OA12805A - Acyl-4-carboxyphenylurea derivatives, processes for their preparation and their use - Google Patents

Abstract

The invention relates to acyl-4-carboxyphenylurea derivatives, the physiologically-acceptable salts, physiologically-functional derivatives thereof and compounds of formula (I), where the groups have the given meanings, the physiologically acceptable salts and method for production thereof. Said compounds are suitable, for example, as anti-diabetics.

Description

The invention relates to acyl-4-carboxyphenylurea derivatives and their physiologically tolerated and physiologically functional salts.

Patent specification EP 0 193 249 (Duphar) describes acylcarboxyphenylurea derivatives which have anti-tumor activity. The aim of the invention was to provide compounds which can be used for the prevention and treatment of type 2 diabetes. In particular, the aim was to make available new compounds which have an effect which is significantly greater than that of the compounds disclosed in the literature of EP 0 193 249. Invention

Therefore, compounds of formula I relate to

wherein R7, R8, R9 and R10 independently of one another are H, F, Cl, Br, OH, NO2, CN, O-C1-C6 alkyl; C2-C6alkyl, C2-C6alkenyl, C6-C6alkyl, C6-C6alkenyl or C6-C6alkynyl, wherein alkyl, alkenyl and alkynyl may be substituted one or more times with F, Cl or Br; R 1 and R 2 represent, independently of one another, an H atom, a C 1 -C 6 alkyl group, wherein alkyl may be substituted with an OH, O-C 1 -C 4 alkyl, NH 2, NH- C1-C4 alkyl or N-C1-C6 alkyl, C2-C6 alkyl, CO-C1-C8 alkyl, COO-C1-C8 alkyl, C1-C8 alkylene-COOH or C 1 -C 6 alkylene-COO-C 1 -C 6 alkyl, R 3 is H, F, Cl, Br, unsubstituted NO 2, CN, O-R 11, O-phenyl, S-R 11, COOR 11, N (R12) (R13), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkyl-C4-C4alkylene, wherealkyl, cycloalkyl and alkynyl may be substituted once or more by F, Cl, Br, OR11, COOR11 or N (R16) (R17); R4 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C6alkyl, C2-alkenyl; -C6, C2-C6 alkynyl, C3-C7 cycloalkyl or C3-C7 cycloalkyl-C1-C4alkylene, wherein alkyl, cycloalkyl and alkynyl may be substituted, once or more, by F, Cl, Br, OR11. , COOR11 or N (R16) (R17); R5 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C8 alkyl, alkenyl C 1 -C 7 alkynyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 4 alkylene, wherein alkyl, cycloalkyl and alkynyl may be substituted, once or

Br, OR11, COOR11 or N (R16) (R17); R6 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C6 alkyl, alkenyl C2-C6, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkyl-C4-C4alkylene, whereinalkyl, cycloalkyl and alkynyl may be substituted one or more times with F, Cl, Br, OR11, COOR11 or N (R16) (R17);

R 11 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, whereinalkyl, alkenyl and alkynyl may be substituted one or more times with F, Cl, Br, OH or O; -C1-C4alkyl; R12 and R13 independently of one another are H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl; C 1 -C 4 alkylene, COO-C 1 -C 4 alkyl, COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted, up to two times, with F, Cl, CN, OH C 1 -C 6 alkyl, C 1 -C 6 alkyl, CF 3, OCF 3, COOH, COO-C 1 -C 6 alkyl or CONH 2; or R12 and R13 form, together with the nitrogen atom which they are bound, a saturated 3- to 7-membered heterocycle which may contain up to 2 additional heteroatoms of the N, O or Set group where the heterocycle may be substituted, up to four times, by F, Cl, Br, OH, Oxo, C 1 -C 4 -alkyl or N (R 14) (R 15); R14 and R15 independently of one another are H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C7cycloalkyl, C3-C7cycloalkyl -alkylene; C 1 -C 4 COO-C 1 -C 4 alkyl, COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted, up to two times, by F, Cl, CN, OH, alkyl C₁-Cg, O-C₁-C C alkyl, CF3, OCF3, COOH, COO-C₁-C alkyle alkyl or CONH₂; R16 and R17 independently of one another are H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl -alkylene in Οχ-Ο4, COO-C 1-4 alkyl, COO-C 2-4 alkenyl, 012805 4 phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted, up to two times, by F, Cl, CN, OH, C1-C6 alkyl, C1-C6-alkyl, CF3, OCF3, COOH, COO-en-6 alkyl or CONH2; Or R16 and R17 form, together with the nitrogen atom which they are bound, a saturated 3 to 7-membered heterocycle which may contain up to 2 additional heteroatoms of the N, O or Set group where the heterocycle may be substituted, up to to four times, by F, Cl, Br, OH, Oxo, alkyl

Cx-C4 or N (R14) (R15); always placing itself in the case where at least one of R3, R7, R8, R9 and R10 is not hydrogen, and their physiologically tolerated salts.

