EP0000833A1 - Dérivés de phosphonoacylprolines et leur usage comme médicaments - Google Patents

Dérivés de phosphonoacylprolines et leur usage comme médicaments Download PDF

Info

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
Authority
EP
European Patent Office
Prior art keywords
lower alkyl
hydrogen
proline
phosphinyl
phenylmethyl
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
EP7878300245A
Other languages
German (de)
English (en)
Other versions
EP0000833B1 (fr
Inventor
Miguel A. Ondetti
Edward W. Petrillo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
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 ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Publication of EP0000833A1 publication Critical patent/EP0000833A1/fr
Application granted granted Critical
Publication of EP0000833B1 publication Critical patent/EP0000833B1/fr
Expired legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Pyrrole Compounds (AREA)
EP78300245A 1977-08-11 1978-08-03 Dérivés de phosphonoacylprolines et leur usage comme médicaments Expired EP0000833B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82381877A 1977-08-11 1977-08-11
US823818 1977-08-11

Publications (2)

Publication Number Publication Date
EP0000833A1 true EP0000833A1 (fr) 1979-02-21
EP0000833B1 EP0000833B1 (fr) 1981-09-02

Family

ID=25239818

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300245A Expired EP0000833B1 (fr) 1977-08-11 1978-08-03 Dérivés de phosphonoacylprolines et leur usage comme médicaments

Country Status (11)

Country Link
US (1) US4151172A (fr)
EP (1) EP0000833B1 (fr)
JP (1) JPS5430158A (fr)
AU (1) AU523323B2 (fr)
CA (1) CA1109476A (fr)
DE (1) DE2860019D1 (fr)
DK (1) DK147422C (fr)
HU (1) HU176712B (fr)
IE (1) IE47170B1 (fr)
IT (1) IT1098006B (fr)
NO (1) NO149923C (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009183A1 (fr) * 1978-09-07 1980-04-02 Merck & Co. Inc. Dérivés phosphoryle d'aminoacides et composition anti-hypertensive les contenant
FR2439790A1 (fr) * 1978-10-23 1980-05-23 Squibb & Sons Inc Phosphinylalcanoyl prolines a action therapeutique, et leurs procedes de preparation
EP0053902A1 (fr) * 1980-12-04 1982-06-16 E.R. Squibb & Sons, Inc. Prolines substituées par un groupe phosphinylalcanoyle
EP0058427A2 (fr) * 1981-02-17 1982-08-25 Merck & Co. Inc. Amides substitués de l'acide phosphonique, procédé pour leur préparation et une composition pharmaceutique pour le traitement de l'hypertension
EP0063896A1 (fr) * 1981-04-27 1982-11-03 E.R. Squibb & Sons, Inc. Compositions contenant des dérivés amino et amino substitué phosphinyl alcanoyle
EP0070131A1 (fr) * 1981-07-09 1983-01-19 Analytical Research Pharmaceuticals Pty. Ltd. Acides phosphonoalcanoylamino
EP0091525A2 (fr) * 1982-04-08 1983-10-19 Analytical Research Pharmaceuticals Pty. Ltd. Acides phosphonoalcanoylaminés
EP0095584A2 (fr) * 1982-04-30 1983-12-07 E.R. Squibb & Sons, Inc. 4-Phénoxy- et 4-phénylthio-prolines substituées
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

