US3872147A - 1-phenoxy-2-hydroxy-3-alkylamino-propanes - Google Patents

1-phenoxy-2-hydroxy-3-alkylamino-propanes Download PDF

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Publication number
US3872147A
US3872147A US204316A US20431671A US3872147A US 3872147 A US3872147 A US 3872147A US 204316 A US204316 A US 204316A US 20431671 A US20431671 A US 20431671A US 3872147 A US3872147 A US 3872147A
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Prior art keywords
phenoxy
formula
hydroxy
amino
propane
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Expired - Lifetime
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US204316A
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English (en)
Inventor
Herbert Koppe
Werner Kummer
Helmut Stahle
Karl Zeile
Albrecht Engelhardt
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CH Boehringer Sohn AG and Co KG
Boehringer Ingelheim GmbH
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CH Boehringer Sohn AG and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

  • R is hydrogen, halogen, cyano, alkyl of 1 to 4 carbon l atoms, alltoxy of l to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms,
  • R is hydrogen, halogen, alkyl of l to 4 carbon atoms or alkoxy of l to 4 carbon atoms
  • R is other than 2-bromo when R is 1,1-diethyl-butyl and R and R are hydrogen, and their non-toxic, pharmacologically acceptable acid addition salts.
  • the compounds ofthe formula 1 may be prepared by various methods involving well known chemical principles, among which the following have proved to be particularly efficient and convenient:
  • Method A By reacting a compound of the formula lit l or CH(OH)CH Hal, where Hal is halogen, with an alkylamine of the formula NH R lll. wherein R has the same meanings as in formula I, in a manner and under conditions which are customary for such reactions.
  • Method B By splitting off an easily removable protective group from a compound of the formula i. (IV) wherein R, R R and R have the same meanings as in formula 1 and G is a hydrolytically removable protective group, such as acyl or acetal.
  • Method C By converting the substituent A in a compound ofthe formula into a substituent R,, as defined in formula I.
  • R, R and R in formula V have the same meanings as in formula 1, and A may have any one of the following meanings:
  • Haloalkyl which is convertible into aminoalkyl, al kylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or alkoxyalkyl by reaction with ammonia, an amine, water or aliphatic alcohols;
  • Amino which is convertible into cyano or halogen by diazotization and heating with copper(l)-cyanide or copper (l)-halide, respectively.
  • the conversion of a compound of the formula V into a compound of the formula 1 is effected by applying the required known reaction, i.e. dehydration exchange reaction, condensation, alkylation, reduction or diazotization and subsequent heating with a coppertl)-salt, etc, to the particular compound of the formula V.
  • Method D By introducing a halogen substituent into the phenyl ring of a compound of the formula wherein R has the same meanings as in formula 1, and Ar is Q go 2 wherein R R and R have the same meanings as in formula 1 and X is hydrogen or a cation, especially an alkali metal cation.
  • An epoxide of the formula 11 may be used for the preparation of other starting compounds; for example, a halohydrin of the formula 11 may be prepared by reacting the corresponding epoxide with a hydrohalic acid.
  • a compound of the formula IV may be prepared by reacting a halohydrin of the formula 11 with a compound which forms a protective group G, such as vinyl ether or dihydropyran, and subsequently reacting the compound of the formula (VIII) formed thereby, wherein R R and R and G have the same meanings as in formula IV and Hal is halogen, with an amine of the formula Ill.
