HRP20041161A2 - N-benzoylureidocinnamate derivatives, method for production and use thereof - Google Patents

Abstract

The invention relates to N-benzoylureidocinnamate derivatives of formula (I), where R1-R11 have the meanings given in the claims, the physiologically acceptable salts and method for production thereof. The compounds are suitable as anti-diabetics, for example.

Description

The invention relates to N-benzoylureido-cinnamic acid derivatives as well as their physiologically tolerable salts and physiologically functional derivatives.

EP 0 193 249 (Duphar) describes acyl-carboxyphenyl-urea derivatives with antitumor activity.

The invention is based on the task of providing compounds with which the prevention and treatment of type 2 diabetes is possible. In addition, these compounds must also cause a significant reduction in the amount of sugar in the blood.

The invention therefore relates to compounds of formula I,

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where

R7, R8, R9, R10 independently represent H, F, Cl, Br, OH, NO2, CN, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6 )-alkynyl, O-SO2-(C1-C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl or Br;

R1, R2 are independently H, (C1-C6)-alkyl, whereby alkyl can be substituted with OH, O-(C1-C4)-alkyl, NH2, NH(C1-C4)-alkyl, N(C1- C6)-alkyl]2, or they are O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6)-alkylene-COOH, (C1-C6)-alkylene-COO-(C1-C6)-alkyl;

R3, R4, R5, R6 are independently H, F, Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14), N(R13)COR15, (C1-C6 )-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R16)(R17);

R 11 is OR 12 or N(R 18 )(R 19 );

R12 is H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl, Br, OH or O- (C1-C4)-alkyl;

R13 and R14 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R13 and R14 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring, which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl, Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl;

R16 and R17 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or with CONH2;

or the radicals R16 and R17 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, 0 or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl , Br, OH, oxo, N(R20) (R21) or (C1-C4)-alkyl;

R18, R19 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R18 and R19 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring that can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl , Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl;

R22 and R23 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R22 and R23 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring, which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl, Br, OH, oxo, N(R20) (R21) or (C1-C4)-alkyl;

R15 is (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl can be multiply substituted with F, NH2, NH(C1-C4)-alkyl, N[(C1-C4)-alkyl]2, OH, O-(C1-C4) -alkyl, O-(C2-C4)-alkenyl), O-CO-(C1-C4)-alkyl, or is COOR12, CON(R13)(R14), heteroaryl, (C6-C10)-aryl, ( C 6 -C 10 )-aryl-(C 1 -C 4 )-alkylene, wherein the heteroaryl and aryl may be substituted with O-(C 1 -C 4 )-alkyl, F or Cl, and wherein the alkyl may be polysubstituted by F;

R20 and R21 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

as well as their physiologically tolerable salts.

Preference is given to compounds of formula 1, in which

R7, R8, R9, R10 are mutually independent H, F, Cl, Br, OH, NO2, CN, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6 )-alkynyl, O-SO2-(C1-C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl or Br;

R1 and R2 are H;

R3, R4, R5, R6 are independently H, F, Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14), N(R13)COR15, (C1-C6 )-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R16)(R17);

R 11 is OR 12 or N(R 18 )(R 19 );

R12 is H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl, Br, OH or O- (C1-C4)-alkyl;

R13, R14 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R13 and R14 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring that can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl , Br, OH, oxo, N(R20) (R21) or (C1-C4)-alkyl;

R16, R17 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R16 and R17 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl , Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl;

R18, R19 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R18 and R19 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring, which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl, Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl;

R22 and R23 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

or the radicals R22 and R23 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring that can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl , Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl;

R15 is (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, NH2, NH (C1-C4)-alkyl, N[(C1-C4)-alkyl]2, OH, O-(C1-C6) -alkyl, O-(C2-C4)-alkenyl), O-CO-(C1-C4)-alkyl, or is COOR12, CON(R13)(R14), heteroaryl, (C6-C10)-aryl, ( C 6 -C 10 )-aryl-(C 1 -C 4 )-alkylene, wherein the heteroaryl and aryl may be substituted with O-(C 1 -C 4 )-alkyl, F or Cl, and wherein the alkyl may be polysubstituted by F;

R20 and R21 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2;

as well as their physiologically tolerable salts.

