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WO1997048682A1 - Derives heterocyclylmethylamino de cyclobutene-3,4-diones modulateurs du canal de potassium - Google Patents

Derives heterocyclylmethylamino de cyclobutene-3,4-diones modulateurs du canal de potassium Download PDF

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Publication number
WO1997048682A1
WO1997048682A1 PCT/US1997/009744 US9709744W WO9748682A1 WO 1997048682 A1 WO1997048682 A1 WO 1997048682A1 US 9709744 W US9709744 W US 9709744W WO 9748682 A1 WO9748682 A1 WO 9748682A1
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Prior art keywords
carbon atoms
pharmaceutically acceptable
acceptable salt
compound
cyclobut
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PCT/US1997/009744
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English (en)
Inventor
David Richard Herbst
John Anthony Butera
Russell Francis Graceffa
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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 BR9709905A priority Critical patent/BR9709905A/pt
Priority to AU33017/97A priority patent/AU727217B2/en
Priority to NZ332859A priority patent/NZ332859A/en
Priority to EP97928856A priority patent/EP0906282A1/fr
Priority to IL12726197A priority patent/IL127261A0/xx
Priority to JP10503051A priority patent/JP2000512655A/ja
Publication of WO1997048682A1 publication Critical patent/WO1997048682A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • 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
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to novel heterocyclylmethylamino derivatives of cyclobutene 3-4-diones 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 modulation.
  • disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, cerebral vascular disease and hypertension.
  • Stemp et al. disclose a class of amino substituted cyclobutenedione derivatives of chromans described as having blood pressure lowering activity and bronchodilatory activity. Takeno et al. report a series of diaminocyclobuten-3,4-diones in Public Patent Disclosure Bulletin No. 6-92915. Our own efforts in this area have been disclosed in the following US Patents: 5,464,867;
  • a 4-pyridinylmethylamino derivative of cyclobutendione was disclosed by Chandrakumar et al. in US Patent 5,354,746 to possess analgesic activity.
  • the compounds of the Chandrakumar series require the presence of a tricyclic dibenzoxazepine moiety.
  • a 3-pyridinylmethylamino derivative of cyclobutendione was disclosed by Ife in EP- 112704 and was reported to be an H-2 antagonist.
  • the compounds of the Ife series require the presence of an N'-pyridyl-diamino moiety.
  • Ri and R.2 are, independently, hydrogen, straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, bicycloalkyl of 4 to 10 carbon atoms or aralkyl of 7 to 20 carbon atoms, wherein the aromatic moiety of the aralkyl group may be optionally substituted with one to three straight chain alkyl of 1 to 10 carbon atoms, branched chain alkyl of 1 to 10 carbon atoms, halogen, nitro, cyano, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 7 carbon atoms, trifluoromethyl or trifluoromethoxy groups;
  • R3 is hydrogen, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkyl- sulfonyl of 7 to 12 carbon atoms;
  • A is selected from the group consisting of:
  • n is 0 or 1 ;
  • R ⁇ R5 and R6 are, independently, cyano, nitro, amino, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy, of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, sulfamyl, alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 12 carbon atoms, alkyl- carboxamido of 2 to 7 carbon atoms, arylcarboxamido of 7 to 13 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl- sulfonyl of 1 to 6 carbon atoms, perfluoroalkylsulfonyl of 1 to
  • a preferred aspect of this invention includes compounds of formula (I) wherein:
  • Rl and R2 are as stated above; R3 is hydrogen; A is selected from the following:
  • R ⁇ R5 and R6 are as defined above; or a pharmaceutically acceptable salt thereof.
  • Ri and R2 are, independently, hydrogen, methyl, ethyl, n- or iso-propyl, n-, iso, sec- or tert-butyl, straight or branched chain pentyl, or phenylalkyl in which the alkyl is methylene or ethylene and in which the phenyl moiety may be optionally substituted with one to three substituents selected from methyl, ethyl, fluorine, chlorine, bromine, nitro, cyano, methoxy, ethoxy, methoxyoxycarbonyl, ethoxyoxycarbonyl, trifluoromethyl and trifluoromethoxy.
  • R3 is preferably hydrogen. Preferably n is 0.
  • R4, R5 and R6 are, independently, hydrogen, cyano, nitro, amino, methyl, methoxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethoxy or carboxyl.
  • R2, R3, R4, R5 or R6 contain asymmetric chiral centers, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of formula (I). The compounds of this invention, throughout this specification, are equivalently named as 3,4-diones or 1,2-diones.
  • 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, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • R4, R5 or R6 contains a carboxyl group
  • salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).
  • the present invention also provides a process for the preparation of a compound of formula (I). More particularly, the compounds of formula (I) may be prepared by reacting a compound of formula (II):
