WO2010000401A1 - Use of substituted pyridinone carboxylic acid derivates for producing pharmaceuticals for the treatment of dyslipidemia - Google Patents

Use of substituted pyridinone carboxylic acid derivates for producing pharmaceuticals for the treatment of dyslipidemia Download PDF

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Publication number
WO2010000401A1
WO2010000401A1 PCT/EP2009/004477 EP2009004477W WO2010000401A1 WO 2010000401 A1 WO2010000401 A1 WO 2010000401A1 EP 2009004477 W EP2009004477 W EP 2009004477W WO 2010000401 A1 WO2010000401 A1 WO 2010000401A1
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Prior art keywords
alkyl
aryl
formula
heterocyclyl
compound
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PCT/EP2009/004477
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German (de)
French (fr)
Inventor
Harm Brummmerhop
Matthias Urmann
Siegfried Stengelin
Thomas Klabunde
Hubert Heuer
Andreas Herling
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Sanofi-Aventis
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Publication of WO2010000401A1 publication Critical patent/WO2010000401A1/en

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    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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

Definitions

  • the invention relates to the use of substituted Pyridinoncarbonklaivaten and their physiologically acceptable salts for the preparation of medicaments for the treatment of dislipidemia.
  • FFA free fatty acids
  • the invention therefore relates to the use of the compounds of the formula I,
  • R (Ci-Co) alkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) -alkynyl, where in the (Ci-Cio) alkyl, (C 2 -C i O) - Alkenyl or (C 2 -C 10) -alkynyl radicals, one or more individual CH 2 groups may be replaced by O and where the alkyl, alkenyl and alkynyl radicals may be monosubstituted or polysubstituted by F, Cl, Br, I, CF 3 , (C 3 -Ci 2 ) - Carbocycle, aryl, where aryl may be mono or polysubstituted with F, Cl, Br, I, CF 3, (Ci-C 6) alkyl;
  • R (C 1 -Co) -AUCyI, (C 2 -C 10 ) -alkenyl, wherein in the (Ci -C 10 ) -AUCyI- or (C 2 -C 10 ) -AUcenylresten one or more individual CH 2 groups O may be replaced and wherein the alkyl radicals may be monosubstituted or polysubstituted with F, Cl, Br, I, (C 3 -C 2 ) -carbocycle, aryl;
  • R (C 1 -Co) -AlkVl wherein in the (Ci-Cio) alkyl radical one or more individual CH 2 groups may be replaced by O and wherein the alkyl radicals may be mono- or polysubstituted with F, Cl, Br, I, (C 3 -C 12 ) -Cyclocycle , Aryl;
  • R (C, -C O) -alkyl where in the (C 1 -C 0) alkyl one or more individual CH 2 groups can be replaced by O and wherein said alkyl radicals can be mono or polysubstituted with F, Cl, Br, I, (C 3 -C 12 ) -carbocycle, phenyl;
  • compounds of formula I are preferred, wherein R is (C 1 - C ö) alkyl, wherein in the (Ci-C] o) alkyl one or more individual CH 2 groups can be replaced by O and wherein the alkyl radical may be monosubstituted or polysubstituted with F, Cl, Br, I, CF 3 .
  • R is (C 2 -C 10) -alkenyl, where in the (C 2 -d0) -alkenyl radical one or more individual CH 2 groups may be replaced by O and where the alkenyl radical may be monosubstituted or polysubstituted with F, Cl, Br, I, CF 3 .
  • compounds of formula I are preferred, wherein R is (C 2 - Cio) -alkynyl, where in the (C 2 -C io) - 2 groups may be replaced by O alkynyl group one or more individual CH.
  • 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.
  • alkyl radical is meant a straight or branched hydrocarbon chain having one or more carbons, e.g. Methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl, hexyl.
  • the alkyl 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 ! -C 6 ) ADCyI, CONH 2 , CONH (C 1 - C 6) alkyl, CON [(C r C6) alkyl] 2> carbocycle, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, aryl, heterocyclyl, 0- ( C 1 -C 6 ) -alkyl, 0-COO- (C 1 -C 6 ) -alkyl, 0-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, 0-CO (C r C 6 ) heterocyclyl, PO 3 H 2 , P (O) (Oalkyl) 2, (C 1 -C
  • N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO-N (aryl) 2 , aryl, O - (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n 0-6, where the aryl or heterocyclyl radical may be substituted one to three times by F, Cl, Br , I, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - alkyl, (Ci-C6) - alkyl, NH 2, NH (C, -C6) - alkyl , N ((QC 6 ) -alkyl) 2 , SF 5 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alky
  • alkenyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having two or more carbons and one or more double bonds, such as, for example, vinyl, allyl, pentenyl.
  • the alkenyl 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 [(C 1 -C 6 ) alkyl] 2; Carbocycle, (C, -C 0) - alkyl, (C 2 -C 6) alkynyl, aryl, heterocyclyl, 0- (C, -C 6) - alkyl 0-CO- (Ci-C6) - alkyl, 0-CO- (C 1 -C 6 ) -aryl, O
  • alkynyl radical is understood to mean a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as ethynyl, propynyl, hexynyl.
  • the alkynyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (Ci-C6) alkyl, CONH 2, CONH ( C, - C 6) alkyl, conf (Ci-C 6) -alkyl] 2, carbocycle, (C 2 -C 6) alkenyl, (Ci -C 0) - alkyl, 0- (Ci-C 6) - alkyl O-CO- (Ci-C 6) -alkyl, 0-CO- (Ci-C6) - aryl, 0-CO- (C 1 -C 6) -Heterozyklyl; PO
  • 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 mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, SF 5, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2; Carbocycle, (Ci -C 0) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, O- (C, -C6) - alkyl 0-CO- (C, - C 6 ) - alkyl, 0-CO- (C 1 -C 6 ) -aryl, 0-CO- (C 1 -C 6 ) -heterocyclyl;
  • suitable groups for example: F, Cl, Br, I, CF 3, NO 2, SF 5, N 3, CN, COOH, COO (
  • 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, for example: 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, CON [(C 1 -C 6 ) alkyl] 2, carbocycle, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) - alkynyl, 0- (C 1 -C 6) - alkyl 0-CO- (C 1 -C 6) - alkyl, 0-CO- (C, -C6) - aryl, 0-CO- (Ci-C 6 ) - heterocyclyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C
  • a carbocycle radical is meant a ring system containing one or more rings which is saturated or partially unsaturated (with one or two Double bonds) understood, which is composed exclusively of carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the Carbocyclusreste may be one or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C 1 - C 6) alkyl, CON [(C, -C 6) alkyl] 2> carbocycle, (C 1 -C 10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6 ) - alkynyl, O - (CC 6 ) - alkyl 0-CO- (C, -C 6 ) -alkyl, 0-CO- (C, -C 6 ) -aryl, 0-CO- (C 1 -C 6 ) - heterocyclyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl)
  • Heterocycle, heterocyclyl 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 condensed with benzene nuclei.
  • Suitable heterocyclic or "heterocyclic radicals” are acridinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, Chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] -tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, hidazolyl, IH-indazolyl
  • 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 eg 1-oxy-2-, 3- or 4-pyridyl.
  • heterocyclic rings or heterocyclic 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) AUCyI, cont (C 1 -C 6) AUCyI] 2, carbocycle, (C, - C O) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, O- (C, -C6) alkyl 0-CO- (C, -C6) - alkyl, O- CO- (C 1 -C 6) aryl, 0-CO - (C, -C 6) -Heterozyklyl;
  • suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulfuric and organic acids, e.g.
  • the chloro salt is used in a particularly preferred manner.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
  • 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 formula I can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of formula I are within the scope of the invention and are a further aspect of the invention.
  • all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) as described above, as well as their salts and solvates as described herein.
  • the compound (s) of formula (I) may also be administered in combination with other active ingredient.
  • the amount of a compound of formula (I) required to achieve the desired biological effect depends on a number of factors, e.g. the specific compound chosen, the intended use, the type of
  • 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, e.g. 3-10 mg / kg / day.
  • An intravenous dose may e.g. in the range of 0.3 mg to 1.0 mg / kg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • 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.
  • 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 abovementioned weights are based on the weight of the benzothiazepine ion derived from the salt.
  • the compounds according to formula (I) may 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.
  • 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 also be present, including further compounds according to formula (I).
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which are essentially lent consist in that the ingredients are mixed 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 the nature and severity of the treatment State and on the nature of the particular compound used according to formula (I) is dependent.
  • 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,
  • Hydroxypropylmethylcellulosephthalat and anionic polymers of methacrylic acid and methyl methacrylate are examples of hydroxypropylmethylcellulosephthalat 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 ingredients.
  • Compressed tablets may 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 / dispersing agent in a suitable machine.
  • Molded tablets can be made by molding the powdered, moistened with an inert liquid diluent compound can be prepared in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges comprising a compound of formula (I) having a
  • Flavoring usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or
  • 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.
  • Preparations are preferably administered intravenously, although the
  • Administration can also be administered subcutaneously, intramuscularly or intradermally as an injection.
  • compositions according to 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%.
  • Transdermal administration is also possible.
  • Suitable pharmaceutical compositions for transdermal applications may be present as single patches for long-term close contact with the epidermis of the patient are suitable.
  • 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 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. If the administration of the active ingredients by separate administration of the active ingredients, so this can be done simultaneously or sequentially.
  • Most of the drugs listed below are disclosed in the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville, 2006.
  • Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir), Humalog ⁇ (insulin lispro), Humulin (R), VIAj ect TM or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such.
  • Lantus ® see www.lantus.com
  • HMR 1964 Levemir® (insulin detemir), Humalog ⁇ (insulin lispro), Humulin (R), VIAj ect TM or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such.
  • Levemir® insulin detemir
  • Humalog ⁇ insulin lispro
  • R Humulin
  • VIAj ect TM those described in WO200500
  • DSf-105 Nobex
  • Oralyn TM Geneex Biotechnology
  • Technosphere (R) insulin MannKind
  • Cobalamin TM oral insulin or insulins as described in WO2007128815, WO2007128817 or insulins which can be administered transdermally ;
  • GLP-I derivatives and GLP-I agonists such as exenatide, liraglutide or those described in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC: exendin-4 (an exendin-4 analogue covalently linked to recombinant human albumin), CVX-73, CVX-98 and CVx-96 (GLP-I analogs covalently linked to a monoclonal antibody, having specific binding sites for the GLP-I peptide), CNTO-736 (a GLP-I analog bound to a domain containing the Fc portion of an antibody), PGC-GLP-I (G
  • Antidiabetic agents also include agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor as described e.g. in WO2006121860 are described.
  • GIP glucose-dependent insulinotropic polypeptide
  • Antidiabetics also include analogs and derivatives of fibroblast growth factor 21 (FGF-21, fibroblast growth factor 21).
  • the orally active hypoglycemic agents preferably comprise sulfonylureas
  • Glucokinase activators inhibitors of fructose 1, 6-bisphosphatase, Glucose Transporter 4 Modulators (GLUT4),
  • Potassium channel opener e.g. Pinacidil, cromakalim, diazoxide, or those described in R.D. Carr et al., Diabetes 52, 2003, 2513, 2518, in J. B. Hansen et al, Current Medicinal
  • DPP-IV dipeptidyl peptidase-IV
  • PTP-IB protein tyrosine phosphatase-1B
  • Nicotinic acid receptor agonists inhibitors of hormone-sensitive or endothelial lipases,
  • Inhibitors of acetyl-CoA carboxylase ACCl and / or ACC2
  • lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents, HMGCoA reductase inhibitors,
  • FXR Farnesoid X receptor
  • CETP inhibitors bile acid resorption inhibitors
  • Sigma-1 receptor antagonists Antagonists of the somatostatin 5 receptor (SST5 receptor); Compounds that reduce food intake and compounds that increase thermogenesis.
  • the compound of the formula I is administered in combination with insulin.
  • the compound of formula I is administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
  • an agent that acts on the ATP-dependent potassium channel of beta cells e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
  • the compound of formula I is administered in combination with a tablet containing both glimepride which is rapidly released and contains metformin which is released over a prolonged period of time (as described, for example, in US2007264331).
  • 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 used in combination with a meglitinide, e.g. Repaglinide, nateglinide or mitiglinide administered.
  • a meglitinide e.g. Repaglinide, nateglinide or mitiglinide administered.
  • the compound of formula I is treated with a combination of mitiglinides with a glitazone, e.g. Pioglitazone hydrochloride, administered.
  • a glitazone e.g. Pioglitazone hydrochloride
  • the compound of formula I is administered with a combination of mitiglinides with an alpha-glucosidase inhibitor.
  • the compound of the formula I is administered in combination with antidiabetic compounds, as described in WO2007095462, WO2007101060, WO2007105650. In a further embodiment, the compound of the formula I is administered in combination with antihypoglycemic compounds, as described in WO2007137008.
  • the compound of formula I is 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, especially 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, especially 5- [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2
  • a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-ol (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone) or those as described in WO2007060992, WO2007100027, WO2007103252, WO2007122970 ,
  • 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 in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist, e.g. TAK-536 administered.
  • the compound of formula I is in combination with a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists, such as GW9578, GW-590735, KH1, LY-674, KRP-101, DRF-10945 , LY-518674, CP-900691, BMS-687453, BMS-711939 or those as described in WO2001040207, WO2007096894, WO2005097076, WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043.
  • a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists such as GW9578, GW-590735, KH1, LY-674, KRP-101, DRF-10945 , LY-518674, CP
  • 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, CKD-501 (Lobeglitazone Sulfate), MBX-213 or as in WO 00/64888, WO 00/64876, WO03 / 020269 , WO2007099553, US2007276041, WO2007085135, WO2007085136 or JPBerger 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, CKD-501 (Lobeglitazone Sulfate),
  • the compound of formula I is used in combination with a PPAR delta agonist, e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887.
  • a PPAR delta agonist e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887.
  • the compound of the formula I is used in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such as e.g. GFT-505 administered.
  • a pan-SPPARM selective PPAR modulator alpha, gamma, delta
  • the compound of the formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonists / antagonists.
  • the compound of formula I is administered in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose or those as described e.g. in WO2007114532, WO2007140230.
  • an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose or those as described e.g. in WO2007114532, WO2007140230.
  • the compound of the formula I in combination with an inhibitor of glycogen phosphorylase, such as PSN-357 or FR-258900 or such as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
  • an inhibitor of glycogen phosphorylase such as PSN-357 or FR-258900 or such 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, WO2006086488, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577.
  • glucagon receptor antagonists such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577.
  • the compound of formula I is used in combination with an antisense compound, e.g. ISIS-325568, which inhibits the production of the glucagon receptor.
  • an antisense compound e.g. ISIS-325568
  • the compound of the formula I in combination with activators of glucokinase such as. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as described e.g. B. in WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040- 42 WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345 , WO2007051846, WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO200707
  • 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-l, 6-bisphosphatase (FBPase) such as CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515, WO2006104030, WO2007014619, WO2007137962.
  • 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), sitagliptin phosphate, saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021 , GRC-8200, GW-825964X, KRP-104, DP-893, ABT-341, ABT-279 or other salt thereof, S-40010, S-40755, PF-00734200, BM 356, PHX-1149, alogliptin or such compounds as described in WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828, WO2005058901, WO20050
  • the compound of formula I is administered in combination with Janumet TM, a solid combination of sitagliptin phosphate with metformin hydrochloride. In one embodiment, the compound of formula I is administered in combination with Eucreas (R) , a solid combination of vildagliptin with metformin hydrochloride.
  • the compound of formula I is administered in combination with a combination of a DPP-IV inhibitor with omega-3 fatty acids or omega-3 fatty acid esters, e.g. in WO2007128801, administered.
  • the compound of formula I in combination with an insulin secretion enhancing substance, such as. KCP-265 (WO2003097064) or those as described in WO2007026761.
  • an insulin secretion enhancing substance such as. KCP-265 (WO2003097064) or those as described in WO2007026761.
  • 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 modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), e.g. KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin, or as described e.g. B.
  • modulators of the sodium-dependent glucose transporter 1 or 2 SGLT1, SGLT2
  • SGLT1 sodium-dependent glucose transporter 1 or 2
  • 11-beta-hydroxysteroid dehydrogenase-1 (1 lß-HSDl)
  • the compound of the formula I in combination with inhibitors of protein tyrosine phosphatase-1B in combination with inhibitors of protein tyrosine phosphatase-1B (PTP-IB), as z.
  • PTP-IB protein tyrosine phosphatase-1B
  • WO200119830-31 WO200117516, WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004 060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755, WO2007115058.
  • the compound of the formula I is administered in combination with an agonist of GPR10A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), such as, for example, nicotinic acid or extended release niacin in combination with MK-0524A (Laropiprant ) or MK-0524 or such compounds as described in WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986.
  • GPR10A HM74A receptor agonists
  • NAR agonists nicotinic acid receptor agonists
  • the compound of formula I is administered in combination with a solid combination of niacin with simvastatin.
  • the compound of the formula I is administered in combination with nicotinic acid or "extended release niacin" in conjunction with MK-0524 A (laropiprant).
  • the compound of the formula I is administered in combination with nicotinic acid or extended release niacin in conjunction with MK-0524A (laropiprant) and with simvastatin.
  • cyclooxygenase-1 or cyclooxygenase-2 e.g. Acetylsalicylic acid, diclofenac, celecoxib, rofecoxib, valdecoxib, etoricoxib, or lumiracoxib.
  • the invention of formula I 1 is used in combination with a DPl receptor antagonist, e.g. Laropiprant, SAR389644 or such compounds as described in WO2008039882 administered.
  • a DPl receptor antagonist e.g. Laropiprant, SAR389644 or such compounds as described in WO2008039882 administered.
  • the compound of formula I is used in combination with an agonist of GPR16, as described e.g. in WO2006067531, WO2006067532.
  • the compound of the formula I is administered in combination with modulators of the GPR40, as described, for example, in WO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622, WO2007136572.
  • the compound of formula I is used in combination with modulators of GPR19 (G protein-coupled glucose-dependent insulinotropic receptor), e.g. PSN-119-1 or such as z.
  • GPR19 G protein-coupled glucose-dependent insulinotropic receptor
  • PSN-119-1 G protein-coupled glucose-dependent insulinotropic receptor
  • WO2005061489 PSN-632408
  • WO2004065380 WO2004065380
  • WO2006018662 WO2007003960-62
  • WO2007003964 WO2007116229
  • WO2007116230 WO2007116230.
  • the compound of formula I is used in combination with modulators of the GPR120, e.g. in EP1688138.
  • the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL) and / or phospholipases, such.
  • HSL hormone-sensitive lipase
  • phospholipases such as WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837.
  • the compound of the formula I in combination with inhibitors of endothelial lipase, such as. As described in WO2007110216 administered.
  • the compound of formula I is used in combination with a phospholipase A2 inhibitor, e.g. Administered darapladib or A-002.
  • the compound of the formula I is administered in combination with myricitrin, a lipase inhibitor (WO2007119827).
  • the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as.
  • an inhibitor of glycogen synthase kinase-3 beta such as.
  • GSK-3 beta glycogen synthase kinase-3 beta
  • GSK-3 beta glycogen synthas
  • 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 serum / glucocorticoid-regulated kinase (SGK), such as.
  • SGK serum / glucocorticoid-regulated kinase
  • the compound of the formula I in combination with an inhibitor of protein kinase C beta such as. B. Ruboxistaurin administered.
  • PLC beta protein kinase C beta
  • the compound of the formula I in combination with an activator of the AMP-activated protein kinase (AMPK), as described, for. As described in WO2007062568 administered.
  • AMPK AMP-activated protein kinase
  • the compound of the formula I in combination with an inhibitor of ceramide kinase, as z. As described in WO2007112914 administered.
  • the compound of the formula I is used in combination with an inhibitor of MAPK-interacting kinase 2 (MNK2), as described e.g. in WO2007104053, WO2007115822 are administered.
  • MNK2 MAPK-interacting kinase 2
  • the compound of the formula I is administered in combination with inhibitors of the "I-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140.
  • the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699 or those as described in US2007249583.
  • the compound of formula I is used in combination with a farnesoid X receptor (FXR) antagonist, such as e.g. in WO2007052843, WO2007070796, WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183.
  • FXR farnesoid X receptor
  • the compound of the formula I is used in combination with a liver X receptor (LXR) ligand, e.g. described in WO2007092965.
  • LXR liver X receptor
  • a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
  • the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate (SLV-348).
  • fibrates e.g. the choline salt of fenofibrate (SLV-348).
  • the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
  • fibrates e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
  • the compound of the formula I is administered in combination with bezafibrate and diflunisal.
  • the compound of formula I is administered in combination with a fixed combination of fenofibrate or a salt thereof with simvastatin, rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin or atorvastatin.
  • the compound of the formula I is administered in combination with Synordia (R), a fixed combination of fenofibrate with metformin.
  • a cholesterol resorption inhibitor 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, WO2005000353 (Kotobuki Pharmaceutical Co.
  • 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, WO2005000353 (Kotobuki Pharmaceutical Co.
  • the compound of formula I is administered in combination with a fixed combination of ezetimibe with atorvastatin.
  • the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.
  • the further active ingredient is a
  • Diphenylazetidinonderivat as described for example in US 6,992,067 or US 7,205,290.
  • the further active ingredient is a diphenylazetidinone derivative as described, for example, in US Pat. No. 6,992,067 or US Pat. No. 7,205,290 combined with a statin such as simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
  • a statin such as simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
  • the compound of formula I is administered in combination with a solid combination of Lapaquistat, a squalene synthase inhibitor, with atorvastatin.
  • a CETP inhibitor e.g. Torcetrapib, anacetrapib or JTT-705 or those as are described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304, WO2007128568 WO2007132906 described, administered.
  • a CETP inhibitor e.g. Torcetrapib, anacetrapib or JTT-705 or those as are described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113
  • 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 those described in DE 10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.
  • bile acid resorption inhibitor see, for example, US 6,245,744, US 6,221,897 or WO00 / 61568
  • HMR 1741 e.g. HMR 1741 or those described in DE 10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.
  • the compound of Formula I is used in combination with agonists of GPBAR1 (G-protein-coupled bile-acid receptor-1; TGR5), as described, e.g. in WO2007110237, WO2007127505.
  • GPBAR1 G-protein-coupled bile-acid receptor-1
  • the compound of formula I is used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam hydrochloride.
  • a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam hydrochloride.
  • the compound of formula I is administered in combination with a phytosterol-containing chewing gum (Reductol TM).
  • the compound of the formula I is used in combination with an inhibitor of the microsomal triglyceride transfer protein (MTP inhibitor), for example Implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR -733 or those as described in WO2005085226, WO2005121091, WO2006010423, WO2006113910.
  • MTP inhibitor microsomal triglyceride transfer protein
  • the compound of formula I is administered in combination with an antagonist of the somatostatin 5 receptor (SST5 receptor), e.g. such as those described in WO2006094682 administered.
  • SST5 receptor somatostatin 5 receptor
  • the compound of the formula I is administered in combination with an ACAT inhibitor, e.g. Avasimibe, SMP-797 or KY-382.
  • ACAT inhibitor e.g. Avasimibe, SMP-797 or KY-382.
  • the compound of the formula I in combination with an inhibitor of hepatic carnitine palmitoyltransferase-1 (L-CPTl), as described e.g. in WO2007063012, WO2007096251 (ST-3473).
  • L-CPTl hepatic carnitine palmitoyltransferase-1
  • the compound of formula I is used in combination with a squalene synthetase inhibitor, e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943.
  • a squalene synthetase inhibitor e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943.
  • the compound of the formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide which is capable of regulating the apolipoprotein B gene.
  • the compound of formula I is used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586, or those as described in WO2005097738.
  • an LDL receptor inducer see US 6,342,512
  • the compound of the formula I is administered in combination with an ABCA1 expression enhancer, as described, for example, in WO2006072393. In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein-lipase modulator such as ibrolipim (NO-1886).
  • a lipoprotein-lipase modulator such as ibrolipim (NO-1886).
  • the compound of formula I is used in combination with a lipoprotein (a) antagonist, e.g. Gemcabene (CI-1027).
  • a lipoprotein (a) antagonist e.g. Gemcabene (CI-1027).
  • the compound of the formula I is administered in combination with an adenosine A2B receptor agonist (adenosine A2B R), e.g. ATL-801 administered.
  • an adenosine A2B receptor agonist e.g. ATL-801 administered.
  • the compound of the formula I in combination with a modulator of the adenosine A2A and / or adenosine A3 receptors such. in WO2007111954, WO2007121918, WO2007121921, WO2007121923.
  • the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2B R), as described in US2007270433.
  • adenosine A2B receptor antagonist adenosine A2B R
  • the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACCl and / or ACC2) such.
  • inhibitors of acetyl-CoA carboxylase ACCl and / or ACC2
  • the compound of the formula I is used in combination with modulators of the microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 3 (GP AT3, described in WO2007100789) or with modulators of the microsomal acyl-CoA: glycerol-3-phosphate - Acyltransferase 4 (GP AT4, described in WO2007100833) administered.
  • modulators of the microsomal acyl-CoA glycerol-3-phosphate acyltransferase 3
  • modulators of the microsomal acyl-CoA glycerol-3-phosphate - Acyltransferase 4
  • the compound of the formula I is administered in combination with modulators of xanthine oxidoreductase (XOR).
