EP0000833A1 - Derivate von phosphonoacylprolinen und ihre Verwendung als Arzneimittel - Google Patents

Derivate von phosphonoacylprolinen und ihre Verwendung als Arzneimittel Download PDF

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Publication number
EP0000833A1
EP0000833A1 EP7878300245A EP78300245A EP0000833A1 EP 0000833 A1 EP0000833 A1 EP 0000833A1 EP 7878300245 A EP7878300245 A EP 7878300245A EP 78300245 A EP78300245 A EP 78300245A EP 0000833 A1 EP0000833 A1 EP 0000833A1
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Prior art keywords
lower alkyl
hydrogen
proline
phosphinyl
phenylmethyl
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Granted
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EP7878300245A
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French (fr)
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EP0000833B1 (de
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Miguel A. Ondetti
Edward W. Petrillo
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • 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

Definitions

  • This invention provides phosphonoacyl prolines and related compounds which have the formula R 1 and R 2 each is hydrogen, lower alkyl, lower alkenyl, unsubstituted or substituted phenyl-lower alkyl or a metal ion; R 3 is hydrogen or lower alkyl; R 4 is hydrogen, lower alkyl, phenyl-lower alkyl or a metal ion; and n is 0 or 1.
  • the lower alkyl groups represented by the symbols are straight or branched chain aliphatic hydrocarbon groups having up to seven carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, t-butyl and the like.
  • the C 1 -C 4 members and especially the C 1 -C 2 members are preferred.
  • the phenyl-lower alkyl groups are aralkyl radicals of the same type, phenylmethyl and phenylethyl being especially preferred.
  • the phenyl substituent of these groups can also be mono substituted, bearing a nitro, halo or lower alkyl group preferably in the 4-position.
  • nitrophenyl-lower alkyl groups are aralkyl radicals of the same type, (4-nitrophenyl)methyl being especially preferred.
  • The'four common halogens are contemplated by the term halo, chlorine and bromine being preferred.
  • the lower alkenyl groups are similar monounsatu- rated, straight or branched chain aliphatic hydrocarbon groups having up to seven carbon atoms. Those having up to four carbons are preferred, especially allyl.
  • the metal ions represented by R 1 , R 2 and R 4 are monovalent metal ions, preferably the alkali metal ions, especially sodium, potassium and lithium.
  • Preferred embodiments of this invention are those compounds of formula I wherein m is 0 or 1, especially 0; R 1 and R 2 each is hydrogen, lower alkyl, especially methyl or ethyl, or alkali metal, especially lithium; R 3 is hydrogen or lower alkyl, especially methyl; and R 4 is hydrogen or alkali metal, especially lithium. Compounds in which at least one of the groups R 1 and R 2 is hydrogen are especially preferred.
  • the compounds of this invention are produced by reacting proline, preferably in the form of a lower alkyl or phenyl-lower alkyl ester in which the ester group is easily removed, e.g., the t-butyl ester, phenylmethyl ester or the like, with a phosphonoacetic acid or phosphonopropionic acid of the formula in the presence of a condensing agent e.g. 1,1'-carbonyldiimidazole or dicyclohexylcarbodiimide and in an inert organic solvent e.g. acetonitrile, dichloromethane, ether, tetrahydrofuran, dioxane or the like.
  • a condensing agent e.g. 1,1'-carbonyldiimidazole or dicyclohexylcarbodiimide
  • an inert organic solvent e.g. acetonitrile, dichloromethane, ether
  • R 1 and/or R 2 is phenylmethyl, 2-propenyl, or (4-nitrophenyl)methyl or R 4 is phenylmethyl, for example, these can be converted to hydrogen by catalytic reduction, e.g., with palladium on carbon or palladium on barium sulfate according to conventional methods.
  • R 4 is an easily removable ester group such as t-butyl
  • treatmentof the ester with trifluoroacetic acid and anisole yields the free acid, i.e., R 4 is hydrogen.
  • the acids form metal salts e.g. alkali metal salts by treatment with a metal hydroxide, e.g., in aqueous solution, according to conventional methods.
