Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • 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
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to substituted, bicyclic 8-pyrrolidino-xanthines and their physiologically acceptable salts and physiologically functional derivatives.
• the invention had the object of providing compounds that develop a therapeutically useful, blood sugar lowering effect.
• the invention therefore relates to compounds of the formula I
• Rl, R2, R3 are independently H, (C r Ci 0) -alkyl, (C 3 -C 0) cycloalkyl, (C 2 -C 10) - alkenyl, (C 2 -C i O) -alkynyl, ( C 6 -C 10 ) -aryl, heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals one or
• 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 ) -
• R9, R10 independently of one another are H, (C 1 -C 4 ) -alkyl, (C 1 -C 6 ) -alkylene (C 6 -C 10 ) -aryl, - (C 6 -C 10 ) -aryl, heterocyclyl, (C 1 -C 6 ) -alkylene heterocyclyl; _,
• R4 and R5 together form a 3-5-membered alkylene chain in which a CH 2 group is replaced by NRL 1, wherein R6 is H or Rl is 2, or R5 and R6 together form a 3 to 5-membered alkylene chain in which a CH 2 group is replaced by NRl 1, wherein R4 is H or R12; wherein the 3 to 5-membered alkylene chain may each be mono- or polysubstituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C C 1 -C 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or 0- (C 1 -C 6 ) -alkyl, where the alkyl groups are on or may be substituted several times with F, Cl, Br, I
• Rl 1 is hydrogen, (C r C6) alkyl, (C 3 -C 8) -cycloalkyl, (C 1 -C 4) - alkylene aryl or (C 1 -
• R 12 is F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, NH (C 3 -
• C 7 ) -cycloalkyl, N ((C 1 -C 6 ) -alkyl) 2 or O- (C 1 -C 6 ) -alkyl, where the alkyl groups may be mono- or polysubstituted by F, Cl, Br, I; n 0, 1, 2, 3, 4;
• Rl, R2, R3 are independently H, (Ci-C) 0) alkyl, (C 3 -C 0) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C i O) alkynyl, (C 6 -C 18) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN , NO 2, SH, OH, (Ci-C 6) - alkyl, -CF 3, -OCF 3, -SCF 3, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, OR7 , OP (O) (OR7) 2 , NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7
• R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl,
• R9, RIO each independently H, (C r C6) alkyl, (Ci-C 6) alkylene- (C 6 -C 10) -aryl, (Ci- C 6) - alkylene-heterocyclyl;
• Al to A6 can be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (CC 6 ) -alkyl, NH (C 3 -C 7 ) -cycloalkyl, N (CC 1 -C 6 ) -alkyl) 2 or O- (C 6 -C 6 ) -alkyl, where , the alkyl groups are mono- or polysubstituted by F , Cl, Br, I may be substituted;
• R 1 is hydrogen, (C -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-aryl or (C 1 -)
• Rl, R2, R3 are independently H, (C] -C O) -alkyl, (C 3 -C 0) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 0) alkynyl, ( C 6 -C 10) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, CN,, OH, (Ci -C 6 ) - alkyl, -CF 3 , - OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, OR 7, NR 7 R 8,
• R7, R8 are independently H, (Ci-C6) - alkyl, (C 3 -C 0) cycloalkyl, (C 6 -C] 0) - aryl, heterocyclyl, (Ci-C 6) -alkylene-CONR9R10, (C r C 6 ) -alkylene-COOR 9,, (CC 6 ) -
• Rl, R2, R3 are independently H, (Ci-Cio) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C io) alkynyl, (C 6 -C 10 ) -aryl, heterocyclyl, where the alkyl,
• Cycloalkyl, mono- alkenyl, alkynyl, aryl and heterocyclyl radicals can be monosubstituted or polysubstituted by F, Cl, CN, (Ci-C6) - alkyl, -CF 3, -OCF 3, - SCF 3, OR7 , NR7R8, COR7, COOR7, CONR7R8, (C 1 -C 6 ) -alkylene-OR7, (C 1 -C 6 ) -alkylene-NR 7 R 8, (C 1 -C 6 ) -alkylene-NR 7 SO 2 R 7, SR 7, SOR 7, SO 2 R7, -SO 2 NR7R8, NR7SO 2 R7, (Ci-C 6) alkylene- (C 6 -C, 0) aryl, (dC 6) alkylene-
• Heterocyclyl (C 3 -C i 0) cycloalkyl, (C 6 -C 10) - aryl or heterocyclyl;
• R7, R8 are independently H, (Ci-C6) - alkyl, (C 3 -C] 0) -cycloalkyl, (C 6 -C 0) -
• the carbon atoms in structures A1 to A6 may be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH (C 1 -C 6) - alkyl, NH (C 3 - C 7) cycloalkyl, N ((Ci-C6) - alkyl) 2, or 0- (Ci-C6) - alkyl, where the alkyl groups one or more times may be substituted with F, Cl, Br, I;
• R1 is hydrogen
• Rl, R2, R3 are independently H, (Ci-Cio) alkyl, (C 3 -C 0) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 0) -alkynyl, (C 6 -C 10 ) -ATyI, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, CN, (C 1 -C 6 ) -alkyl , -CF 3 , -OCF 3 , -
• one of the following structures has Al, A2 or A3
• the carbon atoms in the structures A1 to A6 to be monosubstituted to tetra-substituted by F, Cl, Br, I, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, NH 2 , NH ( Ci-C6) - alkyl, NH (C 3 - C 7) cycloalkyl, N ((Ci-C 6) alkyl) 2, or 0- (C 1 -C 6) - alkyl, where the alkyl groups are mono- or may be substituted several times with F, Cl, Br, I;
• R1 is hydrogen
• the invention relates to 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 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
• 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. the human being, is able; (directly or indirectly) to form 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 meant a straight or branched hydrocarbon chain having one or more carbons, e.g. Methyl, ethyl, iso-propyl, tert-butyl, hexyl.