  • a halohydrin of the formula 11 with a compound which forms a protective group G, such as vinyl ether or dihydropyran, and subsequently reacting the compound of the formula (VIII) formed thereby, wherein R R and R and G have the same meanings as in formula IV and Hal is halogen, with an amine of the formula Ill.
  • compounds of the formulas V and V1 may be prepared pursuant to method A described herein, i.e. starting from a corresponding phenol by way of the corresponding l-phenoxy-2,3-epoxypropane and reaction of the latter with an alkylamine of the formula III.
  • the compounds according to the present invention comprise an asymmetric carbon atom and therefore occur as racemic mixtures as well as in the form of optically active antipodes.
  • the latter may be obtained by separating the racemic mixture with the aid of customary auxiliary acids, such as dibenzoyl-D-tartaric acid or D-3-bromocamphor-8-sulfonic acid, or also by using the corresponding optically active starting compound.
  • the compounds of the formula 1 are organic bases and therefore form acid addition salts with inorganic or organic acids.
  • non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid,
  • Such acid addition salts may be obtained by conventional methods, for instance, by dissolving the free base in a suitable inert solvent and acidifying the solution with the desired inorganic or organic acid.
  • EXAMPLE 1 Preparation of l-(o-cyano-phenoxy)-2-hydroxy-3- [(a,a-dimethyln-propyl)-amino]-propane and its hydrochloride by Method A 14 gm of 82% a,a-dimethyl-n-propyl-amine were added to a solution of 10.5 gm (0.06 mol) of l-(ocyano-phenoxy)-2,3-epoxy-propane in cc of etha- "nol, the mixture was allowed to stand for 24 hours at 20C., and thereafter it was refluxed on a boiling water bath for about 3 hours.
  • the resulting solution was acidified with a solution of 3.8 gm of oxalic acid in acetone, ether was added thereto, and the crystalline precipitate formed thereby was recrystallized from acetone, yielding 4.9 gm of the oxalate, m.p.
  • the precipitated base was dissolved in ethanol, the solution was acidified with ethereal hydrochloric acid, and the precipitate formed thereby was recrystallized from ethanol/ether, yielding 8.0 gm of the hydrochloride, m.p. 1l9l22C., of the formula ether.
  • the aqueous phase was evaporated to dryness in vacuo, and the residue was recrystallized twice from acetonitrile/ether, yielding 8.4 gm of the hydrochloride, m.p.
  • EXAMPLE 38 Preparation of 1-(o-cyano-phenoxy)-2-hydroxy-3 [(a,a-dimethyl n-pentyl)-amino]-propane and its hydrochloride by method A 2.1 gm (0.087 mol) of l-(o-cyano-phenoxy)-2- hydroxy 3-bromo-propane were dissolved in 50 cc of ethanol, 2 gm (0.0175 mol) of tert.heptylamine (a,a-dimethyl-n-pentylamine) were added to the solution, and the mixture was refluxed for two hours.
  • tert.heptylamine a,a-dimethyl-n-pentylamine
  • the starting compound was prepared as follows: 4.6 gm (0.019 mol) of 1-(m-tolyloxy)-2-hydroxy-3-bromopropane were slowly admixed with 1.6 gm of dihydropyran in the presence of a catalytic amount of p-toluene-sulfonic acid, whereby an exothermic reaction occurred. After about 15 minutes the reaction mixture was dissolved in 50 cc of ethanol, 2.2 gm (0.019 mol) ofa,wdimethyl-n-pentyl-amine were added to the solution, and the mixture was refluxed for 5 hours.
  • EXAMPLE 40 Preparation of 1-(m'amino-phenoxyl-2-hydroxy3- [(a,a-dimethyl-n-butyl)-amino]-propane and its dihydrochloride by method C 7.1 gm (0.024 mol) of l-(m-nitro-phcnoxy)-2 hydroxy-3-[(ma-dimethyl-n-butyl)-amino]-propane were hydrogenated at 20C in 50 cc of methanol in the presence of Raney nickel. After absorption ofthe theo retical amount of hydrogen the catalyst was filtered off.
  • the methanol was distilled out of the filtrate, and the residue, raw l-(m-amino-phenoxy)-2-hydroxy-3-[(a,adimethyl-n-butyl)-amino]-propane, was dissolved in ethanol.
