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WO1992019211A2 - Imidazobenzoquinones et composition contenant ces dernieres permettant de prevenir ou de traiter l'hypertension ou l'insuffisance cardiaque - Google Patents

Imidazobenzoquinones et composition contenant ces dernieres permettant de prevenir ou de traiter l'hypertension ou l'insuffisance cardiaque Download PDF

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Publication number
WO1992019211A2
WO1992019211A2 PCT/US1992/003440 US9203440W WO9219211A2 WO 1992019211 A2 WO1992019211 A2 WO 1992019211A2 US 9203440 W US9203440 W US 9203440W WO 9219211 A2 WO9219211 A2 WO 9219211A2
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WO
WIPO (PCT)
Prior art keywords
methyl
dione
butyl
tetrazol
biphenyl
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PCT/US1992/003440
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English (en)
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WO1992019211A3 (fr
Inventor
Keiko Koh
Noriie Itoh
Kazunori Ozawa
Hiroshi Kushida
William W. Mcwhorter, Jr.
Original Assignee
The Upjohn Company
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 to JP3346283A priority Critical patent/JPH05112533A/ja
Application filed by The Upjohn Company filed Critical The Upjohn Company
Priority to US08/122,445 priority patent/US5506361A/en
Priority to JP4510074A priority patent/JPH06507620A/ja
Priority to EP92910914A priority patent/EP0586466A1/fr
Priority to AU17848/92A priority patent/AU650342B2/en
Publication of WO1992019211A2 publication Critical patent/WO1992019211A2/fr
Publication of WO1992019211A3 publication Critical patent/WO1992019211A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel imidazobezoquinone or a pharmacologically acceptable ester or salt thereof and a pharmaceutical composition for preventing or treating hypertension or congestive heart failure which contains the same as an active ingredient.
  • Renin-Angiotensin-Aldosterone system is closely connected with hypertensive pathogeny or pathemia through control of blood pressure and amount of fluid or electrolyte.
  • hypertension including essential hypertension
  • further congestive heart failure by controlling this system have been studied for a long time.
  • angiotensinogen an enzyme which converts angiotensin (I) into angiotensin (II) having strong vasoconstriction action, aldosterone secretion stimulating action, sympathetic nerve function promoting action and the like
  • angiotensin converting enzyme: ACE angiotensin converting enzyme
  • ACE inhibitors are not selective and act toward other systems such as kalliklein-kinin system and the like, there is a clinical problem in that the side effects such as skin rash and dry -cough occur more frequently. For this reason, many attempts to develop a renin inhibitor, which is thought to be more selective, have been tried, but have not successfully been marketed.
  • imidazoquinones are effective, resulting in the present invention.
  • Common quinone structures in the present invention is similar to those of vitamin A, vitamin K, ubiquinone and the likes, and these are known to have the lipidperoxidation inhibiting action. This shows that having both of Ang-II antagonist and lipidperoxidation inhibiting action works more effectively on treatment of hypertension for a long period of time, taking into consideration that the lipidperoxidation inhibiting action is effective for inhibiting development of arterial sclerosis and there is the closer relationship between arterial sclerosis and hypertension.
  • a number of imidazo containing moieties are disclosed as useful in the treatment of hypertension as described above, see, e.g., Japanese Kokai 78/148,788; 81/71,073; 82/98,270 and 83/157,768; published European patent applications EPA 253310; 291969; 392317; 400835; 399732; 399731; 400974; and 415886.
  • EP 400974 discloses imidazoquinones among a wide variety of other possibilities.
  • the present invention provides an imidazobenzoquinone represented by the general formula [1]:
  • R 1 is hydrogen atom, a C 1 -C 8 alkyl group, a C 2 -C 8 alkenyl group, a C 2 -C 8 alkynyl group, -CF 3 group, an aryl group or an aralkyl group;
  • X is oxygen atom or a group of the formula N-OR 6 , N-NHR 5 , or CR 7 R 8 ;
  • Y is a 1H-tetrazol-5-yl group or an alkali metal salt thereof, a -CO 2 R 4 group, a -CONR'R" group or a -CONHSO 2 R 5 group;
  • R 2 and R 3 are independently hydrogen atom, an optionally substituted C 1 -C 8 alkyl group, a C 1 -C 8 alkoxy group, -CN, a
  • R 4 is hydrogen atom, alkali metal or a C 1 -C 8 alkyl group
  • R 5 is a C 1 -C 8 alkyl group, a C 3 -C 10 cycloalkyl group or an aryl group;