  • the proline esters are produced by any of a variety of known esterification methods utilizing a lower alkanol, or phenyl-lower alkanol R 4 -OH (particularly in peptide syntheses) as illustrated in U.S. Patent 4,046,889, September 6, 1977; J. Org. Chem. 28,176(1963); Pettit, Synthetic Peptides, Vol. 3 (Academic Press, 1975) pgs.17-24; Bodanszky et al., Peptide Synthesis, 2nd ed. (Wiley & Sons, 1976) , pgs. 49-56; Greenstein et al., Chemistry of the Amino Acids, Vol.
  • the starting materials of formula II can be produced by various methods.
  • R 1 and R 2 are lower alkyl
  • lower alkenyl or phenyl-lower alkyl other than phenylmethyl compounds of formula II can be made by reacting tris(2-propenyl)phosphite with a bromo ester of the formula wherein R 5 is lower alkyl, preferably methyl or ethyl, to obtain a compound of the formula and saponifying the compound of formula IV with alkali to obtain the compound of formula II.
  • the compounds of this invention are angiotensin converting enzyme inhibitors and are useful as hypotensive agents, particularly for the reduction of angiotensin dependent hypertension.
  • a composition containing one or a combination of angiotensin converting enzyme inhibitors of this invention to a hypertensive mammal, it intervenes in the renin ⁇ angiotensinogen ⁇ angiotension I ⁇ angiotensin II sequence and the hypertension is reduced or alleviated.
  • a single dose, or preferably two to four divided daily doses, provided on a basis of 30 to 300 mg. per kilogram per day and especially about 10 to 100 mg. per kilogram per day is appropriate to bring about a reduction in elevated blood pressure.
  • the animal model experiments described by Engel., Proc. Soc. Exp. Biol. Med. 143, 483 (1973) provide a valuable guide.
  • composition is preferably administered subcutaneously, intramuscularly, intravenously or intraperitoneally, but it can also be administered orally with a dose of 10-1000 mg. per kilogram per day.
  • the compound or compounds of formula I can be formulated as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for parenteral use.
  • a compound or compounds of formula I can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a conventional unit dosage form as called for by accepted pharmaceutical practice.
  • the amount of active substance is selected so as to provide a dosage in the range indicated.
  • Triallyl phosphite (20.2 g., 0.01 mol) and methyl bromoacetate (14.4 g., 0.01 mol) are combined and heated at 110° under a slow stream of nitrogen for 2.5 hours. The mixture is then distilled and the fraction with b.p. 95-102°/0.05mm is collected to obtain a total of 9.0 g (38%) of [bis(2-propenyloxy)phosphinyl]acetic acid, methyl ester.
  • the ester obtained in part a (9.0 g., 0.038 mol.) is dissolved in 40 ml of IN potassium hydroxide and let stand overnight. The mixture is extracted with ether, then the aqueous layer is acidified and extracted with ethyl acetate. The acidic extracts are washed with brine, dried (MgSO 4 ) and evaporated in vacuo to a viscous liquid.
  • the (bis(2-propenyloxy)phosphinyl]-acetic acid weighs 7.1 g (85%).
  • a suspension of 5% palladium on barium sulfate catalyst (200 mg) in 75 ml of water and 75 ml of acetic acid is equilibrated with hydrogen at atmospheric pressure.
  • the proline ester from part c (10.7 g., 0.028 mol.) in 150 ml of methanol is added and the mixture is hydrogenated overnight.
  • the total change in gas volume is -700 ml.
  • the mixture is filtered through Celite and the filtrate evaporated in vacuo to a viscous residue. Trituration with ethyl acetate causes precipitation of a white solid which is filtered and washed.with ethyl acetate, m.p. 130° (decomposition, vigorous foaming).
  • the tert-butyl ester from part d (1.2 g., 0.0041 mol) is dissolved in 36 ml of trifluoroacetic acid and 4 ml of anisole and let stand for 1 hour. The solution is evaporated in vacuo, the residue is taken up in water and the aqueous solution is washed with ether. Two-thirds of the aqueous solution is then lyophilized, yielding 480 mg (74%) of white solid, 1-(phosphono- acetyl)-L-proline, which is transferred into vials in a glove bag under nitrogen.
  • the substance cannot be dried completely without decomposition.
