AU2004205352A1 - Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof - Google Patents

Abstract

The invention relates to compounds of formula (I) wherein the radicals have the cited meaning, in addition to the physiologically compatible salts thereof. The compounds, for example, can be used as medicaments for preventing and treating type 2 diabetes.

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EP2004/000041 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EP2004/000041. Date: 5 April 2005 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd WO 2004/065356 PCT/EP2004/000041 Description Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof 5 The invention relates to carbonylamino-substituted acyl phenyl urea derivatives, and also to their physiologically tolerated salts and physiologically functional derivatives. 10 WO 9946236 (Novo Nordisk) describes carbonylamino-substituted acyl phenyl urea derivatives (Example 1) which are effective in the event of type 2 diabetes. WO 00/07991 (PCT/GB99/02489 Astra Zeneca) describes amide 15 derivatives as inhibitors of the formation of cytokines. It is an object of the invention to provide compounds which make possible prevention and treatment of type 11 diabetes. To this end, the compounds should.in particular exhibit a therapeutically utilizable blood sugar-lowering 20 action. The invention therefore relates to compounds of the formula I R4 R3 R5 R8 N N N R7 R9 | | H R1 R2 R6 R10 R11 25 in which R8, R9, R10, R11 are each independently H, F, Cl, Br, OH, N02, CN, 0-(C 1 -C6)alkyl, 0-(C2-C6)alkenyl, 0-(C2-C6)alkynyl, 30 O-SO 2 -(C1-C4)-alkyl, (C1-C 6 )-alkyl, (C2-C6)-alkenyl or (C2-C6)alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl or Br; WO 2004/065356 2 PCT/EP2004/000041 R1, R2 are each independently H, (C1-C6)-alkyl, where alkyl may be substituted by OH, 0-(C1-C4)-alkyl, NH2, NH(C1-C4)-alkyl, N[(C1-C6)-alkyl]2, or are O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, 5 COO-(C1-C6)-alkyl, (C1-C6)-alkylene-COOH or (C1-C6) alkylene-COO-(C1-C6)-alkyl; R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO 2 , CN, O-R12, 0-phenyl, S-R12, COOR12, N(R13)(R14), (C1-C6)-alkyl, 10 (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7) cycloalkyl-(C 1

-C

4 )-alkylene or O-(C1-C5)-alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R13)(R14); 15 R7 is H, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl (C1-C4)-alkylene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6) alkylcarboxy-(C1-C6)-alkylene, COOR12, (C 6

-C

1 0)-aryl, (C6-C1O)-aryl-(C1-C4)-alkylene, heterocyclic radical, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where 20 alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12, CONH2,

CONH(C

1

-C

6 )-alkyl, CON[(C1-C6)-alkyl]2 or N(R13)(R14), and where aryl and heteroaryl may be polysubstituted by F, Cl, Br, NO 2 , CN, O-R12, S-R12, COOR12, N(R13)(R14) or 25 (C1-C6)-alkyl; R12 is H, (C1-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OH or O-(C1-C4)-alkyl, 30 R13, R14 are each 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 S02-phenyl, where the phenyl ring may be up to 35 disubstituted by F, Cl, CN, OH, (C1-C6)-alkyl, 0-(C1-C6)-alkyl, CF3, OCF 3 , COOH, COO(C1-C6)-alkyl or CONH2; WO 2004/065356 3 PCT/EP2004/000041 where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the group of N, 0 and S, where the heterocyclic ring may be up to 5 trisubstituted by F, Cl, Br, OH, oxo, N(R21)(R22) or (C 1

-C

4

)

alkyl; R21, R22 are each independently H, (C1-C 8 )-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl 10 (C1-C4)-alkylene, COO-(C 1 -C4)-alkyl, COO-(C2-C 4 )-alkenyl, phenyl or S02-phenyl, where the phenyl ring may be up to disubstituted by F, Cl, CN, OH, (C1-C6)-alkyl, 0-(C1-C6)-alkyl,

CF

3 , OCF3, COOH, COO(C1-C6)-alkyl or CONH2; 15 excluding compounds of the formula I in which the radicals are at the same time defined as follows: R5 is halogen or unsubstituted (C1-C6)-alkyl, R7 is heterocyclic radical or heteroaryl; 20 and their physiologically tolerated salts. Preference is given to compounds of the formula I in which one or more radicals are defined as follows: 25 R8, R9, R10, R11 are each independently H, F, Cl, Br, OH, NO 2 , CN, 0-(C1-C6)-alkyl, where alkyl may be polysubstituted by F, CI or Br; R1, R2 are each H; 30 R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO 2 , CN, O-R12, 0-phenyl, S-R12, COOR12, N(R13)(R14), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C 3

