WO2004033416A2 - Carboxyalkoxy-substituierte acyl-carboxyphenyl-harnstoffderivate, verfahren zu ihre herstellung und ihre verwendung als arzneimittel - Google Patents
Carboxyalkoxy-substituierte acyl-carboxyphenyl-harnstoffderivate, verfahren zu ihre herstellung und ihre verwendung als arzneimittel Download PDFInfo
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- WO2004033416A2 WO2004033416A2 PCT/EP2003/010501 EP0310501W WO2004033416A2 WO 2004033416 A2 WO2004033416 A2 WO 2004033416A2 EP 0310501 W EP0310501 W EP 0310501W WO 2004033416 A2 WO2004033416 A2 WO 2004033416A2
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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
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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
- A61P3/06—Antihyperlipidemics
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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
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their physiologically tolerable salts and physiologically functional derivatives.
- the invention had for its object to provide compounds which have a therapeutically utilizable blood sugar-lowering effect.
- the task was to provide compounds with improved activity compared to the compounds from WO 01/94300.
- the invention therefore relates to compounds of the formula I
- R1 H (-CC 6 ) alkyl, (C 0 -C 6 ) -alkyl-phenyl, the phenyl ring up to twice with F, Cl, CN, OH, (CC 6 ) -alkyl, O- (-C. -C 6 ) alkyl, CF 3) OCF 3> COOH, COO (CC 6 ) alkyl or CONH 2 ;
- R2 H (CC 6 ) alkyl, CO- (CC 6 ) -alkyl, COO- (CC 6 ) -alkyl,
- R3 is H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) alkyl, (CC 6 ) alkyl;
- Preferred compounds of the formula I are those in which
- R2 H (-CC 6 ) -A! Kyl, O- (CC 6 ) -alkyl, CO- (CC 6 ) -alkyl, COO- (C 1 -C 6 ) -alkyl, (C 0 -C 6 ) -AIkylen-COOH;
- R3 H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (CC 6 ) alkyl;
- R2 H COO- (-C 6 ) -alkyl, -COOH
- 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 and R3 can be either straight-chain or branched.
- 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, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethione, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.
- inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid
- organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethione, lactic, lactobionic,
- Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.
- Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, 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 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 (directly or indirectly) to 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 may or may not work themselves.
- the compounds of the invention can 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 compounds.
- the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 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
- 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 Condition and on the type of used in each case Compound 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 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 of which contains 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 molding 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 for oral (sublingual) are provided.
- Suitable administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges comprising the compound in an inert base such as gelatin and glycerin 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 they can also be administered subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be produced by subjecting the compound is mixed with water and the resulting solution is made isotonic with the sterile v 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%.
- Transdermal administration is also possible.
- 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 concentration of active ingredient 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 also suitable as active ingredients for the combination preparations: all antidiabetic agents mentioned in the 2001 Red List, Chapter 12. They can be combined with the compounds of the formula I according to the invention in particular to improve the synergistic effect.
- 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 active ingredients preferably include sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists,
- Potassium channel openers e.g. those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes involved in stimulating gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, altering lipid metabolism Compounds such as antihyperlipidemic agents and antilipidemic agents, compounds that reduce food intake, PPAR and PXR agonists and agents that act on the ATP-dependent potassium channel of the beta cells.
- 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 used 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 the formula I are used in combination with a PPAR alpha agonist, e.g. GW 9578, GW 7647.
- a PPAR alpha agonist e.g. GW 9578, GW 7647.
- 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 / US00 / 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 / US00 / 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, for example, US 6,245,744 or US 6,221,897), e.g. HMR 1741.
- a bile acid absorption inhibitor see, for example, US 6,245,744 or US 6,221,897.
- 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. CI-1027 or nicotinic acid.
- a lipoprotein e.g. CI-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 formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.
- a sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.
- the compounds of formula I in combination with a biguanide such as e.g. Metformin.
- the compounds of formula I in combination with a meglitinide, such as e.g. Repaglinide.
- the compounds of formula I in combination with a thiazolidinedione such as 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-thiazo! Idindione.