  • 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 or the compound "NPY-5-BY” from Banyu or as described, for example, in WO2006001318, WO2007103295, WO2007125952;
  • NPY-4 receptor antagonists as they are e.g. As described in WO2007038942;
  • NPY-2 receptor antagonists such as. As described in WO2007038943;
  • 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
  • Cannabinoid Receptor 1 / Cannabinoid Receptor 2 (CB1 / CB2) modulating compounds e.g. delta-9-tetrahydrocannabivarin or those as described e.g. in WO2007001939, WO2007044215, WO2007047737, WO2007095513, WO2007096764, WO2007112399, WO2007112402 are described;
  • FAAH fatty acid amide hydrolase modulators as described, for example, in WO2007140005
  • Vanilloid-1 receptor modulators modulators of the TRPV1
  • Agonists of the prostaglandin receptor e.g. Bimatoprost or such compounds as described in WO2007111806;
  • MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists such as 1-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo) 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141, MK-0493 or those as described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793
  • Orexin receptor 1 antagonists (OXlR antagonists), orexin receptor 2 antagonists (OX2R antagonists) or mixed OX1R / OX2R antagonists (eg l- (2-methylbenzoxazol-6-yl) -3- [l, 5] naphthyridine 4-yl urea hydrochloride (SB-334867-A) or those described, for example, in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374, WO2007122591, WO2007126934, WO2007126935);
  • Histamine H3 receptor antagonists / inverse agonists eg 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) - propan-1-one oxalic acid salt (WO 00/63208) or those as described in WO200064884, WO2005082893, US2005171181 (eg PF-00389027), WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418, WO2007057329, WO2007065820, WO2007068620, WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053, WO2007106349,
  • Histamine Hl / histamine H3 modulators such as. B. Betahistine or its dihydrochloride;
  • CRF antagonists eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585) or those CRF1 antagonists, as described in WO2007105113, WO2007133756);
  • CRF BP antagonists e.g., urocortin
  • Agonists of the 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 -427,353) or N-5984 (KRP-204) or those as described in JP2006111553, WO2002038543, WO2002038544, WO2007048840-843;
  • MSH melanocyte-stimulating hormone
  • MCH (melanin-concentrating hormone) receptor antagonists such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or such compounds, as are described in WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279 WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847, WO
  • CCK-A (CCK-I) agonists such as ⁇ 2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl-t-thiazole) -ylcarbamoyl-SJ-dimethyl indole-1-yl ⁇ -acetic acid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or those as described in WO2005116034, WO2007120655, WO2007120688, WO2007120718;
  • Serotonin reuptake inhibitors e.g., dexfenfluramines
  • mixed serotonin / dopamine reuptake inhibitors e.g., bupropion
  • bupropion or fixed combinations of bupropion with naltrexone or bupropion with zonisamide;
  • mixed reuptake inhibitors such as e.g. DOV 21,947;
  • 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);
  • mixed dopamine / norepinephrine / acetylcholine reuptake inhibitors e.g., tesofensins
  • those as described e.g. in WO2006085118 e.g., WO2006085118;
  • 5-HT2C receptor agonists such as Lorcaserin hydrochloride (APD-356) or BVT-933 or those as described in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025, WO2006103511 WO2007028132, WO2007084622, US2007249709, WO2007132841, WO2007140213 are described); 5-HT6 receptor modulators, such as E-6837, BVT-74316 or PRX-07034 or those as described, for example, in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744;
  • 5-HT6 receptor modulators such as E-6837, BVT-74316 or PRX-07034 or those as described, for example
  • estrogen receptor gamma e.g. in WO2007131005
  • Muscarinic 3 receptor (M3R) antagonists as described e.g. in WO2007110782 are described;
  • BTS-3 agonists Bombesin receptor agonists
  • Growth hormone e.g., human growth hormone or AOD-9604
  • human growth hormone e.g., human growth hormone or AOD-9604
  • Growth Hormone Secretagogue Receptor Antagonists such as A-778193 or those as described in WO2005030734, WO2007127457;
  • Growth Hormone Secretagogue Receptor Modulators e.g. JMV-2959, JMV-3002, JMV-2810, JMV-2951 or those as described in WO2006012577 (e.g., YIL-781 or YIL-870), WO2007079239;
  • TRH agonists see, e.g., EP 0 462 884;
  • Leptin agonists see, eg, Lee, Daniel W, Leinung, Matthew C, Rozhavskaya Arena, Marina, Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity, Drugs of the Future (2001), 26 (9), 873-881);
  • DA agonists bromocriptine, doprexin
  • Lipase / amylase inhibitors e.g., WO 00/40569
  • Inhibitors of diacylglycerol O-acyltransferases such.
  • Inhibitors of fatty acid synthase e.g. C75 or those as described in WO2004005277;
  • Inhibitors of stearoyl-CoA delta9 desaturase as described e.g. in WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746 are described;
  • KB-2115 or DITPA or such as in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864
  • TR-beta thyroid hormone receptor beta
  • the compound of formula I is used in combination with an inhibitor of Site-1 protease (SlP), e.g. PF-429242 administered.
  • SlP Site-1 protease
  • the compound of the formula I is administered in combination with an RNAi therapeutic which is directed against PCSK9 (proprotein convertase subtilisin / kexin type 9).
  • the compound of formula I is administered in combination with Omacor® or Lovaza TM (omega-3 fatty acid esters, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
  • Omacor® or Lovaza TM omega-3 fatty acid esters, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid.
  • the compound of the formula I is administered in combination with lycopene.
  • the compound of formula I is used in combination with an antioxidant, e.g. OPC-14117, succinobucol, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
  • an antioxidant e.g. OPC-14117, succinobucol, 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 B 12 administered.
  • the compound of the formula I is used in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and Metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. administered.
  • the compound of formula I is used in combination with an inhibitor of carbonic anhydrase type 2, such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
  • an inhibitor of carbonic anhydrase type 2 such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
  • the compound of the formula I is administered in combination with topiramate.
  • the compound of formula I is administered in combination with a solid combination of topiramate with phentermine (Qnexa TM).
  • the compound of formula I is used in combination with an antisense compound, e.g. ISIS-377131, which inhibits the production of the glucocorticoid receptor.
  • an antisense compound e.g. ISIS-377131
  • the compound of formula I in combination with an agonist of the RUP3 receptor, such. As described in WO2007035355 administered.
  • the compound of the formula I in combination with an activator of the gene coding for the Ataxia Telangiectasia Mutated (ATM) protein kinase such as. As chloroquine administered.
  • ATM Ataxia Telangiectasia Mutated
  • the compound of the formula I in combination with a tau protein kinase 1 inhibitor (TPKl inhibitor), such as. As described in WO2007119463 administered.
  • TPKl inhibitor tau protein kinase 1 inhibitor
  • the compound of the formula I is administered in combination with a "c-Jun N-terminal kinase" inhibitor (JNK inhibitor), as described, for example, in WO2007125405.
  • JNK inhibitor c-Jun N-terminal kinase inhibitor
  • the compound of the formula I in combination with an endothelin A receptor antagonists, such as. B. avosentan (SPP-301).
  • the compound of formula I is used in combination with modulators of the glucocorticoid receptor (GR), e.g. KB-3305 or such compounds as e.g. As described in WO2005090336, WO2006071609, WO2006135826, WO2007105766.
  • GR glucocorticoid receptor
  • 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 SIRTI (an NAD + -dependent protein deacetylase); this active substance may be, for example, resveratrol in suitable formulations, or such compounds as are mentioned in WO2007019416 (eg SRT-1720).
  • SIRTI an NAD + -dependent protein deacetylase
  • the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanecho 1).
  • the compound of formula I is used in combination with anti-hypercholesterolemic compounds, such as those described e.g. in WO2007107587, WO2007111994.
  • the compound of formula I is used in combination with a cyclic peptide agonist of the VPAC2 receptor, as described e.g. in WO2007101146, WO2007133828.
  • the compound of the formula I is administered in combination with an agonist of the endothelin receptor, as described, for example, in WO2007112069.
  • the compound of the formula I is administered in combination with AKP-020 (bis (ethylmaltolato) oxovanadium-IV).
  • the compound of formula I is administered in combination with tissue-selective androgen receptor modulators (SARMs) as described, for example, in WO2007099200.
  • SARMs tissue-selective androgen receptor modulators
  • 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 further active ingredient is metreleptin (recombinant methionyl-leptin) combined with pramlintide.
  • the further active ingredient is the tetrapeptide ISF-402.
  • the further active ingredient is dexamphetamine or amphetamine.
  • the other active ingredient is fenfluramine or dexfenfluramine.
  • the further active ingredient is sibutramine.
  • the other active ingredient is mazindol or phentermine.
  • the further active ingredient is geniposidic acid (geniposidic acid, WO2007100104).
  • the compound of formula I in combination with dietary fiber, insoluble fiber insoluble fiber
  • 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.RTM ® can in this case in the form of food, such as administered in bakery products or muesli bars.
  • the compounds of formula I are useful in the treatment of dislipidemia for prediabetes treatment, in the prevention of type 2 diabetes and in the treatment of metabolic syndrome (see Datamonitor 11/2002, Chapter 2, pages 19-32). They are especially for the treatment of diabetic dislipidemia.
  • Diabetic dyslipidemia manifests as an increase in plasma triglycerides, a decrease in HDL cholesterol, and often in elevated LDL levels. Due to the increased occurrence of small, dense LDL-cholesterol particles with high atherogenic potency, diabetic dyslipidaemia is a strong cardiovascular risk factor.
  • the compounds are also suitable for the reduction of free fatty acids in the blood.
  • the compounds of the formula I can be formulated, for example, in the following formulations:
  • Dragees containing 50 mg of active ingredient per coated tablet: per Dragee active ingredient 50 mg corn starch 100 mg
  • Example F The following formulations are suitable for the preparation of the contents of hard gelatine capsules: a) Active ingredient 100 mg
  • the substance is administered (zBpo, iv., Ip, sc) and with or without additional stimulation of endogenous lipolysis (eg by bolus injection of 2 mg / kg ip isoprenaline) the effect of the test substance on the lipolysis on the basis of the released free fatty acids (FFA), glycerol and triglycerides determined, for example, 15 min, 30, 60, 120, etc. minutes after po application a blood sample (eg by retroorbital blood sampling) is obtained and analyzed according to standard clinical-chemical methods (eg L. Thomas: Laboratory and Diagnostics, 2nd edition, Medical Publishing Company, Marburg / L., 1984; ISBN 3-921320-10-9)). The inhibition of lipolysis by the inhibitors is evaluated in comparison to the lipolysis rate of appropriately treated control animals.
  • zBpo, iv., Ip, sc endogenous lipolysis
  • endogenous lipolysis eg by bolus injection of 2 mg / kg
  • Example 1 was administered at the dose of 10 mg / kg po, which markedly lowered lipolysis, as shown by the reduction of free fatty acids (FFA), glycerol and triglycerides.
  • FFA free fatty acids
  • n stands for the number of animals. Wistar rats were tested. The effectiveness of the compounds of the formula I was also tested in the following assays:
  • Functional assays were performed by the FLIPR technique ("Fluorescence Imaging Plate Reader", Molecular Devices Corp.) for which agonist-induced changes in the intracellular concentration of Ca + in recombinant HEK293 cells were determined which include both the GPCR FJM74A (niacin receptor ), as well as the hybrid G-protein GD6qi4myr (see, for example, patent application DE10033353) express.
  • Agonists of the G protein-coupled receptor HM74a lead to a decrease of cyclic adenosine monophosphate (cAMP) and to the inhibition of lipolysis in adipocytes (S. Tunaru et al., Nat. Med. 2003, 9, 352-355. ).
  • the inhibition of lipolysis by agonists of the receptor HM74a results in a lowering of free fatty acids and triglycerides in the blood. (Offermanns, Trends in Pharm Sciences 2006, 27, 384-390.).
  • Substances that are identified as agonists of the receptor HM74a are thus suitable for the treatment of dislipidaemia.

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Abstract

The invention relates to the use of substituted pyridinone carboxylic acid derivates and the physiologically acceptable salts thereof for the production of pharmaceuticals for treating dyslipidemia. The invention relates to the use of compound of formula (I), where the group R has the indicated meanings, and to the physiologically acceptable salts thereof for the production of a pharmaceutical for treating dyslipidemia.

Description

Verwendung von substituierten Pyridinoncarbonsäurederivaten zur Herstellung von Medikamenten zur Behandlung der Dislipidämie Use of substituted pyridinonecarboxylic acid derivatives for the preparation of medicaments for the treatment of dislipidemia
Die Erfindung betrifft die Verwendung von substituierten Pyridinoncarbonsäurederivaten sowie derer physiologisch verträglichen Salze zur Herstellung von Medikamenten zur Behandlung der Dislipidämie.The invention relates to the use of substituted Pyridinoncarbonsäurederivaten and their physiologically acceptable salts for the preparation of medicaments for the treatment of dislipidemia.
Der Erfindung lag die Aufgabe zugrunde, Verbindungen zur Verfügung zu stellen, die eine therapeutisch verwertbare lipidsenkende Wirkung entfalten. Weiter bevorzugt sollten sie zur Behandlung der Dislipidämie geeignet sein. Weiter bevorzugt sollte eine Senkung der freien Fettsäuren (FFA), von Glycerol und der Triglyceride im Plasma erreicht werden.It is an object of the present invention to provide compounds which have a therapeutically utilizable lipid-lowering action. More preferably, they should be suitable for the treatment of dislipidemia. More preferably, a reduction of the free fatty acids (FFA), of glycerol and the triglycerides in the plasma should be achieved.
Die Erfindung betrifft daher die Verwendung der Verbindungen der Formel I,The invention therefore relates to the use of the compounds of the formula I,
Figure imgf000003_0001
Figure imgf000003_0001
worin bedeutetwhere is meant
R (Ci-Co)-Alkyl, (C2-C 10)-Alkenyl, (C2-C 10)-Alkinyl, wobei in den (Ci-Cio)-Alkyl-, (C2-C iO)-Alkenyl- oder (C2-C io)- Alkinylresten, ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkyl-, Alkenyl- und Alkinylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, CF3, (C3-Ci2)- Carbocyclus, Aryl, wobei Aryl ein oder mehrfach substituiert sein kann mit F, Cl, Br, I, CF3, (Ci-C6)-Alkyl;R (Ci-Co) alkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) -alkynyl, where in the (Ci-Cio) alkyl, (C 2 -C i O) - Alkenyl or (C 2 -C 10) -alkynyl radicals, one or more individual CH 2 groups may be replaced by O and where the alkyl, alkenyl and alkynyl radicals may be monosubstituted or polysubstituted by F, Cl, Br, I, CF 3 , (C 3 -Ci 2 ) - Carbocycle, aryl, where aryl may be mono or polysubstituted with F, Cl, Br, I, CF 3, (Ci-C 6) alkyl;
sowie derer physiologisch verträglichen Salze, zur Behandlung der Dislipidämie.and their physiologically acceptable salts, for the treatment of dislipidemia.
Weiter bevorzugt ist die Verwendung der Verbindungen der Formel I, worin bedeutetFurther preferred is the use of the compounds of formula I, wherein means
R (C,-C10)-Alkyl, (C2-C10)-Alkenyl, wobei in den (C1-CiO)-AUCyI- oder (C2-C 10)-Alkenylresten ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-Ci2)-Carbocyclus, Aryl, wobei Aryl ein oder mehrfach substituiert sein kann mit F, Cl, Br, I, CF3, (CrC6)-Alkyl;R (C, -C 10 ) -alkyl, (C 2 -C 10 ) -alkenyl, wherein in the (C 1 -Ci O ) -AUCyI- or (C 2 -C 10 ) -alkenyl radicals one or more individual CH 2 Groups may be replaced by O and wherein the alkyl radicals may be monosubstituted or polysubstituted by F, Cl, Br, I, (C 3 -C 2 ) -cyclocycle, aryl, where aryl may be mono- or polysubstituted by F, Cl, Br, I, CF 3 , (C r C 6 ) alkyl;
sowie derer physiologisch verträglichen Salze, zur Behandlung der Dislipidämieand their physiologically acceptable salts, for the treatment of dislipidemia
Weiter bevorzugt ist die Verwendung der Verbindungen der Formel I, worin bedeutetFurther preferred is the use of the compounds of formula I, wherein means
R (C1-Co)-AUCyI, (C2-C 10)-Alkenyl, wobei in den (Ci -C1O)-AUCyI- oder (C2-C io)-AUcenylresten ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-Ci2)-Carbocyclus, Aryl;R (C 1 -Co) -AUCyI, (C 2 -C 10 ) -alkenyl, wherein in the (Ci -C 10 ) -AUCyI- or (C 2 -C 10 ) -AUcenylresten one or more individual CH 2 groups O may be replaced and wherein the alkyl radicals may be monosubstituted or polysubstituted with F, Cl, Br, I, (C 3 -C 2 ) -carbocycle, aryl;
sowie derer physiologisch verträglichen Salze, zur Behandlung der Dislipidämie.and their physiologically acceptable salts, for the treatment of dislipidemia.
Weiter bevorzugt ist die Verwendung der Verbindungen der Formel I, worin bedeutetFurther preferred is the use of the compounds of formula I, wherein means
R (C1-Co)-AIkVl, wobei in dem (Ci-Cio)-Alkylrest ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-C 12)-Carbocyclus, Aryl;R (C 1 -Co) -AlkVl, wherein in the (Ci-Cio) alkyl radical one or more individual CH 2 groups may be replaced by O and wherein the alkyl radicals may be mono- or polysubstituted with F, Cl, Br, I, (C 3 -C 12 ) -Cyclocycle , Aryl;
sowie derer physiologisch verträglichen Salze, zur Behandlung der Dislipidämie.and their physiologically acceptable salts, for the treatment of dislipidemia.
Weiter bevorzugt ist die Verwendung der Verbindungen der Formel I, worin bedeutetFurther preferred is the use of the compounds of formula I, wherein means
R (C,-CiO)-Alkyl, wobei in dem (C1-Ci0)-Alkylrest ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-C12)-Carbocyclus, Phenyl;R (C, -C O) -alkyl, where in the (C 1 -C 0) alkyl one or more individual CH 2 groups can be replaced by O and wherein said alkyl radicals can be mono or polysubstituted with F, Cl, Br, I, (C 3 -C 12 ) -carbocycle, phenyl;
sowie derer physiologisch verträglichen Salze, zur Behandlung der Dislipidämie.and their physiologically acceptable salts, for the treatment of dislipidemia.
In einer Ausfuhrungsform sind Verbindungen der Formel I bevorzugt, worin R gleich (C1- Ciö)-Alkyl ist, wobei in dem (Ci-C]o)-Alkylrest ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei der Alkylrest ein oder mehrfach substituiert sein kann mit F, Cl, Br, I, CF3.In one embodiment compounds of formula I are preferred, wherein R is (C 1 - C ö) alkyl, wherein in the (Ci-C] o) alkyl one or more individual CH 2 groups can be replaced by O and wherein the alkyl radical may be monosubstituted or polysubstituted with F, Cl, Br, I, CF 3 .
In einer Ausführungsform sind Verbindungen der Formel I bevorzugt, worin R gleich (C2- Cio)-Alkenyl ist, wobei in dem (C2-do)-Alkenylresten ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei der Alkenylrest ein oder mehrfach substituiert sein kann mit F, Cl, Br, I, CF3.In one embodiment, preference is given to compounds of the formula I in which R is (C 2 -C 10) -alkenyl, where in the (C 2 -d0) -alkenyl radical one or more individual CH 2 groups may be replaced by O and where the alkenyl radical may be monosubstituted or polysubstituted with F, Cl, Br, I, CF 3 .
In einer Ausführungsform sind Verbindungen der Formel I bevorzugt, worin R gleich (C2- Cio)-Alkinyl ist, wobei in dem (C2-C io)- Alkinylrest ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können. Die Erfindung bezieht sich auf die Verwendung der Verbindungen der Formel I, in Form ihrer Racemate, racemischen Mischungen und reinen Enantiomere sowie auf ihre Diastereomere und Mischungen davon.In one embodiment, compounds of formula I are preferred, wherein R is (C 2 - Cio) -alkynyl, where in the (C 2 -C io) - 2 groups may be replaced by O alkynyl group one or more individual CH. 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.
Unter einem Alkylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit einem oder mehreren Kohlenstoffen verstanden, wie z.B. Methyl, Ethyl, Propyl, Butyl, Hexyl, Isopropyl, Isobutyl, Neopentyl, tert.-Butyl, Hexyl.By an alkyl radical is meant a straight or branched hydrocarbon chain having one or more carbons, e.g. Methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, neopentyl, tert-butyl, hexyl.
Die Alkylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C !-C6)ADCyI, CONH2, CONH(C1- C6)Alkyl, CON[(CrC6)Alkyl]2> Carbocyclus, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, Aryl, Heterozyklyl, 0-(Ci-C6)- Alkyl, 0-COO-(Ci -C6)- Alkyl, 0-CO-(Ci -C6)- Alkyl, 0-CO-(Ci- C6)-Aryl, 0-CO-(C rC6)-Heterozyklyl, PO3H2, P(0)(0Alkyl)2, (Cl-C6)-Alkylen-The alkyl 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 ! -C 6 ) ADCyI, CONH 2 , CONH (C 1 - C 6) alkyl, CON [(C r C6) alkyl] 2> carbocycle, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, aryl, heterocyclyl, 0- ( C 1 -C 6 ) -alkyl, 0-COO- (C 1 -C 6 ) -alkyl, 0-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, 0-CO (C r C 6 ) heterocyclyl, PO 3 H 2 , P (O) (Oalkyl) 2, (C 1 -C 6 ) -alkylene
P(0)(0Alkyl)2, 0-P(O)(OH)2, 0-P(0)(0Alkyl)2, SO3H, SO2-NH2, SO2NH(Ci-C6)-Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(Ci -C6)- Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterozyklyl, SO-(C,- C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterozyklyl, SO2-(C,-C6)-Alkyl, SO2-(CH2)n- Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2- N[((Ci-C6)-Alkyl)(CH2)n-Aryl], SO2-N[((C,-C6)-Alkyl)(CH2)n-Heterozyklyl], SO2-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , 0-P (0) (O-alkyl) 2, SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) Alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S (C 1 -C 6 ) alkyl, S (CH 2 ) n aryl, S (CH 2 ) n heterocyclyl, SO- (C, - C 6) - alkyl, SO- (CH 2) n -aryl, SO- (CH 2) n -Heterozyklyl, SO 2 - (C, -C 6) -alkyl, SO 2 - (CH 2 ) n - aryl, SO 2 - (CH 2 ) n -heterocyclyl, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocyclyl, SO 2 - N [( C 6 ) -alkyl) (CH 2 ) n -aryl], SO 2 -N [((C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocyclyl], SO 2 -
N((CH2)n-Aryl)2, , SO2-N((CH2)n-(Heterozyklyl))2) wobei n = O - 6 sein kann und der Aryl- oder Heterozyklyl- Rest bis zu dreifach mit F, Cl, Br, OH, CF3, SF5, NO2, CN, OCF3, O- (C 1-C6)- Alkyl, (Ci -C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(Ci-C6)-Alkyl, N((CrC6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(Ci- C6)-Alkyl, NH-COO-(C1 -C6)-Alkyl, NH-CO- Aryl, NH-CO-Heterozyklyl, NH-C00- Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(Ci-C6)- Alkyl), NH-CO-NH-Aryl, NH-CO-NH- Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-(C,-C6)- Alkyl, Nt(Ci-C6)- Alkyl]-COO-(Ci-C6)-Alkyl, Nf(Ci-C6)- Alkyl]-CO- Aryl, N[(C, -C6)- Alkyl] -CO-Heterozyklyl, N[(Ci-C6)- Alkyl]-COO- Aryl, N[(Ci-C6)-Alkyl]-COO-Heterozyklyl, N[(C,-C6)-Alkyl]-CO-NH-(Ci-C6)- Alkyl), N[(Ci-C6)-Alkyl]-CO-NH-Aryl, N[(C,-C6)-Alkyl]-CO-NH-Heterozyklyl, N[(Ci-C6)-N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocyclyl)) 2) where n = O - 6 and the aryl or heterocyclyl radical can be up to three times F, Cl, Br, OH, CF 3, SF 5, NO 2, CN, OCF 3, O- (C 1 -C 6) - alkyl, (Ci-C6) - alkyl, NH 2 may be substituted; C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C r C 6 ) alkyl) 2 , NH (C, -C 7 ) acyl, NH-CO (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-C00--aryl, NH-COO-heterocyclyl, NH-- CO-NH- (C 1 -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO- (C, -C 6 ) - alkyl, Nt (Ci-C 6) - alkyl] -COO- (Ci-C6) alkyl, Nf (Ci-C 6) - alkyl] -CO- aryl, N [(C, -C6) - alkyl] -CO-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -COO-aryl, N [(C 1 -C 6 ) -alkyl] -COO-heterocyclyl, N [(C, -C 6 ) - alkyl] -CO-NH- (Ci-C 6) - alkyl), N [(Ci-C 6) -alkyl] -CO-NH-aryl, N [(C, -C 6) -alkyl] -CO- NH-heterocyclyl, N [(Ci-C 6) -
Alkyl]-CO-N((C,-C6)-Alkyl)2, N[(Ci-C6)-Alkyl]-CO-N((C,-C6)-Alkyl)-Aryl, N[(C,-C6)- Alkyl]-CO-N((Ci-C6)-Alkyl)-Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-N(Aryl)2, N[(C,-C6)- Alkyl]-CO-N(Heterozyklyl)2, N(Aryl)-CO-(C,-C6)-Alkyl, N(Heterozyklyl)-CO-(Ci-C6)- Alkyl, N(Aryl)-COO-(Ci-C6)-Alkyl, N(Heterozyklyl)-COO-(Ci-C6)-Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl, N(Aryl)-CO-NH-(Ci -C6)- Alkyl, N(Heterozyklyl)-CO-NH-(Ci -C6)- Alkyl, N(Aryl)-CO- NH-Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((C,-C6)-Alkyl)2, N(Heterozyklyl)-CO-N((Ci-C6)-Alkyl)2, N(Aryl)-CO-N[(Ci-C6)-Alkyl]-Aryl,Alkyl] -CO-N ((C 1 -C 6 ) -alkyl) 2 , N [(C 1 -C 6 ) -alkyl] -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N [ (C 1 -C 6 ) -alkyl] -CO-N ((C 1 -C 6 ) -alkyl) -heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO-N (aryl) 2 , N [( C, -C 6 ) -alkyl] -CO-N (heterocyclyl) 2 , N (aryl) -CO- (C, -C 6 ) -alkyl, N (heterocyclyl) -CO- (C 1 -C 6 ) - Alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -COO- (C 1 -C 6 ) -alkyl, N (aryl) -CO-aryl, N (heterocyclyl) -CO- Aryl, N (aryl) -COO-aryl, N (heterocyclyl) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -CO-NH- (C 1 -C 6 ) -alkyl C 6 ) - alkyl, N (aryl) -CO-NH-aryl, N (heterocyclyl) -CO-NH-aryl, N (aryl) -CO-N ((C, -C 6 ) -alkyl) 2 , N (Heterocyclyl) -CO-N ((C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl,
N(Heterozyklyl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n = 0 - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3 -fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(C1 -C6)- Alkyl, (Ci -C6)- Alkyl, NH2, NH(C ,-C6)- Alkyl, N((Q-C6)- Alkyl)2, SF5, SO2-CH3, COOH, COO-(Ci -C6)- Alkyl, CONH2.N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO-N (aryl) 2 , aryl, O - (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n = 0-6, where the aryl or heterocyclyl radical may be substituted one to three times by F, Cl, Br , I, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - alkyl, (Ci-C6) - alkyl, NH 2, NH (C, -C6) - alkyl , N ((QC 6 ) -alkyl) 2 , SF 5 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CONH 2 .
