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WO1999007670A1 - Analogues d'acide anthranilique - Google Patents

Analogues d'acide anthranilique Download PDF

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Publication number
WO1999007670A1
WO1999007670A1 PCT/US1998/015981 US9815981W WO9907670A1 WO 1999007670 A1 WO1999007670 A1 WO 1999007670A1 US 9815981 W US9815981 W US 9815981W WO 9907670 A1 WO9907670 A1 WO 9907670A1
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Prior art keywords
hydrogen
amino
compound
aryl
alkylcarboxamido
Prior art date
Application number
PCT/US1998/015981
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English (en)
Inventor
Joseph Richard Lennox
Schuyler Adam Antane
John Anthony Butera
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American Home Products Corporation
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Filing date
Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to EP98938221A priority Critical patent/EP1003713A1/fr
Priority to AU86795/98A priority patent/AU734786B2/en
Priority to CA002297409A priority patent/CA2297409A1/fr
Priority to JP2000507206A priority patent/JP2001513527A/ja
Priority to BR9811828-5A priority patent/BR9811828A/pt
Publication of WO1999007670A1 publication Critical patent/WO1999007670A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a novel series of anthranilic acid-derived amides (I) having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel and chloride channel modulation.
  • disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
  • Patent No. J6 0097-946-A discloses a series of substituted carboxamide derivatives which exhibit activity as leucotriene antagonists and phospholipase inhibitors.
  • R , R and R are, independently, hydrogen, nitro, cyano, C. .10 haloalkoxy, amino, C, .10 alkylamino, sulfo, sulfamoyl, C. .10 alkylsulfonamido, C 2.10 alkylcarboxamido C 2.10 alkanoyl, C. .10 alkylsulfonyl, C, .10 haloalkylsulfonyl, C, .10 carboxyl, C. .10 haloalkyl and C g. ,- aryl; with the provisos: (1) that R,, R 2 and R 3 may not all simultaneously be hydrogen, and (2) when R, and R 2 are hydrogen, R 3 may not be meta-CF 3 ;
  • R 4 , R 5 and R fi are, independently, hydrogen, halogen, nitro, cyano, C 0 carboalkoxy, C, . , 0 haloalkoxy, amino C, .10 alkylamino, sulfo, sulfamoyl, C, .10 alkylsulfonamido, C 2.10 alkylcarboxamido C 2.10 alkanoyl, C. .10 alkylsulfonyl, C, .I0 haloalkylsulfonyl, C ⁇ 0 carboxyl, C, .10 haloalkyl, C. .I0 alkyl and C 6.12 aryl;
  • R 7 is hydrogen, metal cation, acetylamido, alkoxyacetoyl or a related moiety which delivers the carboxylate in vivo;
  • X, Y and Z may form a C 3.13 carbocyclic ring, oxazole, isoxazole, thiazole, isothiazole, furan, thiophene, 2H-pyrrole, pyrrole, 2- pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole or 1,2,3- triazole bound to the carbon skeleton.
  • R, , R 2 and R 3 are, independently, hydrogen, nitro, cyano, perhaloalkoxy, amino, C. .10 alkylamino, C, .10 dialkylamino, C arylamino, C, .10 aralkylamino, sulfo, sulfamyl, C,. 10 alkylsulfonamido, C 6.12 arylsulfonamido, C 2.I0 alkylcarboxamido, C 6. , 2 arylcarboxamido,
  • R 4 , R 5 , and R 6 are, independent of each other, hydrogen, halogen, nitro, cyano, carboalkoxy, perhaloalkoxy, amino, C,_ 10 alkylamino, C, .10 dialkylamino, arylamino, C. .10 aralkylamino, sulfo, sulfamyl, C, .
  • haloalkyl C. . , 0 perhaloalkyl, C 2.12 alkenyl (single or multiple olefinic), aryl, haloaryl, perhaloaryl, C, .10 aralkyl;
  • R 7 is a hydrogen, an alkali metal cation, an alkaline earth metal cation, acetylamido, alkoxyacetoyl, or related moieties which deliver the carboxylate in vivo;
  • X, Y and Z may form a C 3.13 carbocyclic ring, oxazole, isoxazole, thiazole, or isothiazole, bound to the carbon skeleton.
  • Still more preferred aspects of this invention includes compounds of formula (I) wherein:
  • R,, R 2 , R 3 , R 4 , R 5 , and R 6 are as hereinbefore defined;
  • R 7 is selected from the group consisting of hydrogen, a metal cation, a moiety selected from:
