United States Patent (19) (11) 4,317,930 Hirose Et Al

United States Patent (19) (11) 4,317,930 Hirose et al. 45) Mar. 2, 1982

(54) PHENETHYLAMINEDERIVATIVES AND 4,012,528 3/1977 Jen et al...... 260/570.6 X BRONCHOILATOR CONTAINING THE Primary Examiner-Robert V. Hines SAME Attorney, Agent, or Firn-Wenderoth, Lind & Ponack 75) Inventors: Noriyasu Hirose, Kokubunji; Shigeru Souda, Tokyo, both of Japan 57 ABSTRACT Novel phenethylamine derivatives represented by the 73) Assignee: Eisai Co., Ltd., Japan general formula: (21) Appl. No.: 778,326 (22 Filed: Mar. 16, 1977 30 Foreign Application Priority Data HO (HCH-NHCH.) . A Mar. 19, 1976 (JP) Japan ...... 51A29 75 OH 51) Int. Cl...... CO7K 91/16 CHOR 52) U.S. Cl...... 564/363; 260/340.9 R; 260/501, 18; 260/501.19; 424/316; 424/330; wherein R is a lower alkyl group, CnH2n is a branched 560/142; 560/231; 564/343; 564/344; 564/358; or straight alkylene group, A is a phenyl group unsub 564/359 stituted or substituted with hydroxy, a lower alkoxy or 58 Field of Search ...... 260/501.18, 501, 19, a lower alkylene dioxy group, and n is an integer from 260/570.6; 564/363 1 to 4, and pharmacologically acceptable acid addition salts thereof, and bronchdilator containing the same. (56) References Cited These bronchdilator has an intense and durable bronc U.S. PATENT DOCUMENTS hdilating effect and a weak heart stimulating action. 3,644,353 2/1972 Lunts et al...... 260/.570.6 X 3,976,695 8/1976 Kaiser et al...... 260/.570.6 4 Claims, No Drawings 4,317,930 1. 2 a lower alkylene dioxy group, and n is an integer from PHENETHYLAMINE DERVATIVES AND 1 to 4. BRONCHDLATOR CONTAINING THE SAME The compound (I) according to this invention may be, if desired, converted into a pharmacologically ac This invention relates to novel phenethylamine deriv s ceptable acid addition salt thereof. As the pharmacolog atives and bronchdilator containing said novel pheneth ically acceptable acid addition salts, there are exempli ylamine derivatives. fied inorganic salts such as hydrochloride, hydrobro As the bronchdilators, there have been used Isoprote mide, sulfate and the like; organic salts such as acetate, renol Isoetharine, Methoxyphenamine, Salbutamol, and maleate, fumarate, citrate, succinate, oxalate, methane the like. The inventors had studied to search com O sulphonate, and the like. pounds which may be used as the bronchdilator having The compounds (I) and the pharmacologically ac a more intense and more durably brochdilating effect, ceptable acid addition salts thereof act more selectively and less stimulating action to the heart than such prior on the bronch-unstriated muscle to exhibit the bronc bronchdilators, and finally accomplished this invention. hdilating effect, and they are f3-adrenergics having The phenethylamine derivative according to this 5 weak heart stimulating action. invention is represented by the general formula (I): Accordingly, an object of this invention is to provide a novel phenethylamine derivative and pharmacologi (I) cally acceptable acid addition salts thereof. Another object of this invention is to provide a novel HO CHCHNHOCH2). A bronchdilator containing said phenethylamine deriva tive or a pharmacologically acceptable acid-addition OH salt thereof, which has intense and durable bronchdilat CHOR ing action. Further objects of this invention will be more clearly wherein R is a lower alkyl group, CnH2n is a branched 25 understood from the following description. or straight alkylene group, A is a phenyl group unsub An example of process for the production of the stituted or substituted with hydroxy, a lower alkoxy or compound according to this invention is illustrated by the following chemical sequences:

Benzylation or HO COCH3 RQH HO CoCH, acci lion

CH2Cl CHOR (1) (2)

RO COCH

(3) CHOR C Bromination

RO COCH2Br

(4) CHOR D HCH.) . A CH2CHs (7)

R"O coCHCH.) . A CH2C6H5 ( 5) CHOR HO H2 (When R' is F E (When R' is acetyl group) benzyl group) 4,317,930

