Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
  • C07C275/48—Y being a hydrogen or a carbon atom
  • C07C275/54—Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• N-benzoylureido-cinnamic acid derivatives process for their preparation and their use
• the invention relates to N-benzoylureido cinnamic acid derivatives and their physiologically tolerable salts and physiologically functional derivatives.
• EP 0 193 249 (Duphar) describes acyl-carboxyphenyl-urea derivatives with antitumor activity.
• the object of the invention was to provide compounds with which the prevention and treatment of type 2 diabetes is possible.
• the compounds are said to bring about a noticeable reduction in the blood sugar level.
• the invention therefore relates to compounds of the formula I
• R7, R8, R9, R10 • independently of one another H, F, Cl, B ' r, OH, N0 2 , CN, 0- (C
• Alkyl, NH 2 , NH (dC 4 ) - alkyl, NKd-CeJ-alkylk, can be substituted, O- (CrC 6 ) -alkyl, CO- (C ⁇ -C 6 ) -alkyl, C ⁇ d- (dC 6 ) - Alkyl, (CC 6 ) alkylene-COOH, (C 1 -C 6 ) alkylene-COO- (C 1 -C 6 ) alkyl;
• R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, S-R12,
• R12 H, (CrC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, alkyl, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OH or 0- (C ⁇ -C 4 ) alkyl may be substituted,
• R13, R14 independently of one another are H, (CrC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (dC 4 ) alkylene, COO- (-C-C 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (dC 6 ) -alkyl, 0- (-C-C 6 ) -alkyl, CF 3 , OCF 3 , COOH, COO- (dC 6 ) -alkyl or CONH 2 can be substituted;
• R16, R17 independently of each other .
• H (C.-C 8 ) alkyl, (G 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl I (C 3 -C 7 ) - Cycloalkyl- (C 1 -C 4 ) alkylene > COO- (-C-C 4 ) alkyl, COO- (C 2 -C) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to can be substituted twice with F, Cl, CN, OH, (CC 6 ) alkyl, 0- (CC 6 ) alkyl, CF 3) OCF 3) COOH, COO- (CC 6 ) alkyl or CONH 2 ;
• R18, R19 independently of one another are H, (d-CsJ-alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (-C-C 4 ) alkylene, COO- (dC 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (CC 6 ) alkyl, 0- (dC 6 ) alkyl, CF 3 , OCF 3 , COOH, COO- (dC 6 ) alkyl or CONH 2 may be substituted;
• R22, R23 independently of one another are H, (CrC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (C.-C) -alkylene, COO- (dC 4 ) -alkyl, COO- (C 2 -C) -alkenyl, phenyl or S ⁇ 2 -phenyl, the phenyl ring being up to twice with F, Cl , CN, OH, (-C -C 6 ) alkyl, 0- (dC 6 ) alkyl, CF 3 , OCF 3>
• COOH, COO- (-CC 6 ) alkyl or CONH 2 may be substituted
• R22 and R23 with the nitrogen atom to which they are bonded form a 3-7-membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, the heterocyclic ring being up to three times with F, Cl, Br, OH, Oxo, N (R20) (R21) or (dd) -alkyl can be substituted.
