WO2003072098A1 - Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique - Google Patents

Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique Download PDF

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Publication number
WO2003072098A1
WO2003072098A1 PCT/EP2003/001560 EP0301560W WO03072098A1 WO 2003072098 A1 WO2003072098 A1 WO 2003072098A1 EP 0301560 W EP0301560 W EP 0301560W WO 03072098 A1 WO03072098 A1 WO 03072098A1
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Prior art keywords
alkyl
substituted
aryl
phenyl
halogen
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PCT/EP2003/001560
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German (de)
English (en)
Inventor
Karl Schoenafinger
Stefan Petry
Guenter Mueller
Armin Bauer
Hubert Otto Heuer
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Aventis Pharma Deutschland Gmbh
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Priority to KR10-2004-7013470A priority Critical patent/KR20040101250A/ko
Priority to JP2003570844A priority patent/JP2005519079A/ja
Priority to EP03742942A priority patent/EP1482929A1/fr
Priority to BR0308045-5A priority patent/BR0308045A/pt
Priority to AU2003210292A priority patent/AU2003210292A1/en
Priority to HU0500093A priority patent/HUP0500093A2/hu
Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to IL16371903A priority patent/IL163719A0/xx
Priority to MXPA04007480A priority patent/MXPA04007480A/es
Priority to CA002477005A priority patent/CA2477005A1/fr
Publication of WO2003072098A1 publication Critical patent/WO2003072098A1/fr
Priority to HR20040783A priority patent/HRP20040783A2/hr
Priority to NO20044091A priority patent/NO20044091L/no

