Nothing Special   »   [go: up one dir, main page]

US20050143456A1 - Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments - Google Patents

Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments Download PDF

Info

Publication number
US20050143456A1
US20050143456A1 US10/978,674 US97867404A US2005143456A1 US 20050143456 A1 US20050143456 A1 US 20050143456A1 US 97867404 A US97867404 A US 97867404A US 2005143456 A1 US2005143456 A1 US 2005143456A1
Authority
US
United States
Prior art keywords
alkyl
phenyl
coo
alkylene
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/978,674
Inventor
Elisabeth Defossa
Thomas Klabunde
Hans-Joerg Burger
Andreas Herling
Erich Roedern
Stefan Peukert
Alfons Enhsen
Armin Bauer
Bernd Neises
Karl Wendt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Aventis Pharma Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10125567A external-priority patent/DE10125567B4/en
Priority claimed from DE10207369A external-priority patent/DE10207369A1/en
Application filed by Aventis Pharma Deutschland GmbH filed Critical Aventis Pharma Deutschland GmbH
Priority to US10/978,674 priority Critical patent/US20050143456A1/en
Publication of US20050143456A1 publication Critical patent/US20050143456A1/en
Assigned to SANOFI-AVENTIS DEUTSCHLAND GMBH reassignment SANOFI-AVENTIS DEUTSCHLAND GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: AVENTIS PHARMA DEUTSCHLAND GMBH
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • 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
    • C07D295/12—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 singly or doubly bound nitrogen atoms
    • C07D295/125—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates to carboxamide-substituted phenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives.
  • the invention is based on the object of providing compounds which display a blood glucose-lowering effect which can be utilized in therapy.
  • the invention therefore, for example, relates to compounds of the formula I, in which
  • the compounds of the formula I are those in which
  • the compounds of the formula I are those in which
  • the invention further relates to the use of the compounds of the formula I in which
  • the compounds of the formula I may be present in the form of their racemates, racemic mixtures, pure enantiomers, and diastereomers, and mixtures thereof.
  • the alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9 and A may be both straight-chain and branched.
  • Suitable pharmaceutically acceptable salts may be particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. In one embodiment, these salts must have a pharmaceutically acceptable anion or cation.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids.
  • 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 with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
  • physiologically functional derivative refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.
  • Physiologically functional derivatives also include prodrugs of the compounds of 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 themselves have activity or not.
  • the compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention.
  • the compound(s) of the formula (I) may also be administered in combination with other active ingredients.
  • the daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day.
  • An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and 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.
  • ampoules for injections may contain, for example, from 1 mg to 100 mg
  • single-dose formulations which can be administered orally, such as, for example, capsules or tablets may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health.
  • 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.
  • Other pharmaceutically active substances may likewise be present, including other compounds of formula I.
  • the pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which may essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
  • compositions of the invention are those 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 depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case.
  • Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes 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 generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary.
  • a tablet mau be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients.
  • Compressed tablets may be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine.
  • Molded tablets may be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.
  • compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • compositions suitable for parenteral administration may, for example, comprise sterile aqueous preparations of a compound of formula I, which are isotonic with the blood of the intended recipient. These preparations may be administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations may be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
  • compositions suitable for rectal administration may be, for example, in the form of single-dose suppositories. These may be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • compositions suitable for topical use on the skin are preferably in the form of ointment, creme, lotion, paste, spray, aerosol or oil.
  • Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances.
  • the active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
  • compositions suitable for transdermal uses may be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis.
  • Such plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is, for example, about 1% to 35%, preferably about 3% to 15%.
  • active ingredients suitable for combination products are: all antidiabetics mentioned in chapter 12 of the Rote Liste 2001. They may be combined with the compounds of the formula I of the invention in particular for synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patients or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
  • Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® or HMR 1964, GLP-1 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients.
  • the orally active hypoglycemic active ingredients include, for example, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed 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, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.
  • the compounds of the formula I are administered in combination with an HMG-CoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • an HMG-CoA 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.
  • a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.
  • the compounds of the formula I are administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.
  • a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.
  • the compounds of the formula I are administered in combination with PPAR alpha agonist such as, for example, GW 9578, GW 7647.
  • the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
  • a mixed PPAR alpha/gamma agonist such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
  • the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.
  • the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, Bay 13-9952, BMS-201038, R-103757.
  • the compounds of the formula I are administered in combination with bile acid adsorption inhibitor such as, for example, HMR 1453.
  • the compounds of the formula I are administered in combination with a CETP inhibitor such as, for example, Bay 194789.
  • the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.
  • a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.
  • the compounds of the formula I are administered in combination with an LDL receptor inducer such as, for example, HMR1171, HMR1586.
  • the compounds of the formula I are administered in combination with an ACAT inhibitor such as, for example, avasimibe.
  • the compounds of the formula I are administered in combination with an antioxidant such as, for example, OPC-14117.
  • the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor such as, for example, NO-1886.
  • the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor such as, for example, SB-204990.
  • the compounds of the formula I are administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494.
  • the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist such as, for example, Cl-1027 or nicotinic acid.
  • a lipoprotein(a) antagonist such as, for example, Cl-1027 or nicotinic acid.
  • the compounds of the formula I are administered in combination with a lipase inhibitor such as, for example, orlistat.
  • the compounds of the formula I are administered in combination with insulin.
  • the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.
  • a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.
  • the compounds of the formula I are administered in combination with a biguanide such as, for example, metformin.
  • a biguanide such as, for example, metformin.
  • the compounds of the formula I are administered in combination with a meglitinide such as, for example, repaglinide.
  • the compounds of the formula I are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.
  • a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidined
  • the compounds of the formula I are administered in combination with an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor such as, for example, 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, such as, for example, tolbutamide, glibenclamide, glipizide, gliclazide or repaglinide.
  • an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliclazide or repaglinide.
  • the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, for example 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 administered in combination with CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR- ⁇ agonists.
  • CART agonists CART agonists
  • NPY agonists MC4 agonists, or
  • the other active ingredient is leptin.
  • the other active ingredient is dexamphetamine or amphetamine.
  • the other active ingredient is fenfluramine or dexfenfluramine.
  • the other active ingredient is sibutramine.
  • the other active ingredient is orlistat.
  • the other active ingredient is mazindol or phentermine.
  • the compounds of the formula I are administered in combination with dietary fiber materials, preferably insoluble dietary fiber materials such as, for example, Caromax®.
  • dietary fiber materials preferably insoluble dietary fiber materials such as, for example, Caromax®.
  • Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®.
  • Caromax® can moreover be administered in the form of foodstuffs such as, for example, in bakery products or muesli bars.
  • the invention further relates to a process for the preparation of the compounds of the formula I, which comprises obtaining the compounds of the formula I by proceeding in accordance with the following reaction scheme:
  • the compounds of the formula I are distinguished by beneficial effects on glucose metabolism; in particular they lower the blood glucose level and are suitable for treating type II diabetes.
  • the compounds can be employed alone or in combination with other blood glucose-lowering active ingredients (antidiabetics).
  • blood glucose-lowering active ingredients are sulfonylureas (such as, for example, glimepiride, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepide), metformin, tolbutamide, glitazones (such as, for example, troglitazone, rosiglitazone, pioglitazone, repaglinide), alpha-glucosidase inhibitors (such as, for example, acarbose, miglitol) or insulins.
  • sulfonylureas such as, for example, glimepiride, glibenclamide, gliclazide, glibornuride, gliquidone,
  • All antidiabetics mentioned in chapter 12 of the Rote Liste 2001 can be combined with the compounds of the formula I of the invention for improving the effect.
  • Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patients or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
  • the compounds of the formula I are additionally suitable for the treatment of late complications of diabetes such as, for example, nephropathy, retinopathy, neuropathy and mycocardial infarction, peripheral arterial occlusive diseases, thromboses, arteriosclerosis, syndrome X, obesity, inflammations, immune diseases, autoimmune diseases such as, for example, AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases.
  • diabetes such as, for example, nephropathy, retinopathy, neuropathy and mycocardial infarction, peripheral arterial occlusive diseases, thromboses, arteriosclerosis, syndrome X, obesity, inflammations, immune diseases, autoimmune diseases such as, for example, AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases.
  • glycogen phosphorylase The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by following the synthesis of glycogen from glucose 1-phosphate by determining the liberation of inorganic phosphate. All the reactions were carried out as duplicate determinations in microtiter plates with 96 wells (Half Area Plates, Costar No 3696), measuring the change in absorption owing to the formation of the reaction product at the wavelength specified hereinafter in a Multiskan Ascent Elisa Reader (Lab Systems, Finland).
  • Test substances were prepared as 10 mM solution in DMSO and diluted to 50 ⁇ M with buffer solution T. To 10 ⁇ l of this solution were added 10 ⁇ l of 37.5 mM glucose, dissolved in buffer solution T, and 5 mg/ml glycogen, plus 10 ⁇ l of a solution of human glycogen phosphorylase a (10 ⁇ g of protein/ml) and 20 ⁇ l of glucose 1-phosphate, 2.5 mM. The baseline glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 ⁇ l of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes, and the liberated inorganic phosphate was measured by the general method of Drueckes et al.
  • the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are thus very suitable for lowering the blood glucose level.
  • 2-Chlorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in stage b without further purification.
  • Examples 2-52 and 188-220 were synthesized in analogy to example 1.
  • Examples 95-152 were synthesized in analogy to example 94. If required, the products were purified by preparative reverse phase HPLC (acetonitrile/water/TFA).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (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)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Psychiatry (AREA)
  • Oncology (AREA)
  • Pulmonology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Virology (AREA)
  • AIDS & HIV (AREA)
  • Dermatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)

Abstract

The invention relates to carboxamide-substituted phenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives.
Compounds of the formula I
Figure US20050143456A1-20050630-C00001
 in which the radicals have the stated meanings, and the physiologically tolerated salts thereof and process for their preparation are described. The compounds are suitable, for example, for treating type II diabetes.

