US3420853A - 1-amino-4-phenyl-3-buten-2-ols and salts thereof - Google Patents

1-amino-4-phenyl-3-buten-2-ols and salts thereof Download PDF

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Publication number
US3420853A
US3420853A US471434A US47143465A US3420853A US 3420853 A US3420853 A US 3420853A US 471434 A US471434 A US 471434A US 47143465 A US47143465 A US 47143465A US 3420853 A US3420853 A US 3420853A
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ether
solution
added
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water
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Hendrik Durk Moed
Gerard Bernard Paerels
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Philips North America LLC
US Philips Corp
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US Philips Corp
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings

Definitions

  • the invention relates to new compounds of Formula I wherein Y and Y are each independently selected from the group consisting of hydrogen, alkyl of l-4 carbon atoms, alkoxy of 1-4 carbon atoms and alkylthio of 1-4 carbon atoms and the pharmaceutically acceptable acid addition salts thereof and to new compounds of the Formula I wherein R is a member selected from the group consisting of alkyl and cycloalkyl, Y and Y are each independently selected from the group consisting of hydrogen, halogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms and alkylthio of 1-4 carbon atoms and the pharmaceutically acceptable acid addition salts thereof and to new compounds of the Formula 1 wherein R is a member selected from the group consisting of aralkyl and nuclear substituted derivatives thereof Y and Y are each independently selected from the group consisting of hydrogen, halogen, alkyl of l-4 carbon atoms, alkoxy of 1-4 carbon atoms and alkylthi
  • the compounds according to the invention have a very significant B-sympatholytic activity. Because of this activity the compounds according to the invention, when brought in a suitable form of administration, may be used in drugs for the treatment arrhythmia and in tachycardia, both in the case that these disturbances of heart regulation are the result of the use of another drug, for example, a uterospasmolytic, and in diseases, for example, angina pectoris and in hypertension. The fall in blood pressure also, as a result of the use of a uterospasmolytic, can be prevented by administering previously one of the compounds according to the invention.
  • a uterospasmolytic can be prevented by administering previously one of the compounds according to the invention.
  • the fi-sym'patholytic activity of the compounds according to the invention was found in experiments with a preparation of the isolated guinea pig atrium suspended in a Ringer solution and connected to a frequency counter. By the addition of N-isopropylnoradrenaline to this solution a strong frequency increase is produced and the measure in which this effect can be checked was measured by previously administering compounds according to the invention.
  • the compound of Formula II Q-CH CH-CHOH-CHa-HN-CHOHa-CHz-Ulla-Q has an activity which lasts many hours longer than that of the known fi-sympatholytic-u-(isopropylaminomethyl)- 2 naphthalene methanol.
  • the compound of Formula 11 gave an effect which was found to last over 6 hours.
  • the compounds according to the invention can be prepared according to methods which are known for the preparation of analogous compounds and according to methods analogous thereto.
  • the compounds according to the invention may be obtained by alkylating, in the reaction of a compound of Formula III, RNH with a compound of Formula IV in which formulae R, Y and Y have the meanings indicated for Formula I, 1*, 1 and I and Z represents one of the groups CHOH-CH Hlg wherein Hlg represents a halogen atom or a hydrate or alcoholate thereof.
  • Hlg preferably is Cl, Br or I atom.
  • the reaction may be carried out in manners well-known for alkylation reactions, preferably in the presence of an acid binder, for which an excess of the starting amine or, for example, a base, for example, triethylamine or calcium carbonate, may be added and preferably in an inert solvent, for example, an alcohol, for example, methanol or ethanol, a hydrocarbon, for example, benzene or toluene, or an ether, for example, diethyl ether or tetrahydrofurane.
  • an acid binder for which an excess of the starting amine or, for example, a base, for example, triethylamine or calcium carbonate, may be added and preferably in an inert solvent, for example, an alcohol, for example, methanol or ethanol, a hydrocarbon, for example, benzene or toluene, or an ether, for example, diethyl ether or te
  • the starting halide may be obtained, for example, by reduction of the corresponding keto halide, that is to say, the compound of Formula IV, in which Z represents a group, which reduction may be carried out, for example, by means of a complex metal hydride, for example, NaBH
  • a complex metal hydride for example, NaBH
  • the epoxide of Formula IV Z is a -C- ⁇ CH2 group
