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

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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.
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