United States Patent (19) 11 4,147,799 Obase et al. 45) Apr. 3, 1979

(54) PROCESS FOR REDUCING BLOOD (56) References Cited PRESSURE AND BLOCKENG B-ADRENERGIC RECEPTOR U.S. PATENT DOCUMENTS 1,073,966 9/1913 Decker ...... 260/340,5 1,964,973 7/1934 Bockmuhl et al. ... 260/340.5 (75) Inventors: Hiroyuki Obase, Sakai; Yutaka 2,011,454 8/1935 Nagai ...... 260/340.5 Kasuya, Kawasaki, both of Japan 3,657,244 4/1972 Mentrup et al...... 260/340.5 Primary Examiner-Anna P. Fagelson 73 Assignee: Kyowa Hakko Kogyo Co., Ltd., Attorney, Agent, or Firm-Fitzpatrick, Cella, Harper & Tokyo, Japan Scinto (21) Appl. No.: 463,833 57 ABSTRACT Ethanolamine derivatives and their acid addition salts are prepared (1) by reacting a 1-(3,4-methylenedioxy (22) Filed: Apr. 24, 1974 phenyl)-2-aminoethanol compound or an a-amino-(3,4- methylenedioxy)acetophenone compound with an alka nal or an alkanone under reduction conditions, (2) by Related U.S. Application Data hydrogenating and/or hydrogenolyzing a 1-(3,4- 63 Continuation of Ser. No. 264,336, Jun. 19, 1972, methylenedioxyphenyl)-2-(N-substituted amino)- abandoned. compound or an a-(N-substituted amino)-(3,4- methylenedioxy)acetophenone compound, and (3) by (30) Foreign Application Priority Data reacting a (3,4-methylenedioxyphenyl)- oxide compound or a 1-(3,4-methylenedioxyphenyl)-2-sub Jun. 24, 1971 JP Japan ...... 46-45206 stituted ethanol compound with an amine. The ethanol Jun. 24, 1971 (JP Japan ...... 46-45207 amine derivatives and their salts show g-adrenergic Jun. 30, 1971 JP Japan ...... 46-47148 receptor blocking activity, and are expected to be useful in the treatment of heart disease, hypertension, myocar 51) Int. Cl’...... A61K 31/36 dites and pheochromocytoma. 52 U.S. C...... 424/282; 260/340.5 R 58) Field of Search ...... 424/282; 260/340.5 8 Claims, 6 Drawing Figures U.S. Patent Apr. 3, 1979 Sheet 1 of 3 4,147,799

109 108 107 106 Dose isoproterenol (M)

3 O O

2 5 O

1 5 O 1010 109 108 107 106 Dose isoproterenol (M) U.S. Patent Apr. 3, 1979 Sheet 2 of 3 4,147,799

1 OO

109 108 107 106

1 OO

•

•

0's 108 107 106 Dose isoproterenol (M) U.S. Patent Apr. 3, 1979 Sheet 3 of 3 4,147,799

1OO F.G. 5

5 O

108 107 106 105 Dose isoproterenol (M)