• Cycloalkyl- (CrC 4 ) -alkylene where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl are used several times with F, NH 2 , NH (dC 4 ) -alkyl, N [(dC 4 ) -alkyl] 2 , OH, O- ( CC 4 ) alkyl, 0- (C 2 -C 4 ) alkenyl), 0 ⁇ CO- (dC 4 ) alkyl can be substituted, COOR12, C0N (R13) (R14), heteroaryl, (C 6 -C 10 ) aryl, (C 6 -C 10 ) aryl- (CC) -alkylene, where heteroaryl and aryl can be substituted with 0- (CrC) -alkyl, where alkyl can be substituted several times with F, F or Cl;
• R20, R21 independently of one another are H, (CC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (C.-C 4 ) -alkylene, COO- (CC 4 ) -alkyl, COO- (C 2 -C) -alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (dC 6 ) -alkyl, 0- (CC 6 ) -alkyl, CF 3 , OCF 3 , COOH, COO- (-C-C 6 ) -alkyl or CONH 2 can be substituted;
• R7, R8, R9, R10 independently of one another H, F, Cl, Br, OH, N0 2 , CN, 0- (d-
• C 6 ) alkyl 0- (C 2 -C 6 ) alkenyl, 0- (C 2 -C 6 ) alkynyl, 0-S0 2 - (C 1 -C 4 ) alkyl, (d- C 6 ) Alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, where alkyl, alkenyl and alkynyl can be substituted several times by F, Cl or Br;
• R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, S-R12,
• R12 is H, (d-Ca) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, where alkyl, alkenyl and
• Alkynyl can be substituted several times with F, Cl, Br, OH or 0- (-C-C) alkyl,
• R13, R14 independently of one another are H, (dC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkylr (-C-C 4 j-alkylene, COO- (-C-C 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring with up to twice with F , Cl, CN, OH, (CC 6 ) -alkyl, O-td-C ⁇ -Alky !, CF 3 , OCF 3 , COOH, COO- (-C-C 6 ) -alkyl or CONH 2 may be substituted;
• R16, R17 independently of one another are H, (CC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (CC 4 ) alkylene, COO- (CC 4 ) alkyl, COO- (C 2 -C) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN , OH, (dC 6) alkyl, 0- (dC 6) -alkyl, CF 3 OCF 3l,
• COOH, COO- (dC 6 ) alkyl or CONH 2 may be substituted
• R18, R19 independently of one another H, (C ⁇ C8) alkyl, (C 2 -C 8) alkenyl, (C 2 -C 8) -alkynyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (CrC4 alkylene, COO- (dC 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (CC 6 ) alkyl, 0- (dC 6 ) alkyl, CF 3 , OCF 3 ,
• COOH, COO- (CC 6 ) alkyl or CONH 2 may be substituted
• R22, R23 independently of one another H, (C, -C 8) alkyl, (C 2 -C 8) alkenyl, (C 2 -C 8) -alkynyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7 ) cycloalkyl (dC 4 ) alkylene, COO (dC 4 ) alkyl,
• Cycloalkyl- (-C-C 4 ) alkylene where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl several times with F, NH 2l NH (CC 4 ) alkyl, N [(CrC 4 ) alkyl] 2 , OH, O- (dC 4 ) -alkyl, 0- (C 2 -C 4 ) -alkenyl), 0-CO- (CC 4 ) -alkyl may be substituted, COOR12, CON (R13) (R14), heteroaryl, (C 6 - C 10 ) aryl, (C 6 -C 10 ) -
• R20, R21 independently of one another H, (-CC 8 ) -alkyl, (C 2 -C 8 ) -alkenyl, (C 2 -C 8 ) -alkynyl, (C 3 -C 7 ) -cycloalkyl, (C 3 - C 7 ) -cycloalkyl- (C.-C 4 ) -alkylene, COO- (dC 4 ) -alkyl,
• R7, R8, R9, R10 independently of one another H, F or Cl;
• R3, R4, R5, R6 independently of one another H, Cl, COOH, COO-td-C ⁇ alkyl or NHCOR15;
• R12 is H or (CC 4 ) alkyl
• R15 (dC 4 ) alkyl where alkyl can be substituted with COOH, or COOH;
• alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 or R23 be both straight and branched.
• radicals or substituents can occur more than once in the compounds of the formula I, such as, for example, 0-R12, they can all independently of one another have the meanings given and be the same or different.
• the invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
• Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid and organic acids, such as e.g.
• 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 ethylene diamine.
• Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the manufacture or purification of pharmaceutically acceptable ones Salts and / or for use in non-therapeutic, for example in vitro, applications.
• physiologically functional derivative denotes any physiologically compatible derivative of a compound of formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able to (directly or indirectly) form a compound of formula I or an active metabolite thereof.
• the 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 a compound according to the invention. These prodrugs themselves may or may not be effective.
• the compounds of the invention may also exist in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong to the scope of the invention and are a further aspect of the invention.
• the compound (s) of the formula (I) can also be administered in combination with other active ingredients.
• the amount of a compound of formula I required to achieve the desired biological effect depends on a number of factors, e.g. the specific compound chosen, the intended one
• the daily dose is in the range of 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, e.g. 3-10 mg / kg / day.
• An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg / kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
• Suitable infusion solutions for these purposes can contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.
• Single doses can contain, for example, from 1 mg to 10 g of the active ingredient.
• ampoules for injections can contain, for example, from 1 mg to 100 mg, and orally administrable single-dose formulations, such as tablets or capsules, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
• the compounds of the formula I themselves can be used as a compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier.
• the carrier must of course be compatible, in the sense that it is compatible with the other components of the composition and is not harmful to the health of the patient.