Preference is given to compounds of formula Id in which one or more radicals have the following meanings: R 7, R 8, R 9 and R 10 represent, independently of one another, an H, F, Cl, Br atom, an OH group , NO2, CN, C1-C6alkyl or C1-C6alkyl, whereinalkyl may be substituted, once or more, with F; R1 and R2 are H; R3 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), Οχ-ΟO-alkyl, C2-alkenyl; -C 6, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 4 alkylene, wherein alkyl, cycloalkyl and alkynyl may be substituted one or more times by F, Cl, Br, OR OR COOR11; R4 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C6alkyl, where alkyl may be substituted, once or more times, by F; R5 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C₁-C alkylealkyl, wherein alkyl may be substituted, one or more times, withF; R6 is H, F, Cl, NO2, O-R11, N (R12) (R13) or (C1-C6) alkyl, wherein alkyl may be substituted, once or more times, with F;

R 11 is H, C 1-10 alkyl, C 1-6 alkyl, C 1-8 alkyl, C 1-8 alkyl, or C 1-6 alkyl.

C 1 -C 8 -OH, wherein alkyl may be substituted, one or more times, with F; RI 2 and RI 3 represent, independently of each other, an H atom or a C 1 -C 15 alkyl group;

or R12 and R13 form, together with the nitrogen atom which they are bonded, a saturated 3- to 7-membered heterocycle which may contain up to 2 additional heteroatoms of the N, O or S group and wherein the heterocycle may be substituted, up to four times with F, Cl, Br, OH, Oxo, C 1 -C 4 -alkyl OR N (R 14) (R 15); R 14 and R 15 independently of one another are H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl, 0-4 alkylene, COO-C 1 -C 4 alkyl COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted up to two times by F, Cl, CN, OH, C₁-C - alkyl, O-C₁-C alkyle alkyl, CF3, OCF3, COOH, COO-C₁-C alkyle alkyl or CONH₂, and their physiologically tolerated salts.

A very particular preference is given to the compounds of formula I wherein one or more radicals have the following meaning: R7, R8, R9 and R10 independently of one another represent an H, F, Cl, Br atom or a group CH3 or CF3; R1, R2, R5 represent an H atom; R3 is H, F, Cl, N02, O-R11, N (R12) (R13) or C1-6alkyl, alkyl may be substituted, one or more times, with F; R4 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C8alkyl, which may be substituted, one or more times, by F; R6 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C₁-C alkylealkyl, which may be substituted one or more times with F;

R 11 is H or C 1 -C 8 alkyl, which alkyl may be substituted one or more times with F; R 12 and R 13 represent an H atom or a C 1-6 alkyl group, or both R 12 and R 13 form, together with the nitrogen atom to which they are bonded, a saturated 5 to 6 membered heterocyclic ring which may contain an oxygen atom additional; and their physiologically tolerated salts.

A very particular preference is furthermore given to the compounds of formula I in which one or more radicals have the following meaning: R7, R8, R9 and R10 represent, independently of one another, an H, F, Cl atom, Br or a CH3 or CF3 group; R1, R2, R4, R5 and R6 are H; R3 is H, F, Cl, NO2, O-

R 11, N (R 12) (R 13) or C 1 -C 6 alkyl, which may be substituted one or more times with F;

R 11 is H or C 1 -C 8 alkyl, which alkyl may be substituted one or more times with F; R 12 and R 13 represent an H atom or a C 1 -C 8 alkyl group, or the two R 12 and R 13 radicals together with the nitrogen atom to which they are attached form a saturated 5 to 6 membered heterocyclic ring which may contain an oxygen atom additional; and their physiologically tolerated salts.

Preference is additionally given to the compounds of formula I in which R3 is not H.

In a particularly preferred manner, R3 is OCF3.

Preference is given to compounds of formula Idans in which at least one of the radicals R7, R8, R9 andRIO is not H.

Particular preference is given to compounds of formula I wherein at least one of R7, R8, R9 and R10 is F or Cl.

Very particular preference is given to the compounds of formula I wherein at least two radicals R7, R8, R9 and R10 are F or Cl.

Very particular preference is given to the compounds of formula I wherein the radicals R 7, R 8, R 9 and R 10 are 2-Cl, 4-F, 5-F and H.

If the radicals or substituents may appear more than once in the compounds of formula I, such as -O-R11, then they may all, independently of one another, have the given meanings and be identical or different. The invention relates to the compounds of formula I, in the form of racemates, racemic mixtures and pure enantiomers, and their diastereoisomers and mixtures thereof.

The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 may be either linear or 012805 δ 10 15 20 25 Branched. Because of their higher solubility in water compared to that of the starting compounds or base compounds, the pharmaceutically tolerated salts are particularly suitable for medical applications. These salts must have a pharmaceutically tolerated anion cation. Suitable acid addition salts of the pharmaceutically acceptable compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and the like. and also organic acids, such as acetic acid, benzenesulphonic acid, benzoic acid, citric acid, ethanesulphonic acid, furaaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts), alkaline earth metal salts (such as magnesium salts and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.

Particular preference is given to the salts of tromethamol (also tris (hydroxymethyl) methylamine) formula I. They present called TRIS, compounds with a higher bioavailability than corresponding free acids

OH

TRIS 9 61280 5

Salts which contain an anion which is not pharmaceutically pasteurized, such as trifluoroacetate, are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically tolerable salts and / or for the use thereof. in non-therapeutic applications, for example in vitro.