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the use of substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones for the production of medicaments which have an inhibitory effect on the pancreatic lipase, PL.
  • the invention therefore relates to the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones of the general formula 1,
  • R 1 Ci-C- ⁇ -alkyl, C 3 -C 9 cycloalkyl, both groups by phenyl, CC 4 - alkyloxy, S-C ⁇ -C 4 alkyl, N (CrC 4 alkyl) 2 one or more times can be substituted and phenyl in turn by halogen, -CC 4 alkyl, CrC alkyloxy, nitro,
  • CF 3 can be substituted one or more times; and R 2 , R 3 , R 4 and R 5 independently of one another hydrogen, halogen, nitro, -CC alkyl; Ci-Cg-alkyloxy, which is substituted by fluorine, C 6 -C ⁇ o-aryl, amino or CrC -alkyl-amino; C 6 -C ⁇ o-aryl -CC 4 -alkyloxy, C 6 -C ⁇ o-aryloxy, C 6 -C ⁇ o-aryl, C 6 -C ⁇ 0 -aryloxy-C ⁇ -C 4 - alkyl, C 3 -C 8 cycloalkyl or OC 3 -C 8 cycloalkyl, which can be mono-, tri-or trisubstituted by halogen, CF 3> CrC 4 -alkyloxy or C 1 -C 8 -alkyl;
  • S0 2 -NH-CrC 6 -alkyl optionally substituted by N (C 1 -C 6 -alkyl) 2 , SO 2 - NH- (2.2 I 6.6 ) -tetramethylpiperidin-4-yl), SO 2 - NH-C 3 -C 8 -cycloalkyl, optionally mono- or polysubstituted by CrC-alkyl, SO 2 -N (-C-C 6 -
  • R 2 , R 3 , R 4 and R 5 do not simultaneously mean hydrogen
  • C 10 aryl, CO-Crd-alkyl, CO-C 6 -C ⁇ 0 aryl, CO-OC C 4 alkyl, SO 2 -CC 4 alkyl or SO 2 -C 6 -C ⁇ o-aryl may be substituted;
  • R 6 is hydrogen, CC 4 alkyl or.
  • A is a simple bond, CO n , SO n or CONH; n 1 or 2;
  • R 7 is hydrogen
  • C 1 -C 8 -alkyl or C 2 -C 18 -alkenyl which is mono- to triple-substituted by CC 4 -alkyl, halogen, CF 3 , dC 4 -alkyloxy, N (CrC 4 -alkyl) 2 , -COOH, dd Alkyloxycarbonyl, C 6 -C 12 aryl, C 6 -C 2 aryloxy, C 6 -C ⁇ 2 arylcarbonyl, Ce-do-aryl-dd-alkyloxy or oxo can be substituted, aryl in turn being substituted by halogen, C- ⁇ -C 4 - alkyl, aminosulfonyl or methyl mercapto may be substituted; Ce-do-aryl-dd-alkyl, Cs-Cs-cycloalkyl-dd-alkyl, C 5 -C 8 cycloalkyl, C 6 -C
  • the aryl radicals mentioned can optionally be substituted one or more times with d-Cg-alkyl, Ci-Cs-alkyloxy, halogen, trifluoromethyl.
  • the cycloalkyl radicals mentioned can optionally be substituted one or more times with C 1 -C 4 -alkyl, C 6 -do-aryl and the alkyl radicals mentioned can be substituted by hydroxy, di-C 4 -C 4 -alkylamino and fluorine.
  • Halogen represents fluorine, chlorine, bromine, preferably fluorine and chlorine.
  • Alkyl, alkenyl, alkyloxy, etc. can be branched or unbranched.
  • R 1 denotes Ci-Ce-alkyl, which may optionally be substituted by phenyl; and / or R 5 is hydrogen; and or R 2 is hydrogen, halogen, -CC 4 -alkyl, -C-Cg-alkyloxy or amino, and their pharmacologically tolerable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic lipase.
  • R 7 C 6 -C ⁇ -aryl-C ⁇ -C 4 alkyl, which can be substituted by halogen, CF 3 , cyano, phenyl-CrC 4 - alkyloxy, CF 3 -phenoxy, C 5 -C 8 cycloalkyl or fluorosulfonyloxy ; -CC 2 -alkyl which can be substituted by -C 4 -alkyloxy, phenyl, CF 3 or phenyl-CrC -alkyloxy;
  • R 2 and R 3 independently of one another are hydrogen, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, optionally substituted by CrC 4 alkyl, C 6 -C ⁇ 0 aryloximethyl, optionally substituted by dC 4 alkyl or halogen.
  • R 4 is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C 6 -C 10 aryl-CrC 4 -alkyloxy, which may be substituted by halogen, and / or
  • R 4 NR 6 -AR 7 , with
  • R 7 hydrogen
  • C 1 -C 2 alkyl which can be mono- or disubstituted by halogen
  • Alkyloxycarbonyl may be substituted; C ⁇ -do-aryl-dd-alkyl, which is substituted by halogen, dC 6 -alkyloxy, CF 3 , cyano, C 5 -C 6 -
  • Cycloalkyl, -CC 4 -alkyloxycarbonyl, C 6 -C -o-aryl-CrC -alkyl, C 6 -C 10 -aryl-C C 4 - alkyloxy may be substituted, where aryl may be substituted again by halogen or CF 3 ;
  • Heterocycle which can be substituted by halogen, dC 4 -alkyloxy or dC 4 -alkyloxycarbonyl, and / or
  • R 7 d-cis-alkyl, which can be substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C 1 -C 4 -alkyloxycarbonyl, where phenoxy can in turn be substituted by methyl, halogen or methylmercapto; C 2 -C 8 alkenyl, which can be substituted by C 6 -C ⁇ o aryl;
  • R 7 d-cis-alkyl which is substituted by CF 3 or phenyl;
  • R 6 hydrogen
  • R 4 NR 6 -AR 7 , with
  • R 6 hydrogen
  • R 7 Ci-Cio-alkyl, which may be substituted by dC 4 -alkyloxycarbonyl, N (CC 4 -alkyl) 2 or phenyl, which in turn may be substituted by halogen or aminosulfonyl;
  • Ce-Cio-aryl the by -CC 6 alkyl, dC 6 alkyloxy, dC 6 alkyloxycarbonyl,
  • Heterocycle which may be substituted with benzyl, and their pharmacologically acceptable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic lipase.
  • R 3 is hydrogen, C 6 -C 10 aryl, OC 6 -C 10 aryl, optionally substituted by CC 4 alkyl C 6 -C ⁇ o-aryloximethyl, O-benzyl, one or more times by fluorine or amino-substituted O-C 6 alkyl, where amino can in turn be substituted one or more times by C 1 -C 4 alkyl, optionally substituted by C 1 -C 4 alkyl one or more times substituted OC 3 -C 8 cycloalkyl and R 4 is hydrogen, C 6 -C 1 -aryl, C 3 -C 8 -cycloalkyl, optionally substituted by CrC -alkyl or halogen OC 6 -C 1 -aryl or OC 3 -C 8 - mono- or polysubstituted
  • Cycloalkyl one or more fluorine-substituted OdC 6 alkyl, SO 2 - NH-CrC 6 alkyl, optionally substituted by N (-C 6 -alkyl) 2 , SO 2 -NH- (2,2,6, 6-tetramethylpiperidin-4-yl), SO 2 -NH-C 3 -C 8 -cycloalkyl, mono- or polysubstituted by CC 4 -alkyl, SO 2 -N (dC 6 -alkyl) 2 or CO-N (dC 6- alkyl) 2 mean, and