-C

7

)

cycloalkyl-(C1-C4)-alkylene or O-(C1-C 5 )-alkyl-COOR12, 35 where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R13)(R14); WO 2004/065356 4 PCT/EP2004/000041 R7 is H, (C1-C6)-alkyl, (C 3 -C7)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkylcarboxy-(C1-C6)-alkylene, COOR12, (C 6 -C10)-aryl, (C6-C1 O)-aryl-(C 1 -C4)-alkylene, heteroaryl, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, 5 where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12, CONH 2 ,

CONH(C

1 -C6)-alkyl, CON[(C1-C6)-alkyl]2 or N(R13)(R14), and where aryl and heteroaryl may be polysubstituted by F, Cl, Br, N02, CN, O-R12, S-R12, COOR12, N(R13)(R14) or 10 (C1-C6)-alkyl; R12 is H, (C1-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OH or O-(C1-C4)-alkyl, 15 R13, R14 are each 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, where the phenyl ring may be up to 20 disubstituted by F, CI, CN, OH, (C1-C6)-alkyl, 0-(C1-C6)-alkyl,

CF

3 , OCF 3 , COOH, COO(C1-C6)-alkyl or CONH2; where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the 25 group of N, 0 and S, where the heterocyclic ring may be up to trisubstituted by F, Cl, Br, OH, oxo, N(R21)(R22) or (C1-C4) alkyl; R21, R22 are each independently H, (C1-C8)-alkyl; 30 excluding compounds of the formula I in which the radicals are at the same time defined as follows: R5 is halogen or unsubstituted (C1-C6)-alkyl, R7 is heterocyclic radical or heteroaryl; 35 and their physiologically tolerated salts.

WO 2004/065356 5 PCT/EP2004/000041 Particular preference is given to compounds of the formula I in which one or more radicals are defined as follows: R8, R9, R10, R11 are each independently H, F or Cl; 5 R1, R2, R4, R6 are each H; R3, R5 are each independently H, Cl, OR12, COOR12, N(R13)(R14) or (C1-C6)-alkyl; 10 R7 is (C 1

-C

6 )-alkyl, where alkyl may be polysubstituted by F, OR12, COOR12 or N(R13)(R14), or is (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C5)-alkylcarboxy (C1-C6)-alkylene, COOR12, phenyl, where phenyl may be 15 polysubstituted by F, OMe or OCF3, or is benzyl whose phenyl ring may be substituted by OMe, pyridyl, thienyl, furanyl, indolylcarbonyl, benzofuranyl, where benzofuranyl may be substituted by Cl or OMe; 20 R12 is H or (C1-C8)-alkyl, where alkyl may be polysubstituted by F; R13, R14 are each independently H or (C1-C8)-alkyl; or 25 R13 and R14, together with the nitrogen atom to which they are bonded, may form a 5-membered, saturated heterocyclic ring; excluding compounds of the formula I in which the radicals are at the same time defined as follows: 30 R5 is halogen or unsubstituted (C1-C6)-alkyl, R7 is heterocyclic radical or heteroaryl; and their physiologically tolerated salts. 35 The invention relates to compounds of the formula 1, in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof.

WO 2004/065356 6 PCT/EP2004/000041 The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R21 and R22 may be either straight-chain or branched. 5 When radicals or substituents can occur more than once in the compounds of the formula 1, for example O-R12, they may each independently be as defined and be the same or different. As a consequence of their higher water solubility compared to the starting 10 or basic compounds, pharmaceutically acceptable salts are particularly suitable for medical applications. These salts have to have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, 15 phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also of organic acids, e.g. acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric 20 acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino 2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine. 25 Salts having a pharmaceutically unacceptable anion, for example trifluoroacetate, are likewise encompassed by the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, 30 applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formula I according to the invention, e.g. an ester which is able, on administration to 35 a mammal, e.g. a human, to (directly or indirectly) form a compound of the formula I or an active metabolite thereof.

