+

WO1991011909A1 - Antagonistes de triazole angiotensine ii incorporant un element de benzyle substitue - Google Patents

Antagonistes de triazole angiotensine ii incorporant un element de benzyle substitue Download PDF

Info

Publication number
WO1991011909A1
WO1991011909A1 PCT/US1991/000963 US9100963W WO9111909A1 WO 1991011909 A1 WO1991011909 A1 WO 1991011909A1 US 9100963 W US9100963 W US 9100963W WO 9111909 A1 WO9111909 A1 WO 9111909A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
aryl
substituted
methyl
Prior art date
Application number
PCT/US1991/000963
Other languages
English (en)
Inventor
William J. Greenlee
Arthur A. Patchett
David Hangauer
Wallace T. Ashton
Kenneth J. Fitch
Thomas Walsh
Ralph A. Rivero
Daljit S. Dhanoa
Original Assignee
Merck & Co., Inc.
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
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO1991011909A1 publication Critical patent/WO1991011909A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur 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
    • C07D403/12—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 chain containing hetero atoms as chain links

Definitions

  • the Renin-angiotensin system plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure.
  • Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the reninangiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
  • ACE angiotensin converting enzyme
  • angiotensin II receptor antagonism One of the possible modes of controlling the RAS is angiotensin II receptor antagonism.
  • Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio. CIin. Exp.
  • Patents, European Applications or articles are substituted triazoles which are bonded through a methylene bridge to a novel substituted phenyl element.
  • DuPont also has filed a European Application (EPO 0,323,841) covering substituted pyrroles, pyrazoles and
  • triazoles The present invention covers novel antagonists which incorporate a novel substituted benzyl element linked to the triazole moiety.
  • novel substituted benzyl element linked to the triazole moiety.
  • the above cited applications are hereby incorporated by reference, serving as an information source as to the preparation of substituted triazoles.
  • a pending Merck application, Serial No. 382,138 discloses other novel triazoles and the synthetic routes to these triazoles are described in the Schemes 1-1 through 1-14 and the incorporation of the sustituted benzyl element is described in Schemes 1-15 through 1-30.
  • the compounds of this invention have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and
  • antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
  • these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia.
  • This invention relates to compounds of Formula I:
  • R 1 is :
  • aryl wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
  • R 2 and R 2a are alkyl substituents on the same nitrogen they can be joined to form a ring; and wherein there is more than one R 2a group in the definition of a structure of Formula I they may be the same or different;
  • R 9 and R 10 are independently:
  • X is:
  • Y is :
  • R 11 and R 12 are independently:
  • aryl-(C 1 -C 2 )-alkyl wherein the aryl group is unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
  • R 13 is:
  • M 1 is O, S, -N(R 15 )-, or -C(O)-; and z is 0 or 1; and r and t are 0 to 2; and
  • V and W are each independently selected from:
  • R 18 is:
  • R 24 groups are independently:
  • R 25 is:
  • alkyl substitutents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
  • alkenyl and alkynyl substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.
  • Cycloalkyl denotes rings composed of 3 to 8 methlene groups, each which may be substituted or unsubstitued with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
  • the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
  • aryl substituent recited above represents phenyl or naphthyl.
  • heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, for example, pyridyl, thienyl, furyl, imidazolyl, and thiazolyl.
  • the preferred compounds of this invention are:
  • N 1 and N 2 of the triazole ring are derived from hydrazine or a
  • the compounds of the present invention may be resolved using the techniques known in the art.
  • R 1 and R 16 represent functionalized or unfunctionalized alkyl, aryl, heteroaryl, aralkyl, and the like.
  • the moiety R 16 Q represents an alkylating agent in which R 16 is typically a functionalized or unfunctionalized alkyl or aralkyl group, while Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or
  • Scheme I-1 outlines some of the most widely applicable routes to compounds of Formula X in which either the 3- or 5-substituent is substituted thio.
  • an appropriate benzylamine 1 may be converted to dithiocarbamate ester 2 in a one-pot two-step sequence involving treatment with carbon disulfide in the presence of a base such as triethylamine followed by alkylation with methyl iodide.
  • Treatment of 2 with hydrazine (preferably in excess) affords the
  • thiosemicarbazide 3 This is also readily obtained upon reaction of hydrazine with the isothiocyanate 4, which in turn is prepared from amine 1 [for example, via an intermediate carbethoxy dithiocarbamate (J.E. Hodgkins and M.G. Ettlinger, J. Org. Chem., 21, 404 (1956)) or by one of the other methods known in the literature].
  • the acylthiosemicarbazide 5. may be prepared either by reaction of 2 with the appropriate acid chloride or anhydride or by addition of an acid hydrazide (readily obtained from the corresponding ester) to the isothiocyanate 4. As described in G.F. Duffin, J.D. Kendall, and H.R.J. Waddington, J. Chem. Soc., 3799 (1959), S.M.
  • acylthiosemicarbazides related to 5 can by cyclized in the presence of hydroxide or alkoxide to the mercaptotriazoles (best represented as triazolinethiones) corresponding to 6.
  • Compounds of type 6 can also be prepared by direct reaction of the thiosemicarbazide derivative 3 with an appropriate acid derivative. For example, reaction of 3 with a trimethyl
  • the S-alkylated mercaptotriazoles of structure 7 are obtained by treatment of the
  • a base such as a trialkylamine
  • the alkylation reaction is generally run at a temperature of from 0°C to 125°C, depending on the reactivity of the alkylating agent.
  • the triazolinethiones 6 may be prepared by alternative, routes. In the method of F. Malbec, R. Milcent, and G. Barbier [J. Heterocycl. Chem., 21, 1689 (1984)] (Scheme 1-2), the imidate hydrochloride 8 is reacted with thiosemicarbazide at ambient temperature to give the ester thiosemicarbazone 9. The conversion of 9 to the triazolinethione 6 can be effected by heating with amine 1 in DMF at reflux.
  • an N 4 -substituted ester thiosemicarbazone 9a which is obtained by reaction of 8 with 3, can be cyclized to 6 by heating in the presence of a base, e.g., 1,8-diazabicyclo ⁇ 5.4.0 ⁇ undec-7-ene (DBU), in a solvent such as tetrahydrofuran.
  • a base e.g., 1,8-diazabicyclo ⁇ 5.4.0 ⁇ undec-7-ene (DBU)
  • DBU 1,8-diazabicyclo ⁇ 5.4.0 ⁇ undec-7-ene
  • R 1 aryl, the method of T. Radha Vakula, V. Ranga Rao, and V.R. Srinivasan [Indian J. Chem., 7, 577
  • thiosemicarbazide derivative 3 is condensed with an aromatic aldehyde 10 to give the thiosemicarbazone 11. Upon treatment of 11 with bromine in acetic acid, the triazolinethione 12 is formed. SCHEME 1-3
  • the methylthiotriazole 15 may be prepared (by alkylation of 6 with methyl iodide) and
  • the S-substituted mercaptotriazoles 7 can be converted to the corresponding sulfoxides 17 and/or sulfones 18 by oxidation with various reagents such as hydrogen peroxide in acetic acid or a suitable peracid. Reactions of this type have been described by E.B. Akerblom and D.E.S. Campbell (see reference above). Whether 17 or 18 is the primary or exclusive product depends on the stoichiometry of the reagents, reaction time, and temperature. SCHEME I-7
  • Aminotriazoles of formula 24, where B is a single bond can be prepared as shown in Scheme 1-8.
  • An analogous route has been reported by E. Akerblom, Acta Chem. Scand., 19, 1135 (1965). Reaction of the isothiocyanate 4 with an appropriate amine gives the thiourea 21, which is alkylated with methyl iodide to give the isothiourea hydriodide 22.
  • acylaminoguanidine 23 obtained by reaction of 22 with a hydrazide in the presence of base, can be thermally cyclized to 24, which is separated from the isomeric byproduct 25. Modest yields of
  • aminotriazoles analogous to 24 have also been obtained by direct thermal reaction of intermediates analogous to 22 with a hydrazide [L. Carey, B.J.
  • aminotriazoles of structure 28 can be heated with an acid anhydride to give the acylaminotriazoles 31. These can be reduced with lithium aluminum hydride to give the
  • Aminotriazoles of structure 24 can also be obtained by heating a chlorotriazole 14 or a
  • Aminomercaptotriazoles of structure 37 can be prepared as outlined in Scheme I-13, which
  • Alkoxy and aryloxytriazoles of formula 38 can be prepared by heating a chlorotriazole 14 or a methanesulfonyl triazole 16 with the appropriate alkoxide or phenoxide anion. Such a transformation has been described by E.B. Akerblom and D.E.S.
  • triazolinethione 44 upon heating with a base such as 1,8-diazabicyclo ⁇ 5.4.0 ⁇ undec-7-ene (DBU) in a suitable solvent such as anhydrous tetrahydrofuran (THF).
  • a base such as 1,8-diazabicyclo ⁇ 5.4.0 ⁇ undec-7-ene (DBU)
  • a suitable solvent such as anhydrous tetrahydrofuran (THF).
  • an alkylating agent e.g., an alkyl or aralkyl bromide
  • 2-methoxyethanol generally affords the S-alkylated derivative 45 as the primary or exclusive product. This reaction is typically carried out at 20-100°C, depending on the reactivity of the alkylating agent. Treatment of 45 with the appropriate
  • ⁇ -bromophenylacetic acid ester 46 in the presence of a base such as anhydrous sodium carbonate or sodium hydride in DMF or dimethyl sulfoxide (DMSO) gives an O-alkylated product which is next saponified to the acid 47.
  • the last step is accomplished by treatment of the intermediate ester with excess sodium or potassium hydroxide in aqueous methanol followed by acidification.
  • a similar sequence may be carried out starting with a ring-substituted 4-hydroxybenzylamine (analog of 39).
  • the triazolinethione 44 may be prepared by alternative methods (Scheme 1-16). In one of these, the thiosemicarbazide 41 is reacted with a trimethyl orthoester, preferably in 2-methoxyethanol at reflux. In another method, 41 is treated with an acid chloride or anhydride to give the acyl
  • the intermediate ester 49 may be converted to a primary amide by treatment with methanolic ammonia.
  • Dehydration of the amide with phosphorus oxychloride in the presence of triethylamine at 0°C gives the cyano derivative 50.
  • 4-(aminomethyl)- benzoic acid (52) can be reduced with lithium aluminum hydride or diborane to the corresponding benzyl alcohol 53, which is converted to a triazole
  • Intermediate 63 may also be directly saponified to give 66.
  • the aldehyde 55 may also be reacted with benzylamine and trimethylsilyl cyanide to give the adduct 67 (Scheme I-20).
  • Treatment of 67 with an acid chloride in the presence of triethylamine yields the acyl derivative 68.
  • transformation of the cyano group to tetrazole by heating with
  • Schemes I-22 and I-23 illustrate a typical synthesis in which the 4-( ⁇ -carboxybenzyloxy)benzyl side chain (see also Schemes I-15 and I-16) is fully constructed before formation of the triazole ring.
  • the appropriate phenylacetic acid 77 is converted to its t-butyl ester 78 by reaction with isobutylene in the presence of concentrated sulfuric acid, in a pressure vessel. Reaction of 78 with bromine under controlled conditions yields the ⁇ -brominated product 79.
  • p-Cresol (80) is converted to its anion (for example, with potassium hydride or potassium t-butoxide in the presence of 18-crown-6 or with anhydrous potassium carbonate in DMF) and treated with 79 to give 81.
  • anion for example, with potassium hydride or potassium t-butoxide in the presence of 18-crown-6 or with anhydrous potassium carbonate in DMF
  • azobis(isobutyronitrile) (AIBN) or benzoyl peroxide provides 82, which is readily converted to the azide derivative 83 (for example, with lithium azide in DMSO).
  • AIBN azobis(isobutyronitrile)
  • benzoyl peroxide provides 82, which is readily converted to the azide derivative 83 (for example, with lithium azide in DMSO).
  • the azide 83 may be converted directly to the isothiocyanate 84 by reaction with
  • triphenylphosphine and carbon disulfide Reaction of 84, which may be used without purification, with hydrazine at room temperature in a solvent such as
  • -CONHSO 2 R 18 may be prepared from the corresponding carboxylic acid derivatives (I) as outlined in Scheme I-24.
  • the carboxylic acid (I) can be converted into the corresponding acid chloride by treatment with refluxing thionyl chloride or preferably with
  • the carboxylic acids can be converted into acyl-imidazole intermediates, which then can be treated with an appropriate aryl or alkylsulfonamide and diazabicycloundecene (DBU) to give the desired acylsulfonamide 89 [J. T. Drummond and G. Johnson - Tetrahedron Lett.- 29, 1653 (1988)].
  • DBU diazabicycloundecene
  • benzaldehyde 89 is reacted with trimethylsilyl cyanide in the presence of potassium cyanide and 18- crown-6 to give the cyanohydrin 90.
  • Treatment of 90 with anhydrous HCl in methanol provides the ⁇ -hydroxy ester 91.
  • reaction of 91 with carbon tetrabromide and triphenylphosphine gives the ⁇ -bromo ester 46.
  • diallyl phenol 105 (Scheme I-28).
  • Scheme I-28 the diallyl phenol 105
  • 105 may be transformed to the 4-hydroxybenzylamine derivative 106 and then to a triazole of structure 107.
  • Scheme I-29 Another example of incorporation of a m-alkyl substituent (R 9 or R 10 ) on the benzyl group of a compound of Formula I is shown in Scheme I-29.
  • This route is useful for the preparation of triazoles wherein the group R 16 is aryl or heterocyclyl and is directly attached to the triazole ring (see also Scheme I-7).
  • Intermediate 102 (from Scheme I-27) may be desilylated with tetrabutylammonium fluoride and then alkylated with methyl ⁇ -bromophenylacetate (46) in the presence of a base such as potassium carbonate to give 108.
  • the benzylic alcohol of 108 may be replaced by bromide and then azide.
  • Triphenylphosphine reduction of the azido group affords the benzylamine derivative 109.
  • Reaction of 109 with the ester acylhydrazone 19 (from Scheme I-7) in ethanol at elevated temperature gives the triazole 110
  • the aniline NH may be deprotonated again with sodium hydride and alkylated with the ⁇ -bromo ester 46 to give 114.
  • 114 may be prepared from the intermediate 31 (from Scheme 1-19) by deprotonation with a strong base such as lithium bis (trimethylsilyl)amide followed by treatment with the alkylating agent RBr. Upon saponification of the methyl ester of 114, the target compound 115 is obtained.
  • the compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.
  • Such salts include ammonium salts, alkai metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine salts, salts with amino acids like arginine, lysine, and the like.
  • salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 , methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
  • HCl, HBr, H 2 SO 4 , H 3 PO 4 methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
  • the salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by
  • Angiotensin II (All) is a powerful arterial vasoconstrictor, and it exerts its action by
  • Tris-0.25M Sucrose, pH 7.4 buffer 50 mL was homogenized, and then centifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4°C. The pellet thus obtained was resuspended in 30 mL of 50 mM Tris-5 mM MgCl 2 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mL Bacitracin and the suspension was used for 100 assay tubes. Samples tested for screening were done in duplicate.
  • Bovine adrenal cortex was selected as the source of All receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris HCl (50 mM), pH 7.7 buffer and homogenized. The
  • %-angiotensin II was presented as a measure of the efficacy of such compounds as All antagonists.
  • the potential antihvpertensive effects of the compounds described in the present invention may be evaluated using the methodology described below: Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p.) and the trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent
  • Ventilator rate - 60 strokes per minute, volume -
  • the right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37°C by a thermostatically controlled heating pad which received input from a rectal temperature probe.
  • Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30 minute intervals and the increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
  • the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic conditions.
  • the compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like.
  • compositions prepared to treat intraocular pressure would typically contain about 0.17. to 157. by weight, and preferably 0.5% to 2.07. by weight of a compound of this invention.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the compounds of this invention can be administered to patients (animals and human) in need of such
  • the dosage range will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will be used.
  • the dosage range will be about 2.5 to 250 mg per patient per day; more preferably about 2.5 to 75 mg per patient per day.
  • the compounds of this invention can also be administered in combination with other antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blockers.
  • the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride,
  • benzthiazide quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide,
  • ethacrynic acid furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril,
  • teprotide zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.
  • the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
  • hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg).
  • triple drug combinations of hydrochlorothiazide (15-200 mg) plus miloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood pressure in hypertensive patients.
  • these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
  • these combinations can be formulated into pharmaceutical compositions as discussed below.
  • acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
  • the amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as microcrystalline cellulose
  • a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like
  • a lubricant such as magnesi ⁇ m stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint, oil of wintergreen or cherry.
  • the dosage unitform may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
  • the compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions,
  • compositions prepared to. treat intraocular pressure would typically contain about 0.17. to 15% by weight, and preferably 0.5% to 2.0% by weight of a compound of this invention.
  • the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic conditions.
  • diabetic nephropathy glomerulonephritis, scleroderma, and the like
  • renal vascular hypertension left ventricular dysfunction
  • diabetic retinopathy renal vascular disorders
  • vascular disorders such as migraine or Raynaud's disease.
  • cholinomimetics such as physostigmine and nootropic agents are known to be active.
  • rats are trained to inhibit their natural tendency to enter dark areas.
  • the test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet.
  • the test animals are pretreated with 0.2 mg/kg of the
  • muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
  • test compounds can overcome the disruptive effect on learning which scopolamine produces.
  • compounds of this invention should be efficacious, in this passive avoidance assay in the dose range of from about 0.1 mg/kg to about 100 mg/kg.
  • the anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay.
  • CER conditioned emotional response
  • Diazepam is a clinically useful anxiolytic which is active in this assay.
  • male Sprague-Dawley rats 250-350 g
  • VI 60 second schedule for food reinforcement in a standard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed L1D1L2D2L3 sequence. During both periods (L or D), pressing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever presses also elicit mild footshock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed during the dark periods reflecting the formation of a conditioned emotional response (CER).
  • CER conditioned emotional response
  • Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, response rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice.
  • a clinically useful antidepressant which serves as a positive control in this assay is desipramine.
  • the method is based on the observations that a mouse suspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation. Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity code and to measure latency, duration and frequency of immobile periods.
  • Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced stereotypy model.
  • a clinically useful antipsychotic drug that is used as a positive control in this assay is haloperidol.
  • the assay method is based upon the observation that stimulation of the dopaminergic system in rats produces stereo- typed motor behavior.
  • Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer.
  • Compounds of the invention should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the dose will vary from patient to patient depending upon the nature and severity of disease, the patient' s weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will generally be about 5 to 6000 mg. per patient per day which can be administered in single or multiple doses.
  • the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.
  • the compounds of this invention may be combined with other cognition-enhancing agents. These include acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (THA; tacrine), muscarinic agonists such as
  • oxotremorine inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers such as nimodipine, and nootropic agents such as piracetam.
  • angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril
  • centrally-acting calcium channel blockers such as nimodipine
  • nootropic agents such as piracetam.
  • the compounds of this invention may be combined with other anxiolytic agents such as
  • alprazolam lorazepam, diazepam, and buspirone.
  • tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone
  • monoamine oxidase inhibitors such as tranylcypromine
  • the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.
  • Example 1 Step A), 27 ml (560 mmol) of hydrazine hydrate, and 72 ml of absolute EtOH was stirred at reflux for 1 hour. The solution was purged with N 2 and then concentrated. The residual oil was treated with 100 ml of CH 2 CI 2 , 100 ml of ethyl acetate, and 100 ml of H 2 O, The solid which separated was washed first with H 2 O and then with ether. This material was recrystallized twice from absolute EtOH to give 2.74 g (50%) of solid, mp 179-179.5°C; homogeneous by TLC in 19:1 CH 2 Cl 2 -MeOH.
  • Step C Ethyl Valerate 4-(4-Hydroxybenzyl)-3- thiosemicarbazone
  • N,N-dimethylformamide (DMF) was stirred overnight at room temperature under N2. It was then concentrated to small volume (oil pump, 50°C) and partitioned between ethyl acetate and H 2 O. The organic phase was washed with H 2 O followed by saturated NaCl. The organic solution was dried (MgSO 4 ), filtered, and concentrated to give a foam, which was
  • DBU 1,8-diazabicyclo ⁇ 5.4.0 ⁇ undec-7-ene
  • THF dry tetrahydrofuran
  • Step E 3-Butyl-4-(4-hydroxybenzyl )-5-(4-nitro- benzylthio)-4H-1.2.4-triazole
  • Step F 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenylmethoxy]phenyl]methyl]-5-(4-nitrobenzylthio)- 4H-1,2,4-triazole
  • Step A 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenyl- methoxy]phenyl]methyl]-5-(4-nitrobenzyl- sulf inyl)-4H-1 , 2 , 4-triazole
  • Step B 3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylsulfinyl)-4H- 1,2-4-triasole
  • Step A 3-Butyl-4-[[4-[1-carbamoyl-1-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)-4H-
  • Step B 3-Butyl-4-[[4-[1-cyano-1-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)-4H- 1,2,4-triazole
  • phosphorus oxychloride 25-30 equivalents is stirred at 0°C under N 2 as triethylamine (2.2 equivalents) is added dropwise over about 1 hour. After the addition is complete, the mixture is gradually warmed to room temperature and then heated to reflux for about 45 minutes or until TLC indicates complete reaction. The cooled mixture is concentrated in vacuo. and the residue is partitioned between ice-water and an organic solvent, such as ether, ethyl acetate, or toluene. The organic phase is washed with dilute NaOH and then with H 2 O. The organic solution is dried over MgSO 4 , filtered, and concentrated to give the title compound, which is used directly or may be purified by chromatography on silica gel.
  • Step C 3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[1- phenyl-1-(tetrazol-5-yl)methoxy]phenyl]- methyl]-4H-1,2,4-triazole
  • Step A 3-Butyl-5-(4-chlorobenzylthio)-4-(4-hydroxy- benzvl)-4H-1,2,4-triazole
  • Step B 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenyl- methoxy]phenyl]methyl]-5-(4-chlorobenzyl- thio)-4H-1,2,4-triasple
  • Step C 3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy)- phenyl]methyl]-5-(4-chlorobenzylthio)-4H- 1,2,4-triazole
  • Step A 3-Butyl-4-(4-hydroxybenzyl)-5-(4-methoxy- benzylthio)-4H-1,2,4-triazole
  • Step B 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenyl- methoxy]phenyl]methyl]-5-(4-methoxybenzyl- thio)-4H-1,2,4-triazole
  • Step A The product from Step A was converted to the title compound by the procedure of Example 5, Step B.
  • the material was obtained in 67% yield as a gum; homogeneous by TLC in 97:3 CH 2 Cl 2 -MeOH.
  • Step B The product from Step B was converted to the title compound according to the procedure of Example 5, Step C.
  • the material was obtained in 85% yield as a white solid, mp 78-79°C; homogeneous by TLC in 90:10:1 CH 2 Cl 2 -MeOH-AcOH.
  • Example 7 By the procedure of Example 6, the title compound was prepared from 3-butyl-4-[[4-[1-carboxy- 1-phenylmethoxy)phenyl]methyl]-5-(4-methoxybenzyl- thio)-4H-1,2,4-triazole (Example 7). The material was obtained in 657. yield as a stiff foam, mp 74-75°C,
  • Step A 2-bromo-2-(2-chlorophenyl)acetate, from Step A, according to the procedure of Example 5, Step B, provided a 75% yield of the title compound as a glass; homogeneous by TLC in 97:3 CH 2 Cl 2 -MeOH.
  • Example 9 4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]phenyl]- methyl]-5-(4-chlorobenzylthio)-4H-1,2,4-triazole (Example 9) according to the method of Example 6.
  • the material was obtained in 71% yield as a stiff foam, mp 89-90°C dec. (preliminary softening).
  • Step A 3-Butyl-4-[[4-[1-(carbomethoxy)-1-(2-chlorophenyl)methoxy]phenyl]methyl]-5-(4-methoxy- benzylthio)-4H-1,2,4-triazole
  • Step B 3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)- methoxy]phenyl]methyl]-5-(4-methoxybenzyl- thio)-4H-1,2,4-triazole
  • Step A The product from Step A was converted to the title compound by the method of Example 5, Step C.
  • the material was obtained in 79% yield as a white solid, mp 84-86°C; homogeneous by TLC in 90:10:1 CH 2 Cl 2 -MeOH-AcOH.
  • Step B Preparation of methyl 4-hydroxy-3-(2-propen-1-yl)benzoate
  • Step C Preparation of methyl 4-(tert-butyldimethyl- silyloxy)-3-(2-propen-1-yl)benzoate
  • Step D Preparation of 4-(tert-butyldimethyl- silyloxy)-3-(2-propen-1-yl)benzyl alcohol
  • a magnetically stirred solution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous THF was added 15.0 mL of a 1.0 M solution of lithium aluminum hydride in THF, and the reaction mixture was stirred under a nitrogen atmosphere for 2 hours. At this point, the reaction was quenched by cautious addition of 10 mL water, the resulting precipitate was dissolved by addition of 1.0 N hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was separated, dried (MgSO 4 ), filtered and evaporated in vacuo to afford 7.258 g (937.) of the title compound.
  • Step L 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenyl- methoxy]-3-propylphenyl]methyl]-5-phenyl-4H-
  • Step M 3-Butyl-4-[ [4-( 1-carboxy-1-phenylmethoxy)-3- propylphenyl]methyl]-5-phenyl-4g-1 , 2 , 4-triazole

Landscapes

  • 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)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des triazoles substitués, accrochés par un pont de méthylène à de nouveaux dérivés de phényle substitué de formule (I) se révèlent utiles comme antagonistes d'angiotensine II.
PCT/US1991/000963 1990-02-13 1991-02-11 Antagonistes de triazole angiotensine ii incorporant un element de benzyle substitue WO1991011909A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47977990A 1990-02-13 1990-02-13
US479,779 1990-02-13

Publications (1)

Publication Number Publication Date
WO1991011909A1 true WO1991011909A1 (fr) 1991-08-22

Family

ID=23905391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/000963 WO1991011909A1 (fr) 1990-02-13 1991-02-11 Antagonistes de triazole angiotensine ii incorporant un element de benzyle substitue

Country Status (4)

Country Link
EP (1) EP0515546A4 (fr)
JP (1) JP2726563B2 (fr)
CA (1) CA2075639A1 (fr)
WO (1) WO1991011909A1 (fr)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5177095A (en) * 1990-02-13 1993-01-05 Merck & Co., Inc. Triazole angiotensin II antagonists incorporating a substituted benzyl element
US5183810A (en) * 1990-02-13 1993-02-02 Merck & Co., Inc. Imidazole angiotensin II antagonists incorporating a substituted benzyl element
US5240938A (en) * 1991-02-13 1993-08-31 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted pyridoimidazolyl ring
US5300668A (en) * 1993-03-10 1994-04-05 Pfizer Inc. Certain esters of 1-(4-X-methylphenyl)cyclopent-3-ene-1-carboxylic acid, wherein X is a trialkylsilyloxy, bromo or hydroxy group, as intermediates
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
JP2927519B2 (ja) 1989-07-28 1999-07-28 メルク エンド カムパニー インコーポレーテツド アンギオテンシン▲ｉｉ▼拮抗薬としての置換トリアゾリノン、トリアゾリンチオンおよびトリアゾリンイミン
WO1999061410A1 (fr) * 1998-05-12 1999-12-02 American Home Products Corporation Diphenyles 2,3,5-substitues utiles pour le traitement de la resistance insulinique et de l'hyperglycemie
US6110963A (en) * 1998-05-12 2000-08-29 American Home Products Corporation Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6166069A (en) * 1998-05-12 2000-12-26 American Home Products Corporation Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6221902B1 (en) 1998-05-12 2001-04-24 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6232322B1 (en) 1998-05-12 2001-05-15 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6310081B1 (en) 1999-05-10 2001-10-30 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6451827B2 (en) 1998-05-12 2002-09-17 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6699896B1 (en) 1998-05-12 2004-03-02 Wyeth Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6894054B2 (en) 2001-02-09 2005-05-17 Telik, Inc. Heterocyclic inhibitors of glycine transporter 2
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
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
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
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
US9573936B2 (en) 2015-05-20 2017-02-21 Amgen Inc. Triazole agonists of the APJ receptor
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
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2010137336A1 (ja) 2009-05-29 2012-11-12 興和株式会社 新規なα−フェノキシベンゼン酢酸誘導体及びこれを含有する医薬

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061488A (en) * 1972-11-13 1977-12-06 Hershey Foods Corporation Plant treating mixtures and methods utilizing spores of Bacillus uniflagellatus
WO1987003303A1 (fr) * 1985-11-20 1987-06-04 Crop Genetics International, N.V. Micro-organismes endosymbiotiques fabricant des produits chimiques agricoles, et leur procede de preparation et d'utilisation
EP0323841A2 (fr) * 1988-01-07 1989-07-12 E.I. Du Pont De Nemours And Company Antagonistes d'angiotensine II du type pyrrole, pyrazole et triazole substitués
JPH02117321A (ja) * 1988-10-26 1990-05-01 Shoichi Ishimoto 栽培植物の育成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061488A (en) * 1972-11-13 1977-12-06 Hershey Foods Corporation Plant treating mixtures and methods utilizing spores of Bacillus uniflagellatus
WO1987003303A1 (fr) * 1985-11-20 1987-06-04 Crop Genetics International, N.V. Micro-organismes endosymbiotiques fabricant des produits chimiques agricoles, et leur procede de preparation et d'utilisation
EP0323841A2 (fr) * 1988-01-07 1989-07-12 E.I. Du Pont De Nemours And Company Antagonistes d'angiotensine II du type pyrrole, pyrazole et triazole substitués
JPH02117321A (ja) * 1988-10-26 1990-05-01 Shoichi Ishimoto 栽培植物の育成方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
International Journal of Systematic Bacteriology, Volume 34, Number 2, issued April 1984, DAVIS et al., "Clavibacter: a New Genus Containing Some Phytopathogenic Coryneform Bacteria, Including Clavibacter xyli subsp. xyli sp. nov., subsp. nov. and Clavibacter xyli subsp. cynodontis subsp. nov., Pathogens That Cause Ratoon Stunting Disease of Sugarcane and Bermudagrass Stunting Disease", pages 107-117. See entire document. *
Phytopathology, Volume 78 Number 12, issued 1988; JOHNSON et al; "Effects of Clavibacter xyli subsp. cynodontis (CXC) colonization on growth and yield of corn"; page 1540 (see Abstract #220). *
Phytopathology; Volume 78 Number 12; issued 1988; KOSTKA et al; "Experimental host range of Clavibacter xyli subsp. cynodontis (CXC) and a CXC/Bacillus thuringiensis recombinant (CXC/BT)" page 1540 (see Abstract # 222). *
Phytopathology; Volume 78 Number 12; issued 1988; REESER et al; "Seed transmission of Clavibacter xyli subsp. cynodontis (CXC) in corn"; page 1540 (see Abstract # 224). *
Plant Disease, Volume 68, Number 12, issued 1984, DAVIS et al., "Occurrence in Florida USA of the bacterium that causes bermudagrass stunting disease", pages 1095-1097. See entire document. *

Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2927519B2 (ja) 1989-07-28 1999-07-28 メルク エンド カムパニー インコーポレーテツド アンギオテンシン▲ｉｉ▼拮抗薬としての置換トリアゾリノン、トリアゾリンチオンおよびトリアゾリンイミン
US5177095A (en) * 1990-02-13 1993-01-05 Merck & Co., Inc. Triazole angiotensin II antagonists incorporating a substituted benzyl element
US5183810A (en) * 1990-02-13 1993-02-02 Merck & Co., Inc. Imidazole angiotensin II antagonists incorporating a substituted benzyl element
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
US5240938A (en) * 1991-02-13 1993-08-31 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted pyridoimidazolyl ring
US5300668A (en) * 1993-03-10 1994-04-05 Pfizer Inc. Certain esters of 1-(4-X-methylphenyl)cyclopent-3-ene-1-carboxylic acid, wherein X is a trialkylsilyloxy, bromo or hydroxy group, as intermediates
US6509360B1 (en) 1998-05-12 2003-01-21 Wyeth Penyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6844358B2 (en) 1998-05-12 2005-01-18 Wyeth Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6166069A (en) * 1998-05-12 2000-12-26 American Home Products Corporation Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6214877B1 (en) 1998-05-12 2001-04-10 John A. Butera 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6221902B1 (en) 1998-05-12 2001-04-24 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6232322B1 (en) 1998-05-12 2001-05-15 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
WO1999061410A1 (fr) * 1998-05-12 1999-12-02 American Home Products Corporation Diphenyles 2,3,5-substitues utiles pour le traitement de la resistance insulinique et de l'hyperglycemie
US6369072B2 (en) 1998-05-12 2002-04-09 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6391897B2 (en) 1998-05-12 2002-05-21 American Home Products Corporation Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6451827B2 (en) 1998-05-12 2002-09-17 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US7141672B2 (en) 1998-05-12 2006-11-28 Wyeth Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6699896B1 (en) 1998-05-12 2004-03-02 Wyeth Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6765021B2 (en) 1998-05-12 2004-07-20 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6110963A (en) * 1998-05-12 2000-08-29 American Home Products Corporation Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US7008636B2 (en) 1998-05-12 2006-03-07 Wyeth 2,3,5-substituted biphenyls useful in the treatment of insulin resistance and hyperglycemia
US6310081B1 (en) 1999-05-10 2001-10-30 American Home Products Corporation Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
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
US6894054B2 (en) 2001-02-09 2005-05-17 Telik, Inc. Heterocyclic inhibitors of glycine transporter 2
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
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
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
US10221162B2 (en) 2015-05-20 2019-03-05 Amgen Inc. Triazole agonists of the APJ receptor
US9745286B2 (en) 2015-05-20 2017-08-29 Amgen Inc. Triazole agonists of the APJ receptor
US9845310B2 (en) 2015-05-20 2017-12-19 Amgen Inc. Intermediates for preparing triazole agonists of the APJ receptor
US9868721B2 (en) 2015-05-20 2018-01-16 Amgen Inc. Triazole agonists of the APJ receptor
US10058550B2 (en) 2015-05-20 2018-08-28 Amgen Inc. Methods of treating heart failure
US9656998B2 (en) 2015-05-20 2017-05-23 Amgen Inc. Intermediates for preparing triazole agonists of the APJ receptor
US10344016B2 (en) 2015-05-20 2019-07-09 Amgen Inc. Bromotriazole intermediates
US9573936B2 (en) 2015-05-20 2017-02-21 Amgen Inc. Triazole agonists of the APJ receptor
US9656997B2 (en) 2015-05-20 2017-05-23 Amgen Inc. Triazole agonists of the APJ receptor
US9751864B2 (en) 2015-05-20 2017-09-05 Amgen Inc. Methods for preparing triazole agonists of the APJ receptor
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10150760B2 (en) 2016-05-03 2018-12-11 Amgen Inc. Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor

Also Published As

Publication number Publication date
CA2075639A1 (fr) 1991-08-14
JPH05503533A (ja) 1993-06-10
JP2726563B2 (ja) 1998-03-11
EP0515546A4 (en) 1993-05-12
EP0515546A1 (fr) 1992-12-02

Similar Documents

Publication Publication Date Title
WO1991011909A1 (fr) Antagonistes de triazole angiotensine ii incorporant un element de benzyle substitue
US5336778A (en) Substituted triazoles as angiotensin II antagonists
US5281614A (en) Substituted 1,2,4-triazoles bearing acidic functional groups as angiotensin II antagonists
US5162325A (en) Angiotensin ii antagonists incorporating a substituted benzyl element
US5238942A (en) Substituted quinazolinones bearing acidic functional groups as angiotensin ii antagonists
CA2021954C (fr) Triazolinones, triazolinethiones et triazolinimines substitues comme antagonistes de l'angiotensine ii
WO1991012001A1 (fr) Agents antagonistes de l'angiotensine ii dans lesquels est incorpore un element de benzyle substitue
US5246944A (en) Quinoline angiotensin ii antagonists incorporating a substituted benzyl element
US5177095A (en) Triazole angiotensin II antagonists incorporating a substituted benzyl element
US5264439A (en) Quinazolinone, triazolinone and pyrimidinone angiotensin II antagonists incorporating a substituted benzyl element
US5236928A (en) Imidazole derivatives bearing acidic functional groups at the 5-position, their compositions and methods of use as angiotensin II antagonists
US5252574A (en) Angiotensin II antagonists incorporating a substituted thiophene or furan
US5175164A (en) Angiotensin ii antagonists incorporating a substituted indole or dihydroindole
US5187179A (en) Angiotensin II antagonists incorporating a substituted imidazo [1,2-b][1,2,4]triazole
US5183810A (en) Imidazole angiotensin II antagonists incorporating a substituted benzyl element
CA2072775A1 (fr) Triazolinones a substitution
WO1991012002A1 (fr) Agents antagonistes de l'angiotensine ii a base d'imidazoles dans lesquels est incorpore un element de benzyle substitue
AU2008326226A1 (en) 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid - 465
US5262412A (en) Substituted pyrazoles, compositions and use
US5436259A (en) Substituted 1,2,4-triazolin-3-one compounds bearing acidic functional groups as balanced angiotensin II antagonists

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 2075639

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1991905207

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1991905207

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1991905207

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1991905207

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载