WO2003084922A1 - Acyl-4-carboxy-phenyl-harnstoffderivate, verfahren zu deren herstellung und deren verwendung - Google Patents
Acyl-4-carboxy-phenyl-harnstoffderivate, verfahren zu deren herstellung und deren verwendung Download PDFInfo
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- WO2003084922A1 WO2003084922A1 PCT/EP2003/003251 EP0303251W WO03084922A1 WO 2003084922 A1 WO2003084922 A1 WO 2003084922A1 EP 0303251 W EP0303251 W EP 0303251W WO 03084922 A1 WO03084922 A1 WO 03084922A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
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- 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
Definitions
- the invention relates to acyl-4-carboxyphenyl-urea derivatives and their physiologically tolerated salts and physiologically functional derivatives.
- EP 0 193 249 discloses acylcarboxyphenyl urea derivatives having antitumor activity.
- the object of the invention was to provide compounds with which a prevention and treatment of type 2 diabetes is possible.
- the object was that new compounds are provided with a significantly improved effect compared to the compounds known from EP 0 193 249.
- the invention therefore relates to compounds of the formula I,
- R7, R8, R9, R10 are independently H, F, Cl, Br, OH, NO 2, CN, O- (d-
- R 1, R 2 independently of one another are H, (CC 6 ) -alkyl, where alkyl is OH, O- (C 1 -C 4 ) -alkyl, NH 2 , NH (CC 4 ) -alkyl, N [(C 1 -C 6 ) -alkyl ] 2 may be substituted, O-
- R 3 is H, F, Cl, Br, NO 2 , CN, O-R 11, unsubstituted O-phenyl, S-R 11, COOR 11, N (R 12) (R 13), (CC 6 ) alkyl, (C 2 -C 6 ) Alkenyl, (C 2 -C 6 ) alkynyl,
- alkyl, cycloalkyl and alkynyl are mono- or polysubstituted by F, Cl, Br, OR 11, COOR 11 or N (R 16 ) (R17) may be substituted;
- R6 H, F, Cl, Br, NO 2, CN, O-R11, unsubstituted O-phenyl, S-R11,
- R 12, R 13 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- (C 1 -C 4 ) -alkylene, COO- (C 1 -C 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring can be reacted up to twice with F, Cl, CN, OH, (C 1 -C 6 ) alkyl, O- (C 1 -C 6 ) alkyl, CF 3 , OCF 3 , COOH, COO- (CC 6 ) alkyl or CONH 2 may be substituted; or R12 and R13 together with the nitrogen
- R14, R15 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 (CrC 4) -alkylene, COO- (dC 4) -alkyl, COO- (C 2 -C 4) -alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring up to two times by F, Cl, CN, OH, (dC 6 ) -alkyl, O- (dC 6 ) -alkyl, CF 3 , OCF 3 , COOH, COO (CC 6 ) -alkyl or CONH 2 may be substituted;
- R 16, R 17 are each independently 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- (CC 4 ) -alkylene, COO- (CC 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring can be reacted up to twice with F, Cl, CN, OH, (C 1 -C 4 ) alkyl, O- (C 1 -C 6 ) -alkyl, CF 3 , OCF 3 ,
- COOH, COO- (CC 6 ) -alkyl or CONH 2 may be substituted; or R 16 and R 17 together with the nitrogen atom to which they are attached form a 3-7 membered, saturated heterocyclic ring which may contain up to 2 further heteroatoms from the group N, O or S and wherein the heterocyclic ring is up to fourfold with F , Cl, Br, OH, oxo, (d-
- R7, R8, R9, R10 are independently H, F, Cl, Br, OH, NO 2, CN, (dC 6) - alkyl or O- (C ⁇ -C6) -alkyl, wherein alkyl is mono- or polysubstituted by F may be substituted;
- R3 is H, F, Cl, Br, NO2 > CN, O-R11, unsubstituted O-phenyl, S-R11,
- R 4 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (C 1 -C 6 ) -alkyl, where alkyl may be mono- or polysubstituted by F;
- R 5 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (C 1 -C 6 ) -alkyl, where alkyl may be mono- or polysubstituted by F;
- R 6 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (C 1 -C 6 ) -alkyl, where alkyl may be mono- or polysubstituted by F;
- R12, R13 independently of one another are H or (CC 8 ) -alkyl; or R12 and R13 together with the nitrogen atom to which they are attached form a 3-7 membered, saturated heterocyclic ring which may contain up to 2 further heteroatoms from the group N, O or S and wherein the heterocyclic ring is up to fourfold with F , Cl, Br, OH, oxo, (d-
- R14, R15 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- (C 1 -C 4 ) -alkylene, COO- (CC 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring up to two times with F , Cl, CN, OH, (CC 6 ) alkyl, O- (CC 6 ) alkyl, CF 3 , OCF 3 , COOH, COO (CC 6 ) alkyl or CONH 2 ;
- R7, R8, R9, R10 are independently H, F, Cl, Br, CH 3 or CF 3;
- R 3 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (CC 6 ) -alkyl, where alkyl may be monosubstituted or polysubstituted by F;
- R 4 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (CC 6 ) -alkyl, where alkyl may be mono- or polysubstituted by F;
- R 6 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (C 1 -C 6 ) -alkyl, where alkyl may be mono- or polysubstituted by F;
- R 11 is H or (C 1 -C 8 ) -alkyl, where alkyl may be monosubstituted or polysubstituted by F,
- R7, R8, R9, R10 are independently H, F, Cl, Br, CH 3 or CF 3;
- R1 R2, R4, R5, R6 H;
- R 3 is H, F, Cl, NO 2 , O-R 11, N (R 12) (R 13) or (C 1 -C 6 ) -alkyl, where alkyl may be mono- or polysubstituted by F;
- R 11 is H or (C 1 -C 5) -alkyl, where alkyl may be substituted one or more times by F,
- R 3 is other than H.
- R3 is particularly preferably equal -OCF third
- radicals or substituents can occur several times in the compounds of the formula I, for example -O-R11, then they may all, independently of one another, have the meanings indicated and be identical 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.
- alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 can be both straight-chain and branched.
- Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrogen bromide, phosphoric, metaphosphoric, nitric and sulfuric acid and also organic acids, such as, for example, acetic acid, benzenesulfone, Benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.
- inorganic acids such as hydrochloric acid, hydrogen bromide, phosphoric, metaphosphoric, nitric and sulfuric acid
- organic acids such as, for example, acetic acid, benzenesulfone, Benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lac
- Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.
- trometamol salts also referred to below as TRIS, tris-hydroxymethyl-methylamine
- TRIS tris-hydroxymethyl-methylamine
- Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
- physiologically functional derivative refers to any physiologically acceptable derivative of a compound of formula I, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) 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 of the invention. These prodrugs may or may not be effective.
- the compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within 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 substances.
- the amount of a compound of Formula I required to achieve the desired biological effect is dependent upon a number of factors, e.g. the chosen specific compound, the intended
- the daily dose ranges from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, eg, 3-10 mg / kg / day.
- an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
- Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
- Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
- vials for injections, and orally administrable unit dose formulations may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
- the compounds according to formula I can themselves be used as compound, but they are preferably present with a compatible carrier in the form of a pharmaceutical composition.
- the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
- the carrier may 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 may contain from 0.05% to 95% by weight of the active ingredient.
- compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients ,
- compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is of the type and severity of the treatment to be treated State and on the nature of the particular compound used according to formula 1 is dependent.
- coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid. and methacrylic acid methyl ester.
- Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a 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 may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
- 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 molded, if necessary.
- a tablet can be made by compressing or molding 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, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
- Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
- compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
- Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to 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 an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.
- Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
- Suitable pharmaceutical compositions for topical application to the skin are preferably as 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 the carrier.
- the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
- Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches 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 about 1% to 35%, preferably about 3% to 15%.
- the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
- active ingredients for the combination preparations are suitable: All Antidiabetika, which are mentioned in the red list 2001, chapter 12. They can be combined with the compounds of the formula I according to the invention in particular for the synergistic effect improvement.
- the administration of the active ingredient combination can be carried out 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 drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
- Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US 6,221, 633), GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
- the orally active hypoglycemic agents preferably include sulphonyl fluorides, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as those described in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, fat metabolism altering compounds such as antihyperlipidemic agents and antilipidemic agents, compounds that reduce food intake, PPAR and PXR agonists and drugs that act on the ATP-dependent potassium channel of beta cells.
- the compounds of 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 formula I are administered in combination with a cholesterol resorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside.
- a cholesterol resorption inhibitor e.g. Ezetimibe, Tiqueside, Pamaqueside.
- the compounds of formula I are administered in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
- a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
- the compounds of formula I in combination with PPAR alpha agonist e.g. GW 9578, GW 7647.
- the compounds of formula I are used in combination with a mixed PPAR alpha / gamma agonist such as GW 1536, AVE 8042, AVE 8134, AVE 0847 or as in PCT / US 11833, PCT / US 11490, DE10142734 .4 administered described.