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690940A (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
US4690937A (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
ZA794723B (en) * 1978-09-11 1980-08-27 Univ Miami Anti-hypertensive agents
US4698355A (en) * 1979-08-14 1987-10-06 University Of Miami Anti-hypertensive agents
US4695577A (en) * 1979-08-14 1987-09-22 University Of Miami Anti-hypertensive agents
US4690939A (en) * 1979-08-14 1987-09-01 University Of Miami Anti-hypertensive agents
US4690936A (en) * 1980-03-05 1987-09-01 University Of Miami Anti-hypertensive agents
US4734420A (en) * 1980-03-05 1988-03-29 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
US4416833A (en) * 1981-05-04 1983-11-22 E. R. Squibb & Sons, Inc. Substituted carbonyl phosphinyl-alkanoyl compounds
US4381297A (en) * 1981-05-04 1983-04-26 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
US4560681A (en) * 1982-04-22 1985-12-24 E. R. Squibb & Sons, Inc. Phosphinylmethylaminocarbonyl imino acid compounds useful for treating hypertension
US4448772A (en) * 1982-04-22 1984-05-15 E. R. Squibb & Sons, Inc. Phosphinylmethylaminocarbonyl imino acid compounds useful for treating hypertension
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
US4616005A (en) * 1982-06-23 1986-10-07 E. R. Squibb & Sons, Inc. Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives
US4567166A (en) * 1982-07-14 1986-01-28 E. R. Squibb & Sons, Inc. Amino and substituted amino phosphinylalkanoyl compounds useful for treating hypertension
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
CA2021409A1 (fr) * 1989-08-21 1991-02-22 Donald S. Karanewsky Amino ou imino acides a groupement phosphonate substitue, utiles comme antihypertenseurs
DE3939142A1 (de) * 1989-11-27 1991-05-29 Hoechst Ag Verfahren zur oxidation von 2-hydroxy-aethylphosphonsaeuredialkylestern
US6011021A (en) * 1996-06-17 2000-01-04 Guilford Pharmaceuticals Inc. Methods of cancer treatment using naaladase inhibitors
US5795877A (en) * 1996-12-31 1998-08-18 Guilford Pharmaceuticals Inc. Inhibitors of NAALADase enzyme activity
US5977090A (en) * 1996-09-27 1999-11-02 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitors
US5863536A (en) * 1996-12-31 1999-01-26 Guilford Pharmaceuticals Inc. Phosphoramidate derivatives
US5672592A (en) * 1996-06-17 1997-09-30 Guilford Pharmaceuticals Inc. Certain phosphonomethyl-pentanedioic acid derivatives thereof
US6054444A (en) 1997-04-24 2000-04-25 Guilford Pharmaceuticals Inc. Phosphonic acid 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
RU2218179C2 (ru) 1996-06-17 2003-12-10 Гилфорд Фармасьютикалз Инк. СПОСОБЫ ЛЕЧЕНИЯ РАКА С ПРИМЕНЕНИЕМ ИНГИБИТОРОВ NAALADазы
US5902817A (en) * 1997-04-09 1999-05-11 Guilford Pharmaceuticals Inc. Certain sulfoxide and sulfone derivatives
US6384022B1 (en) 1996-06-17 2002-05-07 Guilford Pharmaceuticals Inc. Prodrugs of NAALAdase inhibitors
US6046180A (en) * 1996-06-17 2000-04-04 Guilford Pharmaceuticals Inc. NAALADase inhibitors
US5962521A (en) * 1997-04-04 1999-10-05 Guilford Pharmaceuticals Inc. Hydroxamic acid derivatives
US5981209A (en) * 1997-12-04 1999-11-09 Guilford Pharmaceuticals Inc. Use of NAALADase activity to identify prostate cancer and benign prostatic hyperplasia
US6028216A (en) * 1997-12-31 2000-02-22 Guilford Pharmaceuticals Inc. Asymmetric syntheses and intermediates for preparing enantiomer-enriched hydroxyphosphinyl derivatives
US6121252A (en) * 1998-03-30 2000-09-19 Guilford Pharmaceuticals Inc. Phosphinic acid derivatives
US6395718B1 (en) 1998-07-06 2002-05-28 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of inhibiting angiogenesis using naaladase inhibitors
US6265609B1 (en) 1998-07-06 2001-07-24 Guilford Pharmaceuticals Inc. Thio-substituted pentanedioic acid derivatives
DE69927502T2 (de) 1998-07-06 2006-07-06 Mgi Gp, Inc. (N.D.Ges.D. Staates Delaware) Naaladase-hemmer anwendbar als pharmazeutische verbindungen und zusammensetzungen
US6313159B1 (en) 1999-08-20 2001-11-06 Guilford Pharmaceuticals Inc. Metabotropic glutamate receptor ligand derivatives as naaladase inhibitors
ITMI20010395A1 (it) 2001-02-27 2002-08-27 Dompe Spa Omega-amminoalchilammidi di acidi r-2-aril-propionici come inibitori della chemiotassi di cellule polimorfonucleate e mononucleate
WO2004052830A1 (fr) 2002-12-10 2004-06-24 Dompe S.P.A. Arylcetones chirales utilisees pour traiter des maladies inflammatoires dependant des neutrophiles
WO2011080736A1 (fr) * 2009-12-29 2011-07-07 Mapi Pharma Hk Limited Composés intermédiaires et procédés pour la préparation de tapentadol et de composés apparentés