  • a solution of 1.184 g (0.005 mol.) of 1-(phosphono- acetyl)-L-proline in 90 ml of redistilled water is adjusted to pH 9.2 by the addition of 148 ml of 0.1N lithium hydroxide.
  • the resultant solution is filtered through a millipore filter and then lyophilized.
  • the weight of lyophilizate, l-(phosphonoacetyl)-L-proline, lithium salt is 1.219 g (93%).
  • Triallylphosphite (21 g., 0.01 mole) and methyl-3-bromopropionate (16.7 g., 0.01 mole) are stirred at 110° for six hours while a stream of nitrogen is bubbled through the reaction mixture.
  • the mixture is then distilled to yield a main fraction comprising 3-[bis(2-propenyloxy)phosphinyl]propionic acid, methyl ester, b.p. 124-130°/0.05 mm., yield 8.4 g (44%).
  • the methyl ester from part a (4.2 g., 0.016 mole) is stirred with 18 ml of potassium hydroxide for 18 hours.
  • the solution is extracted with ether, and the aqueous layer is acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate.
  • the acidic extracts are dried (Na 2 S0 4 ) and evaporated in vacuo to a clear oil, 3-[bis(2-propenyloxy)phosphinyl]propionic acid, yield 3.4 g (85%).
  • a suspension of 5% palladium on barium sulfate catalyst (80 mg) in 30 ml of water and 30 ml of acetic acid is equilibrated with hydrogen at atmospheric pressure.
  • the proline ester from part c (3.0 g., 0.008 mol) in 40 ml of methanol is added and the mixture hydrogenated overnight.
  • the total change in gas volume is 340 ml.
  • the mixture is filtered through Celite and the filtrate evaporated in vacuo to a viscous oil.
  • Trituration with ethyl acetate yields 460 mg. (19% yield) of crystalline 1-(l-oxo-3-phosphonopropyl)-L-proline, tert-butyl ester, m.p. 157-158° (d).
  • the tert-butyl ester from part d (460 mg., 0.0015 mol.) is dissolved in 15 ml of trifluoroacetic acid and 1.5 ml of anisole and stirred for one hour at room temperature. The solution is evaporated in vacuo, the residue is taken up in water and washed with ether. The aqueous layer (18 ml) is lyophilized to amorphous, white solid l-(l-oxo-3-phosphonopropyl)-L-proline. Total yield 395 mg (quantitative).
  • Ethyl (diethoxyphosphinyl)acetate (11.2 gm., 0.05 mol.) and phosphorus pentachloride (10.5 gm., 0.05 mol.) are dissolved in 200 ml of benzene and refluxed overnight. The solvent is removed in vacuo, leaving yellow, oily, ethyl(ethoxychlorophosphinyl)-acetate as residue (11.5 gm.).
  • the oil from part a is taken up in 100 ml of ether and added to an ice-cooled solution of triethylamine (7.7 ml., 0.055 mol.) and benzyl alcohol (6.0 ml., 0.056 mol.) in 100 ml of ether. After stirring overnight, the mixture is washed with water, brine, dried (MgS0 4 ) and evaporated in vacuo. The resulting oil is distilled and a main fraction, b.p. 126-140°/0.04 mm., comprising ethyl[ethoxy[(phenylmethyl)oxy]phosphinyl]-acetate is collected, yield 7.0 gm. (49%).
  • the residue is chromatographed on 250 gm. of silica gel using ethyl acetate/hexane-ethyl acetate.
  • a suspension of 10% palladium on carbon catalyst (60 mg.) in 50 ml methanol is equilibrated with hydrogen and the ester from part d (2.0 gm., 0.0045 mol.) in 100 ml methanol is added and stirred 3 hours. Hydrogen uptake amounts to 195 ml (0.0085 mol.).
  • the mixture is filtered through Celite, the filtrate evaporated and the residue taken up in water.
  • the solution is filtered through a millipore filter and lyophilized into vials, affording the product, l-[(ethoxyhydroxy- phosphinyl)acetyl]-L-proline, as an extremely hygroscopic white foam (0.9 gm., 75%).
  • Methyl(dimethoxyphosphinyl)acetate (18.2 g., 0.1 mole) and 1 N sodium hydroxide (100 ml., 0.1 mole) are combined and stirred at room temperature overnight.