- a thiazolidinedione such as 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 the formula I are used in combination with an ⁇ -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 sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, 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., In .: Hormone and Metabolie Research (2001), 33 (9), 554-558), NPY-antagonists e.g. naphthalene-1-sulfonic acid ⁇ 4 - [(4-aminoquinazolin-2-yIamino) - methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A) ), MC4 agonists (e.g.
- urocortin urocortin
- urocortin agonists urocortin agonists
- 3 agonists e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl-1 H-indole-6- yloxy) ethylamino] -
- ethanol hydrochloride (WO 01/83451)
- MSH melanocyte-stimulating hormone
- CCK-A agonists e.g. ⁇ 2- [4- (4-chloro-2,5-dimethoxyphenyl) -5- ( 2-cyclohexylethyl) thiazol-2-ylcarbamoyl] -5,7-dimethylindol-1-yl ⁇ -acetic acid, trifluoroacetic acid salt (WO 99/15525)
- Serotonin reuptake inhibitors e.g. dexfenfluramines
- 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 antagonists, 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 0462
- 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
- PPAR modulators e.g. WO 00/78312
- RXR modulators or TR - # agonists.
- the further active ingredient is leptin; see, for example, “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-30 Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 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 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 done in one preparation or by separate administration of compounds of formula I and Caromax ® .
- Caromax ® can also be administered in the form of food, such as in baked goods or granola bars.
- JTT-501 The examples listed below serve to illustrate the invention, but without restricting it.
- the measured fixed or decomposition points (Fp.) Were not corrected and are generally dependent on the heating rate.
- the compounds of formula 1 are characterized by favorable effects on the lipid 5 and carbohydrate metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes, insulin resistance, dyslipidemia and the metabolic syndrome / syndrome X.
- the compounds are also suitable for the prophylaxis and treatment of arteriosclerotic symptoms.
- the compounds can be used alone or in combination with other blood sugar
- the compounds of the formula I are suitable on account of their pharmacological properties (see JL Treadway, P. Mendys, DJ Hoover, Exp. Opin. Invest. Drugs 2001, 10 (3), 439-454) as cardioprotective medicaments for the prevention of infarction and the treatment of infarction as well as for the treatment of angina pectoris
- the compounds can be used alone or in combination with other cardioprotective or antiarrhythmic active ingredients.
- the compounds of the formula I are also suitable for the treatment of tumor diseases on account of their pharmacological properties.
- Various studies have shown that there is a direct relationship between glycogen levels and various parameters of tumor growth and development (see M. Rousset, E. Dussaulx,
- Hepatocytes were isolated from the livers of fed rats (Sprague-Dawley or Wistar, 220-240 g body weight) using a standard 2-stage perfusion first with calcium-free buffer solution followed by perfusion with collagenase-containing solution to dissolve the tissue ( Seglen et al, 1979). The cells were incubated in an incubator with 90% humidity at 37 ° C and an atmosphere with 5% CO 2 in air. The cultivation was usually carried out using Williams Medium E supplemented with 20 mM glucose, 0.1 mM fructose, 1 ⁇ M dexamethasone and 100 nM insulin.
- Glycogenolysis was induced by changing the culture medium to prewarmed Krebs-Henseleit bicarbonate Hepes (20 mM) buffer, pH 7.4, gassed with carbogen and supplemented with glucagon 100 nM (time 0 min).
- the test substances were usually added at 0 min as a 100-fold stock solution in DMSO.
- the final DMSO concentration was not higher than 1% (v / v).
- the amount of glucose in the culture supernatant was determined after the addition of glucagon in the presence or absence of test substance by taking small aliquots of the cell culture supernatant at the times 0, 30, 60 and 90 min.
- the glucose concentration (mM) was determined using enzymatic methods in a clinical-chemical analysis laboratory at Aventis Pharma Germany.
- the glucose production rate was determined by linear regression of the glucose concentration at times 30, 60 and 90 min using the following formula:
- IC 50 values (IC 5 o ".
- concentration ( ⁇ M) of test substance which brings about a reduction of 50% of the glucose production rate) were estimated by means of the percent inhibitions obtained at relevant concentrations of test substance using standard curve fitting methods.
- Example 3 was produced in accordance with this specification.