• alkyl radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example:
• alkenyl radical is a straight or branched hydrocarbon chain having two or more carbons and one or more double bonds is understood ⁇ ' such as vinyl, allyl, pentenyl, 2-methyl-but-2-en-4-yl.
• the alkenyl 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 1 -C 6 ) alkyl, CON [(Ci-C 6 ) alkyl] 2, cycloalkyl, (C 1 -C 0 ) -alkyl, (C 2 -C 6 ) -alkynyl, O- (C ! -C 6) - alkyl 0-C0 "(C r C6) alkyl, 0-CO- (C, -C6) -
• N (heterocyclic) -CO-N ((C, -C 6 ) -alkyl) -aryl, N (aryl) -CO-N- (aryl) 2 , N (heterocycle) -CO-N- (aryl) 2 , Aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocycle, where n O-6, where the aryl radical or heterocyclic radical may be monosubstituted to trisubstituted by F, Cl , Br, I, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - alkyl, (C, -C 6) - alkyl, NH 2, NH (C, -C 6 ) - alkyl, N ((C 1 -C 6 ) -O-C) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 )
• alkynyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as, for example, ethynyl, propynyl, butynyl, hexynyl.
• the alkynyl 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, -C 6) alkyl, CONt (C 1 -C 6) AUCyI] 2, cycloalkyl, (C 2 -C 6) alkenyl, (C, -C] 0) - alkyl, 0- (C, - C 6) - alkyl O-CO- (C, -C6) - alkyl, 0-CO- (C, -C6) - aryl, O-CO- (Ci-C 6) heterocyclic; 0 PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C6) - alkyl, SO 2 N f (C 1 -C 6)
• N (heterocycle) -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, O- (CH 2 ) n -heterocycle, where n O-6, where the Aryl radical or heterocyclic radical may be a 3-fold substituted by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (C, -C 6) alkyl, (C, - C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2) SO 2 -CH 3 , COOH, COO- (C, -C 6 ) Alkyl, CONH 2 .
• 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 (Ci-C6) alkyl, CON [(C, -C 6) alkyl] 2, cycloalkyl, (C, -C 0) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) Alkynyl, O- (C 1 -C 6 ) alkyl, O-CO- (C 1 -C 6 ) alkyl, O-CO- (C 1 -C 6 ) aryl, O-CO- (C, -C 6 ) heterocycle ,; PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C 1 -C 6) - alkyl, SO 2 N
• 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. 5
• the cycloalkyl radical 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 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2) cycloalkyl, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, 0- (C 1 -Ce) -AUCyI 0-CO- (CC 6) - alkyl, 0-CO- (C, -C6) - aryl, O-CO- (C, -C6) heterocycle ,; 0 PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2
• 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, in which the heterocyclic or the heterocyclic radical is fused with benzene nuclei.
• the heterocycle 0 or the heterocyclic radical may be aromatic, saturated aliphatic or partially unsaturated aliphatic.
• heterocyclyl radicals or "heterocyclic radicals” are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl , 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-
• 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 mono- 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 ) -alkyl, CONH 2 , CONH (C iC 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2i cycloalkyl, (C 1 -C 10 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6) -alkynyl, O- (C, -C6) alkyl 0-CO- (C, -C6) - alkyl, 0-CO- (C, - C6) -aryl, O-CO- (Ci -C 6 ) heterocycle;
• suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 ,
• CF 3 NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 may be substituted; C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C, -C 7 ) -acyl, NH-CO - (Ci-C 6 ) - alkyl, NH-COO- (Ci -C 6 ) - alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-C00- aryl, NH-COO heterocycle, NH-CO -NH- (C 1 -C 6 ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-aryl, NH-CO-NH-heterocycle
• 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 from 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 0 may contain, for example, from 1 mg to 10 g of the active ingredient.
• the active ingredient for example, from 1 mg to 100 mg
• ampoules for injections, and orally administered single dose formulations, such as tablets or capsules, may for example be 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 present with a tolerable 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's health.
• 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 0 according to 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 adjuvants become.
• 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 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. 5
• 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 one 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 involving a step the active substance and the carrier (the one or the other) several additional constituents) can be brought into contact.
• 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 produced by compressing or molding a powder or granules of the compound, if appropriate with one or more additional constituents.