Unter einem Alkenylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit zwei oder mehreren Kohlenstoffen sowie einer oder mehreren Doppelbindungen verstanden, wie z.B. Vinyl, Allyl, Pentenyl. Die Alkenylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1 -C6) Alkyl, CONH2, CONH(Ci- C6)Alkyl, CON[(Ci-C6)Alkyl]2; Carbocyclus, (C, -Ci0)- Alkyl, (C2-C6)-Alkinyl, Aryl, Heterozyklyl, 0-(C ,-C6)- Alkyl 0-CO-(Ci -C6)- Alkyl, 0-CO-(Ci -C6)- Aryl, 0-CO-(Ci-C6)- Heterozyklyl, PO3H2, P(O)(O Alkyl)2, (Cl-C6)-Alkylen-P(O)(OAlkyl)2, 0-P(O)(OH)2, O- P(0)(0Alkyl)2, SO3H, SO2-NH2, SO2NH(C ,-C6)- Alkyl, SO2Nt(C1 -C6)- Alkyl]2 , S-(Ci- C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterozyklyl, SO-(CrC6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterozyklyl, SO2-(Ci -C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n- Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2-N((C , -C6)- Alkyl)(CH2)n- Aryl, SO2-N((C,-C6)-Alkyl)(CH2)n-Heterozyklyl, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n- (Heterozyklyl)2 wobei n = O - 6 sein kann und der Arylrest oder heterozyklische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, SF5, NO2, CN, OCF3, 0-(C1 -C6)- Alkyl, (Ci -C6)- Alkyl, NH2 substituiert sein kann;An alkenyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having two or more carbons and one or more double bonds, such as, for example, vinyl, allyl, pentenyl. The alkenyl 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 [(C 1 -C 6 ) alkyl] 2; Carbocycle, (C, -C 0) - alkyl, (C 2 -C 6) alkynyl, aryl, heterocyclyl, 0- (C, -C 6) - alkyl 0-CO- (Ci-C6) - alkyl, 0-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocyclyl, PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6 ) -alkylene-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , O-P (0) (O-alkyl) 2, SO 3 H, SO 2 -NH 2 , SO 2 NH (C, -C 6 ) - alkyl, SO 2 Nt (C 1 -C 6) - alkyl] 2, S- (Ci-C6) -alkyl, S- (CH 2) n -aryl, S- (CH 2) n -Heterozyklyl, SO - (C r C6) -alkyl, SO- (CH 2) n -aryl, SO- (CH 2) n -Heterozyklyl, SO 2 - (Ci-C6) - alkyl, SO 2 - (CH 2) n -Aryl, SO 2 - (CH 2 ) n -heterocyclyl, SO 2 -NH (CH 2 ) n - aryl, SO 2 -NH (CH 2 ) n -heterocyclyl, SO 2 -N ((C, -C 6 ) - alkyl) (CH 2 ) n - aryl, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocyclyl, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n - (heterocyclyl) 2 where n = O-6 and the aryl radical or heterocyclic radical may be up to twice with F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF3, 0- (C 1 -C 6) - alkyl, (Ci-C6) - alkyl, NH 2 may be substituted;
C(NH)(NH2), NH2, NH-(C, -C6)-Alkyl, N((Ci-C6)-Alkyl)2, NH(Ci-C7)-Acyl, NH-CO-(Ci- C6)-Alkyl, NH-C00-(Ci-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterozyklyl, NH-COO-Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(Ci -C6)- Alkyl), NH-CO-NH-Aryl, NH-CO-NH-C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , NH (C 1 -C 7 ) -acyl, NH-CO - (C 1 -C 6 ) -alkyl, NH-C00- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO -NH- (C 1 -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-
Heterozyklyl, Nf(Ci-C6)- Alkyl]-CO-(CrC6)-Alkyl, N[(Ci-C6)-Alkyl]-COO-(Ci-C6)- Alkyl, N[(Ci-C6)-Alkyl]-CO- Aryl, N[(C, -C6)- Alkyl] -CO-Heterozyklyl, N[(C,-C6)- Alkyl]-COO- Aryl, N[(Ci-C6)-Alkyl]-COO-Heterozyklyl, N[(C,-C6)-Alkyl]-CO-NH-(Ci-C6)-Alkyl), N[(CrC6)-Alkyl]-CO-NH-Aryl, N[(Ci-C6)-Alkyl]-CO-NH-Heterozyklyl, N[CC1-C6)- Alkyl]-CO-N((d-C6)-Alkyl)2, N[(Ci-C6)- Alkyl]-CO-N((C,-C6)-Alkyl)-Aryl, N[(Ci-C6)- Alkyl]-CO-N((C,-C6)-Alkyl)-Heterozyklyl, N[(Ci-C6)- Alkyl]-CO-N(Aryl)2, N[(Ci-C6)- Alkyl]-CO-N(Heterozyklyl)2, N(Aryl)-CO-(Ci-C6)- Alkyl, N(Heterozyklyl)-CO-(Ci-C6)- Alkyl, N(Aryl)-COO-(Ci -C6)-Alkyl, N(Heterozyklyl)-COO-(C, -C6)-Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)- Alkyl, N(Heterozyklyl)-CO-NH-(C ,-C6)- Alkyl, N(Aryl)-CO- NH-Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((Ci-C6)-Alkyl)2, N(Heterozyklyl)-CO-N((Ci-C6)-Alkyl)2, N(Aryl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Heterozyklyl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n = O - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3 -fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C,-C6)-Alkyl, (C, -C6)- Alkyl, NH2, NH(C, -C6)- Alkyl, N((CrC6)- Alkyl)2, SF5, SO2-CH3, COOH, COO-(C ,-C6)- Alkyl, CONH2.Heterocyclyl, Nf (Ci-C 6) - alkyl] -CO- (C r C6) alkyl, N [(Ci-C 6) -alkyl] -COO- (Ci-C 6) - alkyl, N [( C 1 -C 6 ) -alkyl] -CO-aryl, N [(C 1 -C 6 ) -alkyl] -CO-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -COO-aryl, N [( C 1 -C 6 ) -alkyl] -COO-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO-NH- (C 1 -C 6 ) -alkyl), N [(CrC 6) alkyl] -CO-NH-aryl, N [(Ci-C 6) -alkyl] -CO-NH-heterocyclyl, N [CC 1 -C 6) - alkyl] -CO-N ( (dC 6) alkyl) 2, N [(Ci-C 6) - alkyl] -CO-N ((C, -C 6) alkyl) aryl, N [(Ci-C 6) - alkyl] - CO-N ((C 1 -C 6 ) -alkyl) -heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO-N (aryl) 2 , N [(C 1 -C 6 ) -alkyl] -CO -N (heterocyclyl) 2 , N (aryl) -CO- (Ci-C 6 ) - alkyl, N (heterocyclyl) -CO- (Ci-C 6 ) - alkyl, N (aryl) -COO- (Ci -C 6 ) -alkyl, N (heterocyclyl) -COO- (C, -C 6 ) -alkyl, N (aryl) -CO-aryl, N (heterocyclyl) -CO-aryl, N (aryl) -COO-aryl, N (Heterocyclyl) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -CO-NH- (C, -C 6 ) -alkyl, N (aryl) - CO-NH-aryl, N (heterocyclyl) -CO-NH-aryl, N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) 2 , N (heterocyclyl) -CO-N ((Ci-C 6 ) -alkyl) 2 , N (aryl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (Aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO-N (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n = O - can be 6, wherein the aryl or heterocyclyl radical substituted one to three times s a can with 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, -C 6) - alkyl, N ((C r C6) - alkyl) 2, SF 5, SO 2 -CH 3, COOH, COO- (C, -C 6) - alkyl, CONH. 2
Unter einem Alkinylrest wird eine geradkettige oder verzweigte Kohlenwasserstoffkette mit zwei oder mehreren Kohlenstoffen sowie einer oder mehreren Dreifachbindungen verstanden, wie z.B. Ethinyl, Propinyl, Hexinyl. Die Alkinylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci -C6) Alkyl, CONH2, CONH(C,- C6)Alkyl, CONf(Ci-C6)AIkVl]2, Carbocyclus, (C2-C6)-Alkenyl, (Ci -Ci0)- Alkyl, 0-(Ci-C6)- Alkyl O-CO-(Ci-C6)-Alkyl, 0-CO-(Ci -C6)- Aryl, 0-CO-(C1 -C6)-Heterozyklyl; PO3H2, P(O)(O Alkyl)2, (Cl-C6)-Alkylen-P(O)(OAlkyl)2, 0-P(O)(OH)2, O- P(0)(0Alkyl)2, SO3H, SO2-NH2, SO2NH(C, -C6)- Alkyl, SO2N[(Ci-C6)-Alkyl]2 , S-(Ci- C6)- Alkyl, S-(CH2)n- Aryl, S-(CH2)n-Heterozyklyl, SO-(C ,-C6)-Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterozyklyl, SO2-(C ,-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2-N((C , -C6)- Alkyl)(CH2)n- Aryl, SO2-N((C,-C6)-Alkyl)(CH2)n-Heterozyklyl, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n- (Heterozyklyl)2 wobei n = O - 6 sein kann und der Arylrest oder Heterozyklische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, SF5, NO2, CN, OCF3, 0-(C, -C6)- Alkyl, (C, -C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(Ci-C6)-Alkyl, N((Ci-C6)-Alkyl)2, NH(Ci -C7)- Acyl, NH-CO-(Ci- C6)-Alkyl, NH-COO-(CrC6)-Alkyl, NH-CO-Aryl, NH-CO-Heterozyklyl, NH-COO-Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(Ci -C6)- Alkyl), NH-CO-NH-Aryl, NH-CO-NH- Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-(Ci-C6)-Alkyl, N[(CrC6)-Alkyl]-COO-(C,-C6)-Alkyl, N[(C,-C6)-Alkyl]-CO-Aryl, N[(Ci-C6)-Alkyl]-CO-Heterozyklyl, Nf(C1 -C6)- Alkyl] -COO- Aryl, N[(Ci-C6)-Alkyl]-COO-Heterozyklyl, N[(C,-C6)-Alkyl]-CO-NH-(Ci-C6)-Alkyl), N[(C1-C6)-Alkyl]-CO-NH-Aryl, N[(Ci-C6)-Alkyl]-CO-NH-Heterozyklyl, N[(Ci-C6)- Alkyl]-CO-N((Ci-C6)-Alkyl)2, N[(C1-C6)-Alkyl]-CO-N((C,-C6)-Alkyl)-Aryl, N[(Ci-C6)- Alkyl]-CO-N((Ci-C6)-Alkyl)-Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-N(Aryl)2, N[(C,-C6)- Alkyl]-CO-N(Heterozyklyl)2, N(Aryl)-CO-(Ci -C6)- Alkyl, N(Heterozyklyl)-CO-(Ci-C6)- Alkyl, N(Aryl)-COO-(Ci-C6)-Alkyl, N(Heterozyklyl)-COO-(Ci -C6)- Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)- Alkyl, N(Heterozyklyl)-CO-NH-(C i -C6)- Alkyl, N(Aryl)-CO- NH-Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((CrC6)-Alkyl)2, N(Heterozyklyl)-CO-N((Ci-C6)-Alkyl)2, N(Aryl)-CO-N[(Ci-C6)-Alkyl]-Aryl,An alkynyl radical is understood to mean a straight-chain or branched hydrocarbon chain having two or more carbons and one or more triple bonds, such as ethynyl, propynyl, hexynyl. The alkynyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (Ci-C6) alkyl, CONH 2, CONH ( C, - C 6) alkyl, conf (Ci-C 6) -alkyl] 2, carbocycle, (C 2 -C 6) alkenyl, (Ci -C 0) - alkyl, 0- (Ci-C 6) - alkyl O-CO- (Ci-C 6) -alkyl, 0-CO- (Ci-C6) - aryl, 0-CO- (C 1 -C 6) -Heterozyklyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , O-P (O) ( 0 alkyl) 2, SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C 1 -C 6 ) - alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocyclyl, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2 ) n -heterocyclyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -aryl, SO 2 - (CH 2 ) n -heterocyclyl, SO 2 -NH (CH 2 ) n - aryl, SO 2 -NH (CH 2) n -Heterozyklyl, SO 2 -N ((C, -C6) - alkyl) (CH 2) n - aryl, SO 2 -N ((C, -C6) - Alkyl) (CH 2 ) n -heterocyclyl, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocyclyl) 2 where n = O-6 and the aryl radical or heterocyclic radical up to twice with F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF 3 , 0- (C 1 -C 6 ) -alkyl, (C, -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 1 -C 7 ) -acyl, NH-CO- (Ci- C 6) alkyl, NH-COO- (C r C6) alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO- NH- (C 1 -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO- (C 1 -C 6 ) -alkyl , N [(C 1 -C 6 ) -alkyl] -COO- (C 1 -C 6 ) -alkyl, N [(C 1 -C 6 ) -alkyl] -CO-aryl, N [(C 1 -C 6 ) -alkyl ] -CO-heterocyclyl, Nf (C1-C6) - alkyl] -COO- aryl, N [(Ci-C 6) -alkyl] -COO-heterocyclyl, N [(C, -C 6) alkyl] -CO-NH- (C 1 -C 6 ) -alkyl), N [(C 1 -C 6 ) -alkyl] -CO-NH-aryl, N [(C 1 -C 6 ) -alkyl] -CO-NH- heterocyclyl, N [(Ci-C 6) - alkyl] -CO-N ((Ci-C 6) alkyl) 2, N [(C 1 -C 6) -alkyl] -CO-N ((C, - C 6) -alkyl) -aryl, N [(Ci-C 6) - alkyl] -CO-N ((Ci-C 6) alkyl) -Heterozyklyl, N [(Ci-C 6) -alkyl] -CO -N (aryl) 2 , N [(C, -C 6 ) -alkyl] -CO-N (heterocyclyl) 2 , N (aryl) -CO- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -CO - (Ci-C 6) - alkyl, N (aryl) -COO- (Ci-C 6) -alkyl, N (heterocyclyl) -COO- (Ci-C6) - alkyl, N (aryl) -CO- aryl , N (heterocyclyl) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclyl) -COO-aryl, N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -CO-NH- (C i -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclyl) -CO-NH-aryl, N (aryl) -CO-N ((C r C 6 ) -alkyl) 2 , N (heterocyclyl ) -CO-N ((C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl,
N(Heterozyklyl)-CO-N[(Ci -C6)- Alkyl] -Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n - 0 - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3 -fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (Ci -C6)- Alkyl, NH2, NH(C, -C6)- Alkyl, N((C,-C6)- Alkyl)2, SF5, SO2-CH3, COOH, COO-(C ,-C6)- Alkyl, CONH2.N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO-N (aryl) 2 , aryl, O - (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n - 0 - may be 6, wherein the aryl or heterocyclyl radical may be substituted one to three times with F, Cl, Br , I, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , SF 5 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CONH 2 .
Unter einem Arylrest wird ein Phenyl, Naphthyl-, Biphenyl-, Tetrahydronaphthyl-, alpha- oder beta-Tetralon-, Indanyl- oder Indan-1-on-ylrest verstanden. Die Arylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, SF5, N3, CN, COOH, COO(C ,-C6) Alkyl, CONH2, CONH(Ci- C6)Alkyl, CON[(Ci-C6)Alkyl]2; Carbocyclus, (Ci -Ci0)- Alkyl, (C2-C6)-Alkenyl, (C2-C6)- Alkinyl, O-(C,-C6)- Alkyl 0-CO-(C ,-C6)- Alkyl, 0-CO-(Ci -C6)- Aryl, 0-CO-(Ci-C6)- Heterozyklyl,;An 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 mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, SF 5, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2; Carbocycle, (Ci -C 0) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, O- (C, -C6) - alkyl 0-CO- (C, - C 6 ) - alkyl, 0-CO- (C 1 -C 6 ) -aryl, 0-CO- (C 1 -C 6 ) -heterocyclyl;
PO3H2, P(O)(O Alkyl)2, (Cl-C6)-Alkylen-P(O)(OAlkyl)2, 0-P(O)(OH)2, O- P(O)(OAlkyl)2, SO3H, SO2-NH2, SO2NH(Ci-C6)-Alkyl, SO2N[(Ci-C6)-Alkyl]2 , S-(Cr C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterozyklyl, SO-(Ci-C6)-Alkyl, SO-(CH2)n-Aryl,PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , O-P (O) ( Oalkyl) 2, SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(C 1 -C 6 ) -alkyl] 2 , S- (C r C 6 ) - Alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocyclyl, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl,
SO-(CH2)n-Heterozyklyl, SO2-(Ci -C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2-N((CrC6)-Alkyl)(CH2)n-Aryl, SO2-N((C1-C6)-Alkyl)(CH2)n-Heterozyklyl, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n- (Heterozyklyl)2 wobei n = 0 - 6 sein kann und der Arylrest oder Heterozyklische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, SF5, CN, OCF3, O-(Ci-C6)-Alkyl, (C,-C6)-Alkyl, NH2 substituiert sein kann;SO- (CH 2) n -Heterozyklyl, SO 2 - (Ci-C6) - alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n -Heterozyklyl, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocyclyl, SO 2 -N ((C r C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -heterocyclyl, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (Heterocyclyl) 2 where n = 0-6 and the aryl radical or heterocyclic radical can be up to two times with F, Cl, Br, OH, CF 3 , NO 2 , SF 5 , CN, OCF 3 , O- (Ci-C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 may be substituted;
C(NH)(NH2), NH2, NH-(Ci -C6)- Alkyl, N((C,-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(C1- C6)- Alkyl, NH-COO-(C ,-C6)- Alkyl, NH-CO- Aryl, NH-CO-Heterozyklyl, NH-COO- Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(C ,-C6)- Alkyl), NH-CO-NH- Aryl, NH-CO-NH- Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-(Ci-C6)-Alkyl, N[(Ci-C6)-Alkyl]-COO-(Ci-C6)-Alkyl, N[(C,-C6)-Alkyl]-CO-Aryl, N[(Ci-C6)- Alkyl]-CO-Heterozyklyl, N[(CrC6)-Alkyl]-COO- Aryl, Nf(Ci-C6)- Alkyl]-COO-Heterozyklyl, N[(C,-C6)-Alkyl]-CO-NH-(C,-C6)- Alkyl), N[(C,-C6)-Alkyl]-CO-NH-Aryl, Nf(C1 -C6)- Alkyl] -CO-NH-Heterozyklyl, N[(C,-C6)- Alkyl]-CO-N((Ci-C6)-Alkyl)2, N[(C,-C6)-Alkyl]-CO-N((C,-C6)-Alkyl)-Aryl, N[(C,-C6)- Alkyl]-CO-N((CrC6)-Alkyl)-Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-N(Aryl)2, N[(Ci-C6)- Alkyl]-CO-N(Heterozyklyl)2, N(Aryl)-CO-(Ci-C6)-Alkyl, N(Heterozyklyl)-CO-(Ci-C6)- Alkyl, N(Aryl)-COO-(C,-C6)- Alkyl, N(Heterozyklyl)-COO-(C, -C6)- Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl,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- (C 1 - C 6) - alkyl, NH-COO- (C, -C 6) - alkyl, NH-CO- aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH- (C 1 -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO- (C 1 -C 4 ) C 6 ) -alkyl, N [(C 1 -C 6 ) -alkyl] -COO- (C 1 -C 6 ) -alkyl, N [(C 1 -C 6 ) -alkyl] -CO-aryl, N [(Ci -C 6) - (alkyl] -CO-heterocyclyl, N [C r C 6) -alkyl] -COO- aryl, Nf (Ci-C 6) - alkyl] -COO-heterocyclyl, N [(C, -C 6) -alkyl] -CO-NH- (C, -C6) - alkyl), N [(C, -C 6) -alkyl] -CO-NH-aryl, Nf (C1-C6) - alkyl ] -CO-NH-heterocyclyl, N [(C, -C 6 ) -alkyl] -CO-N ((C 1 -C 6 ) -alkyl) 2 , N [(C 1 -C 6 ) -alkyl] -CO -N ((C, -C 6) alkyl) aryl, N [(C, -C 6) - alkyl] -CO-N ((C r C6) alkyl) -Heterozyklyl, N [(Ci- C 6) -alkyl] -CO-N (aryl) 2, N [(Ci-C 6) - alkyl] -CO-N (heterocyclyl) 2, N (aryl) -CO- (Ci-C 6) alkyl , N (heterocyclyl) -CO- (C 1 -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -COO- (C 1 -C 6 ) -alkyl , N (aryl) -CO-aryl, N (heterocyclyl ) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclyl) -COO-aryl,
N(Aryl)-CO-NH-(Ci-C6)- Alkyl, N(Heterozyklyl)-CO-NH-(C, -C6)- Alkyl, N(Aryl)-CO- NH- Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((Ci-C6)-Alkyl)2, N(Heterozyklyl)-CO-N((Ci-C6)-Alkyl)2, N(Aryl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Heterozyklyl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n = O - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3 -fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (C ,-C6)- Alkyl, NH2, NH(C ,-C6)- Alkyl, N((Ci-C6)- Alkyl)2, SF5, SO2-CH3, COOH, COO-(Ci -C6)- Alkyl, CONH2.N (aryl) -CO-NH- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -CO-NH- (C 1 -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N ( Heterocyclyl) -CO-NH-aryl, N (aryl) -CO-N ((C 1 -C 6 ) -alkyl) 2 , N (heterocyclyl) -CO-N ((C 1 -C 6 ) -alkyl) 2 , N (Aryl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N ( Aryl) 2 , N (heterocyclyl) -CO-N (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n = O-6, where the Aryl or heterocyclyl radical may be monosubstituted to trisubstituted by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C, -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , SF 5 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, C 6 ) - alkyl, CONH 2 .
Unter einem Arylrest wird ein Phenyl, Naphthyl-, Biphenyl-, Tetrahydronaphthyl-, alpha- oder beta-Tetralon-, Indanyl- oder Indan-1-on-ylrest verstanden.An aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
Die Arylreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(Ci -C6) Alkyl, CONH2, CONH(C,- C6)Alkyl, CON[(C,-C6)Alkyl]2, Carbocyclus, (C,-C10)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)- Alkinyl, 0-(C1 -C6)- Alkyl 0-CO-(C1 -C6)- Alkyl, 0-CO-(C ,-C6)- Aryl, 0-CO-(Ci-C6)- Heterozyklyl,; PO3H2, P(O)(O Alkyl)2, (Cl-C6)-Alkylen-P(O)(OAlkyl)2, 0-P(O)(OH)2, 0- P(O)(O Alkyl)2, SO3H, SO2-NH2, SO2NH(C, -C6)- Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(C1- C6)-Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterozyklyl, SO-(C, -C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterozyklyl, SO2-(C ,-C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2-N((C,-C6)-Alkyl)(CH2)n-Aryl, SO2-N((C,-C6)-Alkyl)(CH2)n-Heterozyklyl, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n- (Heterozyklyl)2 wobei n = O - 6 sein kann und der Arylrest oder Heterozyklische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, SF5, NO2, CN, OCF3, 0-(C, -C6)- Alkyl, (C ,-C6)- Alkyl, NH2 substituiert sein kann; C(NH)(NH2), NH2, NH-(C, -C6)- Alkyl, N((C,-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(C,- C6)- Alkyl, NH-COO-(C ,-C6)- Alkyl, NH-CO- Aryl, NH-CO-Heterozyklyl, NH-COO- Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(Ci -C6)- Alkyl), NH-CO-NH-Aryl, NH-CO-NH- Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-(C,-C6)-Alkyl, N[(Ci-C6)-Alkyl]-COO-(C,-C6)-Alkyl, N[(C,-C6)- Alkyl]-CO- Aryl, N[(C,-C6)- Alkyl] -CO-Heterozyklyl, N[(C, -C6)- Alkyl] -COO- Aryl, N[(Ci-C6)-Alkyl]-COO-Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-NH-(C,-C6)-Alkyl), N[(C, -C6)- Alkyl]-CO-NH- Aryl, N[(Ci-C6)-Alkyl]-CO-NH-Heterozyklyl, N[(CrC6)- Alkyl]-CO-N((Ci-C6)-Alkyl)2, N[(Ci-C6)-Alkyl]-CO-N((Ci-C6)-Alkyl)-Aryl, N[(Ci-C6)- Alkyl]-CO-N((C,-C6)-Alkyl)-Heterozyklyl, N[(Ci-C6)-Alkyl]-CO-N(Aryl)2, Nf(Ci-C6)- Alkyl]-CO-N(Heterozyklyl)2, N(Aryl)-CO-(Ci-C6)-Alkyl, N(Heterozyklyl)-CO-(CrC6)- Alkyl, N(Aryl)-COO-(Ci-C6)-Alkyl, N(Heterozyklyl)-COO-(Ci-C6)-Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl, N(Aryl)-CO-NH-(Ci-C6)- Alkyl, N(Heterozyklyl)-CO-NH-(C i -C6)- Alkyl, N(Aryl)-CO- NH-Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((C,-C6)-Alkyl)2, N(Heterozyklyl)-CO-N((Ci-C6)-Alkyl)2, N(Aryl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Heterozyklyl)-CO-N[(Ci-C6)-Alkyl]-Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n = O - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3 -fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(Ci-C6)-Alkyl, (Ci -C6)- Alkyl, NH2, NH(Ci -C6)- Alkyl, N((C,-C6)- Alkyl)2, SF5, SO2-CH3, COOH, COO-(C ,-C6)- Alkyl, CONH2.The aryl 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, -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2, carbocycle, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) - alkynyl, 0- (C 1 -C 6) - alkyl 0-CO- (C 1 -C 6) - alkyl, 0-CO- (C, -C6) - aryl, 0-CO- (Ci-C 6 ) - heterocyclyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , 0-P (O) ( O alkyl) 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C6) - alkyl, SO 2 N [(C, -C 6) alkyl] 2, S- (C 1 - C 6 ) -alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocyclyl, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- (CH 2) n -Heterozyklyl, SO 2 - (C, -C 6) - alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n -Heterozyklyl, SO 2 -NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocyclyl, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N ((C, -C 6 ) -alkyl) (CH 2 ) n -heterocyclyl, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocyclyl) 2 where n = O-6 can be and the aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF 3 , 0- (C, -C 6 ) -alkyl, (C, - 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- (C, - C 6) - alkyl, NH-COO- (C, -C 6) - alkyl, NH-CO- aryl, NH-CO-heterocyclyl , NH-COO-aryl, NH-COO-he terocyclyl, NH-CO-NH- (C 1 -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -CO- (C , -C 6) alkyl, N [(Ci-C 6) -alkyl] -COO- (C, -C 6) alkyl, N [(C, -C 6) - alkyl] -CO- aryl, N [(C 1 -C 6 ) -alkyl] -CO-heterocyclyl, N [(C 1 -C 6 ) -alkyl] -COO-aryl, N [(C 1 -C 6 ) -alkyl] -COO-heterocyclyl, N [(Ci-C 6) -alkyl] -CO-NH- (C, -C6) -alkyl), N [(C, -C 6) - alkyl] -CO-NH- aryl, N [(Ci- C 6) -alkyl] -CO-NH-heterocyclyl, N [(C r C6) - alkyl] -CO-N ((Ci-C 6) alkyl) 2, N [(Ci-C 6) alkyl ] -CO-N ((Ci-C 6) -alkyl) -aryl, N [(Ci-C 6) - alkyl] -CO-N ((C, -C 6) alkyl) -Heterozyklyl, N [( Ci-C 6) -alkyl] -CO-N (aryl) 2, Nf (Ci-C 6) - alkyl] -CO-N (heterocyclyl) 2, N (aryl) -CO- (Ci-C 6) - alkyl, N (heterocyclyl) -CO- (C r C 6) - alkyl, N (aryl) -COO- (Ci-C 6) -alkyl, N (heterocyclyl) -COO- (Ci-C 6) alkyl, N (aryl) -CO-aryl, N (heterocyclyl) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclyl) -COO-aryl, N (aryl) -CO-NH- (Ci-C 6 ) - alkyl, N (heterocyclyl) -CO-NH- (C i -C 6 ) -alkyl, N (aryl) -CO-NH-aryl, N (heterocyclyl) -CO-NH-aryl, N (aryl) - CO-N ((C, -C 6 ) -alkyl) 2 , N (heterocyclyl) -CO-N ((C 1 -C 6 ) -alkyl) 2 , N (aryl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N ( heterocyclyl) -CO-N [(Ci-C 6) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2, N (heterocyclyl) -CO- N (aryl) 2, aryl, O- ( CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n = O-6, where the aryl or heterocyclyl radical may be substituted one to three times by F, Cl, Br, I , OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N (( C, -C 6 ) -alkyl) 2 , SF 5 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CONH 2 .