  • X is a suitable leaving group, for example, methoxy, ethoxy, isopropoxy, butoxy, halogen or a similar leaving group with a compound of formula (III):
  • a j is A as defined hereinbefore or a group of atoms convertible thereto.
  • the reactions mentioned above may be carried out in a solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran or dioxane at elevated or ambient temperatures.
  • a compound of formula (II) may be allowed to react initially with a compound of formula (IV), The subsequent intermediate may then be allowed to react with a compound of formula (III) as described hereinbefore, to give the compounds of formula (I).
  • the compounds of formula (I) and their pharmaceutically acceptable salts are smooth muscle relaxants functioning via potassium channel activation. 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. Furthermore, the compounds of formula (I) are, as potassium channel activators, useful for treatment of peripheral vascular disease, hypertension, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.
  • 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 pharmaceutical or 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.
  • Acetone oxime (6.34 g, 86.64 mmol) was added to a suspension of sodium hydride (as a 80% dispersion in mineral oil; 2.72 g, 90.82 mmol) in N, N- dimethylformamide (400 mL) at 0°C. The frothy suspension was stirred for 1 hour as the mixture was warmed to 25°C. p-Fluorobenzonitrile (10.00 g, 82.51 mmol) was added and the reaction mixture was stirred at 0°C for 15 minutes and then allowed to warm to room temperature. After stirring overnight, the reaction mixture was poured into brine (300 mL).
  • Example 11 To a solution of the product of paragraph 6 in Example 11 (0.250 g, 0.79 mmol ) in ethanol (17 mL) was added tert-butyl amine (0.17g, 2.37 mmol). The reaction mixture was heated at 70°C and allowed to stir overnight. The solid which had formed was filtered and washed with ethyl acetate, diethyl ether, and hexane.
  • Sprague-Dawley rats (150-200 g) are rendered unconscious by CO2 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, 1 18.4; 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% O2; 2/5% CO 2 ; pH 7.4.
  • PES physiological salt solution
  • 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 uM 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.
  • the isometric force developed by the bladder strips is measured using a concentration required to elicit 50% inhibition of pre-drug contractile activity (IC50 concentration) and is calculated from this concentration-response curve.
  • IC50 concentration concentration required to elicit 50% inhibition of pre-drug contractile activity
  • the maximum percentage inhibition of contractile activity evoked by a test compound is also recorded for concentrations of test compound less than or equal to 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.
  • 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
  • Spontaneous activity mean amplitude of bladder pressure fluctuations during filling
  • 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.
  • 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 compounds by administration, orally, parenterally, or by aspiration to a patient in need thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Composés définis par la formule (I) dans laquelle R1 et R2 sont indépendamment l'hydrogène, un alkyle à chaîne linéaire, un alkyle, le cycloalkyle, bicycloalkyle, ou aralkyle à chaîne ramifiée, la fraction aromatique du groupe aralkyle pouvant être éventuellement substituée par un à trois groupes à chaîne linéaire alkyle, halogène, nitro, cyano, alkoxy, alkoxycarbonyle, trifluorométhyle ou trifluorométhoxy; R3 est l'hydrogène, un formyle, l'alkanoyle, alkénoyle, alkylsulfonyle, aroyle, arylalkenoyle, arylsulfonyle, arylalkanoyle ou arylalkylsulfonyle; A est sélectionné dans un groupe composé de (a), (b), (c), (d) et (e), dans lequel n est 0 ou 1; R4, R5 et R6 sont indépendamment un cyano, nitro, amino, alkyle, perfluoroalkyle, alkoxy, perfluoroalkoxy, alkylamino, dialkylamino, sulfamyl, alkylsulfonamido, arylsulfonamido, alkylcarboxamido, arylcarboxamido, alkanoyle, alkylsulfonyle, perfluoroalkylsulfonyle, arylsulfonyle, chloro, bromo, fluoro, iodo, 1-imidazolyle. carboxyle ou hydrogène; ou un sel pharmaceutiquement acceptable de ces derniers, relaxant les muscles lisses.
PCT/US1997/009744 1996-06-17 1997-06-10 Derives heterocyclylmethylamino de cyclobutene-3,4-diones modulateurs du canal de potassium WO1997048682A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR9709905A BR9709905A (pt) 1996-06-17 1997-06-10 Derivados de heterociclilmetilamino de ciclobuteno-3,4-dionas como moduladores do canal de potássio
AU33017/97A AU727217B2 (en) 1996-06-17 1997-06-10 Heterocyclylmethylamino derivatives of cyclobutene-3,4- diones as potassium channel modulators
NZ332859A NZ332859A (en) 1996-06-17 1997-06-10 pyridinyl, pyrimidinyl or benzofuranyl methylamino substituted cyclobutene-3,4-dione derivatives
EP97928856A EP0906282A1 (fr) 1996-06-17 1997-06-10 Derives heterocyclylmethylamino de cyclobutene-3,4-diones modulateurs du canal de potassium
IL12726197A IL127261A0 (en) 1996-06-17 1997-06-10 Heterocyclylmethylamino derivatives of cyclobutene-3,4- diones as potassium channel modulators
JP10503051A JP2000512655A (ja) 1996-06-17 1997-06-10 カリウムチャネル変調物質としてのシクロブテン―３，４―ジオンの複素環式メチルアミノ誘導体

