• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    For the preparation of novel hydroxyamines of the formula (I) <IMAGE> with the radicals as in Patent Claim 1, and of therapeutically acceptable acid addition salts of these compounds, a starting compound of the formula (II) <IMAGE> is used. This is reacted with an amine of the formula (III) <IMAGE> The resulting isomeric mixtures are separated into the pure isomers and the resulting racemates into the optical antipodes. The resulting free bases can be converted into their salts and the resulting salts converted into the corresponding free bases. Preferred compounds prepared are: 1) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propan-2-ol, 2) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-methoxyethyl)phenoxy-propan-2 -ol, 3) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-allyl-phenoxy)propan -2-ol, 4) 1-[1-methyl-2-(2-methylphenoxy)ethylamino]-3-(2-allylphenoxy)-propan-2 -ol, 5) 1-[1-methyl-2-(4-methylphenoxy)ethylamino]-3-(2-allylphenoxy)-propan-2 -ol, 6) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-methylisonitrosometh ylphenoxy)propan-2-ol, 7) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(3-allylphenoxy)-propan-2-ol. The compounds have a blocking effect on beta -receptors and can be employed for the treatment of cardiovascular disorders.
    公开号:SU906368A3
    申请号:SU752163123
    申请日:1975-08-08
    公开日:1982-02-15
    发明作者:Ингемар Карлссон Энар；Бенны Рогер Замуэльссон Густав；Карл Гуннар Аберг Аксель
    申请人:Аб Хессле (Фирма)；
    IPC主号:
    专利说明:

    39 n is an integer from 0 to 5; W - an integer from O to 2; .LG is phenyl, thiazolyl, or thiadiazolyl, with R being bound to phenyl in position NII 2 or 3, to thiazolyl in position or 5, and R or R being bound to adiazolyl in position k, and if Y is CHI ft, then 1-5, if R is methyl, then it is not bound to phenyl in position 2, except if R is alkoxycarbonylaminoalkyl if R is isobutyl in position 3, then R and R do not mean methyl, and if R is acetylaminomethyl in position 3, then m does not mean O, or their salts, sulfur, or optically active isomers. These compounds possess phacological activity and can be used as stimulators of adrenergic ft-receptors in the treatment of exogenous or endogenous arrhythmias and angina pectoris. Various propanolamine derivatives are known to have ft -adrenergic blocking activity. A known method for producing propanolamines of the formula RCrHrCHOHClI NR -CRR-CHQ (CH, j) x OR where R is Ph. halophenyl, alkylphenyl, alkoxyphenyl, trifluoromethylphenyl or benzyloxy; RH, alkyl or PhCHn; R and or lower alkyl; X 1 or 2; R-Ph, halophenyl, alkylphenyl or alkoxyphenyl, resulting in the reaction of 3- (2-alkoxyphenoxy-propylamine with 1-chloro- (3,2-alkylphenoxy) -propanol-2 at boiling 1) The reaction of opening the epoxy group during the reaction with amine 2. The aim of the invention is to expand the range of agents acting on a living organism. This goal is achieved by the fact that according to the method based on the reaction of opening the epoxy group upon interaction with the amine, a compound of the formula (R) - (R) ArOCHQ CHCH-Z o Where Ar, R, R and R have the indicated meanings; X is a guide an oxyl group; Z is a reactive esterified hydroxyl group, or X and Z together form an epoxy group, are reacted with an amine of the formula KN-C- (ciH2) -YV B where R, R5, Rb, R, RB R, Y, m and n have the indicated meanings, in an inert organic solvent environment at the boiling point of the reaction mass, followed by isolation of the target product in free form, or salt, as racemates or optically active isomers. Racemates can be divided into antipodes using known methods using optically-active acids, for example, L- and D-forms of tartaric acid, di-O-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Example 1. 1.9 g of 1,2-epoxy-3- (2-allylphenoxy) propane and 1.8 g of 4- (2-aminoethoxy) -benzamide and 25 ml of isopropanol are heated under reflux for 1.5 hours. The reaction the mixture is evaporated in vacuo, after which the residue is dissolved in acetone. (It-carbamylphenoxy) -ethylamino-3- (2-allylphenoxy) -propanol-2 hydrochloride is isolated by the addition of an ether containing sky. T. pl. 211 C. The structure is confirmed by a spectrum of nuclear magnetic resonance (NMR. Example 2. 2.8 g1,2-epoxy 3- (2-chloro-5-methylphenoxy) propane and 2.7 g of - (2-aminoethoxy) benzamide in 25 ml of isopropanol are heated under reflux for 5 hours. The resulting mixture is evaporated in vacuo. The residue is dissolved in acetone and the hydrochloride is added 1–2- (-carbamylphenoxy) ethylamino-3 - (2-chloro-5 methylphenoxy) propanol-2 by the addition of a simple ether containing HC2. T. pl. (with decomp.). The structure was confirmed by NMR Spectrum. Example 3. 2.1 g of 1, 2-epoxy-3 C (2-methoxyethyl) phenoxy-propane is subjected to interaction With 1.8 g of 590 4- (2-aminoethoxy) -benzamide as described in Example 1. 1 ft-carbamylphenoxy) ethylamino-3- (2-methoxyethyl) phenoxypropanol-2 hydrochloride is obtained. square 105 ° C. The structure is confirmed by NMR spectrum. Example 4. 0, g of 3- (1,2-epoxy-3-propoxy) - -chlorothiazole is reacted with 0.4 g of C- (2-aminoethoxy) -benzamide in the manner described in example 1. The hydrochloride of 1 (4-carbamylphenoxy) -ethylamino-3- (4-chloro-2-thiazoloxy) propanol-2 is obtained, with an mp. . The structure is confirmed by NMR spectrum. . Example 5. 1.9 g of 1, 2-epoxy-3 (2-allylphenoxy) propane is reacted with 2.5 g of (2-aminopropoxy) benzamide in the manner described in 1. Get 1 - 1-methyl-2- (4-carbamylphenoxy) ethylamino-3- (2-allylphenoxy) -propanol-2 hydrochloride with m. Pl. . The structure is confirmed by NMR spectrum. Example 6. The 1,2-epoxy-3 (2-allylphenoxy) propane is reacted with 3.3 f 1- (2-methylphenoxy) -2-propylamine in the manner described in example 1. Get hydrochloride 1 - P-methyl-2- (2-methylphenoxy) -ethylamino-3 (2-allylphenoxy) -propaiol-2 with so pl. 1h2S. The structure is confirmed by NMR spectrum. Example 7. 2.8 g of 1,2-epoxy-3- (2-allylphenoxy) propane is reacted with 3.3 g of - (k-Methylphenoxy) -2-propylamine in the manner described in Example 5. Get 1 - 1-methyl-2- (4-methylphenoxy) -ethylamino-3- (3-allylphenoxy) -propanol-2 hydrochloride with m. Pl. C. The structure was confirmed by NMR spectrum. Example 8: 1.8 g of 1-amino-3 - (2-methylis6 nitrosomethylphenoxy) propanol-2 and 1.55 g (α-methylcarbonylmethoxybenzamide) are dissolved in 2 ml of methanol and cooled to. Then 1 , 8 g MAbNd for 1/2 h Then 50 ml of water are added and the product is extracted with ethyl acetate.The ethyl acetate phase is evaporated in vacuo and the resulting 1-G1-methyl-2- (4-cabamylphenoxy) -ethylamino-3- (2-methylisonitrosomethylphenoxy) -propanol-2 was washed with ethyl acetate and ethyl acetate, mp 106 ° C (HCl). Example 9. From 1,2-epoxy-3- (2-methylphenoxy) propane and 1 - (4-methoxycarbonylaminoethylphenoxy) ) -286-ethylamine described in example 1 obazu receive (- (2-) 2-methoxycarbonylamino (ethyl phenoxyethylamino-3- (2-methylphenoxy} -propanol-2 in the video base of St. pl. 93 ° C. Example 10. From 1, 2-epoxy -3- (3 allylphenoxy) propane and t-aMnHOethoxybenzamide as described in Example 1, (4-carbamylphenoxy) -ethylamino -3- (3-allylphenoxy) propanol-2 is obtained with melting point as hydrochloride). 11. From 1,2-epoxy-3- (, 2-chlorophenoxy} -propane and 4-aminoethoxybenzamide as described in Example 1, 1-2-2 (4-carbamate-phenoxy) -ethylamino} -3- (.2-chlorophenoxy) -propanol-2 in the form of hydrochloride with t. pl. 2284. Example 12. From 1,2-epoxy-3- (2, 3-dichlorophenoxy) propane and 4-aminoethoxybenzamide, in the manner described in example 1, (, -carbamylphenoxy; -ethylamino -3- (2,3-dichlorophenoxy)} -propanol-2 (mp. hydrochloride, mp of base 156 ° C. Blocking) -receptor new compounds are tested for biological activity, while anesthetized cats (males and females weighing 2.5 to 3.5 kg) 16 h before the beginning of the experiments, reserpine was injected intramuscularly in the amount of 5 mg / kg of body weight to eliminate endogenous sympathetic control of the heart rate and tone of the vessel. smooth muscle. Cats are anesthetized with pentobarbital (30 mg / kg body weight, intraperitoneally. Bilateral vagotomy is performed in the cervix. Blood pressure is measured using a needle inserted into the carotid artery and the heart rate on an ECG linked to an ECG. Internal The i-mimetic activity on the heart is determined by the increased heart rate after drug administration. The test compounds are administered intravenously at logarithmically increasing doses; From the values obtained, dose / response curves are derived from which the dose of ERgQ was determined. At the end of each experiment, high doses of isoprenaline are given to obtain a maximum heart rate response. Compounds are also tested on dogs. Short-legged hounds dogs train so that they calmly
    lay and held in a hundred than a position for 2 minutes, in which their front legs lay on the table. Arterial blood pressure is measured using a transducer located at the height of the canine heart. The heart rate is recorded by an ECG. All dogs are given methylscopolamine in advance to avoid vagal influences. Measurements are made before and (after 15 and 75 minutes after administration of the test compound, first in a supine position for 2 minutes and then in less than two minutes. The test compounds are administered in increasing doses at two-hour intervals.