100 FG. 6

5 O

108 107 106 - 105 Dose isoproterenol (M) 4,147,799 1. 2 PROCESS FOR REDUCING BLOOD PRESSURE O (I), AND BLOCKING B-ADRENERGIC RECEPTOR c?,2 V This is a continuation, of application Ser. No. 5 O -CH-NH. 264,336, filed June 19, 1972, and now abandoned. O BACKGROUND OF THE INVENTION a-amino-(3,4-methylenedioxy)acetophenone with a This invention relates to ethanolamine derivatives lower alkanal or a lower alkanone having 2 to 6 carbon and acid addition salts thereof. More specifically, this 10 atoms under reduction conditions. Lower alkanals such invention relates to 1-(3,4-methylenedioxyphenyl)-2- as acetaldehyde, propionaldehyde, butyraldehyde, iso alkylaminoethanol compounds and to methods for pre butyraldehyde, n-amylaldehyde, isoamylaldehyde and n-hexylaldehyde may be employed. Lower alkanones paring same. The ethanolamine derivatives and their such as , methyl ethyl , methyl n-propyl salts show strong pharmacological activity, especially 15 As-adrenergic receptor blocking activity. The com ketone, diethyl ketone and hexanone-2 may be em ployed. The reaction can be carried out under atmo pounds are, therefore, expected to be useful in the treat spheric pressure or under applied pressure with heating ment or prevention of nervous disorders such as heart and stirring in the presence of hydrogen and a suitable disease, hypertension, myocardites and pheochromocy catalyst. Alternatively, the reaction can be carried out tOnina. 20 in the presence of such reducing agents as lithium alumi The compounds which are the subject of the present num hydride, sodium borohydride, potassium borohy invention are 1-(3,4-methylenedioxyphenyl)-2- dride, and the like. Catalysts generally employed in alkylaminoethanol compounds and are represented by reactions such as, for example, platinum, the formula palladium-carbon and Raney nickel, may be employed. 25 The reaction is generally carried out in an inert diluent or solvent such as , ethanol, isopropyl , dioxane and the like. Generally, the reaction is allowed CH-CH-NHR to proceed until the theoretical amount of hydrogen is 30 absorbed. The reaction is carried out at a temperature OH between 20 and 50° C. The 1-(3,4-methylenedioxy phenyl)-2-alkylaminoethanol compound is collected wherein R represents a straight or branched chain from the reaction mixture and purified by techniques group having 2 to 6 carbon atoms, such as an ethyl, known in the art. n-propyl, isopropyl, n-butyl, sec-butyl, m-amyl, isoamyl The 1-(3,4-methylenedioxyphenyl)-2-alkylaminoe or n-hexyl group. 35 thanol compounds can also be prepared by hydrogenat The 1-(3,4-methylenedioxyphenyl)-2-alkylaminoe ing and/or hydrogenolyzing a compound represented thanol compounds may be employed in the form of the by the formula free amine, or in the form of a salt, Suitable salts are the acid addition salts such as, for example, the salts of 40 (II) inorganic acids such as the hydrochloride, hydrobro mide, phosphate and sulfate, the organic acid salts such as the oxalate, lactate, tartrate, naphthoate, acetate, salicylate, citrate, benzoate, adipate and maleate. The relatively insoluble salts such as 1,1'-methylene-bis-(2- 45 hydroxy-3-naphthoate) are particularly useful since its a-alkylamino-(3,4-methylenedioxy)acetophenone physical properties enable it to remain in the blood at a O (II) constant level. Salts prepared from an acidic synthetic / CH2 R , such as the salts of a sulfonated polystyrene resin, 50 V / may also be employed. The sulfonated polystyrene resin O C-CH-N sold under the trademark ZEO-KARB 225 from The Permutit Co., Ltd., Great Britain is an example of a O CH2 suitable synthetic resin. N -C) DESCRIPTION OF THE PREFERRED 55 a-alkylbenzylamino-(3,4-methylenedioxy)acetophe EMBODIMENTS none The 1-(3,4-methylenedioxyphenyl)-2-alkylaminoe O (II) thanol compounds can be prepared by reacting a com / pound represented by the formula CH2 R V / O CH-CH-N / O (I)a N c OH CH2 o (H-CH-NH. 65 OH 1-(3,4-methylenedioxyyphenyl)-2-alkylbenzylaminoe thanol) wherein R is a straight or branched chain lower 1-(3,4-methylenedioxyphenyl)-2-aminoethanol or alkyl group having 2-6 carbon atoms, in the presence of 4,147,799 3 4. a noble metal catalyst such as a palladium-carbon cata prepared by reducing a compound represented by the lyst or a nickel or nickel alloy catalyst such as Raney formula nickel, in a suitable organic solvent. The reaction can be carried out at room temperature or with heating under atmospheric pressure or under applied pressure. Any 5 solvent usually used in catalytic reduction reactions such as methanol, ethanol, and the like can be employed. Where the reaction is carried out at elevated temperatures, usually a temperature be tween 60-130' C. is employed. The reaction is generally O (3,4-methylenedioxyphenyl)cyanocarbinol) in ether carried out until the theoretical amount of hydrogen has been absorbed. The 1-(3,4-methylenedioxyphenyl)-2- with lithium aluminum hydride J. Ind. Chem., 36,585 alkylaminoethanol compound is collected and purified (1959). The starting material can also be obtained by by techniques known in the art. reducing a compound of the formula Alternatively, the 1-(3,4-methylenedioxyphenyl)-2- 15 O alkylaminoethanol compounds can be prepared by re / CH2 acting a compound represented by the formula V O (III) O (H-CHNo. OH c?t 20 O CH-CH2 1-(3,4-methylenedioxyphenyl)-2-nitroethanol accord N / ing to the process described in J. Org. Chem., 21, 1228 O (1956). The 1-(3,4-methylenedioxyphenyl)-2-nitroe (3,4-methylenedioxyphenyl)ethylene oxide) or 25 thanol compound is obtained by reacting (3,4- methylenedioxy)benzaldehyde with nitromethane in O (III), the presence of a suitable catalyst such as a nickel alloy catalyst or a palladium-carbon catalyst. c?,2 V Where the a-amino-(3,4-methylenedioxy)acetophe O fH-H. 30 none compounds (Db are used as the starting material, OH X the compounds can be prepared according to the pro cess described in Arch. Pharm. 269, 581 (1931). 1-(3,4-methylenedioxyphenyl)-2-substituted ethanol) The a-alkylamino-(3,4-methylenedioxy)acetophe wherein Xa is a halogen atom such as chlorine, bromine none compounds (II)a and al-alkylobenzylamino-(3,4- or iodine, a leaving group such as 35 methylenedioxy)-acetophenone compounds (II)b used as the starting materials in the preparation of the 1-(3,4- methylenedioxyphenyl)-2-alkylaminoethanol CO pounds can be prepared by reacting a compound of the -OSO , -OSO2 CH3, formula -o-, -CH -o--sch, O S and the like, with an amine represented by the formula, 45 H2HR, wherein R is a straight or branched chain lower alkyl group having 2 to 6 carbon atoms. a-substituted-(3,4-methylenedioxy)acetophenone The reaction can be carried out in the presence or wherein Xi, is a halogen atom with the corresponding absence of a solvent. Where a solvent is employed, amine represented by the formula: organic solvents such as , , ethanol, 50 , and the like may be employed. In general, any solvent that does not participate in the reaction may R R be employed. Where a solvent is employed, the reaction HNC H and HNC CH2 is generally carried out at the reflux temperature of the particular solvent employed. Where the reaction is car 55 ried out in the absence of a solvent, the reactants are heated at a temperature between 50 and 130 C. The dry wherein R is a straight or branched chain lower alkyl reaction is preferably carried out in an autoclave with group hving 2-6 carbon atoms. Chlorine and bromine heating. are suitable halogens. The reaction can be carried out at The salts of the 1-(3,4-methylenedioxyphenyl)-2- 60 a temperature ranging from 0 to 5' C. in a suitable alkylaminoethanol compounds can be prepared by the solvent. Inert solvents such as , benzene, usual techniques used to prepare acid addition salts of acetone, and the like may be employed, but any solvent amines. Where the starting compound is already in the that does not participate in the reaction may be used. form of an acid addition salt, the 1-(3,4-methylenedioxy The a-alkylamino-(3,4-methylenedioxy)acetophe phenyl)-2-alkylaminoethanol compound is obtained in 65 none compounds (II)a and the a-alkylbenzylamino-(3,4- the form of the corresponding acid salt. methylenedioxy)acetoxyphenone compounds (II)b can The 1-(3,4-methylenedioxyphenyl)-2-aminoethanol also be prepared by reacting the corresponding com compounds (I) used as the starting material can be pounds of the general formula 4,147,799