- step a) 3-Carboxymethoxy-4- [3- (2-chloro-4-fluoro-benzoyl) -ureido] -benzoic acid
- the crude product from step a) is analogous to Example 1b) to 1d) in 3-methoxycarbonylmethoxy-4- [3 - (2-chloro-4-fluorobenzoyl) -ureido] -benzoic acid methyl ester, of which 50 mg (0.11 mmol) are dissolved in 5 ml of THF and 1 ml of water are added. For this, 27 mg (1.1 mmol) of LiOH are added and the reaction is stirred at room temperature until the starting material has been completely converted. The reaction is controlled by LC-MS.
- step a) 4- [3- (2-chloro-4,5-difluorobenzoyl) -ureido] -3- (3-methoxycarbonylpropoxy) benzoic acid
- the benzyl 3-hydroxy-4-nitrobenzoate from step a) was prepared analogously to instruction 2a) alkylated to form 3- (3-methoxycarbonylpropoxy) -4-nitro-benzoic acid benzyl ester.
- 450 mg (1.2 mmol) of the benzyl ester are dissolved in 20 ml of methanol, 13 mg (0.1 mmol) of palladium on activated carbon (10%) are added and the mixture is hydrogenated at room temperature.
- the reaction is controlled by LC-MS.
- Example 15 was prepared analogously to this procedure.
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003273913A AU2003273913A1 (en) | 2002-10-04 | 2003-09-22 | Carboxyalkoxy-substituted acyl-carboxyphenyl-urea derivatives, production method and use thereof as medicine |
CA002500763A CA2500763A1 (en) | 2002-10-04 | 2003-09-22 | Carboxyalkoxy-substituted acyl-carboxyphenyl-urea derivatives, production method and use thereof as medicine |
MXPA05003320A MXPA05003320A (es) | 2002-10-04 | 2003-09-22 | Derivados de acil - carboxifenilurea sustituidos con carboxialcoxi, metodo para su produccion y su uso como medicamentos. |
JP2004542363A JP4355290B2 (ja) | 2002-10-04 | 2003-09-22 | カルボキシアルコキシ置換アシル−カルボキシフェニル尿素誘導体、その製造方法、および医薬品としてのその使用 |
AT03757879T ATE479653T1 (de) | 2002-10-04 | 2003-09-22 | Carboxyalkoxy-substituierte acyl-carboxyphenyl- harnstoffderivate, verfahren zu ihre herstellung und ihre verwendung als arzneimittel |
EP03757879A EP1556339B1 (de) | 2002-10-04 | 2003-09-22 | Carboxyalkoxy-substituierte acyl-carboxyphenyl-harnstoffderivate, verfahren zu ihre herstellung und ihre verwendung als arzneimittel |
BR0314861-0A BR0314861A (pt) | 2002-10-04 | 2003-09-22 | Derivados de acil-carboxifenil-úreia substituìdos por carboxialcóxi, processo para sua preparação e seu uso como medicamento |
DE50313047T DE50313047D1 (de) | 2002-10-04 | 2003-09-22 | Carboxyalkoxy-substituierte acyl-carboxyphenyl-harnstoffderivate, verfahren zu ihre herstellung und ihre verwendung als arzneimittel |
US10/679,550 US20040157922A1 (en) | 2002-10-04 | 2003-10-06 | Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments |
US11/613,433 US7781459B2 (en) | 2002-10-04 | 2006-12-20 | Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10246434.0 | 2002-10-04 | ||
DE10246434A DE10246434B4 (de) | 2002-10-04 | 2002-10-04 | Carboxyalkoxy-substituierte Acyl-carboxyphenyl-harnstoffderivate und ihre Verwendung als Arzneimittel |
Publications (2)
Publication Number | Publication Date |
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WO2004033416A2 true WO2004033416A2 (de) | 2004-04-22 |