The term "physiologically functional derivative" which is used herein means any physiologically derivatized derivative of a compound according to the invention of formula I, for example an ester which, when administered to a mammal, is a human, forming (directly or indirectly) a compound of formula I or an active metabolite thereof.

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

The compounds according to the invention may also be present in different polymorphic forms, for example as amorphous and polymorphic crystalline forms. All the polymorphic forms of the compounds according to the invention are within the scope of the invention and are another aspect of the invention. In the following, all references to "compound (s) according to formula I" refer to the compounds of formula I as described above and their physiologically functional salts, solvates and derivatives as described herein. The compound (s) of formula (I) may also be administered in combination with other active compounds. 012805 - 10

The amount of a compound according to Formula I that is required in order to achieve the desired biological effect depends on a number of factors, e.g. the specific compound that is selected, the intended use, the nature of the administration and the clinical condition of the patient. In general, the daily dose is in the range of 0.3mg to 100mg (typically 3mg and 50mg) per day of body weight, for example 3-10mg / kg / day. An intravenous dose may, for example, be in the range of 0.3 mg to 1.0 mg / kg, which dose may advantageously be administered by infusion of 10 ng to 100 ng per kilogram per minute. Perfusion solutions which are suitable for these uses may, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individual doses may, for example, contain from 1 mg to 10 g of the active compound. Thus, ampoules for injections may, for example, contain from 1 mg to 100 mg, and administratively administrable individual dose formulations, such as tablets or capsules may, for example, contain 1.0 to 1000 mg, typically 10 to 600 mg. While for the therapy of the above-mentioned conditions, compounds according to formula I can themselves be used as compounds, they are preferably present, together with a tolerated excipient, in the form of a pharmaceutical composition. The carrier must of course be tolerated in the sense that it is compatible with the other components of the composition and is not detrimental to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated together with the compound in an individual dose, for example a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may also be present, including other compounds according to formula I. The pharmaceutical compositions according to the invention may be prepared using one of the known pharmaceutical methods, which essentially consist in mixing the components with excipients. and / or auxiliary substances which are pharmacologically isolated.

The pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) administration, even if the method of administration is It is more appropriate in each individual case to determine the nature and severity of the condition to be treated and the nature of the compound of formula I which is used in each case. Coated formulations and sustained release coated formulations are also within the scope of the invention.

Preference is given to formulations that are acid-resistant and resistant to gastric juice. Suitable cellulose resistant coatings include cellulose acetate phthalate, polyvinyl phthalate acetate, hydroxypropylmethyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical compounds suitable for oral administration may be present in separate units, such as capsules, tablets, chewable tablets or tablets which contain in each case a defined amount of the compound of formula I; as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; oras an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared using any suitable pharmaceutical method which comprises a step in which the active compound and the excipient (which may be composed of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniformly and homogenously mixing the active compound with a finely divided liquid and / or solid carrier, after which the product is molded, if desired. Thus, a tablet, for example, can be prepared by pressing or molding a powder or granule of the compound, appropriately in conjunction with one or more additional components. Pressed tablets can be prepared by compressing the free-flowing compound, such as a powder or granule, suitably mixed with an active agent, lubricant, inert diluent and / or surface active agent (s) / dispersant (s) in a appropriate machine. The molded tablets can be prepared by molding the compound, which is wetted with liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration include sucking tablets, which contain a compound according to the formula, together with a flavoring agent, effector of sucrose and acacia gum, and lozenges, which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions for parenteral administration preferably include sterile aqueous preparations of a compound of formula I which are preferably isotonic with the recipient's blood in person. These preparations are preferably administered intravenously, even though administration may also take place in subcutaneous, intramuscular or intradermal injection. These preparations can preferably be prepared by mixing the compound with water and sterilizing the resulting solution and rendering it isotonic for the blood. In general, the injectable compositions according to the invention comprise from 0.1 to 5% by weight of the active compound.

The pharmaceutical compositions suitable for rectal administration are preferably present as individual dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid excipients, for example cocoa butter, and molding the mixture.

The pharmaceutical compositions suitable for topical use on the skin are preferably present as an ointment, cream, lotion, paste, spray, aerosol or oil. The excipients which can be used are petrolatum, alanine, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is generally present at a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses may be present as individual dressings which are suitable for long-term, intimate contact with the patient's epidermis. Such dressings advantageously contain the active compound in an aqueous solution, which is suitably buffered, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable concentration of the active compound is from approx. 1% to 35%, preferably about 3% to 15%. In particular, the active compound can, as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986), be released by means of electrotransport or ionophoresis.

The following additional active compounds are suitably used for combination preparations:

All the antidiabetics which are named in the "Roten Liste" [Red List] 2001, Chapter 12. They can be combined with the compounds according to the invention of formula I, in particular to improve the effect synergistically. The combination of active compounds can be administered either by administering the active compounds separately to the patient or as combined preparations in which a plurality of active compounds are present in a pharmaceutical preparation. Most of the active compounds listed below are listed in the USAN UD Dictionary and International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetic agents include insulin and insulin derivatives, such as Lantus® (see www.lantus.com) or HMR 1964, rapid-acting insulins (see US 6,221,633), GLP-1 derivatives as well as those disclosed in WO 98/08871 by Novovo Nordisk AIS, and hypoglycemic active compounds that are orally effective.