  • the reaction mixture is poured onto AG50W-X2 cation exchange resin (200 ml) and eluted with double distilled water.
  • the acidic fractions are combined and concentrated in vacuo.
  • the residue is dissolved in dichloromethane, dried over magnesium sulfate and concentrated in vacuo to yield 16.8 g of product, (dimethoxyphosphinyl)acetic acid, yield quantitative.
  • Triethylphosphite (83 g., 0.5 moles) is heated to 140° and treated dropwise over ninety minutes with ethyl 2-bromopropionate (90.5 g., 0.5 moles). As ethyl bromide distills off, the temperature is.gradually raised to 160°. After the addition is complete, the temperature is raised to 190°. After heating the reaction mixture an additional forty-five minutes at 190°, the mixture is distilled in vacuo to yield 105 g of ethyl-2-(diethoxyphosphinyl)propionate, b.p. 105-110° C/2 mm.
  • the solution is then filtered through a millipore filter and lyophilized to yield 640 mg of 1-(1-oxo-2-phosphonopropyl)-L-proline, trilithium salt, m.p. ⁇ 330°.
  • Methyl(dimethoxyphosphinyl)acetate (36.4 gm., 0.2 mol) is treated with phosphorus pentachloride (83.2 gm, 0.4 mol). An exothermic reaction raises the temperature of the mixture to 80°. The reaction mixture is maintained at 80° for one hour, then distilled in vacuo to obtain 13.5 gm of (dichlorophosphinyl)acetic acid, methyl ester, b.p. 95-100° /1.5 mm.
  • the phosphinyl acetic acid ester obtained in part b (4.48 gm., 0.011 mol) is stirred with 1 N sodium hydroxide (12 ml) overnight. The mixture is extracted with ether and the aqueous layer acidified, then extracted with dichloromethane. The dichloromethane extracts are dried (Na 2 SO 4 ) and evaporated to 3.6 gm of viscous oil. Chromatography on 300 ml silica gel with acetic acid/benzene (1:10) yields 3.0 gm of product, [[[(4-nitrophenyl)methyl]oxy][(2-phenylethyl)-oxy]phosphinyl]-acetic acid as a viscous glass.
  • the phosphinyl acetic acid obtained in part c (2.65 gm., 0.007 mol) and 1,1'-carbonyldiimidazole (1.14 gm., 0.007 mol) are combined in 125 ml of acetonitrile at 0° and stirred for 1 hour.
  • L-proline phenylmethyl ester (1.44 gm., 0.007 mol) is added and the mixture is stirred overnight at room temperature.
  • the reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and water.
  • proline ester from part d is substituted for the 1-[[ethoxy[(phenylmethyl)oxy]phosphinyl]acetyl]-L-proline phenylmethyl ester in the procedure of part e, Example 4, to obtain l-[[hydroxy[(2-phenylethyl)oxy]-phosphinyl]acetyl]-L-proline.
  • 0.1 N sodium hydroxide is substituted for the 0.1 N lithium hydroxide in the procedure of Example 2 to obtain l-(phosphonoacetyl)-L-proline, sodium salt.