  • the ethanolic solution was acidified with ethereal hydrochloric acid, and the crystalline precipitate formed thereby was recrystallized by dissolving it in ethanol and adding ether to the solution.
  • the ethereal solution was washed with water,
  • the compounds of the invention are useful for the treatment and prophylaxis of diseases of the'coronary heart vessels and cardiac arrythmia, especially tachicardia, in warmblooded animals.
  • the compounds accord ing to the present invention are administered to warmblooded animals perorally or parenterally as sole active ingredients or in combination with other pharmacodynamically active ingredients, such as coronary dilators or sympathicomimetics, in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like.
  • One effective dosage unit of the compounds according to the present invention is from 0.0166 to 5.0 mgm/kg body weight, preferably 0.083 to 1.67 mgm/kg (peroral) or 0.0166 to 0.34 mgm/kg (parenteral).
  • EXAMPLE 43 Tablets The tablet composition was compounded from the following ingredients:
  • the individual ingredients were intimately admixed with each other, the mixture was granulated in customary fashion, and the granulate was pressed into 445 mgm-tablets.
  • Each tablet contained 40 mgm of the phenoxy-amino-propanol compound and, when administered perorally to a warm-blooded animal of about kg body weight in need of such treatment, produced very good B-adrenolytic effects.
  • the ingredients were intimately admixed with each other, and 200 mgm-portions ofthe mixture were filled into gelatin capsules of suitable size.
  • Each capsule contained 25 mgm of the phenoxy-amino-propanol compound and, when administered perorally to a warmblooded animal of about 60 kg body weight in need of such treatment, produced very good B-adrenolytic effects.
  • the propanol compound and the EDTA salt were dissolved in a sufficient amount of distilled water, and the solution was diluted to the indicated volume with additional distilled water, filtered until free from suspended particles, and filled into l cc-ampules under aseptic conditions, which were finally sterilized and sealed.
  • Each ampule contained 25 mgm of the phenoxy-amino-propanol compound, and when the contents thereof were administered intravenously to a warmblooded animal of about 60 kg body weight in need of such treatment, very good ,B-adrenolytic effects were produced.
  • CMC Carhoxymethyl cellulose
  • CAP Cellulose acetate phthalate
  • the propanol compound, the CMC and the stearic acid were intimately admixed with each other, the mixture was granulated in customary fashion with a solution of the CAP in 200 cc of a mixture of ethanol and ethyl acetate, and the granulate was pressed into 380 mgm-pill cores which were then coated with a sugarcontaining 5% solution of polyvinylpyrrolidone in water.
  • Each pill contained 25 mgm of the phenoxy-aminopropanol compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good ,B-adrenolytic effects.
  • EXAMPLE 47 Tablets with combination of active ingredients
  • the tablet composition was compounded from the following ingredients:
  • the propanol compound, the lactose, the corn starch, the colloidal silicic acid and the polyvinylpyrrolidone were intimately admixed with each other, the mixture was granulated in customary fashion with an aqueous solution of the soluble starch, the granulate was admixed with the magnesium stearate, and the composition was pressed into 500 mgm-tablets.
  • Each tablet contained 35 mgm of the phenoxy-aminocompound and 75 mgm of the pyrimidopyrimidine compound and, when administered perorally to a warmblooded animal of about 60 kg body weight in need of such treatment, produced very good B-adrenolytic and coronary dilating effects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US204316A 1967-12-13 1971-12-02 1-phenoxy-2-hydroxy-3-alkylamino-propanes Expired - Lifetime US3872147A (en)