  • R 6 is hydrogen atom or a C 1 -C 8 alkyl group optionally substituted by Y;
  • R 7 and R 8 are independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, CF 3 , aryl, or aralkyl, or R 7 and R 8 together form an alicyclic structure,
  • R' and R" are independently hydrogen atom or a C 1 -C 8 alkyl group, or R' and R" together form an alicyclic structure; and n is 0, 1 or 2,
  • compositions for preventing or treating hypertension or congestive heart failure which comprises as an active ingredient an imidazobenzoquinone of the general formula [1] or pharmacologically acceptable ester or salt thereof.
  • imidazobenzoqunones which have high activity to hypertension or congestive heart failure, are well abdsorbed into the body upon administration and have long-lasting action. Further, a pharmaceutical composition for preventing or treating hypertension or congestive heart failure containing the same.
  • the carbon atom content of the carbon containing moieties is indicated by a prefix "C i - C j " wherein i is the lowest number of carbon atoms and j is the highest number of carbon atoms.
  • R 1 in the general formula [1] there are an alkyl group having from 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
  • lower alkenyl group there are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl and the like.
  • lower alkynyl group there are an acetylene group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl and the like.
  • aryl group or aralkyl group there .are those having from 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like.
  • These aryl or aralkyl groups may be optionally substituted by substituents such as the lower alkyl group described above, or lower alkoxy group, a halogen atom, nitro group, cyano group and the like.
  • examples of the alkali metal salt are sodium, potassium salt and the like.
  • examples of R 4 in the e -CO 2 R 4 group are a hydrogen atom, an alkali metal, a lower alkyl group.
  • examples of the alkali metal salt are sodium, potassium salt and the like.
  • Examples of the lower alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
  • NR'R" in the -CONR'R” group are amino, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, diisopropylamino, dibutylamino, pyrrolidinyl, piperazino, morpholino and the like.
  • R 5 in the -CONHSO 2 R 5 group are methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like.
  • R 2 or R 3 represents the lower alkyl group
  • the -CO 2 R 4 group, the -CONR'R" group or the -CONHSO 2 R 5 group examples of them are the same as described above about R 1 , R 4 , NR'R" and R 5 .
  • R 2 or R 3 is the substituted lower alkyl group
  • examples of them are hydroxymethyl, carboxy methyl, 2-carboxy ethyl, 3-carboxy-n-propyl, 4-carboxy-n-butyl, 2-hydroxyethyl, 3-hydroxy-n-propyl, 4-hydroxy-n-butyl and the like.
  • the lower alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
  • R 2 and R 3 taken together represent the aromatic or heterocyclic ring
  • examples of the aromatic ring are benzene ring or naphthalene ring
  • examples of the heterocyclic ring are pyridine ring, pyrimidine ring, furan ring or thiophene ring.
  • These aromatic and heterocyclic rings may be optionally substituted by a halogen atom, a lower alkyl group, CF 3 a lower alkoxy group, -CN, a -CO 2 R 4 group, a -COR'R" group, a -SO 3 H group or an alkali metal salt thereof, a -SO 2 NHR 5 group.
  • Examples of these lower alkyl group, lower alkoxy group, -CO 2 R 4 group, -CONHR'R" group, -CONHSO 2 R 5 group, -SO 2 NHR 5 group are the same as those described above.
  • examples of the lower alkyl group, the lower alkenyl group, the lower alkynyl group, the aryl group and the aralkyl group represented by R 1 ' as well as examples of the lower alkyl group represented by R 2 ' and R 3' are as described about R 1 .
  • examples of the optionally substituted alkyl and lower alkoxy groups are as described about R 2 and R 3 .
  • Additional compounds of this invention include:
  • the imidazobenzoquinones of the present invention can form a pharmacologically acceptable ester at a part of R 2 , R 3 or Y in the general formula [1], or at a part of X 1 or X 2 in the general formulas [1a-d].
  • the formed esters there are methoxvcarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl or t-butoxycarbonyl.
  • imidazobenzoquinones of the present invention can form a pharmacologically acceptable salt at a part of imidazole in the general formula [1] when Y is -CO 2 R 4 , -CONR'R".
  • a salt there are hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate and the like.
  • Y is the 1H-tetrazol-5-yl in the general formula [1]
  • they can form an alkali metal salt at a part of the 1H-. In both of cases, these salts may be in the form of a hydrate.