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EP78300245A 1977-08-11 1978-08-03 Derivate von phosphonoacylprolinen und ihre Verwendung als Arzneimittel Expired EP0000833B1 (de)

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EP (1) EP0000833B1 (de)
JP (1) JPS5430158A (de)
AU (1) AU523323B2 (de)
CA (1) CA1109476A (de)
DE (1) DE2860019D1 (de)
DK (1) DK147422C (de)
HU (1) HU176712B (de)
IE (1) IE47170B1 (de)
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FR2439790A1 (fr) * 1978-10-23 1980-05-23 Squibb & Sons Inc Phosphinylalcanoyl prolines a action therapeutique, et leurs procedes de preparation
EP0053902A1 (de) * 1980-12-04 1982-06-16 E.R. Squibb & Sons, Inc. Phosphinylalkanoyl-substituierte Proline
EP0058427A2 (de) * 1981-02-17 1982-08-25 Merck & Co. Inc. Substituierte Phosphonamide, Verfahren zu ihrer Herstellung und eine pharmazeutische Zusammensetzung für die Behandlung von Bluthochdruck
EP0063896A1 (de) * 1981-04-27 1982-11-03 E.R. Squibb & Sons, Inc. Amino- und substituierte Amino-phosphinyl-alkanoyl-Zubereitungen
EP0070131A1 (de) * 1981-07-09 1983-01-19 Analytical Research Pharmaceuticals Pty. Ltd. Phosphonoalkanoylaminosäuren
EP0091525A2 (de) * 1982-04-08 1983-10-19 Analytical Research Pharmaceuticals Pty. Ltd. Phosphonoalkanoylaminosäure
EP0095584A2 (de) * 1982-04-30 1983-12-07 E.R. Squibb & Sons, Inc. Substituierte 4-Phenoxy und 4-Phenylthio-Proline
US4452791A (en) * 1982-03-15 1984-06-05 E. R. Squibb & Sons, Inc. Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors
US4552889A (en) * 1983-06-09 1985-11-12 Eli Lilly And Company 3-Mercaptomethyl-2-oxo-1-pyrrolidine acetic acids and use for hypertension
US4560680A (en) * 1982-03-15 1985-12-24 E. R. Squibb & Sons, Inc. Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors

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US4690939A (en) * 1979-08-14 1987-09-01 University Of Miami Anti-hypertensive agents
US4690940A (en) * 1979-08-14 1987-09-01 University Of Miami Anti-hypertensive agents
US4698356A (en) * 1979-08-14 1987-10-06 University Of Miami Anti-hypertensive agents
US4690937A (en) * 1979-08-14 1987-09-01 University Of Miami Anti-hypertensive agents
US4690938A (en) * 1979-08-14 1987-09-01 University Of Miami Anti-hypertensive agents
ZA794723B (en) * 1978-09-11 1980-08-27 Univ Miami Anti-hypertensive agents
US4695577A (en) * 1979-08-14 1987-09-22 University Of Miami Anti-hypertensive agents
US4698355A (en) * 1979-08-14 1987-10-06 University Of Miami Anti-hypertensive agents
US4734420A (en) * 1980-03-05 1988-03-29 University Of Miami Anti-hypertensive agents
US4690936A (en) * 1980-03-05 1987-09-01 University Of Miami Anti-hypertensive agents
US4416831A (en) * 1981-04-27 1983-11-22 E. R. Squibb & Sons, Inc. Amino and substituted amino phosphinylalkanoyl compounds
US4381297A (en) * 1981-05-04 1983-04-26 E. R. Squibb & Sons, Inc. Substituted carbonyl phosphinyl-alkanoyl compounds
US4416833A (en) * 1981-05-04 1983-11-22 E. R. Squibb & Sons, Inc. Substituted carbonyl phosphinyl-alkanoyl compounds
US4432971A (en) * 1981-08-03 1984-02-21 E. R. Squibb & Sons, Inc. Phosphonamidate compounds
US4371526A (en) * 1981-08-21 1983-02-01 E. R. Squibb & Sons, Inc. Phosphinylalkanoyl substituted 4,5-dihydropyrazole-5-carboxylic acid derivatives and hypotensive method and composition
US4555506A (en) * 1981-12-24 1985-11-26 E. R. Squibb & Sons, Inc. Phosphorus containing compounds and use as hypotensives
US4448772A (en) * 1982-04-22 1984-05-15 E. R. Squibb & Sons, Inc. Phosphinylmethylaminocarbonyl imino acid compounds useful for treating hypertension
US4560681A (en) * 1982-04-22 1985-12-24 E. R. Squibb & Sons, Inc. Phosphinylmethylaminocarbonyl imino acid compounds useful for treating hypertension