Description

  • This application claims the benefit of foreign priority under 35 U.S.C. §119 of German patent application no. 10125567.5, filed on May 25, 2001 and German patent application no 10207369.4, filed on Jan. 22, 2002 the contents of both of which are incorporated by reference herein.
  • The invention relates to carboxamide-substituted phenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives.
  • Acylphenylurea derivatives of similar structure have already been described in the prior art as insecticides (EP 0 136 745, EP 0 167 197, DE 29 26 480, J. Agric. Food Chem. 1999, 47, 3116-3424).
  • In one embodiment, the invention is based on the object of providing compounds which display a blood glucose-lowering effect which can be utilized in therapy.
  • The invention therefore, for example, relates to compounds of the formula I,
    Figure US20050143456A1-20050630-C00002
    in which
    • A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, (C0-C6)-alkylene-COOH, (C0-C6)alkylene-COO—(C1-C7)-alkyl, (C0-C6)-alkylene-COO—(C2-C7)-alkenyl, CONH2, CONH—(C1-C6)-alkyl, CON—[(C1-C6)-alkyl]2, CONH—(C3-C6)-cycloalkyl, (C0-C6)-alkylene-NH2, (C0-C6)-alkylene-NH—(C2-C6)-alkyl, (C0-C6)-alkylene-N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, and NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CONH2;
    • R1, R2 are, independently of one another, H, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CO—(C1-C6)-alkyl, or COO—(C1-C6)-alkyl;
    • R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, COOH, COO—(C1-C6)-alkyl, CO—NH2, CO—NH—(C1-C6)-alkyl, CO—N—[(C1-C6)-alkyl]2, CO—NH—(C3-C7)-cycloalkyl, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, or NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CO—NH2;
    • R7 is H, (C1-C6)-alkyl, or CO(C1-C6)-alkyl;
    • R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl and NCOO—(C1-C4)-alkylene-(C6-C10)-aryl; or
    •  (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
    • R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
      and their physiologically tolerable salts.
  • In one embodiment, the compounds of the formula I are those in which
    • A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;
    • R1, R2 are H;
    • R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO2, O—(C1-C6)-alkyl, or (C1-C6)-alkyl;
    • R7 is H, or CH3;
    • R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl or NCOO—(C1-C4)-alkylene-(C6-C10)-aryl; or
    •  (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
    • R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
      and their physiologically tolerable salts.
  • In another embodiment, the compounds of the formula I are those in which
    • A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;
    • R1, R2 are H;
    • R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO2, O—(C1-C6)-alkyl, or (C1-C6)-alkyl;
    • R7 is H, or CH3;
    • R8 is (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl or NCOO—(C1-C4)-alkylene-(C6-C10)-aryl; or
    •  (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
    • R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)alkyl, S—(C1-C6)-alkyl, (C1-C4)alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
      and their physiologically tolerable salts.
  • In one embodiment, the invention further relates to the use of the compounds of the formula I
    Figure US20050143456A1-20050630-C00003
    in which
    • A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, (C0-C6)-alkylene-COOH, (C0-C6)-alkylene-COO—(C1-C7)-alkyl, (C0-C6)-alkylene-COO—(C2-C7)-alkenyl, CONH2, CONH—(C1-C6)-alkyl, CON—[(C1-C6)-alkyl]2, CONH—(C3-C6)-cycloalkyl, (C0-C6)-alkylene-NH2, (C0-C6)-alkylene-NH—(C1-C6)-alkyl, (C0-C6)-alkylene-N—[(C1-C6) alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)alkyl and CONH2;
    • R1, R2 are, independently of one another, H, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CO—(C1-C6)-alkyl, or COO—(C1-C6)-alkyl;
    • R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, COOH, COO—(C1-C6)-alkyl, CO—NH2, CO—NH—(C1-C6)-alkyl, CO—N—[(C1-C6)-alkyl]2, CO—NH—(C3-C7)-cycloalkyl, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, or NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CO—NH2;
    • R7 is H, (C1-C6)-alkyl, or CO(C1-C6)-alkyl;
    • R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl or NCOO—(C1-C4)-alkylene-(C6-C10)-aryl; or
    •  (CH2)m-aryl, where m can be 0-6, and aryl can be phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
    • R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6) alkyl;
      and their physiologically tolerable salts, for producing a medicament for reducing the blood glucose level and treating type II diabetes. In another embodiments, these compounds are useful in methods for reducing the blood glucose level and treating type II diabetes of a mammal, for example a human.
  • The compounds of the formula I may be present in the form of their racemates, racemic mixtures, pure enantiomers, and diastereomers, and mixtures thereof. The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9 and A may be both straight-chain and branched.
  • Pharmaceutically acceptable salts may be particularly suitable for medical applications because of their greater solubility in water compared with the starting or base compounds. In one embodiment, these salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. 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 pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
  • The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester which is able, on administration to a mammal such as, for example, to a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.
  • Physiologically functional derivatives also include prodrugs of the compounds of 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 themselves have activity or not.
  • The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the scope of the invention and are a further aspect of the invention.
  • All references hereinafter to “compound(s) of formula I” refer to compound(s) of the formula I as described above, and to the salts, solvates and physiologically functional derivatives thereof as described herein.
  • The compound(s) of the formula (I) may also be administered in combination with other active ingredients.
  • The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In one embodiment, the daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and 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. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the abovementioned conditions, the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health. 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. Other pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which may essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
  • Pharmaceutical compositions of the invention are those 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 depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • In one embodiment, suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, wafers, suckable tablets or tablets, each of which contain a defined amount of the compound of formula I; as powders or granules, as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes 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 generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet mau be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets may be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent(s) in a suitable machine. Molded tablets may be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.
  • In one embodiment, pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • The pharmaceutical compositions suitable for parenteral administration may, for example, comprise sterile aqueous preparations of a compound of formula I, which are isotonic with the blood of the intended recipient. These preparations may be administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations may may be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
  • Pharmaceutical compositions suitable for rectal administration may be, for example, in the form of single-dose suppositories. These may be produced by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, creme, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.
  • Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses may be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters, for example, suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is, for example, about 1% to 35%, preferably about 3% to 15%. One embodiment, is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
  • Further active ingredients suitable for combination products are: all antidiabetics mentioned in chapter 12 of the Rote Liste 2001. They may be combined with the compounds of the formula I of the invention in particular for synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patients or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
  • Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® or HMR 1964, GLP-1 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients.
  • The orally active hypoglycemic active ingredients include, for example, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed 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, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, PPAR and PXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMG-CoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist such as, for example, GW 9578, GW 7647.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, Bay 13-9952, BMS-201038, R-103757.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid adsorption inhibitor such as, for example, HMR 1453.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor such as, for example, Bay 194789.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer such as, for example, HMR1171, HMR1586.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor such as, for example, avasimibe.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant such as, for example, OPC-14117.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor such as, for example, NO-1886.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor such as, for example, SB-204990.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494.
  • In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist such as, for example, Cl-1027 or nicotinic acid.
  • In one embodiment of the invention, 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.
  • In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.
  • In one embodiment, the compounds of the formula I are administered in combination with a biguanide such as, for example, metformin.
  • In another embodiment, the compounds of the formula I are administered in combination with a meglitinide such as, for example, repaglinide.
  • In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.
  • In one embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose.
  • In one embodiment, 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, such as, for example, tolbutamide, glibenclamide, glipizide, gliclazide or repaglinide.
  • In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, for example 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.
  • In a further embodiment, the compounds of the formula I are administered in combination with CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-βagonists.
  • In one embodiment of the invention, the other active ingredient is leptin.
  • In one embodiment, the other active ingredient is dexamphetamine or amphetamine.
  • In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
  • In a further 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.
  • In one embodiment, the compounds of the formula I are administered in combination with dietary fiber materials, preferably insoluble dietary fiber materials such as, for example, Caromax®. Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can moreover be administered in the form of foodstuffs such as, for example, in bakery products or muesli bars.
  • It is self-evident that any suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is regarded as falling within the protection conferred by the present invention.
  • The invention further relates to a process for the preparation of the compounds of the formula I, which comprises obtaining the compounds of the formula I by proceeding in accordance with the following reaction scheme:
    Figure US20050143456A1-20050630-C00004
  • For this purpose, compounds of the formula II
    Figure US20050143456A1-20050630-C00005
    in which
    • R9, R10, R11, R12 are, independently of one another, H, F, Cl, Br, O-(PG-1), CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)alkyl, SO2—N-(PG-2)2, (C1-C6)alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)cycloalkyl-(C1-C4)-alkylene, COO-(PG-3), COO—(C1-C6)-alkyl, CON-(PG-2)2, CO—NH—(C1-C6)-alkyl, CO—N—[(C1-C6)-alkyl]2, CO—NH—(C3-C7)-cycloalkyl, N-(PG-2)2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, and NH—SO2-phenyl, wherein, the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, O-(PG-1), (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COO-(PG-3), COO—(C1-C6)-alkyl and CON-(PG-2)2;
      in which R2 has the meaning described above, and
    • PG-1 is a generally known protective group for alcohols, such as, for example, benzyl, allyl, tetrahydropyranyl or tetrahydrofuranyl;
    • PG-2 is a generally known protective group for amino groups, such as, for example, (C1-C6)-alkylcarbonyl, (C1-C6)-alkyloxycarbonyl or (C6-C12)-aryl-(C1-C4)-alkyloxycarbonyl, which replaces either both hydrogen atoms or only one hydrogen atom in the amino group;
    • PG-3 is a generally known protective group for esters, such as, for example, (C1-C6)-alkyl, benzyl or p-methoxybenzyl;
      are reacted with isocyanates of the formula III
      Figure US20050143456A1-20050630-C00006
      in which