  • Imidazobenzoquinones represented by the general formula [1] can be prepared, for example, according to the following scheme.
  • X 1 and X 2 are a hydrogen atom, a halogen atom, a lower alkyl group, -CF 3 , a lower alkoxy group, -CN, -CC 2 R 4 , a
  • R 4 , R', R" and R 5 are as defined above.
  • the compound [2a] which is used in this process is synthesized according to the method reported by J. R. E. Hoover, A. R. Daty in J. Am. Chem. Soc, 76, 4151 (1954). That is, after 2-amino-3-chloro-1,4-naphthoquinone [3a] is subjected to the conventional acylation reaction, a chloro atom is converted into an amino group by treating with ammmmonia gas at about 150°C, and further an intramolecular cyclization reaction is carried under the basic condition to obtain the compound [2a] at high yield.
  • the compound [4] obtained by reacting a hydroquinone derivative and benzenesulfonyl chloride according to the process by E. M. Kampouris (J. Chem. Soc. (c), 1967, 1235) is used as a starting material.
  • Benzyl chloride can be used as a protecting group for phenols instead of benzenesulfonyl chloride.
  • a desirable protecting group must be selected in view of subsequent reactions and the like.
  • the compound [4] can be converted into the dinitro [5a] and/or mononitro [5b] compounds by reacting with fuming nitric acid according to the above-described method.
  • the compound [5a] can be converted into a corresponding diamine by reduction using sodium dithionite, conventional catalytic reduction or reduction using a metal, for example, zinc-acetic acid, zinc-potassium chloride-ethanol/water.
  • the diamine can be converted into the compound [6] according to the reaction by heating with an orthoester which is widely known as the imidazole synthesizing method.
  • the compound [7] can be converted into the imidazoquinone [2b] by subjecting a conventional hydrolysis reaction into a corresponding hydroquinone with an alcoholic solution of sodium or potassium hydroxide, then subjecting to the oxidation reaction.
  • the above-described mononitro compound [5b] can be similarly converted into the compound [7] by reduction reaction and acylating reaction.
  • the compound [7] can be converted into compound [8] using again nitration reaction and reduction reaction.
  • the compound [8] can be synthesiz-ed also by acylating a diamine obtained by reducing the compound [5a].
  • the compound [8] can be converted into the diaminoquinone [9] by subjecting to hydrolysis reaction and then oxidation reaction, and the compound [9] can be fused into an imidazole ring according to the method by J. R. E. Hoover described above.
  • the compound [7] itself can be converted into the compound [3b] by halogenation reaction after hydrolysis and oxidation reaction into a monoaminoquinone.
  • the synthesis of the imidazoquinone [2b] from the compound [3b] via the compound [9] may be carried out according to the method by J. R. E. Hoover.
  • Imidazobenzoquinones in the general formula [1] wherein X is oxygen atom can be derived into a monooxime, for example, by heating with a hydrochloride of hydroxylamine, alkoxyamine and the like in pyridine.
  • a membrane fraction was prepared from mesenteric artery of a male rat, 50 ⁇ g protein equivalent thereof and 0.2 nM 125 I-Ang II as well as various concentrations of test compounds were incubated at 22°C for 90 min. in 200 ⁇ l reaction volume of incubation buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl 2 , 0.25% bovine serum albumin, pH7.2).
  • test compound was tested at the concentration of 0.01 to 1 ⁇ M, and those that inhibited more than 50 % of total specific binding amount at 1 ⁇ M was determined as an active compound, and 50% inhibiting concentration (IC 50 ) was obtained [see Gunther, S., Gimbrone, M.A. and Alexander, R.W., Circ. Res., 17:278-286, 1980].
  • angiotensin II receptor binding assay was carried out by preparing a membrane fraction from an adrenal cortex of a male rat and using this as a receptor material in the same manner as in the above-described pharmacological test 1) [see Capponi, A. M. and Catt, K., J. Biol. Chem. 254:5120-5127(1979)].
  • a rectangular strip-like sample of thoracic aorta isolated from an anethetized rabbit was prepared, and this was suspended at 2.0 g of loaded tension in a Magnus tube filled with KrebsHenseleitoid nutrition solution which was well aerated with 95% O 2 -5% CO 2 , and the constriction tension was measured using an isometric transducer. After the tension of the sample at rest became stable, accumulative administration of angiotensin II was carried out to obtain a concentration-action curve. Thereafter, the sample was washed with the same nutrition solution, and then 10 - 6 M test compound was treated for 20 min. to obtain again a
