专利摘要:
The method of obtaining aminopropanol derivatives of the general formula 1 OCH2CHOHCH2l HR (CH ln-CH iCOiR where R is isopropyl, tert.-butyl; H is Ci-alkyl, alkoxyalkyl, phenyl, phenylethyl; R is hydrogen. Halo, C-alkyl, C. alkenyl, C. alkoxy; 1, 2, p or their salts, characterized in THAT; compound of the general formula: And f OCHjCHCHiZ where R has the indicated meanings; x is a hydroxyl group; Z is a reactive, esterified in a layer}) ester the hydroxyl group and X and Z together form an epoxy group; 2 group of the formula X - (CH,) - CH2-CO R, where R and p have the indicated values, CO or X is a lower carboxylic acid residue that can be transferred to the specified group, containing a carbon-carbon "5 double bond or an oxo group in one the carbon atom is reacted with a compound of the general formula III SP SP j R-HNR, and where R has the indicated meanings; SP hydrogen or a protective group, with co, for example, benzyl, followed, if necessary, by deprotection of the protective group or by transferring X to the group of the formula - (СН2) „- СН2-СО ,, To restoring and isolating the target product in free form or. in the form of salt.
公开号:SU1156592A3
申请号:SU813289351
申请日:1981-06-01
公开日:1985-05-15
发明作者:Ингемар Карлсон Энар;Беньямин Рудольф Густафсон Билл;Торстен Лундгрен Бо
申请人:Аб Хессле (Фирма);
IPC主号:
专利说明:

The invention relates to a process for the preparation of new aminopropanol derivatives, having & blocking / J-receptor activity, in particular, to a method for producing aminopropanol derivatives of the general formula OCH CHOHCRil HR (CHg) p-CHgCOgC isopropyl, tert-butyl; -alkyl, C -, - j-alkoxyalkyl, phenyl, phenylethyl; hydrogen, halogen, C-alkyl C .4 alkenyl, C ,, -alkoxy n - 1, 2, or their salts. Aminopropan derivatives are known to have an α-receptor blocking activity, in particular 3-C2- (3.4 dimethoxyphenyl) -ethylamino J-1-4- (3metry 1) phenoxy} -propanol-2, which is obtained by aminating the corresponding starting compound containing the epoxy group or halogen. When using a reactive ester as the starting compound, the reaction is preferably carried out in the presence of the basic agent and / or excess amine in the alkanol S: at the boiling points of the reaction mass. The disadvantage of these compounds is the long biological half-life. The purpose of the invention is to develop a process for the production of new aminopropanol having a short biological half-life while maintaining a high blocking /} receptor activity. The goal is achieved based on the method of obtaining npoHSBJAHbK aminopropanol of the general formula I, which is known in organic chemistry, in that the compound of the general formula OCH CHCH-iZ de R has the indicated values; X is a hydroxyl group; Z is the ester-reactive esterified ester hydroxy group Xi Z together form an epoxy group; the group of the formula - () ,, R, de R and p have the indicated meanings; whether X is a residue of a lower carboxylic acid transferred to the specified ruppe containing a carbon-carbon double bond or an oxo group of one carbon atom, is borrowed from the compound of the general formula R where has the indicated meanings; R is hydrogen or a protective group, such as benzyl, followed, if necessary, by deprotection of the protective group or by transferring X to the group of the formula - (CE) ,, R by reducing and isolating the desired product in free form or as a salt. A reactive esterified in complex zfir hydroxy group is particularly a hydroxy group esterified to the ester of a strong inorganic or organic acid, preferably a hydrohalic acid, such as, e.g., hydrochloric, hydrobromic, hydroiodic and sulfuric acid or a strong organic sulfonic acid, such as, for example, benzene sulfonic acid, 4-bromobenzenesulfonic acid, 4-toluenesulfonic acid. Thus, Z is preferably chlorine, bromine, iodine. When using a reactive ester as the starting compound, the reaction is preferably carried out in the presence of a basic agent and / or an excess amine. The reaction is preferably carried out in an alkanol environment with 1-4 carbon atoms at the boiling point of the reaction & ion mixture. Example 1, Production of methyl ester (2-hydroxy-3-isopropylaminopropoxy) phenyl propionic acid, 4.5 g of methyl ester (2,3-epoxypropoxy) propane propionic acid, 15 ml of chopropylamine 3 and 25 ml of isopropanol are heated to AB for 5 h. The volatile compounds are evaporated in vacuo and the residue obtained is dissolved in ethyl acetate and treated with sulfuric acid. Obtain 1.8 neutral sulfate of methyl ester (2-hydroxy-3-isopropylaminopropoxy) phenyl propionic acid with m.p. . EXAMPLE 2 7.0 g of ethyl 3- (2,3-epoxypropoxy) phenyl 3-propionic acid ethyl ester and 20 ml of isopropylamine are repeated as starting compounds. In this case, 2.8 g of ethyl (2-hydroxy-3-isopropylaminopropoxy) phenyl} -propanoic acid ethyl ester are obtained with a mp. 149 ° C (1 / 2H2S Example 3) 1 Repeat 1, but 25 ml of isopropylamine and 8.0 g of 2-methoxyethyl ether (2,3-epoxypropoxy) phenyl} -propionic acid are used as starting compounds with a melting point of 98 ° C. (as p-hydroxybenzoate). EXAMPLE 4: 30 ml of isopropylamine and 12.1 g of 2-meter-ethyl ester are used as starting compounds (2, 3-epoxypropoxy) -phenyl-butanoic acid. 4 g of 2-methoxy-ethyl ester of (2-hydroxy-3-isopropylaminopropoxy) phenyl-butanoic acid with mp 90 ° C (as n hydroxybenzoate) Example 5: Example 1 is repeated. With the difference that 9.0 ml of isopropylamine and 3.2 g of propyl ester (2,3-epoxyproc coxy) -phenyl-propionic acid are used as starting compounds. This gives 1.4 g of propyl ester (2-hydroxy-3-isopropylaminopropoxy) phenyl 3-PROPIO of a new acid with mp UOS (as hydrochloride). Example 6 Repeat example 1 but as 10 ml of isopropylamine and 5.0 g of isopropyl ester, 3-epoxypropoxy) -phenyl propionic acid, are used for starting compounds. This gives 3.5 g of isopropyl ester (2-hydroxy-3-isopropylaminopropoxy) -phenyl 3-propionic acid with so pl. (in the form of hydrochloride). 92 Example 7. Example 1 is repeated, but 50 ml of isopropylamine and 13.9 g of ethyl ester, 3-epoxypropoxy) phenyl 7-6-uanoic acid, are used as source compounds. This gives 2.0 g of ethyl ester (2-hydroxy-3-isopropylaminopropoxy) phenyl} -butanoic acid with mp. 85 C (in the form of p-hydroxybenzoate). Example Example 1 is repeated, but 12.5 ml of isopropylamine and 6.0 g of ethyl 4- 3-bromo-4- (2,3-epoxypropoxy) phenyl-butanoic acid are used as starting compounds. This gives 3.7 g of the 4- 3-bromo-4- (2-hydroxy-3-isopropylaminopropoxy) phenyl-butanoic acid type ester ester with m. Pl. 110 ° C (in the form of hydrochloride). EXAMPLE 9 Example 1 is repeated, but 11.9 g of ethyl ethyl 3-bromo-4 - (2,3-epoxypropoxy) phenyl-3-propionic acid and 30 ml are used as starting compounds. isopropylamine. 8.0 g of ethyl 3-3-bromo-4- (2-hydroxy-3-isopropylaminopropoxy) -phenyl-3-propionic acid ethyl ester are obtained, with a mp. (in the form of hydrochloride). Example 10. Example 1 is repeated, but 10.5 g of ethyl 3-3-chloro-4- (2,3-epoxypropoxy) phenyl-propionic acid ethyl ester and 50 ml of isopropylamine are used as starting compounds. This gives 4.0 g of ethyl 3-C-chloro-4- (2-hydroxy-3-ethyl propylaminopropoxy) -phenyl-propionic acid ethyl ester with m.p. 93-94 C (in the form of hydrochloride). Example 11. Example 1 is repeated, but 15.0 g of ethyl 3-3-fluoro-4- (2,3-epoxypropyl: si) phenyl} propionic acid and 100 ml of isopropylamine are used as starting compounds. This gives 5.0 g of ethyl 3-C3-fluoro-4- (2-hydroxy-3-isopropylaminopropoxy) phenyl} -propionic acid ethyl ester with mp. 81 ° C (as hydrochloride). Example 12. 2.6 g of (2,3-epoxyproxy) -phenylJ-3-butenoic acid ethyl ester and 1.5 g of benzshzopropipamine are dissolved in 70 ml of isopropanol and the mixture is heated under reflux
within 2 days. The resulting mixture was evaporated and the residue was dissolved in a sub-zone at a pI of medium 2. The aqueous phase was sequentially extracted with pentane and chloroform. The chloroform phase is shaken with water at pH 10, dried over magnesium sulphate, filtered and evaporated.