-continued

. H HO coCHCH.) A->HO CHCH-NH(CH2). A OH CHOR CHOR (6) (I) wherein R, CnH2n, and A have the same meanings as mentioned above, and R represents benzyl or acetyl group. In the step D, there is used a reaction solvent, such as Step A acetonitrile; an alcoholic solvent, for example, metha 3-Chloromethyl-4-hydroxy acetophenone (1) is re 15 nol, ethanol, isopropyl alcohol and the like; an estereal acted with a lower alcohol in the presence of an alkali solvent, for example, ethyl acetate, and the like; an reagent, to synthesize 3-lower alkoxymethyl-4-hydroxy ethereal solvent, for example, diethyl ether, diisopropyl acetophenone (2). ether and the like. Step B It is preferable to use an alkali reagent such as alkali The compound (2) is subjected to a conventional 20 carbonates, pyridine, triethylamine and the like, as a benzylation or acetylation reaction, to synthesize 4-sub de-acidizing agent in order to accelerate the reaction. stituted 3-lower alkoxymethyl acetophenone (3). Alternatively, an excess amount of N-benzylamine may Step C be used as the de-acidizing agent. The compound (3) is brominated to synthesize the In the step E, catalytic reduction is carried out in the corresponding bromoactophenone compound (4). 25 presence of a catalyst, for example, palladium-carbon, Step D platinum black, Raney nickel and the like at an ambient The compound (4) is reacted with N-benzylamine or elevated temperature under an atmospheric pressure compound (7) to synthesize the corresponding ami or super pressure. noketone compound (5). Alternatively, the reduction for de-benzylation may Step E 30 be carried out after the reduction of the carbonyl group When R' is benzyl group, the compound (5) is sub using sodium borohydride, aluminium isopropoxide, jected to reduction reaction to obtain the compound (I) lithium aluminium hydride and the like. according to this invention. In the step F, hydrolysis is carried out using conven Step F tional acid hydrolyzing agent such as hydrochloric acid When R' is acetyl group, the compound (5) is sub 35 and the like. jected to a conventional hydrolysis operation to synthe In the step G, catalytic reduction is carried out in the size the compound (6). presence of catalyst, such as palladium-carbon, plati Step G num black, Raney nickel and the like, at an ambient or The compound (6) is subjected to reduction reaction elevated temperature under an atmospheric pressure or to obtain the compound (I) according to this invention. 40 super pressure. In the step A, a lower alcohol per se used in the The solvents to be used in the steps E, F and G are reaction plays as the reaction solvent. It is preferable, in selected from alcoholic solvents consisting of methanol, order to accelerate the reaction, to use an alkali reagent ethanol, and isopropyl alcohol, and hydrous alcohols such as sodium bicarbonate, caustic alkalis and alkali and the like, carbonates, and sodium lower alkoxylates and the like 45 The pharmacological action of the compounds ac corresponding to said lower alcohols used, as a de-aci cording to this invention is illustrated by the following dizing agent. experiments. In 4-benzylation reaction of the step B, there is used In these experiments, the compounds according to a reaction solvent, such as an alcoholic solvent, for this invention are examined, comparing with the con example, methanol, ethanol and the like; and a ketone 50 trol compounds, that is, Isoproterenol which is a typical solvent, for example, methyl ethyl ketone, methylisobu p3-adrenaline stimulant and Salbutamol which has a tyl ketone and the like. And, there is used a benzylation chemical structure similar to that of the compound reagent, for example, benzylchloride, benzylbromide, according to this invention. and the like. In 4-acetylation, the reaction is effected in Compounds to be examined: accordance with a conventional process for conversion 55 (i) Control compounds of phenolic hydroxy group to the corresponding ace L-isoproterenol hydrochloride (hereinafter referred to tate. isoproterenol); In the step C, there is used a reaction solvent, such as Salbutamol hydrochloride: 1-(4-hydroxy-3-hydroxyme a halogenous solvent, for example, chloroform, methy thylphenyl)-2-(t-butylamino)-ethanol hydrochloride lene chloride and the like; alcoholic solvent, for exam (hereinafter referred to Salbutamol). ple, ethanol, methanol, isopropyl alcohol, and the like; (ii) Compounds according to this invention: and an ethereal solvent, for example, diethyl ether, 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- dimethyl ether and the like. methoxyphenethylamino)ethanol fumarate (hereinaf. As the brominating agent for the bromination, there is ter referred to compound A of this invention); used a conventional bromination reagent, for example, 65 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl bromine, cupric bromide, pyrolidone hydrotribromide 3,4-methylene dioxyphenethylamine)ethanol oxalate and the like. Bromine is used in a form of bromine perse (hereinafter referred to compound B of this inven or in the presence of alminium chloride. tion); 4,317,930 5 6 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- hydroxyphenethylamino)ethanol oxalate (hereinafter PHARMACOLOGICAL EXPERIMENT 3 referred to compound C of this invention). Effect on the Heart Beat Numbers PHARMACOLOGICAL EXPERIMENT 1. 5 (1) Conscious guinea pigs The guinea pigs were used, in which electrodes of Protecting Effect Against the Dyspnea Caused by the stainless steel were pierced and put in both forelegs of Histamine the respective guinea pigs under previous anesthesia Male guinea pigs of Hartley strain were used. Aque (after 24 hours from this operation). ous solutions of the compounds to be examined were The guinea pigs were isolated one by one in observa prepared in various concentrations, and administered O tion boxes, recorded their electrocardiogram (the first orally to the guinea pigs, in a dose of 10 ml/Kg, respec induction) under quiet circumstances, and heart beat tively. After the oral administration, the guinea pigs numbers were counted. were taken in a dome. Histamine solution in a concen All compounds to be examined were administered tration of 0.1% was sprayed through a nebulizer at a 15 orally. The recording and measuring were carried out blow rate of 3500 ml/min. Two symptoms of hypoxia three times before the administration and with the lapse and fit of caughing were used as indices, and a probable of time until 180 minutes after the administration. appearing time of said two symptoms was watched and observed for 20 minutes from the start of the spraying. Results The protecting effect was judged to be effective with 20 TABLE 2 the appearing time more then the double of the mean The increasing action to the heart appearing time in 33 examples of the groups wherein beat numbers of the guinea pig physiological saline water was administered. Compounds to Dosage (mg/Kg) Results be examined 0.3 3 30 25 Isoproterenol 87.3 86.9 147.0 TABLE 1 Salbutanol 33.2 33.6 94.0 Protecting effect on the asthmatous fit Compound A caused by the histamine spray of Iso this invention 36.8 750 93.7 pro- Sal- Compound Compound Compound Calculation from the product of the intensity action with the durability tete- bu- A of B of this C of this 3O this nol tanol invention invention invention The compound A of this invention showed a distinct ED 50 2.90 2.25 0.39 0.56 0.36 increasing action to the heart beat numbers with the (mg/Kg) dosage of 0.3 mg/Kg. and showed variations corre Ratio to 35 sponding to the dosage. The action of the compound A isopro- 100 129 44 518 806 of this invention was relatively same as that of Sal tererol butamol and weaker than that of Isoproterenol. (2) Anesthetized dogs It was observed that the compounds A, B and C of Using anesthetized dogs as same as the pharmacologi this invention show the protecting effect of the fit with 40 cal experiment 2, and injecting the compounds to be extremely small amount of the compounds, and these examined into the dogs from the femoral vein thereof, effects amounted to 5-7 times of those of two controls, the increasing actions to the heart beat numbers were salbutamol and isoproterenol. The durability action of examined. the compounds A, B and C of this invention extended obviously longer than those of the two controls. Results 45 The increasing action to the heartbeat numbers of the PHARMACOLOGICAL EXPERIMENT 2 anesthetized dogs was shown with the dosage more Inhibitory Effect on the Increasing Reaction of the than 3 g/Kg of the compound A of this invention Airway Resistance of Histamine through intravenous injection. This variation is weaker Normally healthy dogs (body weights were 10-15 50 than that of Isoproterenol, and rather more intense than Kg) were used as subject animals, and anesthetized with that of Salbutamol. sodium pentobarbital urethane. The compounds to be PHARMACOLOGICAL EXPERIMENT 4 examined were injected