Compounds of formula I in which one or more radicals have the following meanings are particularly preferred:

R7, R8, R9, R10 are mutually independently H, F or Cl;

R1, R2, R6 are H;

R3, R4, R5, R6 are mutually independently H, Cl, COOH, COO-(C1-C4)-alkyl or NHCOR15;

R11 is OR12, N(R18)(R19);

R 12 is H or (C 1 -C 4 )-alkyl;

R18, R19 are H or (C1-C4)-alkyl;

R 15 is (C 1 -C 4 )-alkyl, wherein the alkyl may be substituted with COOH, or it is COOH;

as well as their physiologically tolerable salts.

Alkyl residues in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 or R23 can have a straight chain or can be branched.

Radicals or substituents may occur multiple times in the compounds of formula I, such as O-R 12 , and all of them may have the meanings given independently of each other and may be the same or different.

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

Pharmaceutically acceptable salts are especially suitable for medical use due to their greater solubility in water 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 according to the invention are salts with inorganic acids, such as hydrochloric, hydrobromic, phosphoric, meta-phosphoric, nitric and sulfuric acids, as well as with organic acids, such as, for example, acetic acid, benzenesulfonic acid , benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluene-sulfonic 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 salts (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine , lysine or ethylenediamine.

Salts with a pharmaceutically intolerable anion, such as for example trifluoroacetate, are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically tolerable salts and/or for use in non-therapeutic purposes, for example for in-vitro application.

The term "physiologically functional derivative", as used herein, means any physiologically tolerable derivative of a compound of formula I according to the invention, e.g. an ester, which, when administered to a mammal, e.g. a human, can (directly or indirectly) provide a compound of formula I or its active metabolite.

Physiologically functional derivatives also include prodrugs of the compounds according to the invention, as described for example in H. Okada et al., Chem. Pharm. Bul. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to the compound according to the invention. These prodrugs may or may not be effective on their own.

The compounds according to the invention can also exist in different polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention fall within the scope of the invention and represent a further aspect of the invention.

Furthermore, any reference to "compound(s) of formula I" refers to compound(s) of formula I as previously described, as well as their salts, solvates and physiologically functional derivatives as described herein.

The compound(s) of formula (I) can also be given in combination with other active substances.

The amount of a compound of formula I required to achieve the desired biological effect depends on a number of factors, eg, the specific compound selected, the intended use, the route of administration and the clinical condition of the patient. Generally, the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg to 50 mg) per day per kilogram of body weight, eg 3-10 mg/kg/day. The intravenous dose may be, for example, in the range of 0.3 mg to 1.0 mg/kg, which may conveniently be given as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for this purpose may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individual doses can contain, for example, from 1 mg to 10 g of active substance. Thus, injectable ampoules may contain, for example, from 1 mg to 100 mg, and single dose oral formulations, such as for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the above-mentioned conditions, the compounds of formula I can be used alone as such, but they are preferably administered in the form of pharmaceutical compositions with a tolerable carrier. The carrier must of course be tolerable in the sense that it is compatible with the other ingredients of the formulation and that it is not harmful to the health of the patient. The carrier may be a solid or a liquid or both and is formulated with the compound preferably as a single dose, for example as tablets which may contain from 0.05% to 95% by weight. % active substance. Further pharmaceutically active substances may also be present, including further compounds of formula I. Pharmaceutical compositions according to the invention can be produced by known pharmaceutical procedures, which mainly consist in mixing the ingredients with pharmacologically tolerable carriers and/or excipients.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intra-muscular, intradermal or intravenous) administration, although the most suitable route of administration depends in each case on the type and the severity of the treated condition and in any case on the type of compound of formula I used. The scope of the invention also includes formulations in the form of dragees and formulations for slow release in the form of dragees. Preference is given to formulations that are resistant to acid and gastric juice. Suitable gastric acid resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

