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    • 专利摘要:
    A process for preparing substituted phenoxyaminopropanol derivatives of the general formula. where R is branched and alkyl radical containing 3 or 4 carbon atoms; R, hydrogen atom, halogen atom or lower alkyl radical RjHR hydrogen atom, halogen atoms, lower alkyl radicals, lower alkoxyl residues or lower alkylthio groups, or their salts, or their optically active antipodes, characterized in that the phenol derivative of the general formula OH I O-CHg-CH-CHGSH- where R and R, have the indicated meanings, are treated with a basic agent, for example sodium hydride, followed by the interaction of the resulting phenol ta el with a compound of the general formula Ish sd RZ 4 2-CHg-Shg- O-CHg CH, - {O N .. .7 p Kj where 2 and RJ have indicated Z is a lower alkylsulfonyloxy or arylsulfonyloxnyl group, and the target product is found in TU in free form or as a salt, or optically active antipodes.
    公开号:SU1155154A3
    申请号:SU823438752
    申请日:1982-05-19
    公开日:1985-05-07
    发明作者:Джеймс Мечин Питер
    申请人:Ф.Хоффманн-Ля Рош Унд Ко.Аг. (Фирма)；
    IPC主号:
    专利说明:

    Priority on the grounds: 02,06.80 when R is a branched alkyl radical containing 3 or 4 carbon atoms; R, E. is hydrogen; R is hydrogen, rajjorena atom, lower alkyl radicals lower alkoxy residues, lower alkylthio groups; 1 4 17.03,81 with R - branched, containing 3 or 4 carbon atoms alkyl radicals; R is a halogen atom, a lower alkyl radical; Rj and R - hydrogen, halogen atom, lower alkyl radicals, lower alkoxy residues, lower alkylthio groups.
    The invention relates to methods for producing compounds of the general formula O-CHf-CH-CHrNH-R OH "1-t O-CHrCHrO-CHj-CHa where R is an alkyl radical that is branched and contains 3 or 4 carbon atoms, RI is a hydrogen atom, a halogen atom or lower alkyl radicals R and H, hydrogen atoms, aTONfci halogens, lower alkyl radicals, lower alkoxy residues or lower alkylthio groups, either to their salts, or to their optically active antipodes, which have cardioselective, blocking / / adrenaline receptor properties and can be used for treatment or prophylaxis. e heart diseases and disorders of cardiac rhythm. They can also be used as anti-hypertoxic biologically active substances. A known method for the preparation of ureidophenoxy-2-hydroxy-3-aminopropanes of the general formula O-CHt-CH-CHrKftW, where RY is hydrogen, substituted or unsubstituted aliphatic residue R is a substituted or unsubstituted aliphatic residue; or R, and Rj - together mean a bivalent aliphatic residue; R. - aliphatic or cycloaliphatic residue; RX is hydrogen, lower alkyl, lower alkyl, and others, consisting in the interaction of a compound of the general formula rN-C-JiH where R., R "and R have the indicated meanings, with a compound of the general formula Z-CHj-CHX-CH-NH-RJ where R has the indicated meanings, X is a hydroxy group, Z is a reactive esterified into an ester oceanic group, or X j and Z forms a zpoxy group. The process is carried out both in the presence and in the absence of a solvent, in the presence of a basic agent at a low, normal or elevated temperature of a P3. Derivatives of phenoxyaminopropanol are known, for example, fumarate-1 isopropylpamino-3- (-methoxymethoxypheno-C) -2-propanol, and others that are structural analogues of compounds of general formula I and have antagonistic effect on ft-adrenoceptors 2j. However, these compounds do not possess intrinsic sympathetic 31b activity (ISA), i.e., aggression. The aim of the invention is to develop, on the basis of a well-known method, a method of producing new compounds that have biological activity and exhibit antagonistic effect on | E-adrenoreceptors and internal sympathomimetic activity. The goal is achieved by the proposed method of obtaining substituted phenoxyaminopropanol derivatives of general formula 1, which consists in the fact that phenol derivatives of general formula O-CHg-CH-CH.