Applications Claiming Priority (1)

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DE1643262A DE1643262C3 (de) 1967-12-13 1967-12-13 i-Phenoxy^-hydroxy-S-alklyaminopropane, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel

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JP (1) JPS5220457B1 (de)
AT (13) AT292670B (de)
BE (1) BE725490A (de)
BG (9) BG17298A3 (de)
BR (1) BR6804840D0 (de)
CA (1) CA954528A (de)
CH (2) CH532015A (de)
DE (1) DE1643262C3 (de)
DK (1) DK131029B (de)
ES (11) ES361189A1 (de)
FI (1) FI49497C (de)
FR (2) FR1596100A (de)
GB (1) GB1260866A (de)
HU (1) HU162734B (de)
IE (1) IE32758B1 (de)
IL (1) IL31266A (de)
NL (3) NL146709B (de)
PH (1) PH9266A (de)
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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3998874A (en) * 1971-03-23 1976-12-21 Gist-Brocades N.V. Phenylene di-ethers
US4038414A (en) * 1972-06-08 1977-07-26 Ciba-Geigy Corporation Amines and processes for their manufacture
US4039685A (en) * 1967-02-06 1977-08-02 Boehringer Ingelheim Gmbh 1-phenoxy-2-hydroxy-3-tert.-butylamino propane antiarrhythmic compounds
US4086272A (en) * 1970-07-18 1978-04-25 Pfizer Inc. Phenyl-alkanolamine, alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants
US4094991A (en) * 1975-06-17 1978-06-13 Nippon Shinyaku Co., Ltd. Substituted n-(carboxymethyl)-3-aminopropan-2-ol derivatives
US4119728A (en) * 1973-02-28 1978-10-10 Boehringer Ingelheim Gmbh 1-Phenoxy-2-hydroxy-3-alkynylamino-propanes and salts thereof and treatment of coronary diseases therewith
US4161530A (en) * 1975-01-06 1979-07-17 Ciba-Geigy Corporation Pharmaceutical combination preparations as hypnotics
US4243681A (en) * 1977-10-11 1981-01-06 Mead Johnson & Company Alkylthiophenoxypropanolamines and pharmaceutical compositions and uses thereof
US4309443A (en) * 1979-09-06 1982-01-05 Beecham Group Limited Cinnamic acid derivatives, their preparation, and pharmaceutical compositions containing them
WO1982001868A1 (en) * 1980-11-28 1982-06-10 Hospital Supply Corp American Method for treatment or prophylaxis of cardiac disorders
WO1982001869A1 (en) * 1980-11-28 1982-06-10 Hospital Supply Corp American Method for treatment or prophylaxis of cardiac disorders
US4371545A (en) * 1978-09-11 1983-02-01 Dolorgiet Beteiligungs Gmbh Isopropyl amine compounds
US4396629A (en) * 1980-12-29 1983-08-02 Sterling Drug Inc. Compositions, processes and method
US4435397A (en) 1980-04-08 1984-03-06 Nippon Shinyaku Co., Ltd. Carbamylpiperazine compounds
US4593119A (en) * 1980-11-28 1986-06-03 American Hospital Supply Corporation Method for treatment or prophylaxis of cardiac disorders
US4665094A (en) * 1985-08-29 1987-05-12 Merck & Co., Inc. Oculoselective beta-blockers for treatment of elevated intraocular pressure
EP0229507A1 (de) * 1985-12-24 1987-07-22 Merck & Co. Inc. Okuloselektive Betablocker
US4803198A (en) * 1981-08-08 1989-02-07 Kali-Chemie Pharma Gmbh 1-Phenyl-2-aminocarbonylindole compounds, preparation thereof and pharmaceutical compositions containing them
US4945182A (en) * 1985-12-24 1990-07-31 Merck & Co., Inc. Oculoselective beta-blockers
US5017609A (en) * 1984-04-09 1991-05-21 E. I. Du Pont De Nemours And Company Pharmaceutical composition and method of treatment or prophylaxis of cardiac disorders
US5480908A (en) * 1993-12-13 1996-01-02 American Cyanamid Company β3 -adrenergic agents benzodioxole dicarboxylates and their use in pharmaceutical compositions