US4616005A (en) * 1982-06-23 1986-10-07 E. R. Squibb & Sons, Inc. Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives
US4452790A (en) * 1982-06-23 1984-06-05 E. R. Squibb & Sons, Inc. Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives
US4703043A (en) * 1982-06-23 1987-10-27 E. R. Squibb & Sons, Inc. Phosphonyl hydroxyacyl amino acid derivatives as antihypertensive
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JPH0624706B2 (ja) * 1985-10-01 1994-04-06 ミネソタ マイニング アンド マニユフアクチユアリング コンパニ− 研磨パツド
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US5902817A (en) * 1997-04-09 1999-05-11 Guilford Pharmaceuticals Inc. Certain sulfoxide and sulfone derivatives
US6025345A (en) * 1996-06-17 2000-02-15 Guilford Pharmaceuticals Inc. Inhibitors of NAALADase enzyme activity
US6025344A (en) 1996-06-17 2000-02-15 Guilford Pharmaceuticals Inc. Certain dioic acid derivatives useful as NAALADase inhibitors
US6071965A (en) * 1996-06-17 2000-06-06 Guilford Pharmaceuticals Inc. Phosphinic alkanoic acid derivatives
US5863536A (en) * 1996-12-31 1999-01-26 Guilford Pharmaceuticals Inc. Phosphoramidate derivatives
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009183A1 (de) * 1978-09-07 1980-04-02 Merck & Co. Inc. Phosphoryl-aminosäure-Derivate und diese enthaltende Zusammensetzung zur Behandlung erhöhten Blutdrucks
FR2439790A1 (fr) * 1978-10-23 1980-05-23 Squibb & Sons Inc Phosphinylalcanoyl prolines a action therapeutique, et leurs procedes de preparation
EP0053902A1 (de) * 1980-12-04 1982-06-16 E.R. Squibb & Sons, Inc. Phosphinylalkanoyl-substituierte Proline
EP0058427A3 (de) * 1981-02-17 1983-10-05 Merck & Co. Inc. Substituierte Phosphonamide, Verfahren zu ihrer Herstellung und eine pharmazeutische Zusammensetzung für die Behandlung von Bluthochdruck
EP0058427A2 (de) * 1981-02-17 1982-08-25 Merck & Co. Inc. Substituierte Phosphonamide, Verfahren zu ihrer Herstellung und eine pharmazeutische Zusammensetzung für die Behandlung von Bluthochdruck
EP0063896A1 (de) * 1981-04-27 1982-11-03 E.R. Squibb & Sons, Inc. Amino- und substituierte Amino-phosphinyl-alkanoyl-Zubereitungen
EP0070131A1 (de) * 1981-07-09 1983-01-19 Analytical Research Pharmaceuticals Pty. Ltd. Phosphonoalkanoylaminosäuren
US4452791A (en) * 1982-03-15 1984-06-05 E. R. Squibb & Sons, Inc. Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors
US4560680A (en) * 1982-03-15 1985-12-24 E. R. Squibb & Sons, Inc. Aminoalkyl and related substituted phosphinic acid angiotensin converting enzyme inhibitors
EP0091525A2 (de) * 1982-04-08 1983-10-19 Analytical Research Pharmaceuticals Pty. Ltd. Phosphonoalkanoylaminosäure
EP0091525A3 (de) * 1982-04-08 1984-02-29 Analytical Research Pharmaceuticals Pty. Ltd. Phosphonoalkanoylaminosäure
EP0095584A2 (de) * 1982-04-30 1983-12-07 E.R. Squibb & Sons, Inc. Substituierte 4-Phenoxy und 4-Phenylthio-Proline
EP0095584A3 (en) * 1982-04-30 1984-03-28 E.R. Squibb & Sons, Inc. Substituted 4-phenoxy and 4-phenylthio prolines
US4552889A (en) * 1983-06-09 1985-11-12 Eli Lilly And Company 3-Mercaptomethyl-2-oxo-1-pyrrolidine acetic acids and use for hypertension

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DE2860019D1 (en) 1981-04-23
IE781619L (en) 1979-02-11
DK147422C (da) 1985-02-11
IT1098006B (it) 1985-08-31
IT7826549A0 (it) 1978-08-07
CA1109476A (en) 1981-09-22
AU523323B2 (en) 1982-07-22
NO149923C (no) 1984-07-18
JPS5430158A (en) 1979-03-06
NO149923B (no) 1984-04-09
HU176712B (en) 1981-04-28
US4151172A (en) 1979-04-24
NO782724L (no) 1979-02-13
DK147422B (da) 1984-07-30
EP0000833B1 (de) 1981-09-02
DK353378A (da) 1979-02-12
AU3843678A (en) 1980-01-31
IE47170B1 (en) 1984-01-11

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