into the femoral vein of the dog. The inhibitory effect on the increasing reaction of Effect on the Blood Pressure the histamine (10 ug/Kg were administered) to the air 55 Using the anesthetized dogs as same as pharmacologi way resistance was determined by Konzett-Rössler cal experiment 2, and injecting the compounds to be method. examined into the dogs from the femoral vein, the effect Results on the blood pressure was examined. The compound A of this invention exhibited the in- 60 Results hibitory effect of more than 50% with 3 Jug/Kg and also The effect on the blood pressure in the anesthetized durability effect. This effects are almost same as those of dogs showed the remarkable depression effect upon the salbutamol. blood pressure with the dosage more than 3 ug/Kg of Although isoproterenol exhibited a distinct effect the compound A of this invention. Isoproterenol was with about lug/Kg immediately after the administra- 65 relatively short in durability effect, but shows more tion, but the effect decreased to only 10%, notwith intense depression effect than that of the compound A standing a large amount of administration such as 30 of this invention. The depression effect of Salbutanol ug/Kg, after 10 minutes from the administration. had rather weaker tendency. 4,317,930 7 8 after addition of 168g of sodium bicarbonate. After the PHARMACOLOGICAL EXPERIMENT 5 reaction is over, inorganics are filtered off, 3 l of water Acute Toxicity are added to the filtrate, and oily products isolated are There was examined and observed the acute toxicity extracted with toluene. The extracts are dried over of the compounds to be examined for 7 days in the case anhydrous Glauber's salt, and the toluene is distilled off. of oral administration to mice. The resulting crystals are recrystallized from diisopro pyl ether. Results Yield: 147 g. Melting point: 89°-90° C. O Elementary analysis of the product for CoH12O3 Compounds to be examined LD50 (mg/Kg) gives: Compound A of this invention 050 Compound B of C H this invention 200 Compound C of 15 Calculated (%) 66.64 6.73 this invention 1200 Found (%) 66.7 6.72 It was found from the above pharmacological experi ments that the compounds of this invention have very Step B: Synthesis of intense and durable bronchdilating action, and particu 20 4-benzyloxy-3-methoxymethyl-acetophenone larly, when administered orally, the action is more in To 2 l of ethanol, there are added 200 g of the com tense than those of Isoproterenol and Salbutamol. It is pound obtained in the step A1, 154.5 g of benzylchlo therefore considered that the compounds (I) of this ride, 184 g of anhydrous potassium carbonate and a invention and pharmacologically acceptable acid addi small amount of potassium iodide. The mixture is boiled tion salts thereof are effective, as the bronchdilators, 25 for 6 hours with stirring. Inorganics are filtered off and upon the treatment and the prevention of the bronchial the filtrate is concentrated. The resulting oily products asthma, the bronchial convulsion, the brounchoedema, are dissolved in toluene, and the solution is washed with the asthmatic bronchitis, and the like, for example. water, dried and distilled under vacuum. The dosage of the compound (I) of this invention and Boiling point: 175-178° C. (0.5 mm/Hg). pharmacologically acceptable acid addition salts 30 Yield: 293 g. thereof may be varied from 0.1 to 300 mg and prefera Elementary analysis of the product for C17H18O3 bly from 10 to 100 mg a day for an adult, and it is de gives: sired to divisionally administer the compound (I) or salt with proper intervals in accordance with the symptom. In this invention, the compound (I) and the pharma 35 C H cologically acceptable acid addition salts thereof may Calculated (%) 75.53 6.71 be administered by a conventional method, that is, oral Found (%) 75.42 6.90 administration or parenteral administration such, for example, as injection, a nebulizer and the like. Accord ing to this invention, the compound (I) and the pharma 40 Step C1: Synthesis of cologically acceptable acid addition salts thereof may 4-benzyloxy-3-methoxymethyl-a-bromoacetophenone be administered with a sole substance per se, or as a Amounts of 200 g of the compound obtained in the preparation combined with a liquid or a solid carrier step B1 and 13 g of benzoyl peroxide are dissolved in 2 which does not affect the compound and the salt then l of ethanol, and the solution is maintained at a tempera selves. As a form of