Suitable pharmaceutical compounds for oral administration may be in separate units, such as for example capsules, host capsules, lozenges or tablets, which in each case contain a certain amount of the compound of formula I; as a powder or granulate; 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 can be produced, as already mentioned, by any suitable pharmaceutical process, which includes a step in which the active substance is brought into contact with the carrier (which may consist of one or more additional ingredients). In general, the compositions can be produced by uniformly and homogeneously mixing the active substance with a liquid and/or finely divided solid carrier, after which, if necessary, the product is formed. Thus, for example, tablets can be produced, whereby a powder or granulate of the compound is pressed or shaped, with one or more additional ingredients as needed. Pressed tablets can be produced on a suitable machine by tableting the compound in a free-flowing form, such as for example a powder or granulate, which is optionally mixed with a binder, a glidant, an inert diluent and/or one (or more) surfactants. / dispersing agents. Molded tablets can be produced on a suitable machine by molding a powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for peroral (suplingual) administration include lozenges containing the compound of formula I with a flavoring agent, 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 arabica.

Suitable pharmaceutical compositions for parenteral administration preferably include sterile aqueous preparations of the compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration can also be carried out subcutaneously, intramuscularly or intradermally as an injection. These preparations can be produced primarily by mixing the compound with water and the resulting solution is sterilized and made isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5 wt. % of active compound.

Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. They can be produced by mixing a compound of formula I with one or more conventional solid carriers such as for example cocoa butter and molding the resulting mixture in a mold.

Suitable pharmaceutical compositions for surface application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Vaseline, lanolin, polyethylene glycol, alcohols and combinations of two or more of these substances can be used as carriers. The active substance is generally present in a concentration of 0.1 to 15 wt. % composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal administration may be in the form of individual patches suitable for long-term close contact with the patient's epidermis. Such patches suitably contain the active substance in an as needed buffered aqueous solution, dissolved and/or dispersed in an adhesive agent or dispersed in a polymer. A suitable concentration of the active substance is approx. 1 % to 35%, preferably approx. 3% to 15%. As a specific possibility, the active substance can be released by electro-transport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

The following are suitable as further active substances for combined preparations:

All antidiabetics, which are listed in the Roten Liste 2001, chapter 12. They can be combined with the compounds of formula I in particular due to the improvement of the synergistic effect. Administration of a combination of active substances can be carried out by giving the patient separate active substances or in the form of a combined preparation, whereby one pharmaceutical preparation can contain several active substances. Most of the active substances listed below are described in the 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, rapid-acting insulin (see US 6,221,633), GLP-1 derivatives such as all those described in WO 98/08871 of Novo Nordisk A/S, as well as orally effective hypoglycemic active substances.

Orally effective hypoglycemic active substances include primarily sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, such as all agents described in WO 97/26265 and WO 99 /03861 of the company Novo Nordisk A/S, insulin sensitizers, liver enzyme inhibitors, which act on the stimulation of gluconeogenesis and/or glycogenolysis, glucose binding modulators, compounds that change fat metabolism, as antihyperlipidemic active substances and antilipidemic active substances, compounds that limit food intake , PPAR and PXR agonists and active agents acting on the ATP-dependent potassium channel of beta cells.

In one embodiment of the invention, the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, such as, for example, ezetimibe, tikvezide, pamaquezide.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW 9578, GW 7647.

In one embodiment of the invention, compounds of formula I are administered in combination with mixed PPAR alpha/gamma agonists, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as those described in PCT/US 00/11833 , PCT/US 00/11490, DE 10142734.4.

In one embodiment of the invention, the compounds of formula I are administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, such as, for example, implitapide, BMS-201038, R-103757.

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

In one embodiment of the invention, the compounds of formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705.

In one embodiment of the invention, the compounds of formula I are administered in combination with a polymeric agent for bile acid absorption, such as, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of formula I are administered in combination with an agent that induces the LDL receptor (see US 6,342,512), such as, for example, HMR1171, HMR1586.

In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimib.

In one embodiment of the invention, compounds of formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.

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

In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP-citrate-lyase inhibitor, such as, for example, SB-204990.

In one embodiment of the invention, the compounds of formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, C1-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipase inhibitor, such as, for example, orlistat.

In one embodiment of the invention, the compounds of formula I are administered in combination with insulin.