The resulting residue, 2.0 g of ethyl 4-4-3-N-benzylisopropylamino- (2-hydroxypropoxy) phenylJ-3-butenoic acid ethyl ester, is dissolved in 100 ml of ethanol, after which 0.2 g of palladium is added - on, - corner (5% Pd). The mixture is then hydrogenated to absorb 230 ml of hydrogen. The catalyst is filtered and the residue is evaporated. . The residue thus obtained is dissolved in ethyl acetate and the ethyl acetate phase is treated with an equivalent amount of p-hydroxybenzoic acid. An ethyl ester p-hydroxybenzoate (2-hydroxy-3-czopropylaminopropoxy) phenyl J-butanoic acid is obtained with m.p. 85C.
Example 13. 26.4 g of (2,3-epoxypropoxy) -phenyl1-propenoic acid methyl ester are dissolved in 100 ml of isopropanol and 40 ml of isopropylamine. The mixture is heated under reflux for 5 hours, after which the volatile components are evaporated. The residue is dissolved in ethyl acetate and treated with ether, saturated hydrochloric acid to pH 4. The oily product is crystallized after treatment with ethanol. The resulting methyl ester. (2-hydroxy-3-isopropylaminopropoxy) 3-methoxyphenyl-propenoic acid is converted to hydrochloride. 7.1 g of (2-hydroxy-3-isopropylaminopropyloxy) -3-methoxyphenyl propenoic acid hydrochloride are obtained. dissolved in 400 ml of ethanol and hydrogenated in the presence of palladium-on-carbon until the absorption of 500 ml of hydrogen. The catalyst is filtered and the solvent is evaporated. The residue is treated with ether and the desired product is crystallized as hydrochloride. 6.4 g of methyl ester are obtained (2-OX-3-isopropylaminopropoxy-Zmethoxyphenyl-propionic acid with m.p. Pl. 95 ° C (PSE).
Example 14. 5 g (2,3epoxypropoxy) phenyl-propiono: 1
acids dissolve P 200 mp of isoprogol, after chug) add 3 (. ml isopropyltamine. The mixture is heated under reflux for 24 hours and then evaporated. 0.9 g of sodium hydroxide and IJO ml of methanol are added and the resulting suspension is stirred in for 4 hours. The mixture is then evaporated and the residue is acidified. 2.0 g (2-hydroxy-3-isopropylaminopropoxy) phenyl-1-hydroxyionic acid is obtained, which is dissolved in 50 ml of propanol. The solution is heated with hydrogen chloride and heated under reflux. for 2 hours Excess evaporation of propanol t in vacuo and the residue was crystallized from etilapetata. Prepared propyl ester 3-C4- (2-hydroxy-3-phenyl izopropilaminopropoksi -propio.novoy acid with m. pl.
1004: (carried).
PRI me R 15. 5 g of compound g: ropyl ester (2, 3-epoxypropoxy) phenyl-3-oxo-propionic acid is mixed with 100 ml of isopropanol and 10 ml of isopropylamine. The mixture is heated under reflux for 3 hours and evaporated. The residue is stirred in a medium of 100 ml of water containing 20 MP 2 M ESL for 1 hour. Then, chloroform is added, the aqueous phase is alkalinized to pH 10 and the mixture is shaken. The aqueous phase is dried over magnesium sulphate, filtered and evaporated.
The resulting (2-hydroxy-3-isopropylaminopropoxy) -phenyl-3-oxopropionic acid is dissolved in 50 ml of propanol. The solution is saturated with gaseous hydrogen chloride and heated under reflux for 2 hours. Excess propanol is evaporated and the residue is dissolved in chloroform. The chloroform phase is washed with alkaline water, dried over magnesium sulfate, filtered and evaporated. The resulting propyl ester of (2-hydroxy-3-isopropylaminopropoxy) -phenyl-3 oxopropionic acid is mixed with 10 ml of triethylene glycol and 0.35 np 85% hydrazine hydrate. The mixture is heated with an equiped cooler for 90 minutes with the addition of water in order to raise the temperature to. At this temperature, the mixture is boiled in an hour. After cooling to room temperature, 10 ml of boiling water and 6.5 ml are added.