The hypoglycemic active compounds that are orally effective include desulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, calcium channel openers, such as those disclosed by Novo Nordisk AIS in WO 97 / 26265 and WO 99/03861, insulin sensitizers, liver enzyme inhibitors which are involved in the stimulation of gluconeogenesis and / or glycogenolysis, glucose delivery modulators, compounds, active antihyperlipidemic compounds and antilipidemic active compounds. , which alter the metabolism of fats, compounds that decrease the ration of food, PPAR and PXR agonists, and active compounds that act on the ATP-dependent beta channel.

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

In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol absorption inhibitor, such as ezetimibe, tiqueside or pamaqueside.

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

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR alpha agonist, such as GW 9578 or GW7647.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR alpha / gamma mixed agonist, such as GW1536, AVE 8042, AVE 8134 or AVE 0847, or as described in PCT / US 11833, PCT / üS 11490 or DE10142734.4.

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

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

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

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

In one embodiment of the invention, the compounds of formula I are administered in combination with a polymeric bile acid adsorbent, as ischromine or colesevelam.

In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducer (see US6,342,512), such as HMR1171 or HMR1586.

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

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

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

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

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

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein (a) antagonist, such as CI-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 orlistat.

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

In one embodiment, the compounds of Formula I are administered in combination with a sulfonylurea, such as 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 metformin.

In yet another embodiment, the compounds of formula I are administered in combination with a meglitinide, such as repaglinide.

In one embodiment, the compounds of Formula I are administered in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds which are disclosed by Dr. Reddy's Research Foundation in WO97 / 41097, in particular 5 - [[4- (3,4-dihydro-3-methyl-4-oxo-2-quinazolinylméthoxy] phenyl] methyl] -2,4-.thiazolidinedione.

In one embodiment, the compounds of Formula I are administered in combination with an α-glucosidase inhibitor, such as miglitol ouacarbose.

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

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

In another embodiment, the 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, for example {4 - ((4-aminoquinazolin-2-ylamino) methyl] cyclohexylmethyl} amide of naphthalene-1-sulionic acid. hydrochloride (CGP 71683A)), MC4 agonists (e.g. [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydropyrazolo [4,3-c] ] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl] amide 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (WO 01/91752)), orexin antagonists (e.g. 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridin-4-ylurea] hydrochlorides (SB-334867-A)), H3 agonists (3-Cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) propan-1-one oxalic acid (WO 00/63208) ); TNF agonists, CRF antagonists (e.g. [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triazafluoren-4-yl] dipropylamine (WO 00/66585) ), CRF BP (eg urocortin) antagonists, urocortin antagonists, β3 agonists (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl-1H-indol) 6-yloxy) ethylamino] ethanol, hydrochloride (WO 01/83451), MSH (melanocyte stimulating hormone) agonists, CCK-A agonists (eg, trifluoroacetic acid salt).

{2- [4- (4-5,7-dimethylindol-1-yl} acetic acid (WO 99/15525)); lasotronin reuptake inhibitors (eg dexfenfluramines), mixed serotonic compounds and noradrenergic compounds (eg WO 00/71549), 5HT agonists, for example oxalic 1- (3-ethylbenzofuran-7-yl) piperazine acid salt; (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone releasing compounds (tert-butyl 6-benzyloxy-1- ( 2-

diisopropylaminoethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH antagonists (see, for example, EP 0 462 884) desmodulators 2 or 3 of uncoupling proteins, leptin antagonists (See, for example, Lee, Daniel W., Leinung, Matthew C., Rozhavskaya-Arena, Marina, Grasso, Patricia.Leptin agonists as apotential approach to the treatment of obesity.Drugsof the Future (2001), 26 (9) , 873-881), DA agonists (bromocriptine, doprexin), delipase / amylase inhibitors (eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR modulators or βTR agonists.

In one embodiment of the invention, the additional active compound is leptin; 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 additional active compound is dexamphetamine or amphetamine.

In one embodiment, the additional active compound is flenfluramine or dexfenfluramine.

In yet another embodiment, the additional active compound is sibutramine. In one embodiment, the additional active compound 012805 is orlistat.

In one embodiment, the additional active compound is mazindol or phentermine.

In one embodiment, the compounds of Formula I are administered in combination with foodstuffs, preferably insoluble diets, such as Carboax / Caromax® (see, for example, J, et al., US Pat. Carob pulpof hypercholesterolemia, Sep-Oct), 18 (5), 230-6),

Caromax is a product containing carob from the

Nutrinova Company, Ingredients GmbH, Frankfurt / Main)). The 15 20

Nutrition Specialties & FoodIndustriepark Hoechst, 65926 combination with Caromax® can be carried out in a preparation or by administering the compounds of formula I and Caromax® separately. In this vein, Caromax® can also be administered in the form of food additives, such as bakery products or cereal bars.