- the compounds of formula I are administered in combination with a fibrate, such as fenofibrate, clofibrate, bezafibrate.
- the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
- an MTP inhibitor e.g. Implitapide, BMS-201038, R-103757.
- the compounds of formula I are used in combination with a bile acid resorption inhibitor (see, e.g., U.S. 6,245,744 or U.S. 6,221,897), e.g. HMR 1741 administered.
- a bile acid resorption inhibitor see, e.g., U.S. 6,245,744 or U.S. 6,221,897
- the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
- a CETP inhibitor e.g. JTT-705.
- the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
- a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
- the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMR1171, HMR1586.
- the compounds of formula I are administered in combination with an ACAT inhibitor, e.g. Avasimibe, administered.
- an ACAT inhibitor e.g. Avasimibe
- the compounds of formula I are used in combination with an antioxidant, e.g. OPC-14117 administered.
- 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.
- the compounds of formula I are administered in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
- a squalene synthetase inhibitor e.g. BMS-188494.
- the compounds of formula I in combination with a lipoprotein (a) antagonist, e.g. CI-1027 or nicotinic acid.
- a lipoprotein (a) antagonist e.g. CI-1027 or nicotinic acid.
- the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, administered.
- a lipase inhibitor e.g. Orlistat
- the compounds of formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of formula I are used in combination with a biguanide, e.g. Metformin, administered.
- a sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
- a biguanide e.g. Metformin
- the compounds of formula I are administered in combination with a meglitinide, such as repaglinide.
- a meglitinide such as repaglinide.
- the compounds of formula I are used in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med.
- the compounds of formula I are administered in combination with a ⁇ -glucosidase inhibitor such as miglitol or acarbose.
- the compounds of formula I are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
- the compounds of the formula I are used in combination with more than one of the abovementioned compounds, for example in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone , Insulin and lovastatin, etc. administered.
- the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript-influenced energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M.: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide; hydrochloride (CGP 71683A)), MC4 agonists (eg, 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3 , 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-ch
- DA agonists bromocriptine, doprexine
- lipase / amylase inhibitors e.g., WO 00/40569
- PPAR modulators e.g., WO 00/78312
- RXR modulators or TR-agonists.
- the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
- the other active ingredient is dexamphetamine or amphetamine.
- the other active ingredient is fenfluramine or dexfenfluramine. In yet another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat. In one embodiment, the other 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 of the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
- Combination with 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 food, such as in baked goods or muesli bars. It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.
- MS is ok
- MS means that a mass spectrum or HPLC / MS was measured and in this the molecular peak (molecular weight + H + ) was detected.
- Example 5 was synthesized from EP 0 193 249. Comparative Example A has the structure:
- the compounds of the formula I are distinguished by favorable effects on the sugar metabolism, they reduce in particular 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 blood sugar lowering agents (antidiabetics).
- the compounds of formula I are further suitable for the treatment of diabetic late damage, such as e.g. Nephropathy, retinopathy, neuropathy and myocardial infarction, myocardial infarction, peripheral arterial disease, thrombosis, arteriosclerosis, syndrome X, obesity, inflammation,
- diabetic late damage such as e.g. Nephropathy, retinopathy, neuropathy and myocardial infarction, myocardial infarction, peripheral arterial disease, 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.
- the effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by following the glycogen synthesis from glucose-1-phosphate by determination of the release of inorganic phosphate. All reactions were duplicate determinations in 96-well microtiter plates (Half Area Plates, Costar No. 3696), wherein the change in absorbance due to the formation of the reaction product at the wavelength specified below was measured in a Multiskan Ascent Elisa Reader (Lab Systems, Finland). In order to measure the GPa enzyme activity in the reverse direction, the conversion of glucose-1-phosphate to glycogen and inorganic phosphate was determined by the general method of Engers et al.
- buffer T 50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2 , 5 mM MgCl 2 -6H 2 O
- Test substances were prepared as 10 mM solution in DMSO and diluted to 50 uM with buffer solution T.
- glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 ⁇ l of buffer solution T (0.1% DMSO) was incubated for 40 minutes at room temperature and the liberated inorganic phosphate by the general method of Drueckes et al.
- Comparative Example A shows 3% inhibition at 10 ⁇ M.
- the compounds of the formula I inhibit the activity of glycogen phosphorylase a and thereby to lower the blood sugar level are well suited.
- the compounds of the formula I have a 14 to 36 times increased activity over the comparative example A.