  • N (-C 6 alkyl) 2 also represents piperidino, morpholino or piperazino, which may optionally be substituted by C 1 -C alkyl, and their pharmacologically acceptable salts and acid addition salts for the preparation of a medicament with an inhibitory effect on the pancreatic lipase.
  • R 1 is methyl, ethyl, butyl, isopropyl or benzyl and R 2 and R 5 are hydrogen and R 3 is hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5, 5
  • Chlorophenoxy cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexyl-aminosulfonyl, 2,2,6,6, -tetramethyl-piperidin-4-yl-aminosulfonyl, 2- (diisopropylaminoethyl) aminosulfonyl, 4-methyl- piperazin-1 -yl-sulfonyl, 3,3, -Dimethylpiperidino-carbonyl or 3,5-dichlorophenoxy, or the compounds of formula 1, wherein R 1 is methyl, ethyl, butyl, isopropyl or benzyl and R 2 and R 5 stand for hydrogen and
  • R 3 for hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy or phenoxy
  • R 4 represents hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexylaminosulfonyl, and their pharmacologically acceptable salts and acid addition salts for the preparation of a medicament with an inhibitory effect on the pancreatic lipase.
  • R 1 C ⁇ C-4-alkyl
  • R 2 hydrogen
  • R 3 is hydrogen, trifluoromethoxy, benzyloxy,
  • R 4 is hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoylamino, and
  • R 5 is hydrogen and their pharmacologically acceptable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic
  • the invention relates to the use of the compounds of formula 1, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications due to their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of formula 1 are salts of inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, Ethanesulfonic, fumaric, gluconic, glycol, isethionic, lactic, lactobionic, maleic, apple, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acid.
  • the chloride salt and the tartaric acid salt are used in a particularly preferred manner for medical purposes.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the production or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in vitro, applications.
  • physiologically functional derivative means any physiologically acceptable derivative of a compound of the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able (directly or indirectly) to form such a compound or an active metabolite thereof.
  • prodrugs of the compounds of formula 1 can be metabolized in vivo to a compound of formula 1. These prodrugs may or may not be effective themselves.
  • the compounds of formula 1 can also exist in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic Forms of the compounds of formula 1 are within the scope of the invention and are a further aspect of the invention.
  • the amount of a compound of Formula 1 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 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
  • the aforementioned weight data relate to the weight of the salt of the compound of the formula 1.
  • the compounds of the formula 1 themselves can be used as a compound, but they are preferably in a compatible carrier Form of a pharmaceutical composition.
  • 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.
  • Other pharmaceutically active substances can also be present, including further compounds of the formula 1.
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in the fact that the constituents are mixed 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 1 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,
  • Hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate are examples of hydroxypropylmethylcellulose 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, wafer capsules,
  • Lozenges or tablets each containing a certain amount of the compound of formula 1; 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 which comprises a step in which the active ingredient and the carrier (which may 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 made by compressing or molding a powder or granules 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 1 with a flavor, usually sucrose and acacia or tragacanth, and lozenges containing 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 1, 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 1 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).
  • Rectal dosage form containing 40 mg of active ingredient per suppository: per suppository
  • Example D tablets containing 40 mg of active ingredient per tablet 40 mg of active ingredient per tablet
  • Dragee containing 50 mg of active substance per dragees: 50 mg of active substance per dragee
  • Drops can be prepared according to the following recipe (100 mg active ingredient in 1 ml
  • the compounds of general formula 1 can be prepared by methods known per se in various ways.
  • the substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones of general formula 1 can be prepared by reacting hydrazines of general formula 2 with chloroformic acid esters of formula 3 or other reactive carbonic acid ester derivatives, in which R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, to the compounds of formula 4, which acylated with phosgene, carbonyldiimidazole, diphosgene or triphosgene, cyclized and optionally by further chemical modification of the radicals R 2 -R 5 , such as, for example, by reduction of nitro to amino residues by known processes, and subsequent acylation or alkylation, to give the compounds of the formula 1.
  • the hydrazines of the formula 2 can be prepared by known methods, for example by diazotization of the corresponding anilines and
  • phenyl derivatives 6 F, Cl, Br, I, OSO 2 CF 3