  • R 9 , R ]0 , R u and R 12 are, independent of each other, hydrogen, C 0 straight chain alkyl, C, .]0 branched alkyl, C 3.10 cyclic or bicyclic, aryl, or C. .10 aralkyl;
  • X, Y and Z may form a C 3.I3 carbocyclic ring, oxazole, isoxazole, thiazole, or isothiazole, bound to the carbon skeleton;
  • a most preferred aspect of this invention includes compounds of the formula (I) wherein R 7 may be hydrogen, or a metal cation as previously described.
  • the pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • R., R ⁇ , R 3 , R 4 , R 5 , R 6 , or the ring system formed by X, Y and Z contains a carboxyl group
  • salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
  • the present invention also provides a process for the preparation of compounds of the formula (I). Methods of preparation are shown in Schemes 1 through 4.
  • Isoxazoles of the formula (1) may be prepared (Scheme 1) by nitrile oxide cycloaddition of a compound of the formula (II) with an appropriate nitrile oxide (III) to give heterocycle (IV). As above, saponification gives intermediate carboxylic acid (V)
  • Oxazoles of the formula (I) may be prepared (Scheme 2) via condensation of the appropriate benzoyl chloride (VI) with methyl isocyanoacetate (VII) to give the heterocycle (VIII). As above, saponification affords the intermediate carboxylic acid
  • R,, R 2 and R 3 are equivalent to the aforementioned R,, R 2 , and R
  • Carboxylic acid intermediates (V), (VI), or (XII) could subsequently be coupled (Scheme 4) to the amine of an appropriately derivatized anthranilic acid of the formula (XIII) utilizing one of the following established coupling procedures (Method A: (COCl) 2 , cat. DMF, CH 2 C1 2 , then add the neat acid chloride to a solution of anthranilic acid in sodium hydroxide; Method B: diisopropylcarbodiimide, DMAP, CH 2 C1 2 , then add methyl anthranilate; or Method C: (COCl) 2 , cat.
  • the reactions mentioned above may be carried out in aprotic solvents such as diethyl ether, dichloroethane, dioxane or THF at low to ambient temperatures.
  • aprotic solvents such as diethyl ether, dichloroethane, dioxane or THF at low to ambient temperatures.
  • sodium hydroxide is used as a base
  • other inorganic bases which may also suffice are lithium hydroxide or potassium hydroxide, etc.
  • triethylamine may be optionally substituted with any trialkylamine.
  • the compounds of formula (I), and their pharmaceutically acceptable salts have been found to relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence), or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma, and hair loss.
  • the compounds of formula (I) are active as potassium channel activators which render them useful for treatment of peripheral vascular disease, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.
  • compounds of formula(s) (I) and (II) may also be active as chloride channel blockers, which again renders them useful for treatment of the above stated disorders.
  • Compounds of the present invention are characterized by their potent smooth muscle relaxing properties in vitro.
  • the compounds of this invention exert their smooth muscle relaxatory activity via activation of potassium channels and/or blocking of chloride channels (Table 1).
  • Comparative compound, Tranilast ® was shown not to be a potent or bladder selective smooth muscle relaxant.
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.
  • a composition of the invention is in the form of a unit dose.
  • Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
  • Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg.
  • Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
  • the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
  • compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and ⁇ - blocking agents.
  • the present invention further provides a compound of the invention for use as an active therapeutic substance.
  • Compounds of formula (I) are of particular use in the induction of smooth muscle relaxation.
  • the present invention further provides a method of treating smooth muscle disorders in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.