Applications Claiming Priority (2)

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US66458396A 1996-06-17 1996-06-17
US08/664,583 1996-06-17

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WO1997048682A1 true WO1997048682A1 (fr) 1997-12-24

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PCT/US1997/009744 WO1997048682A1 (fr) 1996-06-17 1997-06-10 Derives heterocyclylmethylamino de cyclobutene-3,4-diones modulateurs du canal de potassium

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EP (1) EP0906282A1 (fr)
JP (1) JP2000512655A (fr)
KR (1) KR20000016815A (fr)
CN (1) CN1227543A (fr)
AR (1) AR008238A1 (fr)
AU (1) AU727217B2 (fr)
BR (1) BR9709905A (fr)
CA (1) CA2258536A1 (fr)
IL (1) IL127261A0 (fr)
NZ (1) NZ332859A (fr)
TW (1) TW442473B (fr)
WO (1) WO1997048682A1 (fr)
ZA (1) ZA975287B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006237A1 (fr) * 2000-07-18 2002-01-24 Yamanouchi Pharmaceutical Co., Ltd. Medicament comprenant un derive de dicyanopyridine
US6495576B2 (en) 2001-02-07 2002-12-17 Abbott Laboratories Aminal diones as potassium channel openers
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof

Citations (6)

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Publication number Priority date Publication date Assignee Title
EP0112142A2 (fr) * 1982-12-14 1984-06-27 Smith Kline & French Laboratories Limited Dérivés de pyridine
US4673747A (en) * 1984-06-01 1987-06-16 Ikeda Mohando Co., Ltd. Aminoalkylphenoxy derivatives
JPH0692915A (ja) * 1992-07-28 1994-04-05 Sumitomo Metal Ind Ltd １，２−ジアミノシクロブテン−３，４−ジオン誘導体及びその用途
US5397790A (en) * 1993-11-17 1995-03-14 American Home Products Corporation Substituted isoquinolinyl-1-2-diaminocyclobutene-3,4,-diones
US5464867A (en) * 1994-11-16 1995-11-07 American Home Products Corporation Diaminocyclobutene-3,4-diones
US5466712A (en) * 1994-11-04 1995-11-14 American Home Products Corporation Substituted n-aryl-1,2-diaminocyclobutene-3,4-diones

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112142A2 (fr) * 1982-12-14 1984-06-27 Smith Kline & French Laboratories Limited Dérivés de pyridine
US4673747A (en) * 1984-06-01 1987-06-16 Ikeda Mohando Co., Ltd. Aminoalkylphenoxy derivatives
JPH0692915A (ja) * 1992-07-28 1994-04-05 Sumitomo Metal Ind Ltd １，２−ジアミノシクロブテン−３，４−ジオン誘導体及びその用途
US5397790A (en) * 1993-11-17 1995-03-14 American Home Products Corporation Substituted isoquinolinyl-1-2-diaminocyclobutene-3,4,-diones
US5403854A (en) * 1993-11-17 1995-04-04 American Home Products Corporation Substituted N-heteroaryl -1,2-diaminocyclobutene-3,4-diones
US5403853A (en) * 1993-11-17 1995-04-04 American Home Products Corporation Substituted N-aryl-1,2-diaminocyclobutene-3,4-diones
US5466712A (en) * 1994-11-04 1995-11-14 American Home Products Corporation Substituted n-aryl-1,2-diaminocyclobutene-3,4-diones
US5464867A (en) * 1994-11-16 1995-11-07 American Home Products Corporation Diaminocyclobutene-3,4-diones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 018, no. 361 (C - 1222) 7 July 1994 (1994-07-07) *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006237A1 (fr) * 2000-07-18 2002-01-24 Yamanouchi Pharmaceutical Co., Ltd. Medicament comprenant un derive de dicyanopyridine
US6495576B2 (en) 2001-02-07 2002-12-17 Abbott Laboratories Aminal diones as potassium channel openers
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9453007B2 (en) 2010-12-22 2016-09-27 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9567355B2 (en) 2010-12-22 2017-02-14 Abbvie Inc. Hepatitis C inhibitors and uses thereof

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AU3301797A (en) 1998-01-07
NZ332859A (en) 2000-06-23
JP2000512655A (ja) 2000-09-26
AU727217B2 (en) 2000-12-07
CA2258536A1 (fr) 1997-12-24
BR9709905A (pt) 1999-08-10
EP0906282A1 (fr) 1999-04-07
TW442473B (en) 2001-06-23
ZA975287B (en) 1998-12-14
IL127261A0 (en) 1999-09-22
AR008238A1 (es) 1999-12-29
CN1227543A (zh) 1999-09-01
KR20000016815A (ko) 2000-03-25

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