US3410944A - Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof - Google Patents

Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof Download PDF

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Publication number
US3410944A
US3410944A US435344A US43534465A US3410944A US 3410944 A US3410944 A US 3410944A US 435344 A US435344 A US 435344A US 43534465 A US43534465 A US 43534465A US 3410944 A US3410944 A US 3410944A
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United States
Prior art keywords
hydroxyphenyl
ethylamino
formula
propanol
salts
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Expired - Lifetime
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US435344A
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English (en)
Inventor
Volkert Claassen
Jan Van Dijk
Hendrik Durk Moed
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US Philips Corp
North American Philips Co Inc
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US Philips Corp
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Classifications

    • 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
    • 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
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/10—Mercury compounds

Definitions

  • the invention relates to a new compound of the FormulaI and salts thereof.
  • the compound and its salts are to be considered in particular to be used, after being brought in a therapeutic form of administration known per se, in the treatment of pregnant women with threatened abortion and in the treatment of dysmenorrhea.
  • the uterospasmolytic activity was found inter alia in experiments in which the influence on the spasms, pro prised in the uteri of rats by the administration of pituitrin as a spasmogen, of the compound according to the invention was compared with that of that compound of Formula II in which R is an isobutyl group, which compound is the active constituent of a therapeutic which is known under the name of Dilatol. In this case it appeared that for reaching the same spasmolytic effect as with the known compound, only half of the quantity of the new compound is necessary.
  • hypotensive action between the two compounds was found in experiments in which cats were used as experimental animals. It was found that the known compound has a hypotensive effect which is approximately twice as large as the compound according to the invention.
  • a particularly suitable method is that in which a ketone of the Formula III or a salt thereof, in which formula Y and Y are possibly etherified or esterified hydroxy groups, is converted into the alcohol of the Formula I by reduction if required followed by hydrolysis or hydroge'nolysis of esterified or etherified hydroxy groups Y and/ or Y'.
  • the aminoketones of the Formula IH can be prepared, for example, by reaction of an amine of the Formula IV with a halogenide of the Formula V
  • etherified hydroxy groups Y and/or Y are to be considered preferably ar-alkoxy groups, for example, benzyloxy-, diphenyl-, methoxyor triphenylmethoxy groups.
  • esterified hydroxy groups Y and/or Y" are to be considered, for example, hydroxy groups esterified with lower fatty acids, for example, acetic acid, or with toluenesulphonic acid.
  • the reduction of the keto group to the carbinol group may be carried out in any manner known for this type of reduction, for example, by catalytic hydrogenation by means of Ni, Pt or 'Pd as a catalyst, or by reduction with aluminum amalgam. Very good results are obtained also when this reduction is carried out by means of a complex metal hydride, for example, with LiAlH, or with NaBH.
  • the compounds according to the invention may be prepared by reaction of a. compound of the Formula VI with a compound of the Formula VII where Y and Y have the above indicated meanings and Z and X are groups which, during the coupling reaction,
  • the reduction of the intermediately formed acid amide to the secondary amide is preferably carried out by means of a complex metal hydride or metal alkyl hydride, for example, LiAlH or diisobutylaluminiumhydride.
  • a complex metal hydride or metal alkyl hydride for example, LiAlH or diisobutylaluminiumhydride.
  • racemates are obtained, these may be separated by commonly used methods, by fractional crystallisation. Also by methods known per se the separate optical antipodes may be prepared, either by resolution of the racemates, or by choice of optically active starting substances during the synthesis.
  • Both the free base and salts of the compound according to the invention can be used for the preparation of new pharmaceutical compositions.
  • salts are to be considered, for example, acid addition salts of the base of the Formula I with hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, sul-famic acid, tartaric acid, citric acid and acetic acid.
  • the pharmacologically active substances may be processed in any known manner to pharmaceutical compositions by mixing with or dissolving in solid or liquid carrier materials commonly used in pharmacy, for example, starch, talcum powder, lactose, gelatin, sodium carboxy methyl cellulose, magnesium stearate and/or mixtures thereof as solid carrier materials and, for example, water rendered isotonic with blood by means of salt, or water mixed with, for example, glycerin as liquid carrier.
  • solid or liquid carrier materials commonly used in pharmacy, for example, starch, talcum powder, lactose, gelatin, sodium carboxy methyl cellulose, magnesium stearate and/or mixtures thereof as solid carrier materials and, for example, water rendered isotonic with blood by means of salt, or water mixed with, for example, glycerin as liquid carrier.
  • new pharmaceutical compositions such as injection liquids, powders and solid pharmaceutical dosage unit forms, such as tablets, coated tablets and suppositories, are obtained which are characterized by a content of the new compound of the
  • the resulting residue which consisted of the hydrochloride of 4-hydroxy-2- ⁇ 2-(4-methoxyphenyl)ethylamino ⁇ propiophenone, was mixed with 30 ml. of a 48% hydrobromic acid solution and the mixture was boiled until no methylbromide developed any more, which was the case after approximately 45 minutes. Then the reaction mixture was stored in the refrigerator, after which the hydrobromide of 4'-hydroxy-2- ⁇ 2-(4-hydroxyphenyl)- ethylamino ⁇ propiophenone crystallized.
  • Example II A solution of 12.76 g. of 2-bromo-4' benzyloxypropiophenone, 9.08 g. of 2-(4-benzyloxyphenyl)ethylamine and 4.44 g. of thiethylamine in 40 ml. of ethanol was boiled for three hours. The solution was partially evaporated as a result of which some substance crystallized out. To the mixture were added ml. of water and 3 ml. of ether and the non-dissolved substance (hydrobromide of the reaction product) was removed by filtration. The two layers of the filtrate were separated, the ether layer was washed once again with water and then mixed with an excess of 4 N hydrochloric acid. After all the hydrochloride of the.
  • reaction product had crystallized, it was sucked 01f, washed with water and ether and dried in vacuo over KOH.
  • the yield was 10.3 g. of hydrochloride of 4'-benzyloxy-2- ⁇ 2- 4-benzyloxyphenyl ethylamino ⁇ propiophenone with melting point 202204
  • a solution of 2.00 g. of this product in 60 ml. of 80% ethanol was hydrogenated until the two benzyl groups had been removed hydrogenolytically, which appeared from a considerable decrease of the hydrogenation rate.
  • the catalyst was filtered off and the alcohol removed from the filtrate for the greater part by distilling it off the vacuo.
  • the resulting concentrate was diluted with water and again hydrogenated until no hydrogen was taken up any longer.
  • Example 111 3.45 g. of sodium borohydride were dissolved in a mixture of 75 ml. of ethanol and 1.5 ml. of 2 N sodium hydroxide solution. To this solution was added a solution of g. of hydrochloride of 4'-benzyloxy-2- ⁇ 2-(4- benzyloxyphenyl)ethylamino ⁇ propiophen0ne (Example II) in 450 ml. of methanol, to which 1.2 g. of sodium hydroxide (in a few mls. of water) had been added. The mixture was boiled for three hours and then evaporated in vacuo to approximately 300 g. of residue. Then again 300 ml.
  • a liquid uterospasmolytic composition containing a compound selected from the group consisting of 1-(4- hydroxyphenyl -2- ⁇ 2- (4-hydroxyphenyl) ethylamino ⁇ propanol and the physiologically non-toxic acid addition salts thereof and a liquid non-toxic pharmaceutical carner.
  • a solid uterospasmolytic composition containing a compound selected from the group consisting of 1-(4- hydroxyphenyl -2- ⁇ 2- (4-hydroxyphenyl) ethylamino ⁇ propanol and the physiologically non-toxic acid addition salts thereof and a solid non-toxic pharmaceutical carrier.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US435344A 1964-02-27 1965-02-25 Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof Expired - Lifetime US3410944A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
NL6401871A NL6401871A (de) 1964-02-27 1964-02-27