the preparation, there can be exem 45 ture from 15 to 20 C. To this solution, 215 g of bro plified tablet, granule, powder, capsule, buccal, syrup, mine are added dropwise with stirring. After the addi suspension or injection. The solid carriers capable of tion was over, the solution is stirred for one hour. The mixing with the compound (I) and the pharmacologi crystals precipitated are recovered by filtration, and cally acceptable acid addition salts thereof include for recrystallized from ethanol. example, corn starch, lactose, talc, carboxy methyl cel 50 Yield: 178 g. lulose, crystalline cellulose, hydroxy propyl cellulose, Melting point: 94-96 C. stearic acid, calcium stearate, silicic anhydride, gum, Elementary analysis of the product for C17H7O3 Br and the like. The liquid carriers to be used for the sus gives: pension, the injection and the like include, for example, water, vegetable oil, various emusifying agents, various 55 surfactants, and the like. C H This invention will be more particularly illustrated by Calculated (%) 58.46 4.92 the following examples. Found (%) 58.42 5.10 EXAMPLE 1 60 Step D1: Synthesis of 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- 4-benzyloxy-3-methoxymethyl-a(N-benzyl-N(a-meth methoxyphenethylamino)-ethanol yl-4-methoxyphenethyl)aminoacetophenone Step A: Synthesis of 3-methoxymethyl-4-hydroxyacetophenone Amounts of 39.5 g of the compound obtained in the 65 step C and 57.7 g of N-benzyl-N(a-methyl-4-methoxy An amount of 184.6 g of 3-chloromethyl-4-hydrox phenethyl)amine are stirred for 6 hours in 200 ml of yacetophenone is dissolved in 923 ml of methanol, and acetonitrile. The crystals precipitated are filtered off, the solution is stirred for 3 hours at room temperature and the filtrate is concentrated, to give the object com 4,317,930 9 10 pound. The compound is used for the following step -continued without purification. C H N Step El: a Synthesis of Found (%) 65.29 7.22 3.35 1-(4-benzyloxy-3-methoxymethylphenyl)-2-N-benzyl s N-(a-methyl-4-methoxyphenethyl)amino-ethanol The corresponding hydrochloride: An amount of 14.2 of the compound obtained in the Melting point: 126-127.5' C. step D is dissolved in 70 ml of ethanol. This solution is added dropwise with stirring to a solution which was The corresponding oxalate: prepared by dissolving 4.1 g of sodium borohydride in 10 Melting point: 190.5 C. (with decomposition). 70 ml of ethanol. After stirring for two hours at room EXAMPLE 2 temperature, the ethanol is distilled off. After adding water, the residue is extracted with toluene, washed 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl with water and dried. The toluene is then distilled off. 3,4-methylenedioxy-phenethylamino)ethanol The resulting oily products are crystallized as the hy 15 Step B2: Synthesis of drochloride and recrystallized from acetonitrile. 4-acetoxy-3-methoxymethyl-acetophenone Yield: 12.4 g. Amounts of 55 g of 4-hydroxy-3-methoxymethyl Melting point: 1830-183.5 C. acetophenone obtained in the step A1 of the Example 1, Elementary analysis of the product for 20 C3H39NO4.HCl gives: 260 ml of acetic anhydride, and 10 ml of pyridine are mixed, and the mixture is heated under reflux for 4 hours. After removing the acetic anhydride and the C H N pyridine by conventional process, the reaction mixture Calculated (%) 72.63 7.18 2.49 25 is distilled under reduced pressure. Found (%) 72.38 7.14 2.4 Boiling point: 139-142 C. (0.8 mm/Hg). Yield: 54 g. b Synthesis of Elementary analysis of the product for C12H4O4 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- 30 gives: methoxyphenethylamino)ethanol An amount of 8.5 g of the corresponding free amine C H which is produced by treating the compound obtained Calculated (%) 64.85 6.35 in the above item a with sodium hydroxide, is dissolved Found (%) 65.02 6.26 in 85 ml of ethanol, and the solution is reduced catalyti 35 cally in the presence of 5% palladium-carbon under an atmospheric pressure. Step C2: Synthesis of After filtering off the catalyst, the solvent of the fil 4-acetoxy-3-methoxymethyl-a-bromo-acetophenone trate is distilled off. The residue is recrystallized from diisopropyl ether, to give the object compound in the An amount of 10 g of the compound obtained in the form of needle crystal. above step B is dissolved in 200 ml of chloroform. Yield: 5.9 g. Maintaining the reaction temperature at 10' C., 7.2 g of N.M.R. (CDCl3, TMS): bromine are added dropwise to the solution with stir ring. After stirring for two hours at room temperature, 45 6: 7.2-6.8 ppm (7H, m, aromatic H) the reaction mixture is washed with water, dried and 4.62 (2H, s, CHOCH3) distilled under reduced pressure. 