In one embodiment of the invention, the compounds of formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment of the invention, the compounds of formula I are administered in combination with a biguanide, such as, for example, metformin.

Also, in one embodiment of the invention, compounds of formula I are administered in combination with meglitinide, such as repaglinide.

In one embodiment of the invention, the compounds of formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, or the compounds described in WO 97/41097 from Dr. Reddy's Research Foundation, particularly 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione. In one embodiment of the invention, compounds of the formula And they are given in combination with an α-glucosidase inhibitor, such as miglitol or acarbose.

In one embodiment of the invention, the compounds of formula I are administered in combination with an active substance that acts on the ATP-dependent potassium channel of beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment of the invention, the compounds of formula I are administered in combination with more than one of the above-mentioned compounds, for example in combination with one sulfonylurea and metformin, with one sulfonylurea and acarbose, with repaglinide and metformin, insulin and with one sulfonylurea, with insulin and with metformin, with insulin and troglitazone, with insulin and lovastatin, etc.

In a further embodiment of the invention, compounds of formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences 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)), with MC4 agonists (e.g. 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-chlorophenyl)-2-oxo-ethyl]-amide; (WO 01/91752)), orexin antagonists (e.g. 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 oxalate (WO 00/63208)); TNF agonists, CRF antagonists (eg [2-methyl-9-(2,4,6-trimethyl-phenyl)-9H-1,3,9-triaza-fluoren-4-yl]-dipropyl-amine (WO 00 /66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, β3 agonists (e.g. 1-(4-chloro-3-methanesulfonyl-methyl-phenyl)-2-[2-(2,3-dimethyl- 1H-indol-6-yloxy)-ethyl-amino]-ethanol hydrochloride (WO 01/ 83451)), MSH agonists (melanocyte-stimulating hormone agonists, CCK-A agonists (e.g. {2-[4-(4-chloro -2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-thiazol-2-yl-carbamoyl]-5,7-dimethyl-indol-1-yl}-acetic acid tri-fluoroacetate (WO 99 /15525)); serotonin reuptake inhibitors (such as dexfenfluramine), mixed serotonin and noradrenergic compounds (such as WO 00/71549), 5HT agonists such as 1-(3- ethyl-benzofuran-7-yl)-piperazine oxalate (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (such as human growth hormone), with compounds that release growth hormone tert-butyl ester (6- benzyloxy-1- (2-diiso-propylamino-ethyl-carbamoyl)-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid (WO 01/85695), TRH agonists (see e.g. EP 0 462 84), uncoupled protein 2 modulators or 3, leptin agonists (see, e.g., 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 (such as eg WO 00/40569), PPAR modulators (such as eg WO 00/78312), RXR modulators or TR-β-agonists.

In one embodiment, the further active substance is leptin; see eg "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, the further active substance is dexamfetamine or amphetamine.

In one embodiment, the further active substance is fenfluramine or dexfenfluramine.

Also, in one embodiment, the further active substance is sibutramine.

In one embodiment, the further active substance is orlistat.

In one embodiment, the further active substance is mazindole or phentermine.

In one embodiment, the compounds of formula I are given in combination with bulking substances, preferably with insoluble bulking substances (see e.g. Carob/Caromax (Zunft H J; et al., Carob pulp preparation for treatment of hyper-cholesierolemia, ADVANCES IN THERAPY (2001) Sep-Oct), 18(5), 230-6). Karomaks is a product containing carob from the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main)). The combination with Caromax can be administered as a preparation or by separate administration of the compound of formula I and Caromax. At the same time, Caromax can also be given in the form of food, such as in pastries or flakes.

It is understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and, if necessary, with one or more other pharmacologically effective substances falls within the scope of protection of the proposed invention.

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The examples given below serve to explain the invention, but it is not limited to them.

Table 1: Examples of formula I

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* With the data "MS is ok" it is understood that the mass spectrum or HPLC/MS was measured and a molar peak value (molal mass + H+) was found in it.

The compounds of formula I are characterized by a favorable effect on sugar metabolism, they especially reduce the amount of sugar in the blood and are therefore suitable for the treatment of type 2 diabetes. These compounds can therefore be used alone or in combination with other active substances that lower blood sugar (antidiabetics).