    The table shows the values for ED JQ and intrinsic-mimetic activity in cats that have previously been administered reserpine, and the effect of the new compounds on the blood pressure in dogs. Corresponding comparative values are given for proplolol (1-isopropylamino-3 (1-naphthoxy) - propanol-2), practolol (2-hydroxy-3-isopropylaminopropoxy) acetanilide, metoprolol (1-isopropylamino-3C -) 2-methoxyethyl Gfenoxy1-propanol-21, tolamolol (4- (2-) 2-hydroxy-3-0-tolyloxypropylamino (ethoxy) benzamide) and AH 5158 (5- (1-hydroxy-21- {1-methyl-3-phenylpropyl) amino) (ethyl 1-salicylamide.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining amines where R *
    R * - in position 2 or 3 means the groups - CHqCH = CHq_, -CHqC = ^ 5 CH, -OCHqCH - CHqt, -OCH 2 C 5 CH, lower alkyl, lower alkoxyalkyl, lower alkoxyalkoxy, lower alkoxycarbonylaminoalkyl, lower alkoxy 20 sicarbonylaminoalkoxy, lower alkoxycarbonylaminoalkenyl, HCXUqCHijNHCOCH ^ O, CH 3 OCI I a CH jNH-COCH ^, or CH = NOR - groups where R is hydrogen or alkyl CjC ^;
    - hydrogen, halogen, lower alkyl or lower alkoxyl;
    - hydrogen or - hydrogen,
    5 - hydrogen or - hydrogen or - each lower alkyl or alkoxyl;
    - hydrogen, lower alkoxycarbonylaminoalkyl, cyano group, trifluoromethyl group, -CONR 40 R ^, -CONHR ^ - group, where R 1 * 0 and E and / | - hydrogen or together with a nitrogen atom bound to them form a heterocyclic ring such as pyrrolidine, piperidine, piperazine or morpholine;
    - an oxygen atom or --CH — group - * *. 45 lower alkyl;
    methyl;
    lower alkyl, hydrogen, halogen,
    R 9 PA, - the whole - the whole - phenyl, zolil,
    R1 at position 2 or 3 is linked to phenyl at position 4 or 5 thiazolyl, a R 4 or R 2 · in position 4 with thiadiazolyl, if Y = CH ^, then n = 1-5, and if R 1 - methyl, then it is not connected with phenyl in position 2 <_ η m
    Ar and a number from a number from
    About to 5;
    About to 2; thiazolyl or thiadia50
    VNIIIPI Order 414/77 if I 9 if R ^ - 5 and R 6 is not - acetylto m other than the case alkoxycarbonylaminoalkyl isobutyl at position 3, then R 'is methyl, and if R' 1 is aminomethyl at position 3, it means 0, or their salts, in in the form of racemates or optically active ditches, characterized in that the compound of the formula isometh,
    L 3 P 1 11 (RW ^ ArOCH ^ CHCH - Z where Ar,, R ^ have the indicated indications;
    X is a hydroxyl group;
    Z is a reactive etherealized hydroxyl group, or X and Z together form an epoxy group, are reacted with an amine of the formula znac - where R 4 , R S , R 6 , R 7 , R 6 have the indicated meanings in an inert organic solvent at the boiling temperature of the reaction mixture, followed by isolation of the target product in free form, or salt in the form of racemates or optically active isomers.
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    DE3125870C2|1980-07-09|1994-09-15|William John Louis|3-aminopropoxyphenyl derivatives, their preparation and medicaments containing them|
    FR2508032B1|1981-06-17|1983-12-02|Delalande Sa|
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