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2309887C2 (de) * 1973-02-28 1983-11-10 C.H. Boehringer Sohn, 6507 Ingelheim 1-Aryloxy-2-hydroxy-3-alkinylaminopropan-Derivate und deren physiologisch verträgliche Säureadditionssalze, pharmazeutische Präparate und Herstellungsverfahren für die Verbindungen
US4652584A (en) * 1984-07-13 1987-03-24 Mcneilab, Inc. Acetylenic phenoxypropanol derivatives and pharmaceutical compositions for the treatment of hypertension

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3459782A (en) * 1963-08-26 1969-08-05 Boehringer Sohn Ingelheim 1-substituted phenoxy-2-hydroxy-3-isopropylamino-propanes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3459782A (en) * 1963-08-26 1969-08-05 Boehringer Sohn Ingelheim 1-substituted phenoxy-2-hydroxy-3-isopropylamino-propanes

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4039685A (en) * 1967-02-06 1977-08-02 Boehringer Ingelheim Gmbh 1-phenoxy-2-hydroxy-3-tert.-butylamino propane antiarrhythmic compounds
US4086272A (en) * 1970-07-18 1978-04-25 Pfizer Inc. Phenyl-alkanolamine, alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants
US3998874A (en) * 1971-03-23 1976-12-21 Gist-Brocades N.V. Phenylene di-ethers
US4038414A (en) * 1972-06-08 1977-07-26 Ciba-Geigy Corporation Amines and processes for their manufacture
US4119728A (en) * 1973-02-28 1978-10-10 Boehringer Ingelheim Gmbh 1-Phenoxy-2-hydroxy-3-alkynylamino-propanes and salts thereof and treatment of coronary diseases therewith
US4161530A (en) * 1975-01-06 1979-07-17 Ciba-Geigy Corporation Pharmaceutical combination preparations as hypnotics
US4094991A (en) * 1975-06-17 1978-06-13 Nippon Shinyaku Co., Ltd. Substituted n-(carboxymethyl)-3-aminopropan-2-ol derivatives
US4243681A (en) * 1977-10-11 1981-01-06 Mead Johnson & Company Alkylthiophenoxypropanolamines and pharmaceutical compositions and uses thereof
US4371545A (en) * 1978-09-11 1983-02-01 Dolorgiet Beteiligungs Gmbh Isopropyl amine compounds
US4309443A (en) * 1979-09-06 1982-01-05 Beecham Group Limited Cinnamic acid derivatives, their preparation, and pharmaceutical compositions containing them
US4435397A (en) 1980-04-08 1984-03-06 Nippon Shinyaku Co., Ltd. Carbamylpiperazine compounds
WO1982001869A1 (en) * 1980-11-28 1982-06-10 Hospital Supply Corp American Method for treatment or prophylaxis of cardiac disorders
US4387103A (en) * 1980-11-28 1983-06-07 American Hospital Supply Corporation Method for treatment or prophylaxis of cardiac disorders
WO1982001868A1 (en) * 1980-11-28 1982-06-10 Hospital Supply Corp American Method for treatment or prophylaxis of cardiac disorders
US4593119A (en) * 1980-11-28 1986-06-03 American Hospital Supply Corporation Method for treatment or prophylaxis of cardiac disorders
US4396629A (en) * 1980-12-29 1983-08-02 Sterling Drug Inc. Compositions, processes and method
US4803198A (en) * 1981-08-08 1989-02-07 Kali-Chemie Pharma Gmbh 1-Phenyl-2-aminocarbonylindole compounds, preparation thereof and pharmaceutical compositions containing them
US5017609A (en) * 1984-04-09 1991-05-21 E. I. Du Pont De Nemours And Company Pharmaceutical composition and method of treatment or prophylaxis of cardiac disorders
US4665094A (en) * 1985-08-29 1987-05-12 Merck & Co., Inc. Oculoselective beta-blockers for treatment of elevated intraocular pressure
EP0229507A1 (de) * 1985-12-24 1987-07-22 Merck & Co. Inc. Okuloselektive Betablocker
US4945182A (en) * 1985-12-24 1990-07-31 Merck & Co., Inc. Oculoselective beta-blockers
US5480908A (en) * 1993-12-13 1996-01-02 American Cyanamid Company β3 -adrenergic agents benzodioxole dicarboxylates and their use in pharmaceutical compositions