  • Wistar rat anesthetized with pentobarbital was fixed at dorsal position, and a cannula for measuring blood pressure was inserted into sinister arteria carotis communis, and a cannula for administration of the test compound into dexter external jugular vein and a cannula for administration of angiotensin II into sinister external jugular vein, ambilateral nervous vagus was cut, and artificial respiration was carried out.
  • a thin bar made of metal was stabbed into spinal column through sininster orbita to destroy spine. Blood pressure was recorded on polygraph via pressure transducer from an arterial cannula.
  • angiotensin II was administered intravenously four times every 15 min., and every 5 min. before the administration of angiotensin II from the second admininstration onward, a solvent, a lower dose of the test compound, and a higher dose of the test compound were admininstered intravenously in this order to observe the blood pressure increasing response by angiotensin II.
  • ED 50 values were calculated from the inhibiting rate when the first blood pressure increase by angiotensin II was regarded as 100%.
  • the compounds of the present invention showed high activity.
  • the imidazobenzoquinones or pharmacologically acceptable esters or salts thereof can be formulated, by a conventional method, into a dosage unit forms such as tablets, capsules. pills, powders, granules, powder packet, cachets, sterile parenteral solutions or suspensions. eyedrops, solutions or suspensions, elixirs, suppositories, aerosols and emulsions which contains them in a predetermined amount.
  • solid or fluid unit dosage form can be prepared.
  • the active compound is mixed with an excipient or a carrier such as magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulphate, starch, lactose, acacia, methyl cellulose and the like.
  • a capsule agent is prepared by mixing the compound of the present invention with an inert pharmaceutical excipient, filling the mixture into a hard gelatin capsule having suitable size.
  • a soft gelatin capsule is prepared by machine capsulation of slurry composed of the compound, suitable vegetable oil, light petrolatum or other inert oil.
  • the compound of the present invention is dissolved in aqueous vehicle together with sugar, aromatic flavor and preservative to obtain a syrup.
  • Elixirs are prepared using an alcoholic vehicle such as ethanol, a sweetener such as sugar and saccharin as well as a flavor.
  • Suspensions are prepared using a suspending agent such as acacia, tragacanth or methyl cellulose and an aqueous vehicle.
  • a fluid unit dosage form is prepared using the compound of the present invention and a sterile vehicle.
  • a vehicle such as water, Ringer's solution, isotonic sodium chloride solution and the concentration to be used
  • the compound is suspended or dissolved in the vehicle.
  • the compound is dissolved in water for injection, and this is sterile filtered, filled into a vial or an ampoule., and sealed.
  • an adjuvant such as local anesthetic, preservative and buffer is dissolved in vehicle.
  • a lyophilized powder having good shelf stability can be prepared. In the case of this formulation, the powder is reconstituted upon use.
  • Parenteral suspensions can be similarly prepared using the compound of the present invention.
  • the compound of the present invention can be sterilized by exposure to ethylene oxide before suspended in a sterile vehicle.
  • a surfactant or a wetting agent is added to facilitate dispersion of the compound.
  • the compound of the present invention can be formulated into a local dosage form in combination with a suitable carrier for local administration.
  • a suitable carrier for local administration.
  • a carrier to be used are cream, ointment, lotion, paste, jelly, spray, aerosol and the like.
  • suppositories can be prepared.
  • a base are cacao butter, polyethylene glycol, polyethylene sorbitan monostearate and the like.
  • Imidazobenzoquinones or pharmacologically acceptable esters or salts thereof are administered orally, parenterally by insufflation, rectally, locally.
  • Parenteral administration includes subcutaneous, intravenous, intramuscular, intranasal adminstration or injection.
  • Dose to be administered to an adult is in a range of 1 to 50 mg/day. The exact dose can be selected from the above range, taking into account the age of patient, weight, condition and route of administration into consideration. Frequency of administration is usually one to four times a day.