Unter einem Carbocyclusrest wird ein einen oder mehrere Ringe enthaltendes Ringssystem, welches gesättigt oder partiell ungesättigt (mit einer oder zwei Doppelbindungen) vorliegt, verstanden, das ausschließlich aus Kohlenstoffatomen aufgebaut ist, wie z.B. Cyclopropyl, Cyclopentyl, Cyclopentenyl, Cyclohexyl oder Adamantyl.By a carbocycle radical is meant a ring system containing one or more rings which is saturated or partially unsaturated (with one or two Double bonds) understood, which is composed exclusively of carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
Die Carbocyclusreste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B.: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C, -C6) Alkyl, CONH2, CONH(C1- C6)Alkyl, CON[(C,-C6)Alkyl]2> Carbocyclus, (C 1-C10)- Alkyl, (C2-C6)-Alkenyl, (C2-C6)- Alkinyl, 0-(C-C6)- Alkyl 0-CO-(C ,-C6)- Alkyl, 0-CO-(C, -C6)- Aryl, 0-CO-(C1-C6)- Heterozyklyl,; PO3H2, P(O)(O Alkyl)2, (Cl-C6)-Alkylen-P(O)(OAlkyl)2, 0-P(O)(OH)2, O- P(O)(OAlkyl)2, SO3H, SO2-NH2, SO2NH(C,-C6)-Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(C,- C6)- Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterozyklyl, SO-(C ,-C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterozyklyl, SO2-(C ,-C6)- Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2-N((C,-C6)-Alkyl)(CH2)n-Aryl, SO2-N((C,-C6)-Alkyl)(CH2)n-Heterozyklyl, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n- (Heterozyklyl)2 wobei n = O - 6 sein kann und der Arylrest oder Heterozyklische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, SF5, NO2, CN, OCF3, 0-(C-C6)- Alkyl, (C,-C6)-Alkyl, NH2 substituiert sein kann;The Carbocyclusreste may be one or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C 1 - C 6) alkyl, CON [(C, -C 6) alkyl] 2> carbocycle, (C 1 -C 10) - alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6 ) - alkynyl, O - (CC 6 ) - alkyl 0-CO- (C, -C 6 ) -alkyl, 0-CO- (C, -C 6 ) -aryl, 0-CO- (C 1 -C 6 ) - heterocyclyl; PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , O-P (O) ( Oalkyl) 2, SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S- (C, -C 6 ) - alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocyclyl, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- ( CH 2) n -Heterozyklyl, SO 2 - (C, -C 6) - alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n -Heterozyklyl, SO 2 -NH (CH 2) n -aryl, SO 2 -NH (CH 2 ) n -heterocyclyl, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -N ((C, -C 6 ) -Alkyl) (CH 2 ) n -heterocyclyl, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocyclyl) 2 wherein n = O-6 and the aryl radical or heterocyclic radical can be cleaved up to twice with F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF 3 , O- (CC 6 ) -alkyl, (C, -C 6 ) - Alkyl, NH 2 may be substituted;
C(NH)(NH2), NH2, NH-(C, -C6)- Alkyl, N((C,-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(C1- C6)-Alkyl, NH-COO-(C,-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterozyklyl, NH-COO-Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(C, -C6)- Alkyl), NH-CO-NH-Aryl, NH-CO-NH-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- (C 1 -C 6 ) -alkyl, NH-COO- (C 1 -C 6 ) -alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl , NH-CO-NH- (C 1 -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-
Heterozyklyl, N[(C,-C6)- Alkyl] -CO-(C ,-C6)- Alkyl, N[(C,-C6)- Alkyl] -COO-(C, -C6)- Alkyl, N[(C-C6)-Alkyl]-CO-Aryl, N[(C,-C6)-Alkyl]-CO-Heterozyklyl, N[(C-C6)- Alkyl]-COO- Aryl, N[(C-C6)-Alkyl]-COO-Heterozyklyl, N[(C,-C6)-Alkyl]-CO-NH-(C,-C6)- Alkyl), N[(C,-C6)-Alkyl]-CO-NH-Aryl, N[(C-C6)-Alkyl]-CO-NH-Heterozyklyl, Nt(C-C6)- Alkyl]-CO-N((C, -C6)- Alkyl)2, N[(C, -C6)- Alkyl] -CO-N((C, -C6)- Alkyl)- Aryl, N[(C,-C6)- Alkyl]-CO-N((C,-C6)-Alkyl)-Heterozyklyl, N[(C,-C6)-Alkyl]-CO-N(Aryl)2, Nt(C1-C6)- Alkyl]-CO-N(Heterozyklyl)2, N( Aryl)-CO-(C , -C6)- Alkyl, N(Heterozyklyl)-CO-(C , -C6)- Alkyl, N(Aryl)-COO-(C,-C6)- Alkyl, N(Heterozyklyl)-COO-(C,-C6)-Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl, N(Aryl)-CO-NH-(C, -C6)- Alkyl, N(Heterozyklyl)-CO-NH-(C, -C6)- Alkyl, N(Aryl)-CO- NH- Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((C,-C6)-Alkyl)2, N(Heterozyklyl)-CO-N((C-C6)-Alkyl)2, N(Aryl)-CO-Nt(C-C6)-Alkyl]-Aryl, N(Heterozyklyl)-CO-N[(C, -C6)-Alkyl]-Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n = 0 - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C,-C6)-Alkyl, (C1-Ce)-AnCyI, NH2, NH(C, -C6)- Alkyl, N((CrC6)- Alkyl)2, SF5, SO2-CH3, COOH, COO-(Ci -C6)- Alkyl, CONH2.Heterocyclyl, N [(C, -C 6) - alkyl] -CO- (C, -C 6) - alkyl, N [(C, -C 6) - alkyl] -COO- (C, -C 6) - Alkyl, N [(CC 6 ) -alkyl] -CO-aryl, N [(C 1 -C 6 ) -alkyl] -CO-heterocyclyl, N [(CC 6 ) -alkyl] -COO-aryl, N [( CC 6) -alkyl] -COO-heterocyclyl, N [(C, -C 6) -alkyl] -CO-NH- (C, -C6) - alkyl), N [(C, -C 6) alkyl ] -CO-NH-aryl, N [(CC 6) -alkyl] -CO-NH-heterocyclyl, Nt (CC 6) - alkyl] -CO-N ((C, -C6) - alkyl) 2, N [(C, -C 6 ) -alkyl] -CO-N ((C 1 -C 6 ) -alkyl) -aryl, N [(C, C 6 ) -alkyl] -CO-N ((C, - C 6) alkyl) -Heterozyklyl, N [(C, -C 6) alkyl] -CO-N (aryl) 2, Nt (C 1 -C 6) - alkyl] -CO-N (heterocyclyl) 2, N (aryl) -CO- (C, -C 6 ) -alkyl, N (heterocyclyl) -CO- (C, -C 6 ) -alkyl, N (aryl) -COO- (C, -C 6 ) -alkyl , N (heterocyclyl) -COO- (C, -C 6 ) -alkyl, N (aryl) -CO-aryl, N (heterocyclyl) -CO-aryl, N (aryl) -COO-aryl, N (heterocyclyl) - COO-aryl, N (aryl) -CO-NH- (C, -C 6 ) -alkyl, N (heterocyclyl) -CO-NH- (C, -C 6 ) -alkyl, N (aryl) -CO-NH - aryl, N (heterocyclyl) -CO-NH-aryl, N (aryl) -CO-N ((C, -C 6 ) -alkyl) 2 , N (heterocyclyl) -CO-N ((CC 6 ) -alkyl ) 2 , N (Ar yl) -CO-Nt (CC 6 ) -alkyl] -aryl, N (heterocyclyl) -CO-N [(C 1 -C 6 ) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO- N (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n = 0-6, where the aryl or heterocyclyl radical is one to three times may be substituted with F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (C, -C6) alkyl, (C 1 -Ce) -AnCyI, NH 2, NH (C, -C 6) - alkyl, N ((C r C6) - alkyl) 2, SF 5, SO 2 -CH 3, COOH, COO- (Ci-C6) - alkyl, CONH. 2
Unter Heterozyklus, Heterozyklyl bzw. heterozyklischer Rest werden Ringe und Ringsysteme verstanden, die außer Kohlenstoff noch Heteroatome, wie zum Beispiel Stickstoff, Sauerstoff oder Schwefel enthalten. Ferner gehören auch Ringsysteme zu dieser Definition, worin der Heterocylus bzw. der heterozyklische Rest mit Benzolkernen kondensiert ist.Heterocycle, heterocyclyl 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 condensed with benzene nuclei.
Geeignete Heterozyklyl- bzw. "heterozyklische Reste" sind Acridinyl, Benzimidazolyl, Benzofuryl, Benzothienyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Decahydrochinolinyl, 2H,6H-1,5,2-Dithiazinyl, Dihydrofuro[2,3-b]- Tetrahydrofuran, Furyl, Furazanyl, Imidazolidinyl, Imidazolinyl, hnidazolyl, IH- Indazolyl, hidolinyl, hidolizinyl, Indolyl, 3H-Indolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolyl, Isoxazolyl, Moφholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1,2,3- Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pyridooxazole, Pyridoimidazole, Pyridothiazol, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, 6H-1,2,5-Thiadazinyl, Thiazolyl, 1,2,3- Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, Thienyl, Triazolyl, Tetrazolyl, Aziridinyl, Azetininyl, Azepanyl, Azocanyl und Xanthenyl.Suitable heterocyclic or "heterocyclic radicals" are acridinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, Chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] -tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, hidazolyl, IH-indazolyl, hidolinyl, hidolizinyl, indolyl , 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, monochlorinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, pip eridinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl, aziridinyl, azetininyl, Azepanyl, azocanyl and xanthenyl.
Pyridyl steht sowohl für 2-, 3- als auch 4-Pyridyl. Thienyl steht sowohl für 2- als auch 3- Thienyl. Furyl steht sowohl für 2- als auch 3-Furyl. Umfasst sind weiterhin die entsprechenden N-Oxide dieser Verbindungen, also z.B. 1- Oxy-2-, 3- oder 4-Pyridyl.Pyridyl is both 2-, 3- and 4-pyridyl. Thienyl is both 2- and 3-thienyl. Furyl is both 2- and 3-furyl. Also included are the corresponding N-oxides of these compounds, eg 1-oxy-2-, 3- or 4-pyridyl.
Umfasst sind weiterhin ein oder mehrfach benzoannelierte Derivate dieser Heterozyklen.Also included are one or more benzoannelated derivatives of these heterocycles.
Die heterozyklischen Ringe bzw. Heterozyklische Reste können ein oder mehrfach mit geeigneten Gruppen substituiert sein, wie z.B: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)AUCyI, CONH2, CONH(C1-C6)AUCyI, CONt(C1-C6)AUCyI]2, Carbocyclus, (C,- CiO)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C,-C6)-Alkyl 0-CO-(C, -C6)- Alkyl, O- CO-(C1-C6)- Aryl, 0-CO-(C, -C6)-Heterozyklyl;The heterocyclic rings or heterocyclic 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) AUCyI, cont (C 1 -C 6) AUCyI] 2, carbocycle, (C, - C O) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, O- (C, -C6) alkyl 0-CO- (C, -C6) - alkyl, O- CO- (C 1 -C 6) - aryl, 0-CO - (C, -C 6) -Heterozyklyl;
PO3H2, P(O)(O Alkyl)2, (Cl-C6)-Alkylen-P(O)(OAlkyl)2, 0-P(O)(OH)2, 0- P(O)(O Alkyl)2, SO3H, SO2-NH2, SO2NH(C ,-C6)-Alkyl, SO2N[(C,-C6)-Alkyl]2 , S-(C- C6)- Alkyl, S-(CH2)n-Aryl, S-(CH2)n-Heterozyklyl, SO-(C ,-C6)- Alkyl, SO-(CH2)n-Aryl, SO-(CH2)n-Heterozyklyl, SO2-(C,-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterozyklyl , SO2-NH(CH2)n-Aryl, SO2-NH(CH2)n-Heterozyklyl, SO2-N(Ci-C6)-AUcyl)(CH2)n-Aryl, SO2-N(C, -C6)-Alkyl)(CH2)n-Heterozyklyl, SO2-N((CH2)n-Aryl)2, , SO2-N((CH2)n- (Heterozyklyl)2 wobei n = O - 6 sein kann und der Arylrest oder heterozyklische Rest bis zu zweifach mit F, Cl, Br, OH, CF3, SF5, NO2, CN, OCF3, 0-(C1-C6)- Alkyl, (C-C6)- Alkyl, NH2 substituiert sein kann;PO 3 H 2 , P (O) (O-alkyl) 2, (C 1 -C 6) -alkylene-P (O) (O-alkyl) 2, 0-P (O) (OH) 2 , 0-P (O) ( O alkyl) 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C 6) alkyl, SO 2 N [(C, -C 6) alkyl] 2, S- (C-C 6 ) - alkyl, S- (CH 2 ) n -aryl, S- (CH 2 ) n -heterocyclyl, SO- (C 1 -C 6 ) -alkyl, SO- (CH 2 ) n -aryl, SO- ( CH 2) n -Heterozyklyl, SO 2 - (C, -C 6) -alkyl, SO 2 - (CH 2) n -aryl, SO 2 - (CH 2) n -Heterozyklyl, SO 2 -NH (CH 2) n -aryl, SO 2 -NH (CH 2 ) n -heterocyclyl, SO 2 -N (C 1 -C 6 ) -acyl) (CH 2 ) n -aryl, SO 2 -N (C 1 -C 6 ) -alkyl ) (CH 2 ) n heterocyclyl, SO 2 -N ((CH 2 ) n -aryl) 2 ,, SO 2 -N ((CH 2 ) n - (heterocyclyl) 2 where n = O-6 and the Aryl radical or heterocyclic radical up to two times with F, Cl, Br, OH, CF 3 , SF 5, NO 2 , CN, OCF 3 , 0- (C 1 -C 6 ) -alkyl, (CC 6 ) -alkyl, NH 2 may be substituted;
C(NH)(NH2), NH2, NH-(C, -C6)-Alkyl, N((C-C6)-Alkyl)2, NH(C, -C7)- Acyl, NH-CO-(C- C6)-Alkyl, NH-COO-(C, -C6)- Alkyl, NH-CO- Aryl, NH-CO-Heterozyklyl, NH-C00- Aryl, NH-COO-Heterozyklyl, NH-CO-NH-(C -C6)- Alkyl), NH-CO-NH-Aryl, NH-CO-NH- Heterozyklyl, N[(C,-C6)-Alkyl]-CO-(C-C6)- Alkyl, N[(C-C6)-Alkyl]-COO-(C,-C6)-Alkyl, N[(C-C6)-Alkyl]-CO-Aryl, N[(C,-C6)-Alkyl]-CO-Heterozyklyl, N[(C, -C6)- Alkyl] -COO- Aryl, N[(C-C6)-Alkyl]-COO-Heterozyklyl, N[(C-C6)-Alkyl]-CO-NH-(C,-C6)-Alkyl), N[(C-C6)-Alkyl]-CO-NH-Aryl, N[(C-C6)-Alkyl]-CO-NH-Heterozyklyl, N[(C,-C6)- AUcyl]-CO-N((C,-C6)-Alkyl)2, N[(C,-C6)-Alkyl]-CO-N((C -C6)- Alkyl)- Aryl, Nf(C-C6)- Alkyl]-CO-N((C-C6)-Alkyl)-Heterozyklyl, N[(C-C6)-Alkyl]-CO-N(Aryl)2, N[(C-C6)- Alkyl]-CO-N(Heterozyklyl)2, N(Aryl)-CO-(C,-C6)-Alkyl, N(Heterozyklyl)-CO-(C,-C6)- Alkyl, N(Aryl)-COO-(C,-C6)- Alkyl, N(Heterozyklyl)-COO-(C,-C6)- Alkyl, N(Aryl)-CO- Aryl, N(Heterozyklyl)-CO-Aryl, N(Aryl)-COO-Aryl, N(Heterozyklyl)-COO-Aryl, N(Aryl)-CO-NH-(C i -C6)- Alkyl, N(Heterozyklyl)-CO-NH-(C, -C6)- AUcyl, N(Aryl)-CO- NH-Aryl, N(Heterozyklyl)-CO-NH-Aryl, N(Aryl)-CO-N((Ci-C6)-Alkyl)2, NCHeterozykly^-CO-NCCCi-C^-Alkyl^^CAryO-CO-NCCCrC^-AlkylJ-Aryl, N(Heterozyklyl)-CO-N[(C, -C6)-Alkyl]-Aryl, N(Aryl)-CO-N(Aryl)2, N(Heterozyklyl)-CO- N(Aryl)2, Aryl, O-(CH2)n-Aryl, O-(CH2)n-Heterozyklyl, wobei n = 0 - 6 sein kann, wobei der Aryl- oder Heterozyklyl- Rest ein bis 3 -fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, SF5, 0-(C1-Q)-AIkVl, (Ci-C6)-Alkyl, NH2, NH(C1 -C6)- Alkyl, N((C,-C6)-Alkyl)2, SF5, SO2-CH3, COOH, COO-(Ci -C6)- Alkyl, CONH2.C (NH) (NH 2 ), NH 2 , NH- (C 1 -C 6 ) -alkyl, N ((CC 6 ) -alkyl) 2 , NH (C, -C 7 ) -acyl, NH-CO- (C 6 -C 6 ) alkyl, NH-COO- (C 1 -C 6 ) alkyl, NH-CO-aryl, NH-CO heterocyclyl, NH-C00- aryl, NH-COO heterocyclyl, NH-CO -NH- (C -C 6 ) -alkyl), NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N [(C, -C 6 ) -alkyl] -CO- (CC 6 ) -alkyl , N [(CC 6 ) -alkyl] -COO- (C 1 -C 6 ) -alkyl, N [(CC 6 ) -alkyl] -CO-aryl, N [(C 1 -C 6 ) -alkyl] - CO heterocyclyl, N [(C 1 -C 6 ) alkyl] COO aryl, N [(CC 6 ) alkyl] COO heterocyclyl, N [(CC 6 ) alkyl] CO-NH- ( C, -C 6 ) -alkyl), N [(CC 6 ) -alkyl] -CO-NH-aryl, N [(CC 6 ) -alkyl] -CO-NH-heterocyclyl, N [(C, -C 6 ) - AUcyl] -CO-N ((C 1 -C 6 ) -alkyl) 2 , N [(C 1 -C 6 ) -alkyl] -CO-N ((C 6 -C 6 ) -alkyl) -aryl, Nf (CC 6 ) -alkyl] -CO-N ((CC 6 ) -alkyl) -heterocyclyl, N [(CC 6 ) -alkyl] -CO-N (aryl) 2 , N [(CC 6 ) -alkyl] -CO-N (heterocyclyl) 2 , N (aryl) -CO- (C, -C 6 ) -alkyl, N (heterocyclyl) -CO- (C, -C 6 ) -alkyl, N (aryl) -COO- (C 1 -C 6 ) -alkyl, N (heterocyclyl) -COO- (C 1 -C 6 ) -alkyl, N (aryl) -CO-aryl, N (heterocyclyl) -CO-aryl, N (aryl) - COO aryl, N (Het rozyklyl) -COO-aryl, N (aryl) -CO-NH- (C i -C 6 ) -alkyl, N (heterocyclyl) -CO-NH- (C, -C 6 ) -acyl, N (aryl) - CO NH-aryl, N (heterocyclyl) -CO-NH-aryl, N (aryl) -CO-N ((Ci-C 6 ) -alkyl) 2 , NCHeterozykly ^ -CO-NCCCi-C ^ -alkyl ^^ CAryO- CO-NCCCrC ^ -alkylJ-aryl, N (heterocyclyl) -CO-N [(C, -C 6 ) -alkyl] -aryl, N (aryl) -CO-N (aryl) 2 , N (heterocyclyl) -CO N (aryl) 2 , aryl, O- (CH 2 ) n -aryl, O- (CH 2 ) n -heterocyclyl, where n = 0-6, where the aryl or heterocyclyl radical is one to three times may be substituted with F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, SF 5, 0- (C 1 -Q) -alkyl, (Ci-C 6) -alkyl, NH 2 , NH (C 1 -C 6) - alkyl, N ((C, -C 6) alkyl) 2, SF 5, SO 2 -CH 3, COOH, COO- (Ci-C6) - alkyl, CONH 2 ,
Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche Säureadditionssalze der Verbindungen der Formel I sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor- , Metaphosphor-, Salpeter-, Sulfon- und Schwefelsäure sowie organischer Säuren, wie z.B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isäthion-, Milch-, Lactobion-, Malein-, Apfel-, Methansulfon-, Bernstein-, p-Toluolsulfon-, Wein- und Trifluoressigsäure ferner L-Ascorbinsäure, Salizylsäure, 1,2-Benzisothiazol- 3(2H)-on und 6-Methyl-l,2,3-oxathiazin-4(3H)-on-2,2-dioxid. Für medizinische Zwecke wird in besonders bevorzugter Weise das Chlorsalz verwendet. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, Alkalimetallsalze (wie Natrium- und Kaliumsalze) und Erdalkalisalze (wie Magnesium- und Calciumsalze).Pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulfuric and organic acids, e.g. Acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethioic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, wine and trifluoroacetic acid further L-ascorbic acid, salicylic acid, 1,2-benzisothiazol-3 (2H) -one and 6-methyl-l, 2,3-oxathiazine-4 (3H) -one-2,2-dioxide. For medical purposes, the chloro salt is used in a particularly preferred manner. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
Salze mit einem nicht pharmazeutisch verträglichen Anion gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nicht- therapeutischen, zum Beispiel in-vitro-Anwendungen.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.
Die Verbindungen der Formel I können auch in verschiedenen polymorphen Formen vorliegen, z.B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der Verbindungen der Formel I gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung. Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel (I)" auf Verbindung(en) der Formel (I) wie vorstehend beschrieben, sowie ihre Salze und Solvate wie hierin beschrieben.The compounds of the formula I can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of formula I are within the scope of the invention and are a further aspect of the invention. Hereinafter, all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) as described above, as well as their salts and solvates as described herein.
Die Verbindung(en) der Formel (I) können auch in Kombination mit weiteren Wirkstoff verabreicht werden.The compound (s) of formula (I) may also be administered in combination with other active ingredient.
Die Menge einer Verbindung gemäß Formel (I), die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z.B. der ge- wählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art derThe amount of a compound of formula (I) required to achieve the desired biological effect depends on a number of factors, e.g. the specific compound chosen, the intended use, the type of
Verabreichung und dem klinischen Zustand des Patienten. Im allgemeinen liegt die Tagesdosis im Bereich von 0,3 mg bis 100 mg (typischerweise von 3 mg und 50 mg) pro Tag pro Kilogramm Körpergewicht, z.B. 3-10 mg/kg/Tag. Eine intravenöse Dosis kann z.B. im Bereich von 0,3 mg bis 1,0 mg/kg liegen, die geeigneterweise als Infusion von 10 ng bis 100 ng pro Kilogramm pro Minute verabreicht werden kann. GeeigneteAdministration and the clinical condition of the patient. In general, 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, e.g. 3-10 mg / kg / day. An intravenous dose may e.g. in the range of 0.3 mg to 1.0 mg / kg, which can be suitably administered as an infusion of 10 ng to 100 ng per kilogram per minute. suitable
Infusionslösungen für diese Zwecke können z.B. von 0,1 ng bis 10 mg, typischerweise von 1 ng bis 10 mg pro Milliliter, enthalten. Einzeldosen können z.B. von 1 mg bis 10 g des Wirkstoffs enthalten. Somit können Ampullen für Injektionen beispielsweise von 1 mg bis 100 mg, und oral verabreichbare Einzeldosisformulierungen, wie zum Beispiel Tabletten oder Kapseln, können beispielsweise von 1,0 bis 1000 mg, typischerweise von 10 bis 600 mg enthalten. Im Falle pharmazeutisch verträglicher Salze beziehen sich die vorgenannten Gewichtsangaben auf das Gewicht des vom Salz abgeleiteten Benzothiazepin-Ions. Zur Prophylaxe oder Therapie der oben genannten Zustände können die Verbindungen gemäß Formel (I) selbst als Verbindung verwendet werden, vorzugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muß natürlich verträglich sein, in dem Sinne, daß er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheitsschädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel (I). Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im wesent- liehen darin bestehen, daß die Bestandteile mit pharmakologisch verträglichen Träger- und/oder Hilfsstoffen gemischt werden.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. Thus, for example, from 1 mg to 100 mg, 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. In the case of pharmaceutically acceptable salts, the abovementioned weights are based on the weight of the benzothiazepine ion derived from the salt. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula (I) may 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. 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 also be present, including further compounds according to formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which are essentially lent consist in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.
Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale, rektale, topische, perorale (z.B. sublinguale) und parenterale (z.B. subkutane, intramuskuläre, intradermale oder intravenöse) Verabreichung geeignet sind, wenngleich die geeignetste Verabreichungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel (I) abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Polyvinalacetatphthalat,Pharmaceutical 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 the nature and severity of the treatment State and on the nature of the particular compound used according to 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,
Hydroxypropylmethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.Hydroxypropylmethylcellulosephthalat and anionic polymers of methacrylic acid and methyl methacrylate.
Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tabletten, die jeweils eine bestimmte Menge der Verbindung gemäß Formel (I) enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wäßrigen oder nicht- wäßrigen Flüssigkeit; oder als eine Öl-in- Wasser- oder Wasser-in Öl-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfaßt, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allgemeinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpreßt oder geformt wird, gegebenenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepreßte Tabletten können durch Tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdünner und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.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. As already mentioned, 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). In general, 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. For example, 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 may 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 / dispersing agent in a suitable machine. Molded tablets can be made by molding the powdered, moistened with an inert liquid diluent compound can be prepared in a suitable machine.
Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung geeignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel (I) mit einemPharmaceutical compositions suitable for peroral (sublingual) administration include lozenges comprising a compound of formula (I) having a
Geschmacksstoff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oderFlavoring, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or
Saccharose und Gummi arabicum umfassen.Sucrose and gum arabic.
Geeignete pharmazeutische Zusammensetzungen für die parenterale Verabreichung umfassen vorzugsweise sterile wäßrige Zubereitungen einer Verbindung gemäß Formel (I), die vorzugsweise isotonisch mit dem Blut des vorgesehenen Empfängers sind. DieseSuitable 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
Zubereitungen werden vorzugsweise intravenös verabreicht, wenngleich diePreparations are preferably administered intravenously, although the
Verabreichung auch subkutan, intramuskulär oder intradermal als Injektion erfolgen kann.Administration can also be administered subcutaneously, intramuscularly or intradermally as an injection.
Diese Zubereitungen können vorzugsweise hergestellt werden, indem die Verbindung mit Wasser gemischt wird und die erhaltene Lösung steril und mit dem Blut isotonisch gemacht wird. Injizierbare erfindungs gemäße Zusammensetzungen enthalten im allgemeinen von 0,1 bis 5 Gew.-% der aktiven Verbindung.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 according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Geeignete pharmazeutische Zusammensetzungen für die rektale Verabreichung liegen vor- zugsweise als Einzeldosis-Zäpfchen vor. Diese können hergestellt werden, indem man eine Verbindung gemäß Formel (I) mit einem oder mehreren herkömmlichen festen Trägern, beispielsweise Kakaobutter, mischt und das entstehende Gemisch in Form bringt.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.
Geeignete pharmazeutische Zusammensetzungen für die topische Anwendung auf der Haut liegen vorzugsweise als Salbe, Creme, Lotion, Paste, Spray, Aerosol oder Öl vor. Als Träger können Vaseline, Lanolin, Polyethylenglycole, Alkohole und Kombinationen von zwei oder mehreren dieser Substanzen verwendet werden. Der Wirkstoff ist im allgemeinen in einer Konzentration von 0,1 bis 15 Gew.-% der Zusammensetzung vorhanden, beispielsweise von 0,5 bis 2%.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%.
Auch eine transdermale Verabreichung ist möglich. Geeignete pharmazeutische Zusammensetzungen für transdermale Anwendungen können als einzelne Pflaster vorliegen, die für einen langzeitigen engen Kontakt mit der Epidermis des Patienten geeignet sind. Solche Pflaster enthalten geeigneterweise den Wirkstoff in einer gegebenenfalls gepufferten wäßrigen Lösung, gelöst und/oder dispergiert in einem Haftmittel oder dispergiert in einem Polymer. Eine geeignete Wirkstoff-Konzentration beträgt ca. 1% bis 35%, vorzugsweise ca. 3% bis 15%. Als eine besondere Möglichkeit kann der Wirkstoff, wie beispielsweise in Pharmaceutical Research, 2(6): 318 (1986) beschrieben, durch Elektrotransport oder Iontophorese freigesetzt werden.Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be present as single patches for long-term close contact with the epidermis of the patient are suitable. 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%. As a particular possibility, the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
Als weitere Wirkstoffe für die Kombinationspräparate sind geeignet: Alle Antidiabetika, die in der Roten Liste 2008, Kapitel 12 genannt sind; alleAs further active ingredients for the combination preparations are suitable: All Antidiabetika, which are mentioned in the red list 2008, chapter 12; all
Abmagerungsmittel/ Appetitzügler, die in der Roten Liste 2008, Kapitel 1 genannt sind; alle Diuretika, die in der Roten Liste 2008, Kapitel 36 genannt sind; alle Lipidsenker, die in der Roten Liste 2008, Kapitel 58 genannt sind. Sie können mit der erfindungsgemäßen Verbindung der Formel I insbesondere zur synergistischen Wirkungsverbesserung kombiniert werden. Die Verabreichung der Wirkstoffkombination kann entweder durch getrennte Gabe der Wirkstoffe an den Patienten oder in Form von Kombinationspräparaten, worin mehrere Wirkstoffe in einer pharmazeutischen Zubereitung vorliegen, erfolgen. Erfolgt die Gabe der Wirkstoffe durch getrennte Verabreichung der Wirkstoffe, so kann diese gleichzeitig oder nacheinander erfolgen. Die meisten der nachfolgend aufgeführten Wirkstoffe sind in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2006, offenbart.Slimming / appetite suppressants listed in the Red List 2008, Chapter 1; all diuretics mentioned in the Red List 2008, chapter 36; all lipid-lowering drugs mentioned in the 2008 Red List, 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. If the administration of the active ingredients by separate administration of the active ingredients, so this can be done simultaneously or sequentially. Most of the drugs listed below are disclosed in the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville, 2006.
Antidiabetika umfassen Insulin und Insulinderivate, wie z.B. Lantus® (siehe www.lantus.com) oder HMR 1964 oder Levemir® (insulin detemir), Humalog^ (Insulin Lispro), Humulin(R), VIAj ect™ oder solche, wie sie in WO2005005477 (Novo Nordisk) beschrieben sind, schnell wirkende Insuline (siehe US 6,221,633), inhalierbare Insuline, wie z. B. Exubera ® , Nasulin™, oder orale Insuline, wie z. B. DSf-105 (Nobex) oder Oral- lyn ™ (Generex Biotechnology) oder Technosphere(R) Insulin (MannKind) oder Cobalamin™ orales Insulin oder Insuline, wie sie in WO2007128815, WO2007128817 beschrieben sind oder Insuline, die transdermal verabreicht werden können;Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir), Humalog ^ (insulin lispro), Humulin (R), VIAj ect ™ or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such. B. Exubera ®, Nasulin ™, or oral insulins such. DSf-105 (Nobex) or Oralyn ™ (Generex Biotechnology) or Technosphere (R) insulin (MannKind) or Cobalamin ™ oral insulin or insulins as described in WO2007128815, WO2007128817 or insulins which can be administered transdermally ;
GLP-I -Derivate und GLP-I Agonisten wie z.B. Exenatide, Liraglutide oder diejenigen die in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 von Novo Nordisk A/S, in WO 01/04156 von Zealand oder in WO 00/34331 von Beaufour-Ipsen offenbart wurden, Pramlintide Acetat (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC :Exendin-4 (ein Exendin-4 Analogon, welches kovalent an rekombinantes menschliches Albumin gebunden ist), CVX-73, CVX-98 und CVx-96 (GLP-I Analoga, welche kovalent an einen monoklonalen Antikörper gebunden sind, der spezifische Bindungsstellen für das GLP-I Peptid aufweist), CNTO-736 (ein GLP-I Analogon, welches an eine Domäne gebunden ist, welche den Fc-Teil eines Antikörpers beinhaltet), PGC-GLP-I (GLP-I gebunden an einen Nanocarrier), Agonisten wie sie z.B. bei D. Chen et al., Proc. Natl. Acad. Sei. USA 104 (2007) 943 beschrieben sind, solche wie sie in WO2006124529, WO2007124461 beschrieben sind, Peptide wie z.B. Obinepitide (TM-30338), Amylinrezeptor Agonisten, wie sie z.B. in WO2007104789 beschrieben sind, Analoga des humanen GLP-I, wie sie in WO2007120899 beschrieben sind, sowie oral wirksame hypoglykämische Wirkstoffe.GLP-I derivatives and GLP-I agonists such as exenatide, liraglutide or those described in WO 98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A / S, in WO 01/04156 of Zealand or in WO 00/34331 of Beaufour-Ipsen, Pramlintide acetate (Symlin; Amylin Pharmaceuticals), AVE-0010, BIM-51077 (R-1583, ITM-077), PC-DAC: exendin-4 (an exendin-4 analogue covalently linked to recombinant human albumin), CVX-73, CVX-98 and CVx-96 (GLP-I analogs covalently linked to a monoclonal antibody, having specific binding sites for the GLP-I peptide), CNTO-736 (a GLP-I analog bound to a domain containing the Fc portion of an antibody), PGC-GLP-I (GLP-I attached a nanocarrier), agonists as described, for example, in D. Chen et al., Proc. Natl. Acad. Be. USA 104 (2007) 943, such as those described in WO2006124529, WO2007124461, peptides such as obine epitides (TM-30338), amylin receptor agonists, as described, for example, in WO2007104789, analogs of human GLP-I, as described in US Pat WO2007120899 are described as well as orally active hypoglycemic agents.
Antidiabetika umfassen auch Agonisten des Glukose-abhängigen insulinotropen Polypeptids (GIP) Rezeptors wie sie z.B. in WO2006121860 beschrieben sind.Antidiabetic agents also include agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor as described e.g. in WO2006121860 are described.
Antidiabetika umfassen auch Analoga und Derivate des Fibroblastenwachstumsfaktors 21 (FGF-21, fibroblast growth factor 21).Antidiabetics also include analogs and derivatives of fibroblast growth factor 21 (FGF-21, fibroblast growth factor 21).
Die oral wirksamen hypoglykämischen Wirkstoffe umfassen vorzugsweise Sulfonylharnstoffe,The orally active hypoglycemic agents preferably comprise sulfonylureas,
Biguanidine,biguanides,
Meglitinide,meglitinides,
Oxadiazolidindione,oxadiazolidinediones,
Thiazolidindione, PPAR- und RXR-Modulatoren,Thiazolidinediones, PPAR and RXR modulators,
Glukosidase-Inhibitoren,Glucosidase inhibitors,
Hemmstoffe der Glykogenphosphorylase,Inhibitors of glycogen phosphorylase,
Glukagonrezeptor- Antagonisten,Glucagon receptor antagonists,
Glukokinaseaktivatoren, Inhibitoren der Fructose- 1 ,6-bisphosphatase, Modulatoren des Glukosetransporters-4 (GLUT4),Glucokinase activators, inhibitors of fructose 1, 6-bisphosphatase, Glucose Transporter 4 Modulators (GLUT4),
Inhibitoren der Glutamin-Fructose-6-Phosphat-Amidotransferase (GFAT),Inhibitors of glutamine-fructose 6-phosphate amidotransferase (GFAT),
GLP- 1 -Agonisten,GLP-1 agonist,
Kaliumkanalöffiier, wie z.B. Pinacidil, Cromakalim, Diazoxid oder solche wie sie bei R. D. Carr et al., Diabetes 52, 2003, 2513.2518, bei J. B. Hansen et al, Current MedicinalPotassium channel opener, e.g. Pinacidil, cromakalim, diazoxide, or those described in R.D. Carr et al., Diabetes 52, 2003, 2513, 2518, in J. B. Hansen et al, Current Medicinal
Chemistry 11, 2004, 1595-1615, bei T. M. Tagmose et al., J. Med. Chem. 47, 2004, 3202-Chemistry 11, 2004, 1595-1615, in T.M. Tagmose et al., J. Med. Chem. 47, 2004, 3202-
3211 oder bei M. J. Coghlan et al., J. Med. Chem. 44, 2001, 1627-1653 beschrieben sind, oder diejenigen, die in WO 97/26265 und WO 99/03861 von Novo Nordisk A/S offenbart wurden, Wirkstoffe, die auf den ATP-abhängigen Kaliumkanal der Betazellen wirken,Chem. 44, 2001, 1627-1653, or those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S. which act on the ATP-dependent potassium channel of beta cells,
Inhibitoren der Dipeptidylpeptidase-IV (DPP-IV),Inhibitors of dipeptidyl peptidase-IV (DPP-IV),
Insulin-Sensitizer,Insulin sensitizers,
Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oderInhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or
Glykogenolyse beteiligt sind, Modulatoren der Glukoseaufnahme, des Glukosetransports und der Glukoserückresorption,Glycogenolysis, modulators of glucose uptake, glucose transport and glucose reabsorption,
Modulatoren der natrium-abhängigen Glukosetransporter 1 oder 2 (SGLTl, SGLT2),Modulators of the Sodium-Dependent Glucose Transporter 1 or 2 (SGLT1, SGLT2),
Hemmstoffe der 11-beta-Hydroxysteroid-Dehydrogenase-l (l lß-HSDl),Inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (l lß-HSDl),
Inhibitoren der Protein-Tyrosin-Phosphatase-1B (PTP-IB),Inhibitors of protein tyrosine phosphatase-1B (PTP-IB),
Nikotinsäurerezeptoragonisten, Inhibitoren der hormon-sensitiven bzw. endothelialen Lipasen,Nicotinic acid receptor agonists, inhibitors of hormone-sensitive or endothelial lipases,
Hemmstoffen der Acetyl-CoA Carboxylase (ACCl und/oder ACC2) oderInhibitors of acetyl-CoA carboxylase (ACCl and / or ACC2) or
Inhibitoren der GSK-3 beta.Inhibitors of GSK-3 beta.
Weiterhin sind umfasst den Fettstoffwechsel verändernde Verbindungen wie antihyperlipidämische Wirkstoffe und antilipidämische Wirkstoffe, HMGCoA-Reduktase-Inhibitoren,Also included are lipid metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents, HMGCoA reductase inhibitors,
Farnesoid X Rezeptor (FXR) Antagonisten,Farnesoid X receptor (FXR) antagonists,
Fibrate,fibrates,
Cholesterinresreptionsinhibitoren,Cholesterinresreptionsinhibitoren,
CETP-Inhibitoren, Gallensäureresorptionsinhibitoren,CETP inhibitors, bile acid resorption inhibitors,
MTP-Inhibitoren,MTP inhibitors
Agonisten des Estrogenrezeptors gamma (ERRD Agonisten),Agonists of the estrogen receptor gamma (ERRD agonists),
Sigma-1 Rezeptorantagonisten, Antagonisten des Somatostatin 5 Rezeptors (SST5 Rezeptor); Verbindungen, die die Nahrungsmitteleinnahme verringern und Verbindungen, die die Thermogenese erhöhen.Sigma-1 receptor antagonists, Antagonists of the somatostatin 5 receptor (SST5 receptor); Compounds that reduce food intake and compounds that increase thermogenesis.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Insulin verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with insulin.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Wirkstoff, der auf den ATP-abhängigen Kaliumkanal der Betazellen wirkt, z.B. Sulfonylharnstoffe, wie z.B. Tolbutamid, Glibenclamid, Glipizid, Gliclazide oder Glimepirid, verabreicht.In one embodiment, the compound of formula I is administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, e.g. Sulfonylureas, e.g. Tolbutamide, glibenclamide, glipizide, gliclazide or glimepiride.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einer Tablette verabreicht, die sowohl Glimeprid enthält, welches schnell freigesetzt wird wie auch Metformin enthält, welches über einen längeren Zeitraum freigesetzt wird (wie z.B. in US2007264331 beschrieben).In one embodiment, the compound of formula I is administered in combination with a tablet containing both glimepride which is rapidly released and contains metformin which is released over a prolonged period of time (as described, for example, in US2007264331).
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Biguanid, wie z.B. Metformin, verabreicht.In one embodiment, the compound of formula I is used in combination with a biguanide, e.g. Metformin, administered.
Bei wieder einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Meglitinid, wie z.B. Repaglinide, Nateglinid oder Mitiglinide verabreicht.In yet another embodiment, the compound of formula I is used in combination with a meglitinide, e.g. Repaglinide, nateglinide or mitiglinide administered.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I mit einer Kombination von Mitiglinide mit einem Glitazon, z.B. Pioglitazon Hydrochlorid, verabreicht.In another embodiment, the compound of formula I is treated with a combination of mitiglinides with a glitazone, e.g. Pioglitazone hydrochloride, administered.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I mit einer Kombination von Mitiglinide mit einem alpha-Glukosidaseinhibitor verabreicht.In another embodiment, the compound of formula I is administered with a combination of mitiglinides with an alpha-glucosidase inhibitor.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit antidiabetischen Verbindungen, wie sie in WO2007095462, WO2007101060, WO2007105650 beschrieben sind, verabreicht. Bei einer weiteren Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit antihypoglykämischen Verbindungen, wie sie in WO2007137008 beschrieben sind, verabreicht.In a further embodiment, the compound of the formula I is administered in combination with antidiabetic compounds, as described in WO2007095462, WO2007101060, WO2007105650. In a further embodiment, the compound of the formula I is administered in combination with antihypoglycemic compounds, as described in WO2007137008.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Thiazolidindion, wie z.B. Troglitazon, Ciglitazon, Pioglitazon, Rosiglitazon oder den in WO 97/41097 von Dr. Reddy's Research Foundation offenbarten Verbindungen, insbesondere 5-[ [4- [(3 ,4-Dihydro-3 -methyl-4-oxo-2-chinazolinylmethoxy]phenyl]methyl] - 2,4-thiazolidindion, verabreicht.In one embodiment, the compound of formula I is 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, especially 5- [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit einem PPAR gamma Agonisten, wie z.B. Rosiglitazon, Pioglitazon, JTT- 501, Gl 262570, R-483, CS-OI l (Rivoglitazon), DRL-17564, DRF-2593 (Balaglitazon) oder solchen, wie sie in WO2007060992, WO2007100027, WO2007103252, WO2007122970 beschrieben sind, verabreicht.Combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-ol (rivoglitazone), DRL-17564, DRF-2593 (balaglitazone) or those as described in WO2007060992, WO2007100027, WO2007103252, WO2007122970 ,
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Competact™, einer festen Kombination von Pioglitazon Hydrochlorid mit Metformin Hydrochlorid, verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with Competact ™, a solid combination of pioglitazone hydrochloride with metformin hydrochloride.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit Tandemact™, einer festen Kombination von Pioglitazon mit Glimeprid, verabreicht.Combination with Tandemact ™, a fixed combination of pioglitazone with glimepride.
Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Pioglitazon Hydrochlorid mit einem Angiotensin II Agonisten, wie z.B. TAK-536, verabreicht.In a further embodiment of the invention, the compound of formula I in combination with a solid combination of pioglitazone hydrochloride with an angiotensin II agonist, e.g. TAK-536 administered.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem PPAR alpha Agonisten bzw. gemischten PPAR alpha/PPAR delta Agonisten, wie z.B. GW9578, GW-590735, K-H l, LY-674, KRP-101, DRF-10945, LY- 518674, CP-900691, BMS-687453, BMS-711939 oder solchen wie sie in WO2001040207, WO2002096894, WO2005097076, WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043 beschrieben sind, verabreicht.In one embodiment of the invention, the compound of formula I is in combination with a PPAR alpha agonist or mixed PPAR alpha / PPAR delta agonists, such as GW9578, GW-590735, KH1, LY-674, KRP-101, DRF-10945 , LY-518674, CP-900691, BMS-687453, BMS-711939 or those as described in WO2001040207, WO2007096894, WO2005097076, WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515, WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem gemischten PPAR alpha/gamma Agonisten, wie z.B. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD- 501 (Lobeglitazon Sulfat), MBX-213 oder wie in WO 00/64888, WO 00/64876, WO03/020269, WO2007099553, US2007276041, WO2007085135, WO2007085136 oder in J.P.Berger et al., TRENDS in Pharmacological Sciences 28(5), 244-251 , 2005 beschrieben, verabreicht.In one embodiment of the invention, 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, CKD-501 (Lobeglitazone Sulfate), MBX-213 or as in WO 00/64888, WO 00/64876, WO03 / 020269 , WO2007099553, US2007276041, WO2007085135, WO2007085136 or JPBerger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem PPAR delta Agonisten, wie z.B. GW-501516 oder wie sie in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887 beschrieben sind, verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with a PPAR delta agonist, e.g. GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094, WO2007119887.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem pan-SPPARM (selective PPAR modulator alpha, gamma, delta), wie z.B. GFT-505, verabreicht.In one embodiment of the invention, the compound of the formula I is used in combination with a pan-SPPARM (selective PPAR modulator alpha, gamma, delta), such as e.g. GFT-505 administered.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Metaglidasen oder mit MBX-2044 oder anderen partiellen PPAR gamma Agonisten/ Antagonisten verabreicht.In one embodiment, the compound of the formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonists / antagonists.
Bei einer Ausfiihrungsform wird die Verbindung der Formel I in Kombination mit einem α-Glukosidase-Inhibitor, wie z.B. Miglitol oder Acarbose oder solchen, wie sie z.B. in WO2007114532, WO2007140230 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is administered in combination with an α-glucosidase inhibitor, e.g. Miglitol or acarbose or those as described e.g. in WO2007114532, WO2007140230.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Hemmstoff der Glykogenphosphorylase, wie z.B. PSN-357 oder FR-258900 oder solchen wie in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of glycogen phosphorylase, such as PSN-357 or FR-258900 or such as described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Glukagon-Rezeptor-Antagonisten, wie z.B. A-770077 oder NNC-25-2504 oder wie in WO2004100875, WO2005065680, WO2006086488, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577 beschrieben, verabreicht.In one embodiment, 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, WO2006086488, WO2007106181, WO2007111864, WO2007120270, WO2007120284, WO2007123581, WO2007136577.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit einer Antisense-Verbindung, z.B. ISIS-325568, verabreicht, welche die Produktion des Glukagonrezeptors inhibiert.In another embodiment, the compound of formula I is used in combination with an antisense compound, e.g. ISIS-325568, which inhibits the production of the glucagon receptor.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Aktivatoren der Glukokinase, wie z. B. LY-2121260 (WO2004063179), PSN- 105, PSN- 110, GKA-50 oder solchen wie sie z. B. in WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040- 42, WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846, WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847, WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103, WO2007125105, US2007281942 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with activators of glucokinase, such as. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as described e.g. B. in WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040- 42 WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345 , WO2007051846, WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847, WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103, WO2007125105, US2007281942.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Glukoneogenese, wie z. B. FR-225654, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of gluconeogenesis, such as. FR-225654.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Fructose-l,6-bisphosphatase (FBPase) wie z.B. CS-917 (MB-06322) oder MB-07803 oder solchen wie sie in WO2006023515, WO2006104030, WO2007014619, WO2007137962 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is used in combination with inhibitors of fructose-l, 6-bisphosphatase (FBPase) such as CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515, WO2006104030, WO2007014619, WO2007137962.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des Glukosetransporters-4 (GLUT4), wie z. B. KST-48 (D.-O. Lee et al.: Arzneim. -Forsch. Drug Res. 54 (12), 835 (2004)), verabreicht.In one embodiment, 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)).
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Glutamin-Fructose-6-Phosphat-Amidotransferase (GFAT), wie sie z. B. in WO2004101528 beschrieben sind, verabreicht.In one embodiment, 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.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Dipeptidylpeptidase-IV (DPP-IV), wie z. B. Vildagliptin (LAF-237), Sitagliptin (MK-0431), Sitagliptin Phosphat, Saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893, ABT-341, ABT-279 oder ein anderes Salz davon, S-40010, S-40755, PF- 00734200, BM 356, PHX-1149, Alogliptin oder solchen Verbindungen wie sie in WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828, WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064, WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117, WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826, WO2006078676, WO2006073167, WO2006068163, WO2006085685, WO2006090915, WO2006104356, WO2006127530, WO2006111261, WO2007015767 (LY-2463665), WO2007024993, WO2007029086, WO2007063928, WO2007070434, WO2007071738, WO2007077508, WO2007087231, WO2007097931, WO2007099385, WO2007100374, WO2007112347, WO2007112669, WO2007113226, WO2007113634, WO2007115821, WO2007116092, US2007259900, EP1852108, US2007270492, WO2007126745, WO2007136603 beschrieben sind, verabreicht.In one embodiment, the compound of formula I in combination with inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as. Vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptin phosphate, saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021 , GRC-8200, GW-825964X, KRP-104, DP-893, ABT-341, ABT-279 or other salt thereof, S-40010, S-40755, PF-00734200, BM 356, PHX-1149, alogliptin or such compounds as described in WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828, WO2005058901, WO2005012312, WO2005 / 012308, WO2006039325, WO2006058064, WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117, WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826, WO2006078676, WO2006073167, WO2006068163, WO2006085685, WO2006090915, WO2006104356, WO2006127530, WO2006111261, WO2007015767 (LY-2463665), WO2007024993, WO2007029086, WO2007063928, WO2007070434, WO2007071738, WO2007077508, WO2007087231, WO2007097931, WO2007099385, WO2007100374, WO2007112347, WO2007112669, WO2007113226, WO2007113634, WO2007115821 , WO2007116092, US2007259900, EP18 52108, US2007270492, WO2007126745, WO2007136603.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Janumet™, einer festen Kombination von Sitagliptin Phosphat mit Metformin Hydrochlorid, verabreicht. Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Eucreas(R), einer festen Kombination von Vildagliptin mit Metformin Hydrochlorid, verabreicht.In one embodiment, the compound of formula I is administered in combination with Janumet ™, a solid combination of sitagliptin phosphate with metformin hydrochloride. In one embodiment, the compound of formula I is administered in combination with Eucreas (R) , a solid combination of vildagliptin with metformin hydrochloride.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einer Kombination eines DPP-IV-Inhibitors mit omega-3-Fettsäuren oder omega-3- Fettsäureestern, wie z.B. in WO2007128801 beschrieben, verabreicht.In one embodiment, the compound of formula I is administered in combination with a combination of a DPP-IV inhibitor with omega-3 fatty acids or omega-3 fatty acid esters, e.g. in WO2007128801, administered.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einer die Insulinsekretion verstärkende Substanz, wie z. B. KCP-265 (WO2003097064), oder solchen wie sie in WO2007026761 beschrieben sind, verabreicht.In one embodiment, the compound of formula I in combination with an insulin secretion enhancing substance, such as. KCP-265 (WO2003097064) or those as described in WO2007026761.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Agonisten des glucose-abhängigen insulinotropischen Rezeptors (GDIR) wie z. B. APD- 668 verabreicht.In one embodiment, the compound of the formula I in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR) such. B. APD-668 administered.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit einem ATP-Citrat-Lyase Inhibitor, wie z.B. SB-204990, verabreicht.Combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des natrium-abhängigen Glukosetransporters 1 oder 2 (SGLTl, SGLT2), wie z.B. KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083, SGL-5085, SGL- 5094, ISIS-388626, Sergliflozin oder Dapagliflozin oder wie sie z. B. in WO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842, WO2007000445, WO2007014895, WO2007080170, WO2007093610, WO2007126117, WO2007128480, WO2007129668, US2007275907, WO2007136116 oder von A. L. Handion in Expert Opin. Ther. Patents (2005) 15(11), 1531-1540 beschrieben sind, verabreicht.In one embodiment, 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, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin or dapagliflozin, or as described e.g. B. in WO2004007517, WO200452903, WO200452902, PCT / EP2005 / 005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842, WO2007000445, WO2007014895, WO2007080170, WO2007093610, WO2007126117, WO2007128480, WO2007129668 , US2007275907, WO2007136116 or AL Handion in Expert Opin. Ther. Patents (2005) 15 (11), 1531-1540.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Hemmstoffen der 11-beta-Hydroxysteroid-Dehydrogenase-l (1 lß-HSDl), wie z. B. BVT- 2733, JNJ-25918646, INCB-13739, DIO-92 ((-)-Ketoconazol) oder solche, wie sie z. B. in WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896,In one embodiment, the compound of formula I in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (1 lß-HSDl), such. B. BVT-2733, JNJ-25918646, INCB-13739, DIO-92 ((-) - ketoconazole) or those, such as. In WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896,
WO2005016877, WO2005063247, WO2005097759, WO2006010546, WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329, WO2006066109, WO2006074244, WO2006078006, WO2006106423, WO2006132436, WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138508, WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584, WO2007029021, WO2007047625, WO2007051811, WO2007051810, WO2007057768, WO2007058346, WO2007061661, WO2007068330, WO2007070506, WO2007087150, WO2007092435, WO2007089683, WO2007101270, WO2007105753, WO2007107470, WO2007107550, WO2007111921, US2007207985, US2007208001, WO2007115935, WO2007118185, WO2007122411, WO2007124329, WO2007124337, WO2007124254, WO2007127688, WO2007127693, WO2007127704, WO2007127726, WO2007127763, WO2007127765, WO2007127901, US2007270424, JP2007291075, WO2007130898, WO2007135427 beschrieben sind, verabreicht.WO2005016877, WO2005063247, WO2005097759, WO2006010546, WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329, WO2006066109, WO2006074244, WO2006078006, WO2006106423, WO2006132436, WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138508, WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584, WO2007029021, WO2007047625, WO2007051811, WO2007051810, WO2007057768, WO2007058346, WO2007061661, WO2007068330, WO2007070506, WO2007087150, WO2007092435, WO2007089683, WO2007101270, WO2007105753, WO2007107470, WO2007107550, WO2007111921, US2007207985, US2007208001, WO2007115935, WO2007118185, WO2007122411, WO2007124329, WO2007124337, WO2007124254, WO2007127688, WO2007127693, WO2007127704, WO2007127726, WO2007127763, WO2007127765, WO2007127901, US2007270424, JP2007291075, WO2007130898, WO2007135427.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der Protein-Tyrosin-Phosphatase-1B (PTP-IB), wie sie z. B. in WO200119830-31, WO200117516, WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004 060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755, WO2007115058 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of protein tyrosine phosphatase-1B (PTP-IB), as z. In WO200119830-31, WO200117516, WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004 060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755, WO2007115058.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Agonisten des GPRl 09 A (HM74A Rezeptor Agonisten; NAR- Agonisten (Nikotinsäurerezeptoragonisten)), wie z.B. Nicotinsäure oder „extended release niacin" in Verbindung mit MK-0524A (Laropiprant) oder MK-0524 oder solchen Verbindungen, wie sie in WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986 beschrieben sind, verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with an agonist of GPR10A (HM74A receptor agonists; NAR agonists (nicotinic acid receptor agonists)), such as, for example, nicotinic acid or extended release niacin in combination with MK-0524A (Laropiprant ) or MK-0524 or such compounds as described in WO2006045565, WO2006045564, WO2006069242, WO2006085108, WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532, WO2007092364, WO2007120575, WO2007134986.