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YU237474A (en) 1977-12-31
ES375447A1 (es) 1972-05-01
YU237874A (en) 1977-12-31
NL7501794A (nl) 1975-05-30
YU237574A (en) 1978-02-28
YU33774B (en) 1978-05-15
ES375452A1 (es) 1972-05-16
ES375445A1 (es) 1972-05-16
YU33856B (en) 1978-06-30
YU237774A (en) 1978-02-28
AT292681B (de) 1971-08-15
YU238074A (en) 1977-12-31
ES375451A1 (es) 1972-05-01
YU237974A (en) 1977-12-31
YU33852B (en) 1978-06-30
DK131029C (de) 1975-10-06
NL7501792A (nl) 1975-05-30
FR8328M (de) 1970-12-07
FR1596100A (de) 1970-06-15
FI49497B (de) 1975-04-01
ES375453A1 (es) 1972-05-16
BG16445A3 (bg) 1972-11-20
FI49497C (fi) 1975-07-10
BG16330A3 (bg) 1972-08-20
YU33948B (en) 1978-09-08
YU33853B (en) 1978-06-30
YU33946B (en) 1978-09-08
YU294968A (en) 1978-02-28
CH532015A (de) 1972-12-31
AT298463B (de) 1972-05-10
IL31266A (en) 1974-09-10
NL151354B (nl) 1976-11-15
YU238274A (en) 1977-12-31
ES375450A1 (es) 1972-05-01
DE1643262B2 (de) 1974-11-07
BG16331A3 (bg) 1972-08-20
YU33851B (en) 1978-06-30
AT298459B (de) 1972-05-10
AT294799B (de) 1971-12-10
AT292677B (de) 1971-09-10
NL6817768A (de) 1969-06-17
DE1643262C3 (de) 1975-06-26
AT292679B (de) 1971-09-10
BG17298A3 (de) 1973-07-25
AT292678B (de) 1971-09-10
YU237674A (en) 1977-10-31
BG17297A3 (de) 1973-07-25
ES375444A1 (es) 1972-05-01
NL146709B (nl) 1975-08-15
YU33854B (en) 1978-06-30
GB1260866A (en) 1972-01-19
ES375449A1 (es) 1972-05-01
ES375448A1 (es) 1972-05-01
SE367396B (de) 1974-05-27
ES375446A1 (es) 1972-05-01
YU33773B (en) 1978-05-15
YU33947B (en) 1978-09-08
DK131029B (da) 1975-05-20
DE1643262A1 (de) 1972-04-20
IL31266A0 (en) 1969-02-27
ES361189A1 (es) 1970-08-16
AT292670B (de) 1971-09-10
YU238474A (en) 1978-02-28
BE725490A (de) 1969-06-13
YU33949B (en) 1978-09-08
IE32758L (en) 1969-06-13
AT292673B (de) 1971-09-10
HU162734B (de) 1973-04-28
AT292680B (de) 1971-09-10
BR6804840D0 (pt) 1973-03-08
BG19135A3 (de) 1975-04-30
BG16332A3 (bg) 1972-08-20
PH9266A (en) 1975-07-30
BG16444A3 (bg) 1972-11-20
YU238374A (en) 1977-12-31
AT292676B (de) 1971-09-10
AT292675B (de) 1971-09-10
BG16329A3 (bg) 1972-08-20
CH556816A (de) 1974-12-13
YU33855B (en) 1978-06-30
CA954528A (en) 1974-09-10
JPS5220457B1 (de) 1977-06-03
AT292674B (de) 1971-09-10
IE32758B1 (en) 1973-11-28
YU238174A (en) 1977-10-31

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