4.50 ph Boiling point; 173-173.5° C. (0.8 mm/Hg). (1H, n, -CH-CH2) Yield: 7.5 g. 4.2-3.6 (3H, broad, 2-OH and NH) Elementary analysis of the product for C12H13O4Br 3.80 50 (3H, s, -( )-OCH.) gives: 3.42 (3H, s, CH2OCH3) 3.0-2.7 (5H, m, -CH2N-CH-CH2-) C H 40 55 Calculated (%) 47.84 4.36 (3H, d, -CH-CH3) Found (%) 47.68 435 The object compound (free amine) obtained in the above item b may form crystalline salts with various Step D2: Synthesis of 4-acetoxy-3-methoxymethyl-d acids. 60 N-benzyl-N(a-methyl-3,4-methylenedioxyphenethyl The corresponding fumarate: )aminoacetophenone Melting point: 165 C. (with decomposition). Amounts of 17.3 g of the compound obtained in the Elementary analysis of the product for C20H27NO4. above step C2 and 31.0 g of N-benzyl-N-(a-methyl-3,4- C4H4O4: methylenedioxyphenethyl)amine are stirred for 5 hours in 230 ml of acetonitrile. After-treatment is achieved in the same manner with the step D1. The product is used Calculated (%) 65.48 7.26 3.47 for the following step without purification. 4,317,930 11 12 Step F2: Synthesis of yl-4-benzyloxyphenethyl)amine in accordance with the 4-hydroxy-3-methoxymethyl-a(N-benzyl-N(a-methyl step D2 in the Example 2. The resulting product is used 3,4-methylenedioxyphenethyl)aminoacetophenone for the following step, without purification. An amount of 22 g of the compound obtained in the 5 Step F3: Synthesis of above step D2 is dissolved in 150 ml of 6N hydrochloric 4-hydroxy-3-methoxymethyl-a(N-benzyl-N(a-methyl acid, and the solution is allowed to stand for 10 hours at 4-benzyloxyphenethyl)aminoacetophenone room temperature. The crystals precipitated are recov An amount of 16.6 g of the compound obtained in the ered by filtration, and recrystallized from isopropyl step D3 of the Example 2 is treated with concentrated alcohol, to form the hydrochloride mono-hydrate of the O hydrochloric acid in accordance with the step F2 of the object compound. Example 2. The product is recrystallized with ethanol, Yield: 17 g. to give the hydrochloride of the object compound as Melting point: 219 C. (with decomposition). colorless crystalline masses. Elementary analysis of the product for Yield: 12 g. C27H3oNO5.HCl gives: 5 Melting point: 108 C. Elementary analysis of the product for C H N C33H35NO4.HCl gives: Calculated (%) 6459 6.43 2.79 Found (%) 64.30 6.2 2.75 2O, C H N Calculated (%) 72.57 6.65 2.56 Found (%) 7260 6.57 2.56 1-(4-hydroxy-3-methoxymethylphenyl)-2-(o-methylStep G2: Synthesis of 3,4-methylenedioxyphenethylamino)ethanol 25 Step G3: Synthesis of An amount of 7.7 g of the hydrochloride obtained in 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- the step F2 is dissolved in 80 ml of methanol, and the hydroxy-phenethylamino)ethanol solution is subjected to the hydrogenolysis in the pres An amount of 3.9 g of the compound obtained in the ence of palladium-carbon in accordance with the Exam step F3 is dissolved in 40 ml of methanol, and the solu ple 1 (Step E1, b). The reactants are then alkalified with 30 tion is subjected to reduction reaction in the presence of aqueous ammonia. The object compound is extracted palladium-carbon catalyst in accordance with the step with ether, G2. The object compound is crystallized as the oxalate, The resulting object compound is made to equiva which is purified by recrystallizing from aqueous meth lent oxalate and crystallized. anol. 35 Yield: 2.1 g, Yield: 4.5 g. Melting point: 158-160" C. Melting point: 202.5' C. (with decomposition). Elementary analysis of the product for.. Elementary analysis of the product for C20H25NO5. C2H2O4 gives: C19H25NO4C2H2O4 gives: 40 C H N C H N Calculated (%) 63.80 6.97 3.72 Calculated (%) 62.35 6.49 3.46 Found (%) 63.74 6,92 3.52 Found (%) 62.59 6.49 3.62 45 NMR(DMSO-de, TMS): 8: 4.39 ppm (2H, s, NMR(DMSO-ds, TMS): 6: 4.41 ppm (2H, s, CH2OCH3); 3.32 (3H, 's, CH2OCH3). CH2OCH3); 3.35 (3H, s, CHOCH3). The following Table 3 shows examples wherein the EXAMPLE 3 compounds according to this invention are listed. 1-(4-hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- hydroxy-phenethylamino)ethanol Step D3: Synthesis of 4-acetoxy-3-methoxymethyl-a(N-benzyl-N(a-methyl 4-benzyloxyphenethyl)aminoacetophenone An amount of 12.0 g of the compound obtained in the step C2 is condensed with 26.4 g of N-benzyl-N(a-meth TABLE 3

Elementary Analysis to-)-listicalOH (I) Calculated (%) CHOR Molecular Formula Found (%) Example R (CH2) A. Appearance Melting Point ("C.) C H N 4. CH3 -C(CH3)2-CH2- Fine needle C20H27NO3. HCl 65.63 7.72 3.82 -() 85-186 65.56 7.76 3.73 5 C2H5 -C(CH3)2-CH- Fine needle C2H9NO3. HCl 66.38 7.97 3.69 - -() 160-61 66.56 8.10 3.37 4,317,930 13 14 TABLE 3-continued

Elementary Analysis re-- OHshCH-NHC.H.A (I) Calculated (%) CHOR Molecular Formula Found (%) Example R (CH2) A Appearance Melting Point (C.) C H N 6 CH CH Fine needle C19H25NO3. HC 64.84 7.46 3.98 / 152-153.5 64.67 7.40 3.87 -CH N CH2 CHS CH3 Fine needle C20H27NO3. HCI 65.63 7.72 3.82 / -() 167.5 65.39 7.70 3.79 -CH (with decomposition) CH

-continued Inhalant 2O Chlorobutanol 0.5g Citric acid 1.0 g EXAMPLE 8 Sodium hydroxide 0.375g Purified water sufficient to make up the total to 100 ml Tablet for oral administration 1-(4-hydroxy-3-methoxymethylphenyl)- 25 The inhalant is prepared using the above formulation 2-(a-methyl-4-methoxyphenethylamino)- ethanol fumarate and according to a conventional process. This inhalant Lactose 3 is used for a spray inhalation treatment by means of Corn starch s aerosol, a nebulizer, and the like. Carboxy methyl cellulose l What is claimed is: Crystalline cellulose 4. 30 1. A phenethylamine derivative represented by the Magnesium stearate 0. formula: Using the above formulation and according to a con ventional process, tablets are prepared, in which 5 mg of 1-(4-hydroxy-3-methoxymethylphenyl)-2-(o-methyl 35 HO CHCH-NHCHCH OR 4-methoxyphenethylamino)ethanol fumarate per tablet are contained. OH CH3 CHOCH3 EXAMPLE 9 wherein R1 is hydrogen or methyl, or a pharmacologi Injection cally acceptable acid-addition salt thereof. 1-(4-hydroxy-3-methoxymethylphenyl)-2- 2. The phenethylamine derivative of claim 1, wherein (a-methyl-4-hydroxyphenethylamino)- R1 is hydrogen. ethanol oxalate 5 g 3. The phenethylamine derivative of claim 1, wherein Distilled water for injection 45 R1 is methyl. sufficient to make up the total to Ol 4. A bronchdilator composition comprising a bronc hdilating amount of phenethylamine derivative repre The injection is prepared using the above formulation sented by the formula: and according to a conventional process. Said injection is packed into ampoules in an amount of 2 ml, respec 50 tively. Thus, each ampoule contains 1 mg of 1-(4- hydroxy-3-methoxymethylphenyl)-2-(a-methyl-4- HO shCH-NH HCH, OR hydroxy-phenethylamio)ethanol oxalate. OH CH3 EXAMPLE 10 55 CHOCH3

Inhalant wherein R1 is hydrogen or methyl, or a pharmacologi 1-(4-hydroxy-3-methoxymethylphenyl)- cally acceptable acid-addition salt thereof and a phar 2-(a-methyl-4-methoxyphenethylamino)- macologically acceptable carrier therefor. ethanol fumarate 2.0 g 60 k