WO 2004/065356 7 PCT/EP2004/000041 The physiologically functional derivatives also include prodrugs of the compounds according to the invention, for example as described in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound according to the invention. These 5 prodrugs may or may not be active themselves. The compounds according to the invention can also exist in different polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according 10 to the invention are encompassed by the scope of the invention and are a further aspect of the invention. All references given below to "compound(s) of formula I" refer to compound(s) of the formula I as described above, and also to their salts, 15 solvates and physiologically functional derivatives as described herein. In this context, an aryl radical is a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon, indanyl or indan-1-onyl radical. 20 The terms "heterocyclic ring" and "heterocyclic radical" used herein relate to heteroaryl radicals and heterocycloalkyl radicals which derive from 3 to 10 membered carbon rings in which one or more carbon atoms are replaced by one or more atoms selected from the group of oxygen, sulfur and nitrogen. 25 Suitable "heterocyclic rings" and "heterocyclic radicals" are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, 30 quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2 dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, 35 isoindolyl, isoquinolinyl, (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3 oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, WO 2004/065356 8 PCT/EP2004/000041 phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, 5 pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahyd rofuranyl, tetrahyd roisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl. 10 Pyridyl is either 2-, 3- or 4-pyridyl. Thienyl is either 2- or 3-thienyl. Furyl is either 2- or 3-furyl. Also included are the corresponding N-oxides of these compounds, for example 1-oxy-2-, 3- or 4-pyridyl. 15 Also included are one or more benzofused derivatives of these heterocycles. The compound(s) of the formula (1) can also be administered in 20 combination with further active ingredient. The amount of a compound of formula I which is required in order to achieve the desired biological effect is dependent upon a series of factors, for example the specific compound selected, the intended use, the mode of 25 administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may, for example, be in the range from 0.3 mg to 1.0 mg/kg and may advantageously be administered as an infusion of from 30 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Individual doses may contain, for example, from 1 mg to 10 g of the active ingredient. Ampoules for injections may therefore contain, for example, from 1 mg to 100 mg, and single dose 35 formulations which can be administered orally, for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. The compounds of formula I may be used for therapy of the abovementioned conditions as the compounds themselves, although they WO 2004/065356 9 PCT/EP2004/000041 are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier of course has to be acceptable, in the sense that it is compatible with the other constituents of the composition and is not damaging to the health of the patient. The carrier may be a solid or a 5 liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05 to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including further compounds of formula 1. The pharmaceutical compositions according to the invention may be produced 10 by one of the known pharmaceutical methods which consist essentially of mixing the ingredients with pharmacologically acceptable carriers and/or excipients. Pharmaceutical compositions according to the invention are those which 15 are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the type of the compound of formula I 20 used in each case. Coated formulations and coated slow-release formulations are also encompassed by the scope of the invention. Preference is given to acid- and gastric fluid-resistant formulations. Suitable gastric fluid-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic 25 polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical compounds for oral administration may be in the form of separate units, for example capsules, cachets, lozenges or tablets, each of which contains a certain amount of the compound of formula l; as 30 powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) 35 are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. For example, a tablet can be produced by compressing or WO 2004/065356 10 PCT/EP2004/000041 shaping a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets can be prepared by tableting the compound in free-flowing form, for example a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or one (or more) 5 surfactants/dispersants in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions which are suitable for peroral (sublingual) 10 administration include lozenges which contain the compound of formula I with a flavoring, customarily sucrose, and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. 15 Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous preparations of a compound of formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as 20 an injection. These preparations can preferably be produced by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. The injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound. 25 Suitable pharmaceutical compositions for rectal administration are preferably in the form of single dose suppositories. These can be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. 30 Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Useful carriers include petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by 35 weight of the composition, preferably from 0.5 to 2%. Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be in the form of single WO 2004/065356 11 PCT/EP2004/000041 plasters which are suitable for long-term close contact with the epidermis of the patient. Such plasters advantageously contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in a tackifier or dispersed in a polymer. A suitable active ingredient 5 concentration is from approx. 1% to 35%, preferably from approx. 3 to 15%. A particular means of releasing the active ingredient is by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). 10 Further useful active ingredients for combination products are as follows: All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They can be combined with the compounds of the formula I according to the invention, in particular for synergistic enhancement of the action. The active ingredient combination can be administered either by separately 15 administering the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed hereinbelow are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. 20 Antidiabetics include insulin and insulin derivatives, for example Lantus@ (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221,633), GLP-1 derivatives, for example those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients. 25 The orally active hypoglycemic active ingredients preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, for example those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, 30 inhibitors of liver enzymes which are involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists and active ingredients which act on 35 the ATP-dependent potassium channel of the beta cells. In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as WO 2004/065356 12 PCT/EP2004/000041 simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin. In one embodiment of the invention, the compounds of the formula I are 5 administered in combination with a cholesterol absorption inhibitor, for example, ezetimibe, tiqueside, pamaqueside. In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, for example, 10 rosiglitazone, pioglitazone, JTT-501, GI 262570. In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist, for example, GW 9578, GW 7647. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT/US 11833, PCT/US 11490, DE10142734.4. 20 In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, for example, fenofibrate, clofibrate, bezafibrate. 25 In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, for example, implitapide, BMS-201038, R-103757. In one embodiment of the invention, the compounds of the formula I are 30 administered in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), for example, HMR 1741. In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example, JTT-705. 35 In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent, for example, cholestyramine, colesevelam.

WO 2004/065356 13 PCT/EP2004/000041 In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see US 6,342,512), for example, HMR1171, HMR1586. 5 In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, for example, avasimibe. In one embodiment of the invention, the compounds of the formula I are 10 administered in combination with an antioxidant, for example, OPC-14117. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, for example, NO-1 886. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyase inhibitor, for example, SB-204990. 20 In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, for example, BMS-1188494. In one embodiment of the invention, the compounds of the formula I are 25 administered in combination with a lipoprotein(a) antagonist, for example, C1-1027 or nicotinic acid. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example, orlistat. 30 In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin. In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea, for example, tolbutamide, glibenclamide, 35 glipizide or glimepiride. In one embodiment, the compounds of the formula I are administered in combination with a biguanide, for example, metformin.