  • suitable phenyl derivatives can be nitro-substituted halogenobenzenes, preferably fluoro- and chloro-nitrobenzenes, from which, at a suitable point in the synthesis route, reduction and reaction with acylating or alkylating agents, such as, for example, acid chlorides, anhydrides, isocyanates, chloroformates, sulfonic acid chlorides or alkyl and Arylalkyl halides, or by reductive alkylation with aldehydes according to known methods to prepare the compounds of formula 1.
  • acylating or alkylating agents such as, for example, acid chlorides, anhydrides, isocyanates, chloroformates, sulfonic acid chlorides or alkyl and Arylalkyl halides, or by reductive alkylation with aldehydes according to known methods to prepare the compounds of formula 1.
  • the starting compound, 2-fluoro-4- (4-fluorobenzyloxy) nitrobenzene (mp: 99 ° C.) was prepared by alkylation of 3-fluoro-4-nitro-phenol with 4-fluorobenzyl chloride in DMF in the presence of potash.
  • Example 16 N '- (4- (4-chlorophenoxy) -3-nitro-phenyl) -hydrazino-formic acid methyl ester, mp: 147 ° C.
  • This compound and the compound of Example 18 were prepared by reacting N '- (3-fluoro-4-nitro-phenyl) -hydrazino-formic acid methyl ester with piperidine or N-benzyl-piperazine in NMP at 80 ° C.
  • This compound was obtained by reacting 5-methoxy-3- (4-amino-3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one with equimolar amounts of 3,4-dichlorophenyl isocyanate in toluene obtained at 50 ° C.
  • Example 48 5-methoxy-3- (4 - (- 2- (4'-chlorobiphenyl) ethyl) sulfonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 165 ° C
  • This compound was obtained by reaction of 5-methoxy-3- (4-amino-3-methyl-phenyl) -3-H- (1, 3,4) oxdiazol-2-one with equimolar amounts of acetylacetone in glacial acetic acid at 80 ° C and isolated by precipitation by adding water and filtration.
  • This compound was obtained by reaction of 5-methoxy-3- (4-amino-3-methylphenyI) -3- H- (1, 3,4) oxdiazol-2-one with equimolar amounts of acetonylacetone in glacial acetic acid at 80 ° C , The mixture was worked up by dilution with water, shaking with ethyl acetate and column chromatography (silica gel, methylene chloride) of the crude product obtained after concentrating the dried organic phase.
  • Example 62 5-methoxy-3- (3-methyl-4- (2-chlorobenzyloxicarbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 161 ° C
  • Example 63 5-methoxy-3- (3-methyl-4- (2-chlorobenzyloxicarbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 161 ° C
  • Example 63 5-methoxy-3- (3-methyl-4- (2-chlorobenzyloxicarbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 161 ° C
  • Example 63 5-methoxy-3- (3-methyl-4- (2-chlorobenzyloxicarbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 161 ° C
  • Example 80 5-methoxy-3- (3-methyl-4- (pyrid-3-yl-carbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: oil
  • Example 81 5-methoxy-3- (3-methyl-4- (indan-2-yl-aminocarbonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one
  • 4-hydrazino-benzenesulfonic acid-morpholide (intermediate) 5 g of 4-fluoro-benzenesulfonic acid-morpholide were dissolved in 15 ml of N-methylpyrrolidone, mixed with 2.5 g of hydrazine hydrate and heated to 100 ° C. for 1 hour. After cooling to room temperature, 75 ml of water were added and the mixture was stirred at room temperature. After 2 hours the solid was suction filtered and recrystallized from isopropanol. Yield: 3.2 g mp: 164 ° C
  • Example 206 30 N '- (4-Morpholinosulfonyl-phenyl) -hydrazino-formic acid ethyl ester (intermediate) To the mixture consisting of 0.275 g of 4-hydrazino-benzenesulfonic acid morpholide, 5 ml of methylene chloride and 1 ml of pyridine, 114 mg of ethyl chloroformate were carefully added dropwise with ice cooling and the mixture was then stirred with slow warming to RT.
  • MethanokMethylenchlorid 2: 98) cleaned.
  • Example 221 3- (4- (2,2,6,6-Tetramethyl-piperidin-4-yl-aminosulfonyl) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one
  • Example 225 3- (4- (4-Methyl-piperazin-1-yl-sulfonyl) phenyl) -5-isopropoxy-1, 3,4-oxdiazol-2-one m.p .: Resin
  • Example 231 3- (4- (3,3,5-Trimethyl-cyclohexylaminosulfonyl) phenyl) -5-isopropoxy-1,3,4-oxdiazol-2-one mp: oil
  • Example 232 3- (3-phenoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 89 ° C
  • Example 233 3- (3-phenoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 89 ° C
  • Example 233 3- (3-phenoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 89 ° C
  • Example 233 3- (3-phenoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 89 ° C
  • Example 240 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C
  • Example 241 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C
  • Example 241 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C
  • Example 241 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C
  • Example 241 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C
  • Example 241 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C
  • the compounds of formula 1 show an inhibitory effect on pancreatic lipase (PL). As inhibitors of PL, they can prevent the absorption of the fat consumed with food and thus lead to a reduction in fat intake and body weight or prevent an increase in body weight.
  • the compounds of formula 1 are particularly suitable for the production of medicaments for the treatment of obesity and of type 1 and 2 diabetes mellitus.
  • Lipase buffer 80 mM Tris / HCl (pH 7.6), 600 mM NaCl, 8 mM CaCl 2 , 8 mM benzamidine, 2 mM Pefabloc (Röche Biochemicals) (add inhibitors only on the day of the test)
  • Pancreatic lipase Enriched preparation from pig pancreas (Sigma Order No. L-0382) dissolved in lipase buffer (100000 units / 500 ⁇ l)
  • test substance in 100% DMSO
  • DMSO control
  • lipase in this order