The compounds of formula I are further suitable for the treatment of diabetic late damage, such as, for example, nephropathy, retinopathy, neuropathy as well as heart attack, myocardial infarction, peripheral arterial occlusion diseases, thrombosis, arteriosclerosis, syndrome X, obesity, inflammation, immune diseases, autoimmune diseases, such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease, schizophrenia and infectious diseases.

The efficacy of the compounds was tested as follows.

Examination of glycogen phosphorylase activity

The effect of the compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in reverse, by monitoring the synthesis of glycogen from glucose-1-phosphate by determining the release of inorganic phosphate. All reactions were carried out twice in microtiter plates with 96 wells (Half Area Plates, Costar no. 3696), and the change in absorbance due to the formation of the reaction product at the indicated wavelength was measured in a Multiskan Ascent Elisa Reader (Lab Svstems, Finland ). To measure the enzymatic activity of GPa in the reverse direction, the measurement of the conversion of glucose 1-phosphate into glycogen and inorganic phosphate was applied using the general method described by Engers et al. (Engers H.D, Shechosky S., Madsen N.B., Can. J. Biochem 1970 Jul; 48(7):746-754) with the following modifications. Human glycogen phosphorylase (for example with approx. 0.76 mg protein/ml (Aventis Pharma Deutschland GmbH) is dissolved in a solution of buffer E (25 mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) and diluted with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl2-6H2O) and 5 mg/ml glycogen diluted to a concentration of 10 μg protein/ml was added. Test substances are prepared as 10 mM solutions in DMSO and diluted to 50 μM with buffer solution T. 10 μl of 37.5 mM glucose (dissolved in buffer solution T and 5 mg/ml glycogen) is added to 10 μl of this solution, and 10 μl of human glycogen phosphorylase solution (10 μg protein/ml) and 20 μl of glucose 1-phosphate, 2.5 g mM. The basal value of glycogen phosphorylase activity in the absence of the test substance was determined by the addition of 10 μl of buffer T solution (0.1% DMSO ).The mixture is incubated for 40 minutes at room temperature and the released inorganic phosphate is measured by the general method described by Drueckes et al. Sep 1;230 (1) : 173-177) with the following modifications: 50 μl of a stop solution containing 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid and 0.9% SDS. After incubation for 60 minutes at 45°C, measure the absorbance at 820 nm. To determine the background absorbance, a stop solution is added to the special mixture immediately after the addition of the glucose 1-phosphate solution.

This experiment was performed with a test substance at a concentration of 10 μM specifically to determine the inhibition of glycogen phosphorylase in vitro by the test substance.

Table 2: Biological action

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It is obvious from the table that the compounds of formula I inhibit the action of glycogen phosphorylase and are therefore suitable for reducing the amount of sugar in the blood. They are therefore particularly suitable for the prevention and treatment of type 2 diabetes.

In the following, the preparation of several examples will be described in detail, while the remaining compounds of formula I can be obtained by an analogous procedure.

Example 2

3-{2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl}-acrylic acid

a) 2-chloro-4,5-difluorobenzoyl iocyanate

2-Chloro-4,5-difluorobenzamide is dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated under reflux for 16 hours. The reaction mixture is concentrated under high vacuum and used without further purification in step b.

b) 3-(2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl}-acrylic acid

0.41 g (2.5 mmol) of 3-(2-aminophenyl)-acrylic acid was mixed with 0.76 g (3.5 mmol) of 2-chloro-4,5-difluorobenzoyl-isocyanate from step a) in 6 ml of acetonitrile and brought to the reaction by stirring for 2 hours at 40°C. When it cools down to room temperature, the precipitate is suctioned off, washed twice with acetonitrile, suctioned to dryness and dried. 0.72 g (76%) of the desired product is obtained. Melting point: 188.5°C, decomposition.

Analogously to example 2, examples 1, 8, 9 and 10 were obtained from the corresponding aminoacrylic acids and the corresponding isocyanates.