WO 2004/065356 14 PCT/EP2004/000041 In yet another embodiment, the compounds of the formula I are administered in combination with a meglitinide, for example, repaglinide. In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, for example, troglitazone, ciglitazone, 5 pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3 methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione. In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor, for example, miglitol or 10 acarbose. In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. 15 In one embodiment, the compounds of the formula I are administered in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and mefformin, insulin and troglitazone, insulin and lovastatin, etc. 20 In a further embodiment, the compounds of the 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 25 (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4 tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo 2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1 -(4-chlorophenyl)-2 30 oxo-ethyl]amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2 methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB 334867-A)), H3 agonists (3-cyclohexyl-1 -(4,4-dimethy-1,4,6,7 tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1 -one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6 35 trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, P3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6 yloxy)ethylamino]ethanol hydrochloride (WO 01/83451)), MSH WO 2004/065356 15 PCT/EP2004/000041 (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-{4-(4 chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl] 5,7- dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed serotoninergic 5 and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3 ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2 diisopropylaminoethylcarbamoyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylic 10 acid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, 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 15 agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR p agonists. In one embodiment of the invention, the other active ingredient is leptin, 20 see, for example, "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 other active ingredient is dexamphatamine or 25 amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat. 30 In one embodiment, the other active ingredient is mazindol or phentermine. In one embodiment, the compounds of the formula I are administered in combination with dietary fiber materials, preferably insoluble dietary fiber materials (see, for example, Carob/Caromax@ (Zunft H J; et al., Carob pulp 35 preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob-containing product supplied by Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark H6chst, 65926 Frankfurt/Main)). Combination with WO 2004/065356 16 PCT/EP2004/000041 Caromax@ is possible in one preparation or by separate administration of compounds of the formula I and Caromax@. Caromax@ can also be administered in the form of foodstuffs, for example, in bakery products or muesli bars. 5 It will be appreciated that any suitable combination of the compounds according to the invention with one or more of the abovementioned compounds and optionally one or more further pharmacologically active substances is regarded as being covered by the scope of protection of the 10 present invention.

WO 2004/065356 17 PCT/EP2004/000041

CH

3

CH

3 0 N 0 CH 3 OH HN N 0 NH CH 3

H

3 C CH 3

S

3

CH

3

CH

3 OPC-14117

CH

3 JTT-705 CI O00 Br 01 SB-204990 HO O CH N 0 CH 3 NO-1886 0 OH

H

3 C OH CH 3 HC CH 3 O C1-1027 * ~HO /H0 H H CH 0 O H 3 01!" H 3 0'0 OH 3 BMS-188494

CH

3 N 0

OH

3 0 CH3 OH H

-

N 0 0 GI 262570 0 CH /0 N N N0 0 H JTT-501 The examples recited hereinbelow serve to illustrate the invention, but without restricting it.

WO 2004/065356 18 PCT/EP2004/000041 No example which is exactly analogous to compounds of the formula I is cited in WO 9946236. Example A was therefore selected as the most similar compound. The compounds of this application are distinguished from Comparative Example A are distinguished by an increased activity on 5 glycogen phosphorylase a, see Table 2.

U:LL L CO u) CN NC N zz 0 0 0D 10 00 oZ -=

Z

00 00 (DI 'a000 Cuu E

M

00

.