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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Nutrition Science (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de 3-phényl-5-alcoxy-1,3,4-oxdiazol-2-ones substituées, ainsi que de leurs sels et leurs sels d'addition acides pharmacologiquement compatibles, pour la fabrication de médicaments présentant un effet inhibiteur sur la lipase pancréatique, PL. L'invention concerne l'utilisation de composés de formule (1), dans laquelle les restes ont les significations spécifiées, et de leurs sels et leurs sels d'addition acides pharmacologiquement compatibles, pour la fabrication d'un médicament pour la prophylaxie ou le traitement de l'obésité ou du diabète mellitus types 1 et 2.
PCT/EP2003/001560 2002-02-28 2003-02-17 Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique WO2003072098A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
JP2003570844A JP2005519079A (ja) 2002-02-28 2003-02-17 膵臓リパーゼを阻害する薬剤を製造するための、置換された３−フェニル−５−アルコキシ−１，３，４−オキサジアゾール−２−オンの使用
EP03742942A EP1482929A1 (fr) 2002-02-28 2003-02-17 Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique
BR0308045-5A BR0308045A (pt) 2002-02-28 2003-02-17 Aplicação de 3-fenil-5-alcóxi-1,3,4-oxdiazol-2-onas substituìdas para a preparação de medicamentos com efeito inibidor na lipase pancreática
AU2003210292A AU2003210292A1 (en) 2002-02-28 2003-02-17 Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazole-2-one for producing medicaments that inhibit pancreatic lipase
HU0500093A HUP0500093A2 (hu) 2002-02-28 2003-02-17 Szubsztituált 3-fenil-5-alkoxi-1,3,4-oxadiazol-2-on alkalmazása hasnyálmirigy lipázt gátló gyógyszerkészítmények előállítására
KR10-2004-7013470A KR20040101250A (ko) 2002-02-28 2003-02-17 췌장 리파제를 억제하는 약제를 제조하기 위한 치환된3-페닐-5-알콕시-1,3,4-옥스디아졸-2-온의 용도
IL16371903A IL163719A0 (en) 2002-02-28 2003-02-17 Use of substituted phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones for producing medicaments with an inhibitory effect on pancreatic lipase
MXPA04007480A MXPA04007480A (es) 2002-02-28 2003-02-17 Uso de 3-fenil-5-alcoxi-1,3,4-oxdiazol-2-onas sustituidas para producir medicamentos que inhiben la lipasa pancreatica.
CA002477005A CA2477005A1 (fr) 2002-02-28 2003-02-17 Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique
HR20040783A HRP20040783A2 (en) 2002-02-28 2004-08-27 Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazole-2-one for producing medicaments that inhibit pancreatic lipase
NO20044091A NO20044091L (no) 2002-02-28 2004-09-27 Anvendelse av substituerte 3-fenyl-5-alkoksy-1,3,4-oksdiazol-2-on for fremstilling av medikamenter som inhiberer pankreatisk lipase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10208986A DE10208986A1 (de) 2002-02-28 2002-02-28 Verwendung substituierter 3-Phenyl-5-alkoxi-1,3,4-oxdiazol-2-one zur Herstellung von Arzneimitteln mit hemmender Wirkung an der pankreatischen Lipase
DE10208986.8 2002-02-28