HO HN C CH2 HO C-CH-NHR 5 O wherein R is a lower alkyl group having 2-6 carbon 4-(alkylaminoacetyl)catechol) atoms, and Xa is a halogen such as chlorine or bromine. O The dry reactants can be reacted together or the 10 reaction can be carried out in a suitable solvent. Sol HO vents such as benzene, toluene, ethanol, chloroform, and the like may be employed, but any solvent that does not participate in the reaction can be used. In carrying HO out the reactior, the reaction temperature is not specifi 15 cally limited, but is suitably selected depending upon the reflux temperature of the solvent. When a solvent is not used, the reaction is carried out with heating at a temperature of 50° to 130° C. When heat is employed to 4-(alkylbenzylaminoacetyl)catechol wherein R is a effect the reaction, the reaction is preferably carried out straight or branched chain lower alkyl group having 20 in an autoclave. 2-6 carbon atoms with a compound of the formula Now, the present invention will be further explained, X-CH2X wherein X is a halogen atom, in the presence referring to the following examples, but these examples of a suitable catalyst. Chlorine, bromine and iodine are are merely illustrative and do not restrict the scope of suitable halogens. As the catalyst, an alkali such as, for the present invention. example, potassium hydroxide, , po 25 tassium bicarbonate and sodium bicarbonate, or Tobin EXAMPLE 1 bronze shavings (consisting of 60% Cu, 38% Zn, 1.5% 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO Sn., 0.2% Fe and 0.3% PbO) may be employed. PROPYLAMINOETHANOL The above formulated 4-(alkylaminoacetyl)catechol 30 18.1 g of 1-(3,4-methylenedioxyphenyl)-2-aminoe compounds and 4-(alkylbenzylaminoacetyl)catechol thanol hydrochloride are dissolved in 20 ml. of acetone compounds can be prepared by reacting a compound of and 300 ml. of ethanol. To the resulting solution are the formula added 10 g. of extended Raney nickel and the mixture is heated and stirred at 70° C. in an atmosphere of hydro HO 35 gen in an autoclave. After the absorption of hydrogen is complete, the catalyst is filtered off and the filtrate is concentrated to dryness. Upon recrystallization of the HO C-CH2X crude crystalline residue from isopropyl alcohol, 14.4g. of 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe thanol hydrochloride are obtained as white needles. 4-(haloacetyl)cathecol) : 182-182.5° C. Elementary analysis: as wherein X represents a halogen atom with a compound C12H17NO3.HCL; Calculated: C=55.49, H = 6.99, N=5.39; Found: C=55.38, H=6.78, N=5.51. of the formula 5 g. of 1-(3,4-methylenedioxyphenyl)-2-iso R R 45 propylaminoethanol hydrochloride are dissolved in 20 HN1. mol. of water, and the resulting aqueous solution is H and HNC CH2 made basic with 1N caustic soda. The liberated oil is extracted with ether. The ether layer is separated and dried and the ether is removed by distillation. Upon recrystallization of the crystalline residue from petro wherein R is a straight or branched chain lower alkyl 50 leum ether, 1-(3,4-methylenedioxyphenyl)-2-iso group having 2-6 carbon atoms. As the halogen, chlo propylaminoethanol is obtained as white needle crystals rine and bromine are suitable. The reaction can be car having a melting point of 117-118° C. ried out at low temperature ranging from 0 to 5 C. EXAMPLE 2 using a suitable solvent such as ethyl acetate, benzene, 55 acetone and the like. Any inert solvent that does not 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO participate in the reaction may be used. PROPYLAMINOETHANOL HYDROCHLORIDE The 1-(3,4-methylenedioxyphenyl)-2-alkylben 2 g of extended Raney nickel are added to a solution zylaminoethanol compounds (II)- can be prepared by of 17.9 g of a-amino-(3,4-methylenedioxy)acetophe reacting a compound of the formula none, 50 ml. of acetone and 100 ml. of ethanol, and the resulting mixture is hydrogenated with vigorous stir O O / ring at a reaction temperature of 50 C. and a reaction CH2 CH2 pressure of 50 atmospheres. After the absorption of V V O CH-CH2 or O CH-CH2 hydrogen is complete, the catalyst is filtered off, and the N / 65 filtrate is concentrated under a reduced pressure to O OH Xd dryness. The crude crystalline residue is dissolved in ethyl acetate and ethyl acetate acidified with hydro with a compound of the formula chloric acid is added to the solution until the white 4,147,799 7 8 turbidity ceases to form. The crystals which form on hydrogenolyzed with vigorous stirring at room temper standing are filtered off and washed with ethyl acetate. ature under atmospheric pressure. After the theoretical Upon recrystallization from isopropyl alcohol, 22.3 g. amount of hydrogen is absorbed, the stirring is stopped of 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe and the reaction solution is filtered. Upon removal of thanol hydrochloride are obtained. 5 the solvent by distillation under reduced pressure, 23g. Melting point: 182-182.7 C. Elementary analysis: as of crude crystals are obtained. Upon recrystallization of C12H17NO3.HCl; Caliculated: C=55.49, H = 6.99, the crude crystals from isopropyl alcohol, 22.5 g. of Ns 5.39; Found: C=55.39, H = 6.98, N=5.42. 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe EXAMPLE 3 thanol hydrochloride are obtained as white needles. 10 Melting point: 182-182.5° C. Elementary analysis: as 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO C12H17NO3.HCl; Calculated: C=55.49, H = 6.99, PROPYLAMINOETHANOL HYDROCHLORIDE N=5.39; Found: C=55.63, H=6.72, N=5.37. 6.5 g. of ot-isopropylamino-(3,4-methylenedioxy)- acetophenone hydrochloride are dissolved in 300 ml. of EXAMPLE 6 methanol and to the solution are added with stirring 2 g. 15 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO of palladium-carbon. The resulting mixture is hydroge PROPYLAMINOETHANOL HYDROCHLORIDE nated with vigorous stirring under atmospheric pres sure. After about 2 hours, the theoretical amount of A solution of 16.4 g of (3,4-methylenedioxyphenyl)- hydrogen is absorbed. The catalyst is filtered off and ethylene oxide, 150 g. of isopropylamine in 100 ml. of upon concentrating the filtrate, 7.5 g. of crude crystals 20 ethanol is mildly refluxed for 6 hours. After cooling, the are obtained. Upon recrystallization of the crude crys ethanol and excess amine are distilled off under reduced tals from isopropyl alcohol, 5 g. of 1-(3,4-methylenedi pressure. The residue is extracted with 100 ml. of 1N oxyphenyl)-2-isopropylaminoethanol hydrochloride HCl and the extract is washed twice with 50 ml. of are obtained as white crystalline needles having a melt ether. The hydrochloric acid extract solution is made ing point of 182-182.7 C. 25 basic with 1N caustic soda, and the liberated oil is ex The crystals are dissolved in 20 ml. of water and the tracted with ether. The ether extract is dried and an resulting aqueous solution is made basic with an aque etherial hydrochloric acid solution is added thereto. ous saturated solution of sodium hydrogen carbonate. The crystalline hydrochloride settles out of solution and The liberated oil is extracted with ether. The resulting is filtered and dried to yield 8.7 g of crude product. ether layer is separated and dried and the ether is re- 30 Upon recrystallization from isopropyl alcohol, 8.1 g of moved by distillation. Upon recrystallization of the 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe residual crystals from petroleum ether, 1-(3,4- thanol hydrochloride are obtained. methylenedioxyphenyl)-2-isopropylaminoethanol is ob Melting point: 182-182.7 C. Elementary analysis: as tained as white crystalline needles having a melting C12H17NO3.HCl; Calculated: C=55.49, H=6.99, point of 117-118° C. 35 N=5.39; Found: Cs55.43, H=6.87, Na5.53. Elementary analysis: as C12H17NO3.HCl; Calculated: 5 g. of 1-(3,4-methylenedioxyphenyl)-2-iso C=55.49, H=6.99, N=5.39; Found: C=55.56, propylaminoethanol hydrochloride are dissolved in 20 H=7.25, N=5.36. ml. of water and the resulting aqueous solution is made basic with 1N caustic soda. The liberated oil is extracted EXAMPLE 4 with ether and the ether layer is separated and dried. 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO The ether is then removed by distillation. Upon recrys PROPYLAMINOETHANOL HYDROCHLORIDE tallization of the residual crystals from petroleum ether, 52.5g of a-isopropylbenzylamino-(3,4-methylenedi 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe oxy)acetophenone hydrochloride are dissolved in 21. of 45 thanol is obtained as white crystalline needles having a methanol and to the solution are added with stirring 1 g. melting point of 117-118° C. of palladium-carbon. The resulting mixture is hydroge nated and hydrogenolyzed simultaneously with vigor EXAMPLE 7 ous stirring under atmospheric pressure. After about 5 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO hours, the theoretical amount of hydrogen is absorbed. PROPYLAMINOETHANOL HYDROCHLORIDE The catalyst is filtered off and upon concentrating the 50 20.5 g. of 1-(3,4-methylenedioxyphenyl)-2-chloroe filtrate, 31 g. of the crude crystals are obtained. Upon thanol are mixed with 30 g. of isopropylamine and 100 recrystallization of the crude crystals from isopropyl ml. of ethanol and the mixture is refluxed for 8 hours. alcohol, 25 g. of 1-(3,4-methylenedioxyphenyl)-2-iso After cooling, the ethanol and excess amine are re propylaminoethanol hydrochloride are obtained as is moved by distillation under reduced pressure. The resi white crystaline needles having melting point of due is extracted with 100 ml. of 1N HCl and the extract 182-182.7 C, is washed twice with 50 ml. of ether. The hydrochloric Elementary analysis: as C12H17NO3.HCl; Calculated: acid extract is made basic with 1N caustic soda, and the C=55.49, H=6.99, N=5.39; Found: C=55.53, liberated oil is extracted with ether. The ether extract is H=7.21, N-5.38. 60 dried and an etherial hydrochloric acid solution is EXAMPLE 5 added. The crystalline hydrochloride settles out of solu tion and is filtered and dried. Upon recrystallization of 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO the crude crystals from isopropyl alcohol, 6.4 g of PROPYLAMINOETHANOL HYDROCHLORIDE 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe 35 g. of 1-(3,4-methylenedioxyphenyl)-2-isopropyl- 65 thanol hydrochloride are obtained. benzylaminoethanol hydrochloride are dissolved in 1 Melting point: 182-182.7 C. Elementary analysis: as liter of methanol with stirring. To the resulting solution C12H17NO3.HCl; Calculated: C=55.49, H= 6.99, are added 3 g of palladium carbon and the mixture is N=5.39; Found: Cs55.62, H=7.01, Na5.38. 4,147,799 9 10 EXAMPLE 8 of 1-(3,4-methylenedioxyphenyl)-2-t-butylaminoethanol hydrochloride are obtained as white crystalline needles. 1-(3,4-METHYLENEDIOXYPHENYL)-2- Elementary analysis: as C13H19NO3.HCl; Calculated: ETHYLAMINOETHANOL HYDROCHLORIDE C=57.04, H = 7.36, N=5.12; Found: C=57.01, 18 g. of 1-(3,4-methylenedioxyphenyl)-2-aminoe H=748, N=4.97. thanol hydrochloride are dissolved in 300 ml. of ethanol and 50 ml. of 80% aqueous solution of acetaldehyde. To EXAMPLE 12 the resulting solution are added 0.5 g. of extended 1-(3,4-METHYLENEDIOXYPHENYL)-2-t- Raney nickel and the mixture is heated at 70° C. in an 10 BUTYLAMINOETHANOL HYDROCHLORIDE atmosphere of hydrogen in a 1 liter-autoclave. After the absorption of hydrogen is complete, the mixture is The procedure described in Example 6 is repeated cooled. Then the catalyst is filtered off and the filtrate is except that 186 g. of t-butylamine are used in place of concentrated to dryness. Upon recrystallization of the the isopropylamine, 8.5 g. of 1-(3,4-methylenedioxy crude crystalline residue from isopropyl alcohol, 12.5g. 15 phenyl)-2-t-butylaminoethanol hydrochloride are ob of 1-(3,4-methylenedioxyphenyl)-2-ethylaminoethanol tained. hydrochloride are obtained as white needles. Elementary analysis: as C13H19NO3.HCl; Calculated: Elementary analysis: as C11H15NO3.HCl; Calculated: C=57.04, H=7.36, N=5.12; Found: C=56.86, C=53.77, H=6.56, N=5.70; Found: C=53.82, H=7.38, N=5.31. H=6.62, N=5.71. 20 PREPARATION OF STARTING MATERIALS EXAMPLE 9 1-(3,4-METHYLENEDIOXYPHENYL)-2- EXAMPLEA ETHYLAMINOETHANOL HYDROCHLORIDE 1-(3,4-METHYLENEDIOXYPHENYL)-2-AMINO 19.5 g. of 1-(3,4-methylenedioxyphenyl)-2-chloroe 25 ETHANOL HYDROCHLORIDE thanol are added to a solution of 170 g. of ethylamine in 10.5 g. of 1-(3,4-methylenedioxyphenyl)-2-nitroe 200 ml. of cooled ethanol and the mixture is heated at thanol are dissolved in 150 ml. of methanol and to the 80' C. for 8 hours in an autoclave. After cooling, the solution is added 1 g of palladium carbon. The resulting ethanol and excess ethylamine are distilled off under mixture is hydrogenolyzed with vigorous stirring. After reduced pressure. The residue is extracted with 100 ml. 30 the absorption of hydrogen is complete, the stirring is of 1N HCl and the extract is washed twice with 100 ml. of ether. The hydrochloric acid extract solution is made discontinued and the catalyst is filtered off and the fil basic with 1N caustic soda and the liberated oil is ex trate is concentrated to dryness. The residue is dis tracted with ether. The ether extract is dried and an solved in ethyl acetate and ethyl acetate acidified with etherial hydrochloric acid solution is added thereto. 35 hydrochloric acid is added to the solution until the The crystals which settle out on standing are filtered off white turbidity ceases to form. The crystals which form and washed with ether. Upon recrystallization from on standing are filtered off and washed thoroughly with isopropyl alcohol 7.8 g. of 1-(3,4-methylenedioxy ethyl acetate. Upon recrystallization from isopropyl phenyl)-2-ethylaminoethanol hydrochloride are ob alcohol, 8.3 g of 1-(3,4-methylenedioxyphenyl)-2- tained. aminoethanol hydrochloride are obtained. Elementary analysis: as CH5NO3.HCl; Calculated: Melting point: 181-182' C. Elementary analysis: as C=53.77, H=6.56, N=5.70; Found: C=53.68, C9H11NO3.HCl; Calculated: C=49.65, H=5.51, H=6.43, N=5.77. N=6.43; Found: C=49.73, H=5.57, N=6.32. EXAMPLE 10 45 EXAMPLE B 1-(3,4-METHYLENEDIOXYPHENYL)-2-t- a-ISOPROPYLAMINO-(3,4-METHYLENEDIOX BUTYLAMINOETHANOL HYDROCHLORIDE Y)ACETOPHENONE HYDROBROMIDE The procedure described in Example 5 is repeated 10 g. ofa-bromo-(3,4-methylenedioxy)acetophenone except that 38 g. of 1-(3,4-methylenedioxyphenyl)-2-t- 50 butylbenzylaminoethanol hydrochloride are used in are dissolved in 100 ml. of ethyl acetate and to the solu place of the 1-(3,4-methylenedioxyphenyl)-2-(iso tion are added dropwise with stirring 9 g, ofisopropyla propylbenzylaminoethanol hydrochloride. 23.9 g, 1 mine at 3’-5’ C. After completion of the dropwise addi (3,4-methylenedioxyphenyl)-2-t-butylaminoethanol hy tion, the stirring is continued for 30 minutes, and then drochloride are obtained. 55 the solvent and isopropylamine are removed under Elementary analysis: as C3H19NO3.HCl; Calculated: reduced pressure to obtain 8.9 g of a-isopropylamino C=57.04, H=7.36, N=5.12; Found: C=5741, (3,4-methylenedioxy)acetophenone hydrobromide hav H=7.29, N=4.87. ing a melting point of 206'-208 C. Elementary analysis: as C12H15NO3.HBr; Calculated: EXAMPLE 11 C=47.70, H = 5.34, N=4.64; Found: C=47.81, 1-(3,4-METHYLENEDIOXYPHENYL)-2-t- H=5.42, N=4.49. BUTYLAMINOETHANOL HYDROCHLORIDE The free amine is obtained by dissolving the salt in The procedure described in Example 4 is repeated water and making the aqueous solution alkaline with an except that 72 g of a-(t-butylbenzylamino)-(3,4- 65 aqueous saturated solution of sodium hydrogen carbon methylenedioxy)acetophenone hydrochloride are used ate. The aqueous solution is extracted with chloroform in place of the a-isopropylbenzylamino-(3,4- to obtain a-isopropylamino-(3,4-methylenediox methylenedioxy)acetophenone hydrochloride. 47.3 g. y)acetophenone in its free form. 4,147,799 11 12 off. To the filtrate, ethyl acetate acidified with hydro EXAMPLE C chloric acid is added until the white turbidity ceases to a-ISOPROPYLAMINO-(3,4-METHYLENEDIOX form. The crystals which form on standing are filtered Y)ACETOPHENONE off and washed with ethyl acetate. Upon recrystalliza 50 g. of 4-(chloroacetyl)catechol are dissolved in 500 5 tion from isopropyl alcohol, 52.5 g. of a-isopropylben ml. of ethyl acetate and to the solution are added drop Zylamino-(3,4-methylenedioxy)acetophenone hydro wise with stirring 45 g. of isopropylamine at 3’-5’ C. chloride are obtained. After completion of the dropwise addition, the stirring Elementary analysis: as C19H21NO3.HCl; Calculated: is continued for 30 minutes. The solvent, and isopropyla C=65.61, H = 6.38, N=4.03; Found: C=65.58, mine are then removed under reduced pressure to ob 10 H=6.36, N=4.07. tain 42.5 g. of 4-(isopropylaminoacetyl)catechol hydro chloride. EXAMPLE E Elementary analysis: as C11H15NO3.HCl; Calculated: 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO C=53.76, H=6.58, N=5.70; Found: C=53.82, PROPYLBENZYLAMINOETHANOL H = 6.61, N=5.66. 15 HYDROCHLORIDE 4-(isopropylaminoacetyl)catechol hydrochloride (34 g.) is dissolved in 60 ml. of water and the aqueous solu 16.4g. of (3,4-methylenedioxyphenyl)ethylene oxide tion is made alkaline with an aqueous saturated sodium are refluxed for 6 hours together with 75 g. of iso hydrogen carbonate solution. The resulting alkaline propylbenzylamine in 100 ml. of ethanol. After cooling, solution is extracted with chloroform. Upon removal of 20 the ethanol and the excess amine are distilled off under the chloroform by distillation, crude 4-(iso reduced pressure. The residue is extracted with 100 ml. propylaminoacetyl)catechol is obtained. The crude of 1N HCl and the extract is washed twice with 50 ml. product is purified by recrystallization from benzene of ether. The hydrochloric acid extract is made basic petroleum ether. 20.9 g of 4-(isopropylaminoacetyl)- with 1N NaOH and the liberated oil is extracted with catechol and 10.2g. of methylene chloride are dissolved 25 ether. After drying the extract, the product is crystal in 20 ml. of methanol and the resulting solution is placed lized out of solution as the hydrochloride by adding a in a glass pressure reactor together with 3 g of Tobin hydrochloric acid-acidified ether solution to the dried bronze shavings. An additional 40 ml. of methanol are ether extract. The crystals are isolated by filtration and added to the solution and the reactor is cooled with ice. upon drying, 17.9 g, of 1-(3,4-methylenedioxyphenyl)-2- An ice cold aqueous KOH solution (consisting of 11 g. 30 isopropylbenzylaminoethanol hydrochloride are ob of KOH and 15 ml. of water) is added thereto dropwise tained. with stirring and, after the addition is complete, the Melting point: 163-164° C. Elementary analysis: as reactor is sealed. The reaction is carried out with stir C19H23NO3.HCl; Calculated: C= 65.23, H=6.91, ring at 100-110° C. for 18 hours. After the reaction is N=4.00; Found: C=65.41, H=6.90, N=4.02. complete, the methanol is distilled of under reduced 35 pressure. The residual aqueous alkaline solution is EXAMPLE F mixed with 100 ml. of water and then extracted with 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO ether. The ether extract is washed with N KOH and PROPYLBENZYLAMINOETHANOL water and then dried. Upon distillation of the ether, HYDROCHLORIDE crude a-isopropylamino-(3,4-methylenediox 40 y)acetophenone is obtained. Upon recrystallization of 20.5 g. of 1-(3,4-methylenedioxyphenyl)-2-chloroe the crude product from benzene-petroluem ether, 8.2g. thanol are refluxed for 8 hours together with 75 g. of of crystalline a-isopropylamino-(3,4-methylenediox isopropylbenzylamine in 100 ml. of ethanol. After cool y)acetophenone are obtained. ing the reaction mixture, the ethanol and the excess The crystalline a-isopropylamino-(3,4-methylenedi 45 amine are distilled of under reduced pressure. The resi oxy)acetophenone (8.2 g) is dissolved in ethyl acetate, due is extracted with 100 ml. of 1N HCl and the extract and ethyl acetate acidified with hydrobromic acid is is washed twice with 50 ml. of ether. The hydrochloric added to the solution until the white turbidity ceases to acid extract is made alkaline with 1N NaOH and the oil form. The crystals which form on standing are filtered which separates is extracted with ether. After drying off and washed thoroughly with ethyl acetate. Upon 50 the ether extract, the product is crystallized out of solu recrystallization from isopropyl alcohol, 9.6 g. of a-iso tion as the hydrochloride by adding an ether solution propylamino-(3,4-methylenedioxy)acetophenone hy acidified with hydrochloric acid to the dry ether ex drobromide are obtained. tract. The crystals are isolated by filtration and upon Melting point: 206-208 C. Elementary analysis: as drying, 15.5 g. of 1-(3,4-methylenedioxyphenyl)-2-iso C12H15NO3.HBr; Calculated: C= 47.70, H-5.34, 55 propylbenzylaminoethanol hydrochloride are obtained. N=4.64; Found: C-47.67, H=5.32, N=4.66. Melting point: 163-164 C. Elementary analysis: as EXAMPLED C19H23NO3.HCl; Calculated: C=65.23, H= 6.91, a-ISOPROPYLBENZYLAMINO-(3,4- N=4.00; Found: C=65.29, H=7.20, N=4.19. METHYLENEDIOXY)ACETOPHENONE 60 EXAMPLE G HYDROCHLORIDE 1-(3,4-METHYLENEDIOXYPHENYL)-2-t-BUTYL 50 g. of a-bromo-(3,4-methylenedioxy)acetophenone BENZYLAMINOETHANOL HYDROCHLORIDE are dissolved in 700 ml. of ethyl acetate and to the solu tion are added dropwise with stirring 62.5 g. of iso The procedure described in Example F is repeated propylbenzylamine at 3’-5’ C. After completion of the 65 except that 87 g. of t-butylbenzylamine are used in place dropwise addition, the stirring is continued for 30 min of the isopropylbenzylamine. 16.3 g of 1-(3,4- utes. Then the isopropylbenzylamine hydrobromide methylenedioxyphenyl)-2-t-butylbenzylaminoethanol which separates out in the reaction mixture is filtered hydrochloride are obtained. 4,147,799 13 14 Elementary analysis: as C20H25NO3.HCl; Calculated: C= 66.01, H=7.20, N=3.84; Found: C=65.97, 2. EFFECT ON INOTROPIC RESPONSE TO H=7.23, N=3.80. ISOPROTERENOL IN TRACHAEL CHAIN OF GUINEA PIGS EXAMPLE H 5 Whole trachea tube is excised from a male guinea pig a-(t-BUTYLBENZYLAMINO)-(3,4- and cut open longitudinally along the anterior side of METHYLENEDIOXY)ACETOPHENONE the trachea. The opened trachea is cut transversely HYDROCHLORIDE along the ring cartilage into strips of 1-2 mm. in width. The procedure described in Example D is repeated Six of these strips are tied in series to form a tracheal except that 67.5 g. of t-butylbenzylamine are used in 10 chain. The trachael chain preparation is set up in Krebs place of the isopropylbenzylamine. 56.5 g. of d-(t-butyl Ringer's organ bath gassed with 95% O2 and 5% CO2 benzylamino)-(3,4-methylenedioxy)acetophenone hy and maintained at 37 C. The contraction and relaxation drochloride are obtained. of the tracheal chain are isotonically recorded on an Elementary analysis: as C20H23NO3.HCl; Calculated: ink-writing kymograph. Isoproterenol is cumulatively C= 66.38, H = 6.68, N=3.87; Found: C=66.41, 15 applied to the tracheal chain which is in nearly maxi H = 6.65, N=3.84. - mum contraction induced by 2X 10-5M histamine. Ef. fects of the test compound and the control compound BETA-ADRENERGIC BLOCKING ACTIVITY on the dose-relaxation relations of the trachea in re OF 20 sponse to isoproterenol are investigated. The results are 1-(3,4-METHYLENEDIOXYPHENYL)-2-ISO shown in FIGS. 3 and 4. PROPYLAMINOETHANOL f3-Adrenergic blocking activity of the test compound, 3. EFFECT ON INOTROPIC RESPONSE TO 1-(3,4-methylenedioxyphenyl)-2-isopropylaminoe ISOPROTERENOL IN TAENA COL OF GUINEA PIGS thanol, is studied of its effects on chronotropic response 25 to isoproterenol in isolated guinea pig atrial prepara A taenia coli is excised from a male guinea pig to have tions (Test 1) and inotropic responses to isoproterenol in a length of about 2 cm. and suspended in Krebs-Ringer's a tracheal chain of guinea pigs (Test 2) and in a taenia organ bath. The bath fluid is maintained at 37 C. and coli of guinea pigs (Test 3). The results are respectively gassed with 95% O2 and 5% CO2. The contraction and shown in FIGS. 1, 3 and 5. Experiments are also carried relaxation are recorded with an isotonic lever on a ky out using 1-(4-methylsulfonylaminophenyl)-2-iso mograph. Since the preparation spontaneously pre propylaminoethanol as a control compound. The results serves certain tones, isoproterenol is cumulatively ap are shown in FIGS. 2, 4 and 6. Experiments are carried plied without any pre-treatment. Effects of the test out using Krebs-Ringer's organ bath in the absence and compound and the control compound on the dose in the presence of the test compound or the control 35 relaxation relations of the taenia coli in response to compound. Where either of the compounds is present, isoproterenol are investigated. The results are shown in the concentration of the compound in the bath is FIGS. 5 and 6. 10°g/ml. Effects of the test compound and the control From FIGS. 1 to 6, it is apparent that 1-(3,4- compound are determined twice in Tests 1 and 2 while methylenedioxyphenyl)-2-isopropylaminoethanol has those are determined only once in Test 3. In the figures, f3-adrenergic blocking activity and that the activity is Curves I and II show the dose-response relations in the not significantly different from that of 1-(4-methylsul absence of the test or control compound and corre fonylaminophenyl)-2-isopropylaminoethanol. sponding Curves I" and II' show those in the presence of What is claimed is: the compound. 1. A process for reducing blood pressure and block 1. EFFECT ON CHRONOTROPIC RESPONSE TO 45 ing £8-adrenergic receptor, which comprises the admin ISOPROTERENOL IN ISOLATED GUINEA PIG istration of an effective amount of a composition com ATRIAL PREPARATION prising as its active ingredient a 1-(3,4-methylenedioxy phenyl)-2-alkylaminoethanol compound represented by Male guinea pigs weighing from 300 to 400 g. are the formula: killed by a blow on the head. Through a thoracic inci 50 sion, the heart is quickly dissected out and freed from connective and adipose tissues in oxygenated Krebs 1 O Ringer's solution. Both left and right atria are detached H2C from ventricles. Each end of the atria is ligated with a No CH-CH-NHR cotton thread and mounted in 30 ml. Krebs-Ringer's 55 OH organ bath gassed with 95% O2 and 5% CO2 and main tained at 37 C. The isometric contraction and heart rate wherein R is an alkyl group having 2 to 6 carbon atoms, are measured by means of a strain gauge transducer and or a pharmaceutically acceptable acid addition salt a pulse rate tachometer, respectively. These are re thereof. corded on an ink-writing oscillograph. Effects of the 2. The process according to claim 1, wherein the test compound and the control compound on the dose active ingredient is 1-(3,4-methylenedioxyphenyl)-2-iso heart rate relations of the atrial preparation in response propylaminoethanol. to isoproterenol are investigated. Since isoproterenol is 3. The process according to claim 1, wherein the cumulatively added to the organ bath, inotropic re active ingredient is 1-(3,4-methylenedioxyphenyl)-2-t- sponses do not appear in a precise dose-dependent 65 butylaminoethanol. shape, and the dose-response curves are obtained from 4. The process according to claim 1 wherein said the chronotropic responses of the atria. The results are active ingredient is in the form of a pharmaceutically illustrated in FIGS. 1 and 2. acceptable acid addition salt selected from the group 4,147,799 15 16 6. The process according to claim 1 wherein said consisting of oxalate, lactate, tartrate, naphthoate, ace active ingredient is 1-(3,4-methylenedioxyphenyl)-2-iso tate, salicylate, citrate, benzoate, adipate, and maleate. propylaminoethanol hydrochloride. 7. The process according to claim 1 wherein said 5. The process according to claim 1 wherein said active ingredient is 1-(3,4-methylendioxyphenyl)-2- active ingredient is in the form of a pharmaceutically ethylaminethanol hydrochloride. 8. The process according to claim 1 wherein said acceptable acid addition salt selected from the group active ingredient is 1-(3,4methylenedioxyphenyl)-2-t- consisting of hydrochloride, hydrobromide, phosphate butylaminoethanol hydrochloride. and sulfate. 10 k k k k

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UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION

Patent No. 4, l47, 799 Dated April 3, 1979

Inventor(s) Hiroyuki Obase, et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2, line 66, "methylenedioxyyphenyl" should be --methylenedioxyphenyl--;

Col. 3, line 46, "HHR" should be --HNR

Col. 6 line l4, "reactior" should be --reaction--;

line 46, "mol. " should be --m1. --;

Col. 7, line 7, "Caliculated" should be --Calculated.--;

Col. 8, line 43, "methyllenedioxyphenyl" should be --methylenedioxyphenyl-- ; Col, ll line 35, "of" should be --off--. signed and sealed this Seventeenth D ay of July 1979 SEAL Attest:

LUTRELLE F. PARKER Attesting Officer Acting Commissioner of Patents and Trademarks