&ULL UU:L: LU:L:L: L L LO LO ) fL L In L LLO U)) LO LO ) ) V ) L) V) 1U) U) U) LO) U) Uf) U-) U) in) LO LO in) in cNj C.10 C' C4 CN C'J C AN (N( N( N( N(N( N( N( N(N( N( N N NM 0 0 z' 0 0' 0 00 0 00 0 10 0- M, T9, 0 09 M: 0o : 0 D M 3 0 f L) lo C) ) CO 0 0010 0OU i0ON~ 0 U-00 00t- ,-0--~ U0 o0 0 0 2 CN N NY N 00000000000m0,0C.,0000000000e~04 (0UMMMOOOO 0000 ~ ~ 0 ololoooooo0000 00 I'O 'C M1 c MI M 1001001 LL U LL LL: U..:L:U:L:L:L: L L L L:L:L LLLLLLL :U LC L ILL7 06 0 a u a 0 L) U 0 0 L) Q -2 C . L O LL;I EU IL L~ - 5, i oC - 0 - l () i.. = -u0 0 2c - 0 0 -(D 2- C~ 0) 02 N) C_ N2= NNN C0 a -L 0 : 2 04OO O~ N CV mLo0vNC c;- o N 13 0 Y l0u NO, -, M, 3.: -- C 3: NO M NO MM3 Ma ~ ~ i a. QIE: :=11III: MMMX3 :M:l :M 7: 7.±o MmmmmWD 0000000001000000000001000 0000 NOOOOOO000000 00 m ' ,.CMM34rMM3:MZ Q) (1) cu) uru Lo L 0 tnLo 0 o Lh6 L L66 L L6L6 .. .Lo o U 0 n + . . . . . . . . . . . I u- - u u-u-u- . u u u-u- - u L LCU: : 5 55 55 5U:LC Z L:+ Cu ~ 0 CD 00 0 o o ON0 0 00 o oE M0 o'9 00003 ,M 0 C. M 1' 00 0 0110 U0 00 0 0 -N II 001 u- N C- -,o991 N 55 N" N MMV Yc N 3: 04 1:0 C14 000I 0000000000 000000 0:00 0 00C CA cu Lo E 0 0I I I I I I I I I I I I I I 7: ~ ~~~ ~ ~ ~ ~ U) M II I IMMMMjMMMMII :M Z C ~ 2 ___ W_ w w- WC UL C4o ------------------------------ MM M 2 Cu M II :31:T ZMTlll :MXMXM1 0 ---- --- --- ---- --- --- --- E) a) 0. u WO 2004/065356 23 PCT/EP2004/000041 The effectiveness of the compounds was tested as follows: Glycogen phophorylase a activity test 5 The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by monitoring the synthesis of glycogen from glucose 1-phosphate by determining the release of inorganic phosphate. All reactions were carried out as duplicate determinations in 96-well microtiter plates (half area plates, Costar No. 10 3696), and the change in absorption as a consequence of the formation of the reaction product was measured at 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 15 was measured 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 containing 0.76 mg of protein / ml (Aventis Pharma Deutschland GmbH), dissolved in buffer solution E (25 mM p-glycerophosphate, pH 7.0, 1 mM 20 EDTA and 1 mM dithiotreitol) was diluted to a concentration of 10 pg of protein/ml with buffer T (50 mM Hepes, pH 7.0, 100 mM KCI, 2.5 mM EDTA, 2.5 mM MgCI2.6H20) and addition of 5 mg/ml of glycogen. Test substances were prepared as a 10 mM solution in DMSO and diluted to 50 pM with buffer solution T. To 10 pl of this solution were added 10 pl of 37.5 25 mM glucose dissolved in buffer solution T and 5 mg/ml of glycogen, and also 10 pl of a solution of human glycogen phosphorylase a (10 pg of protein/ml) and 20 pl of 2.5 mM glucose 1-phosphate. The base value of the activity of glycogen phosphorylase a in the absence of test substance was determined by adding 10 pl of buffer solution T (0.1% DMSO). The 30 mixture was incubated at room temperature for 40 minutes and the released inorganic phosphate was determined by means of 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 pl of a stop solution of 7.3 mM of ammonium molybdate, 10.9 mM of zinc acetate, 35 3.6% of ascorbic acid, 0.9% of SDS are added to 50 pl of the enzyme mixture. After 60 minutes of incubation at 45 0 C, the absorption was measured at 820 nm. To determine the background absorption, the stop solution was added immediately after the addition of the glucose 1- WO 2004/065356 24 PCT/EP2004/000041 phosphate solution in a separate reaction. This test was carried out at a concentration of 10 pM of the test substance, in order to determine the respective inhibition of glycogen phosphorylase a by the test substance in vitro. 5 Table 2: Biological activity Ex. % Inhibition Ex. % Inhibition at 10 pM at 10 pM 1 99 35 99 2 99 36 101 3 104 37 101 4 97 38 102 5 99 39 101 6 100 40 98 7 100 41 104 8 100 42 83 10 95 43 98 11 96 44 101 12 90 45 97 13 94 46 102 14 91 47 105 15 101 48 97 16 95 49 99 17 100 50 94 18 99 51 92 19 97 52 101 20 95 53 100 22 96 54 100 25 95 55 100 26 97 56 99 27 98 57 99 28 89 58 99 29 98 59 103 30 101 60 103 31 98 61 100 32 102 62 101 33 96 64 101 34 97 65 98 WO 2004/065356 25 PCT/EP2004/000041 Ex. % Inhibition Ex. % Inhibition at 10 pM at 10 pM 66 100 79 80 67 101 80 98 68 101 81 97 69 100 82 102 70 99 83 103 71 97 84 100 72 96 85 98 73 97 86 95 74 98 87 96 75 100 88 97 76 99 77 98 78 86 Comparative Example A exhibits no inhibition at a concentration of 10 pM 5 and 11% inhibition at a concentration of 100 pM. It can be seen from the Table that the compounds of the formula I inhibit the activity of glycogenphosphorylase a and are therefore very suitable for lowering the blood sugar level. In particular, the compounds of the formula I 10 exhibit distinctly increased action compared to Comparative Example A.

