tablets each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
• these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
• the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
• a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional components.
• Compressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
• Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
• compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
• Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
• Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
• Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
• Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as the carrier.
• the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
• Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
• a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
• the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
• active ingredients for the combination preparations are suitable: All Antidiabetika, which are mentioned in the red list 2006, chapter 12; all weight loss / appetite suppressants listed in the Red List 2006, Chapter 1; all lipid-lowering drugs mentioned in the Red List 2006, chapter 58. They can be combined with the compound of the formula I according to the invention in particular for the synergistic effect improvement.
• the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
• Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir) or those as are described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221, 633), inhalable insulins such. B. Exubera ® or oral insulins such as.
• GLP-1 derivatives such as Exenatide, liraglutide or those disclosed in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 of Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), as well as orally active hypoglycemic agents.
• GLP-1 derivatives such as Exenatide, liraglutide or those disclosed in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 of Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), as well as orally active hypoglycemic agents.
• the orally active hypoglycemic agents preferably comprise
• Glucagon antagonists glucokinase activators
• GLP-1 agonists e.g. those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S or those described in WO2006045799 (Solvay),
• DPP-IV dipeptidyl peptidase-IV
• Inhibitors of protein tyrosine phosphatase-1 B PTP1 B
• modulators of the sodium-dependent glucose transporter 1 or 2 SGLT1, SGLT2
• fat metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents
• the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699.
• an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699.
• the compound of the formula I is administered in combination with a cholesterol absorption inhibitor, such as e.g. Ezetimibe, Tiqueside, Pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate, Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co.
• a cholesterol absorption inhibitor such as e.g. Ezetimibe, Tiqueside, Pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate, Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co.
• the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.
• the compound of formula I is administered in combination with a fixed combination of fenofibrate with rosuvastatin.
• an antisense oligonucleotide capable of regulating apolipoprotein B gene.
• the compound of formula I is administered in combination with a PPAR gamma agonist such as rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011 (rivoglitazone).
• the compound of formula I is administered in combination with Competact TM, a solid combination of pioglitazone hydrochloride with metformin hydrochloride.
• the compound of formula I is administered in KKoommbbiinnaattiioonni mmiitt dduueettaacct TM, a solid combination of pioglitazone hydrochloride with glimepiride.
• the compound of formula I in combination with Avandamet ®, a fixed combination of rosiglitazone maleate with metformin hydrochloride is administered.
• the compound of formula I is administered in combination with PPAR alpha agonists, e.g. GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945.
• PPAR alpha agonists e.g. GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945.
• the compound of formula I is used in combination with a mixed PPAR alpha / gamma agonist, e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 00/11833, PCT / US 00/11490, DE10142734.4 or JP Berger et al. , TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.
• a mixed PPAR alpha / gamma agonist e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 00/11833, PCT / US 00/11490, DE10142734.4 or JP Berger et al. , TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.
• the compound of formula I is used in combination with a PPAR delta agonist, e.g. GW-501516 administered.
• a PPAR delta agonist e.g. GW-501516 administered.
• the compound of formula I is combined with metaglidases or with MBX-2044 or other partial PPAR gamma Agonists / antagonists administered
• AMPK AMP-activated protein kinase
• the compound of formula I is used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
• a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
• the compound of formula I is administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757 or those as described in WO2005085226, WO2005121091, WO2006010423.
• an MTP inhibitor e.g. Implitapide, BMS-201038, R-103757 or those as described in WO2005085226, WO2005121091, WO2006010423.
• the compound of formula I is used in combination with a CETP inhibitor, e.g. Torcetrapib or JTT-705 or those as described in WO2006002342, WO2006010422, WO2006012093.
• a CETP inhibitor e.g. Torcetrapib or JTT-705 or those as described in WO2006002342, WO2006010422, WO2006012093.
• the compound of formula I is used in combination with bile acid resorption inhibitor (see, for example, US 6,245,744, US 6,221,897 or WO00 / 61568), e.g. HMR 1741 or as described in DE 10 2005 033099.1 and DE 10 2005 033100.9.