2N. CHLORISTOVODORODPS I (.: .. PacTBoi) are extracted with chloroform, dried with magrgic sulfate and evaporated in vacuo. The residue is crystallized from tilyl acetate. A 3-f4- (2-hydroxy-3-isopropyl-aminopropoxy) propyl ester is obtained by phenyl J-n-nioiiHoHoic acid with m.p. And) 0 ° C (in the form of hydrochloride) .-. Example 16, 3.3 g of methyl (2-hydroxy-3-meta-sulphonous: hydroxypropoxy) phenyl-propionic acid methyl ester ,. 25 ml of isopropanol and 15 ml of isopropylamine are heated in an autoclave on a steam bath for 5 hours. The volatile compounds are evaporated in vacuo and the residue is distributed between methylene chloride and water at pH 10. Then the organic phase is dried and concentrated. The residue is dissolved in ethyl acetate and treated with sulfuric acid to give 3-G4- (2-hydroxy-3-isopropylaminopropoxy) phenylJ-propionic acid methyl ester as a neutral sulfate, m.p. Analogously to Examples 1-16, the following compounds are obtained: 1, 3-f4- (2-Oxy-3-isopropylaminopropoxy) -3 methoxyphenyl-propionic acid ethyl ester with m.p., 69-7Gc (HCP); I, ethyl ester of 3-3-fluto 4- (2-hydroxy-3-tert, -butyl-aminopropoxy phenyl} -propionic acid with t, mp, (HCG); W, ethyl ester 3- 3-allyl- 4- (2-hydroxy-3-isopropylaminopropoxy) phenylJ-propioic acid with mp 40 ° C; IV, 3-f3-H-propyl-4- (2-hydroxy-3-isopropylaminopropoxy) phenyl propionic ethyl ester acids in the form of oil with refractive index Pd 1.525; V, Phenyl ester (2 hydroxy-3-isopropylaminopropoxy) phenyl propionic acid in the form of 1 SS7 with refractive index II - I, j: j /, У1. Phenethyl ester (2 -oxy-3-isopropsinaminopropoxy) phenyl propionic acid, t, mp, 80-82 s (HSO; UE, 4-G4- (2-hydroxy-3-isopropylaminopropyloxy) n-heptyl ester in the form of an oil with a refractive index, 510 ( HC1); YAO, 3-NW-ethoxy-4 ethyl ester (2-hydroxy-3-isopropyl-aminopropoxy) phenyl-propionic acid with mp (HCf); 1X. (2-hydroxy-3-isopropylaminopropoxy) isopropyl ester -3-methoxyphenyl-propionic acid in the form of an oil (1/2) with a refractive index, 316. Biological activity of new compounds. The compounds listed in the table in two experiments were tested on anesthetized cats (males and females weighing 2.5-3.5 kg), which, 16 hours before the start of the experiments, reserpine was administered intramuscularly in an amount of 5 mg / kg body weight, Reserpine was given for elimination of endogenous sympathetic control of heart rate and vascular smooth muscle tone. Cats are anesthetized with pentobarbital (30 mg / kg of body weight, intraperitoneally). In the neck, bilateral vagotomy is performed. Blood pressure is measured using a needle inserted into the carotid artery, and the heart rate is measured on a cardiotachometer associated with an ECG. In the femoral artery of the hind leg zvod t zglu. Selected blood is pumped into the distal part of the artery in a constant amount. Perfusion pressure (DP) is measured, with changes indicating a change in peripheral vascular resistance in the leg. Test A, Maximum heart rate and vasodilation are determined by injecting a high dose of isoprenaline (2, -0 µmol / kg}. The dose of injected isoprenaline, which causes about 80% of the maximum heart rate, is usually determined. Usually, this dose of isoprenaline 0, 25 µmol / kg-min. The reaction of the vessels - on, this dose of isolrenaline is also about 80% of the maximum value. Then the dose of isoprenaline is sprinkled for 20 minutes, with 20-minute pauses between the injection periods and the injection under study to be injected intravenously 7 minutes after the injection of isoprenaline. The dose of the test compound is tested until a complete block for isoprenaline is reached. For each dose of the test compound, a decrease in the heart rate is determined by the isoprenaline cotyline (percentage of blockade by the formula, a decrease in the heart rate caused by isoprenaline). Xox- control of the frequency of the heartbeat caused by isoprenaline (beats / min) According to the values of the percentage blockade (for each dose) and the log-dose of the test compound, there are curves according to which Determine the dose of ED: 50, i.e. a dose that provides 50% of the maximum blockade. In addition, the plasma half-life is determined. At the same time, the time from the maximum inhibitory activity of each dose of the studied compound to 50% recovery is determined. According to the obtained values and the log dose of the test compound, curves are made. The slope of the resulting curve is determined by linear regression. The slope is 2.303 / Kg, where Kg is a constant value. The plasma half-life (t 1/2) is then determined according to the ratio t, 693 / Kg. Experience B. The maximum heart rate and vasodilatation is determined by injecting a high dose of isoprenal (2.0 µmol / kg). Then, the dose of injected ioprenaline, which causes about 80% of the maximum heart rate, is determined. Usually this dose is 0.4 µmol / kg. The reaction of the vessels to this isoprenaline dose is also about 80% of the maximum value. 