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composés actifs au niveau pharmacologique qui sont très efficaces pour traiter l'hypertension ou l'insuffisance cardiaque, qui sont bien absorbées dans le corps et qui ont un effet durable. Cette invention concerne donc un composé représenté par la formule (I) ou un ester pharmacologiquement acceptable ou un de ses sels, et une composition pharmacologique permettant de prévenir ou de traiter l'hypertension ou l'insuffisance cardiaque, qui contient ledit composé en tant qu'ingrédient actif.
PCT/US1992/003440 1991-05-08 1992-04-30 Imidazobenzoquinones et composition contenant ces dernieres permettant de prevenir ou de traiter l'hypertension ou l'insuffisance cardiaque WO1992019211A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP3346283A JPH05112533A (ja) 1991-05-08 1991-12-27 イミダゾベンゾキノン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤
US08/122,445 US5506361A (en) 1991-05-08 1992-04-30 Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same
JP4510074A JPH06507620A (ja) 1991-05-08 1992-04-30 イミダゾベンゾキノン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤
EP92910914A EP0586466A1 (fr) 1991-05-08 1992-04-30 Imidazobenzoquinones et composition contenant ces dernieres permettant de prevenir ou de traiter l'hypertension ou l'insuffisance cardiaque
AU17848/92A AU650342B2 (en) 1991-05-08 1992-04-30 Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP10263991 1991-05-08
JP3/102639 1991-05-08
JP14005791 1991-06-12
JP3/140057 1991-06-12
JP3/205879 1991-08-16
JP20587991 1991-08-16
JP3/346283 1991-12-27
JP3346283A JPH05112533A (ja) 1991-05-08 1991-12-27 イミダゾベンゾキノン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤

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WO1992019211A2 true WO1992019211A2 (fr) 1992-11-12
WO1992019211A3 WO1992019211A3 (fr) 1993-01-21

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JP (2) JPH05112533A (fr)
AU (1) AU650342B2 (fr)
CA (1) CA2106968A1 (fr)
MX (1) MX9202132A (fr)
WO (1) WO1992019211A2 (fr)

Cited By (16)

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WO1995032198A1 (fr) * 1994-05-21 1995-11-30 Korea Research Institute Of Chemical Technology Derives d'imidazole et leurs procedes de preparation
FR2742154A1 (fr) * 1995-12-12 1997-06-13 Innothera Lab Sa Utilisation de derives de tetracycles mono ou dicetoniques, nouveaux composes obtenus et leur application en therapeutique
FR2742153A1 (fr) * 1995-12-12 1997-06-13 Innothera Lab Sa Utilisation de derives tricycliques du 1,4-dihydro-1,4- dioxo-1h-naphtalene, nouveaux composes obtenus et leur application en therapeutique
FR2742155A1 (fr) * 1995-12-12 1997-06-13 Innothera Lab Sa Utilisation de derives heteroaromatiques et tricycliques du 1,4-dihydro-1,4-dioxonaphtalene, nouveaux composes obtenus et leur application en therapeutique
WO2002034263A1 (fr) * 2000-10-25 2002-05-02 Takeda Chemical Industries, Ltd. Agents preventifs/remedes destines a l'hypertension portale
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US10450281B1 (en) 2014-02-25 2019-10-22 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
US10653676B2 (en) 2010-04-30 2020-05-19 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity

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WO2008096820A1 (fr) * 2007-02-07 2008-08-14 Kyowa Hakko Kirin Co., Ltd. Dérivé diphényle
ES2449396T3 (es) * 2008-07-22 2014-03-19 Trustees Of Dartmouth College Cianoenonas monocíclicas y métodos de uso de las mismas

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WO1995032198A1 (fr) * 1994-05-21 1995-11-30 Korea Research Institute Of Chemical Technology Derives d'imidazole et leurs procedes de preparation
AU677524B2 (en) * 1994-05-21 1997-04-24 Korea Research Institute Of Chemical Technology Imidazole derivatives and processes for the preparation thereof
FR2742154A1 (fr) * 1995-12-12 1997-06-13 Innothera Lab Sa Utilisation de derives de tetracycles mono ou dicetoniques, nouveaux composes obtenus et leur application en therapeutique
FR2742153A1 (fr) * 1995-12-12 1997-06-13 Innothera Lab Sa Utilisation de derives tricycliques du 1,4-dihydro-1,4- dioxo-1h-naphtalene, nouveaux composes obtenus et leur application en therapeutique
FR2742155A1 (fr) * 1995-12-12 1997-06-13 Innothera Lab Sa Utilisation de derives heteroaromatiques et tricycliques du 1,4-dihydro-1,4-dioxonaphtalene, nouveaux composes obtenus et leur application en therapeutique
WO1997021684A1 (fr) * 1995-12-12 1997-06-19 Laboratoire Innothera, Societe Anonyme Utilisation de derives tricycliques du 1,4-dihydro-1,4-dioxo-1h-naphtalene, nouveaux composes obtenus et leur application en therapeutique
WO1997021709A1 (fr) * 1995-12-12 1997-06-19 Laboratoire Innothera Utilisation de derives de tetracycles mono ou dicetoniques, nouveaux composes obtenus et leur application en therapeutique
WO1997021710A1 (fr) * 1995-12-12 1997-06-19 Laboratoire Innothera Utilisation de derives heteroaromatiques et tricycliques du 1,4-dihydro-1,4-dioxo-naphtalene, nouveaux composes obtenus et leur application en therapeutique
US5981544A (en) * 1995-12-12 1999-11-09 Laboratoire Innothera Mono-- or diketone tetracyclic derivatives and therapeutical uses thereof
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US6262095B1 (en) 1995-12-12 2001-07-17 Laboratoire Innothera Use of tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene, novel compounds obtained and their application in theraphy
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP2277519A2 (fr) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
WO2002034263A1 (fr) * 2000-10-25 2002-05-02 Takeda Chemical Industries, Ltd. Agents preventifs/remedes destines a l'hypertension portale
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
US10653676B2 (en) 2010-04-30 2020-05-19 Dana-Farber Cancer Institute, Inc. Small molecule inhibitors of USP1 deubiquitinating enzyme activity
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
US10450281B1 (en) 2014-02-25 2019-10-22 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer

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WO1992019211A3 (fr) 1993-01-21
AU650342B2 (en) 1994-06-16
JPH06507620A (ja) 1994-09-01
EP0586466A1 (fr) 1994-03-16
MX9202132A (es) 1993-04-01
AU1784892A (en) 1992-12-21
CA2106968A1 (fr) 1992-11-09
JPH05112533A (ja) 1993-05-07

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