• the compound of formula I is used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
• a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
• the compound of the formula I is administered in combination with an LDL receptor inducer (see US Pat. No. 6,342,512), for example HMR1171, HMR1586 or those as described in WO2005097738.
• the compound of formula I is administered in combination with Omacor® (omega-3 fatty acids, high-concentration ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
• the compound of formula I is administered in combination with an ACAT inhibitor, e.g. Avasimibe or SMP-797.
• an ACAT inhibitor e.g. Avasimibe or SMP-797.
• the compound of formula I is used in combination with an antioxidant, e.g. OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
• an antioxidant e.g. OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
• the compound of the formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B12 administered.
• the compound of the formula I is administered in combination with a lipoprotein-lipase modulator, e.g. Ibrolipim (NO-1886).
• a lipoprotein-lipase modulator e.g. Ibrolipim (NO-1886).
• the compound of formula I is used in combination with a squalene synthetase inhibitor, e.g. BMS-188494 or as described in WO2005077907.
• a squalene synthetase inhibitor e.g. BMS-188494 or as described in WO2005077907.
• the compound of formula I in combination with a lipoprotein (a) antagonist such as e.g. Gemcabene (CI-1027).
• the compound of formula I is used in combination with an agonist of GPR109A (HM74A receptor agonist), such as For example, nicotinic acid or "extended release niacin" in conjunction with MK-0524A or such compounds as described in WO2006045565, WO2006045564, WO2006069242 administered.
• GPR109A HM74A receptor agonist
• the compound of formula I is used in combination with an agonist of GPR116, as described e.g. in WO2006067531, WO2006067532.
• the compound of formula I is administered in combination with a lipase inhibitor, e.g. Orlistat or cetilistat (ATL-962).
• a lipase inhibitor e.g. Orlistat or cetilistat (ATL-962).
• the compound of the formula I is administered in combination with insulin.
• the compound of formula I is used in combination with a sulfonylurea, such as e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
• a sulfonylurea such as e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
• the compound of formula I in combination with an insulin secretion enhancing substance, such as. KCP-265 (WO2003097064).
• the compound of the formula I in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR) such.
• GDIR glucose-dependent insulinotropic receptor
• the compound of formula I is used in combination with a biguanide, e.g. Metformin, administered.
• a biguanide e.g. Metformin
• the compound of formula I is administered in combination with a meglitinide such as repaglinide or nateglinide.
• a meglitinide such as repaglinide or nateglinide.
• the compound of formula I is used in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
• the compound of formula I is administered in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
• an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose
• the compound of formula I is administered in combination with an agent which acts on the ATP-dependent potassium channel of beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• an agent which acts on the ATP-dependent potassium channel of beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• the compound of formula I is used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
• the compound of formula I is used in combination with a glycogen phosphorylase inhibitor, e.g. PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
• a glycogen phosphorylase inhibitor e.g. PSN-357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
• the compound of formula I is used in combination with glucagon receptor antagonists, such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680.
• glucagon receptor antagonists such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680.
• the compound of the formula I is used in combination with
• glucokinase such as. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50, or those as described e.g. As described in WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923.
• the compound of the formula I in combination with an inhibitor of gluconeogenesis, such as. FR-225654.
• the compound of formula I is used in combination with inhibitors of fructose-1, 6-bisphosphatase (FBPase), e.g. CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515.
• FBPase 6-bisphosphatase
• the compound of the formula I in combination with modulators of the glucose transporter-4 (GLUT4), such as. KST-48 (D.O. Lee et al .: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
• the compound of formula I is used in combination with inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT), as described e.g. As described in WO2004101528 administered.
• GFAT glutamine-fructose 6-phosphate amidotransferase
• the compound of formula I in combination with inhibitors of dipeptidyl peptidase-IV in combination with inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as. Vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC- 8200, GW-825964X, KRP-104, DP-893 or as described in WO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312, WO2005 / 012308, WO2006039325, WO2006058064, PCT / EP2005 / 007821, PCT / EP2005 / 008005, PCT / EP2005 / 008002, PCT / EP2005 / 008004,
• the compound of formula I is administered in combination with Januvia TM, a solid combination of sitagliptin phosphate with metformin hydrochloride.
• the compound of the formula I in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11 ß-HSD1), such. B. BVT-2733, JNJ-25918646, INCB-13739 or such as z.
• 11 ß-HSD1 11-beta-hydroxysteroid dehydrogenase-1
• the compound of formula I in combination with inhibitors of protein tyrosine phosphatase-1 B (PTP1 B), as z.
• PTP1 B protein tyrosine phosphatase-1 B
• WO200119830-31 WO200117516, WO2004506446, WO2005012295, WO2005116003, PCT / EP2005 / 005311, PCT / EP2005 / 005321, PCT / EP2005 / 007151, PCT / EP2005 / 01294 or DE 10 2004 060542.4.
• the compound of formula I is used in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), e.g. KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as described e.g. In WO2004007517, WO200452903, WO200452902, PCT / EP2005 / 005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597 or by A.L. Handion in Expert Opin. Ther. Patents (2005) 15 (11), 1531-1540.
• SGLT1, SGLT2 the sodium-dependent glucose transporter 1 or 2
• the compound of formula I is administered in combination with modulators of GPR40.
• the compound of formula I is used in combination with modulators of GPR119b, as described e.g. As described in WO2004041274 administered. In one embodiment, the compound of the formula I is used in combination with modulators of the GPR119, as described, for. As described in WO2005061489 (PSN-632408) administered.
• the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL), such.
• HSL hormone-sensitive lipase
• the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACC) such. B. such as in
• the compound of formula I is used in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), e.g. such as described in WO2004074288 administered.
• PPCK phosphoenolpyruvate carboxykinase
• the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as.
• GSK-3 beta glycogen synthase kinase-3 beta
• the compound of formula I in combination with an inhibitor of protein kinase C beta (PKC beta), such as. B. Ruboxistaurin administered.
• the compound of formula I in combination with an endothelin A receptor antagonist, such as. B. avosentan (SPP-301).
• an endothelin A receptor antagonist such as. B. avosentan (SPP-301).
• the compound of the formula I is administered in combination with inhibitors of the "1-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022553, WO2005097129.
• IKK inhibitors inhibitors of the "1-kappaB kinase"
• the compound of the formula I in combination with modulators of the glucocorticoid receptor, as described, for. As described in WO2005090336 administered.
• the compound of the formula I is used in combination with CART modulators (see “cocaine-amphetamine-regulated transcript-influenced transient-energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al .: Hormone and Metabolism Research (2001 ), 33 (9), 554-558); NPY antagonists, e.g. Naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A); NPY-5 receptor antagonists such as L-152804, S-2367 or as such.
• CART modulators see “cocaine-amphetamine-regulated transcript-influenced transient-energy metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al .: Hormone and Metabolism Research (2001 ), 33 (9), 554-558); NPY antagonists, e.g.
• Peptide YY 3-36 PYY3-36 or analogous compounds such.