WO 2004/065356 26 PCT/EP2004/000041 The preparation of some examples is described in detail hereinbelow, and the remaining compounds of the formula I were obtained in a similar manner: 5 Experimental section: Example 1: N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4 methoxyphenyl}acetamide 10 a) 2-Chloro-4,5-difluorobenzoyl isocyanate 2-Chloro-4,5-difluorobenzamide was dissolved in dichloromethane, admixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in 15 stage b without further purification. b) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea 1 g (5.9 mmol) of 2-methoxy-5-nitroaniline were admixed with 1.3 g 20 (5.9 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from stage a in 2 ml of N-methylpyrrolidone and reacted at room temperature for one hour. The precipitate was filtered off, washed twice with 5 ml of acetonitrile each time and dried under high vacuum. 2.2 g of the desired product were obtained which were used in stage c without further purification. 25 c) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(5-amino-2-methoxyphenyl)urea 2.2 g (5.7 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5 nitrophenyl)urea were heated to the boiling temperature in 50 ml of ethyl 30 acetate and admixed with 6.4 g (28.5 mmol) of SnC2 monohydrate. After 1 hour, the mixture was allowed to cool to room temperature and the pH was adjusted to 8 using 2 N sodium hydroxide solution. The precipitate which formed was filtered off and washed with methanol, and the mother liquor was washed twice with H20, dried and concentrated under reduced 35 pressure. The resulting product (1.4 g) was reacted in step d without further purification.

WO 2004/065356 27 PCT/EP2004/000041 d) N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4 methoxyphenyl}acetamide 0.10 g (0.3 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(5-amino-2 5 methoxyphenyl)urea was admixed with 1 ml of N-methylpyrrolidone, 0.11 g (0.3 mmol) of acetic anhydride and stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of H20 and extracted three times with 20 ml of ethyl acetate each time. The combined organic phase was washed with H 2 0, concentrated and dried. The crude product was purified by 10 preparative HPLC (column: Waters XterraTM MS C18, 5 pm, 30 x 100 mm, eluent: A: H 2 0 + 0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 0.03 g of the desired product was obtained. Melting point 225-228*C. 15 In a similar manner to Example 1, Examples 2-8, 27-62 and 78-88 were prepared from the corresponding nitroanilines and the corresponding isocyanates, if necessary with the use of appropriate protecting group techniques. 20 Example 64: N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4 trifluoromethoxyphenyl}acetamide a) 3-Nitro-4-trifluoromethoxyaniline 25 Method according to Syn. Commun. 1988, 18 (16+17), 2161-2165 3.0 g (17 mmol) of 4-trifluoromethoxyaniline were dissolved in 10 ml of conc. sulfuric acid, cooled to 0-10*C and admixed in portions with 2.1 g (17 mmol) of urea nitrate, in such a way that the temperature did not 30 exceed 100C. After the addition had ended, stirring was continued for 10 minutes and then the solution was poured into ice. The mixture was extracted using dichloromethane, the combined organic phases were dried and the solvent was distilled off under reduced pressure. The product was used in the next stage without further purification (yield 2.8 g, 75%). 35 The 3-nitro-4-trifluoromethoxyaniline obtained in this way was reacted with acetyl chloride in a similar manner to method d for Example 1, WO 2004/065356 28 PCT/EP2004/000041 hydrogenated with hydrogen in the presence of Pd/C and reacted with 2 chloro-4,5-difluorobenzoyl isocyanate to give the acyl urea. Melting point 216-218 0 C 5 In a similar manner, Examples 65 to 70 were prepared by using other acylating agents in accordance with Example 1d. Example 73: N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-pyrrolidin-1 ylphenyl}acetamide 10 a) N-(2-Fluoro-5-nitrophenyl)acetamide 5.0 g (32 mmol) of 2-fluoro-5-nitroaniline were admixed with 10 ml (110 mmol) of acetic anhydride and 0.1 ml of conc. sulfuric acid and stirred 15 at 100 0 C for 1.5 hours. The solution was added to 100 ml of ice/water, and the precipitate which formed was filtered off and washed with water. The crude product was purified by chromatography (1:1 ethyl acetate/heptane) on silica gel (yield 5.4 g, 85%). Melting point 174-176 0 C 20 b) N-(5-Nitro-2-pyrrolidin-1-ylphenyl)acetamide 0.5 g (2.5 mmol) of N-(2-fluoro-5-nitrophenyl)acetamide was admixed in a pressure reaction vessel with 1 ml (12.6 mmol) of pyrrolidine and stirred at 25 90*C for 2.5 hours. After the mixture had been cooled, it was diluted with 20 ml of dichloromethane, adjusted to pH 4 using citric acid solution (10%) and washed four times with water. After the organic phase had been dried, the solvent was removed under reduced pressure. In the aqueous phase, a solid is precipitated out. It was filtered off with suction and washed with 30 water, and combined with the residue from the organic phase (yield 0.58 g, 93%). The product was reacted in stage c without further purification. Melting point 210-213 0 C c) 5-Nitro-2-pyrrolidin-1-ylaniline 35 0.58 g (2.3 mmol) of N-(5-nitro-2-pyrrolidin-1-ylphenyl)acetamide was admixed with 12 ml of conc. hydrochloric acid and heated to reflux for 1.5 hours. The solution was added to 100 ml of ice/water, neutralized with 2 N WO 2004/065356 29 PCT/EP2004/000041 sodium hydroxide solution and admixed three times with ethyl acetate. After the mixture had been dried, the solvent was distilled off under reduced pressure to obtain the product quantitatively as a red solid which was used for the reactions a-d described in Example 1 without further 5 purification (reaction with the acyl isocyanate, reduction with SnCl 2 and acylation with Ac20). Melting point 175-180 0 C In a similar manner to Example 73, Examples 71, 72 and 74-77 were 10 prepared from the corresponding amines and the particular acylating agents, if necessary with the use of customary protecting group techniques. In the synthesis of Examples 19-26 and 63, 4-amino-3-methoxybenzoic acid was nitrated with urea nitrate in a similar manner to Example 64a. The 15 synthetic route which followed proceeded in a similar manner to that described in Example 1. To synthesize Examples 9-18, N-(4-methoxy-2-methylphenyl)acetamide or N-(2-methoxy-4-methylphenyl)acetamide were nitrated under customary conditions (HNO 3 /HOAc), the amide was hydrolyzed using conc. 20 hydrochloric acid (in a similar manner to Example 73c) and reacted further as described for Example 1.