Publications (1)

Publication Number Publication Date
WO2003072098A1 true WO2003072098A1 (fr) 2003-09-04

Family

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Family Applications (1)

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PCT/EP2003/001560 WO2003072098A1 (fr) 2002-02-28 2003-02-17 Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique

Country Status (20)

Country Link
EP (1) EP1482929A1 (fr)
JP (1) JP2005519079A (fr)
KR (1) KR20040101250A (fr)
CN (1) CN1638766A (fr)
AR (1) AR038702A1 (fr)
AU (1) AU2003210292A1 (fr)
BR (1) BR0308045A (fr)
CA (1) CA2477005A1 (fr)
CO (1) CO5611144A2 (fr)
DE (1) DE10208986A1 (fr)
HR (1) HRP20040783A2 (fr)
HU (1) HUP0500093A2 (fr)
IL (1) IL163719A0 (fr)
MA (1) MA27173A1 (fr)
MX (1) MXPA04007480A (fr)
NO (1) NO20044091L (fr)
PL (1) PL371310A1 (fr)
RU (1) RU2004128932A (fr)
TW (1) TW200400026A (fr)
WO (1) WO2003072098A1 (fr)

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US7507735B2 (en) 2004-06-17 2009-03-24 Cytokinetics, Inc. Compounds, compositions and methods
WO2010074587A2 (fr) 2008-12-23 2010-07-01 Bial - Portela & Ca., S.A. 3-n-aryl-1,3,4-oxadiazolones 5-o-substituées destinées à une utilisation médicale
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US8058264B2 (en) 2004-10-25 2011-11-15 Abbott Products Gmbh Pharmaceutical compositions comprising CB1 cannabinoid receptor antagonists and potassium channel openers for the treatment of obesity and related conditions
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods

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MX2010006882A (es) * 2007-12-25 2010-10-05 Kissei Pharmaceutical Derivado novedoso de catecol, composición farmaceutica que contiene el mismo, uso del derivado de catecol, y uso de la composición farmaceutica.
CN103086859B (zh) * 2011-11-08 2015-11-11 清华大学 2,4-二羟基-5,6-取代-1-卤代苯衍生物、其合成方法及其应用
EP3676243A4 (fr) * 2017-09-01 2021-05-26 Curtin University Dérivés synthétiques de oléoyl-lysophosphatidylinositol (oléolyl-lpi) et utilisations associées
CN109879839B (zh) * 2019-03-12 2023-04-25 沈阳大学 6-哌嗪甲基-7-羟基苯并呋喃类化合物及其医药用途

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WO2001017981A1 (fr) * 1999-09-04 2001-03-15 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees, leur production et leur utilisation comme inhibiteurs de lipase
WO2001066531A1 (fr) * 2000-03-07 2001-09-13 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees et leur utilisation pour inhiber la lipase sensible aux hormones

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WO2001017981A1 (fr) * 1999-09-04 2001-03-15 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees, leur production et leur utilisation comme inhibiteurs de lipase
WO2001066531A1 (fr) * 2000-03-07 2001-09-13 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees et leur utilisation pour inhiber la lipase sensible aux hormones

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US8871769B2 (en) 2004-06-17 2014-10-28 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
US10975034B2 (en) 2004-06-17 2021-04-13 Cytokinetics, Inc. Compounds, compositions and methods
US10385023B2 (en) 2004-06-17 2019-08-20 Cytokinetics, Inc. Compounds, compositions and methods
US10035770B2 (en) 2004-06-17 2018-07-31 Cytokinetics, Incorporated Compounds, compositions and methods
US9643925B2 (en) 2004-06-17 2017-05-09 Cytokinetics, Incorporated Compounds, compositions and methods
US8101617B2 (en) 2004-06-17 2012-01-24 Amgen, Inc. Disubstituted ureas and uses thereof in treating heart failure
US8110595B2 (en) 2004-06-17 2012-02-07 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
US7507735B2 (en) 2004-06-17 2009-03-24 Cytokinetics, Inc. Compounds, compositions and methods
US8513257B2 (en) 2004-06-17 2013-08-20 Cytokinetics, Incorporated Ureas and their use in the treatment of heart failure
US9150564B2 (en) 2004-06-17 2015-10-06 Cytokinetics, Inc. Compounds, compositions and methods
US8058264B2 (en) 2004-10-25 2011-11-15 Abbott Products Gmbh Pharmaceutical compositions comprising CB1 cannabinoid receptor antagonists and potassium channel openers for the treatment of obesity and related conditions
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
US8871768B2 (en) 2005-12-15 2014-10-28 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
WO2010074587A3 (fr) * 2008-12-23 2010-11-11 Bial - Portela & Ca., S.A. 3-n-aryl-1,3,4-oxadiazolones 5-o-substituées destinées à une utilisation médicale
WO2010074587A2 (fr) 2008-12-23 2010-07-01 Bial - Portela & Ca., S.A. 3-n-aryl-1,3,4-oxadiazolones 5-o-substituées destinées à une utilisation médicale

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HRP20040783A2 (en) 2005-04-30
JP2005519079A (ja) 2005-06-30
EP1482929A1 (fr) 2004-12-08
CA2477005A1 (fr) 2003-09-04
CN1638766A (zh) 2005-07-13
MA27173A1 (fr) 2005-01-03
KR20040101250A (ko) 2004-12-02
RU2004128932A (ru) 2005-04-10
AU2003210292A1 (en) 2003-09-09
NO20044091L (no) 2004-09-27
IL163719A0 (en) 2005-12-18
MXPA04007480A (es) 2004-11-10
TW200400026A (en) 2004-01-01
PL371310A1 (en) 2005-06-13
DE10208986A1 (de) 2003-09-11
AR038702A1 (es) 2005-01-26
CO5611144A2 (es) 2006-02-28
HUP0500093A2 (hu) 2005-04-28
BR0308045A (pt) 2004-12-21

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