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US3410944A true US3410944A (en) 1968-11-12

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US435344A Expired - Lifetime US3410944A (en) 1964-02-27 1965-02-25 Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof

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US (1) US3410944A (de)
AT (4) AT270618B (de)
BE (1) BE660244A (de)
BR (1) BR6567446D0 (de)
CH (3) CH472368A (de)
DE (1) DE1293782B (de)
DK (2) DK118827B (de)
ES (1) ES309809A1 (de)
FR (2) FR1483718A (de)
GB (1) GB1111451A (de)
NL (1) NL6401871A (de)
SE (1) SE339481B (de)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966814A (en) * 1969-12-12 1976-06-29 Boehringer Ingelheim Gmbh 1-Phenyl-2-(Naphthylalkyl-amino)-ethanols and salts thereof
US4704407A (en) * 1984-12-20 1987-11-03 Eli Lilly And Company Soluble dobutamine salts
EP1095932A1 (de) * 1998-07-08 2001-05-02 Kissei Pharmaceutical Co., Ltd. Phenoxyessigsäure-verbindungen und medizinische zusammensetzungen, die diese enthalten
CN102060716A (zh) * 2009-11-15 2011-05-18 海南中化联合制药工业股份有限公司 一种盐酸利托君的制备方法
ITMI20100740A1 (it) * 2010-04-29 2011-10-30 Lundbeck Pharmaceuticals Italy S Pa Processo di preparazione di ritodrina cloridrato
CN102976959A (zh) * 2012-12-07 2013-03-20 许学农 利托君的制备方法
US10288602B2 (en) 2013-01-08 2019-05-14 Atrogi Ab Screening method, a kit, a method of treatment and a compound for use in a method of treatement
US11357757B2 (en) 2017-09-13 2022-06-14 Atrogi Ab Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia
US11427539B2 (en) 2017-09-13 2022-08-30 Atrogi Ab Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia
US11648216B2 (en) 2017-09-13 2023-05-16 Atrogi Ab Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia
US11793774B2 (en) 2017-09-13 2023-10-24 Atrogi Ab Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB202205895D0 (en) 2022-04-22 2022-06-08 Atrogi Ab New medical uses