    • A′ is phenyl or naphthyl, where the phenyl or naphthyl is unssubstituted or substituted 1, 2 or 3 times wherein each substituent is independently chosen from F, Cl, Br, O-PG-1, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—N-(PG-2)2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, (C0-C6)-alkylene-COO-(PG-3), (C0-C6)-alkylene-COO—(C1-C7)-alkyl, (C0-C6)-alkylene-COO—(C2-C7)-alkenyl, CO—N-(PG-2)2, CO—NH—(C1-C6)-alkyl, CO—N—[(C1-C6)-alkyl]2, CONH—(C3-C6)-cycloalkyl, (C0-C6)-alkylene-N-(PG-2)2, (C0-C6)-alkylene-NH—(C1-C6)-alkyl, (C0-C6)-alkylene-N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, and NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, O-(PG-1), (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COO-(PG-3), COO—(C1-C6)-alkyl and CO—N-(PG-2)2;
      in which PG-3, PG-2 and PG-1 have the meaning described above,
      in anhydrous organic solvents such as, for example, benzene, toluene or acetonitrile, under a protective gas atmosphere at reaction temperatures between 10° C. and the boiling point of the solvent employed, to give compounds of the formula IV
      Figure US20050143456A1-20050630-C00007
      in which R2, R9, R10, R11, R12, and A′ have the meaning described above.
  • Compounds of the formula IV are reacted with coupling reagents customary in peptide synthesis, such as, for example, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, carbonyldiazoles such as carbonyldiimidazole and similar reagents, propylphosphonic anhydrides, O-((cyano(ethoxycarbonyl)methylene)amino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU) and many others, or with formation of the acid chloride, for example using thionyl chloride, with compounds of the formula V
    Figure US20050143456A1-20050630-C00008
    in which R7 has the meaning described above, and
    • R13 is (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2 or 3 time wherein each substituent is independently chosen from 0-(PG-1), CF3, CN, COO-(PG-3), COO—(C1-C6)-alkyl, CO—N-(PG-2)2, NH-(PG-2), NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2;
      • phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, and morpholinyl, where the rings are each independently unsubstituted or substituted by at least one R14;
    • R14 is F, Cl, Br; O-(PG-1), NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COO-(PG-3), or COO—(C1-C6)-alkyl;
      to give compounds of the formula VI
      Figure US20050143456A1-20050630-C00009
      the compounds of the formula VI can, if R1 in compounds of the formula I is not a hydrogen atom, be alkylated by reaction with compounds of the formula VII
      R15-LG  (VII)
      in which
    • LG is a generally known leaving group such as, for example, halogen, arylsulfonyloxy or alkylsulfonyloxy; and
    • R15 is (C1-C6)-alkyl, O—(C1-C6)-alkyl, CO—(C1-C6)-alkyl, or COO—(C1-C6) alkyl,
      using a base such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene, in organic solvents such as, for example, dichloromethane or acetonitrile, to give compounds of the formula VIII
      Figure US20050143456A1-20050630-C00010
      in which R2, R7, R9, R10, R11, R12, R13, R15 and A′ have the meaning described above,
      and after elimination known from the literature of some or all protective groups which may be present, for example, in the radicals R9, R10, R11, R12, R13, R14 and A′, compounds of the formula I are obtained. Compounds of the formula I are converted into the salts thereof by adding one equivalent of the appropriate acid or base in an organic solvent such as, for example, acetonitrile or dioxane or in water and by subsequent removal of the solvent.
  • Another possibility for preparing compounds of the formula I in which R2 is a hydrogen atom is depicted in the following scheme:
    Figure US20050143456A1-20050630-C00011
    in which compounds of the formula XIII
    Figure US20050143456A1-20050630-C00012
    in which R9, R10, R11, R12 and PG-3 have the meaning described above, are converted into isocyanates of the formula X
    Figure US20050143456A1-20050630-C00013
    by known methods, such as, for example, reaction with oxalyl chloride in organic solvents such as, for example, 1,2-dichloroethane or dichloromethane, at reaction temperatures between room temperature and the boiling point of the solvent, the isocyanates of the formula X are reacted with amides of the formula XI
    Figure US20050143456A1-20050630-C00014
    in which A′ has the meaning described above, to result in compounds of the formula XI
    Figure US20050143456A1-20050630-C00015
    in which R9, R10, R11, R12 and PG-3 have the meaning described above, compounds of the formula XII can, if R1 is not a hydrogen atom, be converted as described above by alkylation with compounds of the formula VII to give compounds of the formula XIII, selective deprotection of the COO-(PG-3) group and subsequent amide coupling with compounds of the formula V to give compounds of the formula XIV and, if necessary, by subsequent elimination of the protective groups into compounds of the formula I. Compounds of the formula I are converted into the salts thereof by addition of one equivalent of the appropriate acid or base in an organic solvent such as, for example, acetonitrile or dioxane or in water and by subsequent removal of the solvent.
  • The examples detailed below serve to illustrate the invention without, however, restricting it. The measured solidification and decomposition points (Fp.) have not been corrected and generally depend on the heating rate.
    TABLE 1
    Examples
    Figure US20050143456A1-20050630-C00016
    Ex. A R1* R2 R3 R4 R6 R5 Amide** R7 R8*** MS****
    1 Phenyl-2-Cl H H 2-Cl 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00017
         		ok
    2 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00018
         		ok
    3 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH2)5—OH ok
    4 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH2)6—OH ok
    5 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00019
         		ok
    6 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00020
         		ok
    7 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00021
         		ok
    8 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00022
         		ok
    9 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00023
         		ok
    10 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00024
         		ok
    11 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00025
         		ok
    12 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH2)3—COOtBu ok
    13 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00026
         		ok
    14 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00027
         		ok
    15 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH2)5—CH3 ok
    16 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H (CH2)5—OH ok
    17 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H (CH2)6—OH ok
    18 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00028
         		ok
    19 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00029
         		ok
    20 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00030
         		ok
    21 Phenyl-2-Cl H H 2-H 4-Cl 5-H 6-H 3 H (CH2)5—CH3 ok
    22 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00031
         		ok
    23 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H (CH2)5—OH ok
    24 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H (CH2)6—OH ok
    25 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00032
         		ok
    26 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00033
         		ok
    27 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00034
         		ok
    28 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00035
         		ok
    29 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00036
         		ok
    30 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00037
         		ok
    31 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00038
         		ok
    32 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00039
         		ok
    33 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00040
         		ok
    34 Phenyl-2-Cl H H 2-CH3 3-H 4-H 6-H 5 H (CH2)5—CH3 ok
    35 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00041
         		ok
    36 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00042
         		ok
    37 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)5—OH ok
    38 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)8—OH ok
    39 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00043
         		ok
    40 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00044
         		ok
    41 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00045
         		ok
    42 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00046
         		ok
    43 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)5—CH3 ok
    44 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00047
         		ok
    45 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00048
         		ok
    46 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00049
         		ok
    47 Phenyl-2-Cl H H 2-H 4-NO2 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00050
         		ok
    48 Phenyl-2-Cl H H 2-H 4-NO2 5-H 6-H 3 H (CH2)5—OH ok
    49 Phenyl-2-Cl H H 2-H 4-NO2 5-H 6-H 3 H (CH2)6—OH ok
    50 Phenyl-2-Cl H H 2-H 4-NO2 5-H 6-H 3 H (CH2)5—CH3 ok
    51 Phenyl-2-Cl H H 2-H 4-H 5-H 6-H 3 H (CH2)3—COOH ok
    52 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)3—COOH ok
    53 Phenyl-2,6-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00051
         		ok
    54 Phenyl-2,6-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00052
         		ok
    55 Phenyl-2,6-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00053
         		ok
    56 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00054
         		ok
    57 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00055
         		ok
    58 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00056
         		ok
    59 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00057
         		ok
    60 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00058
         		ok
    61 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00059
         		ok
    62 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00060
         		ok
    63 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00061
         		ok
    64 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00062
         		ok
    65 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00063
         		ok
    66 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00064
         		ok
    67 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00065
         		ok
    68 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00066
         		ok
    69 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00067
         		ok
    70 Phenyl-2-Cl H H 2-H 4-NO2 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00068
         		ok
    71 Phenyl-2-Cl H H 2-H 4-NO2 5-H 6-H 3 H
    Figure US20050143456A1-20050630-C00069
         		ok
    72 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00070
         		ok
    73 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00071
         		ok
    74 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H CH2—CF3 ok
    75 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00072
         		ok
    76 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00073
         		ok
    77 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00074
         		ok
    78 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00075
         		ok
    79 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)2—CH3 ok
    80 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00076
         		ok
    81 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00077
         		ok
    82 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00078
         		ok
    83 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00079
         		ok
    84 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00080
         		ok
    85 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00081
         		ok
    86 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00082
         		ok
    87 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00083
         		ok
    88 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00084
         		ok
    89 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00085
         		ok
    90 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00086
         		ok
    91 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00087
         		ok
    92 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00088
         		ok
    93 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00089
         		ok
    94 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00090
         		ok
    95 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00091
         		ok
    96 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00092
         		ok
    97 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00093
         		ok
    98 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00094
         		ok
    99 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00095
         		ok
    100 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00096
         		ok
    101 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00097
         		ok
    102 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00098
         		ok
    103 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00099
         		ok
    104 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00100
         		ok
    105 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H (CH2)5—CN ok
    106 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00101
         		ok
    107 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00102
         		ok
    108 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00103
         		ok
    109 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00104
         		ok
    110 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00105
         		ok
    111 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00106
         		ok