It will be understood that each suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and, as desired, one or more additional pharmacologically active substances, is considered within the scope of the present invention. 25 21 - 012805 10 15 20 25- 30 35 40

JTT-705

° Ί H, C. OzCH3 ° x% XCH, BMS-188494

JTT-501

The Examples which are produced below serve to explain the invention without, however, limiting it. 45 50 22 01280 5

Table 1: Formula I Examples

X

O

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M.p. one in o CM 303 300 261 *. \ * - W 2 .rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr <uw 1 '1. · 1 1 1 t 1 1 1 1 "I CM <DX CE XXXXXXXXX X- <X 2 XU)'. · Ci XXXXXXXXXXXXX • V ce XXXXXX X. XXTX X '· X« CM JX X fO [CO CO CO CO CO CO X X XXXXXXXX o XX CO - '. Z'? - '/? - ... ·: Z ·.: · -' · '-: <1 --- OO oooo X oo ci 1; o o 2 ··· o o s X X X X X X X --- x <X X X X X * - - this x X X X X X X X X X X X X? - '<O r * X X X X X x' <X X X X X X this ·>. LU i LU x Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx It is a matter of course that it is not possible to use it as an example. 00 Tfr J Xj CO 4 CO CO CO CO. -M X - uT .'-- X- · -: X X X M - bT O O O O C O O L O o o o ce CM 1 CM 1 CM 1 CM 1 CM 1 CM 1 CM 1 CM! CM 1 CM i CM I CM »CM X in O CM CO CO CO-CO CO o LU 00 in en en en en en en en or O 012805 - 28 - ♦ Decomposition ** Information« MS is OK "means that a background spectrum or HPLC / MS was measured and the molar peak (massemolar + H +) was detected in this spectrum. Example 5 of the patent specification EP 0 193 249 was synthesized as in Comparative Example A.Example A has the structure:

15 20 25 30

The compounds of formula I are characterized by advantageous effects on the metabolism of sugars, in particular, they lower the level of sugarsanguin and are suitable for treating type 2 diabetes. The compounds can therefore be used alone or in combination with other active compounds decreasing blood sugar (antidiabetic).

The compounds of formula I are, moreover, suitable for the treatment of diabetic complications, such as nephropathy, retinopathy, neuropathy and cardiac infarction, myocardial infarction, peripheral arterial occlusion diseases, thromboses, arteriosclerosis , X syndrome, obesity, inflammations, immune diseases, autoimmune diseases, as well as AIDS, asthma, osteoporosis, cancer, lepsoriasis, Alzheimer's disease, schizophrenia and infectious diseases. The activity of the compounds was tested as follows: test for glycogen phosphorylase a

The effect of the compounds on the activity of the active form of glycogen phosphorylase (GPa) in the reverse direction was measured by controlling deglycogen synthesis from glucose 1-phosphate, which determines the release of inorganic phosphate. All reactions were determined in double determinations in 96-well microtiter plates (Half Area Plates, Costar No. 3696), with the change in absorption due to the formation of the reaction product to be measured at the same time. wavelength specified below, in a Multiscan Ascent ElisaReader (Lab Systems, Finland). In order to measure the enzymatic activity of GPa in the opposite direction, the conversion of glucose 1-phosphate and inorganic phosphate was measured according to the general method of Engers et al. (Engers HD, Shechosky S, NB Madsen, Can J Biochem 1970 Jul; 48 (7): 746-754) but with the following modifications: Laglycogen phosphorylase a human was diluted (eg containing 0.76 mg protein / ml ( Aventis PharmaDeutschland GmbH), dissolved in E buffer solution (25 mM b-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol), with T buffer (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, MgCl 2 2.5 mM), and addition of 5 mg glycogen / ml, at a concentration of 10 mg protein / ml .The test substances were prepared at 10 mM in DMSO and adiluted to 50 mM with T buffer solution. 10 ml of 37.5 mM glucose, dissolved in buffer solution T and 5 mg / ml of glycogen, and also 10 ml of a solution of glycogenphosphorylase a human (10 mg protein / ml) and 20 ml were added. of 2.5 mM glucose-1-phosphate at 10 ml of the solution The baseline for glycogen phosphorylase activity was determined in absence of substance test by adding 10 ml of T buffer solution (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes and the inorganic phosphate which was released was measured using the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D, Anal Biochem 1955 Sep 1; 230 (10): 173-177) but with the following modifications: 50 ml of a stop solution of 31 012805 ammonium molybdate 7 were added, 3 mM, 10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS at 50 ml of the enzyme mixture. After 60 minutes of incubation at 45 ° C, absorption was measured at 820 nm. In order to determine the background absorption, the stop solution was added immediately after adding the glucose 1-phosphate solution in a separate test. This test was performed using a 10 μΜ concentration of the test substance to determine The respective inhibition of phosphorylated glycogen by the test substance in vitro. 32 012805

Table 2: Biological activity

012805 33

Comparative Example A shows 3% inhibition at 10 μΜ.

From the table it can be seen that the compounds of formula I inhibit the activity of lglycogen phosphorylase a and are therefore suitable for lowering blood sugar. In particular, the compounds of formula I show an effect which is from 14 to 36 times greater than that of Comparative Example A.

