Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61P3/08—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
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

• the invention relates to the use of amino-substituted 8-N-benzimidazoles and those physiologically acceptable salts for the manufacture of a medicament for lowering blood sugar. These compounds are said to be particularly useful in the manufacture of a medicament for the treatment of diabetes.
• EP 1069124 describes 2-benzimidazolylamines as ORL-I receptor agonists.
• WO 97/12615 describes benzimidazole derivatives as 15-LO inhibitors.
• WO 02/04425 describes structure-like virus polymerase inhibitors.
• the invention had the object of providing compounds that develop a therapeutically useful blood sugar lowering effect. These compounds should be particularly suitable for the treatment of diabetes.
• the invention therefore relates to the use of the compounds of the formula I,
• R 20, R 21 independently of one another H, (C 1 -C 10 ) -AUCyI, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -
• Cio aryl or heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN 5 NO 2 , SH, OH , (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR 7, OP (O) (OR 7) 2 , NR7R8, NR7CONR7R8, COR7,
• R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, -CF 3 , (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl, heterocyclyl, (C ! -C 6 ) Alkylene-CONR9R10, C0NR9R10, (QC ⁇ -alkylene-
• R9, RIO each independently H, (Ci-C 6) -alkyl, (C 1 -C 6) alkylene- (C 6 -C 10) -aryl, - (C 6 - C 10) - aryl, heterocyclyl or ( CrC 6 ) -alkylene heterocyclyl;
• R4, R5 independently of one another are H, (QC ⁇ -alkyl or (C 3 -Cs) -cycloalkyl, where (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl may be substituted by F, Cl, Br, I, CN,
• n 0, 1 or 2;
• R 20, R 21 independently of one another H, (C 1 -C 10 ) -AUCyI, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -
• Alkyl, cycloalkyl, alkenyl, alkynyl, acyl, aryl and heterocyclyl radicals may be monosubstituted or polysubstituted with F, Cl, Br, I, CN, NO 2 , SH, OH, (C 1 - Ce) -AUCyI, O- (C 1 -Ce) -AUCyI or S - (C 1 -C 6 ) -alkyl;
• R 3 is (C 2 -C 10 ) -AUcenyl, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl;
• R 4, R 5 independently of one another are H, (C 1 -C 6) -AUCyI or (C 3 -C 8 ) -cycloalkyl, where (C 1 -
• C 6 ) - alkyl or (C 3 -C 8 ) -cycloalkyl may be substituted by F 5 Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -Ce) -AUCyI, Nt (C 1 -Q) -AlkVl) 2 , OH, 0 (C 1 -C 6 ) -alkyl, O-aryl, OHeteroaryl, S (C 1 -Ce) -AUCyI, S (O) (C 1 -Ce) -AlkVl or S ( O) 2 (C 1 -
• R 20, R 21 independently of one another are H, (C 1 -C 6 ) -alkylene- (C 6 -C 10 ) -aryl or S (O) 2 -aryl, where the aryl radicals may be monosubstituted or polysubstituted by F, Cl, Br,
• R 3 is (C 2 -C 10 ) alkenyl, (C 1 -C 6 ) alkylene (C 6 -C 10 ) aryl;
• the invention relates to the use of the compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
• radicals or substituents can occur several times in the compounds of the formula I, they may all independently of one another have the meanings indicated and be identical or different.
• Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid
• organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethionic,
• 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-l, 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.
• physiologically functional derivative denotes any physiologically acceptable derivative of a compound of the formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
• the physiologically functional derivatives also include prodrugs of the compounds according to the invention.
• prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
• 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 is understood as meaning a straight-chain or branched hydrocarbon chain having one or more carbons, such as, for example, methyl, ethyl, isopropyl, tert-butyl, hexyl.
• the alkyl radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F 5 Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C i -QOalkyl, CONt (C 1 -C 6 ) AUCyI] 2 , cycloalkyl, (C 2 -C 6 ) alkenyl 5 (C 2 -C 6 ) alkynyl, O- (C 1 -Ce) -AUCyI , O-CO- (C 1 -Ce) -AUCyI, 0-CO- (C
• N (heterocyclic) -CO-N ((C 1 -C 6) alkyl) aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocycle) -CO-N- (aryl) 2 , aryl , O- (CH 2 ) n -aryl and O- (CH 2 ) n -heterocycle, where n O-6, where the aryl radical or heterocyclic radical can be monosubstituted to trisubstituted by F 5 Cl, Br , I, OH 5 CF 3 , NO 2 , CN 5 OCF 3 , 0- (C 1 -Ce) -AUCyI 5 (C 1 -Ce) -AUCyI 5 NH 2 , NH (C 1 -Ce) -AUCyI 5 N ((C r C6) - alkyl) 2, SO 2 -CH 3, COOH, COO- (C 1 -Ce)
• the alkenyl radicals may be substituted one or more times by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C 1 -C 6) AIlCyI 5 CONH 2, CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 4 ) alkyl 6 ) - alkyl, O-CO- (C 1 -Cg) -AlkVl, 0-CO- (C 1 -Ce) -ATyI, O-CO- (dC 6 ) -heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1
• AlMnylrest is meant a straight or branched hydrocarbon chain having two or more carbons and one or more triple bonds, e.g. Ethynyl, propynyl, butynyl, hexynyl.
• the alkynyl radicals may be mono- or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) AUCyI, CONH 2 , CONH (C 1 -C 6) alkyl, CONt (Ci-C 6) AIlCyI] 2, cycloalkyl, (C 2 -C 6) - alkenyl, (C 2 -C 6) - alkynyl, 0- (C 1 -C 6 ) - alkyl, 0-CO- (C 1 -Ce) -AUCyI, 0-CO- (C 1 -Ce) -ATyI, 0-CO- (C 1 -C 6 ) -heterocycle;
• suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C
• aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
• the aryl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(Ci-C 6 ) alkyl] 2> cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (Ci-C 6 ) Alkyl, 0-C0- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (dC 6 ) -heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -Ce) -Allyl, SO 2 N [(dC 6
• C ( NH) (NH 2), NH 2, NH- (Ci-C 6) -alkyl, N ((C r C6) alkyl) 2, NH-CO- (C 1 -C 6) alkyl , NH-C00- (C 1 -Ce) -AlkVl, NH-CO-aryl, NH-CO heterocycle, NH-COO-aryl, NH-COO heterocycle, NH-CO-NH- (C 1 -C 6 ) -Alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N ((C 1 -C 6 ) -alkyl) - CO- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) - Alkyl) -COO- (dC 6 ) -alkyl, Nt (C 1 -Ce) -AlkVl) -CO-ATyI
• a cycloalkyl radical is to be understood as meaning a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds), which is composed exclusively of carbon atoms, e.g. Cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
• the cycloalkyl radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br 5 , CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) AuCyI, CON [(C 1 -C 6 ) alkyl] 2 , cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) - alkyl, 0-C0- (CrC f O-alkyl, 0-CO- (C 1 -Ce) -ATyI, O-CO ⁇ CrC ⁇ heterocycle;
• suitable groups such as, for example: F, Cl, Br 5 , CF 3 , NO 2 , N 3 , CN, COOH, COO (
• Heterocyclyl, heterocycle or heterocyclic radical are understood as meaning rings and ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, wherein the
• Heterocyclic or the heterocyclic radical is fused with benzene nuclei.
• the heterocycle or the heterocyclic radical may be aromatic, saturated aliphatic or partially unsaturated aliphatic.
• heterocyclyl radicals or "heterocyclic radicals" are acridinyl, azocinyl,
• Pyridyl is both 2-, 3- and 4-pyridyl.
• Thienyl is both 2- and 3-thienyl.
• Furyl is both 2- and 3-furyl.
• N-oxides of these compounds e.g. l-oxy-2-, 3- or 4-pyridyl.
• heterocyclic rings or heterocyclic radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) AlCl y , CONH 2 , CONH (C 1 -C 6 ) AlCl y, CONt (C 1 -C 6 ) acyl] 2 , cycloalkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, O- (Ci-C 6) -alkyl, 0-CO- (Ci-C6) - alkyl, 0-CO- (C 1 -C 6) - aryl, O-CO- (QC ⁇ heterocycle; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C r C 6 ) alkyl,
• the compound (s) of the formula (I) can also be administered in combination with other active substances.
• 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 conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
• Suitable infusion solutions for these purposes may include, for example, from 0.1 ng to 10 ng, typically from 1 ng to 10 ng per milliliter.
• Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
• injectable ampoules, and orally administrable unit dose formulations such as tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
• the compounds according to formula I can themselves be used as compound, but they are preferably with a tolerable carrier in the form of a pharmaceutical Composition before.
• 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 may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
• 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 administration in each individual case is of the type and the severity of the condition to be treated and on the nature of the particular compound used in accordance with formula I.
• 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 teabags, 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 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 ingredients.
• 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 can be prepared by molding 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.
• a carrier For example, petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances may be used.
• 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).
• the compounds of the formula I can be administered alone, but also in combination with other active substances.
• active ingredients for the combination preparations are suitable:
• Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or Apidra ®, fast-acting insulins (see US No. 6,221,633), GLP-I derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
• insulin derivatives such as Lantus ® (see www.lantus.com) or Apidra ®, fast-acting insulins (see US No. 6,221,633), GLP-I derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
• PPAR peroxisome
• the compounds of formula I are administered in combination with a cholesterol reso ⁇ tion inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside, or with a compound as described in PCTYEP 2004/00269, WO 2004/000804, WO 2004/000803, WO 2004/000805, EP 0114531, US 6,498,156 described.
• a cholesterol reso ⁇ tion inhibitor e.g. Ezetimibe, Tiqueside, Pamaqueside
• the compounds of formula I are administered in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
• a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
• the compounds of formula I in combination with PPAR alfa agonist such as e.g. GW 9578, GW 7647.
• a mixed PPAR alfa / gamma agonist such as GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in WO 00/64888, WO 00/64876, DE10142734.4.