    112 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00107
         		ok
    113 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00108
         		ok
    114 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00109
         		ok
    115 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00110
         		ok
    116 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00111
         		ok
    117 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00112
         		ok
    118 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00113
         		ok
    119 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00114
         		ok
    120 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00115
         		ok
    121 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00116
         		ok
    122 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00117
         		ok
    123 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00118
         		ok
    124 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00119
         		ok
    125 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00120
         		ok
    126 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00121
         		ok
    127 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00122
         		ok
    128 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00123
         		ok
    129 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00124
         		ok
    130 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00125
         		ok
    131 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00126
         		ok
    132 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00127
         		ok
    133 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00128
         		ok
    134 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00129
         		ok
    135 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00130
         		ok
    136 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00131
         		ok
    137 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00132
         		ok
    138 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00133
         		ok
    139 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00134
         		ok
    140 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00135
         		ok
    141 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00136
         		ok
    142 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00137
         		ok
    143 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00138
         		ok
    144 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00139
         		ok
    145 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00140
         		ok
    146 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00141
         		ok
    147 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00142
         		ok
    148 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00143
         		ok
    149 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00144
         		ok
    150 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00145
         		ok
    151 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00146
         		ok
    152 Phenyl-2,4-Cl2 Na H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00147
         		ok
    153 Phenyl-2-Cl H H 2-H 4-H 5-NO2 6-H 3 H (CH2)5—OH ok
    154 Phenyl-2-Cl H H 2-H 4-H 5-NO2 6-H 3 H (CH2)6—OH ok
    155 Phenyl-2-Cl H H 2-H 4-H 5-NO2 6-H 3 H
    Figure US20050143456A1-20050630-C00148
         		ok
    156 Phenyl-2-Cl H H 2-H 4-H 5-NO2 6-H 3 H
    Figure US20050143456A1-20050630-C00149
         		ok
    157 Phenyl-2-Cl H H 2-F 4-F 5-F 6-H 3 H
    Figure US20050143456A1-20050630-C00150
         		ok
    158 Phenyl-2-Cl H H 2-F 4-F 5-F 6-H 3 H
    Figure US20050143456A1-20050630-C00151
         		ok
    159 Phenyl-2-Cl H H 2-F 4-F 5-F 6-H 3 H
    Figure US20050143456A1-20050630-C00152
         		ok
    160 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H (CH2)5—OH ok
    161 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00153
         		ok
    162 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00154
         		ok
    163 Phenyl-2-Cl H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00155
         		ok
    164 Phenyl-2,4-Cl2 H H 2-H 4-H 5-NO2 6-H 3 H (CH2)5—OH ok
    165 Phenyl-2,4-Cl2 H H 2-F 4-F 5-F 6-H 3 H (CH2)5—OH ok
    166 Phenyl-2,4-Cl2 H H 2-F 4-F 5-F 6-H 3 H (CH2)6—OH ok
    167 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H (CH2)5—OH ok
    168 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H (CH2)6—OH ok
    169 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00156
         		ok
    170 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00157
         		ok
    171 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00158
         		ok
    172 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00159
         		ok
    173 Phenyl-2,4-Cl2 H H 2-F 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00160
         		ok
    174 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00161
         		ok
    175 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00162
         		ok
    176 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)2—COOH ok
    177 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)3—COOH ok
    178 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00163
         		ok
    179 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00164
         		ok
    180 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00165
         		ok
    181 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)4—COOH ok
    182 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)5—COOH ok
    183 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00166
         		ok
    184 Phenyl-2-Cl H H 2-OCH3 3-H 4-H 6-H 5 H (CH2)4—COOH ok
    185 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00167
         		ok
    186 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00168
         		ok
    187 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H (CH2)5—OH ok
    188 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H (CH2)6—OH ok
    189 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00169
         		ok
    190 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00170
         		ok
    191 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00171
         		ok
    192 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00172
         		ok
    193 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00173
         		ok
    194 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00174
         		ok
    195 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00175
         		ok
    196 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00176
         		ok
    197 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00177
         		ok
    198 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H (CH2)5—OH ok
    199 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00178
         		ok
    200 Phenyl-2-Cl H H 2-H 3-Cl 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00179
         		ok
    201 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H (CH2)5—OH ok
    202 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H (CH2)6—OH ok
    203 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00180
         		ok
    204 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00181
         		ok
    205 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00182
         		ok
    206 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00183
         		ok
    207 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00184
         		ok
    208 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00185
         		ok
    209 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00186
         		ok
    210 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00187
         		ok
    211 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-Cl 4 H (CH2)6—OH ok
    212 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-Cl 4 H (CH2)5—OH ok
    213 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H (CH2)5—OH ok
    214 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H (CH2)6—OH ok
    215 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H
    Figure US20050143456A1-20050630-C00188
         		ok
    216 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H
    Figure US20050143456A1-20050630-C00189
         		ok
    217 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H
    Figure US20050143456A1-20050630-C00190
         		ok
    218 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H
    Figure US20050143456A1-20050630-C00191
         		ok
    219 Phenyl-2-Cl H H 2-Cl 3-H 5-OCH3 6-H 4 H
    Figure US20050143456A1-20050630-C00192
         		ok
    220 Phenyl-2-Cl H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00193
         		ok
    221 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00194
         		ok
    222 Phenyl-2-Cl H H 2-H 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00195
         		ok
    223 Phenyl-2-Cl H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)5—OH ok
    224 Phenyl-2-Cl H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)6—OH ok
    225 Phenyl-2-Cl H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00196
         		ok
    226 Phenyl-2-Cl H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00197
         		ok
    227 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H (CH2)5—OH ok
    228 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H (CH2)6—OH ok
    229 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00198
         		ok
    230 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00199
         		ok
    231 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00200
         		ok
    232 Phenyl-2-Cl H H 2-F 3-F 5-F 6-F 4 H (CH2)5—OH ok
    233 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)5—OH ok
    234 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)6—OH ok
    235 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00201
         		ok
    236 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00202
         		ok
    237 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00203
         		ok
    238 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00204
         		ok
    239 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00205
         		ok
    240 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H (CH2)5—OH ok
    241 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H (CH2)6—OH ok
    242 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00206
         		ok
    243 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00207
         		ok
    244 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00208
         		ok
    245 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00209
         		ok
    246 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00210
         		ok
    247 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00211
         		ok
    248 Phenyl-2,4-Cl2 H H 2-OH 3-H 5-H 6-H 4 H (CH2)6—OH ok
    249 Phenyl-2,4-Cl2 H H 2-NO2 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00212
         		ok
    250 Phenyl-2-Cl H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00213
         		ok
    251 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00214
         		ok
    252 Phenyl-2-Cl H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00215
         		ok
    253 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H
    Figure US20050143456A1-20050630-C00216
         		ok
    254 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 4-H 6-H 5 H
    Figure US20050143456A1-20050630-C00217
         		ok
    255 Phenyl-2-Cl-4-F H H 2-OCH3 3-H 5-H 6-H 4 H H ok
    256 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H H ok
    257 Phenyl-2-Cl-4-F H H 2-OCH3 3-H 5-H 6-H 4 H CH3 ok
    258 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 H CH3 ok
    259 Phenyl-2-Cl-4-F H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)3—NHCOO—CH2—Ph ok
    260 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)3—NHCOO—CH2—Ph ok
    261 Phenyl-2-Cl-4-F H H 2-OCH3 3-H 5-H 6-H 4 CH3 CH3 ok
    262 Phenyl-2,4-Cl2 H H 2-OCH3 3-H 5-H 6-H 4 CH3 CH3 ok
    263 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H CH3 ok
    264 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 CH3 CH3 ok
    265 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)2—NHCO—CH3 ok
    266 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)3—NH2 ok
    TFA
    267 Phenyl-2-Cl-4,5-F2 H H 2-Cl 3-H 5-H 6-H 4 H CH3 ok
    268 Phenyl-2-Cl-4,5-F2 H H 2-Cl 3-H 5-H 6-H 4 CH3 CH3 ok
    269 Phenyl-2-Cl-4,5-F2 H H 2-Cl 3-H 5-H 6-H 4 H H ok
    270 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)3—N(CH3)2 ok
    TFA
    271 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)2—N(CH3)2 ok
    TFA
    272 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H (CH2)2—NHCOO—CH2— ok
    CH═CH2
    273 Phenyl-2-Cl-4,5-F2 H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)4—NH2 ok
    TFA
    274 Phenyl-2,4-Cl2 H H 2-Cl 3-H 5-H 6-H 4 H (CH2)2—NH2 ok
    TFA
    275 Phenyl-2-Cl-4-F H H 2-OCH3 3-H 5-H 6-H 4 H (CH2)3—NH2 ok
    TFA
    276 Phenyl-2-Cl-4,5-F2 H H 3-H 4-H 5- 6-H 2 H CH3 ok
    COOH
    277 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H CH3 ok
    278 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 CH3 CH3 ok
    279 Phenyl-2-Cl-4,5-F2 H H 3-H 4-H 5-H 6-H 2 H H ok
    280 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H CH2—COO—CH3 ok
    281 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 CH3 CH2—COO—CH3 ok
    282 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H (CH2)2—COO—CH3 ok
    283 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H (CH2)3—COO—CH3 ok
    284 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H CH2—COOH ok
    285 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 CH3 CH2—COOH ok
    286 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H (CH2)2—COOH ok
    287 Phenyl-2-Cl-4,5-F2 H H 2-OCF3 3-H 5-H 6-H 4 H (CH2)3—COOH ok

    *“Na” means the sodium salt of the corresponding compound with R1 = H

    **In the “Amide” column, the position of the carboxamide group —(C═O)—N(R7)(R8) on the phenyl radical is indicated.

    ***Where structural formulae are indicated for R8, the bonding of R8 to the nitrogen takes place via the short depicted bond

    ****The statement “MS is ok” means that a mass spectrum was measured and, in this, the molecular peak (molecular mass +H+) was detected.
  • The compounds of the formula I are distinguished by beneficial effects on glucose metabolism; in particular they lower the blood glucose level and are suitable for treating type II diabetes. The compounds can be employed alone or in combination with other blood glucose-lowering active ingredients (antidiabetics). Examples of such blood glucose-lowering active ingredients are sulfonylureas (such as, for example, glimepiride, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepide), metformin, tolbutamide, glitazones (such as, for example, troglitazone, rosiglitazone, pioglitazone, repaglinide), alpha-glucosidase inhibitors (such as, for example, acarbose, miglitol) or insulins. All antidiabetics mentioned in chapter 12 of the Rote Liste 2001 can be combined with the compounds of the formula I of the invention for improving the effect. Administration of the active ingredient combination can take place either by separate administration of the active ingredients to the patients or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation.
  • The compounds of the formula I are additionally suitable for the treatment of late complications of diabetes such as, for example, nephropathy, retinopathy, neuropathy and mycocardial infarction, peripheral arterial occlusive diseases, thromboses, arteriosclerosis, syndrome X, obesity, inflammations, immune diseases, autoimmune diseases such as, for example, AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases.
  • The activity of the compounds was assayed as follows:
  • Glycogen Phosphorylase a Activity Assay
  • The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by following the synthesis of glycogen from glucose 1-phosphate by determining the liberation of inorganic phosphate. All the reactions were carried out as duplicate determinations in microtiter plates with 96 wells (Half Area Plates, Costar No 3696), measuring the change in absorption owing to the formation of the reaction product at the wavelength specified hereinafter in a Multiskan Ascent Elisa Reader (Lab Systems, Finland).
  • In order to measure the GPa enzymic activity in the reverse direction, the general method of Engers et al. (Engers H D, Shechosky S, Madsen N B, Can J Biochem 1970 July; 48(7): 746-754) was used to measure the conversion of glucose 1-phosphate into glycogen and inorganic phosphate, with the following modifications: human glycogen phosphorylase a (for example with 0.76 mg of protein/ml (Aventis Pharma Deutschland GmbH), dissolved in buffer solution E (25 mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol) was diluted with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl2.6H2O) and addition of 5 mg/ml glycogen to a concentration of 10 μg of protein/ml. Test substances were prepared as 10 mM solution in DMSO and diluted to 50 μM with buffer solution T. To 10 μl of this solution were added 10 μl of 37.5 mM glucose, dissolved in buffer solution T, and 5 mg/ml glycogen, plus 10 μl of a solution of human glycogen phosphorylase a (10 μg of protein/ml) and 20 μl of glucose 1-phosphate, 2.5 mM. The baseline glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 μl of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes, and the liberated inorganic phosphate was measured by the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D, Anal Biochem 1995 Sep. 1; 230(1): 173-177) with the following modifications: 50 μl of a stop solution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 μl of the enzyme mixture. After incubation at 45° C. for 60 minutes, the absorption at 820 nm was measured. To determine the background absorption, in a separate mixture the stop solution was added immediately after addition of the glucose 1-phosphate solution.
  • This test was carried out with a concentration of 10 μM of the test substance in order to determine the particular inhibition of glycogen phosphorylase a in vitro by the test substance.
    TABLE 2
    Biological activity:
    % inhibition at
    Ex. 10 μM
    1 87
    2 73
    3 75
    4 79
    5 77
    12 92
    20 35
    29 78
    30 76
    31 86
    41 50
    44 11
    46 36
    47 46
    49 13
    51 36
    53 22
    60 36
    70 86
    75 41
    80 50
    84 44
    89 90
    90 34
    100 78
    101 93
    102 14
    106 35
    111 88
    112 100
    116 100
    117 99
    118 70
    119 97
    120 40
    122 12
    128 95
    147 88
    149 76
  • It is to be inferred from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are thus very suitable for lowering the blood glucose level.
  • The preparation of some examples is described in detail below, and the other compounds of the formula I were obtained analogously:
  • Experimental Part:
    • EXAMPLE 1 a) 2-Chlorobenzoyl Isocyanate
  • 2-Chlorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in stage b without further purification.
    • b) 4-Chloro-3-[3-(2-chlorobenzoyl)ureido]Benzoic Acid
  • 1 g (5.8 mmol) of 3-amino-4-chlorobenzoic acid were mixed with 0.75 g (5.8 mmol) of diisopropylethylamine and 1.06 g (5.8 mmol) of 2-chlorobenzoyl isocyanate in 5 ml of dichloromethane and reacted at room temperature for 12 hours. The solvent was evaporated, the residue was mixed with 5% strength sodium bicarbonate solution and extracted twice with diethyl ether, and the aqueous phase was adjusted to pH 3 with HCl. The resulting precipitate was filtered off with suction.
    • c) Ethyl 4-{4-chloro-3-[3-(2-chlorobenzoyl)ureido]benzoylamino}piperidine-1-carboxylate
  • 100 mg (0.28 mmol) of 4-chloro-3-[3-(2-chlorobenzoyl)ureido]benzoic acid, 93 mg (0.28 mmol) of TOTU and 37 mg (0.28 mmol) of diisopropylethylamine were coupled in 1 ml of dimethylformamide. The reaction solution was washed once each with 5% strength sodium bicarbonate solution and 10% strength citric acid solution, and the organic phase was dried and concentrated.
  • Examples 2-52 and 188-220 were synthesized in analogy to example 1.
    • EXAMPLE 94 a) 4-[3-(2,4-Dichlorobenzoyl)ureido]-3-methoxybenzoic Acid
  • 36.1 g (167.5 mmol) of 2,4-dichlorobenzoyl isocyanate, which was prepared in analogy to example 1 a, were added to a solution of 20 g (119.6 mmol) of 4-amino-3-methoxybenzoic acid in 400 ml of acetonitrile. The mixture was heated to reflux for 2 hours and cooled to room temperature. The precipitate was filtered off with suction, washed with acetonitrile and methanol, stirred with 5% strength potassium bisulfate solution, again filtered off with suction and dried under high vacuum. 44 g (96%) of the desired product were obtained.
    • b) 4-[3-(2,4-Dichlorobenzoyl)ureido]-3-methoxybenzoyl Chloride
  • 11.25 g (37.2 mmol) of 4-[3-(2,4-dichlorobenzoyl)ureido]-3-methoxybenzoic acid from stage a were heated to reflux with 150 ml of thionyl chloride for 3 hours and evaporated in a rotary evaporator under high vacuum. The residue was twice mixed with toluene and again evaporated under high vacuum to result in 10.88 g (27.09 mmol, 73%) of acid chloride (loss due to foaming over). The product obtained in this way was employed in the next stage without further purification.
    • c) 3-[3-(2,4-Dichlorobenzoyl)ureido]-4-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide Sodium Salt
  • A suspension of 157 mg (0.39 mmol) of acid chloride from stage b and 4 ml of dichloromethane was added to a solution of 65 μl (0.8 mmol) of pyridine and 63 mg (0.4 mmol) of 2,2,6,6-tetramethylpiperidin-4-ylamine in 2 ml of dichloromethane, and the reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with 2.5 ml of acetonitrile, filtered and washed with 5 ml of acetonitrile, and the filtrate was evaporated. The residue was taken up in a mixture of 2N of sodium hydroxide solution, acetonitrile and dimethylformamide (1/2/2), whereupon the product precipitated.
  • Examples 95-152 were synthesized in analogy to example 94. If required, the products were purified by preparative reverse phase HPLC (acetonitrile/water/TFA).