-NH-R where Ne and R, take the indicated values, are treated with the main agent, by pk mer hydride sodium, followed by reaction with the compound of the general formula A: Z-CHj-CHrO-CHf-CH2 -l R where R- and Ra take the indicated values; Z is a lower alkylsulfonyloxy or arylsulfonyl group, and the desired product is isolated in free form or as a salt, or as optically active antipodes. The reaction of the phenol derivative of the formula II with the basic agent is most expediently carried out in an inert organic solvent, such as dimethylformamide, dioxane, dimethoxyethane and tetrahydrofuran, and it is most preferable to use dimethylformamide. The phenol derivative of the formula II with the main agent is obtained from the acidic phenol and the basic agent, alkali metal hydride or alkali metal amide 4A, especially sodium hydride1. The process is carried out at an elevated temperature, preferably at 60 ° C. The obtained racemic compounds can be divided into optical antipodes, for example, by fractional crystallization of salts obtained with optically active acids. In addition, the phenol of the general II used as the starting material can also be in optically active form, in which case an optically active compound of the general formula I is obtained. Compounds of the general formula I can be converted by processing; pharmaceutical point of view with inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, etc.) or pharmaceutically acceptable organic acids (e.g. acetic, tartaric, citric, fumaric, maleic, block, methanesulfonic acid, paratoluenesulfonic acid) and the like) in acidible salts capable of being used for pharmaceutical purposes. P1, the phenols of the general formula I used as starting sources, are known compounds or mono-. can be obtained by analogy with known compounds by known methods. Compounds of general formula III used as starting materials belong to compounds of a known class and can be obtained, for example, by reacting an alcohol of the general formula HO-CHg-CHz where R and R take the indicated values with chloroacetic acid, resulting in a total acid forms. HOOS-Shg 0-SNg CKj
    7t
    the same pressure. M.p. 14 O-14 2C / / 15 mmHg
    c) The product obtained in b) is dissolved in 100 ml of pyridine. The prepared solution is treated with 4.48 ml of pyridine-. (39 mmol) of methanesulfonyl chloride and the reaction mixture is stirred for 0.5 h at room temperature. Immediately after this, the reaction mixture is evaporated, and the resulting residue is treated with ethyl acetate and 2N. hydrochloric acid solution. The organic phase is washed with water, dried over sodium sulfate, filtered, and the filtrate is evaporated. The result is 8.1 g (85%) of 2- (2-phenylethoxy) -2 ethyl methane sulfonate as an oily substance, which is homogeneous according to chromatography.
    Example 2. By analogy with example 1 of 1.6.9 g of 1-isopropylamino-3- (4-hydroxyphenoxy) -2-propanol and 1.97 g of (4-fluorophenyl) -ethoxy-ethylmethanesulfonate get 1.6 g (50 %) hydrochloride (4-fluorophenethoxy) of etoxyphenyl-3-eoprotein Iamimo-2-propanol with So pl. 88-92 C (from isopropyl alcohol).
    (4-fluorophenyl) -ethioxyethyl methanesulfonate is prepared according to the following procedure.
    a) By analogy with example 1a is subjected to the interaction of 7.0 g
    (50 mmol) of 4-fluorophenethyl alcohol with 4.7.3 g (50 mmol) of chloroacetic acid. As a result, 7.8 g (79%) of 2- (4-fluorophenyl) -ethoxy-acetic acid with m.p. 82-85C (from methylcyclohexane) are obtained.
    b) The product obtained in a), by analogy with Example 16, is reduced with lithium aluminum hydride. The result is 6.6 g (91%) of (4-fluorophenyl) ethoxyethanol as an oily substance, which is homogeneous according to the given chromatography.
    c) By analogy with example 1c, the material obtained in paragraph b) is sulfonated with methanesulfonyl chloride. The result is 8.2 g (87%) of (4-torphenyl) ethoxyethyl methane sulfonate as an oily substance, which is homogeneous according to chromatography.
    Example Z. By analogy with example 1 of 1.69 g of 1-isopropylamino1548
    -: 3- (4-hydroxyphenoxy) 2-propanol and 1.94 g of (4-methylphenyl) -ethoxy1-ethyl methanesulfonate give 1.6 g (50%) of 1- {4-G2- (4-methylfetiethyloxy) -ethoxy hydrochloride | -phenoxy7 -3-isopropylamino-2-propanol with so pl. 104106 С (from isopropyl alcohol).
    2- 2- (4-methylphenyl) -ethoxy-nitromethanesulfonate is prepared as follows.
    a) 6.8 g (50 mmol) of 4-methylphene ethyl alcohol are reacted with 4.73 g (50 mmol) of chloroacetic acid. The result is 8, 1 g (84%) of 2- (4-Methylphenyl) -ethoxyacetic acid with so pl. 6567 C (from methylcyclohexane).
    b) The resulting product is reduced with lithium aluminum hydride. The result is 6.6 g (88%) of (4-methylphenyl) -ethoxy - :) as an oily substance, which according to chromatography is homogeneous,
    c) The latter is sulfonated with methanesulfonyl chloride. As a result, 7.8 g (83%) of (4-methylphenyl) ethoxy ethylmethanesulfonate are obtained in the form of an oily substance, which according to chromatography is homogeneous.
    Example 4. By analogy with example 1, from 1.69 g of 1-isopropylammono-3- (4-hydroxyphenoxy) -2-propanol and 2.16 g (4-methylthiophenyl) -ethoxyethylmethanesulfonate, 1.40 g (41% ) 1- {4-C2- (4-metnpitiophenethyloxy) -ethoxy-phenoxy-3-: -isopropyl-amino-2-propanol hydrochloride with m.p. 98-101 ° C (from ethyl acetate).
    (4-Methylthiophenyl) -ethoxyJ-ethlmethanesulfonate is prepared according to the following procedure.
    a) 6.27 g (37 mmol) of 4-methylthiophenethyl alcohol are treated in 100 MP of dimethyl sulfoxide 3.58 g (74 mmol) of sodium hydride (50% dispersion in oil). The prepared mixture is stirred for 10 minutes at, then mixed with 3.53 g (37 mmol of chloroacetic acid, and immediately thereafter further heated with stirring for 3 hours at 80 ° C. Then the reaction mixture is cooled, washed into water and washed with ethyl s. The aqueous phase is acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl acetate. 0) The organic phase is separated, washed thoroughly with water, dried with sodium sulfate, filtered and evaporated to dryness. The resulting residue is recrystallized from a mixture of toluene and hexane, resulting in a gain of 3.89 g (46%) of 2- (4-methylthiophenyl) -ethoxyacetic acid with so pl. 58-60 C. Further, the product is reduced with lithium minor hydride. The result is 1.97 g (54%) of (4-methylthiophenyl) ethoxy-ethanol, in the form of an oily substance, which according to chromatography is homogeneous. It is sulfonated with methanesulfonyl chloride. The result is 2.41 g (90%) of 2-f2- (4-methylthiophenyl) -ethoxyJ-ethyl methanesulfonate in the form of an oily substance, which according to chromatography is homogeneous. Example 5. By analogy with Example 1, but using 1-tert-butylamino-3- (4-hydroxyphenoxy) 2-propanol instead of 1-isopropyl-3- (4-hydroxyphenoxy) -2-propanol, hydrochloride 1 is obtained ter. butylamino-3- t + - (2-feiethyloxyethoxy) - enoxy -2. -propanol with so pl. 87-88 ° C (from a mixture of ethyl alcohol and diethyl ether). Example 6. Similarly, 3.4 g (77%) hydrochloride are obtained from 2.25 g of 1-isopropylamo-3- (4-hydroxyphenoxy) -2-propanol and 2.74 g of (4-methoxyphenyl) -ethoxy-ethylmethanesulfonate. (4-methoxyphenethyloxy) -ethoxy-phenoxy; -3-isopropylamino-2-propanol with m.p. 99-101 ° C (isopropyl alcohol). Used as the starting material (4-methoxyphenyl) -ethis of this si-ethylmethanesulfonate obtained as follows. a) 6.08 g of 4-methoxyphenethyl alcohol is reacted with 3.8 g of chloroacetic acid. As a result, 6.64 g (79%) of 2- (4-methoxyphenyl) -ethoxyacetic acid with t, pl.82-b4c (from toluene) are obtained. 2- (4-Methoxyphenyl) -ethoxyacetic acid, obtained in a), is reduced with lithium aluminum hydride. The result is 5.4 g (96%) of 2- (2- (4-methoxyphenyl) -ethoxy-ethanol as an oily substance, which according to chromatography is homogeneous. 10 Then 2-2- (A-ketox. iphenyl) -ethoxy-ethanol is sulfonated with methanesulfonyl chloride, yielding 8.05g (100%) (4-methoxyphenyl) -ethoxy-ethylmethanesulfonate n in the form of an oily substance, which according to chromatography is homogeneous. Example 7. By afrajiopHH with Example 1 of 1 , 08 g of 1-iso-11-propylamino-3- (4-hydroxyphenoxy) -2-propanol and 1.42 g of (4-chlorofequyl) -ethoxy-ethylmethanesulfonate give 1.3 g (57%) of hydrochloride Porida (chlorophene ethyloxy) -ethoxyJ-phenoxy-3-isopropylamino-2-propanol with mp 99-101 ° C (from ethyl acetate). (4-Chlorophenyl) -ethoxy-ethyl methane sulfonate is prepared as follows. 3.15 g of 4-chlorophenethyl alcohol is introduced into the reaction with 2.2 g of chloroacetic acid. The result is 4.55 g (91%) of 2- (4-chlorophenyl) -TOXYUXIC acid with T. PL.7777 ° C (from ethyl ether acetic acid and hexane). 