Bei einer anderen Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Niacin mit Simvastatin verabreicht.In another embodiment of the invention, the compound of formula I is administered in combination with a solid combination of niacin with simvastatin.
Bei einer anderen Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Nicotinsäure oder „extended release niacin" in Verbindung mit MK- 0524 A (Laropiprant) verabreicht.In another embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or "extended release niacin" in conjunction with MK-0524 A (laropiprant).
Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Nicotinsäure oder „extended release niacin" in Verbindung mit MK- 0524A (Laropiprant) und mit Simvastatin verabreicht.In a further embodiment of the invention, the compound of the formula I is administered in combination with nicotinic acid or extended release niacin in conjunction with MK-0524A (laropiprant) and with simvastatin.
Bei einer anderen Ausführungsform der Erfindung wird die Erfindung der Formel I inIn another embodiment of the invention, the invention of the formula I in
Kombination mit einem Inhibitor der Cyclooxygenase-1 oder Cyclooxygenase-2, wie z.B. Acetylsalicylsäure, Diclofenac, Celecoxib , Rofecoxib , Valdecoxib, Etoricoxib, oder Lumiracoxib verabreicht.Combination with an inhibitor of cyclooxygenase-1 or cyclooxygenase-2, e.g. Acetylsalicylic acid, diclofenac, celecoxib, rofecoxib, valdecoxib, etoricoxib, or lumiracoxib.
Bei einer anderen Ausführungsform der Erfindung wird die Erfindung der Formel 1 1 in Kombination mit einem DPl-Rezeptorantagonist, wie z.B. Laropiprant, SAR389644 oder solche Verbindungen, wie sie in WO2008039882 beschrieben sind, verabreicht.In another embodiment of the invention, the invention of formula I 1 is used in combination with a DPl receptor antagonist, e.g. Laropiprant, SAR389644 or such compounds as described in WO2008039882 administered.
.Bei einer anderen Ausfuhrungsförrn der Erfindung wird die Verbindung der Formel I in Kombination mit einem Agonisten des GPRl 16, wie sie z.B. in WO2006067531 , WO2006067532 beschrieben sind, verabreicht.In another embodiment of the invention, the compound of formula I is used in combination with an agonist of GPR16, as described e.g. in WO2006067531, WO2006067532.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPR40, wie sie z.B. in WO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622, WO2007136572 beschrieben sind, verabreicht. Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPRl 19b wie sie z. B. in WO2004041274 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I is administered in combination with modulators of the GPR40, as described, for example, in WO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225, WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622, WO2007136572. In one embodiment, the compound of formula I in combination with modulators of GPRl 19b as z. As described in WO2004041274 administered.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPRl 19 (G-Protein-gekoppelter Glukose-abhängiger insulinotroper Rezeptor), wie z.B. PSN-119-1 oder solchen wie sie z. B. in WO2005061489 (PSN- 632408), WO2004065380, WO2006018662, WO2007003960-62 und WO2007003964, WO2007116229, WO2007116230 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is used in combination with modulators of GPR19 (G protein-coupled glucose-dependent insulinotropic receptor), e.g. PSN-119-1 or such as z. In WO2005061489 (PSN-632408), WO2004065380, WO2006018662, WO2007003960-62 and WO2007003964, WO2007116229, WO2007116230.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des GPR120, wie sie z.B. in EP1688138 beschrieben sind, verabreicht.In a further embodiment, the compound of formula I is used in combination with modulators of the GPR120, e.g. in EP1688138.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der hormon-sensitiven Lipase (HSL) und/oder Phospholipasen, wie z. B. in WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL) and / or phospholipases, such. As described in WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der endothelialen Lipase, wie z. B. in WO2007110216 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of endothelial lipase, such as. As described in WO2007110216 administered.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Phospho lipase A2 Inhibitor wie z.B. Darapladib oder A-002 verabreicht.In one embodiment, the compound of formula I is used in combination with a phospholipase A2 inhibitor, e.g. Administered darapladib or A-002.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Myricitrin, einem Lipase-Inhibitor (WO2007119827), verabreicht.In one embodiment, the compound of the formula I is administered in combination with myricitrin, a lipase inhibitor (WO2007119827).
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Glykogen Synthase Kinase-3 beta (GSK-3 beta), wie z. B. in US2005222220, WO2005085230, WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117, WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109, WO2007125110 beschrieben.In one embodiment, the compound of the formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), such as. In US2005222220, WO2005085230, WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117, WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109, WO2007125110.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Phosphoenolpyruvatcarboxykinase (PEPCK), wie z.B. solchen, wie in WO2004074288 beschrieben, verabreicht.In one embodiment, the compound of formula I is used in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), e.g. such as described in WO2004074288 administered.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Serum/Glucocorticoid regulierten Kinase (SGK), wie z. B. in WO2006072354, WO2007093264 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of serum / glucocorticoid-regulated kinase (SGK), such as. As described in WO2006072354, WO2007093264.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Protein Kinase C beta (PKC beta), wie z. B. Ruboxistaurin, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of protein kinase C beta (PKC beta), such as. B. Ruboxistaurin administered.
Bei einer weiteren Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Aktivator der AMP-aktivierten Proteinkinase (AMPK), wie sie z. B. in WO2007062568 beschrieben sind, verabreicht.In another embodiment, the compound of the formula I in combination with an activator of the AMP-activated protein kinase (AMPK), as described, for. As described in WO2007062568 administered.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Ceramidkinase, wie sie z. B. in WO2007112914 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I in combination with an inhibitor of ceramide kinase, as z. As described in WO2007112914 administered.
Bei einer weiteren Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der MAPK-interagierenden Kinase 2 (MNK2), wie sie z.B. in WO2007104053, WO2007115822 beschrieben sind, verabreicht.In another embodiment, the compound of the formula I is used in combination with an inhibitor of MAPK-interacting kinase 2 (MNK2), as described e.g. in WO2007104053, WO2007115822 are administered.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Inhibitoren der „I-kappaB kinase" (IKK Inhibitoren), wie sie z. B. in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140 beschrieben sind, verabreicht. Bei einer Ausfuhrungsform der Erfindung wird die Verbindungen der Formel I in Kombination mit einem HMGCoA-Reduktase Inhibitor wie Simvastatin, Fluvastatin, Pravastatin, Lovastatin, Atorvastatin, Cerivastatin, Rosuvastatin, L-659699 oder solchen, wie sie in US2007249583 beschrieben sind, verabreicht.In one embodiment, the compound of the formula I is administered in combination with inhibitors of the "I-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022057, WO2004022553, WO2005097129, WO2005113544, US2007244140. In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699 or those as described in US2007249583.
Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Farnesoid X Rezeptor (FXR) Antagonisten, wie z.B. in WO2007052843, WO2007070796, WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183 beschrieben, verabreicht.In a further embodiment of the invention, the compound of formula I is used in combination with a farnesoid X receptor (FXR) antagonist, such as e.g. in WO2007052843, WO2007070796, WO2007092751, JP2007230909, WO2007095174, WO2007140174, WO2007140183.
Bei einer anderen Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Liganden des Leber X Rezeptors (liver X receptor; LXR), wie z.B. in WO2007092965 beschrieben, verabreicht.In another embodiment of the invention, the compound of the formula I is used in combination with a liver X receptor (LXR) ligand, e.g. described in WO2007092965.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit einem Fibrat, wie z.B. Fenofibrat, Clofibrat, Bezafibrat, verabreicht.Combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Fibraten, wie z.B. dem Cholinsalz von Fenofibrat (SLV-348), verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate (SLV-348).
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Fibraten, wie z.B. dem Cholinsalz von Fenofibrat und einem HMGCoA Reduktase Inhibitor, wie z.B. Rosuvastatin, verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with fibrates, e.g. the choline salt of fenofibrate and a HMGCoA reductase inhibitor, e.g. Rosuvastatin, administered.
Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Bezafibrat und Diflunisal verabreicht.In a further embodiment of the invention, the compound of the formula I is administered in combination with bezafibrate and diflunisal.
Bei einer weiteren Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Fenofibrat oder einem Salz davon mit Simvastatin, Rosuvastatin, Fluvastatin, Lovastatin, Cerivastatin, Pravastatin oder Atorvastatin verabreicht. Bei einer weiteren Ausfϊihrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Synordia (R), einer festen Kombination von Fenofibrat mit Metformin, verabreicht.In another embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of fenofibrate or a salt thereof with simvastatin, rosuvastatin, fluvastatin, lovastatin, cerivastatin, pravastatin or atorvastatin. In a further embodiment of the invention, the compound of the formula I is administered in combination with Synordia (R), a fixed combination of fenofibrate with metformin.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit einem Cholesterinresorptionsinhibitor, wie z.B. Ezetimibe, Tiqueside, Pamaqueside, FM- VP4 (sitostanol/campesterol ascorbyl phosphat; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) oder mit Verbindungen, wie in WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) oder WO2005044256 oder WO2005062824 (Merck & Co.) oder WO2005061451 und WO2005061452 (AstraZeneca AB) und WO2006017257 (Phenomix) oder WO2005033100 (Lipideon Biotechnology AG) oder wie in WO2002050060, WO2002050068, WO2004000803, WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248, WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186, WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163, WO2007059871, US2007232688, WO2007126358 beschrieben, verabreicht.Combination with a cholesterol resorption inhibitor, 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, WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 or WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon Biotechnology AG) or as in WO2002050060, WO2002050068, WO2004000803, WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248, WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186, WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163, WO2007059871, US2007232688, WO2007126358.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit Vytorin™, einer festen Kombination von Ezetimibe mit Simvastatin, verabreicht.Combination with Vytorin ™, a fixed combination of ezetimibe with simvastatin.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Ezetimibe mit Atorvastatin, verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of ezetimibe with atorvastatin.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Ezetimibe mit Fenofibrat verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.
Bei einer Ausführungsform der Erfindung ist der weitere Wirkstoff einIn one embodiment of the invention, the further active ingredient is a
Diphenylazetidinonderivat, wie z.B. in US 6,992,067 oder US 7,205,290 beschrieben. Bei einer weiteren Ausführungsform der Erfindung ist der weitere Wirkstoff ein Diphenylazetidinonderivat, wie z.B. in US 6,992,067 oder US 7,205,290 beschrieben, kombiniert mit einem Statin, wie z.B. Simvastatin, Fluvastatin, Pravastatin, Lovastatin, Cerivastatin, Atorvastatin oder Rosuvastatin.Diphenylazetidinonderivat, as described for example in US 6,992,067 or US 7,205,290. In a further embodiment of the invention, the further active ingredient is a diphenylazetidinone derivative as described, for example, in US Pat. No. 6,992,067 or US Pat. No. 7,205,290 combined with a statin such as simvastatin, fluvastatin, pravastatin, lovastatin, cerivastatin, atorvastatin or rosuvastatin.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Lapaquistat, einem Squalensynthase- Inhibitor, mit Atorvastatin verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with a solid combination of Lapaquistat, a squalene synthase inhibitor, with atorvastatin.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit einem CETP-Inhibitor, wie z.B. Torcetrapib, Anacetrapib oder JTT-705 oder solchen wie sie in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304, WO2007128568, WO2007132906 beschrieben sind, verabreicht.Combination with a CETP inhibitor, e.g. Torcetrapib, anacetrapib or JTT-705 or those as are described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154, US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243, WO2007120621, US2007265252, US2007265304, WO2007128568 WO2007132906 described, administered.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit Gallensäureresorptionsinhibitor (siehe z.B. US 6,245,744, US 6,221,897 oder WO00/61568), wie z.B. HMR 1741 oder solchen wie in DE 10 2005 033099.1 und DE 10 2005 033100.9, WO2007009655-56 beschrieben, verabreicht.In one embodiment of the invention, 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 those described in DE 10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Agonisten des GPBARl (G-protein-coupled-bile-acid-receptor-l; TGR5), wie sie z.B. in WO2007110237, WO2007127505 beschrieben sind, verabreicht.In one embodiment, the compound of Formula I is used in combination with agonists of GPBAR1 (G-protein-coupled bile-acid receptor-1; TGR5), as described, e.g. in WO2007110237, WO2007127505.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem polymeren Gallensäureadsorber, wie z.B. Cholestyramin, Colesevelam Hydrochlorid, verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam hydrochloride.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Phytosterole enthaltenden Kaugummi (Reductol™) verabreicht. Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Inhibitor des mikrosomalen Triglycerid-Transfer-Proteins (MTP- Inhibitor), wie z.B. Implitapide , BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733 oder solchen wie in WO2005085226, WO2005121091, WO2006010423, WO2006113910 beschrieben, verabreicht.In one embodiment of the invention, the compound of formula I is administered in combination with a phytosterol-containing chewing gum (Reductol ™). In one embodiment of the invention, the compound of the formula I is used in combination with an inhibitor of the microsomal triglyceride transfer protein (MTP inhibitor), for example Implitapide, BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR -733 or those as described in WO2005085226, WO2005121091, WO2006010423, WO2006113910.
Bei einer anderen Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Antagonisten des Somatostatin 5 Rezeptors (SST5 Rezeptor), wie z.B. solchen wie sie in WO2006094682 beschrieben sind, verabreicht.In another embodiment of the invention, the compound of formula I is administered in combination with an antagonist of the somatostatin 5 receptor (SST5 receptor), e.g. such as those described in WO2006094682 administered.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem ACAT-Inhibitor, wie z.B. Avasimibe, SMP-797 oder KY-382, verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with an ACAT inhibitor, e.g. Avasimibe, SMP-797 or KY-382.
Bei einer weiteren Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Leber-Carnitin Palmitoyltransferase-1 (L-CPTl), wie sie z.B. in WO2007063012, WO2007096251 (ST-3473) beschrieben sind, verabreicht.In a further embodiment of the invention, the compound of the formula I in combination with an inhibitor of hepatic carnitine palmitoyltransferase-1 (L-CPTl), as described e.g. in WO2007063012, WO2007096251 (ST-3473).
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Squalen Synthetase Inhibitor, wie z.B. BMS-188494, TAK-475 (Lapaquistat Acetat) oder wie in WO2005077907, JP2007022943 beschrieben, verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with a squalene synthetase inhibitor, e.g. BMS-188494, TAK-475 (Lapaquistat acetate) or as described in WO2005077907, JP2007022943.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit ISIS-301012 (Mipomersen), einem Antisense-Oligonukleotid, welches in der Lage ist, das Apolipoprotein B Gen zu regulieren, verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with ISIS-301012 (mipomersen), an antisense oligonucleotide which is capable of regulating the apolipoprotein B gene.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem LDL-Rezeptorinducer (siehe US 6,342,512), wie z.B. HMRl 171, HMRl 586, oder solchen wie in WO2005097738 beschrieben, verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMRI 586, or those as described in WO2005097738.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem ABCAl Expressionsverstäker, wie sie z.B. in WO2006072393 beschrieben, verabreicht. Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Lipoprotein-Lipase Modulator, wie z.B. Ibrolipim (NO-1886), verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with an ABCA1 expression enhancer, as described, for example, in WO2006072393. In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein-lipase modulator such as ibrolipim (NO-1886).
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Lipoprotein(a) antagonist, wie z.B. Gemcabene (CI- 1027) verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with a lipoprotein (a) antagonist, e.g. Gemcabene (CI-1027).
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I inIn one embodiment of the invention, the compound of the formula I is described in
Kombination mit einem Lipase Inhibitor, wie z.B. Orlistat oder Cetilistat (ATL-962), verabreicht.Combination with a lipase inhibitor, e.g. Orlistat or cetilistat (ATL-962).
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Adenosin A2B Rezeptor Agonisten (Adenosin A2B R) wie z.B. ATL-801 verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A2B receptor agonist (adenosine A2B R), e.g. ATL-801 administered.
Bei einer anderen Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Modulator der Adenosin A2A und/oder Adenosin A3 Rezeptoren, wie z.B. in WO2007111954, WO2007121918, WO2007121921, WO2007121923 beschrieben, verabreicht.In another embodiment of the invention, the compound of the formula I in combination with a modulator of the adenosine A2A and / or adenosine A3 receptors, such. in WO2007111954, WO2007121918, WO2007121921, WO2007121923.
Bei einer Ausführungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Adenosin A2B Rezeptor Antagonisten (Adenosin A2B R), wie sie in US2007270433 beschrieben sind, verabreicht.In one embodiment of the invention, the compound of the formula I is administered in combination with an adenosine A2B receptor antagonist (adenosine A2B R), as described in US2007270433.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Hemmstoffen der Acetyl-CoA Carboxylase (ACCl und/oder ACC2) wie z. B. solchen wie in WO199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809, WO2007011811, WO2007013691, WO2007095601- 603, WO2007119833 beschrieben, verabreicht. Bei einer anderen Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Modulatoren der mikrosomalen Acyl-CoA:Glycerol-3-Phosphat-Acyltransferase 3 (GP AT3, beschrieben in WO2007100789) oder mit Modulatoren der mikrosomalen Acyl- CoA: Glycerol-3 -Phosphat- Acyltransferase 4 (GP AT4, beschrieben in WO2007100833) verabreicht.In one embodiment, the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACCl and / or ACC2) such. For example, those described in WO199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809, WO2007011811, WO2007013691, WO2007095601-603, WO2007119833. In another embodiment, the compound of the formula I is used in combination with modulators of the microsomal acyl-CoA: glycerol-3-phosphate acyltransferase 3 (GP AT3, described in WO2007100789) or with modulators of the microsomal acyl-CoA: glycerol-3-phosphate - Acyltransferase 4 (GP AT4, described in WO2007100833) administered.
Bei einer weiteren Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Modulatoren der Xanthin-Oxidoreductase (XOR) verabreicht.In a further embodiment, the compound of the formula I is administered in combination with modulators of xanthine oxidoreductase (XOR).