• CJC-1682 PYY3-36 conjugated to human serum albumin via Cys34
• CJC-1643 derivative of PYY3-36 conjugated to serum albumin in vivo
• CB1R (cannabinoid receptor 1) antagonists such as rimonabant, SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof or those as described, for example, in EP 0656354, WO 00/15609, WO2001 / 64632, WO200001 / 64633, WO2001 / 64634, WO02 / 076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037, WO2004048317, WO2004058145 , WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO
• WO200500974, WO2004111033-34, WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837, WO2005028456, WO2005063761-62, WO2005061509, WO2005077897, WO2006047516, WO2006060461, WO2006067428, WO2006067443 are described);
• MC4 agonists eg 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3-benzyl-2-methyl-3-oxo-2,3,3a, 4,6, 7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxo-ethyl] -amide (WO 01/91752) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those as described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WO20050222014, US20050176728, US20050164914, US20050124636, US200501
• Orexin receptor antagonists eg 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] naphthyridin-4-yl-urea hydrochloride (SB-334867-A) or those as described, for example, in US Pat in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224); Histamine H3 receptor agonists (eg, 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propane-1 oxalic acid salt (WO 00/63208) or those as described in WO200064884, WO2005082893); CRF antagonists (eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00
• beta-3 adrenoceptor such as e.g. 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethyl-amino] -ethanol hydrochloride (WO 01/83451) or solabegron ( GW-427353) or N-5984 (KRP-204) or those as described in JP2006111553;
• MSH melanocyte-stimulating hormone
• MCH melanin-concentrating hormone receptor antagonists
• CCK-A agonists such as ⁇ 2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl- indol-1-yl ⁇ -acetic acid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or those as described in WO2005116034;
• Serotonin reuptake inhibitors e.g., dexfenfluramines
• mixed sertonine and noradrenergic compounds e.g., WO 00/71549
• 5-HT receptor agonists e.g. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111);
• 5-HT2C receptor agonists such as Lorcaserin hydrochloride (APD-356) or BAT
• 5-HT6 receptor antagonists as e.g. in WO2005058858 are described; Bombesin receptor agonists (BRS-3 agonists;
• Growth hormone e.g., human growth hormone or AOD-9604
• human growth hormone e.g., human growth hormone or AOD-9604
• Ghrelin antagonists such as
• TRH agonists see, e.g., EP 0 462 884; decoupling protein 2- or 3-modulators; Leptin agonists (See, e.g., Lee, Daniel W., Leinung, Matthew C; Rozhavskaya Arena,
• DGATs diacylglycerol O-acyltransferases
• Inhibitors of fatty acid synthase e.g. C75 or those as described in WO2004005277; oxyntomodulin; Oleoyl-estrone
• thyroid hormone receptor agonists such as. B: KB-2115 or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316.
• the other active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
• the other active ingredient is trodusquemine.
• the further active ingredient is a modulator of the enzyme SIRT1, a member of the human sirtuin enzyme family.
• the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
• the other active ingredient is dexamphetamine or amphetamine.
• the other active ingredient is fenfluramine or dexfenfluramine. In yet another embodiment, the other active ingredient is sibutramine.
• the other active ingredient is mazindol or phentermine.
• the further active ingredient is a diphenylazetidinone derivative, e.g. in US 6,992,067 or US 7,205,290.
• the compound of formula I in combination with bulking agents preferably insoluble bulking agents
• bulking agents preferably insoluble bulking agents
• Caromax is a carob-containing product of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
• Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®.
• Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars.
• the expression vector for human IBAT was introduced by stable transfection into CHO (Chinese hamster ovary) cells.
• CHO Choinese hamster ovary
• 400 ⁇ g / ml geneticin was added to the cell culture medium (Ham's F12 medium supplemented with 10% fetal calf serum, 100 units / ml penicillin, 100 units / ml streptomycin).
• the functionality of the individual cell clones resulting from the selection was tested by their uptake activity for radiolabelled taurocholic acid ([ 3 H] -TCA).
• Uptake activity for [ 3 H] -TCA hereinafter referred to as CHO-hlBAT, was selected for the further tests and further cultured in the presence of 400 ⁇ g / ml of geneticin.
• CHO-hlBAT cells were seeded at a concentration of 40,000 cells per well in poly-D-lysine-coated 96-well plates in cell culture medium and cultured for 24 h. The cells were then washed once with sodium-free transport assay buffer (14 oMM choline chloride, 2 mM potassium chloride, 1 mM magnesium chloride, 1 mM calcium chloride, 10 mM HEPES / Tris, pH 7.5) and then either with sodium-free transport assay buffer as a negative control or with sodium-containing transport assay buffer (14 mM sodium chloride, 2 mM potassium chloride, 1 mM magnesium chloride, 1 mM calcium chloride, 1 mM HEPES / Tris, pH 7.5) as a positive control for 30 min at room temperature.
• sodium-free transport assay buffer 14 oMM choline chloride, 2 mM potassium chloride, 1 mM magnesium chloride, 1 mM calcium chloride, 10 mM HEPES
• test wells were also incubated in different concentrations in the presence of the compound to be investigated for 30 min at room temperature in sodium-containing transport assay buffer.
• the test substances were diluted starting from a 10 mM stock solution in dimethyl sulphoxide corresponding to transport assay buffer (40 .mu.l / well).