Claims (11)

1. Compounds of the formula I R4 R3 R5 R8 N N N R7 R9 | H RI R2 R6 5 RIO RII in which R8, R9, R10, R11 are each independently H, F, Cl, Br, OH, N02, CN, 10 0-(C 1 -C6)alkyl, 0-(C2-C6)alkenyl, 0-(C2-C6)alkynyl, Q-S0 2 -(C 1 -C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, CI or Br; 15 R1, R2 are each independently H, (C1-C 6 )-alkyl, where alkyl may be substituted by OH, 0-(Cl-C4)-alkyl, NH2, NH(C1-C 4 )-alkyl, N[(C1-C6)-alkyl]2, or are O-(C 1 -C6)-alkyl, CO-(C 1 -C6)-alkyl, COO-(C 1 -C6)-alkyl, (C1-C6)-alkylene-COOH or (C1-C6) alkylene-COO-(C1-C6)-alkyl; 20 R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO 2 , CN, 0-R12, 0-phenyl, S-R12, COOR12, N(R13)(R14), (C 1 -C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7) cycloalkyl-(C1-C4)-alkylene or O-(C1-C 5 )-alkyl-COOR12, 25 where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R13)(R14); R7 is H, (C1-C 6 )-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl (C 1 -C4)-alkylene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6) 30 alkylcarboxy-(C1-C6)-alkylene, COOR12, (C6-C1o)-aryl, (C6-C10)-aryl-(C1-C4)-alkylene, heterocyclic radical, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where WO 2004/065356 31 PCT/EP2004/000041 alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, CI, Br, OR12, COOR12, CONH 2 , CONH(C1-C 6 )-alkyl, CON[(Cl-C6)-alkyl]2 or N(RI13)(R14), and where aryl and heteroaryl may be polysubstituted by F, 5 CI, Br, N02, CN, O-R12, S-R12, COOR12, N(R13)(R14) or (C1-C6)-alkyl; R12 is H, (C1-C8)-alkyl, (C2-C 8 )-alkenyl or (C2-C8)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, 10 OH or O-(C1-C4)-alkyl, R13, R14 are each independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl (C1-C4)-alkylene, COO-(C 1 -C 4 )-alkyl, COO-(C2-C 4 )-alkenyl, 15 phenyl or S02-phenyl, where the phenyl ring may be up to disubstituted by F, Cl, CN, OH, (C1-C6)-alkyl, 0-(C1-C6)-alkyl, CF3, OCF 3 , COOH, COO(C1-C6)-alkyl or CONH 2 ; where R13 and R14, together with the nitrogen atom to which they are 20 bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the group of N, 0 and S, where the heterocyclic ring may be up to trisubstituted by F, CI, Br, OH, oxo, N(R21)(R22) or (C 1 -C 4 ) alkyl; 25 R21, R22 are each independently H, (C1-C 8 )-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl (C1-C4)-alkylene, COO-(C 1 -C4)-alkyl, COO-(C2-C 4 )-alkenyl, phenyl or S02-phenyl, where the phenyl ring may be up to 30 disubstituted by F, CI, CN, OH, (C1-C6)-alkyl, 0-(C1-C 6 )-alkyl, CF3, OCF3, COOH, COO(C1-C 6 )-alkyl or CONH2; excluding compounds of the formula I in which the radicals are at the same time defined as follows: 35 R5 is halogen or unsubstituted (C1-C6)-alkyl, R7 is heterocyclic radical or heteroaryl; WO 2004/065356 32 PCT/EP2004/000041 and their physiologically tolerated salts.