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL86359C (de) *
US2661373A (en) * 1953-03-02 1953-12-01 Kulz Ida Certain amino alcohols and ketones
CA623286A (en) * 1961-07-04 N.V. Philips Gloeilampenfabrieken Production of optically active 1-(3',4'-dihydroxyphenyl)-2-amino ethanols
AT228786B (de) * 1961-01-23 1963-08-12 Philips Nv Verfahren zur Herstellung des neuen (-)-Enantiomeren des 1-(p-Hydroxyphenyl)-2-(α-methyl- γ-phenyl-propylamino)-propanols-(1) und seiner Säureadditionssalze
US3211792A (en) * 1963-01-24 1965-10-12 Hoffmann La Roche 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof
US3250803A (en) * 1961-07-06 1966-05-10 Philips Corp Method of manufacturing the individual racemates of n-(p-hydroxyphenylisopropyl) arterenol and products

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE612995A (fr) * 1961-01-23 1962-07-23 Philips Nv Procédé de préparation d'un nouveau composé à activité optique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL86359C (de) *
CA623286A (en) * 1961-07-04 N.V. Philips Gloeilampenfabrieken Production of optically active 1-(3',4'-dihydroxyphenyl)-2-amino ethanols
US2661373A (en) * 1953-03-02 1953-12-01 Kulz Ida Certain amino alcohols and ketones
AT228786B (de) * 1961-01-23 1963-08-12 Philips Nv Verfahren zur Herstellung des neuen (-)-Enantiomeren des 1-(p-Hydroxyphenyl)-2-(α-methyl- γ-phenyl-propylamino)-propanols-(1) und seiner Säureadditionssalze
US3250803A (en) * 1961-07-06 1966-05-10 Philips Corp Method of manufacturing the individual racemates of n-(p-hydroxyphenylisopropyl) arterenol and products
US3211792A (en) * 1963-01-24 1965-10-12 Hoffmann La Roche 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966814A (en) * 1969-12-12 1976-06-29 Boehringer Ingelheim Gmbh 1-Phenyl-2-(Naphthylalkyl-amino)-ethanols and salts thereof
US4704407A (en) * 1984-12-20 1987-11-03 Eli Lilly And Company Soluble dobutamine salts
EP1095932A1 (de) * 1998-07-08 2001-05-02 Kissei Pharmaceutical Co., Ltd. Phenoxyessigsäure-verbindungen und medizinische zusammensetzungen, die diese enthalten
EP1095932A4 (de) * 1998-07-08 2002-10-16 Kissei Pharmaceutical Phenoxyessigsäure-verbindungen und medizinische zusammensetzungen, die diese enthalten
US6538152B1 (en) 1998-07-08 2003-03-25 Kissei Pharmaceutical Co., Ltd. Phenoxyacetic acid derivatives and medicinal compositions containing the same
CN102060716A (zh) * 2009-11-15 2011-05-18 海南中化联合制药工业股份有限公司 一种盐酸利托君的制备方法
WO2011134724A3 (en) * 2010-04-29 2012-03-15 Lundbeck Pharmaceuticals Italy S.P.A. Method for preparing ritodrine hydrochloride
WO2011134724A2 (en) 2010-04-29 2011-11-03 Lundbeck Pharmaceuticals Italy S.P.A. Method for preparing ritodrine hydrochloride
ITMI20100740A1 (it) * 2010-04-29 2011-10-30 Lundbeck Pharmaceuticals Italy S Pa Processo di preparazione di ritodrina cloridrato
US8912360B2 (en) 2010-04-29 2014-12-16 Lundbeck Pharmaceuticals Italy S.P.A. Methods for preparing ritodrine hydrochloride
CN102976959A (zh) * 2012-12-07 2013-03-20 许学农 利托君的制备方法
CN102976959B (zh) * 2012-12-07 2014-06-04 许学农 利托君的制备方法
US10288602B2 (en) 2013-01-08 2019-05-14 Atrogi Ab Screening method, a kit, a method of treatment and a compound for use in a method of treatement
US11357757B2 (en) 2017-09-13 2022-06-14 Atrogi Ab Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia
US11427539B2 (en) 2017-09-13 2022-08-30 Atrogi Ab Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia
US11648216B2 (en) 2017-09-13 2023-05-16 Atrogi Ab Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia
US11793774B2 (en) 2017-09-13 2023-10-24 Atrogi Ab Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia

Also Published As

Publication number Publication date
AT270618B (de) 1969-05-12
SE339481B (de) 1971-10-11
CH472368A (de) 1969-05-15
BR6567446D0 (pt) 1973-08-02
FR4404M (de) 1966-10-10
CH539604A (de) 1973-07-31
AT261590B (de) 1968-05-10
DE1293782B (de) 1969-04-30
AT268252B (de) 1969-02-10
ES309809A1 (es) 1965-07-01
BE660244A (de) 1965-08-25
FR1483718A (fr) 1967-06-09
NL6401871A (de) 1965-08-30
CH503692A (de) 1971-02-28
AT264502B (de) 1968-09-10
DK118827B (da) 1970-10-12
GB1111451A (en) 1968-04-24
DK116740B (da) 1970-02-09

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