- 2-Chlorobenzoyl isocyanate (stage a) was taken up in 8 ml of acetonitrile and admixed with a suspension of 1.1 g (6 mmol) of 4-amino-3-nitrobenzoic acid in 24 ml of acetonitrile. The mixture was heated to reflux for 3.5 hours, after cooling, the precipitate was filtered off, washed with acetonitrile and dried in vacuo. This gave 1.68 g (77%) of the desired product. M.p .: 240 ° C (decomposition)
- reaction mixture was stirred for 1.5 h and then treated with 0.1 ml of pyridine. After a further 1.5 h at 60 ° C., 90 ml of liquid were distilled off from the batch at atmospheric pressure (maximum bath temperature 125 ° C.). The reaction solution was then cooled to 20 ° C and introduced at 20-35 ° C (cooling with ice bath) ammonia gas to saturation of the solution. Subsequently, 160 ml of THF and 120 ml of deionized water were added to the batch at 20 ° C. The aqueous phase was separated and the organic phase with 5% aqueous
- the compounds of the formula I can be prepared by reacting ureas of the formula 2 or aniline derivatives of the formula 3 with aroyl isocyanates, with reactive acid derivatives, with acid chlorides or with anhydrides of the formula 4,
- the production of I can generally be done in a one-pot process, which greatly simplifies the large-scale production.
- 4b is converted into the acid chloride in a suitable solvent, such as, for example, toluene, by means of a suitable reagent, such as, for example, thionyl chloride or oxalyl chloride.
- a suitable catalyst such as pyridine, NMP or DMF, is added as needed to complete the reaction.
- the acid chloride is purified by suitable reagents, such as introducing ammonia gas into the reaction solution, or adding a solution of ammonia in a suitable solvent, such as THF, into acid amide 4b transferred.
- suitable reagents such as introducing ammonia gas into the reaction solution, or adding a solution of ammonia in a suitable solvent, such as THF, into acid amide 4b transferred.
- the reaction mixture is treated with as much water and a suitable solvent, such as THF, so that any solid goes into solution.
- THF a suitable solvent
- the aniline 3a is dissolved in a suitable solvent such as THF and added to the solution of the aroyl isocyanate 4a, whereby the reaction product precipitates out of the solution.
- a suitable solvent such as THF
- the compound of formula I is separated by filtration.
- the TRIS salt of the compound of formula I crystallizes after. Dissolve the compound of formula I with TRIS in a suitable solvent, such as 2-propanol, in the boiling heat during subsequent cooling of the solution.
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Abstract
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Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL16424902A IL164249A0 (en) | 2002-04-11 | 2002-04-11 | Acyl-3-carboxphenylurea derivatives, processes forpreparing them and their use |
MXPA04009468A MXPA04009468A (es) | 2002-04-11 | 2003-03-28 | Derivados de acil-4-carboxifenilurea, procedimientos para su preparacion y su uso. |
NZ535834A NZ535834A (en) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxyphenylurea derivatives, processes for preparing them and their use |
AT03712111T ATE476412T1 (de) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxy-phenyl-harnstoffderivate, verfahren zu deren herstellung und deren verwendung |
BR0309242-9A BR0309242A (pt) | 2002-04-11 | 2003-03-28 | Derivados de acil-4-carboxifenil-uréia, processo para a sua preparação e sua aplicação |
AU2003216900A AU2003216900A1 (en) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxyphenylurea derivatives, method for production and use thereof |
CA002481817A CA2481817A1 (en) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxyphenylurea derivatives, method for production and use thereof |
EP03712111A EP1497262B1 (de) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxy-phenyl-harnstoffderivate, verfahren zu deren herstellung und deren verwendung |