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4048156A (en) * 1968-05-24 1977-09-13 E. I Du Pont De Nemours And Company Carbamoylphosphonates
US4025332A (en) * 1974-10-01 1977-05-24 Monsanto Company Increasing sucrose content of sugarcane plants with N-phosphonomethylglycinamides
US4046889A (en) * 1976-02-13 1977-09-06 E. R. Squibb & Sons, Inc. Azetidine-2-carboxylic acid derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 79, 5598s (1973) *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009183A1 (fr) * 1978-09-07 1980-04-02 Merck & Co. Inc. Dérivés phosphoryle d'aminoacides et composition anti-hypertensive les contenant
FR2439790A1 (fr) * 1978-10-23 1980-05-23 Squibb & Sons Inc Phosphinylalcanoyl prolines a action therapeutique, et leurs procedes de preparation
EP0053902A1 (fr) * 1980-12-04 1982-06-16 E.R. Squibb & Sons, Inc. Prolines substituées par un groupe phosphinylalcanoyle
EP0058427A3 (fr) * 1981-02-17 1983-10-05 Merck & Co. Inc. Amides substitués de l'acide phosphonique, procédé pour leur préparation et une composition pharmaceutique pour le traitement de l'hypertension
EP0058427A2 (fr) * 1981-02-17 1982-08-25 Merck & Co. Inc. Amides substitués de l'acide phosphonique, procédé pour leur préparation et une composition pharmaceutique pour le traitement de l'hypertension
EP0063896A1 (fr) * 1981-04-27 1982-11-03 E.R. Squibb & Sons, Inc. Compositions contenant des dérivés amino et amino substitué phosphinyl alcanoyle
EP0070131A1 (fr) * 1981-07-09 1983-01-19 Analytical Research Pharmaceuticals Pty. Ltd. Acides phosphonoalcanoylamino
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 (fr) * 1982-04-08 1983-10-19 Analytical Research Pharmaceuticals Pty. Ltd. Acides phosphonoalcanoylaminés
EP0091525A3 (fr) * 1982-04-08 1984-02-29 Analytical Research Pharmaceuticals Pty. Ltd. Acides phosphonoalcanoylaminés
EP0095584A2 (fr) * 1982-04-30 1983-12-07 E.R. Squibb & Sons, Inc. 4-Phénoxy- et 4-phénylthio-prolines substituées
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

Also Published As

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

Similar Documents

Publication Publication Date Title
EP0000833B1 (fr) Dérivés de phosphonoacylprolines et leur usage comme médicaments
US4168267A (en) Phosphinylalkanoyl prolines
US4337201A (en) Phosphinylalkanoyl substituted prolines
EP0063896B1 (fr) Compositions contenant des dérivés amino et amino substitué phosphinyl alcanoyle
HU189207B (en) Process for the preparation of phosphor containing compounds
JPS58210097A (ja) ホスフイニルアルカノイル置換イミノ酸類
KR900003533B1 (ko) 불포화 아미노산 및 이의 제조방법
US4384123A (en) Phosphinylalkanoyl substituted prolines
Liu et al. Asymmetric synthesis of N‐protected chiral 1‐aminoalkylphosphonic acids and synthesis of side chain–functionalized depsiphosphonopeptides
US4186268A (en) Mercaptoacylpyrrolidine phosphonic acids and related compounds
US4396772A (en) Phosphinylalkanoyl amino acids
KR100297180B1 (ko) 인지질유도체및이의제조방법
US4206122A (en) Derivatives of pyrrolidinecarboxaldehyde and piperidinecarboxaldehyde and intermediates therefor
EP0095584B1 (fr) 4-Phénoxy- et 4-phénylthio-prolines substituées
US5583123A (en) Certain tetrazole derivatives
EP0070131A1 (fr) Acides phosphonoalcanoylamino
US5473092A (en) Synthesis of optically-active phosphono analogs of succinates
EP0091525A2 (fr) Acides phosphonoalcanoylaminés
CA2271814A1 (fr) Nouveaux phosphonates, leur procede de preparation et medicaments

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB LU NL SE

17P Request for examination filed
XX Miscellaneous (additional remarks)

Free format text: IN HEFT 42 V.16.10.80 S.546,SP.1 IST DIE VEROEFF.NR.IN 0000883 ZU BERICHTIGEN

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): BE CH DE FR GB LU NL SE

REF Corresponds to:

Ref document number: 2861012

Country of ref document: DE

Date of ref document: 19811126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19820831

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19830517

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19840625

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19840809

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19840930

Year of fee payment: 7

Ref country code: BE

Payment date: 19840930

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19841031

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19850831

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19860804

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19860831

BERE Be: lapsed

Owner name: E.R. SQUIBB & SONS INC.

Effective date: 19860831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19870301

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19870430

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19870501

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881117

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Effective date: 19890831

EUG Se: european patent has lapsed

Ref document number: 78300245.4

Effective date: 19870812

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT