Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
  • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
  • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
  • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

• ABSTRACT OF THE DISCLOSURE 3amino-1-aryloxy-2-propanol derivatives in which the aryl nucleus is anthryl, dihydro-anthryl or iluorenyl. These compounds possess B-adrenergic blocking activity and are useful in the treatment of heart diseases.
• This invention relates to new homocyclic derivatives which possess fl-adrenergic blocking activity and which are therefore useful in the treatment or prophylaxis of heart diseases, for example angina pectoris and cardiac arrhythmias, and in the treatment of hypertension and phaeochrom-ocytoma.
• R stands for an alkyl, alkenyl or cycloalkyl radical, any of which may optionally be substituted, and R stands for a tricyclic hydrocarbon residue, and the esters thereof, and the salts thereof, and aldehyde condensation products thereof as hereinafter defined.
• R when it stands for an alkyl radical there may be mentioned, for example, an alkyl radical of not more than 12 carbon atoms, for example the ethyl, n-propyl, isopropyl, s-butyl, t-butyl or l-methyloctyl radical.
• R when it stands for a substituted alkyl radical there may be mentioned, for example, an alkyl radical of not more than 12 carbon atoms bearing a hydroxy radical.
• a specific value for R when it stands for a substituted alkyl radical is the Z-hydroxy-1,1-dimethylethyl radical.
• R when it stands for a cycloalkyl radical there may be mentioned, for example, a cycloalkyl radical of not more than 10 carbon atoms, for example the cyclopentyl radical.
• R when it stands for an alkenyl radical there may be mentioned, for example, an alkenyl radical of not more than 6 carbon atoms, for example the allyl radical.
• R there may be mentioned, for example, a tricyclic hydrocarbon residue in which two or all three of the rings are unsaturated, for example a tricyclic hydrocarbon residue in which two or all three of the rings are aromatic in nature.
• the rings in the tricyclic hydrocarbon residue R may, for example, all be 6-membered rings, or one of them may be a S-membered ring while the remainder are 6-membered.
• R there may be mentioned, for example, an anthryl, dihydro-anthryl or fiuorenyl radical.
• esters of the invention there may be mentioned, for example O-esters derived from a saturated or unsaturated aliphatic carboxylic acid, for example a saturated or unsaturated aliphatic carboxylic acid of not more than 20 carbon atoms, for example acetic, palmitic, stearic or oleic acid, or O-esters derived from an aromatic carboxylic acid, for example an aromatic carboxylic acid of not more than 15 carbon atoms, for example benzoic acid.
• a saturated or unsaturated aliphatic carboxylic acid for example a saturated or unsaturated aliphatic carboxylic acid of not more than 20 carbon atoms, for example acetic, palmitic, stearic or oleic acid
• O-esters derived from an aromatic carboxylic acid for example an aromatic carboxylic acid of not more than 15 carbon atoms, for example benzoic acid.
• R O.GHz.Cl-ICI-Iz oHR wherein R and R have the meanings stated above, and R stands for hydrogen or an alkyl radical, and the salts thereof.
• R when it stands for an alkyl radical, there may be mentioned, for example, an alkyl radical of not more than 6 carbon atoms, for example the isopropyl radical.
• Specific homocyclic derivatives of the invention are, for example, 1-( l-anthryloxy -3-isopropylamino'2-propanol, 1 (9,10-dihydro-1-anthryloxy)-3-isopropylamino-2-propanol, 1-(4-fluorenyloxy)-3-isopropylamino-2-propanol, 1 (2-fluorenyloxy)-3-isopropylamino2-propanol, 1-(1- fluorenyloxy) -3-t-butylamino-Z-propanol, 1- 1-fluorenyloxy)-3-isopropylamino-Z-propanol and 1-(l-anthryloxy)- 3 (2-hydroxy-l,l-dimethylethylamino)-2-propanol, and the salts thereof.
• acid-addition salts for example salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates or sulphates, or salts derived from organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, B-naphthoates, adipates or 1,1'-methylene-bis-(2-hydroxy-3- naphthoates), or salts derived from acidic synthetic resins, for example sulp honated polystyrene resins, for example Zeo-Karb 225 (Zeo-Karb is a Trademark).
• Relatively insoluble salts for example the l,1-methy1enebis-(Z-hydroxy-3-naphthoates), have the advantage that they afford prolonged blood levels of the
• R has the meaning stated above
• A stands for the group wherein Z stands for a halogen atom, with an amine of the formula R NH wherein R has the meaning stated above.
• Z there may be mentioned, for example, a chlorine or bromine atom.
• the interaction may be accelerated or completed. by the application of heat, it may be carried out at atmospheric or at elevated pressure, and it may be carried out in an inert diluent or solvent, for example ethanol.
• I provide a process for the manufacture of the homocyclic derivatives of the invention which comprises the hydrogenolysis of a compound of the formula:
• R and R have the meanings stated above, and R stands for a hydrogenolysable radical.
• the hydrogenolysis may be effected, for example, by catalytic hydrogenation, for example hydrogenation in the presence of a palladium-on-charcoal catalyst, in an inert diluent or solvent, for example ethanol.
• esters of the invention which comprises the interaction of the appropriate homocyclic derivative, or a salt thereof, with an acylating agent.
• acylating agents there may be mentioned acid halides or anhydrides derived from saturated or unsaturated aliphatic carboxylic acids or from aromatic carboxylic acids, for example acetyl chloride, acetic anhydride or benzoyl chloride.
• the acylation may be carried out in a diluent or solvent which, in the case where an acid anhydride is used as acylating agent, may conveniently be the acid from which the anhydride is derived.
• R and R have the meanings stated above, with an aldehyde of the formula R .CHO, wherein R has the meaning stated above.
• the last-named interaction may be carried out in a diluent or solvent, for example ethanol, and it may be accelerated or completed by the application of heat.
• a diluent or solvent for example ethanol
• the Water formed during the reaction may be removed by azeotropic distillation using a suitable solvent, for example benzene, toluene or chloroform, as an entraining agent, or it may be removed by means of a dehydrating agent, for example anhydrous potassium carbonate.
• the homocyclic derivatives of the invention are of value in the treatment or prophylaxis of heart diseases, and in the treatment of hypertension and phaeochromocytoma.
• compositions comprising as active ingredient one or more homocyclic derivatives of the invention, or an ester or esters thereof, or a salt or salts thereof, or one or more aldehyde condensation products as defined hereinbefore, together with a pharmaceutically-acceptable diluent or carrier.
• compositions there may be mentioned for example, tablets, capsules, aqueous or oily solutions, aqueous or oily suspensions, emulsions, injectable aqueous or oily solutions or suspensions, and dispersible powders.
• EXAMPLE 1 A mixture of 1 part of 1-(l-anthryloxy)-3-chloro-2- propanol, 10 parts of isopropylamine and 5 parts of ethanol is heated in a sealed vessel at 100 C. for hours. The vessel is cooled and then the excess of isopropylamine and the ethanol are evaporated. The residual gum is shaken together with 50 parts of 2 N-hydrochloric acid and 50 parts of ether. The ethereal layer is separated from the mixture, and the residue is washed 5 times, each time with 50 parts of ether. The said residue is then made alkaline with 10 N-sodium hydroxide solution, and the mixture is extracted 3 times, each time with 50 parts of a mixture of ether and ethyl acetate (1:1 v./v. mixture).
• the l-(l-anthryloxy) 3 chloro 2 propanol used as starting material may be obtained as follows:
• EXAMPLE 2 A mixture of 1 part of 3-chloro-l-(9,l0-dihydro-1-anthryloxy)-2-propanol, 10 parts of isopropylamine and l0 parts of ethanol is heated in a sealed vessel at 100 C. for 10 hours. The vessel is cooled and the excess of isopropylamine and the ethanol are evaporated. The residual gum is shaken together with 50 parts of 2 N-hydrochloric acid and 50 parts of ether. The aqueous acid layer is then separated and washed three times with ether, each time with 50 parts. The aqueous solution is made alkaline with 10 Nsodium hydroxide solution and the mixture is extracted three times, each time with 50 parts of ether.
• the 3-chlorol-(9,10-dihydro-l-anthryloxy)-2-propanol used as starting material may be obtained as follows:
• EXAMPLE 2 A mixture of 5 parts of 3-chloro-l-(4-fiuoroenyl0xy)- 2-propanol and 40 parts of isopropylamine is heated in a sealed vessel at 100 C. for 10 hours. The vessel is cooled and then the excess of isopropylamine is evaporated. The residual gum is shaken with 200 parts of 2 N-hydrochloric acid. The viscous oil so formed is separated by decantation from the mother liquors and washed 3 times, each time with 50 parts of ether. The mother liquors are washed twice, each time with 50 parts of ether, and then combined with the oil.
• the mixture is then made alkaline with 10 N-aqueous sodium hydroxide, and extracted 3 times each time with 100 parts of ether.
• the combined ether extracts are washed with Water, dried with anhydrous magnesium sulphate, and then evaporated to dryness.
• the solid residue is crystallised from petroleum ether (B.P. 80-l00 C.) and then from a mixture of petroleum ether (31. 40-60 C.) and benzene. There is thus obtained 1 (4 fiuorenyloxy)-3-isopropylamino-2- propanol, M.P. ll8l C.
• the 3-chloro-l-(4-fluorenyloxy)-2-propanol used as starting material may be obtained as follows:
• EXAMPLE 4 The process described in Example 3 is repeated except that the 5 parts of 3-chloro-l-(4-fluorenyloxy)-2-propanol are replaced by 5 parts of 3-chloro-1-(l-fluorenyloxy)-2- propanol. There is thus obtained 1(1-fluoroenyloxy)-2- isopropylamino-Z-propanol, M.P. 96.597.5 C. (crystallised from petroleum ether. B.P. 80-100 C.).
• the 3-chloro-l-(l-fiuorenyloxy)-2-propanol used as starting material is obtained by repeating the process described in Example 3 for the preparation of 3-chloro-l- (4-fluorenyloxy)-2-propanol except that the 5 parts of 4-hydroxyfluorene are replaced by 5 parts of l-hydroxyfluorene. There is thus obtained 3-chloro-l-(l-fluorenyloxy)-2-propanol as an oil.
• EXAMPLE 5 The process described in Example 3 is repeated except that the 5 parts of 3-chloro-1-(4-fluorenyloxy)-2- propanol are replaced by 5 parts of 3-chloro-1-(2-fluorenyloxy)-2-propanol. There is thus obtained 1-(2-fluorenyloxy)-3-isopropylamino-2propanol, M.P. 127-129 C. (crystallised from petroleum ether, B.P. l-120 C. and then from a mixture of petroleum ether, B.P. 100- 120 C. and benzene).
• the 3chloro1-(2-fluorenyloxy)-2-pr0panol used as starting material is obtained by repeating the process described in Example 3 for the preparation of 3-chloro-1- (4-fluorenyloxy)-2-propanol except that the 5 parts of 4-hydroxyfluorene are replaced by 5 parts of Z-hydroxyfluorene. There is thus obtained 3-chloro l-(2-fluorenyloxy)'2-propanol as an oil.
• EXAMPLE 6 The process described in Example 3 is repeated except that the 5 parts of 3-chloro-1'(4-fluorenyloxy)-2-propanol are replaced by 5 parts of 3-chloro-1(3-fiuorenyloxy)-2- propanol. There is thus obtained l-(3-fiuorenyloxy)-3-isopropylamino-Z-propanol, M.P. l17121 C. (Crystallised from petroleum ether, B.P. 80100 C.)
• the 3-chl0ro-l-( 3-fluorenyloxy)-2-propanol used as starting material is obtained by repeating the process described in Example 3 for the preparation of 3-chloro-1-(4- fluorenyloxy)-2-propanol except that the 5 parts of 4-hydroxyfiuorene are replaced by 5 parts of 3-hydroxyfluorene. There is thus obtained 3-chloro-1-(3-fiuorenyloxy)-2-propanol as an oil.
• EXAMPLE 7 A mixture of 0.5 part of 3-chloro1-(l-fiuorenyloxy)-2- propanol and 5 parts of t-butylamine is heated in a sealed vessel at 100 C. for 10 hours. The vessel is cooled and the excess of isopropylamine is evaporated. The residual gum is shaken with 50 parts of 2 N-hydrochloric acid. The viscous oil so formed is separated from the mother liquors by decantation and washed 3 times, each time with parts of ether. The mother liquors are washed twice, each time with 20 parts of ether and then combined with the oil. The mixture is then made alkaline with 10 N-aqueous sodium hydroxide, and extracted 3 times, each time with 50 parts of ether.
• EXAMPLE 8 EXAMPLE 9 The process described in Example 1 is repeated except that the 10 parts of isopropylamine are replaced by 10 parts of cyclopentylamine.
• the extraction procedure is modified as described in Example 8. There is thus obtained l (1-anthryloxy)-3-cycl-opentylamino 2 propanol, M.P. 109.5-111 C. (Crystallised first from petroleum ether, 100120 C., and then from a mixture of petroleum ether, B.P. 4060 C. and benzene.)
• EXAMPLE 10 The process described in Example 1 is repeated except that the 10 parts of isopropylamine are replaced by 10 parts of Z-amino-Z-methylpropanol.
• the extraction procedure is modified as described in Example 8. There is thus obtained l-(1-anthryloxy)-3-(2-hydroxy-1,l-dimethylethylamino)-2-propanol, M.P. 138.5141 C. (Crystallised from a mixture of petroleum ether, B.P. -100" C. and benzene.)
• EXAMPLE 11 1 part of l-hydroxyfiuorene is dissolved. in a solution of 0.26 part of sodium hydroxide in 5 parts of water. The solution is stirred and kept at a temperature of 10-20 C. while 0.64 part of epichlorohydrin is added. The mixture is stirred at ambient temperature during 18 hours, and is then extracted with 40 parts of chloroform. The chloroform extracts are washed with water, dried over anhydrous magnesium sulphate, and the chloroform is removed by distillation under reduced pressure. There is thus obtained 1(1-fiuorenyloxy)-2,3- epoxypropanol as an oil, which is dissolved in 10 parts of isopropylamine and the mixture is heated at -100 C. during 2 hours.
• the excess of isopropylamine is then removed by distillation under reduced pressure and the residual gum is shaken with 50 parts of 2 N-hydrochloric acid.
• the viscous oil so formed is separated from the mother liquors by decantation and Washed 3 times, each time with 10 parts of ether.
• the mother liquors are washed twice, each time with 20 parts of ether, and then combined with the oil.
• the mixture is then made alkaline with 10 N-aqueous hydroxide, and extracted 3 times, each time with 50 parts of ether.
• the combined ether extracts are washed with water, dried with anhydrous magnesium sulphate and then evaporated to dryness.
• the solid residue is crystallised from petroleum ether, B.P. 80400" C.
• EXAMPLE 12 A mixture of 3 parts of 3-(Nbenzyl-N-isopropylamino)-l-(4-fluorenyloxy)-2-propanol, 20 parts of ethanol, 1 part of a saturated solution of hydrogen chloride in ether and 0.2 part of a 10% palladium-on-charcoal catalyst is shaken in an atmosphere of hydrogen at ambient temperature and atmospheric pressure until no further uptake of hydrogen is observed. The mixture is filtered and the ethanol is removed from the filtrate by distillation under reduced pressure. The residue is triturated with parts of a saturated solution of hydrogen chloride in ether, and then with 20 parts of ethyl acetate. The solid obtained is crystallised from a mixture of ethanol and ether. There is thus obtained 1-(4-fluorenyloxy)-3-isopropylamino-2- propanol hydrochloride, M.P. 183l85 C.