  • a base it may consequently be assumed that on alkylation of the compound of formula RNH with the alcohol halide of Formula IV an epoxide of Formula IV is also formed intermediately.
  • the epoxide may also be used as the starting material which has been obtained, for example, by treating the alcohol halide of Formula IV with dilute alkali.
  • reaction of the epoxide of Formula IV with the compound of formula RNH runs off particularly simply and may be carried out in the presence or in the absence of an inert solvent.
  • a Schiif base is intermediately formed which is reduced preferably during the alkylation reaction to the amine of Formula I.
  • Z is a keto aldehyde
  • the keto group is reduced to a carbinol group.
  • a complex metal hydride for example, NaBH is preferably used as a reduction agent.
  • the starting substance of Formula IV, in which Z is a group may be obtained, for example, by oxidation of a benzal ace-tone of Formula VI for example, with selenium dioxide, or of a keto halide of Formula VII for example, with dimethylsulphoxide.
  • the compound of Formula IV in which is a CHOH-- CHO group may be obtained, for @Xgmple, by reduction 4 of the nitrile of Formula IV, in whch Z is a CHOH-CN group, to the aldimine followed by hydrolysis.
  • Another example of a mode of preparing the compounds according to the invention is that in which in a keto compound of Formula VIII the keto group is reduced to a carbinol group.
  • this reduction only reduction agents are to be considered which do not reduce the alkene bond.
  • reduction agents may be mentioned complex metal hydrides, for example NaBH
  • the reduction may be carried out, for example, according to the so-called Meerwein-Pondorf method by means of aluminum isopropylate in isopropanol.
  • the amino ketones of Formula VIII may be obtained in different manners.
  • a benzal acetone of Formula VI is reacted with isoamylnitrite after which the resulting oxim of Formula IX is converted, by reduction, for example, with stannic chloride, into the primary amino ketone of Formula VIII. If required, this primary amino ketone may be converted into a secondary amine of Formula VIII by alkylation.
  • amino ketones of Formula VIII may be obtained by reaction of a com ound of Formula III with a halogen ketone of Formula VII.
  • Another example of a method of preparing amino ketones of Formula VIII is that in which an acid chloride of the Formula X is converted with diazomethane into a diazoketone of Formula XI Y1 CHN:
  • the primary amine of Formula I may be obtained also, in addition to any of the above methods, by reduction of a compound of formula IV, in which Z represents one of the groups
  • the compound of Formula IV, in which Z represents the group CI-I(OH)-CN, the cyanhydrin of a cinnamic aldehyde may be obtained in a simple manner by the addition of HCN to the corresponding cinnamic aldehyde.
  • the reduction to the primary amine is preferably carried out by means of a complex metal hydride, in particular with LiAlI-I
  • a complex metal hydride in particular with LiAlI-I
  • the compounds of Formula IV, in which Z represents a C ON group may be obtained, for example, by replacing in the corresponding cinnamic acid chloride the chlorine atom by the cyano group by means of copper cyanide or silver cyanide or with HCN in pyridine.
  • the reduction of the keto cyano compound to the primary amine alcohol of Formula I is preferably carried out by means of a complex metal hydride as a reduction agent. Good results are obtained in particular with LiAlH
  • These secondary amines according to the invention may be prepared, for example, by reacting the primary amine of Formula XII with a halide RHlg, in which R represents an alkyl group having 1 to 8 carbon atoms or an aralkyl group or phenoxy alkyl group possibly substituted in the phenyl group by one or two alkyl groups, alkoxy groups or hydroxy groups, and Hlg represents a halogen atom, preferably a chlorine, a bromine or iodine atom.
  • RHlg halide
  • R represents an alkyl group having 1 to 8 carbon atoms or an aralkyl group or phenoxy alkyl group possibly substituted in the phenyl group by one or two alkyl groups, alkoxy groups or hydroxy groups
  • Hlg represents a halogen atom, preferably a chlorine, a bromine or iodine atom.
  • salts of the compounds according to the invention are to be considered in particular acid addition salts, for example, those formed from the amine with hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, sulphamic acid, acetic acid, tartaric acid, citric aid, ascorbic acid, benzoic acid, p.amino benzoic acid, or salicylic acid.
  • the new compounds of Formula I 1*, 1, I and their salts are brought, according to methods known per se, into a form of administration suitable for the therapy.
  • new pharmaceutical compositions are obtained which are characterized by a content of at least one of the new compounds according to the invention.
  • compositions may be mentioned injection liquids, draughts, powders, pills, suppositories, tablets and coated tablets.