The preparation of an example is described in detail below;

The other compounds of formula I were obtained in a similar manner, suitably using the usual techniques of group protection:

Experimental section: 34 012805

Example 1: a) 2-Chlorobenzoyl isocyanate

1.03 g (6.6 mmol) of 2-chlorobenzamide was resuspended in 3 ml of dichloromethane. After adding 1.17 g (9.2 mmol) of oxalyl chloride, the mixture was refluxed for 17 hours. The reaction mixture was then concentrated under high vacuum and reacted in step b without any additional purification. B) 3- [3- (2,4-Dichlorobenzoyl) ureido] -4-methoxybenzoic acid

2-Chlorobenzoyl isocyanate (Etapea) was taken up in 8 ml of acetonitrile and a suspension of 1.1 g (6 mmol) of 4-amino-3-nitrobenzoic acid in 24 ml of acetonitrile was added. The mixture was refluxed for 3.5 hours and, after being allowed to cool, the precipitate was filtered, washed with acetonitrile and dried in vacuo. 1.68 g (77%) of the desired product was obtained. M.p .: 240 ° C (decomposition)

Example 2: a) 4 [3- (2-Chloro-4,5-difluorobenzoyl) ureido] -3-trifluoromethoxybenzoic acid

The compound was prepared in a pot reaction.

30.0 g (155.8 mmol) of 2-chloro-4,5-difluorobenzoic acid, under a protective gaseous atmosphere, was initially introduced into a round-bottomed flask equipped with a gas-tight mechanical stirrer. and a distillation head. After 300 ml of toluene was added, 29.01 ml of thionyl chloride was added with stirring and the mixture was heated to 60 ° C. At 60 ° C the reaction mixture was then stirred for 1.5 h, after which 0.1 ml of pyridine was added. After a further 1.5 hours at 60 ° C, 90 ml of 012805 liquid was distilled from the mixture under normal pressure (max. Bath temperature, 125 ° C). The reaction solution was allowed to cool to 20 ° C and ammonia gas was passed at 20-35 ° C (ice-cooling) until the solution was saturated. After this, 160 ml of THF and 120 ml of deionized water were added to the mixture at 20 ° C. The aqueous phase was separated and the organic phase was washed with 5% aqueous sodium hydrogen carbonate solution. The organic phase was then azeotropically dried by distilling 250 ml of liquid under vacuum at 50 ° C. The mixture was allowed to cool to 20 ° C and a solution of 26.49 g (119.8 mmol) of 4-amino-3- (trifluoromethoxy) benzoic acid in 75 ml of THF was added. The product was filtered off through a glass suction filter and dried to constant weight under vacuum at 50 ° C. 52.6 g of the desired product were obtained.

M.p .: 236 ° C (b) TRIS salt of 4- [3- (2-chloro-4,5-difluorobenzoyl) urecido] -3-trifluoromethoxybenzoic acid

A mixture of 10.0 g (22.79 mmol) of 4- [3- (2-chloro-4,5-difluoro-benzoyl) urecido] -3-trifluoromethoxybenzoic acid and 3 was refluxed. 0 g of α, α, α-tris (hydroxy-methyl) methylamine in 400 ml of propan-2-ol until a clear solution is formed. The solution was filtered through heat and concentrated to a volume of 310 ml. The product crystallized from the solution while cooling to 20 ° C. 10.4 g of the desired product were obtained.M.p .: 176 ° C

The compounds of Formula I can be prepared by reacting ureas of formula 2 or aniline derivatives of formula 3 with aroyl isocyanates, with reactive acid derivatives, with acid chlorides or with anhydrides, of formula 4,

in which RImentionnées above. The resulting free acids of formula I can then be converted, with the corresponding enzymes, to the corresponding physiologically-tolerated salts of compounds of formula I. For clarification: if formula 4 is an acid chloride, Y is Cl, if formula 4 is an isocyanate, Y is N = C = o and if formula 4 is an anhydride, Y is

Preference is given to the method for preparing the compounds of formula I by the aroyl isocyanate route 4a, as shown in the following scheme:

For example 1. SOCI2, toluene 2. NH ^ j

3. THF, H2O 4. NaHCO3 (aqj

38 012805

The preparation of I can generally be carried out in a single pot process, thereby greatly simplifying its preparation on an industrial scale. For this purpose, 4b is converted to the acid chloride in a suitable solvent, for example toluene, using a suitable reagent such as deionyl chloride or oxalyl chloride. As required, a suitable catalyst, such as pyridine, NMP or DMF, is added to accomplish the reaction. After removing the unreacted reagent (such as thionyl chloride), the acid chloride is converted to the acid amide 4b using appropriate reagents, such as passing gaseous ammonia into the reaction solution or adding a reaction mixture. The solution of ammonia in a suitable solvent, such as THF, with enough water and a suitable solvent, such as THF, is added to the reaction mixture to ensure that any solid is dissolved. After the separation of the phases, the washing is carried out with sodium hydrogen carbonate solution and the organic phase is then dried. Acid amide 4b is converted to aroyl isocyanate 4a by adding oxalyl chloride and then heating. After removal of the unreacted oxalyl chloride, aniline 3a is dissolved in a suitable solvent, as THF, and added to the solution of aroyl isocyanate 4a, with the reaction product precipitating from the solution. The compound of formula I is separated by filtration. The salt of the compound of formula I crystallizes after the compound of formula I has been dissolved with boiling TRIS in a suitable solvent, such as propan-2-ol, when the solution is then cooled.