• the carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active ingredient.
• Further pharmaceutically active substances can also be present, including further compounds of the formula I.
• the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods which essentially consist in mixing the constituents with pharmacologically acceptable carriers and / or auxiliaries ,
• compositions according to the invention are those which 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 in each individual case depends on the type and severity of the to be treated State and on the type of compound used according to formula I is dependent.
• Coated formulations and coated slow-release formulations also fall within the scope of the invention.
• Formulations which are resistant to acid and gastric juice are preferred.
• Suitable enteric-coated Coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.
• Suitable pharmaceutical compounds for oral administration can be present in separate units, such as capsules, capsules, lozenges or tablets, each containing a certain amount of the compound of the formula I; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
• these compositions can be prepared by any suitable pharmaceutical method comprising a step in which the active ingredient and the carrier (which can consist of one or more additional ingredients) are brought into contact.
• the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary.
• a tablet can be produced by compressing or shaping a powder or granulate of the compound, optionally with one or more additional components.
• Compressed tablets can be prepared by tabletting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (several) surface-active / dispersing agent in a suitable machine.
• Molded tablets can be made by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.
• compositions suitable for oral (sublingual) administration include lozenges containing a compound of Formula I with a flavoring agent, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and include glycerin or sucrose and gum arabic.
• Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound of the formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they can also be administered subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be prepared by mixing the compound with water and making the solution obtained sterile and isotonic with the blood.
• Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
• Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be prepared by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
• Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil.
• Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as carriers.
• the active ingredient is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.
• Suitable pharmaceutical compositions for transdermal applications can be presented as individual patches which are suitable for long-term close contact with the patient's epidermis.
• Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
• a suitable active ingredient concentration is approximately 1% to 35%, preferably approximately 3% to 15%.
• the active ingredient can be released by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
• the following are also suitable as active ingredients for the combination preparations: all antidiabetic agents mentioned in the 2001 Red List, Chapter 12.
• the active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
• Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US 6,221, 633), GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk AS have been disclosed, as well as orally active hypoglycemic agents.
• the orally active hypoglycemic agents preferably include
• Sulphonyl ureas biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, e.g.
• the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
• an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
• the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, such as, for example, ezetimibe, tiqueside, pamaqueside.
• the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, ' GI 262570.
• a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, ' GI 262570.
• the compounds of the formula I are used in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647 administered,
• the compounds of the formula I are used in combination with a mixed PPAR alpha / gamma agonist, e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US00 / 11833, PCT / US0O / 11490, DE10142734.4.
• a mixed PPAR alpha / gamma agonist e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US00 / 11833, PCT / US0O / 11490, DE10142734.4.
• the compounds of the formula I in combination with a fibrate such as e.g. Fenofibrate, clofibrate, bezafibrate.
• the compounds of the formula I in combination with an MTP inhibitor such as e.g. Implitapide, BMS-201038, R-103757.
• the compounds of the formula I are used in combination with a bile acid absorption inhibitor (see e.g. US 6,245,744 or US 6,221,897), e.g. HMR 1741.
• the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705.
• a CETP inhibitor such as, for example, JTT-705.
• the compounds of the formula I are administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, colesevelam.
• the compounds of the formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMR1171, HMR1586.
• the compounds of the formula I in combination with an ACAT inhibitor such as e.g. Avasimibe administered.
• the compounds of the formula I in combination with an antioxidant, such as e.g. OPC-14117.
• the compounds of the formula I in combination with a lipoprotein lipase inhibitor, such as e.g. NO-1886.
• the compounds of the formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990.
• the compounds of the formula I are used in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
• a squalene synthetase inhibitor e.g. BMS-188494.
• the compounds of the formula I are antagonized in combination with a lipoprotein (a), e.g. Cl-1027 or nicotinic acid.
• a lipoprotein e.g. Cl-1027 or nicotinic acid.
• the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, orlistat. In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
• the compounds of the formula I are used in combination with a sulphonyl urea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.
• a sulphonyl urea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.
• the compounds of formula I in combination with a biguanide e.g. Metformin.
• the compounds of formula I are used in combination with a meglitinide, e.g. Repaglinide.
• the compounds of formula I are used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione.
• a thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl]
• the compounds of formula I in combination with a ⁇ -glucosidase inhibitor, such as e.g. Miglitol or Acarbose.