Claims (12)

1. A compound of the formula I,
Figure US20050143456A1-20050630-C00218
in which
A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, (C0-C6)-alkylene-COOH, (C0-C6)-alkylene-COO—(C1-C7)-alkyl, (C0-C6)-alkylene-COO—(C2-C7)-alkenyl, CONH2, CONH—(C1-C6)-alkyl, CON—[(C1-C6)-alkyl]2, CONH—(C3-C6)-cycloalkyl, (C0-C6)-alkylene-NH2, (C0-C6)-alkylene-NH—(C2-C6)-alkyl, (C0-C6)-alkylene-N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, and NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CONH2;
R1, R2 are, independently of one another, H, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CO—(C1-C6)-alkyl, or COO—(C1-C6)-alkyl;
R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, COOH, COO—(C1-C6)-alkyl, CO—NH2, CO—NH—(C1-C6)-alkyl, CO—N—[(C1-C6)-alkyl]2, CO—NH—(C3-C7)-cycloalkyl, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, or NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CO—NH2;
R7 is H, (C1-C6)-alkyl, or CO(C1-C6)-alkyl;
R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl and NCOO—(C1-C4)-alkylene-(C6-C10)— aryl; or
 (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
2. The compound as claimed in claim 1, in which
A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;
R1, R2 are H;
R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO2, O—(C1-C6)-alkyl, or (C1-C6)-alkyl;
R7 is H, or CH3;
R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl or NCOO—(C1-C4)-alkylene-(C6-C10)-aryl; or
 (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
or a pharmaceutically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
3. The compound as claimed in claim 1, in which
A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;
R1, R2 are H;
R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO2, O—(C1-C6)-alkyl, or (C1-C6)-alkyl;
R7 is H, or CH3;
R8 is (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl or NCOO—(C1-C4)-alkylene-(C6-C10)-aryl; or
 (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
or a pharmaceutically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.
4. A medicament, comprising at least one compound as claimed claim 1 and at least one pharmaceutically acceptable carrier.
5. A medicament, comprising at least one compound as claimed claim 1, at least one additional blood glucose-lowering active ingredient, and at least one pharmaceutically acceptable carrier.
6. A method for treating type II diabetes comprising, administering to a patient in need thereof at least one compound as claimed claim 1 and at least one additional blood glucose-lowering active ingredients.
7. The method of treating type II diabetes of claim 6, wherein the at least, one compound as claimed claim 1 and the at least one additional blood glucose-lowering active ingredients are administered sequentially.
8. A method for lowering blood glucose comprising, administering to a patient in need thereof at least one compound as claimed claim 1 and at least one additional blood glucose-lowering active ingredients.
9. The method for lowering blood glucose of claim 8, wherein the at least one compound as claimed claim 1 and the at least one additional blood glucose-lowering active ingredients are administered sequentially.
10. A process for producing a medicament comprising at least one compound as claimed claim 1, which comprises mixing the at least one compound as claimed claim 1 with a pharmaceutically-suitable carrier and converting this mixture into a form suitable for administration.
11. A method of lowering blood glucose comprising administering to a patient in need thereof at least one compound chosen from compounds of the formula I,
Figure US20050143456A1-20050630-C00219
in which
A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, (C0-C6)-alkylene-COOH, (C0-C6)-alkylene-COO—(C1-C7)-alkyl, (C0-C6)-alkylene-COO—(C2-C7)-alkenyl, CONH2, CONH—(C1-C6)-alkyl, CON—[(C1-C6)-alkyl]2, CONH—(C3-C6)-cycloalkyl, (C0-C6)-alkylene-NH2, (C0-C6)-alkylene-NH—(C2-C6)-alkyl, (C0-C6)-alkylene-N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, and NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CONH2;
R1, R2 are, independently of one another, H, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CO—(C1-C6)-alkyl, or COO—(C1-C6)-alkyl;
R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C4)-alkylene, COOH, COO—(C1-C6)alkyl, CO—NH2, CO—NH—(C1-C6)-alkyl, CO—N—[(C1-C6)-alkyl]2, CO—NH—(C3-C7)cycloalkyl, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, or NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CO—NH2;
R7 is H, (C1-C6)-alkyl, or CO(C1-C6)-alkyl;
R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl and NCOO—(C1-C4)-alkylene-(C6-C10)— aryl; or
 (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
and physiologically tolerable salts thereof, in any stereoisomeric form, and any mixture of any such compounds in any ratio.
12. A method for treating type II diabetes comprising administering to a patient in need thereof at least one compound chosen from compounds of the formula I,
Figure US20050143456A1-20050630-C00220
in which
A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, (C0-C6)-alkylene-COOH, (C0-C6)-alkylene-COO—(C1-C7)-alkyl, (C0-C6)-alkylene-COO—(C2-C7)-alkenyl, CONH2, CONH—(C1-C6)-alkyl, CON—[(C1-C6)-alkyl]2, CONH—(C3-C6)-cycloalkyl, (C0-C6)-alkylene-NH2, (C0-C6)-alkylene-NH—(C2-C6)-alkyl, (C0-C6)-alkylene-N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, and NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO—(C1-C6)-alkyl and CONH2;
R1, R2 are, independently of one another, H, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CO—(C1-C6)-alkyl, or COO—(C1-C6)-alkyl;
R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C2-C6)-alkenyl, O—(C2-C6)-alkynyl, S—(C1-C6)-alkyl, S—(C2-C6)-alkenyl, S—(C2-C6)-alkynyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2—NH2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkylene, COOH, COO—(C1-C6)-alkyl, CO—NH2, CO—NH—(C1-C6)alkyl, CO—N—[(C1-C6)-alkyl]2, CO—NH—(C3-C7)cycloalkyl, NH2, NH—(C1-C6)alkyl, N—[(C1-C6)-alkyl]2, NH—CO—(C1-C6)-alkyl, NH—CO-phenyl, or NH—SO2-phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO2-phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl and CO—NH2;
R7 is H, (C1-C6)-alkyl, or CO(C1-C6)-alkyl;
R8 is H, (C1-C10)-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF3, CN, COOH, COO—(C1-C6)-alkyl, CO—NH2, NH2, NH—(C1-C6)-alkyl, N—[(C1-C6)-alkyl]2, NCO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkyl, NCOO—(C1-C6)-alkenyl, NCOO—(C1-C6)-alkynyl and NCOO—(C1-C4)-alkylene-(C6-C10)—aryl; or
 (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;
R9 is F, Cl, Br; OH, NO2, CF3, OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, (C1-C4)-alkylphenyl, COOH, or COO—(C1-C6)-alkyl;
and physiologically tolerable salts thereof, in any stereoisomeric form, and any mixture of any such compounds in any ratio.
US10/978,674 2001-05-25 2004-11-01 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments Abandoned US20050143456A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/978,674 US20050143456A1 (en) 2001-05-25 2004-11-01 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE10125567A DE10125567B4 (en) 2001-05-25 2001-05-25 Carbonamide substituted phenylurea derivatives, process for their preparation and their use as medicines
DE10125567.5-42 2001-05-25
DE10207369A DE10207369A1 (en) 2002-02-21 2002-02-21 New N-aroyl-N'-(carbamoyl-phenyl)-urea derivatives, are glycogen phosphorylase a inhibiting hypoglycemic agents, especially useful for treating type II diabetes
DE10207369.4 2002-02-21
US10/153,597 US6812250B2 (en) 2001-05-25 2002-05-24 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments
US10/978,674 US20050143456A1 (en) 2001-05-25 2004-11-01 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/153,597 Division US6812250B2 (en) 2001-05-25 2002-05-24 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Publications (1)

