DE102004033405A1 - New 7-phenylamino-quinolone or 1,8-naphthyridone derivatives, useful e.g. for treating type II diabetes or arteriosclerosis, are inhibitors of glycogen phosphorylase - Google Patents

Abstract

worin die Reste die angegebenen Bedeutungen haben, sowie deren physiologisch verträgliche Salze. Die Verbindungen eignen sich z. B. als Medikamente zur Prävention und Behandlung von Diabetes Typ 2.The invention relates to 7-phenylamino-4-quinolone-3-carboxylic acid derivatives and their physiologically acceptable salts and physiologically functional derivatives.
The invention relates to compounds of the formula I,

wherein the radicals have the meanings indicated, and their physiologically acceptable salts. The compounds are suitable for. As drugs for the prevention and treatment of type 2 diabetes.

Description

The The invention relates to 7-phenylamino-4-quinolone-3-carboxylic acid derivatives as well as their physiologically compatible Salts and physiologically functional derivatives.

It are already structurally similar Compounds described in the prior art (Link, Helmut; Bernauer, Karl; Englert Gerhard, Helvetica Chimica Acta 65 (8), 1982, 2645-2667 and Bennet et al. J. Chem. Soc., 1949, 227-229).

Of the Invention was the object of the compounds available provide a therapeutically useful blood sugar lowering Unfold their effect.

worin bedeuten
R1 OH, O-(C₁-C₆)-Alkyl, NH₂, NH-(C₁-C₆)-Alkyl, N-((C₁-C₆)-Alkyl)₂ oder O-(C₁-C₆)-Alkyl-OCO-(C₁-C₆)-Alkyl;
R2 H, (C₁-C₆)-Alkyl oder Phenyl;
R3 H, (C₁-C₈)-Alkyl, (C₃-C₇)-Cycloalkyl, Pyridyl oder Phenyl, wobei Alkyl durch R9 und wobei Phenyl oder Pyridyl durch R10 substituiert sein können;
R9 NH₂, NH-(C₁-C₆)-Alkyl, N-((C₁-C₆)-Alkyl)₂, COOH, COO-(C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, Heteroalkyl, Heteroaryl, O-Phenyl oder Phenyl, wobei Phenyl und Heteroaryl durch R11 substituiert sein können;
R10 F, Cl, Br, (C₁-C₆-Alkyl), O-(C₁-C₆)-Alkyl, COOH, COO-(C₁-C₆)-Alkyl, NH₂, NH-(C₁-C₆)-Alkyl oder N-((C₁-C₆)-Alkyl)₂;
R11 F, Cl, (C₁-C₆-Alkyl), O-(C₁-C₆)-Alkyl, NH₂, NH-(C₁-C₆)-Alkyl, N-((C₁-C₆)-Alkyl)₂, COOH oder COO-(C₁-C₄)-alkyl;
X C-R4 oder N;
R4 H, F, Cl, Br, OH, NO₂, CN, (C₁-C₆)-Alkyl oder O-(C₁-C₆)-Alkyl, wobei Alkyl mehrfach durch F, Cl oder Br substituiert sein kann;
R5 H, F, Cl, Br, OH, NO₂, CN, (C₁-C₆)-Alkyl oder O-(C₁-C₆)-Alkyl, wobei Alkyl mehrfach durch F, Cl oder Br substituiert sein kann;
R6 H, F, Cl, Br, NO₂, CN oder (C₁-C₆)-Alkyl, wobei Alkyl mehrfach durch F, Cl oder Br substituiert sein kann;
R7 H oder (C₁-C₆)-Alkyl;
R8 Phenyl, wobei Phenyl bis zu fünf mal substituiert sein kann durch F, Cl, Br, CN, NO₂, (C₁-C₈)-Alkyl, O-(C₁-C₈)-Alkyl, S-(C₁-C₈)-Alkyl, (C₂-C₈)-Alkenyl, (C₃-C₇)-Cycloalkyl, CO-(C₁-C₄)-Alkyl, Phenyl, Benzyl, Benzoyl, NH₂, NH-(C₁-C₆)-Alkyl, N-((C₁-C₆)-Alkyl)₂, P(O)-(O-(C₁-C₄)-Alkyl)₂ oder Heteroalkyl, wobei Alkyl und Alkenyl mehrfach durch F, Cl, Br, COOH, oder COO-(C₁-C₄)-Alkyl substituiert sein können;
Heteroalkyl heterozyklischer, gesättigter oder ungesättigter 4- bis 7-gliedrigen Ring, der bis zu 3 Heteroatome N, O oder S als Ringglieder enthalten kann, wobei der Ring substituiert sein kann durch F, Cl, Br, CN, NO₂, (C₁-C₄)-Alkyl, OH, COOH, COO-(C₁-C₄)-Alkyl;
wobei Verbindungen der Formel I ausgenommen sind, in denen die Reste gleichzeitig folgende Bedeutung haben:
X gleich N, R1 gleich OH, R2, R3, R4, R5 und R7 gleich H und R8 gleich unsubstituiertes Phenyl;
sowie deren physiologisch verträgliche Salze.The invention therefore relates to compounds of the formula I,

in which mean
R _{1 is} OH, O- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ or O- (C ₁ -C ₆ ) alkyl-OCO- (C ₁ -C ₆ ) -alkyl;
R 2 is H, (C ₁ -C ₆ ) -alkyl or phenyl;
R _{3 is} H, (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, pyridyl or phenyl, wherein alkyl may be substituted by R 9 and wherein phenyl or pyridyl may be substituted by R 10;
R 9 is NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH, COO- (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted by R11;
R 10 is F, Cl, Br, (C ₁ -C ₆ -alkyl), O- (C ₁ -C ₆ ) -alkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl or N - ((C ₁ -C ₆ ) -alkyl) ₂ ;
R 11 is F, Cl, (C ₁ -C ₆ alkyl), O- (C ₁ -C ₆ ) alkyl, NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH or COO- (C ₁ -C ₄ ) -alkyl;
X is C-R4 or N;
R _{4 is} H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ;
R 5 is H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ;
R _{6 is} H, F, Cl, Br, NO ₂ , CN or (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br;
R 7 is H or (C ₁ -C ₆ ) -alkyl;
R _{8 is} phenyl, wherein phenyl may be substituted up to five times by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₈ ) -alkyl, O- (C ₁ -C ₈ ) -alkyl, S- (C ₁ -C ₈ ) -alkyl, (C ₂ -C ₈ ) -alkenyl, (C ₃ -C ₇ ) -cycloalkyl, CO- (C ₁ -C ₄ ) -alkyl, phenyl, benzyl, benzoyl, NH ₂ , NH - (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , P (O) - (O- (C ₁ -C ₄ ) -alkyl) ₂ or heteroalkyl, where alkyl and alkenyl may be substituted several times by F, Cl, Br, COOH, or COO- (C ₁ -C ₄ ) -alkyl;
Heteroalkyl heterocyclic, saturated or unsaturated 4- to 7-membered ring, which may contain up to 3 heteroatoms N, O or S as ring members, which ring may be substituted by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₄ ) -alkyl, OH, COOH, COO- (C ₁ -C ₄ ) -alkyl;
in which compounds of the formula I are excluded, in which the radicals have the following meaning:
X is N, R 1 is OH, R 2, R 3, R 4, R 5 and R 7 are H and R 8 is unsubstituted phenyl;
and their physiologically acceptable salts.

Preference is given to compounds of the formula I, in which one or more radicals have the following meaning:
R _{1 is} OH, O- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ or O- (C ₁ -C ₆ ) alkyl-OCO- (C ₁ -C ₆ ) -alkyl;
R 2 is H, (C ₁ -C ₆ ) -alkyl or phenyl;
R _{3 is} (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, pyridyl or phenyl, wherein alkyl may be substituted by R 9 and wherein phenyl or pyridyl may be substituted by R 10;
R 9 is NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH, COO- (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted by R11;
R 10 is F, Cl, Br, (C ₁ -C ₆ -alkyl), O- (C ₁ -C ₆ ) -alkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl or N - ((C ₁ -C ₆ ) -alkyl) ₂ ;
R 11 is F, Cl, (C ₁ -C ₆ alkyl), O- (C ₁ -C ₆ ) alkyl, NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH or COO- (C ₁ -C ₄ ) -alkyl;
X is C-R4 or N;
R _{4 is} H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ;
R 5 is H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ;
R _{6 is} H, F, Cl, Br, NO ₂ , CN or (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br;
R 7 is H or (C ₁ -C ₆ ) -alkyl;
R _{8 is} phenyl, wherein phenyl may be substituted up to five times by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₈ ) -alkyl, O- (C ₁ -C ₈ ) -alkyl, S- (C ₁ -C ₈ ) -alkyl, (C ₂ -C ₈ ) -alkenyl, (C ₃ -C ₇ ) -cycloalkyl, CO- (C ₁ -C ₄ ) -alkyl, phenyl, benzyl, benzoyl, NH ₂ , NH - (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , P (O) - (O- (C ₁ -C ₄ ) -alkyl) ₂ or heteroalkyl, where alkyl and alkenyl may be substituted several times by F, Cl, Br, COOH, or COO- (C ₁ -C ₄ ) -alkyl;
Heteroalkyl heterocyclic, saturated or unsaturated 4- to 7-membered ring, which may contain up to 3 heteroatoms N, O or S as ring members, which ring may be substituted by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₄ ) -alkyl, OH, COOH, COO- (C ₁ -C ₄ ) -alkyl;
and their physiologically acceptable salts.

Particular preference is given to compounds of the formula I in which one or more radicals have the following meaning:
R _{1 is} OH, O- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ or O- (C ₁ -C ₆ ) alkyl-OCO- (C ₁ -C ₆ ) -alkyl;
R2H;
R3 is phenyl, wherein phenyl may be substituted by R10;
R 10 is F, Cl, Br, (C ₁ -C ₆ -alkyl), O- (C ₁ -C ₆ ) -alkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl or N - ((C ₁ -C ₆ ) -alkyl) ₂ ;
R 11 is F, Cl, (C ₁ -C ₆ alkyl), O- (C ₁ -C ₆ ) alkyl, NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH or COO- (C ₁ -C ₄ ) -alkyl;
X C-R4;
R 4 is H, (C ₁ -C ₆ ) -alkyl;
R 5 is H, Cl, (C ₁ -C ₆ ) -alkyl;
R6 H;
R7 H;
R8 is phenyl, wherein phenyl may be substituted up to five times by F, Cl;
and their physiologically acceptable salts.

Farther preferred are compounds of formula I wherein R8 is phenyl is and this twice with F or Cl in ortho and para position substituted or trisubstituted by F or Cl in ortho, ortho and para Position is substituted.

Farther particular preference is given to compounds of the formula I in which R 8 is identical Phenyl is triple and with F or Cl in ortho, ortho and para position is substituted.

The The invention relates to compounds of the formula I, in the form of their Racemates, racemic mixtures and pure enantiomers as well their diastereomers and mixtures thereof.

The Alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and heteroalkyl can be both straight-chain and branched.

Can leftovers or substituents occur several times in the compounds of formula I, they can do that all independent have the meanings given to each other and the same or different be.

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 Ditionssalze the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric and sulfuric acid and organic acids such as acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, glucone- , Glycol, isethione, milk, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine, or ethylenediamine.

salts with a non-pharmaceutically acceptable anion, such as Trifluoroacetate, also belong in the context 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.

Of the term used herein "physiological functional derivative " each physiologically acceptable Derivative of a compound of the invention of the formula I, e.g. an ester which, when administered to a mammal, such as e.g. the human being, who is able (directly or indirectly) one Compound of formula I or an active metabolite thereof form.

To the physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can in vivo to a compound of the invention be metabolized. These prodrugs can be effective themselves or Not.

The Compounds of the invention can also in different polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention.

following all references to "compound (s) according to formula I "on connection (s) of the Formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.

Under a heteroaryl radical is a pyridinyl, pyrrolyl, pyrimidinyl, Pyrazinyl, indolyl, benzimidazolyl, imidazolyl, pyrazolyl, Thiazolyl, thiophenyl or furanyl understood.

The Compound (s) of formula (I) may also be administered in combination with other active ingredient.

The Quantity of a compound according to formula I, which is required to achieve the desired biological effect to reach is dependent from a number of factors, e.g. the chosen specific compound, the intended use, route of administration and clinical use Condition of the patient. In general, the daily dose is in the range from 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 can e.g. in the range of 0.3 mg to 1.0 mg / kg, the suitably as an infusion from 10 ng to 100 ng per kilogram can be administered per minute. Suitable infusion solutions for these Purposes can e.g. from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per Milliliters, included. Single doses may e.g. from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections for example from 1 mg to 100 mg, and orally administrable single dose formulations, such as tablets or capsules, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For therapy the above states can they Compounds according to formula I myself are used as a compound, preferably they are but with a tolerable carrier in the form of a pharmaceutical composition. The carrier must Naturally compatible be, in the sense that he is with the other constituents of the composition is compatible and is not harmful to the patient. The carrier can a solid or a liquid or be both and preferably with the compound as a single dose formulated, for example as a tablet, from 0.05% to 95% by weight. may contain the active ingredient. Other pharmaceutically active substances can also be present, including other compounds according to formula I. The pharmaceutical according to the invention Compositions can produced according to one of the known pharmaceutical methods, which consist essentially in that the ingredients with pharmacologically acceptable Carrier- and / or adjuvants are mixed.

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 depends on the type and severity of the condition to be treated and on the nature of the particular compound of formula I used. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

suitable pharmaceutical compounds for oral administration in separate units, such as capsules, cachets, Lozenges or tablets, each containing a certain amount the compound according to formula I included; as a powder or granules; as a solution or suspension in one aqueous or non-aqueous Liquid; or as an oil-in-water or water-in-oil emulsion. These compositions can, As already mentioned, prepared according to any suitable pharmaceutical method, which comprises a step in which the active ingredient and the carrier (the one or more additional ones Constituents can be) brought into contact. In general the compositions become uniform and homogeneous of the active ingredient with a liquid and / or finely divided solid support, after which the Product is molded if necessary. So, for example A tablet can be prepared by adding a powder or granules the compound is pressed or molded, optionally with a or several additional ones Ingredients. Pressed tablets can be made by tableting Connection in free-flowing Mold, such as a powder or granules, optionally mixed with a binder, lubricant, inert thinner and / or one (several) surface-active / dispersing Means be made in a suitable machine. molded Tablets can by molding the powdery, with an inert liquid thinner moistened connection made in a suitable machine become.

pharmaceutical Compositions for peroral (sublingual) administration Lozenges containing a compound of formula I with a flavor usually Sucrose and gum arabic or tragacanth, and lozenges containing the Compound in an inert base such as gelatin and glycerin or Sucrose and gum arabic.

suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous Preparations of a compound according to formula I, preferably isotonic with the blood of the intended recipient. These preparations are preferably intravenous although administered also subcutaneously, intramuscularly or intradermally can be done as an injection. These preparations may preferably can be prepared by mixing the compound with water and the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be made be prepared by adding a compound according to formula I with one or more usual solid straps, For example, cocoa butter, mixes and the resulting mixture in Form brings.

suitable pharmaceutical compositions for topical application the skin are preferably as ointment, cream, lotion, paste, spray, Aerosol or oil in front. As a carrier can Vaseline, lanolin, polyethylene glycols, alcohols and combinations used by two or more of these substances. The active substance is generally in a concentration of 0.1 to 15 wt .-% of the composition, for example from 0.5 to 2%.

Also transdermal administration is possible. Suitable pharmaceutical Compositions for transdermal applications can as single patches exist, for a long-term close contact are suitable with the epidermis of the patient. Such patches contain suitably the active ingredient in an optionally buffered aqueous Solution, solved and / or dispersed in an adhesive or dispersed in one Polymer. A suitable drug concentration is about 1% to 35%, preferably about 3% to 15%. As a special possibility For example, the active ingredient, such as in Pharmaceutical Research, 2 (6): 318 (1986), by electrotransport or iontophoresis be released.

As further active ingredients for the combination preparations are suitable: All Antidiabetika, which in the red list 2003; Chapter 12 are called. You can with the. Compounds of formula I according to the invention are combined in particular for the synergistic effect improvement. The administration of the drug combination can either by separate administration of the drugs to the patient or in the form of combi nationspräparaten, wherein several active ingredients are present in a pharmaceutical preparation carried out. Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives, such as Lantus ^® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US 6,221,633 ), GLP-1 derivatives such as those disclosed in WO 98/08871 by Novo Nordisk A / S, as well as orally active hypoglycemic agents.

The orally effective hypoglycemic Active ingredients preferably include sulphonylfharnates, biguanidines, Meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, Glucagon antagonists, GLP-1 agonists, potassium channel openers, such as e.g. those described in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes, those involved in the stimulation of gluconeogenesis and / or glycogenolysis involved, modulators of glucose uptake, lipid metabolism changing Compounds such as antihyperlipidemic Active ingredients and antilipidemic Active ingredients, compounds that reduce food intake, PPAR and PXR agonists and agents acting on the ATP-dependent potassium channel the beta cells act.

at an embodiment The invention relates to the compounds of the formula I in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, Pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin administered.

at an embodiment The invention relates to the compounds of the formula I in combination with a cholesterol absorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside administered.

at an embodiment The invention relates to the compounds of the formula I in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, G1 262570.

at an embodiment The invention relates to the compounds of the formula I in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647.

In one embodiment of the invention, the compounds of formula I are used in combination with a mixed PPAR alphalgamma agonist, such as GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 11833, PCT / US 11490, DE10142734.4 described administered.

at an embodiment The invention relates to the compounds of the formula I in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.

at an embodiment The invention relates to the compounds of the formula I in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757, administered.

In one embodiment of the invention, the compounds of the formula I are used in combination with bile acid resorption inhibitor (see, for example, US Pat US 6,245,744 or US 6,221,897 ), such as HMR 1741.

at an embodiment The invention relates to the compounds of the formula I in combination with a CETP inhibitor, e.g. JTT-705.

at an embodiment The invention relates to the compounds of the formula I in combination with a polymeric bile acid adsorber, such as. Cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I in combination with an LDL receptor inducers (see US 6,342,512 ), such as HMR1171, HMR1586.

at an embodiment The invention relates to the compounds of the formula I in combination with an ACAT inhibitor, e.g. Avasimibe, administered.

at an embodiment The invention relates to the compounds of the formula I in combination with an antioxidant, e.g. OPC-14117 administered.

In one embodiment of the invention, the compounds of the formula I are used in combination with a lipoprotein lipase inhibitor such as NO-1886.

at an embodiment The invention relates to the compounds of the formula I in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.

at an embodiment The invention relates to the compounds of the formula I in combination with a squalene synthetase inhibitor, e.g. BMS-188494.

at an embodiment The invention relates to the compounds of the formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.

at an embodiment The invention relates to the compounds of the formula I in combination with a lipase inhibitor, e.g. Orlistat, administered.

at an embodiment The invention relates to the compounds of the formula I in combination administered with insulin.

at an embodiment are the compounds of formula I in combination with a sulfonylurea such as. Tolbutamide, glibenclamide, glipizide or glimepiride.

at an embodiment are the compounds of formula I in combination with a biguanide, such as e.g. Metformin, administered.

at again an embodiment are the compounds of the formula I in combination with a meglitinide, such as. Repaglinide, administered.

at an embodiment are the compounds of the formula I in combination with a thiazolidinedione, such as. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 by Dr. med. Reddy's Research Disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl) -2,4-thiazolidinedione, administered.

at an embodiment are the compounds of the formula I in combination with an α-glucosidase inhibitor, such as. Miglitol or acarbose, administered.

at an embodiment the compounds of the formula I are administered in combination with an active substance, on the ATP-dependent Potassium channel of the beta cells acts, e.g. Tolbutamide, glibenclamide, glipizide, Glimepiride or repaglinide.

at an embodiment the compounds of the formula I in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea Insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. administered.

In a further embodiment, the compounds of the formula I are used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormone and Metabolic Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide hydrochloride ( CGP 71683A)), MC4 agonists (eg 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a , 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)) , Orexin antagonists (eg, 1- (2-methyl-benzoxazol-6-yl) -3- [1,5] -naphthyridin-4-yl-urea hydrochloride (SB-334867-A)), H3 agonists (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)); TNF agonists, CRF antagonists (eg, [2-methyl-9- (2,4,6-timethyl-phenyl) -9H-1,3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585)), CRF BP antagonists (eg, urocortin), urocortin agonists, β3 agonists (eg, 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl- 1H-indol-6-yloxy) -ethylamino] -ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (eg, {2- [4- (4-chloro-2 , 5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl-indol-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin Reuptake inhibitors (eg dexfenfluramine), mixed sertonine and noradrenergic compounds (eg WO 00/71549), 5HT agonists eg 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111), bombesin Agonists, gala nin-antagonists, growth hormone (eg, human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, eg EP 0 462 884 ) 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 the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR Modulators or TR-β agonists

calibrates.

at an embodiment the invention is the further active ingredient 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.

at an embodiment is the other active ingredient dexamphatamine or amphetamine.

at an embodiment is the other active ingredient fenfluramine or dexfenfluramine.

at yet another embodiment is the other active substance sibutramine.

at an embodiment is the other active substance orlistat.

at an embodiment is the other ingredient mazindol or phentermine.

In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (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 formula I and Caroma ^®. Caromax ^® can also be administered in the form of food, such as in baked goods or muesli bars.

It it is understood that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active Substances than within the scope of the present invention is considered falling.

The preparation of the compounds of the formula I is described in the following schemes:
Compounds of formula II are under Buchwald conditions with amines of formula III to the Verbindun implemented in the formula IV, in which R1 'has the meaning of an ester. Y stands for Br, I or triflate. Catalyst systems with Pd (OAc) ₂ or Pd ₂ (dba) ₃ as palladium sources, BINAP, xanthphos and DPPF as ligands and Cs ₂ CO ₃ , K ₃ PO ₄ or NaO ^t Bu as bases can be used at these Buchwald conditions. As the solvent, for example, toluene, DME, dioxane, THF or DMF can be used. The reaction conditions can be selected under conventional heating or heating and reaction in the microwave. (References: Buchwald, Acc. Chem. Res. 1998, 31, 805)

any subsequent Saponification of the compounds of the formula IV leads to compounds of the formula I.

Scheme 1:

The Compounds of formula II can according to various well-known regulations, such as in WO2002 048113.

To the one can Compounds of general formula II in which X is a carbon atom represents from the corresponding anilines of formula V on the Gould Jacobs route can be synthesized as shown in Scheme 2. The alkylation on the nitrogen can at any point of the Synthesis performed become.

Scheme 2:

One Another object of this invention is a new production process for the preparation of the quinolones of the formula I according to Scheme 2, characterized the radical Y is an unsubstituted or substituted aniline radical represents.

To the others can Compounds of the formula II in which X represents a carbon atom starting from carboxylic acids of the general formula VIII by conversion into the acid chloride and reaction with malonic acid ester and orthoformate, the reaction with amines and subsequent cyclization (Scheme 3).

Scheme 3:

One Another object of this invention is a new production process for the preparation of the quinolones of the formula I according to Scheme 3a, characterized the radical Y is an unsubstituted or substituted aniline radical represents.

Scheme 3a:

at this preparation method are compounds of formula VIIIa under Buchwald conditions (see above) with anilines of the general Formula R7R8-NH converted to compounds of general formula VIIIb, where R 'is a hydrogen atom or an easily cleavable ester radical. If needed the ester VIIIb to compounds of the formula VIII with the choice of suitable Conditions split. The compounds of general formula VIII can as described in Scheme 3 the compounds of the formula IX and VII to compounds of the general Formula I to be implemented.

Or else compounds of general formula VIII are converted into the acid chloride and reacted with 3-dimethylamino-acrylic acid esters or by reaction with silylmalonic esters and subsequent reaction with dimethylacetal-dimethylformamide to give compounds of general formula IXa. Compounds of the general formula IXa can be converted into compounds of the general formula I by reaction with amines H ₂ N-R ₃ and subsequent basic ring closure.

Compounds of the formula II in which X represents a nitrogen atom can be prepared according to Scheme 4: Scheme 4:

2-amino-pyridine be by heating implemented with EMME to the compounds of the structure type XI. These cyclize to the desired Naldixinsäurederivaten XII at temperatures above 200 ° C in a suitable solvent such as DOWTHERM A or diphenyl ether. The cyclization succeeds only then in the above-described form when the substituent R5 is not Represents hydrogen atom. (Literature: Edmont, Rocher, Plisson, Chenault, Bioorg. Med. Chem. Lett. 2000, 1831)

The following examples serve to illustrate the invention, but without limiting it. Table 1.

The Effectiveness of the compounds was tested as follows:

glycogen phosphorylase a activity test

Of the Effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was in the reverse direction, by following the glycogen synthesis from glucose 1-phosphate by determination of the release of inorganic phosphate, measured. All reactions were considered duplicate determinations in 96-well microtiter plates (Half Area Plates, Costar No. 3696), with the change the absorption due to the formation of the reaction product in the Wavelength specified below in a Multiskan Ascent Elisa Reader (Lab Systems, Finland).

In order to measure the GPa enzyme activity in the reverse direction, the conversion of glucose 1-phosphate to glycogen and inorganic phosphate was determined by the general method of Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970 Jul; 48 (7): 746-754) with the following modifications: Human glycogen phosphorylase a (for example with 0.76 mg protein / ml (Aventis Pharma Deutschland GmbH) dissolved in buffer solution E (25 mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) was treated with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl ₂ · 6H ₂ O) and supplemented with 5 mg / ml glycogen to a concentration of 10 ug protein / ml. Test substances were prepared as 10 mM solution in DMSO and diluted to 50 uM with buffer solution T. to 10 10 μl of 37.5 mM glucose, dissolved in buffer solution T and 5 mg / ml glycogen, and 10 μl of a solution of human glycogen phosphorylase a (10 μg protein / ml) and 20 μl glucose-1-phosphate, 2.5 mM added. The basal level of glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 μl of buffer solution T (0.1% DMSO). The mixture was incubated for 40 minutes at room temperature and the liberated inorganic phosphate by the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D, Anal Biochem 1995 Sep 1; 230 (1): 173-177) with the following modifications: 50 μl of a stop solution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3 , 6% ascorbic acid, 0.9% SDS are added to 50 μl of the enzyme mixture. After 60 minutes incubation at 45 ° C, the absorbance at 820 nm was measured. To determine the background absorption, the stop solution was added in a separate batch immediately after addition of the glucose-1-phosphate solution.

This The test was performed with a concentration of 10 μM of the test substance the respective inhibition of glycogen phosphorylase a in vitro the test substance to determine.

Table 2: Biological activity

Out From the table it can be read that the compounds of the formula I the activity inhibit glycogen phosphorylase a and thereby lowering the blood sugar level are well suited.

following the production of some examples is described in detail, the remaining Compounds of the formula I were obtained analogously:

Experimental part:

example 1

1-ethyl-6- (4-ethyl-phenylamino) -7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylate

(Variant A of the palladium-catalyzed amination)

100 mg of ethyl 6-bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylate were added together with 37 mg of 4-ethylaniline, 20 mg of Pd (OAc) ₂ , Transferred 60 mg BINAP and 250 mg cesium carbonate into a suitable reaction vessel, it was generated with argon, a protective gas atmosphere and mixed with 10 ml of dioxane. It was then heated to 80 ° C for 8 h.

The pure product was isolated from the reaction solution by chromatography on an HPLC. Here, a Merck Purospher RP-18 column and an acetonitrile: water mixture was used as the eluent, the initial content of acetonitrile was 15% and increased within 20 minutes to 95%.
Yield: 45%

Example 167

1-ethyl-6- (4-methoxy-2-methyl-phenylamino) -8-methyl-4-oxo-1,4-dihydro-quinolone-3-carbonsäuremethylester

(Variant B of the palladium-catalyzed amination)

100 Methyl 6-bromo-1-ethyl-8-methyl-4-oxo-1,4-dihydro-quinolone-3-carboxylate together with 42.3 mg 4-methoxy-2-methylaniline, 20 mg Pd (OAc) 2, 60 mg XANTPHOS and 250 mg cesium carbonate transferred to a suitable reaction vessel, man produced a protective gas atmosphere with argon and added 10 ml Dioxane. Subsequently you heated for 8 h at 80 ° C.

The pure product was isolated from the reaction solution by chromatography on an HPLC. In this case, a Merck Purospher RP-18 column and an acetonitrile: water mixture was used as eluent, the initial content of acetonitrile was 15% and increased within 20 minutes to 100%.
Yield: 40%

Example 199

1-ethyl-6- (4-methoxy-2-methyl-phenylamino) -8-methyl-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid

Methyl 1-ethyl-6- (4-methoxy-2-methyl-phenylamino) -8-methyl-4-oxo-1,4-dihydro-quinolone-3-carboxylate (30 mg) was dissolved in 5 ml of dioxane, added with 2 , 5 equivalents of a 1 N NaOH solution and heated for 4 h at 60 ° C. After removal of the solvent in vacuo, the product was purified by chromatography on an HPLC. In this case, a Merck Purospher RP18 column and an acetonitrile: water mixture was used as the eluent, the initial acetonitrile content was 15% and increased to 95% within 20 minutes.
Yield: 75%

All other ester cleavages were carried out by analogous means.

Preparation of Intermediate IXa

Option A:

a) 2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoic acid ethyl ester

F-35032-041

A solution of 100 mg (0.34 mmol) of ethyl 5-bromo-2,4-dichloro-benzoate, 197 mg (0.6 mmol) cesium carbonate, 70 mg (0.12 mmol) of xantphos, 23 mg (0.10 mmol) of palladium acetate and 60 mg (0.37 mmol) of 6-chloro-2,4-difluoroaniline in 3 ml of dimethoxyethane was for 2 hours at 100 ° C heated. After cooling At room temperature, the mixture was filtered through kieselguhr and chromatographed on silica gel (heptane: Esigester = 99: 1 to 90:10 in 90 minutes). There were obtained 70 mg (55%) of the product.

b) 2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoic acid

F-35032-044

120 mg (0.31 mmol) of 2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoic acid ethyl ester were dissolved in 6 ml of ethanol - 2 Sodium hydroxide solution (1: 1) suspended and heated to 90 ° C for 3 hours. To Cool down Room temperature was adjusted to pH 2 with 2N sulfuric acid and the sucked out precipitate. There were 98 mg (88%) of the Product received.

c) 2- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoyl] -3-dimethylaminoacrylic acid ethyl ester

F-35032-045

95 mg (0.27 mmol) of 2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoic acid were refluxed with 0.98 ml of thionyl chloride for 3 hours. The thionyl chloride was distilled off, the residue was treated with 3 ml of toluene and concentrated in vacuo. The residue was taken up in 2 ml of toluene and added to a solution of 39 mg (0.27 mmol) of ethyl 3-dimethylaminoacrylate, 6 μl of triethylamine and 1 ml of toluene. It was heated to 90 ° C for 3 hours. The batch was concentrated and chromatographed on silica gel (heptane: ethyl acetate = 75: 25 to 0: 100 in 45 minutes). There were obtained 30 mg (23%) of the desired product.
MS: M + H = 477/479

This Intermediate was, for example, for the synthesis of Beipsiel 327 used.

Variant B:

a) Ethyl 3- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -phenyl] -3-oxo-propionate

F-35032-134

3.0 g (8.51 mmol)) 2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoic acid (variant A b)) and 9.3 ml of thionyl chloride were heated to 70 ° C for 1.5 hours. Of the The mixture was diluted with 20 ml of dry toluene and concentrated. The residue was added twice with toluene and concentrated again.

To a solution of 3.47 g (17.0 mmol) of ethyl trimethylsilylmalonate in 45 ml of diethyl ether was added at -75 ° C 1.4 ml a 1.6 n solution of butyllithium in hexane so that the temperature did not rise above -60 ° C. Subsequently was Stirred at -75 ° C for 30 minutes. The 2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoic acid chloride was dissolved in 45 ml of dimethoxyethane and added dropwise in 40 minutes. The batch slowly increased to 10 ° C heated and stirred at this temperature for 2.5 hours. The reaction mixture was with ethyl acetate dilute and washed twice each with 250 ml of water and saturated sodium bicarbonate solution. The organic phase was dried and concentrated. There were 3.88 g of the crude mixture obtained without further purification in the next stage have been implemented.

b) 2- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoyl] -3-dimethylaminoacrylic acid ethyl ester

F-35032-138

A solution of 3.88 g (crude) of 3- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -phenyl] -3-oxo-propi ethyl acetate and 1.22 g (0.10 mmol) of dimethylformamide dimethyl acetal in 10 ml of toluene were heated to reflux for 1.5 hours. The reaction was cooled to room temperature and concentrated in vacuo. Purification on silica gel (petroleum spirit (45-70 ° C) / ethyl acetate, 8 minutes isocratic 35% ethyl acetate, then in 7 minutes to 60% ethyl acetate, flow 400 ml / minute) gave 3.59 g (82% over both stages) of desired product.
MS: M + H = 477/479

Example 327:

7-chloro-6- (2-chloro-4,6-difluoro-phenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydro-quinolone-3-carboxylic acid

a) Ethyl 2- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoyl] -3- (pyridin-3-ylamino) -acrylate

F-35032-048

A solution of 30 mg (0.06 mmol) of ethyl 2- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoyl] -3-dimethylaminoacrylate and 15 mg (0.16 mmol) of 3-aminopyridine in 2 ml of toluene were added 7 hours to 150 ° C heated. Concentration gave 33 mg of the desired product without further cleaning in the next Stage were used.

b) 7-Chloro-6- (2-chloro-4,6-difluoro-phenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydro-quinolone-3-carboxylic acid ethyl ester

F-35032-049

A Suspension of 33 mg (0.06 mmol) of ethyl 2- [2,4-dichloro-5- (2-chloro-4,6-difluoro-phenylamino) -benzoyl] -3- (pyridin-3-ylamino) -acrylate, 10 mg (0.08 mmol) of potassium carbonate and 1 ml of dimethylformamide 5 hours at 90 ° C heated. The batch was concentrated and over Reversed phase HPLC purified (Purospher RP-18, acetonitrile-water). There were 12 mg (37%) of the desired Product received.

c) 7-Chloro-6- (2-chloro-4,6-difluoro-phenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydro-quinolone-3-carboxylic acid

F-35032-057

12 mg (0.02 mmol) of 7-chloro-6- (2-chloro-4,6-difluoro-phenylamino) -4-oxo-1-pyridin-3-yl-1,4-dihydro-quinolone-3 carboxylic acid ethyl ester were suspended in 6 ml of ethanol - 2 N sodium hydroxide mixture (1: 1) and heated to 90 ° C for 3 hours. After cooling to room temperature was adjusted to pH 2 with 2 N sulfuric acid and the precipitate was filtered off with suction. 6 mg (53%) of the product were obtained.
MS: M + H = 462/464

Claims (13)

Compounds of the formula I,

wherein R _{1 is} OH, O- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ or O- ( C ₁ -C ₆ ) -alkyl-OCO- (C ₁ -C ₆ ) -alkyl; R 2 is H, (C ₁ -C ₆ ) -alkyl or phenyl; R _{3 is} H, (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, pyridyl or phenyl, wherein alkyl may be substituted by R 9 and wherein phenyl or pyridyl may be substituted by R 10; R 9 is NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH, COO- (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) cycloalkyl, heteroalkyl, he teroaryl, O-phenyl or phenyl, where phenyl and heteroaryl may be substituted by R11; R 10 is F, Cl, Br, (C ₁ -C ₆ -alkyl), O- (C ₁ -C ₆ ) -alkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl or N - ((C ₁ -C ₆ ) -alkyl) ₂ ; R 11 is F, Cl, (C ₁ -C ₆ alkyl), O- (C ₁ -C ₆ ) alkyl, NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH or COO- (C ₁ -C ₄ ) -alkyl; X is C-R4 or N; R _{4 is} H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ; R 5 is H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ; R _{6 is} H, F, Cl, Br, NO ₂ , CN or (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br; R 7 is H or (C ₁ -C ₆ ) -alkyl; R _{8 is} phenyl, wherein phenyl may be substituted up to five times by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₈ ) -alkyl, O- (C ₁ -C ₈ ) -alkyl, S- (C ₁ -C ₈ ) -alkyl, (C ₂ -C ₈ ) -alkenyl, (C ₃ -C ₇ ) -cycloalkyl, CO- (C ₁ -C ₄ ) -alkyl, phenyl, benzyl, benzoyl, NH ₂ , NH - (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , P (O) - (O- (C ₁ -C ₄ ) -alkyl) ₂ or heteroalkyl, where alkyl and alkenyl may be substituted several times by F, Cl, Br, COOH, or COO- (C ₁ -C ₄ ) -alkyl; Heteroalkyl heterocyclic, saturated or unsaturated 4- to 7-membered ring, which may contain up to 3 heteroatoms N, O or S as ring members, which ring may be substituted by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₄ ) -alkyl, OH, COOH, COO- (C ₁ -C ₄ ) -alkyl; wherein compounds of the formula I are excluded, in which the radicals have the following meaning: X is N, R1 is OH, R2, R3, R4, R5 and R7 are H and R8 is unsubstituted phenyl; and their physiologically acceptable salts. Compounds of formula I, according to claim 1, characterized in that R1 is OH, O- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ or O- (C ₁ -C ₆ ) -alkyl-OCO- (C ₁ -C ₆ ) -alkyl; R 2 is H, (C ₁ -C ₆ ) -alkyl or phenyl; R _{3 is} (C ₁ -C ₈ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, pyridyl or phenyl, wherein alkyl may be substituted by R 9 and wherein phenyl or pyridyl may be substituted by R 10; R 9 is NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH, COO- (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, heteroalkyl, heteroaryl, O-phenyl or phenyl, wherein phenyl and heteroaryl may be substituted by R11; R 10 is F, Cl, Br, (C ₁ -C ₆ -alkyl), O- (C ₁ -C ₆ ) -alkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl or N - ((C ₁ -C ₆ ) -alkyl) ₂ ; R 11 is F, Cl, (C ₁ -C ₆ alkyl), O- (C ₁ -C ₆ ) alkyl, NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH or COO- (C ₁ -C ₄ ) -alkyl; X is C-R4 or N; R _{4 is} H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ; R 5 is H, F, Cl, Br, OH, NO ₂ , CN, (C ₁ -C ₆ ) -alkyl or O- (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br ; R _{6 is} H, F, Cl, Br, NO ₂ , CN or (C ₁ -C ₆ ) -alkyl, where alkyl may be substituted several times by F, Cl or Br; R 7 is H or (C ₁ -C ₆ ) -alkyl; R _{8 is} phenyl, wherein phenyl may be substituted up to five times by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₈ ) -alkyl, O- (C ₁ -C ₈ ) -alkyl, S- (C ₁ -C ₈ ) -alkyl, (C ₂ -C ₈ ) -alkenyl, (C ₃ -C ₇ ) -cycloalkyl, CO- (C ₁ -C ₄ ) -alkyl, phenyl, benzyl, benzoyl, NH ₂ , NH - (C ₁ -C ₆ ) -alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , P (O) - (O- (C ₁ -C ₄ ) -alkyl) ₂ or heteroalkyl, where alkyl and alkenyl may be substituted several times by F, Cl, Br, COOH, or COO- (C ₁ -C ₄ ) -alkyl; Heteroalkyl heterocyclic, saturated or unsaturated 4- to 7-membered ring, which may contain up to 3 heteroatoms N, O or S as ring members, which ring may be substituted by F, Cl, Br, CN, NO ₂ , (C ₁ -C ₄ ) -alkyl, OH, COOH, COO- (C ₁ -C ₄ ) -alkyl; and their physiologically acceptable salts. Compounds of the formula I according to Claim 1 or 2, characterized in that R1 is OH, O- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl, N- ( (C ₁ -C ₆ ) -alkyl) ₂ or O- (C ₁ -C ₆ ) -alkyl-OCO- (C ₁ -C ₆ ) -alkyl; R2H; R3 is phenyl, wherein phenyl may be substituted by R10; R 10 is F, Cl, Br, (C ₁ -C ₆ -alkyl), O- (C ₁ -C ₆ ) -alkyl, COOH, COO- (C ₁ -C ₆ ) -alkyl, NH ₂ , NH- (C ₁ -C ₆ ) -alkyl or N - ((C ₁ -C ₆ ) -alkyl) ₂ ; R 11 is F, Cl, (C ₁ -C ₆ alkyl), O- (C ₁ -C ₆ ) alkyl, NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N - ((C ₁ -C ₆ ) -alkyl) ₂ , COOH or COO- (C ₁ -C ₄ ) -alkyl; X C-R4; R 4 is H, (C ₁ -C ₆ ) -alkyl; R 5 is H, Cl, (C ₁ -C ₆ ) -alkyl; R6 H; R7 H; R8 is phenyl, wherein phenyl may be substituted up to five times by F, Cl; and their physiologically acceptable salts. Compounds according to a or more of the claims 1 to 3 for use as a medicament. Medicament containing one or more of the compounds according to one or more of the claims 1 to 3. Medicament containing one or more of the compounds according to one or more of the claims 1 to 3 and at least one further active ingredient. Medicament according to claim 6, characterized in that it as one further active ingredient one or more Hypoglycemic, hypoglycemic Active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha / gamma agonists, Fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, lipase inhibitors, insulins, sulphonylureas, Biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors the ATP-dependent Potassium channel of beta cells acting drugs, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating Hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed Sertonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, Growth hormones, growth hormone releasing compounds, TRH agonists, decoupling protein 2- or 3-modulators, leptin agonists, DA agonists (bromocriptine, doprexine), Lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists or contains amphetamines. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for lowering blood sugar. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of type II diabetes. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of lipid and Carbohydrate metabolism disorders. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of arteriosclerotic Phenomena. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of insulin resistance. A process for the preparation of a medicament containing one or more of the compounds according to one or more of claims 1 to 3, characterized in that the active ingredient with a pharmaceutical suitable carrier is mixed and this mixture in a suitable for administration Shape is brought.