• a ⁇ -glucosidase inhibitor such as e.g. Miglitol or Acarbose.
• 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, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
• the compounds of the formula I are used 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 Metabolie Research (2001), 33 (9), 554-558), NPY-antagonists e.g. naphthalene-1 -sulfonic acid- ⁇ 4 - [(4-amino-quinazolin-2-ylamino) - methyl] -cyclohexylmethyl ⁇ -amide hydrochloride ( CGP 71683A)), MC4 agonists (e.g.
• ethylaminoj-ethanol hydrochloride (WO 01/83451)
• MSH melanocyte-stimulating hormone
• CCK-A agonists e.g. ⁇ 2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5 - ' (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl-indol-1-yl ⁇ -acetic acid trifluoroacetic acid salt (WO 99/15525)
• serotonin reuptake inhibitors eg dexfenfluramine
• mixed serotonin and noradrenergic compounds e.g. WO
• 5HT agonists e.g. 1- (3-ethyl-benzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonist, growth hormone (e.g. human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2nd -diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 462
• decoupling protein 2 or 3 modulators decoupling protein 2 or 3 modulators, leptin agonists (see e.g. Lee, Daniel W .; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase. Inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR-
• the further active ingredient is leptin; see, for example, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 30 2 (10), 1615-1622.
• the further active ingredient is dexamphetamine or amphetamine.
• the further active ingredient is fenfluramine or dexfenfluramine. In another embodiment, the further active ingredient is sibutramine. In one embodiment, the further active ingredient is orlistat. In one embodiment, the further active ingredient is mazindol or phentermine.
• the compounds of formula I in combination with bulking agents preferably insoluble bulking agents
• bulking agents preferably insoluble bulking agents
• Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)).
• the combination with Caromax ® can be carried out in one preparation or by separate administration of compounds of the formula I and Caromax ® .
• Caromax ® can also be administered in the form of food, such as in baked goods or granola bars.
• the compounds of the formula I are distinguished by favorable effects on the sugar metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes.
• the compounds can therefore be used alone or in combination with other antihypertensive agents (antidiabetic agents).
• the compounds of formula I are also suitable for the treatment of late diabetic damage, such as e.g. Nephropathy, retinopathy, neuropathy and heart attack, myocardial infarction, peripheral arterial occlusive diseases, thrombosis, arteriosclerosis, syndrome X, obesity, inflammation,
• late diabetic damage such as e.g. Nephropathy, retinopathy, neuropathy and heart attack, myocardial infarction, peripheral arterial occlusive diseases, thrombosis, arteriosclerosis, syndrome X, obesity, inflammation,
• Immune diseases autoimmune diseases, e.g. AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases.
• autoimmune diseases e.g. AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases.
• glycogen phosphorylase The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the opposite direction by monitoring glycogen synthesis 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. 3696), the change in absorption due to the formation of the reaction product at the wavelength specified below in a Multiskan Ascent Elisa Reader (Lab Systems, Finland) was measured. In order to measure the GPa enzyme activity in the reverse direction, the conversion of glucose-1-phosphate into glycogen and inorganic phosphate was carried out according to the general method of Engers et al.
• glycerophosphate pH 7.0, 1 mM EDTA and 1 mM dithiotreitol
• buffer T 50 mM Hepes, pH 7.0, 100 mM KCI, 2.5 mM EDTA, 2.5 mM MgCI 2 -6H 2 0
• 5 mg / ml glycogen diluted to a concentration of 10 ⁇ g protein / ml.
• Test substances were prepared as a 10 mM solution in DMSO and diluted to 50 ⁇ M with buffer solution T.
• the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are therefore very suitable for lowering the blood sugar level. They are particularly suitable for the prevention and treatment of type 2 diabetes.
• Example 3 3- ⁇ 4-Acetylamino-2- [3- (2-chloro-4,5-difluorobenzoyl) -ureido] phenyl ⁇ acrylic acid
• Example 7 4- [3- (2-Chloro-4,5-difluorobenzoyl) -ureido] -3- (2-methoxycarbonyl-vinyl) -benzoic acid
• Acrylic acid methyl ester 2.5 eq. Cesium carbonate, 1 eq. ( n Bu) NHS0 4 , 0.1 eq. Triphenylphosphine, 0.1 eq. Palladium acetate, 2 ml of acetonitrile and 2 ml of H 2 0 were heated under an argon atmosphere for 5 minutes in the microwave to 120 ° C at 140 Watt.

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