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit CART-Modulatoren (siehe "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al.: Hormone and Metabolie Research (2001), 33(9), 554-558);In a further embodiment, 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- Antagonisten wie z.B. Naphthalin- l-sulfonsäure-{4-[(4-amino-quinazolin-2- ylamino)-methyl]-cyclohexylmethyl}-amid Hydrochlorid (CGP 71683A);NPY antagonists, e.g. Naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide hydrochloride (CGP 71683A);
NPY-5 Rezeptorantagonisten wie L-152804 oder die Verbindung „NPY-5-BY" der Firma Banyu oder wie sie z. B. in WO2006001318, WO2007103295, WO2007125952 beschrieben sind;NPY-5 receptor antagonists such as L-152804 or the compound "NPY-5-BY" from Banyu or as described, for example, in WO2006001318, WO2007103295, WO2007125952;
NPY-4-Rezeptorantagonisten wie sie z. B. in WO2007038942 beschrieben sind;NPY-4 receptor antagonists as they are e.g. As described in WO2007038942;
NPY-2-Rezeptorantagonisten wie sie z. B. in WO2007038943 beschrieben sind;NPY-2 receptor antagonists such as. As described in WO2007038943;
Peptid YY 3-36 (PYY3-36) oder analoge Verbindungen wie z. B. CJC-1682 (PYY3-36 konjugiert mit humanem Serum Albumin über Cys34) oder CJC- 1643 (Derivat des PYY3- 36, welches sich in vivo an Serum Albumin konjugiert) oder solche, wie sie in WO2005080424, WO2006095166 beschrieben sind;Peptide YY 3-36 (PYY3-36) or analogous compounds such. CJC-1682 (PYY3-36 conjugated to human serum albumin via Cys34) or CJC-1643 (derivative of PYY3-36 conjugated to serum albumin in vivo) or those described in WO2005080424, WO2006095166;
Derivaten des Peptids Obestatin wie sie WO2006096847 beschrieben sind; CBlR (Cannabinoid Rezeptor 1) Antagonisten (wie z.B. Rimonabant, Surinabant (SR147778), SLV-319, AVE-1625, Taranabant (MK-0364) oder Salze davon, V-24343 oder solche Verbindungen wie sie in z. B. EP 0656354, WO 00/15609, WO2001/64632- 64634, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820, US20050009870, WO200500974, WO2004111033-34, WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837, WO2005028456, WO2005063761-62, WO2005061509, WO2005077897, WO2006047516, WO2006060461, WO2006067428, WO2006067443, WO2006087480, WO2006087476, WO2006100208, WO2006106054, WO2006111849, WO2006113704, WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007018460, WO2007016460, WO2007020502, WO2007026215, WO2007028849, WO2007031720, WO2007031721, WO2007036945, WO2007038045, WO2007039740, US20070015810, WO2007046548, WO2007047737, WO2007057687, WO2007062193, WO2007064272, WO2007079681, WO2007084319, WO2007084450, WO2007086080, EP1816125, US2007213302, WO2007095513, WO2007096764, US2007254863, WO2007119001, WO2007120454, WO2007121687, WO2007123949, US2007259934, WO2007131219, WO2007133820, WO2007136607, WO2007136571, US7297710, WO2007138050, WO2007140385, WO2007140439 beschrieben sind);Derivatives of the peptide obestatin as described WO2006096847; CBIR (Cannabinoid Receptor 1) antagonists (such as Rimonabant, Surinabant (SR147778), SLV-319, AVE-1625, Taranabant (MK-0364) or salts thereof, V-24343 or such compounds as described in, for example, EP 0656354 WO 00/15609, WO200001 / 64632-64634, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO20017700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037 , WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820 , US20050009870, WO200500974, WO2004111033-34, WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837, WO2005028456, WO2005063761-62, WO2005061509, WO2005 077897, WO2006047516, WO2006060461, WO2006067428, WO2006067443, WO2006087480, WO2006087476, WO2006100208, WO2006106054, WO2006111849, WO2006113704, WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007018460, WO2007016460, WO2007020502, WO2007026215, WO2007028849, WO2007031720, WO2007031721, WO2007036945, WO2007038045, WO2007039740, US20070015810, WO2007046548, WO2007047737, WO2007057687, WO2007062193, WO2007064272, WO2007079681, WO2007084319, WO2007084450, WO2007086080, EP1816125, US2007213302, WO2007095513, WO2007096764, US2007254863, WO2007119001, WO2007120454, WO2007121687, WO2007123949, US2007259934, WO2007131219, WO2007133820, WO2007136607, WO2007136571, US7297710, WO2007138050, WO2007140385, WO2007140439 are described);
Cannabinoid Rezeptor 1 / Cannabinoid Rezeptor 2 (CB1/CB2) modulierende Verbindungen wie z.B. delta-9-Tetrahydrocannabivarin oder solchen wie sie z.B. in WO2007001939, WO2007044215, WO2007047737, WO2007095513, WO2007096764, WO2007112399, WO2007112402 beschrieben sind;Cannabinoid Receptor 1 / Cannabinoid Receptor 2 (CB1 / CB2) modulating compounds, e.g. delta-9-tetrahydrocannabivarin or those as described e.g. in WO2007001939, WO2007044215, WO2007047737, WO2007095513, WO2007096764, WO2007112399, WO2007112402 are described;
Modulatoren der FAAH (fatty acid amide hydrolase) wie sie z.B. in WO2007140005 beschrieben sind; Vanilloid-1 -Rezeptor Modulatoren (Modulatoren des TRPVl), wie sie z.B. in WO2007091948, WO2007129188, WO2007133637 beschrieben sind;FAAH (fatty acid amide hydrolase) modulators as described, for example, in WO2007140005; Vanilloid-1 receptor modulators (modulators of the TRPV1), as described, for example, in WO2007091948, WO2007129188, WO2007133637;
Aktivatoren des Capsaicinrezeptors, wie sie z.B. in JP2007210969 beschrieben sind;Activators of the capsaicin receptor, as e.g. in JP2007210969;
Agonisten des Prostaglandinrezeptors, wie z.B. Bimatoprost oder solchen Verbindungen wie sie in WO2007111806 beschrieben sind;Agonists of the prostaglandin receptor, e.g. Bimatoprost or such compounds as described in WO2007111806;
MC4-Rezeptor Agonisten (Melanocortin-4 Rezeptor Agonisten, MC4R Agonisten wie z.B. l-Amino-l,2,3,4-tetrahydro-naphthalin-2-carbonsäure [2-(3a-benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-l-(4-chloro-phenyl)-2-oxo-ethyl]- amid; (WO 01/91752)) oder LB53280, LB53279, LB53278 oder THIQ, MB243, RY764, CHIR-785, PT-141, MK-0493 oder solche wie sie in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159, WO2004072076, WO2004072077, WO2006021655-57, WO2007009894, WO2007015162, WO2007041061, WO2007041052, JP2007131570, EP-1842846, WO2007096186, WO2007096763 beschrieben sind;MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists such as 1-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo) 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141, MK-0493 or those as described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159, WO2004072076, WO2004072077, WO2006021655-57, WO2007009894, WO2007015162, WO2007041061, WO2007041052, JP2007131570, EP-1842846, WO2007096186, WO2007096763 are described;
Orexin-Rezeptor 1 Antagonisten (OXlR Antagonisten), Orexin-Rezeptor 2 Antagonisten (OX2R Antagonisten) oder gemischte OX1R/OX2R Antagonisten (z.B. l-(2-Methyl- benzoxazol-6-yl)-3-[l,5]naphthyridin-4-yl-harnstoffHydrochlorid (SB-334867-A) oder solche, wie sie z. B. in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374;WO2007122591, WO2007126934, WO2007126935 beschrieben sind);Orexin receptor 1 antagonists (OXlR antagonists), orexin receptor 2 antagonists (OX2R antagonists) or mixed OX1R / OX2R antagonists (eg l- (2-methylbenzoxazol-6-yl) -3- [l, 5] naphthyridine 4-yl urea hydrochloride (SB-334867-A) or those described, for example, in WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718, WO2007088276, WO2007116374, WO2007122591, WO2007126934, WO2007126935);
Histamin H3 Rezeptor Antagonisten/inverse Agonisten (z. B. 3-Cyclohexyl-l-(4,4- dimethyl-l,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-propan-l-on Oxalsäuresalz (WO 00/63208) oder solche, wie sie in WO200064884, WO2005082893, US2005171181 (z.B. PF-00389027), WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418, WO2007057329, WO2007065820, WO2007068620, WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053, WO2007106349, WO2007110364, WO2007115938, WO2007131907, WO2007133561, US2007270440, WO2007135111 beschrieben sind);Histamine H3 receptor antagonists / inverse agonists (eg 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) - propan-1-one oxalic acid salt (WO 00/63208) or those as described in WO200064884, WO2005082893, US2005171181 (eg PF-00389027), WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798, WO2007055418, WO2007057329, WO2007065820, WO2007068620, WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450, WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053, WO2007106349, WO2007110364, WO2007115938, WO2007131907, WO2007133561, US2007270440, WO2007135111 are described);
Histamin Hl / Histamin H3 Modulatoren, wie z. B. Betahistin bzw. seinem Dihydrochlorid;Histamine Hl / histamine H3 modulators, such as. B. Betahistine or its dihydrochloride;
CRF- Antagonisten (z.B. [2-Methyl-9-(2,4,6-trimethyl-phenyl)-9H-l ,3,9-triaza-fluoren-4- yl]-dipropyl-amin (WO 00/66585) oder solche CRFl -Antagonisten, wie sie in WO2007105113, WO2007133756 beschrieben sind);CRF antagonists (eg [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585) or those CRF1 antagonists, as described in WO2007105113, WO2007133756);
CRF BP-Antagonisten (z.B. Urocortin);CRF BP antagonists (e.g., urocortin);
Urocortin-Agonisten;Urocortin agonists;
Agonisten des beta-3 Adrenoceptors wie z.B. l-(4-Chloro-3-methanesulfonylmethyl- phenyl)-2-[2-(2,3-dimethyl-lH-indol-6-yloxy)-ethylamino]-ethanol Hydrochlorid (WO 01/83451) oder Solabegron (GW-427353) oder N-5984 (KRP-204) oder solche, wie sie in JP2006111553, WO2002038543, WO2002038544, WO2007048840-843 beschrieben sind;Agonists of the 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 -427,353) or N-5984 (KRP-204) or those as described in JP2006111553, WO2002038543, WO2002038544, WO2007048840-843;
MSH (Melanocyt-stimulierendes Hormon)-Agonisten;MSH (melanocyte-stimulating hormone) agonists;
MCH (melanin-konzentrierendes Hormon) Rezeptor Antagonisten (wie z. B. NBI-845, A- 761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 oder solche Verbindungen, wie sie in WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847, WO2007024004, WO2007039462, WO2007042660, WO2007042668, WO2007042669, US2007093508, US2007093509, WO2007048802, JP2007091649, WO2007092416; WO2007093363-366, WO2007114902, WO2007114916 beschrieben sind);MCH (melanin-concentrating hormone) receptor antagonists (such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or such compounds, as are described in WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279 WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847, WO2007024004, WO2007039462, WO2007042660, WO2007042668, WO2007042669, US2007093508, US2007093509, WO2007048802, JP2007091649, WO2007092416; WO2007093363-366, WO2007114902, WO2007114916 are described);
CCK-A (CCK-I) Agonisten (wie z.B. {2-[4-(4-Chloro-2,5-dimethoxy-phenyl)-5-(2- cyclohexyl-ethyty-thiazol^-ylcarbamoy^-SJ-dimethyl-indol- 1 -yl} -essigsaure Trifluoressigsäuresalz (WO 99/15525) oder SR-146131 (WO 0244150) oder SSR-125180) oder solchen, wie sie in WO2005116034, WO2007120655, WO2007120688, WO2007120718 beschrieben sind;CCK-A (CCK-I) agonists (such as {2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl-t-thiazole) -ylcarbamoyl-SJ-dimethyl indole-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or those as described in WO2005116034, WO2007120655, WO2007120688, WO2007120718;
Serotonin- Wiederaufnahme-Inhibitoren (z.B. Dexfenfluramine);Serotonin reuptake inhibitors (e.g., dexfenfluramines);
gemischte Serotonin-/Dopamin- Wiederaufnahme-Inhibitoren (z.B. Bupropion) oder feste Kombinationen von Bupropion mit Naltrexon oder Bupropion mit Zonisamid;mixed serotonin / dopamine reuptake inhibitors (e.g., bupropion) or fixed combinations of bupropion with naltrexone or bupropion with zonisamide;
gemischte Wiederaufhahmeinhibitoren wie z.B. DOV-21947;mixed reuptake inhibitors such as e.g. DOV 21,947;
gemischte Sertonin- und noradrenerge Verbindungen (z.B. WO 00/71549);mixed sertonine and noradrenergic compounds (e.g., WO 00/71549);
5-HT-Rezeptor Agonisten z.B. l-(3-Ethyl-benzofuran-7-yl)-piperazin Oxalsäuresalz (WO 01/09111);5-HT receptor agonists e.g. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111);
gemischte Dopamin/Norepinephrin/ Acetylcholin- Wiederaufhahme-Inhibitoren (z.B . Tesofensine) oder solchen wie sie z.B. in WO2006085118 beschrieben sind;mixed dopamine / norepinephrine / acetylcholine reuptake inhibitors (e.g., tesofensins) or those as described e.g. in WO2006085118;
5-HT2C Rezeptor Agonisten (wie z.B. Lorcaserin Hydrochlorid (APD-356) oder BVT-933 oder solche, wie sie in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025, WO2006103511, WO2007028132, WO2007084622, US2007249709; WO2007132841, WO2007140213 beschrieben sind); 5-HT6 Rezeptor Modulatoren, wie z.B. E-6837, BVT-74316 oder PRX-07034 oder solche wie sie z.B. in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744 beschrieben sind;5-HT2C receptor agonists (such as Lorcaserin hydrochloride (APD-356) or BVT-933 or those as described in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025, WO2006103511 WO2007028132, WO2007084622, US2007249709, WO2007132841, WO2007140213 are described); 5-HT6 receptor modulators, such as E-6837, BVT-74316 or PRX-07034 or those as described, for example, in WO2005058858, WO2007054257, WO2007107373, WO2007108569, WO2007108742-744;
Agonisten des Estrogenrezeptors gamma (ERRD Agonisten), wie sie z.B. in WO2007131005 beschrieben sind;Agonists of the estrogen receptor gamma (ERRD agonists), e.g. in WO2007131005 are described;
Sigma-1 Rezeptorantagonisten, wie sie z.B. in WO2007098953, WO2007098961 beschrieben sind;Sigma-1 receptor antagonists, as described e.g. in WO2007098953, WO2007098961 are described;
Muscarin 3 Rezeptor (M3R) Antagonisten, wie sie z.B. in WO2007110782 beschrieben sind;Muscarinic 3 receptor (M3R) antagonists as described e.g. in WO2007110782 are described;
Bombesin-Rezeptor Agonisten (BRS-3 Agonisten);Bombesin receptor agonists (BRS-3 agonists);
Galanin-Rezeptor Antagonisten;Galanin receptor antagonists;
Wachstumshormon (z.B. humanes Wachstumshormon oder AOD-9604);Growth hormone (e.g., human growth hormone or AOD-9604);
Wachstumshormon freisetzende Verbindungen (6-Benzyloxy-l-(2-diisopropylamino- ethylcarbamoyl)-3,4-dihydro-lH-isochinolin-2-carbonsäuretertiärbutylester (WO 01/85695));Growth hormone releasing compounds (6-Benzyloxy-l- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695));
Growth Hormone Secretagogue Receptor Antagonisten (Ghrelin Antagonisten) wie z. B. A-778193 oder solchen, wie sie in WO2005030734, WO2007127457 beschrieben sind;Growth Hormone Secretagogue Receptor Antagonists (ghrelin antagonists) such as A-778193 or those as described in WO2005030734, WO2007127457;
Growth Hormone Secretagogue Receptor Modulatoren wie z.B. JMV-2959, JMV-3002, JMV-2810, JMV-2951 oder solchen, wie sie in WO2006012577 (z.B. YIL-781 oder YIL- 870), WO2007079239 beschrieben sind;Growth Hormone Secretagogue Receptor Modulators, e.g. JMV-2959, JMV-3002, JMV-2810, JMV-2951 or those as described in WO2006012577 (e.g., YIL-781 or YIL-870), WO2007079239;
TRH- Agonisten (siehe z.B. EP 0 462 884);TRH agonists (see, e.g., EP 0 462 884);
entkoppelnde Protein 2- oder 3-Modulatoren; Leptinagonisten (siehe z.B. Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya- Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881);decoupling protein 2- or 3-modulators; Leptin agonists (see, eg, Lee, Daniel W, Leinung, Matthew C, Rozhavskaya Arena, Marina, Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity, Drugs of the Future (2001), 26 (9), 873-881);
DA-Agonisten (Bromocriptin, Doprexin);DA agonists (bromocriptine, doprexin);
Lipase/Amylase-Inhibitoren (z.B. WO 00/40569);Lipase / amylase inhibitors (e.g., WO 00/40569);
Inhibitoren der Diacylglycerol O-Acyltransferasen (DGATs) wie z. B. BAY-74-4113 oder wie z. B. in US2004/0224997, WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492, WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952, WO2006120125, WO2006113919, WO2006134317, WO2007016538, WO2007060140, JP2007131584, WO2007071966, WO2007126957, WO2007137103, WO2007137107, WO2007138304, WO2007138311 beschrieben;Inhibitors of diacylglycerol O-acyltransferases (DGATs) such. B. BAY-74-4113 or such. B. US2004 / 0224997, WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492, WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952, WO2006120125, WO2006113919, WO2006134317, WO2007016538, WO2007060140, JP2007131584, WO2007071966, WO2007126957, WO2007137103, WO2007137107, WO2007138304, WO2007138311 described;
Inhibitoren der Fettsäuresynthase (FAS) wie z.B. C75 oder solchen, wie in WO2004005277 beschrieben;Inhibitors of fatty acid synthase (FAS), e.g. C75 or those as described in WO2004005277;
Inhibitoren der Stearoyl-CoA delta9 Desaturase (SCDl) wie sie z.B. in WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746 beschrieben sind;Inhibitors of stearoyl-CoA delta9 desaturase (SCDI) as described e.g. in WO2007009236, WO2007044085, WO2007046867, WO2007046868, WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457, WO2007136746 are described;
Inhibitoren des „Adipocyte fatty acid-binding protein aP2" wie z.B. BMS-309403; Aktivatoren der Adiponectinsekretion, wie z.B. in WO2006082978 beschrieben; Promotoren der Adiponectinproduktion, wie z.B. in WO2007125946 beschrieben;Inhibitors of adipocyte fatty acid-binding protein aP2, such as BMS-309403; activators of adiponectin secretion as described, for example, in WO2006082978; promoters of adiponectin production as described, for example, in WO2007125946;
Oxyntomodulin;oxyntomodulin;
Oleoyl-EstronOleoyl-estrone
oder Agonisten oder partiellen Agonisten des Schilddrüsenhormonrezeptors (thyroid hormone receptor agonists) wie z. B: KB-2115 oder DITPA oder solche, wie in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864 beschriebenor agonists or partial agonists of the thyroid hormone receptor agonists such as. B: KB-2115 or DITPA or such as in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864
oder Agonisten des Schilddrüsenhormonrezeptors beta (TR-beta) wie z. B. MB-07811 oder MB-07344, verabreicht.or agonists of the thyroid hormone receptor beta (TR-beta) such. MB-07811 or MB-07344.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Site-1 Protease (SlP), wie z.B. PF-429242, verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with an inhibitor of Site-1 protease (SlP), e.g. PF-429242 administered.
Bei einer weiteren Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem RNAi Therapeutikum, welches gegen PCSK9 (Proprotein Convertase Subtilisin/Kexin Typ 9) gerichtet ist, verabreicht.In a further embodiment of the invention, the compound of the formula I is administered in combination with an RNAi therapeutic which is directed against PCSK9 (proprotein convertase subtilisin / kexin type 9).
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Omacor® oder Lovaza™ (Omega-3 -Fettsäureester; hochkonzentrierte Ethylester der Eicosapentaensäure und der Docosahexaensäure) verabreicht.In one embodiment, the compound of formula I is administered in combination with Omacor® or Lovaza ™ (omega-3 fatty acid esters, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Lycopin verabreicht.In one embodiment, the compound of the formula I is administered in combination with lycopene.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Antioxidans, wie z.B. OPC-14117, Succinobucol, Probucol, Tocopherol, Ascorbinsäure, ß-Caroten oder Selen verabreicht.In one embodiment of the invention, the compound of formula I is used in combination with an antioxidant, e.g. OPC-14117, succinobucol, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
Bei einer Ausfuhrungsform der Erfindung wird die Verbindung der Formel I in Kombination mit einem Vitamin, wie z. B. Vitamin B6 oder Vitamin B 12 verabreicht.In one embodiment of the invention, the compound of the formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B 12 administered.
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit mehr als einer der vorstehend genannten Verbindungen, z.B. in Kombination mit einem Sulfonylharnstoff und Metformin, einem Sulfonylharnstoff und Acarbose, Repaglinid und Metformin, Insulin und einem Sulfonylharnstoff, Insulin und Metformin, Insulin und Troglitazon, Insulin und Lovastatin, etc. verabreicht.In one embodiment, the compound of the formula I is used in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and Metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. administered.
Bei einer anderen Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Inhibitor der Carboanhydrase Typ 2 (Carbonic anhydrase type 2), wie z.B. solchen, wie in WO2007065948 beschrieben, verabreicht.In another embodiment, the compound of formula I is used in combination with an inhibitor of carbonic anhydrase type 2, such as carbonic anhydrase type 2, e.g. such as described in WO2007065948 administered.
Bei einer anderen Ausführungsform wird die Verbindung der Formel I in Kombination mit Topiramat verabreicht.In another embodiment, the compound of the formula I is administered in combination with topiramate.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit einer festen Kombination von Topiramat mit Phentermin (Qnexa™) verabreicht.In another embodiment, the compound of formula I is administered in combination with a solid combination of topiramate with phentermine (Qnexa ™).
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit einer Antisense- Verbindung, z.B. ISIS-377131, verabreicht, welche die Produktion des Glukokortikoidrezeptors inhibiert.In another embodiment, the compound of formula I is used in combination with an antisense compound, e.g. ISIS-377131, which inhibits the production of the glucocorticoid receptor.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Agonisten des RUP3 Rezeptors, wie z. B. in WO2007035355 beschrieben, verabreicht.In one embodiment, the compound of formula I in combination with an agonist of the RUP3 receptor, such. As described in WO2007035355 administered.
Bei einer anderen Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Aktivator des Gens, welches für die Ataxia Telangiectasia Mutated (ATM) Proteinkinase kodiert, wie z. B. Chloroquin, verabreicht.In another embodiment, the compound of the formula I in combination with an activator of the gene coding for the Ataxia Telangiectasia Mutated (ATM) protein kinase, such as. As chloroquine administered.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Tau-Protein-Kinase-1 -Inhibitor (TPKl Inhibitor), wie z. B. in WO2007119463 beschrieben, verabreicht.In one embodiment, the compound of the formula I in combination with a tau protein kinase 1 inhibitor (TPKl inhibitor), such as. As described in WO2007119463 administered.
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit einem „c-Jun N-terminal kinase" Inhibitor (JNK-Inhibitor), wie z. B. in WO2007125405 beschrieben, verabreicht. Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit einem Endothelin- A-Rezeptor Antagonisten, wie z. B. Avosentan (SPP-301), verabreicht.In one embodiment, the compound of the formula I is administered in combination with a "c-Jun N-terminal kinase" inhibitor (JNK inhibitor), as described, for example, in WO2007125405. In one embodiment, the compound of the formula I in combination with an endothelin A receptor antagonists, such as. B. avosentan (SPP-301).
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit Modulatoren des Glukokortikoidrezeptors (GR), wie z.B. KB-3305 oder solchen Verbindungen wie sie z. B. in WO2005090336, WO2006071609, WO2006135826, WO2007105766 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is used in combination with modulators of the glucocorticoid receptor (GR), e.g. KB-3305 or such compounds as e.g. As described in WO2005090336, WO2006071609, WO2006135826, WO2007105766.
Bei einer Ausfuhrungsform ist der weitere Wirkstoff Varenicline Tartrate, ein partieller Agonist des alpha 4-beta 2 nikotinischen Acetylcholinrezeptors.In one embodiment, the other active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
Bei einer Ausfuhrungsform ist der weitere Wirkstoff Trodusquemine.In one embodiment, the other active ingredient is trodusquemine.
Bei einer Ausführungsform ist der weitere Wirkstoff ein Modulator des Enzyms SIRTl (einer NAD+-abhängigen Proteindeacetylase); dieser Wirkstoff kann z.B. Resveratrol in geeigneten Formulierungen sein, oder solche Verbindungen wie sie in WO2007019416 (z.B. SRT- 1720) genannt sind.In one embodiment, the further active ingredient is a modulator of the enzyme SIRTI (an NAD + -dependent protein deacetylase); this active substance may be, for example, resveratrol in suitable formulations, or such compounds as are mentioned in WO2007019416 (eg SRT-1720).
Bei einer Ausführungsform der Erfindung ist der weitere Wirkstoff DM-71 (N-Acetyl-L- Cystein mit Bethanecho 1).In one embodiment of the invention, the further active ingredient is DM-71 (N-acetyl-L-cysteine with bethanecho 1).
Bei einer Ausführungsform wird die Verbindung der Formel I in Kombination mit anti- hypercholesterolemisch wirkenden Verbindungen, wie sie z.B. in WO2007107587, WO2007111994 beschrieben sind, verabreicht.In one embodiment, the compound of formula I is used in combination with anti-hypercholesterolemic compounds, such as those described e.g. in WO2007107587, WO2007111994.
Bei einer anderen Ausführungsform wird die Verbindung der Formel I in Kombination mit einem cyclischen Peptidagonisten des VPAC2 Rezeptors, wie sie z.B. in WO2007101146, WO2007133828 beschrieben sind, verabreicht.In another embodiment, the compound of formula I is used in combination with a cyclic peptide agonist of the VPAC2 receptor, as described e.g. in WO2007101146, WO2007133828.
Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit einem Agonisten des Endothelinrezeptors, wie sie z.B. in WO2007112069 beschrieben sind, verabreicht. Bei einer weiteren Ausführungsform wird die Verbindung der Formel I in Kombination mit AKP-020 (Bis(ethylmaltolato)oxovanadium-IV) verabreicht.In a further embodiment, the compound of the formula I is administered in combination with an agonist of the endothelin receptor, as described, for example, in WO2007112069. In a further embodiment, the compound of the formula I is administered in combination with AKP-020 (bis (ethylmaltolato) oxovanadium-IV).
Bei einer anderen Ausführungsform wird die Verbindung der Formel I in Kombination mit gewebe-selektiven Androgenrezeptor Modulatoren („tissue-selective androgen receptor modulators"; SARM), wie sie z.B. in WO2007099200 beschrieben sind, verabreicht.In another embodiment, the compound of formula I is administered in combination with tissue-selective androgen receptor modulators (SARMs) as described, for example, in WO2007099200.
Bei einer Ausfuhrungsform der Erfindung ist der weitere Wirkstoff Leptin; siehe z.B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez- Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.In one embodiment of the invention, 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.
Bei einer anderen Ausführungsform der Erfindung ist der weitere Wirkstoff Metreleptin (rekombinantes Methionyl-Leptin) kombiniert mit Pramlintide.In another embodiment of the invention, the further active ingredient is metreleptin (recombinant methionyl-leptin) combined with pramlintide.
Bei einer weiteren Ausfuhrungsform der Erfindung ist der weitere Wirkstoff das Tetrapeptid ISF-402.In a further embodiment of the invention, the further active ingredient is the tetrapeptide ISF-402.
Bei einer Ausfuhrungsform ist der weitere Wirkstoff Dexamphetamin oder Amphetamin.In one embodiment, the further active ingredient is dexamphetamine or amphetamine.
Bei einer Ausfuhrungsform ist der weitere Wirkstoff Fenfluramin oder Dexfenfluramin.In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
Bei noch einer Ausfuhrungsform ist der weitere Wirkstoff Sibutramin.In yet another embodiment, the further active ingredient is sibutramine.
Bei einer Ausfuhrungsform ist der weitere Wirkstoff Mazindol oder Phentermin.In one embodiment, the other active ingredient is mazindol or phentermine.
Bei einer weiteren Ausfuhrungsform ist der weitere Wirkstoff Geniposidinsäure (geniposidic acid; WO2007100104).In another embodiment, the further active ingredient is geniposidic acid (geniposidic acid, WO2007100104).
Bei einer Ausfuhrungsform wird die Verbindung der Formel I in Kombination mit Ballaststoffen, vorzugsweise unlöslichen Ballaststoffen (siehe z.B. Carob/ Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax ist ein Carob enthaltendes Produkt der Fa. Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) verabreicht. Die Kombination mit Caromax® kann in einer Zubereitung erfolgen, oder durch getrennte Gabe von Verbindungen der Formel I und Caromax®. Caromax® kann dabei auch in Form von Lebensmitteln, wie z.B. in Backwaren oder Müsliriegeln, verabreicht werden.In one embodiment, the compound of formula I in combination with dietary fiber, insoluble fiber (see for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for 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 Höchst, 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.RTM ® can in this case in the form of food, such as administered in bakery products or muesli bars.
Es versteht sich, dass jede geeignete Kombination der erfindungs gemäßen Verbindungen mit einer oder mehreren der vorstehend genannten Verbindungen und wahlweise einer oder mehreren weiteren pharmakologisch wirksamen Substanzen als unter den Schutzbereich der vorliegenden Erfindung fallend angesehen wird. It is understood that any suitable combination of the compounds according to the invention with one or more of the abovementioned compounds and optionally one or more further pharmacologically active substances is considered to fall within the scope of the present invention.
Figure imgf000049_0001
Figure imgf000049_0002
JTT-501
Figure imgf000049_0001
Figure imgf000049_0002
JTT-501
Figure imgf000049_0003
Figure imgf000049_0003
LY-518674 KRP-101
Figure imgf000049_0004
LY-518674 KRP-101
Figure imgf000049_0004
LY-510929 GW-501516
Figure imgf000049_0005
Figure imgf000050_0001
LY-510929 GW-501516
Figure imgf000049_0005
Figure imgf000050_0001
FR-225654
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
FR-225654
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
KB-2115 KCP-265
Figure imgf000053_0002
KB-2115 KCP-265
Figure imgf000053_0002
JNJ-25918646 JNJ-25918646
Figure imgf000054_0001
Figure imgf000054_0001
PSN-632408 SYR-322
Figure imgf000054_0002
PSN-632408 SYR-322
Figure imgf000054_0002
DP-893
Figure imgf000054_0003
DP-893
Figure imgf000054_0003
Varenicline TartratVarenicline tartrate
Figure imgf000054_0004
Figure imgf000054_0004
Trodusquemine
Figure imgf000055_0001
trodusquemine
Figure imgf000055_0001
Solabegron
Figure imgf000055_0002
Solabegron
Figure imgf000055_0002
Lorcaserin HydrochloridLorcaserin hydrochloride
Figure imgf000055_0003
Figure imgf000055_0004
Figure imgf000055_0003
Figure imgf000055_0004
«»,— HiS Iu — GIy — Thr — P he — Thr
Figure imgf000056_0001
«», - HiS Iu - GIy - Thr - P he - Thr
Figure imgf000056_0001
Leu — Tyr — Se r — S er — VaI — Asp — Se rLeu - Tyr - Se r - S er - VaI - Asp - Se r
GIu — GIy — GIn — AIa — AIa . ys — GIu Trp — AIa -He ■ ■PheGlu - Gly - GIn - Ala - Ala. ys - Glu Trp - Ala - He ■ ■ Phe
Figure imgf000056_0002
Figure imgf000056_0002
BIM-51077 TAK-536BIM-51077 TAK-536
Figure imgf000056_0003
Figure imgf000056_0003
E-6837 TesofensineE-6837 tesofensine
Figure imgf000056_0004
Figure imgf000056_0004
BVT-74316 ABT-341
Figure imgf000057_0001
Figure imgf000057_0002
BVT-74316 ABT-341
Figure imgf000057_0001
Figure imgf000057_0002
Sergliflozin SLV-319
Figure imgf000057_0003
Sergliflozin SLV-319
Figure imgf000057_0003
AVE 1625 TAK-475 (Lapaquistat Acetat)
Figure imgf000057_0004
AVE 1625 TAK-475 (Lapaquistat acetate)
Figure imgf000057_0004
AS-1552133 MB-07344
Figure imgf000058_0001
x H2SO4
Figure imgf000058_0002
AS-1552133 MB-07344
Figure imgf000058_0001
x H 2 SO 4
Figure imgf000058_0002
CKD-501 (Lobeglitazon Sulfat) MB-07811
Figure imgf000058_0003
CKD-501 (Lobeglitazone Sulfate) MB-07811
Figure imgf000058_0003
JMV-2959 JMV-3002
Figure imgf000058_0004
JMV-2959 JMV-3002
Figure imgf000058_0004
JMV-2810 JMV-2951 JMV-2810 JMV-2951
Figure imgf000059_0001
Figure imgf000059_0001
BMS-309403 PSN-119-1
Figure imgf000059_0002
BMS-309403 PSN-119-1
Figure imgf000059_0002
S-40755 LY-2463665
Figure imgf000059_0003
S-40755 LY-2463665
Figure imgf000059_0003
Dapagliflozin, BMS-512148 BI-1356
Figure imgf000060_0001
Dapagliflozin, BMS-512148 BI-1356
Figure imgf000060_0001
PF-429242 SLV-348
Figure imgf000060_0002
PF-429242 SLV-348
Figure imgf000060_0002
Balaglitazon 'NPY-5-BY"
Figure imgf000060_0003
Balaglitazone 'NPY-5-BY'
Figure imgf000060_0003
BMS-711939 BMS-687453
Figure imgf000060_0004
BMS-711939 BMS-687453
Figure imgf000060_0004
ST-3473 DOV-21947
Figure imgf000061_0001
ST-3473 DOV-21947
Figure imgf000061_0001
DM-71 AEGR-733
Figure imgf000061_0002
Figure imgf000061_0003
DM-71 AEGR-733
Figure imgf000061_0002
Figure imgf000061_0003
YIL-870 PRX-07034
Figure imgf000061_0004
YIL-870 PRX-07034
Figure imgf000061_0004
PF-00389027 KB-3305
Figure imgf000062_0001
PF-00389027 KB-3305
Figure imgf000062_0001
ISF-402 SRT- 1720
Figure imgf000062_0002
darapladib A-002
Figure imgf000062_0003
ISF-402 SRT-1720
Figure imgf000062_0002
darapladib A-002
Figure imgf000062_0003
DITPA DITPA
Die nachfolgend aufgeführten Beispiele dienen zur Erläuterung der Erfindung, ohne diese jedoch einzuschränken.