• the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
• a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
• MTP Microsomal triglyceride transfer protein
• the compounds of formula I are used in combination with bile acid resorption inhibitor (see for example US 6,245,744 or US 6,221,897), e.g. HMR 1741 administered.
• CETP cholesteryl ester transfer protein
• the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
• a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
• LDL Low Density Lipids
• ACAT acyl-coenzyme Axholesterol acyltransferase
• the compounds of formula I are administered in combination with an antioxidant, such as OPC-14117. In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor such as NO-1886.
• the compounds of formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
• the compounds of formula I are administered in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
• a squalene synthetase inhibitor e.g. BMS-188494.
• the compounds of formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
• a lipoprotein (a) antagonist e.g. CI-1027 or nicotinic acid.
• the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
• a lipase inhibitor e.g. Orlistat
• the compounds of the formula I are administered in combination with insulin.
• the compounds of formula I are used in combination with a sulfonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of formula I are used in combination with a biguanide, e.g. Metformin, administered.
• a sulfonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
• a biguanide e.g. Metformin
• the compounds of formula I in combination with a meglitinide, e.g. Repaglinide, administered.
• a meglitinide e.g. Repaglinide
• the compounds of formula I are used in combination with a thiazolidinedione, e.g. 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.
• a thiazolidinedione e.g. 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]
• the compounds of formula I are administered in combination with an ⁇ -glucosidase inhibitor, such as miglitol or acarbose. In one embodiment, the compounds of the formula I in combination with an adenosine Al agonists, such as. B. those described in WO 2004/003002 administered.
• the compounds of formula I are administered in combination with an agent which acts on the ATP-dependent potassium channel of the beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• an agent which acts on the ATP-dependent potassium channel of the beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• the compounds of formula I are 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 compounds of the formula I are administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M .: Hormones and
• NPY neuropeptide Y, eg naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-qumazolin-2-ylamino) -methyl] cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A))
• the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
• the further active ingredient is dexamphetamine or amphetamine.
• the other active ingredient is fenfluramine or dexfenfluramine.
• the other active ingredient is sibutramine.
• the other active ingredient is orlistat. In one embodiment, the other active ingredient is mazindol or phentermine.
• the other active ingredient is rimonabant.
• the compounds of the formula I are administered in combination with fiber, preferably insoluble fiber (see, for example, Carob / Caromax "(Zunft HJ; et al., Carob pulp preparation for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6.); Caromax is a carob-containing product of the company. Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)). 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 compounds of the formula I can be prepared by suitable starting materials of the formula II in which X is a leaving group such as chlorine, bromine, iodine, sulfonyloxy, sulfinyl or sulfoxyl, with a compound of the formula IV, if appropriate in the presence of suitable Bases and in suitable solvents.
• X is a leaving group such as chlorine, bromine, iodine, sulfonyloxy, sulfinyl or sulfoxyl
• Suitable halogenating agents may be exemplified
• Halogens such as chlorine and bromine, N-bromosuccinimide, phosphorus pentachloride or
• Presence of a catalyst can be produced.
• amines IV The synthesis of the amines IV can be carried out by literature methods. Some derivatives of formula IV, such as piperidin-3-ylamines, are available commercially.
• the compounds of the formula I are distinguished by favorable effects on the lipid and carbohydrate metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes, insulin resistance, dyslipidaemias and the metabolic syndrome / syndrome X. Furthermore, the compounds are suitable for the prophylaxis and treatment of arteriosclerotic phenomena.
• the compounds may be used alone or in combination with other blood sugar lowering agents.
• the compounds act as DPP-W (dipeptidyl peptidase IV) inhibitors and are also useful in the treatment of disorders of sensation and other psychiatric indications such as depression, anxiety, anxiety disorders, schizophrenia and the treatment of disorders associated with the circadian rhythm Weight loss in mammals, for the treatment of immune disorders and for the treatment of substance abuse.
• H-Ala-Pro-AFC (15 ⁇ M final concentration) in Tris / HCl (40 mM, pH 7.4), total volume 0.2 ml
• the reaction was carried out at room temperature for various periods of time (typically 10 minutes) and stopped at the end of the reaction by adding 20 ⁇ l of ZnCl 2 (1 M).
• the conversion of H-Ala-Pro-AFC was determined fluorimetrically by measuring the emission at 535 nm after excitation at 405 nm.
• the added buffer volume was adjusted to maintain a total volume of the test mixture of 200 ⁇ l.
• % Inhibition at a fixed concentration was calculated as follows:
• IC 50 values for inhibitors were determined by varying the inhibitor concentrations at the stated substrate concentration of 15 ⁇ M.
• Kj and K m values were as described by enst Schemeende variation of substrate and inhibitor concentration (Dixon, M. and Webb, EC (1979) Enzymes, third edition, pp. 47-206, Academic Press) determined.
• the values for K m , IC 50 and Kj were calculated using a commercially available software package (Leatherbarrow, RJ. (1992) GraFit Version 3.0, Erithacus Software Ltd. Staines, UK).

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