Claims (20)

012805 39 Claims 1. Compound of formula I R8 N R1 R2 R9 R10 O X, R4 O R3 N Wherein R7, R8, R9 and R10 independently of one another are H, F, Cl, Br, OH, NO2, CN, O-alkyl, Οχ-Ο6, O- C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, wherein alkyl, alkenyl and alkynyl may be substituted, one or several times, by F, Cl or Br; R 1 and R 2 are, independently of one another, H, C 1 -C 6 alkyl, wherein alkyl may be substituted with OH, O-C 1 -C 4 alkyl, NH 2, NH-C 1-4 alkyl; Or N- (C₁-CΟ) alkyl, C₁-C O alkyl, CO₂-C₁-C - alkyl, COO-C₁-C C alkyl, C₁-C C alkylene-COOH or C1-C8alkyl-COO-C1-C8alkyl, R3 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkyl-C1-C4alkylene, wherealkyl, cycloalkyl and alkynyl may be substituted, once or more, by F, Cl, Br, OR, COOR, OR N (R16) (R17); R4 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C8alkyl, alkenyl; C2-C6 alkynyl, C2-C8 alkynyl, C3-C7 cycloalkyl or C3-C7cycloalkyl-C1-C4alkylene, whereinalkyl, cycloalkyl and alkynyl may be substituted one or more times by F, Cl, Br, OR11, COOR11 or N (R16) (R17); R5 represents H, F, Cl, Br atom, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C6 alkyl, C2-alkenyl; -C 6, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 4 alkylene wherein alkyl, cycloalkyl and alkynyl may be substituted once or more by F, Cl, Br, ORR , COOR11 OR N (R16) (R17); R6 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C8 alkyl, alkenyl C1-2alkyl, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkyl-C1-C4alkylene, whereinalkyl, cycloalkyl and alkynyl may be substituted one or more times with F, Cl, Br, OR11; , COOR11 OR N (R16) (R17); R 11 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, whereinalkyl, alkenyl and alkynyl may be substituted one or more times with F, Cl, Br, OH or O-C 1 -C 4 alkyl; R12 and R13 independently of one another are H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C7cycloalkyl, C3-C7cycloalkyl; C 1 -C 4 alkylene, COO-C 1 -C 4 alkyl, COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring can be substituted, up to two times, by F, Cl, CN, OH C1-C6alkyl, C1-C6alkyl, CF3, OCF3, COOH, COO-C1-C6alkyl or CONH2; or R12 and R13 form, together with the nitrogen atom to which they are bonded, a 7-membered saturated heterocycle which may contain up to 2 additional heteroatoms of the N, O or Set group where the heterocycle may be substituted, up to four times with F, Cl, Br, OH, Oxo, C 1 -C 4 alkyl or N (R 14) (R 15); R14 and R15 independently of one another are H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl, -alkylene, and the like; C 1 -C 4, COO-C 1 -C 4 alkyl, COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted, up to two times, with F, Cl, CN, OH, C1-C6alkyl, C1-C6alkyl, CF3, OCF3, COOH, COO-C1-C6alkyl or CONH2; R16 and R17 independently of one another are H, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C7cycloalkyl, C3-C7cycloalkyl- C 1 -C 4 alkylene, COO-C 1 -C 4 alkyl, COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted, up to two times, by F, Cl, CN, OH, C1-C6 alkyl, O-C1-C6 alkyl, CF3, OCF3, COOH, COO-C1-C6 alkyl or CONH2; or R16 and R17 form, together with the nitrogen atom to which they are bound, a saturated 3- to 7-membered heterocycle which may contain up to 2 additional heteroatoms of the N, O or Set group where the heterocycle may be substituted up to four times with F, Cl, Br, OH, Oxo, C 1 -C 4 -alkyl OR N (R 14) (R 15); always placing itself in the case where at least one of R3, R7, R8, R9 and R10 is not hydrogen, and their physiologically tolerated salts. 2. A compound of formula I as claimed in claim 1, wherein R7, R8, R9 and R10 are, independently of one another, an H, F, Cl, Br atom, an OH group , NO2, CN, en-Ο6 alkyl or O-Ο6-alkyl, where alkyl may be substituted, once or more, with F; R1 and R2 represent an H atom; R3 is H, F, Cl, Br, unsubstituted NO2, CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), C1-C6alkyl, C2-alkenyl; -C6, C2-C6 alkynyl, C3-C7 cycloalkyl or C3-C7cycloalkyl-ylène-ΰ4alkylene, whereinalkyl, cycloalkyl and alkynyl may be substituted one or more times by F, Cl, Br, OR11 or COOR11; R4 is H, F, Cl, NO2, O-R11, N (R12) (R13) or Cr-CS1 alkyl wherein alkyl may be substituted, once or more, with F; R5 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C6alkyl, where alkyl may be substituted, once or more times, byF; R6 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C6alkyl, wherealkyl may be substituted, one or more times, withF; R11 is H, C1-C8alkyl, C1-C8alkyl-O-C1-C8alkyl or C1-C8alkyl-OH, wherein alkyl may be substituted one or more times with F; R 12 and R 13 represent, independently of one another, an H atom or a C 1 -C 6 alkyl group or R 12 and R 13 form, together with the nitrogen atom which they are bonded, a saturated 3- to 7-membered heterocycle; which may contain up to 2 additional heteroatoms of the N, O or Set group where the heterocycle may be substituted, up to four times, by F, Cl, Br, OH, Oxo, C 1 -C 4 alkyl or N (R 14 ) (R15); R14 and R15 independently of one another are H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl, -alkylene, and