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
The following examples serve to illustrate the invention, but without limiting it.
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Die Verbindungen der Formel I eignen sich zur Behandlung der Dislipidämiezur Prädiabetes Behandlung, zur Prophylaxe von Diabetes Typ 2 und zur Behandlung des Metabolischen Syndroms (siehe Datamonitor 11/2002, Kapitel 2, Seiten 19- 32). Sie einen sich insbesonders zur Behandlung der Diabetischen Dislipidämie. Die diabetische Dyslipidämie manifestiert sich in einer Erhöhung der Plasmatriglyzeride, einer Verminderung des HDL-Cholesterins sowie oft in erhöhten LDL-Spiegeln. Durch das gehäufte Auftreten kleiner, dichter LDL-Cholesterinpartikel mit hoher atherogener Potenz ist die Diabetische Dyslipidämie ein starker kardiovaskulärer Risiko faktor. Die Verbindungen eignen sich weiterhin zur Reduktion freier Fettsäuren im Blut. The compounds of formula I are useful in the treatment of dislipidemia for prediabetes treatment, in the prevention of type 2 diabetes and in the treatment of metabolic syndrome (see Datamonitor 11/2002, Chapter 2, pages 19-32). They are especially for the treatment of diabetic dislipidemia. Diabetic dyslipidemia manifests as an increase in plasma triglycerides, a decrease in HDL cholesterol, and often in elevated LDL levels. Due to the increased occurrence of small, dense LDL-cholesterol particles with high atherogenic potency, diabetic dyslipidaemia is a strong cardiovascular risk factor. The compounds are also suitable for the reduction of free fatty acids in the blood.
Die Verbindungen der Formel I können beispielsweise in folgenden Zubereitungen formuliert werden:The compounds of the formula I can be formulated, for example, in the following formulations:
Beispiel A Gelatineweichkapseln, enthaltend 100 mg Wirkstoff pro Kapsel: pro KapselExample A Gelatin soft capsules containing 100 mg of active ingredient per capsule: per capsule
Wirkstoff 100 mg aus Kokosfett fraktioniertesActive ingredient 100 mg fractionated from coconut oil
Triclycerid-Gemisch 400 mg Kapselinhalt 500 mgTriclyceride mixture 400 mg capsule content 500 mg
Beispiel BExample B
Emulsion, enthaltend 60 mg Wirkstoff pro 5 ml: pro 100 ml EmulsionEmulsion containing 60 mg of active ingredient per 5 ml: per 100 ml of emulsion
Wirkstoff 1,2 gActive ingredient 1.2 g
Neutralöl q.s.Neutral oil q.s.
Natriumcarboxymethylcellulose 0,6 gSodium carboxymethyl cellulose 0.6 g
Polyoxyethylen-stearat q.s. Glycerin rein 0,2 bis 2,0 gPolyoxyethylene stearate q.s. Glycerin pure 0.2 to 2.0 g
Geschmacksstoff q.s.Flavor q.s.
Wasser (entsalzt oder destilliert) ad 100 mlWater (desalted or distilled) ad 100 ml
Beispiel CExample C
Rektale Arzneiform, enthaltend 40 mg Wirkstoff pro Suppositorium: pro SuppositoriumRectal dosage form containing 40 mg of active ingredient per suppository: per suppository
Wirkstoff 40 mgActive substance 40 mg
Suppositoriengrundmasse ad 2 g Beispiel DSuppository base ad 2 g Example D
Tabletten, enthaltend 40 mg Wirkstoff pro Tablette: pro TabletteTablets containing 40 mg of active ingredient per tablet: per tablet
Lactose 600 mgLactose 600 mg
Maisstärke 300 mg lösliche Stärke 20 mgCorn starch 300 mg soluble starch 20 mg
Magnesiumstearat 40 mgMagnesium stearate 40 mg
1000 mg1000 mg
Beispiel EExample E
Dragees, enthaltend 50 mg Wirkstoff pro Dragees: pro Dragee Wirkstoff 50 mg Maisstärke 100 mgDragees, containing 50 mg of active ingredient per coated tablet: per Dragee active ingredient 50 mg corn starch 100 mg
Lactose 60 mg sec. Calciumphosphat 30 mg lösliche Stärke 5 mgLactose 60 mg sec. Calcium phosphate 30 mg Soluble starch 5 mg
Magnesiumstearat 10 mg kolloidale Kieselsäure 5 mgMagnesium stearate 10 mg colloidal silica 5 mg
260 mg260 mg
Beispiel F Für die Herstellung des Inhalts von Hartgelatinekapseln eignen sich die folgenden Rezepturen: a) Wirkstoff 100 mgExample F The following formulations are suitable for the preparation of the contents of hard gelatine capsules: a) Active ingredient 100 mg
Maisstärke 300 mgCornstarch 300 mg
400 mg b) Wirkstoff 140 mg400 mg b) active ingredient 140 mg
Milchzucker 180 mgLactose 180 mg
Maisstärke 180 mgCorn starch 180 mg
500 mg Beispiel G500 mg Example G
Tropfen können nach folgender Rezeptur hergestellt werden (100 mg Wirkstoff in 1 ml =Drops can be prepared according to the following recipe (100 mg active ingredient in 1 ml =
20 Tropfen): Wirkstoff 10 g20 drops): active ingredient 10 g
Benzoesäuremethylester 0,07 gBenzoic acid methyl ester 0.07 g
Benzoesäureethylester 0,03 gBenzoic acid ethyl ester 0.03 g
Ethanol 96 %ig 5 ml entmineralisiertes Wasser ad 100 mlEthanol 96% 5 ml demineralised water ad 100 ml
Die Wirksamkeit der Verbindungen der Formel I wurde wie folgt getestet:The effectiveness of the compounds of formula I was tested as follows:
Biologisches Prüfmodell:Biological test model:
Die Prüfung der Wirkung erfolgteThe examination of the effect took place
Am Ganztier (Maus, Ratte, Hamster oder Hund) wird nach einer Fastenperiode (z.B. von ca. 16 Stunden, die Substanz appliziert (z.B. p.o., iv., i.p., s.c. ) und mit oder ohne zusätzliche Stimulation der endogenen Lipolyse (z.B. durch eine Bolusinjektion von 2 mg/kg i.p. Isoprenaline) die Wirkung der Testsubstanz auf die Lipolyse anhand der freigesetzten freien Fettsäuren (FFA), Glycerol und Triglyceride bestimmt, indem z.B. 15 min, 30, 60, 120 usw. Minuten nach p.o. Applikation eine Blutprobe (z.B. durch retroorbitale Blutentnahme) gewonnen wird und nach Standard klinisch-chemischen Methoden (z.B. L.Thomas: Labor und Diagnose, 2. Auflage, Medizinische Verlagsgesellschaft, Marburg/L. 1984; ISBN 3-921320-10-9)) analysiert wird. Die Hemmung der Lipolyse durch die Inhibitoren wird im Vergleich zur Lipolyserate an entsprechend behandelten Kontrolltieren ausgewertet.On the whole animal (mouse, rat, hamster or dog), after a fasting period (eg of about 16 hours, the substance is administered (zBpo, iv., Ip, sc) and with or without additional stimulation of endogenous lipolysis (eg by bolus injection of 2 mg / kg ip isoprenaline) the effect of the test substance on the lipolysis on the basis of the released free fatty acids (FFA), glycerol and triglycerides determined, for example, 15 min, 30, 60, 120, etc. minutes after po application a blood sample (eg by retroorbital blood sampling) is obtained and analyzed according to standard clinical-chemical methods (eg L. Thomas: Laboratory and Diagnostics, 2nd edition, Medical Publishing Company, Marburg / L., 1984; ISBN 3-921320-10-9)). The inhibition of lipolysis by the inhibitors is evaluated in comparison to the lipolysis rate of appropriately treated control animals.
Beispiel 1 wurde in der Dosis von 10 mg/kg po verabreicht, wodurch die Lipolyse deutlich abgesenkt wurde, wie an der Reduktion von freien Fettsäuren (FFA), Glycerol und Triglyceriden gezeigt werden konnte.
Figure imgf000070_0001
Example 1 was administered at the dose of 10 mg / kg po, which markedly lowered lipolysis, as shown by the reduction of free fatty acids (FFA), glycerol and triglycerides.
Figure imgf000070_0001
"n" steht für die Anzahl der Tiere. Es wurden Wistar Ratten getestet. Die Wirksamkeit der Verbindungen der Formel I wurde auch in folgenden Assays getestet:"n" stands for the number of animals. Wistar rats were tested. The effectiveness of the compounds of the formula I was also tested in the following assays:
In vitro funktionale Assays mit rekombinanten ZellenIn vitro functional assays with recombinant cells
Funktionsüberprüfende Assays wurden mittels der FLIPR-Technik („Fluorescence Imaging Plate Reader", Molecular Devices Corp.) durchgeführt. Hierzu wurden agonist- induzierte Änderungen der intrazellulären Konzentration von Ca + in rekombinanten HEK293 Zellen bestimmt, die sowohl den GPCR FJM74A (Niacin-Receptor), als auch das hybride G-protein GD6qi4myr (siehe z.B. Patentanmeldung DE10033353) exprimieren.Functional assays were performed by the FLIPR technique ("Fluorescence Imaging Plate Reader", Molecular Devices Corp.) for which agonist-induced changes in the intracellular concentration of Ca + in recombinant HEK293 cells were determined which include both the GPCR FJM74A (niacin receptor ), as well as the hybrid G-protein GD6qi4myr (see, for example, patent application DE10033353) express.
Für die Untersuchungen wurden Zellen in 96-well-Mikrotiterplatten (60000 Zellen/well) ausgesät und Übernacht wachsengelassen. Das Medium wurde entfernt und die Zellen in Puffer inkubiert, der den Fluoreszenzfarbstoff Fluo-4 enthielt. Nach dieser Beladung mit Farbstoff wurden die Zellen gewaschen, Testsubstanz zugegeben und Änderungen in der intrazellulären Ca2+-Konzentration im FLEPR-Gerät gemessen. Ergebnisse wurden als prozentuale Änderung relativ zur Kontrolle dargestellt (0%: keine Testsubstanz addiert; 100%: 1 μM Referenzagonist Niacin addiert), zur Berechnung von Dosis/Wirkungskurven verwendet und EC50- Werte bestimmt.For the investigations, cells were seeded in 96-well microtiter plates (60000 cells / well) and grown overnight. The medium was removed and the cells incubated in buffer containing the fluorescent dye fluo-4. After this loading with dye, the cells were washed, test substance added, and changes in intracellular Ca 2+ concentration measured in the FLEPR instrument. Results were expressed as percentage change relative to control (0%: no test substance added, 100%: 1 μM reference agonist niacin added), used to calculate dose / response curves and EC50 values determined.
Tabelle 2: Biologische AktivitätTable 2: Biological activity
Beispiel Nr. EC50 (HM74a) μMExample No. EC50 (HM74a) μM
1 0.1581 0.158
2 0.8892 0.889
3 17.0043 17.004
4 4.3824,4382
5 5.1925 5,192
6 8.7466 8,746
9 1.5919 1,591
10 0.33910 0.339
12 0.98012 0.980
14 17.00414 17.004
15 11.74815 11,748
16 0.129
Figure imgf000072_0001
16 0.129
Figure imgf000072_0001
Agonisten des G-Protein gekoppelten Rezeptors HM74a (GPRl 09a) führen zu einer Abnahme von cyclischem Adenosin Monophosphat (cAMP) und zur Inhibition der Lipolyse in Adipocyten (S. Tunaru et al., Nat. Med. 2003 , 9, 352-355.). Die Inhibition der Lipolyse durch Agonisten des Rezeptors HM74a resultiert in einer Absenkung der freien Fettsäuren und von Triglyceriden im Blut. (S. Offermanns, Trends in Pharm Sciences 2006, 27, 384-390.). Substanzen, die als Agonisten des Rezeptors HM74a identifiziert werden, sind damit zur Behandlung von Dislipidaemie geeignet. Agonists of the G protein-coupled receptor HM74a (GPR10a) lead to a decrease of cyclic adenosine monophosphate (cAMP) and to the inhibition of lipolysis in adipocytes (S. Tunaru et al., Nat. Med. 2003, 9, 352-355. ). The inhibition of lipolysis by agonists of the receptor HM74a results in a lowering of free fatty acids and triglycerides in the blood. (Offermanns, Trends in Pharm Sciences 2006, 27, 384-390.). Substances that are identified as agonists of the receptor HM74a are thus suitable for the treatment of dislipidaemia.
Synthesesynthesis
Synthese von l-Butyl-2-oxo-l ,2-dihydro-pyridin-4-carbonsäuremethylester:Synthesis of 1-butyl-2-oxo-l, 2-dihydro-pyridine-4-carboxylic acid methyl ester:
Figure imgf000073_0001
Figure imgf000073_0001
1.00 g 2-Oxo-l,2-dihydro-pyridin-4-carbonsäuremethylester (Firma CHEMSTEP, Carbon Blanc, Frankreich) wurden in 30 mL DMF gelöst, mit 5.32 g Cäsiumcarbonat und 1.75 mL 1 -Brombutan versetzt und 18h bei Raumtemperatur gerührt. Die Reaktionslösung wurde mit 60 mL Dichlormethan versetzt und mit 100 mL einer gesättigten Lösung von Ammoniumchlorid in Wasser extrahiert. Die organische Phase wurde abgetrennt und am Rotationsverdampfer eingeengt. Die organische Phase wurde über Magnesiumsulfat getrocknet und am Rotationsverdampfer eingeengt. Anschließend wurde das Rohprodukt an einer HPLC (Agilent-Prep.-C18, Laufmittel MeCN / H2O / TFA) gereinigt. Man erhält 408 mg l-Butyl-2-oxo-l,2-dihydro-pyridin-4-carbonsäuremethylester als farbloses Wachs. LCMS: m = 210.15 (M+H)+.1.00 g of methyl 2-oxo-1,2-dihydro-pyridine-4-carboxylate (from CHEMSTEP, Carbon Blanc, France) were dissolved in 30 ml of DMF, combined with 5.32 g of cesium carbonate and 1.75 ml of 1-bromobutane and stirred at room temperature for 18 hours. The reaction solution was combined with 60 ml of dichloromethane and extracted with 100 ml of a saturated solution of ammonium chloride in water. The organic phase was separated and concentrated on a rotary evaporator. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. Subsequently, the crude product was purified on an HPLC (Agilent-Prep. C18, eluent MeCN / H 2 O / TFA). This gives 408 mg of 1-butyl-2-oxo-l, 2-dihydro-pyridine-4-carboxylic acid methyl ester as a colorless wax. LCMS: m = 210.15 (M + H) + .
Synthese von l-Butyl-2-oxo-l,2-dihydro-pyridin-4-carbonsäure (Beispiel 1):Synthesis of 1-butyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (Example 1):
Figure imgf000073_0002
Figure imgf000073_0002
252 mg 2-Oxo-l,2-dihydro-pyridin-4-carbonsäuremethylester wurden in 5.0 mL THF gelöst und mit 2.5 mL Methanol und 2.5 mL einer 1-molaren, wässrigen Lithiumhydroxid- Lösung versetzt. Das Reaktionsgemisch wurde 16h bei Raumtemperatur gerührt. Das Reaktionsgemisch wurde mit 1 -molarer, methanolischer HCL-Lösung neutralisiert und anschließend am Rotationsverdampfer von Lösungsmitteln befreit. Anschließend wurde das Rohprodukt an einer HPLC (Agilent-Prep.-C18, Laufmittel MeCN / H2O / TFA) gereinigt. Man erhält 148 mg l-Butyl-2-oxo-l,2-dihydro-pyridin-4-carbonsäure als farbloses Wachs. LCMS: m = 196.13 (M+H)+.252 mg of 2-oxo-l, 2-dihydro-pyridine-4-carboxylic acid methyl ester were dissolved in 5.0 mL THF and treated with 2.5 mL of methanol and 2.5 mL of a 1 molar aqueous lithium hydroxide solution. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was neutralized with 1 molar methanolic HCl solution and then freed from solvents on a rotary evaporator. Subsequently, the crude product was subjected to HPLC (Agilent Prep. C18, eluent MeCN / H 2 O / TFA). cleaned. This gives 148 mg of 1-butyl-2-oxo-l, 2-dihydro-pyridine-4-carboxylic acid as a colorless wax. LCMS: m = 196.13 (M + H) + .
Die Verbindung der Beispiele 2-20 wurden analog dieser allgemeinen Arbeitsvorschrift ausgehend von 2-Oxo- 1 ,2-dihydro-pyridin-4-carbonsäuremethylester synthetisiert. The compounds of Examples 2-20 were synthesized analogously to this general procedure starting from 2-oxo-1,2-dihydro-pyridine-4-carboxylic acid methyl ester.

Claims

Patentansprüche: claims:
1. Verwendung der Verbindungen der Formel I,1. Use of the compounds of the formula I,
R (C-Cio)-Alkyl, (C2-C 10)-Alkenyl, (C2-Ci0)-Alkinyl, wobei in den (Ci-Cio)-Alkyl-, (C2-C10)-Alkenyl- oder (C2-C10)- Alkinylresten, ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkyl-, Alkenyl- und Alkinylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, CF3, (C3-Ci2)- Carbocyclus, Aryl, wobei Aryl ein oder mehrfach substituiert sein kann mit F, Cl, Br, I, CF3, (C ,-C6)- Alkyl; R (C-Cio) alkyl, (C 2 -C 10) alkenyl, (C 2 -C 0) -alkynyl, where in the (Ci-Cio) alkyl, (C 2 -C 10) alkenyl or (C 2 -C 10 ) alkynyl radicals, one or more individual CH 2 groups may be replaced by O, and where the alkyl, alkenyl and alkynyl radicals may be monosubstituted or polysubstituted by F, Cl, Br, I, CF 3 , (C 3 -C 2 ) -carbocycle, aryl, where aryl may be monosubstituted or polysubstituted by F, Cl, Br, I, CF 3 , (C 1 -C 6 ) -alkyl;
sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Dislipidämieand their physiologically acceptable salts for the manufacture of a medicament for the treatment of dislipidemia
2. Verwendung der Verbindungen der Formel I, gemäß Anspruch 1, dadurch gekennzeichnet, dass darin bedeutet2. Use of the compounds of formula I, according to claim 1, characterized in that means
R (C-C^-AlkyUCrCo^Alkenyl, wobei in den (Ci -Ci0)- Alkyl- oder (C2-Cio)-Alkenylresten ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-C i2)-Carbocyclus, Aryl, wobei Aryl ein oder mehrfach substituiert sein kann mit F, Cl, Br, I, CF3, (C-C6)-Alkyl;R (CC ^ -AlkyUCrCo ^ alkenyl, wherein in the (Ci -Ci 0 ) - alkyl or (C 2 -Cio) alkenyl radicals one or more individual CH 2 groups may be replaced by O and wherein the alkyl radicals can be monosubstituted or polysubstituted by F, Cl, Br, I, (C 3 -C i 2) carbocycle, aryl, where aryl may be mono or polysubstituted with F, Cl, Br, I, CF 3 (CC 6 ) alkyl;
sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Dislipidämie.and their physiologically acceptable salts for the manufacture of a medicament for the treatment of dislipidemia.
3. Verwendung der Verbindungen der Formel I, gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass darin bedeutet3. Use of the compounds of formula I, according to claim 1 or 2, characterized in that means
R (C1-Co)-AIkVl, (C2-Ci0)-Alkenyl, wobei in den (Ci-Cio)-Alkyl- oder (C2-Cio)-Alkenylresten ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-C i2)-Carbocyclus, Aryl;R (C 1 -Co) -AlkVl, (C 2 -Ci 0 ) alkenyl, wherein in the (Ci-Cio) alkyl or (C 2 -Cio) alkenyl radicals one or more individual CH 2 groups replaced by O. can be and where the alkyl radicals may be substituted one or more times by F, Cl, Br, I, (C 3 -C i 2) carbocycle, aryl;
sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Dislipidämie.and their physiologically acceptable salts for the manufacture of a medicament for the treatment of dislipidemia.
4. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass darin bedeutet4. Use of the compounds of the formula I, according to one or more of claims 1 to 3, characterized in that means therein
R (C1-Co)-AIkVl, wobei in dem (C-Co)-Alkylrest ein oder mehrere einzelne CH2 R (C 1 -Co) -AlkVl, wherein in the (C-Co) -alkyl radical one or more individual CH 2
Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-C2)-Carbocyclus, Aryl; sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Dislipidämie.Groups may be replaced by O and wherein the alkyl radicals may be mono- or polysubstituted with F, Cl, Br, I, (C 3 -C 2 ) -Cyclocycle, aryl; and their physiologically acceptable salts for the manufacture of a medicament for the treatment of dislipidemia.
5. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass darin bedeutet5. Use of the compounds of the formula I, according to one or more of claims 1 to 4, characterized in that means
R (Ci-Co)-AIkVl, wobei in dem (CrCio)-Alkylrest ein oder mehrere einzelne CH2 Gruppen durch O ersetzt sein können und wobei die Alkylreste ein oder mehrfach substituiert sein können mit F, Cl, Br, I, (C3-C ^-Carbocyclus, Phenyl;R (Ci-Co) -AlkVl, wherein in the (CrCio) alkyl radical one or more individual CH 2 groups may be replaced by O and wherein the alkyl radicals may be mono- or polysubstituted with F, Cl, Br, I, (C C 3 -C 4 carbocycle, phenyl;
sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Dislipidämie.and their physiologically acceptable salts for the manufacture of a medicament for the treatment of dislipidemia.
6. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der6. Use of the compounds of the formula I, according to one or more of
Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Lipidsenkung im Plasma.Claims 1 to 5, as well as their physiologically acceptable salts for the preparation of a medicament for lipid lowering in the plasma.
7. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines7. Use of the compounds of the formula I, according to one or more of claims 1 to 5, as well as those physiologically acceptable salts for the preparation of a
Medikaments zur Senkung der freien Fettsäuren (FFA) im Plasma.Drug for the reduction of free fatty acids (FFA) in plasma.
8. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Senkung von Glycerol im Plasma.8. Use of the compounds of formula I, according to one or more of claims 1 to 5, as well as those physiologically acceptable salts for the manufacture of a medicament for lowering plasma glycerol.
9. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Senkung der Triglyceride im Plasma. 9. Use of the compounds of formula I, according to one or more of claims 1 to 5, as well as those physiologically acceptable salts for the manufacture of a medicament for lowering plasma triglycerides.
10. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Prophylaxe von Diabetes Typ 2.10. Use of the compounds of formula I, according to one or more of claims 1 to 5, and their physiologically acceptable salts for the manufacture of a medicament for the prophylaxis of diabetes type 2.
11. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Diabetischen Dislipidämie.11. Use of the compounds of the formula I, according to one or more of claims 1 to 5, as well as their physiologically acceptable salts for the manufacture of a medicament for the treatment of diabetic dislipidemia.
12. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung der Obesitas.12. Use of the compounds of formula I, according to one or more of claims 1 to 5, as well as their physiologically acceptable salts for the manufacture of a medicament for the treatment of obesity.
13. Verwendung der Verbindungen der Formel I, gemäß einem oder mehreren der Ansprüche 1 bis 5, sowie derer physiologisch verträglichen Salze zur Herstellung eines Medikaments zur Behandlung des Metabolischen Syndroms. 13. Use of the compounds of the formula I according to one or more of claims 1 to 5, as well as their physiologically acceptable salts for the preparation of a medicament for the treatment of the metabolic syndrome.
PCT/EP2009/004477 2008-07-04 2009-06-20 Use of substituted pyridinone carboxylic acid derivates for producing pharmaceuticals for the treatment of dyslipidemia WO2010000401A1 (en)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BEAK P, SIEGEL B: "Mechanism of decarboxylation of 1,3-dimethylorotic acid. A model for orotidine 5'-phosphate decarboxylase", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 98, no. 12, 9 June 1976 (1976-06-09), pages 3601 - 3606, XP002506278 *
FRONK H M, MOSHER H S: "Ethyl N-methyl-2-pyridone-4-carboxylate and derivatives", JOURNAL OF ORGANIC CHEMISTRY, vol. 24, February 1959 (1959-02-01), pages 196 - 198, XP002506279 *
POLLEX R L; JOY T R; HEGELE R A: "Emerging antidyslipidemic drugs", EXPERT OPINION ON EMERGING DRUGS, vol. 13, no. 2, June 2008 (2008-06-01), pages 363 - 381, XP009109184 *
SUGASAWA SHIGEHIKO; KIRISAWA MAKOTO: "Oxidation of 4-(1,1-Ethylenedioxyethyl)-and 4-(Ethylenedioxymethyl)-1-methylpyridinium Salts", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 6, no. 6, 15 December 1958 (1958-12-15), pages 615 - 618, XP009109199 *
YUYAMA S; SUZUKI T: "The excretion of N1-methyl-2-pyridone-5-carboxylic acid and related compounds in human subjects after oral administration of nicotinic acid, trigonelline and N1-methyl-2-pyridone-5-carboxylic acid", ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, vol. 294, 1991, pages 475 - 479, XP009109158 *

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