Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/60—Three or more oxygen or sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • 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
• • 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
  • A61P7/10—Antioedematous agents; Diuretics
• • 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
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
• • 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
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/34—One oxygen atom

Definitions

• the present invention relates to new carbamate and urea derivatives, their production and use as endothelin receptor antagonists.
• R 1 stands for tetrazole or for a group
• R 9 is hydrogen, C ⁇ -C 4 ⁇ alkyl; or NR 9 forms with R 5 and a corresponding number of methylene groups a three- to seven-membered saturated ring which can be simply substituted by C ⁇ -C 4 alkyl and in which up to two of the methylene groups by oxygen, sulfur, NH or N ( C ⁇ -C 4 ⁇ alkyl) can be replaced;
• R 10 and R 11 (which may be the same or different):
• Organic ammonium ions are protonated amines such as e.g. Ethanol amine, diethanolamine, ethylenediamine, diethylamine, triethylamine or piperazine;
• C ⁇ -C 4 alkylcarbonyl can be linear or branched such as acetyl, ethylcarbonyl or 2-propylcarbonyl;
• the compounds and also the intermediates for their preparation can have one or more asymmetric substituted carbon atoms.
• Such compounds can exist as pure enantiomers or pure diastereomers or as a mixture thereof.
• the use of an enantiomerically pure compound as the active ingredient is preferred.
• the invention furthermore relates to the use of the carbamate and urea derivatives mentioned above for the production of medicaments, in particular for the production of inhibitors for endothelin receptors.
• the compounds of the general formula I according to the invention in which A is oxygen (I) can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula III with chloroformic acid esters of the general formula IV.
• the compounds mentioned are reacted in a molar ratio of about 1: 1 to 1: 5 in the presence of a base and a suitable diluent. All solvents which are inert to the reagents used can be used for this purpose.
• Dioxane and tetrahydrofuran Dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.
• nitriles such as acetonitrile and propionitrile
• acid amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone
• sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane.
• carbamate and urea derivatives of the general formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are preferred, in which the substituents have the following meaning:
• R 2 and R 3 (which may be the same or different):
• C ⁇ -C 4 -haloalkoxy amino, NH (C ⁇ -C 4 -alkyl), N (C ⁇ -C4-alkyl) 2 or phenyl, which can be substituted one or more times by halogen, C ⁇ -C 4 -alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy;
• R 5 C ⁇ -C 8 ⁇ alkyl, which can be simply substituted by halogen, hydroxy, C ⁇ -C 4 ⁇ alkoxy or phenyl, which in turn can carry one to three of the following substituents: halogen, cyano, C ⁇ -C 4 alkoxy, C ⁇ -C 4 alkyl or carboxy;
• R 5 C ⁇ -C 4 alkyl, which can be simply substituted by hydroxy, C ⁇ -C 4 alkoxy or phenyl, which in turn can carry one to three of the following substituents: halogen, C ⁇ -C 4 alkoxy or C ⁇ -C 4 alkyl;
• CR 10 or CR 11 together with CR 10 or CR 11 forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C ⁇ _-alkyl groups and in which a methylene group can be replaced by oxygen.
• the invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor).
• VEGF vascular endothelial growth factor
• substances which block the action of VEGF are, for example, antibodies directed against VEGF or specific binding proteins or also low molecular weight substances which can specifically inhibit VEGF release or receptor binding.
• the combinations mentioned above can be administered simultaneously or sequentially in time. They can be used both in a single pharmaceutical formulation or in separate formulations.
• the form of administration can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors parenterally.
• the ET A or ET B receptor expressing CHO cells were in DMEM NUT MIX F 12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022) , 1 mm
• othndothelin antagonists are applied to other preparations in the same vessel 15 minutes before the endothelin dose-response curve begins.
• the effects of endothelin are calculated in% of the K + contracture. With effective endothelin antagonists the endothelin dose-response curve is shifted to the right.
• big endothelin (20 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) or ET-1 (0.3 ⁇ g / kg, Appl. Vol. 0.5 ml / kg) is given intravenously. Blood pressure and heart rate are continuously recorded over 30 minutes. The significant and long-lasting changes in blood pressure are calculated as the area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.
• the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intra-perotoneal). It can also be applied with vapors or sprays through the nasopharynx.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.
• the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, dragées, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Urology & Nephrology (AREA)
• Endocrinology (AREA)
• Hematology (AREA)
• Vascular Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Gynecology & Obstetrics (AREA)
• Diabetes (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pyridine Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2000
  • 2000-05-25 DE DE10025728A patent/DE10025728A1/de not_active Withdrawn
• 2001
  • 2001-05-18 MX MXPA02011512A patent/MXPA02011512A/es unknown
  • 2001-05-18 JP JP2001586268A patent/JP2003534329A/ja not_active Abandoned
  • 2001-05-18 EP EP01943411A patent/EP1286973A2/de not_active Withdrawn
  • 2001-05-18 CA CA002410304A patent/CA2410304A1/en not_active Abandoned
  • 2001-05-18 AU AU2001265995A patent/AU2001265995A1/en not_active Abandoned
  • 2001-05-18 WO PCT/EP2001/005742 patent/WO2001090079A2/de not_active Application Discontinuation
  • 2001-05-18 US US10/296,443 patent/US20040034076A1/en not_active Abandoned

Non-Patent Citations (1)

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