  • the neat acid chloride was then added to a homogeneous solution of anthranilic acid (535 mg, 3.90 mmol) in 2.5 N aqueous NaOH (3.12 mL, 7.80 mmol) at 5°C, resulting in the instantaneous formation of a white precipitate.
  • the reaction mixture was then warmed to RT, whereupon it was diluted with a minimal amount of water to facilitate stirring, which was continued for an additional 1.5 h.
  • the mixture was acidified to pH 2 by addition of concentrated HC1 (0.75 mL), diluted with 2.0 N HC1, and stirred for 1.5 h.
  • Step 1) Preparation of 5-(4-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid methyl ester
  • 4-trifluoromethylbenzoyl chloride 8.42 g, 40.4 mmol
  • triethylamine 12.3 g, 122 mmol
  • methyl isocyanoacetate 3.60 g, 36.3 mmol
  • the resultant mixture was stirred at RT for 72 h whereupon all volatiles were removed via rotary evaporation, giving a residue which was partitioned between EtOAc (300 mL) and water (100 mL).
  • the dibromoolefin was dissolved in anhydrous THF (115 mL) and chilled to -78°C. To this solution was added dropwise via syringe pump over 1 h 2.5 M butyllithium (18.4 mL, 46.0 mmol). The resultant mixture was then stirred fo 0.5 h at -78°C, then treated with methyl chloroformate (5.00 mL, 64.7 mmol), followed by slow warming to RT, whereupon it was concentrated to an oily residue which was partitioned between ether (500 mL) and water (250 mL).
  • the acid chloride was then added to a homogeneous solution of anthranilic acid (1.19 g, 8.69 mmol) in 2.5 N aqueous NaOH (6.95 mL, 17.4 mmol) at 5°C, resulting in the instantaneous formation of a white precipitate.
  • the reaction mixture was then warmed to RT, whereupon it was diluted with a minimal amount of water to facilitate stirring, which was continued for an additional 1.5 h.
  • the mixture was acidified to pH 2 by addition of concentrated HCl (1.63 mL), diluted with 2.0 N HCl, and stirred for 1.5 h. Filtration of the suspension followed by washing with water, air drying and subsequent recrystallization from MeOH.
  • Sprague-Dawley rats (150-200 g) are rendered unconscious by CO 2 asphyxiation and then euthanized by cervical dislocation.
  • the bladder is removed into warm (37 deg.C) physiological salt solution (PSS) of the following composition (mM): NaCl, 118.4; KC1, 4.7; CaCl 2 , 2.5; MgSO 4 , 4.7; H 2 O, 1.2; NaHCO 3 , 24.9; KH 2 PO 4 , 1.2; glucose, 11.1; EDTA, 0.023; gassed with 95% O 2 ; 2/5% CO 2 ; pH 7.4.
  • the bladder is opened and then cut into strips 1-2 mm in width and 7-10 mm in length.
  • the strips are subsequently suspended in a 10 mL tissue bath under an initial resting tension of 1.5 g.
  • the strips are held in place by two surgical clips one of which is attached to a fixed hook while the other is attached to an isometric force transducer.
  • the preparations which usually exhibit small spontaneous contractions, are allowed to recover for a period of 1 hour prior to a challenge with 0.1 ⁇ M carbachol.
  • the carbachol is then washed out and the tissue allowed to relax to its resting level of activity. Following a further 30 min period of recovery an additional 15 mM KC1 are introduced into the tissue bath.
  • Tranilast ® ⁇ 2 14.4 ⁇ 4.5 5 15.59 ⁇ 8.96 1.08
  • Tranilast is (E)-2-[3-(3,4-Dimethoxy-phenyl)-acryloylamino]-benzoic acid. *Percent inhibition at 30 ⁇ M
  • mice Female Sprague-Dawley rats, ranging in weight from 190-210g are used. Up to 25 animals are prepared each time. After development of bladder hypertrophy 4-8 animals are used per test. Compounds are dissolved in PEG-200 and administered by gastric gavage or intraveneously in a volume of 5 mL/kg. For primary screening all drugs are administered at the arbitrary dose of 10 mg/kg p.o. to groups of 4 rats.
  • the animals are anesthetized with halothane.
  • halothane Through a midline incision the bladder and urethra are exposed and a ligature of 4-0 silk is tied around the proximal urethra in the presence of a stainless steel rod (1 mm diameter) to produce a partial occlusion. The rod is then removed. The abdominal region is closed using surgical staples and each rat receives 150,000 units of bicillin C-R. The animals are allowed six weeks to develop sufficient bladder hypertrophy. After six weeks, the ligature is removed under halothane anesthesia and a catheter (PE 60) with a cuff is placed in the dome of the bladder and secured with a purse string suture.
  • PE 60 catheter
  • the catheter is tunneled under the skin and exteriorized through an opening in the back of the neck.
  • the abdominal incision is sutured and the free end of the catheter sealed.
  • the rats receive an injection of bicillin C-R (150000 units/rat).
  • Two days later the animals are used in cystometrical evaluations.
  • the animals are placed in the metabolic cages and the catheter is attached (using a "T" connector) to a Statham pressure transducer (Model P23Db) and to a Harvard infusion pump.
  • a plastic beaker attached to a force displacement transducer (Grass FTO3) is placed under the rat's cage to collect and record urine volume.
  • Basal bladder pressure the lowest bladder pressure during cystometry
  • Threshold pressure bladder pressure immediately prior to micturition
  • Micturition volume volume expelled
  • the mean value of each variable is calculated before and after compound administration. For each compound the changes in the variables measured are compared to the values obtained before treatment and expressed as percent inhibition.
  • the data are also subjected to 2-way analysis of variance to determine significant (p ⁇ 0.05) changes in the variable measured.
  • Criteria for Activity The most characteristic finding in this rat model is spontaneous bladder contractions which develop during filling.
  • the compounds which inhibit spontaneous contractions by at least 50% at 10 mg/kg p.o. or i.v. (arbitrary chosen dose) are considered active.
  • the compounds of this invention have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, stroke, and similar diseases as mentioned above, which are amenable to treatment with potassium channel activating and/or chloride channel blocking compounds by administration, orally, parenterally, or by aspiration to a patient in need thereof.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Composés de formule (I), dans laquelle R1, R2 et R3 représentent indépendamment, hydrogène, nitro, cyano, haloalcoxy C1-10, amino, alkylamino C1-10, sulfo, sulfamoyle, alkylsulfonamido C1-10, alkylcarboxamido C2-10 alcanoyle C2-10, alkylsulfonyle C1-10, haloalkylsulfonyle C1-10, carboxyle C1-10, haloalkyle C1-10 et aryle C6-12; à condition: (1) que R1, R2 et R3 ne peuvent pas être simultanément hydrogène, et (2) lorsque R1 et R2 représentent hydrogène, R3 ne peut pas être méta-CF3; R4, R5 et R6 représentent séparément hydrogène, halogène, nitro, cyano, carboalcoxy C1-10, haloalcoxy C1-10, amino C1-10 alkylamino, sulfo, sulfamoyle, alkylsulfonamido C1-10, alkylcarboxamido C2-10 alcanoyle, alkylsulfonyle C1-10, haloalkylsulfonyle C1-10, carboxyle C1-10, haloalkyle C1-10, alkyle C1-10 et aryle C6-12; R7 représente hydrogène, cation métal, acétylamido, alcoxyacétoyle, ou une partie associée qui dégage le carboxylate in vivo; et X, Y et Z peuvent former un cycle carboxylique, oxazole, isoxazole, thiazole, isothiazole, furane, thiophène, 2H-pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, imidazole, pyrazole, 1,2,3-oxadiazole ou 1,2,3-triazole lié au squelette carboné; ou des sels pharmaceutiquement acceptables de ceux-ci, utiles dans le traitement de troubles associés à une contraction d'un muscle lisse, par modulation du canal potassium et le canal chlorure.
PCT/US1998/015981 1997-08-05 1998-08-03 Analogues d'acide anthranilique WO1999007670A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP98938221A EP1003713A1 (fr) 1997-08-05 1998-08-03 Analogues d'acide anthranilique
AU86795/98A AU734786B2 (en) 1997-08-05 1998-08-03 Anthranilic acid analogs
CA002297409A CA2297409A1 (fr) 1997-08-05 1998-08-03 Analogues d'acide anthranilique
JP2000507206A JP2001513527A (ja) 1997-08-05 1998-08-03 アントラニル酸類似体
BR9811828-5A BR9811828A (pt) 1997-08-05 1998-08-03 Análogos do ácido antranìlico