  • compositions for example, for the preparation of injection liquids solutions in water of salts of the new amines in a concentration of 1-50 mg./ml. are rendered isotonic with blood by means of kitchen salt.
  • mixtures of water and alcohols for example, glycerol or benzyl alcohol, may be used as liquid diluents.
  • Solid pharmaceutical dosage unit forms are prepared in the normal manner by taking up the active substance in solid pharmaceutical carrier materials, for example, lactose, powdered sugar, potato starch, talcum, magnesium stearate, gum arabic, gelatin, calcium, phosphate and/or titanium dioxide and processing the mixture to tablets or coated tablets.
  • solid pharmaceutical carrier materials for example, lactose, powdered sugar, potato starch, talcum, magnesium stearate, gum arabic, gelatin, calcium, phosphate and/or titanium dioxide
  • EXAMPLE III 1-methyl-3-phenylpropylamino -4-phenyl-3 -butene-2- ol-HCl To a solution of 2.3 g. (0.0145 mol) of 1-amino-4- phenyl-3-butene-2-ol in 45 ml. of methanol were added 4.5 g. (0.03 mol) of benzylacetone, 5 ml. of 2 N aqueous sodium hydroxide and 2.3 g. of 91% (0.055 mol) of sodium borohydride respectively. The mixture was boiled for two hours, after which the methanol was evaporated in vacuo. 25 ml. of water were added to the residue and the whole was shaken three times with 25 ml.
  • EXAMPLE V 1-isopropylamino-4- (4-methoxyphenyl) -3butene-2-olhydrochloride 3.86 g. of the amine obtained according to Example IV and 3.0 ml. of acetone were dissolved in m1. of methanol, after which 0.25 ml. of 2.3 N alcoholic HCl were added. After the mixture had been left to stand at room temperature for 30 minutes, 1.2 g. of approximately 90% NaBH was added and the mixture was then boiled for one hour. After cooling 4 ml. of acetone were added and, after having been left to stand at room temperature again half an hour, 1.6 g. of 90% NaBH; were added and the mixture was boiled for another hour.
  • the HCl-solution was made alkaline and extracted with water.
  • the ether solution was dried on gMgSO After filtration a solution of 4 g. of oxalic acid in 18 ml. of ethanol was added to the concentrated solution. A precipitate was formed which was washed with ether. Melting point C. (decomposition).
  • EXAMPLE VIII l-isopropylamino-4-p-tolyl-3-butene-2-ol hydrochloride (a) 1-amino-4-p-tolyl-3butene-2-ol.-A solution of 49 g. (0.34 mol) of p-methyl cinnamic aldehyde in 50 ml. of ether was stirred for 30 minutes with a solution of 44 g. (0.23 mol) of sodium metabisulphite in 250 ml. of water. 450 ml. of ether were then added and the resulting reaction mixture was cooled while stirring in an ice bath. When the temperature was 5 an ice-cold solution of 41 g.
  • EXAMPLE X 4-( 2,6-dimethoxyphenyl)-1-isopropylamino-3-butene-2-0l hydrochloride (a) 2,6 dimethoxybenzaldehyde diethylacetal.This substance was prepared according to the same method as described sub 9a. Yield 92%, boiling point 103-104/ 0.3 mm., melting point 4244 C.
  • the mixture was then cooled in an ice bath to 5 and, while stirring, a solution of 31 g. of sodium cyanide in 75 ml. of water which was cooled in ice was added in one portion.
  • the mixture was then stirred at 0-5 for 60 minutes, 3.6 g. of sodium metabisulphite were then added and stirring at 05 was continued for another 90 minutes.
  • the layers were then separated and the water layer extracted two times with ml. of ether.
  • the collected ether extracts were washed twice with 100 ml. of a 20% sodium metabisulphite solution, twice with 100 ml. of water and finally dried on sodium sulphate.
  • the Water layer was made alkaline with NaOH 2 N and extracted three times with ether (80 ml.).
  • the ether extract was Washed with 20 ml. of water and saturated NaCl-solution and dried on MgSO After filtration the ether was removed in vacuo. The residue was crystallised from a mixture of 20 ml. of benzene and 20 ml. of petroleum ether 40-60. Yield 1.69 g. (59%) melting point 77-78.5 C.
  • the temperature was kept below The mixture was stirred for another three hours while cooling with ice after which the layers were separated.
  • the water layer was shaken four times with 15 ml. of ether.
  • the ether layers were washed two times with water and then dried over Na SO at 0.
  • the solution was filtered after which, while cooling with ice, a mixture of 3 m1. of pyridine and 8 ml. of acetic acid anhydride was added dropwise. After leaving to stand the weekend over at 1 room temperature the solution was evaporated to dryness in vacuo 4.57 g. of residue were obtained which were further processed without further purification.
  • R is a member selected from the group consisting of alkyl of 1 to 8 carbon atoms inclusive and cyclopentyl
  • Y and Y are each independently selected from the group consisting of hydrogen, chlorine, bromine, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms and alkylthio of 1-4 carbon atoms and the pharmaceuticaly acceptable acid addition salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
US471434A 1964-07-11 1965-07-12 1-amino-4-phenyl-3-buten-2-ols and salts thereof Expired - Lifetime US3420853A (en)

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US (2) US3420853A (enrdf_load_stackoverflow)
AT (2) AT262259B (enrdf_load_stackoverflow)
BE (1) BE666781A (enrdf_load_stackoverflow)
CH (1) CH470345A (enrdf_load_stackoverflow)
DE (1) DE1238898B (enrdf_load_stackoverflow)
ES (1) ES315132A1 (enrdf_load_stackoverflow)
FR (2) FR1476551A (enrdf_load_stackoverflow)
GB (1) GB1117226A (enrdf_load_stackoverflow)
NL (1) NL6407943A (enrdf_load_stackoverflow)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4062978A (en) * 1974-07-04 1977-12-13 Beecham Group Limited Phenyl butanones
US4335124A (en) * 1973-08-20 1982-06-15 Sandoz, Inc. 1-Alkyl, 1-phenyl-butenes
US4908481A (en) * 1980-04-22 1990-03-13 Basf Aktiengesellschaft Preparation of 1-(4-hydroxy-phenyl)-butan-3-one and novel intermediates
CN114395379A (zh) * 2022-01-24 2022-04-26 西南石油大学 一种插层改性纳米碳化钛复合水凝胶封堵剂及水基钻井液

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4080474A (en) * 1975-02-19 1978-03-21 Beecham Group Limited Hypolipidaemic compositions
DE2732750A1 (de) * 1977-07-20 1979-02-08 Merck Patent Gmbh Basische thioaether und verfahren zu ihrer herstellung
FR2473518A1 (fr) * 1980-01-16 1981-07-17 Unicler Derives du phenyl-1 morpholino-4 butene-1 ol-3, leur preparation et leur application en therapeutique
DE10048714A1 (de) * 2000-09-30 2002-04-11 Gruenenthal Gmbh 5-Amino-1-penlen-3-ol-Derivate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4335124A (en) * 1973-08-20 1982-06-15 Sandoz, Inc. 1-Alkyl, 1-phenyl-butenes
US4062978A (en) * 1974-07-04 1977-12-13 Beecham Group Limited Phenyl butanones
US4908481A (en) * 1980-04-22 1990-03-13 Basf Aktiengesellschaft Preparation of 1-(4-hydroxy-phenyl)-butan-3-one and novel intermediates
CN114395379A (zh) * 2022-01-24 2022-04-26 西南石油大学 一种插层改性纳米碳化钛复合水凝胶封堵剂及水基钻井液

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NL6407943A (enrdf_load_stackoverflow) 1966-01-12
FR5740M (enrdf_load_stackoverflow) 1968-01-29
AT262259B (de) 1968-06-10
GB1117226A (en) 1968-06-19
ES315132A1 (es) 1966-03-16
DE1238898C2 (enrdf_load_stackoverflow) 1967-11-23
BE666781A (enrdf_load_stackoverflow) 1966-01-12
FR1476551A (fr) 1967-04-14
DE1238898B (de) 1967-04-20
CH470345A (de) 1969-03-31
US3557148A (en) 1971-01-19
AT258272B (de) 1967-11-10

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