2. Compounds of the formula I as claimed in claim 1, wherein 5 R8, R9, R10, R11 are each independently H, F, Cl, Br, OH, N02, CN, 0-(C1-C6)-alkyl, where alkyl may be polysubstituted by F, Cl or Br; R1, R2 are each H; 10 R3, R4, R5, R6 are each independently,.H, F, Cl, Br, N02, CN, O-R12, 0-phenyl, S-R12, COOR12, N(R13)(R14), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7) cycloalkyl-(C1-C4)-alkylene or O-(C1-C5)-alkyl-COOR12, 15 where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R13)(R14); R7 is H, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkylcarboxy-(C1-C6)-alkylene, 20 COOR12, (C 6 -C1o)-aryl, (C6-C1O)-aryl-(C1-C4)-alkylene, heteroaryl, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON[(C 1 -C 6 )-alkyl] 2 or N(R13)(R14), 25 and where aryl and heteroaryl may be polysubstituted by F, Cl, Br, NO 2 , CN, O-R12, S-R12, COOR12, N(R13)(R14) or (C1-C6)-alkyl; R12 is H, (Cl-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-alkynyl, where 30 alkyl, alkenyl and alkynyl may be polysubstituted by F, C1, Br, OH or O-(C1-C4)-alkyl, R13, R14 are each independently H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl 35 (C1-C4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or S02-phenyl, where the phenyl ring may be up to disubstituted by F, Cl, CN, OH, (C1-C6)-alkyl, 0-(C1-C6)-alkyl, WO 2004/065356 33 PCT/EP2004/000041 CF 3 , OCF 3 , COOH, COO(C 1 -C 6 )-alkyl or CONH 2 ; where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further 5 heteroatoms from the group of N, 0 and S, where the heterocyclic ring may be up to trisubstituted by F, Cl, Br, OH, oxo, N(R21)(R22) or (C1-C 4 )-alkyl; R21, R22 are each independently H, (Cl-C8)-alkyl; 10 excluding compounds of the formula I in which the radicals are at the same time defined as follows: R5 is halogen or unsubstituted (C1-C6)-alkyl, R7 is heterocyclic radical or heteroaryl; 15 and their physiologically tolerated salts.

3. Compounds of the formula I as claimed in claim 1 or 2, where 20 R8, R9, R1O, R11 are each independently H, F or Cl; R1, R2, R4, R6 are each H; R3, R5 are each independently H, Cl, OR12, COOR12, N(R13)(R14) 25 or (C1-C6)-alkyl; R7 is (C1-C6)-alkyl, where alkyl may be polysubstituted by F, OR12, COOR12 or N(R13)(R14), or is (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C5)-alkylcarboxy 30 (C1-C6)-alkylene, COOR12, phenyl, where phenyl may be polysubstituted by F, OMe or OCF3, or is benzyl whose phenyl ring may be substituted by OMe, pyridyl, thienyl, furanyl, indolylcarbonyl, benzofuranyl, where benzofuranyl may be substituted by Cl or OMe; 35 R12 is H or (C1-C8)-alkyl, where alkyl may be polysubstituted by F; WO 2004/065356 34 PCT/EP2004/000041 R13, R14 are each independently H or (C1-C8)-alkyl; and where R13 and R14, together with the nitrogen atom to which they are bonded, 5 may form a 5-membered, saturated heterocyclic ring; excluding compounds of the formula I in which the radicals are at the same time defined as follows: R5 is halogen or unsubstituted (C1-C6)-alkyl, R7 is heterocyclic radical or 10 heteroaryl; and their physiologically tolerated salts.

4. A pharmaceutical comprising one or more of the compounds as 15 claimed in one or more of claims 1 to 3.

5. A pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3 and one or more blood sugar reducing active ingredients. 20

6. A pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3 and one or more statins.

7. The use of the compounds as claimed in one or more of claims 1 to 25 3 for producing a medicament for treating type 2 diabetes.

8. The use of the compounds as claimed in one or more of claims 1 to 3 for producing a medicament for lowering blood sugar. 30

9. The use of the compounds as claimed in one or more of claims 1 to 3 in combination with at least one further blood sugar-reducing active ingredient for producing a medicament for treating type 2 diabetes

10. The use of the compounds as claimed in one or more of claims 1 to 35 3 in combination with at least one further blood sugar-reducing active ingredient for producing a medicament for lowering blood sugar. WO 2004/065356 35 PCT/EP2004/000041

11. A process for producing a pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and bringing this mixture into a form which is suitable for 5 administration.