2- (4-Chlorophenyl) -ethoxyacetic acid is reduced with lithium aluminum hydride. The result is 1.6 g (43%) (4-chlorophenyl) -ethoxy-ethanol as an oily substance, which according to chromatography is homogeneous, 2- C2- (4-Chlorophenyl) -ethoxy-ethanol is sulfonated with methaneulfonyl chloride . 1.5 g (92%) of 2 (4-chlorophenyl) -ethoxy3-ethyl methane sulfonate are obtained in the form of an oily substance, which is homogeneous according to chromatography. Example 8. By analogy with example 1, from 2.52 g of 1-isopropylamino-3- (4-hydroxyphenoxy) -2-propanol and 3.12 g (2,4-difluorophenyl) -ethoxy1-ethyl methane sulfonate get 2.3 g (46% a) hydrochloride of 1- {4- 2- (2,4-diprophephenethyloxy) -ethoxy phenoxy-3-isopropylamino-2-propanol with T.GSh.6972 C (from a mixture of isopropyl alcohol and diethyl ester). 2- (2- (2,4 -Difluorophenyl) ethoxy J-ethyl methane sulfonate is prepared as follows. A) A solution of 25.7 g (124 mmol) of 2,4-difluorobenzyl bromide in 100 ml of tetrahydrofuran is added dropwise to
    I1155
    of a stirred suspension of 3.0 (124 mmol) of magnesium chips, located in 30 MP of tetrahydrofuran, for 0.5 h. After completion of the addition, the reaction mass is further stirred for 5 min for 10 min and immediately after this is treated with carbon dioxide gas for 1 h . Thereafter, the reaction mass is evaporated to dryness, and the residue 50 is partitioned between dithyl ether and dilute hydrochloric acid. The diethyl ether phase is separated and shaken with 2N sodium hydroxide solution. The alkaline extract is acidified with concentrated hydrochloric acid and shaken with diethyl ether. As a result, 5.1 g (24%) of crude 2,4-difluorophenylacetic acid is obtained, which, without additional 20 purification, is dissolved in 25 mp tetrahydrofuranium. This solution was added dropwise to a stirred suspension of 2.0 g of lithium alkyl hydride in 100 ml of tetrahydrofuran. After completing 25 additions, the reaction mixture is additionally stirred for 1 h, and immediately thereafter, the excess amount of lithium aluminum hydride is destroyed by adding dropwise 2 ml of hydrogen in 20 ml of tetrahydrofuran, followed by the addition of 2 ml of 15% sodium hydroxide solution and 6 ml of water. The suspension is filtered using a separate yogic filter and j, followed by thorough washing with diethyl ether. The combined filtrates are evaporated to dryness. The residue is dissolved in methylene chloride, dried with sodium sulfate, filtered, and 40 are evaporated. The result is 3.95 g (84%) of 2,4-difluorophenethyl alcohol as an oily substance, which is homogeneous according to chromatography.
    b) By analogy with example 1a, but by heating the reaction mixture for 1 h, 3.63 g (23 mmol) of 2,4-difluorophenethyl alcohol is reacted with g (23 mmol 50 chloroacetic acid). The result is 2.7 g (54%) of 2- (2,4-difluorophenyl) -ethoxyacetic acid as an oily substance, which according to chromatography is homogeneous.
    c) By analogy with example 16, 2- (2,4-difluorophenyl) -ethoxyacetic
    15412
    the acid obtained in paragraph 5) is reduced by lithium fuses. The result is 2.31 g (93%) (2,4-difluorophenyl) - ethoxy-ethanol in the form of an oily substance, which according to chromatography is homogeneous.
    d) Obtained according to c) (2,4-dfluorophenyl) -ethoxy-α-ethanol, dissolved in 40 ml of methylene chloride containing 1.13 g of triethylamine. The resulting solution “bobout” 1.28 g of methanesulfonyl chloride, the mixture is stirred for 15 minutes and then thoroughly washed with water. The hydrochloric phase is separated, dried with sodium sulfate, filtered and evaporated. The result is 3.12 g (100%) of 2- 2- (2,4-difluorophenyl) -ethoxy-methyl methanesulfonate. In the form of an oily substance, which according to chromatography is homogeneous.
    Example 9: Preparing the following compounds in a similar manner.
    Hydrochloride 1 | 2-chloro-4- 2- (phenetloxy) -toxy-phenoxy-3-isoproshamino-2-prop. Nola with m.p. 82-84 ° C (and isopropanol), 1 -2-methyl-4-2 hydrochloride - (Fenzythyloxy) -ethoxy-phenyl C 3-isopropylamino-2-propanol with so pl. 85-87 ° C (isopropanol), 1- | 2-fluoro-4- 2- (4-fluorophenethyloxy) -ethoxy-phenoxy-3-isopropylamino-2-prop 1-1p-toluenesulfonate with so pl. 77-80 ° C (from isopropanol) and 1-z-fluoro-4- 2- (4-fluorophenethyloxy) -ethoxy 3-phenoxy-3-isopropylamino-2-propanol hydrochloride-t. 7476 ° C (from isopropanol).
    Example 10. 5.32 g of racemic (4-fluorophenethyloxy) -toxy-phenoxy-3-isopropylamino-2-propanol and 5.25 g of (+) - di-0,0-p-toluoyl-B-tartaric acid are dissolved in 50 ml of boiling acetone. The solution is cooled for 18 hours at 0 ° C. The precipitated crystals are filtered, washed with cold acetone and then recrystallized twice from acetone, crawling 3.38 g of (-) (4-fluorophenethoxy) -ethoxy-phenoxy) -3-isopropylamino-2-propo ) -di-0,0-p-toluoyl-D-hydrotartrate with so pl. 146-1A7 with; MD - + 65, 5 ° (in-methanol).
    To isolate the free enantiomeric base, the above salt is distributed between toluene and an excess of 151% sodium carbonate solution. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate, from which (+) - di-0.0 - -toluoyl-B-tartaric acid is recovered. The toluene phase is dried with sodium sulfate, filtered and evaporated. The residue is dissolved in 20 MP of ethanol saturated with hydrogen chloride, the residue is evaporated to dryness. The crystalline residue is recrystallized from ethyl acetate to obtain 1.51 g of pure (-) (4-fluorophenethyloxy) -ethoxy} phenoxy (-3-isopropylamino-2-propanol hydrochloride with mp. 78, -5-80 s, J ° -16.5% +0.5 (in methanol). Example 11. 1.69 g (7.5 mmol of 1-isopropylamino-3- (4-hydroxyphenoxy) -2-propanol in 10 ml of dimethylformamide is treated with 0.36 g (7.5 mmol) 50% sodium hydride dispersion in mineral oil. The mixture is then stirred for 5 minutes. Then 1, 97 g (7.5 mmol) of (4-fluorophenyl) -ethoxy} ethylmethanesulfonate is added, and the mixture is half an hour. heated at 60 ° C with stirring. After this, see After evaporation to dryness, the residue is partitioned between 2N sodium hydroxide solution and dichloromethane. The organic phase is separated, washed thoroughly with water, dried with sodium sulfate, filtered and evaporated. The residue is recrystallized from isopropanol to obtain 1.46 g (50%) 1 -G4- 2- (4-fluorophenethyloxy) -ethoxy-phenoxy-3-isopropylamino-2-propanol, mp 68-70 C. Calculated,%: C 67.50; H, 7.72; N, 3.58. Found,%: C, 67.64; H 7.63; N 3.56. (4-Fluorophenethyl) -ethoxy-ethyl methanesulfonate used as the starting product is prepared analogously to example 2. Proposed substituted phenoxyaminopropanol derivatives ob1C (form I has cardio-selective, blocking D-adrenalinreceptor properties and, therefore, can be affected by treatment or the prevention of heart diseases such as Angina pectoris and heart rhythm disturbances.They can also be used as antihypertensive 4 biologically active substances. Antagonistic effect on rats 3-adrenergic receptors Rats are anesthetized with pentabarbitone and bilaterally vagotomized. Blood pressure is measured using a catheter inserted into the carotid artery, the heart rate is measured using a cardiotachometer driven by a pulse. pressure is taken. Punched compounds are administered intravenously through a catheter inserted into the femoral vein. Antagonistic effects on | 3 -adrenoreceptors are measured based on the percentage of contractions caused isoprenaline tachycardia and vasodilator reaction. Doses of the compound (in the 95% range), causing a 50% reduction in the response to isoprenaline, are detected. Testing agonistic effects on β-adrenoreceptors in rats. Rats pretreated with reserpine to deplete endogenous catecholamines are anesthetized with pentobarbitone. Blood pressure is measured using a catheter inserted into the carotid artery, and heart rate is measured using a cardiotachometer, which is activated by a blood pressure pulse. Each dose of individual test compounds was administered intravenously to 4-5 rats. Register the maximum change in heart rate. Doses of compounds (in the 95% range) are determined, causing an increase in the heart rate to 30 beats / min. Test for agonistic and antagonistic effects on / -adrenoreceptors on anesthetized cats. Cats that have been pretreated with reserpine for the purpose of depletion of Etsogenic catecholamines are anesthetized with o6-chloralose and bilaterally heated. Blood pressure is measured using a pressure probe with a microtip inserted into the carotid artery, and heart rate is measured using a cardiotachometer triggered by a blood sweep pulse. One hind limb is subjected to autoperfusion with recording the pressure of the latter. The agonist 151 effect on / -adrenoreceptors is measured as an increase in the frequency of cardiac contractions and / or a reduction in perfusion pressure. Antagonistic effect on p-adremoreceptors is measured as antagonizing between isoprenaline-induced tachycardia and a decrease in the pressure of the hindlimb perfusion. Test antagonistic effect on β-adrenoreceptors on awake cats. First, cats that are under anesthesia are implanted with a single catheter into the carotid artery with a tip located in the aorta, and a second into the strap vein. One week after implantation, cats are placed in separate cells and blood pressure and heart rate are measured using an arterial catheter. Control reactions to isoprenaline administered through a venous catheter are recorded and the test substance is administered orally. The antagonistic effect on α-adrenoreceptors is measured as a reduction in isoprenaline-induced tachycardia and as a vasodilatory effect recorded within 24 hours after the administration of the test compound. The following compounds are studied: 1-Isopropylamino 3-C4 (2-pheneti. Siethoxy) -phenoxy | -2-propanrl HC I (compound A); 1 - (4-Fluorophenethyloxy) -ethoxy-phenoxy-3-isopropylamino-2-propanol HC I (compound B); S-enantiomer (B-2); fumarate-8-enantiomer (); 1-14- 2- (4-Methylphenethyloxy) -etoxy phenoxy-3-isopropylamino-2-propanol HC (compound C), 1-T4- 2- (4-Methylthiophenethenloxy) -ethoxy-phenoxy-3- Isopropylamino-2-propanol HC 1 (compound D); 1-t ret.-Butylamino-3- 4- (2-fe and ethyl-F ethoxy) -fecoxy-2-propanol HC I (compound E); 1 - {2-Chloro-4- 2- (phenethyloxy) -ethoxy-phenoxy-3-3-isopropylamino-2-PRP-E-enol HC (compound F); 1-1 2-Methyl - 4- 2- (phenethyloxy) -ethoxy-J-phenoxy-3-isopropyl amino-2-propanol HC I (compound G); G4- 1-2- (4-Metoksifenetshyuksi) -etokciJ-phenoxy (izoppopilamino -3-2- propanol NA I (compound H) and (4-Hlorfenetiloksi) -3-ethoxy izopropklamino phenoxy-2-propanol NA I (compound 1); 1- 2-Fluoro-4-C2- (4-fluorophenethyloxy) -toxy-phenoxy-3-3-isopropylamine-2-propanol HC I (compound J); 1- {3-Fluoro-4- C2- (4-fluorophenethyloxy) -ethoxy-phenoxy-3-isopropylamino-2-propanol HC I (compound K); 1-- 2-Fluoro-4- 2- (2,4-difluorophenethyloxy) -ethoxy1-phenoxy (- 3-isopropylNffino-2-propanol HC I (compound L). Known compounds similar to those given by the structure: T-isopropylamino-3- hydrochloride (p labels seethoxyphenoxy) propanol-2 (compound O) 3j, Fumarate 1-isopropylamino-3- (p-me-. toxymethoxyphenoxy) 2-propanol (compound P) 2, Fumarate 1-tert.-butylamino-3- (o-benzyloxymethoxyphenoxy ) -2-propano- ate (compound Q) 4J. B Table 1 shows the comparative data of the biological activity of the predicted and known compounds.
    Table 1 Compounds are proposed at B1, and compounds of P-4J are suggested. ISA - evyvpesiMa sympatom1metiic activity .. 191 Table 2 gives the ratio, all to lexality for the proposed and known compounds. Table 2 100-300 10C 100-300 7.6 Substituted derivatives of iopropanol phenoxy can be used as medicines in the form of pharmaceutical preparations containing these derivatives in combination with pharmaceutical carriers suitable for pharmaceutical purposes. These Thinner carriers can be inert organic or inorganic catalysts that are suitable for internal administration (for example, through the mouth) or for parenteral administration, such as water, gelatin, lacto 4 gum1-1rabic, polyalkylene glycols, vegetable oils, petroleum jelly, and similar substances. Pharmaceutical preparations can be made in the form of solid dosage forms (for example, in the form of tablets, dragees, suppositories or capsules) or in the form of liquid dosage forms (for example, in the form of solutions, suspensions or emulsions). Pharmaceutical preparations can be subjected to the usual post-processing in pharmaceutical practice, for example, sterilization. In addition, pharmaceutical preparations may contain common excipients, for example, a preservative, a stabilizer, an emulsifier, aromatics, a wetting agent, salts added to change the osmotic pressure, buffer substances. The proposed substituted derivatives of phenoxyakinopropanol can be administered to an adult patient in daily doses of from about 1 to W mg / kg or in several doses. The data given in. The tables show that the proposed compounds, in particular the compounds A-L, have a mixed effect on the β-adrenoreceptors. Thus, they exhibit antagonism on UZ / -adrenoreceptors, i.e. appear to be cardioselective (/ -selective), as well as internal sympathomimetic activity (ISA), i.e. / 3-agonism. The tables show that the known compound O is a non-selective antagonist relative to / -adrenerceptors in cats, the known compound P exhibits intrinsic sympathomimetic activity and does not show antagonism on -adrenoreceptors, and the known compound Q is an antagonist to -adrenoreceptors and is not shows intrinsic sympathomimetic activity (ISA). The proposed compounds (A-L) also exhibit antagonistic action on α3, α-adrenoreceptors, and. internal sympato number 1metic activity. Such a combination of properties is not observed in any of the known ones among 211115513422
    neny. Internal sympathomimetic types also make them more beneficial when the activity of compounds reduces them. treatment of angina pectoris, cardiac arrhythmias and side effects in clinical uelo-hypertension.
    权利要求:
    Claims (1)
    [1]
    A method of obtaining substituted derivatives. phenoxyaminopropanol of the general formula
    - a hydrogen atom, a halogen atom or a lower alkyl radical * R and - hydrogen atoms, halogen atoms, lower alkyl radicals, lower alkoxyl radicals or lower alkylthio groups, or their salts, or their optically active antipodes, characterized in that it is a phenol derivative of the general formula
    I о - ОН 2 ~ СН-СН g · NH-н it where R and R, have the indicated meanings, are treated with the main agent, for example sodium hydride, with the subsequent interaction of the obtained phenolate with the compound of the general formula o-sn g sn-sn 2 - plural
    OH where R is branched and containing 3 or 4 carbon atoms is an alkyl radical;
    where D 2 and Rj have the indicated meanings, Z represents a lower alkylsulfonyloxy or aryl 'sulfonyloxy group, and the desired product is isolated! in free form or in the form of a salt, or optically active antipodes.
    AND
    SI sl
    Nama
    Priority by signs:
    06/02/80 when R is a branched alkyl radical containing 3 or 4 carbon atoms; R ( , R 3 ~ hydrogen; R ^ - hydrogen, halogen atom, lower alkyl radicals ) lower alkoxyl radicals, lower alkylthio groups;
    03.03.81 when R is a branched alkyl radical containing 3 or 4 carbon atoms; R, is a halogen atom, a lower alkyl radical; Rj and R $ are hydrogen, a halogen atom, lower alkyl radicals, lower alkoxyl radicals, lower alkylthio groups.
    The invention relates to methods for producing compounds of the general formula
    O-CHf-CH-CHjrNH-R he
    A 0)
    O-SNGSN g -O-SHAG
    R 2 is a substituted or unsubstituted aliphatic residue;
    or R and R 2 - together mean a divalent 5 aliphatic residue;
    R ^ is an aliphatic or cycloaliphatic residue;
    R ^ - hydrogen, lower alkyl, lower alkynyl and others,
    10 consisting in the interaction of compounds of General formula where R is a branched and containing 3 or 4 carbon atoms of an alkyl radical;
    Rj is a hydrogen atom, a halogen atom or a lower alkyl radical; R ^ hR ^ - hydrogen atoms, halogen atoms, lower alkyl radicals, lower alkoxyl radicals or lower alkylthio
    R t , R 2 HR ^ have these indications, more importantly, of the group, or their salts, or their optically active antipodes, which have cardioselective, β-blocking β-adrenaline receptor properties and 25 can be used in the treatment or prevention of heart disease and cardiac disorders rhythm. They can also be used as antihypertensive biologically active substances.
    A known method of producing ureidophenoxy-2-hydroxy-3-aminopropanes of the General formula
    0-CH G he where R v “hydrogen, substituted or unsubstituted aliphatic residue;
    with a compound of the general formula
    Z - CH 2 - CHX - CH - NH - R where RJ has the indicated meanings,
    X is an oxy group,
    Z is a reactive esterified ester group or X ( and Z form an epoxy group.
    类似技术:
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    同族专利:
    公开号 | 公开日
    DK231581A|1981-12-03|
    MC1387A1|1982-04-27|
    AU538634B2|1984-08-23|
    AR227046A1|1982-09-15|
    NZ197184A|1984-05-31|
    DK154021B|1988-10-03|
    NO150152B|1984-05-21|
    IE811212L|1981-12-02|
    SU1194270A3|1985-11-23|
    EP0041233B1|1984-02-15|
    AU7101481A|1981-12-10|
    BR8103439A|1982-02-24|
    PT73113A|1981-07-01|
    AR226946A1|1982-08-31|
    PL231453A1|1982-08-02|
    NO811852L|1981-12-03|
    CA1220488A|1987-04-14|
    KR830006176A|1983-09-20|
    PT73113B|1983-05-11|
    PL135306B1|1985-10-31|
    PL135317B1|1985-10-31|
    EP0041233A1|1981-12-09|
    IE51812B1|1987-04-01|
    DD159327A5|1983-03-02|
    ES8207505A1|1982-10-01|
    ES8301888A1|1982-12-16|
    HU182341B|1983-12-28|
    US4649160A|1987-03-10|
    ZW9881A1|1981-12-23|
    FI811706L|1981-12-03|
    KR840001919B1|1984-10-25|
    ES502649A0|1982-10-01|
    CS221963B2|1983-04-29|
    CS221962B2|1983-04-29|
    PH16940A|1984-04-24|
    KR840001920B1|1984-10-25|
    YU156883A|1983-12-31|
    YU133581A|1983-12-31|
    DE3162256D1|1984-03-22|
    ES509168A0|1982-12-16|
    AT6250T|1984-03-15|
    YU42079B|1988-04-30|
    DK154021C|1989-02-06|
    GR75681B|1984-08-02|
    IL62970D0|1981-07-31|
    NO150152C|1984-08-29|
    IL62970A|1985-01-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DD8731A|
    CA956632A|1969-05-16|1974-10-22|Yoshitomi Pharmaceutical Industries|Phenoxy-aminopropanol derivatives|
    SE372762B|1969-05-21|1975-01-13|Haessle Ab|
    GB1320453A|1971-03-24|1973-06-13|Biosedra Lab|Aromatic diethers|
    SE384853B|1972-04-04|1976-05-24|Haessle Ab|PROCEDURE FOR THE PREPARATION OF NEW AMINES|
    AR205618A1|1973-01-17|1976-05-21|Ciba Geigy Ag|PROCEDURE FOR THE ELABORATION OF DERIVATIVES OF 1- -PENOXI - 2 - HIDROXI-3-ALKYLAMINOPROPANO|
    FR2330383B1|1975-11-06|1979-09-21|Synthelabo|
    GB2079750B|1980-07-09|1984-08-22|Sandoz Ltd|3 aminopropoxyphenyl derivatives their preparation and pharmaceutical compositions containing them|DE3125870C2|1980-07-09|1994-09-15|William John Louis|3-aminopropoxyphenyl derivatives, their preparation and medicaments containing them|
    CA1262729A|1983-10-19|1989-11-07|Leo Alig|Phenoxypropanolamines|
    US5380755A|1992-07-24|1995-01-10|The Du Pont Merck Pharmaceutical Company|Alkyl and alkylbenzyl ethers of substituted hydroquinones|
    US6835691B2|2000-01-05|2004-12-28|Appleton Papers Inc.|Thermally-responsive record material|
    DE60025953T2|2000-01-05|2006-10-05|Appleton Papers Inc., Appleton|Heat-sensitive recording material|
    US8703821B2|2006-04-18|2014-04-22|Emisphere Technologies Inc.|Dialkyl ether delivery agents|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8017983|1980-06-02|
    GB8108345|1981-03-17|
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