JP2003582121A JP4328211B2 (ja) | 2002-04-11 | 2003-03-28 | アシル−4−カルボキシフェニル尿素誘導体、その製造方法およびその使用 |
UA20041109224A UA78040C2 (en) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxyphenyl urea derivatives, a process for preparation thereof (variants), a medicament based thereon and a process for preparation thereof |
KR10-2004-7016158A KR20040097333A (ko) | 2002-04-11 | 2003-03-28 | 아실-4-카복시페닐우레아 유도체, 이의 제조방법 및 용도 |
HU0500440A HUP0500440A2 (hu) | 2002-04-11 | 2003-03-28 | Acil-4-karboxi-fenil-karbamid-származékok, azokat tartalmazó gyógyszerkészítmények, eljárás ezek előállítására és ezek alkalmazása |
DE50312949T DE50312949D1 (de) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxy-phenyl-harnstoffderivate, verfahren zu deren herstellung und deren verwendung |
HR20040930A HRPK20040930B3 (en) | 2002-04-11 | 2004-10-07 | Acyl-4-carboxyphenylurea derivatives, method for production and use thereof |
TNP2004000199A TNSN04199A1 (en) | 2002-04-11 | 2004-10-08 | Acyl-4-carboxyphenylurea derivatives, processes for preparing them and their use |
NO20044882A NO20044882L (no) | 2002-04-11 | 2004-11-09 | Acyl-4-karboksylfenylurinstoffderivater, deres fremstilling og anvendelse |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10215907A DE10215907A1 (de) | 2002-04-11 | 2002-04-11 | Acyl-4-carboxyphenyl-harnstoffderivate, Verfahren zu deren Herstellung und deren Verwendung |
DE10215907.6 | 2002-04-11 |
Publications (2)
Publication Number | Publication Date |
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WO2003084922A1 true WO2003084922A1 (de) | 2003-10-16 |
WO2003084922A8 WO2003084922A8 (de) | 2005-01-13 |
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ID=28684935
Family Applications (1)
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PCT/EP2003/003251 WO2003084922A1 (de) | 2002-04-11 | 2003-03-28 | Acyl-4-carboxy-phenyl-harnstoffderivate, verfahren zu deren herstellung und deren verwendung |
Country Status (28)
Country | Link |
---|---|
EP (1) | EP1497262B1 (de) |
JP (1) | JP4328211B2 (de) |
KR (1) | KR20040097333A (de) |
CN (1) | CN1286805C (de) |
AR (1) | AR039403A1 (de) |
AT (1) | ATE476412T1 (de) |
AU (1) | AU2003216900A1 (de) |
BR (1) | BR0309242A (de) |
CA (1) | CA2481817A1 (de) |
DE (2) | DE10215907A1 (de) |
EC (1) | ECSP045347A (de) |
HR (1) | HRPK20040930B3 (de) |
HU (1) | HUP0500440A2 (de) |
IL (1) | IL164249A0 (de) |
MA (1) | MA26390A1 (de) |
MX (1) | MXPA04009468A (de) |
NO (1) | NO20044882L (de) |
NZ (1) | NZ535834A (de) |
OA (1) | OA12805A (de) |
PA (1) | PA8570901A1 (de) |
PE (1) | PE20040374A1 (de) |
PL (1) | PL371279A1 (de) |
RU (1) | RU2004133045A (de) |
TN (1) | TNSN04199A1 (de) |
TW (1) | TW200404762A (de) |
UA (1) | UA78040C2 (de) |
UY (1) | UY27761A1 (de) |
WO (1) | WO2003084922A1 (de) |
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Cited By (46)
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PL371279A1 (en) | 2005-06-13 |
TW200404762A (en) | 2004-04-01 |
ECSP045347A (es) | 2004-11-26 |
HUP0500440A2 (hu) | 2005-08-29 |
CN1646485A (zh) | 2005-07-27 |
UA78040C2 (en) | 2007-02-15 |
EP1497262A1 (de) | 2005-01-19 |
DE50312949D1 (de) | 2010-09-16 |
EP1497262B1 (de) | 2010-08-04 |
PE20040374A1 (es) | 2004-07-20 |
DE10215907A1 (de) | 2003-11-06 |
MXPA04009468A (es) | 2005-01-25 |
UY27761A1 (es) | 2003-10-31 |
TNSN04199A1 (en) | 2007-03-12 |
NO20044882L (no) | 2004-11-09 |
HRP20040930A2 (en) | 2005-04-30 |
OA12805A (fr) | 2006-07-11 |
JP4328211B2 (ja) | 2009-09-09 |
MA26390A1 (fr) | 2004-11-01 |
BR0309242A (pt) | 2005-02-09 |
PA8570901A1 (es) | 2003-11-12 |
RU2004133045A (ru) | 2005-05-27 |
NZ535834A (en) | 2006-07-28 |
ATE476412T1 (de) | 2010-08-15 |
AR039403A1 (es) | 2005-02-16 |
KR20040097333A (ko) | 2004-11-17 |
AU2003216900A1 (en) | 2003-10-20 |
HRPK20040930B3 (en) | 2006-09-30 |
CA2481817A1 (en) | 2003-10-16 |
JP2005522480A (ja) | 2005-07-28 |
IL164249A0 (en) | 2005-12-18 |
CN1286805C (zh) | 2006-11-29 |
WO2003084922A8 (de) | 2005-01-13 |
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