• EXAMPLE 13 0.2 part of 1-( 4-fluorenyloxy)-3-isopropylamino-2-propanol hydrochloride is heated with 6 parts of acetyl chloride at 90-100 C. for 1 hour. The solution thus obtained is then evaporated to dryness under reduced pressure and the residual oil is triturated with parts of ether. The solid so formed is crystallised from a mixture of ethanol and ether. There is thus obtained l-(4-fiuorenyloxymethyl)-2-isopropylaminoethyl acetate, M.P. 169172 C.
• the l-(4-fiuorenyloxy)-3-isopropylamino 2 propanol hydrochloride used as starting material is obtained from the base described in Example 3.
• the free base is dissolved in ether and treated with a saturated ethereal solution of hydrogen chloride.
• the solid so formed is crystallised from a mixture of ethanol and ether. There is thus obtained 1-(4-fluorenyloxy)-3-isopropylarnino-Z-propanol hydrochloride, M.P. 183-185 C.
• EXAMPLE 14 A solution of 0.5 part of l-(4-fiuorenyloxy)-3-isopropylamino-2-propanol and 3 parts of formalin in 20 parts of ethanol is heated under reflux during 18 hours, and then the solvent is removed by evaporation under reduced pressure. The residual oil is triturated with a small volume of petroleum ether, B.P. 4060 C., and the resulting solid is crystallised from petroleum ether, B.P. 4060 C., after removal by filtration of a small amount of insoluble ma terial. There is thus obtained 5-(4-fluorenyloxymethyl)-3- isopropyloxazolidine, M.P. 7983 C.
• EXAMPLE 15 A mixture of parts of 1-(4 fluorenyloxy) 3 isopropylamino-Z-propanol, 125 parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a 16- mesh screen. The resultant granules are compressed into tablets according to the known art. There are thus obtained tablets which are suitable for oral use for therapeutic purposes.
• a homocyclic compound selected from the group consisting of compounds of the formula:
• R is selected from the group consisting of alkyl of 19 carbon atoms, 2-hydroxy-l,l-dimethylethyl, cyclopentyl and allyl, and R is selected from the group consisting of anthryl, dihydroanthryl and fluorenyl, and the pharmaceutically-acceptable acid addition salts thereof.
• a salt as claimed in claim 1 which is selected from the group consisting of the hydrochlorides, hydrobromides, phosphates or sulphates, oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, ,B-naphthoates, adipates and 1,1'-methylene bis (2'hydroxy-3-naphthoates), and salts derived from acidic synthetic resins.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Citations (4)

• 1964
  • 1964-03-12 GB GB10529/64A patent/GB1046001A/en not_active Expired
• 1965
  • 1965-02-11 US US431969A patent/US3394171A/en not_active Expired - Lifetime
  • 1965-02-23 DE DE19651543049 patent/DE1543049A1/de active Pending
  • 1965-03-10 CH CH332165A patent/CH452547A/de unknown
  • 1965-03-10 CH CH154568A patent/CH458393A/de unknown
  • 1965-03-12 NL NL6503196A patent/NL6503196A/xx unknown
  • 1965-03-12 DK DK127765AA patent/DK114984B/da unknown
  • 1965-03-12 BE BE661066A patent/BE661066A/xx unknown
  • 1965-03-12 FR FR1584959D patent/FR1584959A/fr not_active Expired
  • 1965-06-11 FR FR20561A patent/FR4680M/fr not_active Expired
• 1966
  • 1966-10-31 DK DK565966AA patent/DK115187B/da unknown
• 1967
  • 1967-01-11 SE SE00386/67A patent/SE326953B/xx unknown

Patent Citations (4)

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