the like; C 1 -C 4, COO-C 1 -C 4 alkyl, COO-C 2 -C 4 alkenyl, phenyl or SO 2 -phenyl, wherein the phenyl ring may be substituted, up to two times, by F, Cl, CN, OH, alkyl C 1 -C 6, O-C 1 -C 6 alkyl, CF 3, OCF 3, COOH, COO-C 1 -C 6 alkyl or CONH 2; and their physiologically tolerated salts. A compound of formula I as claimed in claim 1 or 2, wherein R 7, R 8, R 9 and R 10 independently of one another are H, F, Cl, Br or CH 3 or CF 3 ; R1, R2, R5 represent an H atom; R3 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C6alkyl, which may be substituted, one or more times, by F; R4 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C6alkyl, which may be substituted one or more times by F; R6 is H, F, Cl, NO2, O-R11, N (R12) (R13) or C1-C6alkyl, which may be substituted, one or more times, by F; R 11 is H or C 1 -C 8 alkyl, which alkyl may be substituted one or more times with F; R12 and R13 are H or C1-C8alkyl, or both R12 and R13 form, together with the nitrogen atom to which they are attached, a 5- to 6-membered saturated heterocycle which may contain an atom; additional oxygen; and their physiologically tolerated salts. A compound of formula I as claimed in one or more of claims 1 to 3, wherein R 7, R 8, R 9 and R 10 independently of one another are H, F, Cl, Br or CH 3 or CF3; R1, R2, R4, R5 and R6 are H; R3 is H, F, Cl, NO2, O-R11, N (R12) (R13) or alkyl, which may be substituted one or more times with F; R 11 is H or C 1 -C 8 alkyl, which alkyl may be substituted one or more times with F; R12 and R13 represent an H atom or a C1-C8 alkyl group, or both R12 and R13 together with the nitrogen atom to which they are attached form a saturated 5 to 6-membered heterocyclic ring which may contain an oxygen atom; additional; and their physiologically tolerated salts. 5. A compound of formula I as claimed in one or more of claims 1 to 4, wherein it is in each case the dehydromethyl salt. A medicament which comprises one or more of the compounds as claimed in one or more of claims 1 to 5. A medicament which comprises one or more of the compounds as claimed in one or more of claims 1 to 5 and one or more active compounds decreasing blood sugar. A drug which comprises one or more of the compounds as claimed in one or more of claims 1 to 5 and one or more statins. 9. Use of the compounds as claimed in one or more of claims 1 to 5 for the manufacture of a medicament for the treatment of type 2 diabetes. 10. Use of the compounds as claimed in one or more of claims 1 to 5 for the manufacture of a medicament for decreasing blood sugar. 11. Use of the compounds as claimed in one or more of claims 1 to 5 in combination with at least one additional blood sugar reducing active compound for the manufacture of a medicament for the treatment of type 2 diabetes. 12. Use of the compounds as claimed in one or more of claims 1 to 5 in combination with at least one additional active blood sugar reducing compound for the manufacture of a medicament for decreasing blood sugar. A process for the manufacture of a medicament which comprises one or more of the compounds as claimed in one or more of Claims 1 to 5, which comprises mixing the active compound with a pharmaceutically appropriate excipient and supplying the mixture in a form which is suitable for administration. . 14. Process for preparing the compounds of Formula I, which comprises reacting Formula 2 urea or aniline derivatives of Formula 3 with aroyl isocyanates, with reactive acid derivatives, with acid chlorides or with In which R1 to R10 have the meanings given in claim 1. 15. A process for the preparation of the compounds of the formula I as claimed in claim 14, wherein the aroyl isocyanate 4a is reacted with the acid of the formula 3a, wherein R1 to R10 have the meanings given in claim 1. 16. A process for the preparation of physiologically selenolated compounds of the formula I which comprises reacting free acids of the compounds of the formula I with a corresponding base. 17. A process as claimed in claim 16 wherein the base is α, α, α-tris- (hydroxymethyl) methylamine (tromethamol). 18. A process for the preparation of the compounds of formula I, which comprises, in accordance with the following scheme wherein R1 to RIO have the meaning given in claim 1, 012805 3. THF, H2O 4. NaHCO 3, for example: I.SOGI 3, toluene 2. not isolated In a first step, using a reagent suitable for converting compound 4b, in a solvent which is suitable for this purpose, to the acid chloride, and in a second step, using a reagent suitable for converting the acidizing chloride. , in a solvent which is suitable in this case, to the acid amide 4b, and in a third step, by converting the acid amide 4b, by the reaction thereof with oxalyl chloride, into the aroyl isocyanate 4a, and in a fourth step, reacting the aroyl isocyanate 4a with aniline 3a, in a suitable solvent, to give the free acid of the compound of formula I, and in a fifth step by reacting the free acid of the compound of formula I with a base to give a physiologically tolerated salt of the compound of formula I.