• 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 glycerine 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 can 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 be 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 such as in Pharmaceutical
• Antidiabetika which are mentioned in the red list 2004, chapter 12. They can be combined with the compounds 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 fast-acting insulins (see US No.
• the orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, Kaliumkanalöffher such 'as those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S 5, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents, compounds that regulate food intake PPAR and PXR agonists and drugs that act on
• the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin 5.
• an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin 5.
• the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside, or with a compound as described in PCT / EP 2004/00269, PCT / EP 2003/05815, PCT / EP 2003/05814, PCT / EP 2003/05816, EP 0114531, US 6,498,156, administered.
• a cholesterol resorption 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, 5, Gl 262570.
• a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, 5, Gl 262570.
• the compounds of formula I are administered in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647.
• the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
• a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
• the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
• an MTP inhibitor e.g. Implitapide, BMS-201038, R-103757.
• 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.
• the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
• a CETP inhibitor e.g. JTT-705.
• 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.
• the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586.
• the compounds of formula I are administered in combination with an ACAT inhibitor, e.g. Avasimibe, administered.
• an ACAT inhibitor e.g. Avasimibe
• 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 in, combination be administered with an ATP citrate lyase inhibitor, such as SB-204990.
• 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 sulphonylurea, 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 sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
• a biguanide e.g. Metformin
• the compounds of formula I are used in combination with a meglitinide, e.g. Repaglinide, administered.
• 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.
• an adenosine Al agonists such as.
• the compounds of formula I are administered in combination with a drug which acts on the ATP-dependent potassium channel of beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• a drug which acts on the ATP-dependent potassium channel of beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• the compounds of the formula I are used in combination with more than one of the abovementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and 10 metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
• the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript
• NPY antagonists eg naphthalen-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A)
• MC4 agonists eg 1-amino-1,2,3,4-tetrahydronaphthalene
• 2-Carboxylic acid 2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5-
• CRF BP antagonists eg urocortin
• urocortin agonists eg 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3- dimethyl-lH-indol-6-yloxy) - ethylamino] ethanol hydrochloride (WO 01/83451)
• CBl cannabinoid receptor 1 * receptor antagonists (for example rimonabant, or those mentioned in WO 02/28346 agents MSH.
• CCK-A agonists e.g., ⁇ 2- [4- (4-chloro-2,5-)
• 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 dexamphatamine or amphetamine.
• the other active ingredient is fenfluramine or dexfenfiuramine.
• 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 formula I in combination with bulking agents preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft H
• Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926
• 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, 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, sulfoxyl
• Rl 1 is hydrogen
• Rl 1 it may be appropriate to use the radical IV protected in the nitrogen function form and cleave the protecting group after reaction with II again.
• suitable protecting groups and the methods of incorporation and cleavage are known (See: Theodora W. Greene and Peter GM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc., New York, 1999)
• Suitable halogenating agents may be, for example, halogens, such as chlorine and bromine, N-bromosuccinimide / phosphorus pentachloride or phosphorus oxychloride.
• halogens such as chlorine and bromine, N-bromosuccinimide / phosphorus pentachloride or phosphorus oxychloride.
• the synthesis of compounds of the formula II is described in the literature (see Houben Weyl E9b / 2, p. 331 ff and literature cited therein). They can be obtained, for example, starting from diaminopyrimidine derivatives or aminoimidazolecarboxamides by reaction with suitable reagents and by specific chemical modifications, such as hydrolysis, Alkylation, halogenation or acylation into the desired starting compounds of
• the radicals R 1 to R 3 can be prepared by methods known per se by alkylating correspondingly known precursors, the sequence being able to be varied. 5. However, they can also be introduced by appropriate selection of suitable precursors in the preparation of the xanthine skeleton.
• the compounds of the formula I have 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-IV (dipeptidyl peptidase 0 FV) inhibitors and are also useful in treating disorders of sensation and other psychiatric indications, such as depression, anxiety, anxiety disorders, schizophrenia, and circadian rhythm disorders, for 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) 15 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 addition of 20 ⁇ l of ZnCl 2 (1 M).
• the conversion of H-Ala-Pro-AFC was confirmed fluorometrically by measuring the emission
• the added buffer volume was adjusted so that a total volume of the test mixture of 200 ⁇ l was maintained.
• IC50 values for inhibitors were determined by varying the inhibitor concentrations at the stated substrate concentration of 15 ⁇ M. Ki and Km values were passed through
• Example 4 8- (cis -Hydahydro-pyrrolo [3,4-b] pyrrol-5-yl) -3-methyl-7- (3-methylbut-2-enyl) -1- (2-oxo-2 - phenyl-ethyl) -3,7-dihydro-purine-2,6-dione was obtained analogously to Example 5 starting from cis-octahydro-pyrrolo [3,4-b] pyrrole.
• Fp. Resin MS: M + 1 463
• Example 28
• Example 52 (2-Ethoxy-ethyl) -7- (4-fluoro-benzyl) -8- (hexahydro-pyrrolo [3,4-b] pyrrol-1-yl) -3-methyl-3,7- dihydro-purine-2,6-d

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