WO2004033416A3 WO2004033416A3 (de) | 2004-05-13 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2003/010501 WO2004033416A2 (de) | 2002-10-04 | 2003-09-22 | Carboxyalkoxy-substituierte acyl-carboxyphenyl-harnstoffderivate, verfahren zu ihre herstellung und ihre verwendung als arzneimittel |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1556339B1 (de) |
JP (1) | JP4355290B2 (de) |
AT (1) | ATE479653T1 (de) |
AU (1) | AU2003273913A1 (de) |
BR (1) | BR0314861A (de) |
CA (1) | CA2500763A1 (de) |
DE (2) | DE10246434B4 (de) |
MX (1) | MXPA05003320A (de) |
WO (1) | WO2004033416A2 (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007128761A2 (de) | 2006-05-04 | 2007-11-15 | Boehringer Ingelheim International Gmbh | Verwendungen von dpp iv inhibitoren |
WO2012030165A2 (ko) | 2010-08-31 | 2012-03-08 | 서울대학교산학협력단 | P P A R δ 활성물질의 태자재프로그래밍용도 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10306502B4 (de) * | 2003-02-17 | 2005-03-17 | Aventis Pharma Deutschland Gmbh | Substituierte 3-(Benzoylureido)-thiophenderivate und sie enthaltende Arzneimittel |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0193249A2 (de) * | 1985-03-01 | 1986-09-03 | Duphar International Research B.V | Benzoylharnstoffderivate mit Antikrebs-Wirkung |
WO2001094300A1 (de) * | 2000-06-09 | 2001-12-13 | Aventis Pharma Deutschland Gmbh | Acylphenylharnstoffderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9313268D0 (en) * | 1993-06-28 | 1993-08-11 | Zeneca Ltd | Chemical compounds |
-
2002
- 2002-10-04 DE DE10246434A patent/DE10246434B4/de not_active Expired - Fee Related
-
2003
- 2003-09-22 JP JP2004542363A patent/JP4355290B2/ja not_active Expired - Fee Related
- 2003-09-22 WO PCT/EP2003/010501 patent/WO2004033416A2/de active Application Filing
- 2003-09-22 EP EP03757879A patent/EP1556339B1/de not_active Expired - Lifetime
- 2003-09-22 BR BR0314861-0A patent/BR0314861A/pt not_active IP Right Cessation
- 2003-09-22 MX MXPA05003320A patent/MXPA05003320A/es unknown
- 2003-09-22 CA CA002500763A patent/CA2500763A1/en not_active Abandoned
- 2003-09-22 AT AT03757879T patent/ATE479653T1/de not_active IP Right Cessation
- 2003-09-22 AU AU2003273913A patent/AU2003273913A1/en not_active Abandoned
- 2003-09-22 DE DE50313047T patent/DE50313047D1/de not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0193249A2 (de) * | 1985-03-01 | 1986-09-03 | Duphar International Research B.V | Benzoylharnstoffderivate mit Antikrebs-Wirkung |
WO2001094300A1 (de) * | 2000-06-09 | 2001-12-13 | Aventis Pharma Deutschland Gmbh | Acylphenylharnstoffderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007128761A2 (de) | 2006-05-04 | 2007-11-15 | Boehringer Ingelheim International Gmbh | Verwendungen von dpp iv inhibitoren |
EP2351568A2 (de) | 2006-05-04 | 2011-08-03 | Boehringer Ingelheim International GmbH | Verwendungen von dpp iv Inhibitoren |
WO2012030165A2 (ko) | 2010-08-31 | 2012-03-08 | 서울대학교산학협력단 | P P A R δ 활성물질의 태자재프로그래밍용도 |
Also Published As
Publication number | Publication date |
---|---|
EP1556339A2 (de) | 2005-07-27 |
CA2500763A1 (en) | 2004-04-22 |
DE10246434B4 (de) | 2005-08-04 |
EP1556339B1 (de) | 2010-09-01 |
ATE479653T1 (de) | 2010-09-15 |
DE10246434A1 (de) | 2004-04-15 |
AU2003273913A1 (en) | 2004-05-04 |
JP2006502206A (ja) | 2006-01-19 |
MXPA05003320A (es) | 2005-07-05 |
BR0314861A (pt) | 2005-08-02 |
WO2004033416A3 (de) | 2004-05-13 |
JP4355290B2 (ja) | 2009-10-28 |
DE50313047D1 (de) | 2010-10-14 |
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