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90593097A 1997-08-05 1997-08-05
US08/905,930 1997-08-05

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WO1999007670A1 true WO1999007670A1 (fr) 1999-02-18

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EP (1) EP1003713A1 (fr)
JP (1) JP2001513527A (fr)
CN (1) CN1265643A (fr)
AU (1) AU734786B2 (fr)
BR (1) BR9811828A (fr)
CA (1) CA2297409A1 (fr)
WO (1) WO1999007670A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002048131A1 (fr) * 2000-12-12 2002-06-20 Aventis Pharma Deutschland Gmbh Amides d'acides furane et thiophene carboxyliques aryles ayant un effet de blocage de canal de potassium
EP1565190A2 (fr) * 2002-11-22 2005-08-24 Bristol-Myers Squibb Company Amides arylcyclopropylcarboxyliques utilises en tant qu'agents d'ouverture des canaux potassiques
EP1670749A1 (fr) * 2003-08-14 2006-06-21 Smithkline Beecham Corporation Derives d'acide benzoique 2-substitue en tant qu'agoniste du recepteur hm74a
US7666888B2 (en) 2006-07-20 2010-02-23 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11β-HSD-1

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2434794A (en) * 2006-02-03 2007-08-08 Prom Ltd Continuous process for forming anthranilic acid and treatment of waste water containing organic material

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Publication number Priority date Publication date Assignee Title
JPS5970654A (ja) * 1982-10-15 1984-04-21 Nippon Redarii Kk アントラニル酸誘導体
JPS6097946A (ja) * 1983-11-01 1985-05-31 Ono Pharmaceut Co Ltd カルボキサミド誘導体
EP0524781A1 (fr) * 1991-07-25 1993-01-27 Zeneca Limited Amides thérapeutiques
WO1994022807A1 (fr) * 1993-04-07 1994-10-13 Neurosearch A/S Derives ureiques et amidiques et leur utilisation dans la regulation des canaux a potassium des membranes cellulaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5970654A (ja) * 1982-10-15 1984-04-21 Nippon Redarii Kk アントラニル酸誘導体
JPS6097946A (ja) * 1983-11-01 1985-05-31 Ono Pharmaceut Co Ltd カルボキサミド誘導体
EP0524781A1 (fr) * 1991-07-25 1993-01-27 Zeneca Limited Amides thérapeutiques
WO1994022807A1 (fr) * 1993-04-07 1994-10-13 Neurosearch A/S Derives ureiques et amidiques et leur utilisation dans la regulation des canaux a potassium des membranes cellulaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 8422, Derwent World Patents Index; Class B05, AN 84-137183, XP002080859 *
DATABASE WPI Section Ch Week 8528, Derwent World Patents Index; Class B03, AN 85-168505, XP002080860 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002048131A1 (fr) * 2000-12-12 2002-06-20 Aventis Pharma Deutschland Gmbh Amides d'acides furane et thiophene carboxyliques aryles ayant un effet de blocage de canal de potassium
US6982279B2 (en) 2000-12-12 2006-01-03 Aventis Pharm Deutschland Gmbh Arylated furan- and thiophenecarboxamides, processes for their preparation, their use as medicaments, and pharmaceutical preparations comprising them
EP1565190A2 (fr) * 2002-11-22 2005-08-24 Bristol-Myers Squibb Company Amides arylcyclopropylcarboxyliques utilises en tant qu'agents d'ouverture des canaux potassiques
EP1565190A4 (fr) * 2002-11-22 2006-04-26 Bristol Myers Squibb Co Amides arylcyclopropylcarboxyliques utilises en tant qu'agents d'ouverture des canaux potassiques
EP1670749A1 (fr) * 2003-08-14 2006-06-21 Smithkline Beecham Corporation Derives d'acide benzoique 2-substitue en tant qu'agoniste du recepteur hm74a
US7666888B2 (en) 2006-07-20 2010-02-23 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11β-HSD-1

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EP1003713A1 (fr) 2000-05-31
BR9811828A (pt) 2000-08-15
AU734786B2 (en) 2001-06-21
CA2297409A1 (fr) 1999-02-18
AU8679598A (en) 1999-03-01
JP2001513527A (ja) 2001-09-04
CN1265643A (zh) 2000-09-06

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