1 Then the test compound is injected in increasing doses. Each dose is given for 12 minutes, and 18-minute pauses are made between doses. After each dacha of the test compound, a dose of isoprenal is injected. The dose of the test compound is increased logarithmically until a complete blockade of the reaction to isoprenaline is achieved. The inhibition effect of each dose of the test compound is determined as a percentage blockade according to the formula: reaction to isoprenaline and isoprenaline during injection of the test compound 10Ox to isoprenaline. The values of the percentage blockade and the log dose of the test compound are the curves that determine the dose of ED: 50. Then it is possible to compare the dose EDA: 50 for the blockade of vascular dilation, and thereby determine the selectivity for the test compound. Sympathomimetic activity is detected as an increase in the maximum heart rate during injection of the test compound. The results of experiments A and B are summarized in the table. As can be seen from the above data, the compounds synthesized in accordance with the invention have a short biological half-life while maintaining a high blocking (3-receptor activity. / - -
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权利要求:
Claims (1)
[1]
A method of obtaining derivatives of aminopropanol of the general formula 1 och 2 chohch ^ hr 1 where R * is isopropyl, tert.-butyl;
R 2 is 7- alkyl, C-alkoxyalkyl, phenyl, phenylethyl;
R 3 - is hydrogen, halogen, C 14 alkyl, C 7 _ 4 alkenyl, alkoxy;
η = 1, 2, or their salts, characterized in that; compound of general formula II
X 1
OCH 2 CHCH 2 Z where R 3 has the indicated meanings;
one *
X is a hydroxyl group;
Ζ - reactive esterified hydroxyl group
Ζ together form an epoxy group;
X 2 is a group of the formula - (ch 2 ) „- ch 2 -co, r 2 , where R 2 and the indicated values are taken, or X 2 is the lower carboxylic acid residue transferred to the indicated group containing a carbon-carbon® double bond or oxo group at one carbon atom, is reacted with a compound of general formula III
R'HNR 2 where R * has the indicated meanings;
R * is hydrogen or a protective group, for example benzyl, followed by optionally removing the protective group or transferring X 2 to a group of the formula _ (CH 2 ^ _CH 2 CO 1 K2 reduction and isolation of the target product in free form or in the form of a salt.
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同族专利:
公开号 | 公开日
IE811217L|1981-12-02|
DK154208C|1989-03-20|
AU7116681A|1982-12-02|
CS404781A2|1985-06-13|
CS241484B2|1986-03-13|
AU548290B2|1985-12-05|
HU184860B|1984-10-29|
FI71725B|1986-10-31|
PL231450A1|1983-03-28|
FI811671L|1981-12-03|
NO151282B|1984-12-03|
PT73111B|1983-05-11|
EP0041491A1|1981-12-09|
NO151282C|1985-03-13|
NO811799L|1981-12-03|
KR830006177A|1983-09-20|
ES8300679A1|1982-11-01|
LU88348I2|1994-09-09|
KR850000869B1|1985-06-22|
SE8004087L|1981-12-03|
DD159328A5|1983-03-02|
NL930102I2|1994-12-01|
DK239581A|1981-12-03|
IE53801B1|1989-03-01|
NZ197237A|1985-01-31|
MY8600219A|1986-12-31|
GR74571B|1984-06-29|
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AT11529T|1985-02-15|
EP0041491B1|1985-01-30|
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JPS639501B2|1988-02-29|
JPS5724335A|1982-02-08|
FI71725C|1987-02-09|
DE3168595D1|1985-03-14|
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NL930102I1|1993-10-01|
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法律状态:
优先权:
申请号 | 申请日 | 专利标题
SE8004087A|SE8004087L|1980-06-02|1980-06-02|NEW PARA-SUBSTITUTED 3-PHENOXY-1-ALKYLAMINOPROPANOL-2 WITH BETARETTY RECEPTOR BLOCKING PROPERTIES, AND PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME, AND METHOD OF ACCOUNTING ...|
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