• the test was then started by adding 10 ⁇ l / well of a mixture of radiolabelled taurocholic acid ([ 3 H] -TCA) and unlabeled taurocholic acid.
• the final concentration of taurocholic acid in the test was 10 ⁇ M.
• IC50 value The half-maximal inhibitory activity of the test compound (IC50 value, inhibitory concentration 50) was determined as follows:
• Diabetes mellitus especially type 2 diabetes, including the prevention of associated sequelae.
• Special aspects in this context are hyperglycemia,
• Desaturation index (e.g., ratio 18: 1/18: 0n-9, 16: 1/16: 0 n-7 or 18: 1 n-9 + 16: 1 n-7/16: 0 fatty acids)
• abdominal circumference - dyslipidemia e.g., hypertriglyceridemia and / or low HDL
• Cardiac insufficiency for example (but not limited to), after heart attack, hypertensive heart disease or cardiomyopathy
• NASH non-alcoholic hepatitis - non-alcoholic steatohepatitis
• Apolipoprotein deficiency e.g., ApoCII or ApoE deficiency
• Reactions or cell differentiation may be involved are:
• Atherosclerosis such as (but not limited to) coronary sclerosis including angina pectoris or myocardial infarction, stroke, ischemic stroke and transient ischemic attack (TIA) - peripheral occlusive disease
• lipomatous carcinomas such as liposarcomas - solid tumors and neoplasms such as, but not limited to, cancers of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, lung, kidney and urinary tract carcinomas. genital tract, prostate cancer, etc.
• Parkinson's disease Erythematosquamous dermatoses such as psoriasis
• dermatitis such as seborrheic dermatitis or light dermatitis
• Keratitis and keratoses such as seborrheic keratoses, senile keratoses, actinic keratoses, light-induced keratoses or keratosis follicularis
• HPV Human papillomavirus
• Skin cancer such as basal cell carcinoma, melanoma or cutaneous T cell lymphoma - localized benign epidermal tumors such as keratoderma, epidermal nevi
• PCOS polycystic ovary syndrome
• ARDS acute respiratory distress syndrome
• Myopathies and lipid myopathies (such as carnitine palmitoyltransferase I or II)
• Example 2 is prepared starting from amines 3 and di-n-butylaniline (US Pat. No. 5,994,391) with triphosgene analogously to the synthesis of Example 1, and Bsp 2 is obtained in 90% yield as a colorless solid.
• Example 3 is prepared starting from amines 9 and the aniline 4 (US 5,994,391) with triphosgene analogous to the synthesis of Example 1 and is obtained in 80% yield Bsp 3 as a colorless solid.
• TLC methylene chloride / methanol / concentrated ammonia 100/7/1).
• R f 0.5.
• MS (M + H) + 816.48.
• This disulfate can also be obtained as a major product using twice the amount of sulfur trioxide complex.
• Ex 4 (ammonium salt) dissolved in 150 ml of methanol are vigorously stirred together with 200 g of potassium-loaded Amberlite IR 120 at room temperature for one hour. The ion exchange resin is then separated and washed 2 times with methanol. The solvent is einumblegt and gives 9 g of crude product. This is dissolved in 40 ml of methanol and diluted with 150 ml of ethanol. 4.5 g of potassium salt Ex. 4 with a melting point of 220 ° C. (under Decomposition).
• Example 4 By slow crystal growth from a solution of 2.5 g of potassium salt Ex 4 in 50 ml of methanol and 100 ml of ethanol (over 2 days) to obtain single crystals using this, the structure and stereochemistry of Example 4 could be confirmed by a single crystal X-ray structure.
• Ex 4 (ammonium salt) are dissolved in 11 ml of water (yellowish clear solution) and treated with a solution of 120 mg of zinc chloride in 13 ml of water. The spontaneously precipitate is stirred for 2 hours at room temperature and then filtered with suction. This gives crystalline zinc salt (977 mg 88%) Ex. 4.
• Example 6 is prepared analogously to the synthesis described for Example 4 starting from 105 mg of Example 2 and 67 mg (65%) of ammonium salt are obtained.

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