Publication Number Publication Date
US20050143456A1 true US20050143456A1 (en) 2005-06-30

Family

ID=26009397

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/153,597 Expired - Lifetime US6812250B2 (en) 2001-05-25 2002-05-24 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments
US10/978,674 Abandoned US20050143456A1 (en) 2001-05-25 2004-11-01 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/153,597 Expired - Lifetime US6812250B2 (en) 2001-05-25 2002-05-24 Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Country Status (25)

Country Link
US (2) US6812250B2 (en)
EP (1) EP1404650B1 (en)
JP (1) JP4167592B2 (en)
KR (1) KR20040003007A (en)
CN (1) CN1218936C (en)
AR (1) AR036029A1 (en)
AT (1) ATE386017T1 (en)
AU (1) AU2002344151B2 (en)
BG (1) BG108318A (en)
BR (1) BR0210008A (en)
CA (1) CA2448023A1 (en)
CZ (1) CZ20033200A3 (en)
DE (1) DE50211685D1 (en)
EE (1) EE200300581A (en)
HR (1) HRP20030971A2 (en)
HU (1) HUP0400052A3 (en)
IL (1) IL159031A0 (en)
MX (1) MXPA03009840A (en)
NO (1) NO20035220D0 (en)
NZ (1) NZ529697A (en)
PE (1) PE20021091A1 (en)
PL (1) PL363871A1 (en)
RU (1) RU2291858C2 (en)
SK (1) SK14442003A3 (en)
WO (1) WO2002096864A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032529A1 (en) * 2005-05-23 2007-02-08 Japan Tobacco Inc. Pyrazole compounds and their use as antidiabetes agents
US20080045289A1 (en) * 2006-08-10 2008-02-21 Wayne Odom System and device for conducting a game of chance
US20090036450A1 (en) * 2006-11-20 2009-02-05 Japan Tobacco, Inc. Pyrazole compounds and use thereof
US8375455B2 (en) 2006-08-10 2013-02-12 Wayne Odom System, method, and device for storing and delivering data
US8448236B1 (en) 2012-12-07 2013-05-21 Wayne Odom System, method, and device for storing and delivering data
US8572720B1 (en) 2013-05-20 2013-10-29 Wayne Odom System, method, and device for communicating and storing and delivering data
US8677510B2 (en) 2012-04-06 2014-03-18 Wayne Odom System, method, and device for communicating and storing and delivering data
US8844054B2 (en) 2012-04-06 2014-09-23 Wayne Odom System, method, and device for communicating and storing and delivering data
US9043934B2 (en) 2012-04-06 2015-05-26 Wayne Odom System, method, and device for delivering communications and storing and delivering data
US9378339B2 (en) 2012-04-06 2016-06-28 Wayne Odom System, method, and device for delivering communications and storing and delivering data

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0205170D0 (en) 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
GB0205176D0 (en) 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
GB0205175D0 (en) 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
GB0205165D0 (en) 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
GB0205162D0 (en) 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
GB0205166D0 (en) 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
IL164249A0 (en) * 2002-04-11 2005-12-18 Aventis Pharma Gmbh Acyl-3-carboxphenylurea derivatives, processes forpreparing them and their use
DE10215908B4 (en) * 2002-04-11 2005-08-18 Aventis Pharma Deutschland Gmbh Acyl-3-carboxyphenyl-urea derivatives and their use as medicaments
US7223796B2 (en) 2002-04-11 2007-05-29 Sanofi-Aventis Deutschland Gmbh Acyl-4-carboxyphenylurea derivatives, processes for preparing them and their use
US7262220B2 (en) * 2002-07-11 2007-08-28 Sanofi-Aventis Deutschland Gmbh Urea- and urethane-substituted acylureas, process for their preparation and their use
MXPA05000055A (en) * 2002-07-11 2005-04-08 Aventis Pharma Gmbh Urea-substituted and urethane-substituted acylureas, methods for the production thereof and their use as medicaments.
HRP20050022A2 (en) 2002-07-12 2006-03-31 Sanofi-Aventis Deutschland Gmbh Heterocyclically substituted benzoylureas, method for their production and their use as medicaments
DE10302452B4 (en) * 2003-01-23 2005-02-24 Aventis Pharma Deutschland Gmbh Carbonylamino-substituted acyl-phenyl-urea derivatives, processes for their preparation and their use
DE10306502B4 (en) * 2003-02-17 2005-03-17 Aventis Pharma Deutschland Gmbh Substituted 3- (benzoylureido) thiophene derivatives and medicaments containing them
DE10308351A1 (en) 2003-02-27 2004-11-25 Aventis Pharma Deutschland Gmbh 1,3-substituted cycloalkyl derivatives having acidic, usually heterocyclic groups, processes for their preparation and their use as medicaments
DE10308352A1 (en) 2003-02-27 2004-09-09 Aventis Pharma Deutschland Gmbh Branched side chain arylcycloalkyl derivatives, process for their preparation and their use as medicaments
DE10308355A1 (en) 2003-02-27 2004-12-23 Aventis Pharma Deutschland Gmbh Aryl-cycloalkyl-substituted alkanoic acid derivatives, process for their preparation and their use as medicaments
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
US7173151B2 (en) 2003-02-27 2007-02-06 Sanofi-Aventisdeutschand Gmbh Cycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
DE10308353A1 (en) 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkyl derivatives, processes for their preparation and their use as medicines
US7501440B2 (en) 2003-03-07 2009-03-10 Sanofi-Aventis Deutschland Gmbh Substituted benzoylureidopyridylpiperidine-and-pyrrolidinecarboxylic acid derivatives, processes for preparing them and their use
DE10309929B4 (en) * 2003-03-07 2006-02-23 Sanofi-Aventis Deutschland Gmbh Substituted benzoylureidopyridyl-piperidine and -pyrrolidine-carboxylic acid derivatives, process for their preparation and their use
DE10335092B3 (en) 2003-08-01 2005-02-03 Aventis Pharma Deutschland Gmbh Substituted benzoylureido-o-benzoylamides, process for their preparation and their use
JP2007502283A (en) * 2003-08-13 2007-02-08 アムジェン インコーポレイテッド Melanin-concentrating hormone receptor antagonist
US7241787B2 (en) 2004-01-25 2007-07-10 Sanofi-Aventis Deutschland Gmbh Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments
EP1586573B1 (en) 2004-04-01 2007-02-07 Sanofi-Aventis Deutschland GmbH Oxadiazolones, processes for their preparation and their use as pharmaceuticals
US7618981B2 (en) 2004-05-06 2009-11-17 Cytokinetics, Inc. Imidazopyridinyl-benzamide anti-cancer agents
US7504413B2 (en) 2004-05-06 2009-03-17 Cytokinetics, Inc. N-(4-(imidazo[1,2A]pyridin-YL)phenethyl)benzamide inhibitors of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases
US7795448B2 (en) 2004-05-06 2010-09-14 Cytokinetics, Incorporated Imidazoyl-benzamide anti-cancer agents
DE102005026762A1 (en) 2005-06-09 2006-12-21 Sanofi-Aventis Deutschland Gmbh Azolopyridin-2-one derivatives as inhibitors of lipases and phospholipases
PE20080251A1 (en) 2006-05-04 2008-04-25 Boehringer Ingelheim Int USES OF DPP IV INHIBITORS
US8634162B2 (en) * 2007-03-08 2014-01-21 HGST Netherlands B.V. Perpendicular write head having a stepped flare structure and method of manufacture thereof
DE102007012284A1 (en) 2007-03-16 2008-09-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals
CL2008000979A1 (en) * 2007-04-11 2008-10-17 Sumitomo Chemical Co PROCESS TO PRODUCE A COMPOUND DERIVED FROM 2-PIRIDIN-2-IL-2H-PIRAZOL-3-PHENYLAMIDE; INTERMEDIARY COMPOUNDS; THE COMPOUND IN YES; PESTICIDE COMPOSITION CONTAINING SUCH COMPOUND; USE OF SUCH COMPOUND AS A PESTICIDE; AND METHOD FOR CONTROL
DE102007035334A1 (en) 2007-07-27 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals
DE102007035333A1 (en) 2007-07-27 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted arylsulfonylglycines, their preparation and their use as pharmaceuticals
DE102007042154A1 (en) 2007-09-05 2009-03-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Arylsulfonylaminomethyphosphonsäure derivatives, their preparation and their use as medicaments
FR2930552B1 (en) * 2008-04-24 2012-10-12 Centre Nat Rech Scient N-ACYLTHIOUREES AND N-ACYLUREES INHIBITORS OF THE HEDGEHOG PROTEIN SIGNALING PATHWAY