Example 3

3-{4-acetylamino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl}-acrylic acid

a) 3-{2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-4-nitrophenyl}-acrylic acid methyl ester

1.0 g (4.5 mmol) 3-(2-amino-4-nitrophenyl)-acrylic acid methyl ester (produced by nitration of 3-(2-amino-phenyl)-acrylic acid methyl ester with urea nitrate in conc. sulfur acid) is reacted with 0.98 g (4.5 mmol) of 2-chloro-4,5-difluorobenzoylisocyanate (example 2a) in 6 ml of acetonitrile and stirred for 30 minutes at room temperature. The precipitate is filtered off with suction, washed with diethyl ether and dried. 1.9 g (96%) of the desired product is obtained.

b) Methyl ester of 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl}-acrylic acid

1.9 g (4.3 mmol) of 3-(2-[3-(2-chloro-4,5-di-fluorobenzoyl)-ureido]-4-nitro-phenyl}-acrylic acid methyl ester is heated in 100 ml of acetic acid ethyl ester at boiling temperature and mixed with 4.86 g (21.6 mmol) of SnCl2 monohydrate. After one hour, let it cool to room temperature and adjust to pH 8 with a 10% sodium hydrogen carbonate solution The resulting precipitate is suctioned off and washed with methanol. The organic phase is washed twice with water, dried and concentrated in vacuo. The resulting product is used without further purification in step c).

c) Methyl ester of 3-{4-acetylamino-2-[3-(2-chloro-4,5-difluoro-benzoyl)-ureido]-phenyl}-acrylic acid

0.70 g (1.7 mmol) of 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl}-acrylic acid methyl ester was mixed with 6 ml of N -methylpyrrolidone, 1.11 g (3.4 mmol) of cesium carbonate and 0.27 g (3.4 mmol) of acetyl chloride and stirred for 30 minutes at room temperature. It is diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated. 0.65 g (85%) of the desired product is obtained.

d) 3-{4-acetylamino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl}-acrylic acid

0.65 g (1.4 mmol) of 3-(4-acetylamino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-phenyl)-acrylic acid methyl ester is dissolved in 8 ml of tetrahydrofuran and mixed with 8 ml of water and 0.17 g (7.2 mmol) of lithium hydroxide. After 15 hours at room temperature, it is acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried, concentrated and mixed with diethyl ether. The resulting precipitate is filtered off and 77 mg (13%) of the desired product is obtained. Melting point: 196°C, decomposition.

Example 7

4-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-3-(2-methoxy-carbonyl-vinyl)-benzoic acid

0.22 g (0.5 mmol) of 4-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-3-(2-methoxycarbonyl-vinyl)-benzoic acid methyl ester (example 11 c) dissolve in 10 ml of THF and mixed with 10 ml of water and 0.06 g (2.4 mmol) of lithium hydroxide. After 2 hours, it is acidified with 2 N hydrochloric acid, extracted with ethyl acetate and concentrated. After preparative HPLC (column: Waters Xterra ™MS Cia 5 μm, 30x100 mm, eluant: A: H2O + 0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17 .5 minutes 10% A/90% B) 0.02 g (10%) of the desired product is obtained. Melting point: 99°C

Example 11

4-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-3-(2-methoxy-carbonyl-vinyl)-benzoic acid methyl ester

a) Methyl ester of 4-amino-3-iodobenzoic acid

10.4 g (68.8 mmol) of 4-aminobenzoic acid methyl ester are dissolved in 100 ml of acetic acid and mixed with 11.17 g (68.8 mmol) of iodine monochloride in 100 ml of acetic acid. At the same time, the reaction temperature rises to 30°C. After one hour at room temperature, it is poured onto a 10% solution of sodium hydrogen carbonate, extracted with dichloromethane, the organic phase is dried and concentrated. 14 g (73%) of the desired product is obtained.

b) Methyl ester of 4-amino-3-(2-methoxycarbonyl-vinyl)-benzoic acid

0.5 g (1.8 mmol) methyl ester of 4-amino-3-iodobenzoic acid, 1.1 equiv. acrylic acid methyl ester, 2.5 equiv. of cesium carbonate, 1 eq. (nBu)4NHSO4], 0.1 equiv. of triphenyl-phosphine, 0.1 equiv. of palladium acetate, 2 ml of acetonitrile and 2 ml of water are heated for 5 minutes under an argon atmosphere in a microwave heating chamber at 120°C with 140 Watts. The reaction mixture is mixed with ethyl acetic acid, washed with water, dried and concentrated. 0.3 g (71%) of the desired product is obtained, which reacts in step c) without further purification.

c) Methyl ester of 4-[3-(2-chloro-4, 5-difluorobenzoyl)-ureido]-3-(2-methoxycarbonyl-vinyl)-benzoic acid

Methyl ester of 4-amino-3-(2-methoxycarbonyl-vinyl)-benzoic acid was obtained analogously to example 3 from methyl ester of 4-amino-3-(2-methoxycarbonyl-vinyl)-benzoic acid and 2-chloro-4,5 -difluorobenzoyl isocyanate. Melting point: 183°C

Example 12

a) 4-amino-3-iodobenzoic acid

6.0 g (21.7 mmol) of 4-amino-3-iodo-benzoic acid methyl ester was mixed with 1.73 g (43.3 mmol) of sodium hydroxide in 100 ml of methanol and 100 ml of water and stirred for 16 hours at room temperature. It is adjusted to pH 9 with 2 N hydrochloric acid and extracted with acetic acid ethyl ester. The organic phase is dried and concentrated. 5.1 g (89%) of the desired product is obtained.

b) 4-amino-3-(2-methoxycarbonyl-vinyl)-benzoic acid

0.5 g (1.9 mmol) of 4-amino-3-iodobenzoic acid, 0.18 g (2.1 mmol) of acrylic acid methyl ester, 1.54 g (4.8 mmol) of cesium carbonate, 0.64 g (1.9 mmol) (nBu)4NHSO4, 0.05 g (0.2 mmol) triphenylphosphine and 0.04 g (0.2 mmol) palladium acetate, 1.5 ml acetonitrile and 1.5 ml water are heated for 5 minutes under an argon atmosphere in a microwave heating device at 120°C with 140 Watts.

The reaction mixture is mixed with ethyl acetic acid, washed with water, dried and concentrated. The crude product reacts without further purification in step c).

c) 4-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]-3-(2-methoxycarbonyl-vinyl)-benzoic acid

4-amino-3-(2-methoxycarbonyl-vinyl)-benzoic acid reacts analogously to example 2 b) with 2-chloro-4,5-difluoro-benzoyl isocyanate to give the desired product. Melting point: 216°C.

Claims (10)

1. Compounds of formula I [image] indicated by the fact that in them R7, R8, R9, R10 independently represent H, F, Cl, Br, OH, NO2, CN, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6 )-alkynyl, O-SO2-(C1-C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl or Br; R1, R2 are independently H, (C1-C6)-alkyl, whereby alkyl can be substituted with OH, O-(C1-C4)-alkyl, NH2, NH(C1-C4)-alkyl, N(C1- C6)-alkyl]2, or they are O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6)-alkylene-COOH, (C1-C6)-alkylene-COO-(C1-C6)-alkyl; R3, R4, R5, R6 are independently H, F, Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14), N(R13)COR15, (C1-C6 )-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R16)(R17); R 11 is OR 12 or N(R 18 )(R 19 ); R12 is H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl, Br, OH or O- (C1-C4)-alkyl; R13 and R14 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R13 and R14 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring, which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl, Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl; R16 and R17 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or with CONH2; or the radicals R16 and R17 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring that can contain up to 2 further heteroatoms from the group N, 0 or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl , Br, OH, oxo, N(R20) (R21) or (C1-C4)-alkyl; R18, R19 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R18 and R19 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring that can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl , Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl; R22 and R23 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R22 and R23 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring, which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be up to three times substituted with F, Cl, Br, OH, oxo, N(R20) (R21) or (C1-C4)-alkyl; R15 is (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl can be multiply substituted with F, NH2, NH(C1-C4)-alkyl, N[(C1-C4)-alkyl]2, OH, O-(C1-C4) -alkyl, O-(C2-C4)-alkenyl), O-CO-(C1-C4)-alkyl, or is COOR12, CON(R13)(R14), heteroaryl, (C6-C10)-aryl, ( C 6 -C 10 )-aryl-(C 1 -C 4 )-alkylene, wherein the heteroaryl and aryl may be substituted with O-(C 1 -C 4 )-alkyl, F or Cl, and wherein the alkyl may be polysubstituted by F; R20 and R21 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; as well as their physiologically tolerable salts. 2. Compounds of formula 1, according to claim 1, characterized in that in them R7, R8, R9, R10 are mutually independent H, F, Cl, Br, OH, NO2, CN, O-(C1-C6)-alkyl, O-(C2-C6)-alkenyl, O-(C2-C6 )-alkynyl, O-SO2-(C1-C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl or Br; R1 and R2 are H; R3, R4, R5, R6 are independently H, F, Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14), N(R13)COR15, (C1-C6 )-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R16)(R17); R 11 is OR 12 or N(R 18 )(R 19 ); R12 is H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, wherein alkyl, alkenyl and alkynyl can be multiple substituted with F, Cl, Br, OH or O- (C1-C4)-alkyl; R13, R14 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R13 and R14 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl , Br, OH, oxo, N(R20) (R21) or (C1-C4)-alkyl; R16, R17 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R16 and R17 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl , Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl; R18, R19 are independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R18 and R19 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring, which can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl, Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl; R22 and R23 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; or the radicals R22 and R23 with the nitrogen atom to which they are attached form a 3-7-membered saturated heterocyclic ring that can contain up to 2 further heteroatoms from the group N, O or S, whereby the heterocyclic ring can be substituted up to three times with F, Cl , Br, OH, oxo, N(R20)(R21) or (C1-C4)-alkyl; R15 is (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, wherein alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, NH2, NH (C1-C4)-alkyl, N[(C1-C4)-alkyl]2, OH, O-(C1-C6) -alkyl, O-(C2-C4)-alkenyl), O-CO-(C1-C4)-alkyl, or is COOR12, CON(R13)(R14), heteroaryl, (C6-C10)-aryl, ( C 6 -C 10 )-aryl-(C 1 -C 4 )-alkylene, wherein the heteroaryl and aryl may be substituted with O-(C 1 -C 4 )-alkyl, F or Cl, and wherein the alkyl may be polysubstituted by F; R20 and R21 are mutually independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1 -C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, whereby the phenyl ring can be up to twice substituted with F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO-(C1-C6)-alkyl or CONH2; as well as their physiologically tolerable salts. 3. Compounds of formula I according to claim 1 or 2, characterized in that in them R7, R8, R9, R10 are mutually independently H, F or Cl; R1, R2, R6 are H; R3, R4, R5, R6 are mutually independently H, Cl, COOH, COO-(C1-C4)-alkyl or NHCOR15; R11 is 0R12, N(R18)(R19); R 12 is H or (C 1 -C 4 )-alkyl; R18, R19 are H or (C1-C4)-alkyl; R 15 is (C 1 -C 4 )-alkyl, wherein the alkyl may be substituted with COOH, or it is COOH; as well as their physiologically tolerable salts. 4. Medicine, characterized in that it contains one or more compounds according to one or more claims 1 to 3. 5. Medicine, characterized in that it contains one or more compounds according to one or more claims 1 to 3 and one or more active substances that lower blood sugar. 6. Use of compounds according to one or more claims 1 to 3, characterized in that they are used for the production of a drug for the treatment of type 2 diabetes. 7. The use of compounds according to one or more claims 1 to 3, characterized in that they are used for the production of a medicine for reducing blood sugar. 8. Use of compounds according to one or more of claims 1 to 3, characterized in that they are used in combination with at least one further active substance that lowers blood sugar for the production of a drug for the treatment of type 2 diabetes. 9. The use of compounds according to one or more of claims 1 to 3, characterized in that they are used in combination with at least one further active substance that lowers blood sugar for the production of a medicine for lowering blood sugar. 10. Method for the production of a medicine containing one or more compounds according to one or more claims 1 to 3, characterized in that the active substance is mixed with a pharmaceutically suitable carrier and this mixture is brought into a form suitable for application.