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350706A (en) * 1978-07-06 1982-09-21 Duphar International Research B.V. Urea and thiourea compounds and insecticidal compositions
US6506778B2 (en) * 2000-06-09 2003-01-14 Aventis Pharma Deutschland Gmbh Acylphenylurea derivatives, a process for their preparation and their use as pharmaceuticals

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3478573D1 (en) 1983-09-01 1989-07-13 Duphar Int Res Benzoyl urea derivatives having anti-tumor activity
EP0167197B1 (en) 1984-07-05 1989-01-18 Duphar International Research B.V Benzoylurea compounds, and insecticidal and acaricidal compositions comprising same
TW255880B (en) * 1992-09-09 1995-09-01 Hoechst Ag
JP3071832B2 (en) 1996-01-17 2000-07-31 ノボ ノルディスク アクティーゼルスカブ Condensed 1,2,4-thiadiazine and condensed 1,4-thiazine derivatives, their production and use
ES2283025T3 (en) 1996-08-30 2007-10-16 Novo Nordisk A/S DERIVATIVES OF GLP-1.1.
DE69723869T2 (en) 1996-12-31 2004-04-22 Dr. Reddy's Laboratories Ltd. HETEROCYCLIC COMPOUNDS, METHOD FOR THEIR PRODUCTION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEIR AND THEIR APPLICATION IN THE TREATMENT OF DIABETIS AND RELATED DISEASES
EP1000066A1 (en) 1997-07-16 2000-05-17 Novo Nordisk A/S Fused 1,2,4-thiadiazine derivatives, their preparation and use
TWI234557B (en) * 1999-05-26 2005-06-21 Telik Inc Novel naphthalene ureas as glucose uptake enhancers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350706A (en) * 1978-07-06 1982-09-21 Duphar International Research B.V. Urea and thiourea compounds and insecticidal compositions
US6506778B2 (en) * 2000-06-09 2003-01-14 Aventis Pharma Deutschland Gmbh Acylphenylurea derivatives, a process for their preparation and their use as pharmaceuticals

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032529A1 (en) * 2005-05-23 2007-02-08 Japan Tobacco Inc. Pyrazole compounds and their use as antidiabetes agents
US20080045289A1 (en) * 2006-08-10 2008-02-21 Wayne Odom System and device for conducting a game of chance
US8375455B2 (en) 2006-08-10 2013-02-12 Wayne Odom System, method, and device for storing and delivering data
US20090036450A1 (en) * 2006-11-20 2009-02-05 Japan Tobacco, Inc. Pyrazole compounds and use thereof
US8677510B2 (en) 2012-04-06 2014-03-18 Wayne Odom System, method, and device for communicating and storing and delivering data
US8844054B2 (en) 2012-04-06 2014-09-23 Wayne Odom System, method, and device for communicating and storing and delivering data
US9043934B2 (en) 2012-04-06 2015-05-26 Wayne Odom System, method, and device for delivering communications and storing and delivering data
US9378339B2 (en) 2012-04-06 2016-06-28 Wayne Odom System, method, and device for delivering communications and storing and delivering data
US8448236B1 (en) 2012-12-07 2013-05-21 Wayne Odom System, method, and device for storing and delivering data
US8572720B1 (en) 2013-05-20 2013-10-29 Wayne Odom System, method, and device for communicating and storing and delivering data

Also Published As

Publication number Publication date
HUP0400052A3 (en) 2008-12-29
JP2004529194A (en) 2004-09-24
PE20021091A1 (en) 2003-02-04
EE200300581A (en) 2004-02-16
NO20035220D0 (en) 2003-11-24
CA2448023A1 (en) 2002-12-05
RU2003137222A (en) 2005-05-20
NZ529697A (en) 2005-12-23
ATE386017T1 (en) 2008-03-15
EP1404650B1 (en) 2008-02-13
CN1525955A (en) 2004-09-01
BR0210008A (en) 2004-08-10
HK1065027A1 (en) 2005-02-08
CN1218936C (en) 2005-09-14
EP1404650A1 (en) 2004-04-07
SK14442003A3 (en) 2004-05-04
MXPA03009840A (en) 2004-04-02
HUP0400052A2 (en) 2004-04-28
HRP20030971A2 (en) 2005-08-31
IL159031A0 (en) 2004-05-12
KR20040003007A (en) 2004-01-07
US6812250B2 (en) 2004-11-02
AR036029A1 (en) 2004-08-04
US20030176497A1 (en) 2003-09-18
RU2291858C2 (en) 2007-01-20
PL363871A1 (en) 2004-11-29
CZ20033200A3 (en) 2004-02-18
JP4167592B2 (en) 2008-10-15
BG108318A (en) 2005-01-31
DE50211685D1 (en) 2008-03-27
AU2002344151B2 (en) 2007-01-18
WO2002096864A1 (en) 2002-12-05

Similar Documents

Publication Publication Date Title
US6812250B2 (en) Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments
US6506778B2 (en) Acylphenylurea derivatives, a process for their preparation and their use as pharmaceuticals
MXPA04009468A (en) Acyl-4-carboxyphenylurea derivatives, method for production and use thereof.
US8247452B2 (en) Urea- and urethane-substituted acylureas, process for their preparation and their use
OA13364A (en) 7-phenylamino-4-quinolone-3-carboxylic acid derivatives, methods for production and use thereof as medicaments.
ZA200408887B (en) N-Benzoylureidocinnamate derivatives, method for production and use thereof.
AU2003281027A1 (en) Urea-substituted and urethane-substituted acylureas, methods for the production thereof and their use as medicaments
MXPA04009239A (en) Acyl-3-carboxyphenylurea derivatives, method for production and use thereof.
US7671047B2 (en) Cationically substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
US7781459B2 (en) Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments
US7078404B2 (en) Acyl-3-carboxyphenylurea derivatives, processes for preparing them and their use
JP4355290B2 (en) Carboxyalkoxy substituted acyl-carboxyphenylurea derivatives, processes for their preparation and their use as pharmaceuticals
US7049341B2 (en) N-benzoylureidocinnamic acid derivatives, processes for preparing them and their use
ZA200308308B (en) Carboxamide-substituted phenylurea derivatives and method for production thereof as medicaments.
DE10207369A1 (en) New N-aroyl-N'-(carbamoyl-phenyl)-urea derivatives, are glycogen phosphorylase a inhibiting hypoglycemic agents, especially useful for treating type II diabetes

Legal Events

Date Code Title Description
AS Assignment

Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH, GERMANY

Free format text: CHANGE OF NAME;ASSIGNOR:AVENTIS PHARMA DEUTSCHLAND GMBH;REEL/FRAME:016793/0789

Effective date: 20050901

Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH,GERMANY

Free format text: CHANGE OF NAME;ASSIGNOR:AVENTIS PHARMA DEUTSCHLAND GMBH;REEL/FRAME:016793/0789

Effective date: 20050901

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION