• 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:
    The invention relates to substituted amino ethers, in particular, aryloxypropanolamine in the general formula jRj R -Cg H-CH, -CH (OH) -CH -NH-X-NH- A RRRRR, 567 89 where R, R are the same or different H, F, OH lower alkoxy or benzyloxy; X C2-C-alkylene; A MONO-, bi- or tricyclic 5 or 6-membered heterocyclic residue that can be hydrogenated, or thiophene, or if at least one of R is R is not hydrogen, it represents phenyl with the restriction that if A is a residue uracil-6-yl, then the substituent in the 5th position of uracil should not be hydrogen; - the same or different; H, NH, hydroxymethyl, lower alkyl, phenyl. O, S, or their pharmacologically compatible salts, which have a cardiotonic effect and can be used in medicine. To detect activity among substituted amino ethers, new compounds were obtained in two variants. The first version of the preparation is carried out by the reaction: R,., B H-O-CH -S-JON) - CH - Y + + HN-X-NH-A - compoundCO of the general formula, where is methyl mercapto group; R are listed above. The second production variant is carried out by the reaction: H-0-CH-CH (OH) -CH-NH-X-W + Y-A - 1, where, methyl mercapto group; R and X are listed above. Tests show that the compounds N9 neither exhibit cardiotonic effect at the level of the known 1-phenoxy
    公开号:SU1272976A3
    申请号:SU833535714
    申请日:1983-01-14
    公开日:1986-11-23
    发明作者:Видеманн Фритц；Кампе Вольфганг；Дитманн Карл；Шпонер Гисберт
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    I The invention relates to a process for the preparation of new derivatives of aryloxy propanolamines of the general formula f4 -0-CH, CHCH, -NH-X-NHH I where R, R are the same or different and denote hydrogen, fluorine, hydroxy, lower alkoxy, benzyloxy ; X - alkylene C - A - MONO-, bi- or tricyclic five- or six-membered heterocyclic residue containing nitrogen, which can be hydrogenated, or thiophene, or in case at least one of the residues R, R, Rj or R does not denote hydrogen, is also a phenyl residue, with the restriction that, if A is a uracil6-yl residue, then the substituent in position 5 of the uracil part of the molecule is not hydrogen; R - RQ are the same or different and denote hydrogen, aminooxymethyl group, lower alkyl, phenyl, and oxygen, sulfur and, in particular, pharmacologically compatible salts of these compounds, which have cardiotonic action. The purpose of the invention is to obtain new Propanolamine derivatives having improved properties. Example 1. Benzoate 1-phenoxy-2- (4-indazolylamino) etylamino propan-2-ol. 3.5 g of 1-chloro-2-hydroxy-3-phenoxyglycerol and 7.0 g of 4- (2-aminoethylamino) indazole are dissolved in 7 ml of dimethylformamide by heating, and then settled for 25 hours at room temperature. It is dissolved in methylenech loride, shaken twice with water, dried over sodium sulfate, the solution is treated with bleaching clay, evaporated, dissolved in ethyl acetate, and 3.0 g of benzoic acid is added. The salt obtained is recrystallized from isopropanol by adding bleaching clay and activated carbon. Yield 4.1 g (44% of theory), without colored crystals, mp 156-157 ° C. The 4- (2-aminoethylamino) indus 762 sol used as the starting compound can be obtained from 4-hydroxyindazole and an excess amount of ethylene diamine sulphate with a yield of 43% of theory (in aqueous solution for 1 h when heated to reflux temperature): light beige crystals, mp PL.138-140 ° C (from methylene chloride). The following compounds are prepared in a similar manner. Oxalate 1-phenoxy-3- 2- (1,2,4-trimethyl-5-pyrazolone-3-yl-aminoethylamino-propan-2-ol, mp. 141-142 ° C (decomp.). 1-phenoxy -3-2- (2,4,5-trimethylpyrimidine-6-Sh1-amino) -thylamino propan-2-ol, mp 119-121 ° C. 1- (4-Benzyloxyphenoxy) (2,6dimethylphenylamino) -ethylamino-propane-2-ol, maly. 1- (4-Propoxyphenoxy) (2,6 dimethylphenylamino) -thylamino propan2-ol, mp 51-54 ° C, neutral fumarate, mp 1668-169 ° C (ethanol). 1- (3,4-Dimethoxyphenoxy) (1,3,5-trimethylpyrimidine-2,4-dione-yl-amino) ethylamino-propan-2-ol, mp 103-104 ° C Neutral fumarate 1-phenoxy-3 3 (1,3,5-trimethylpyrimidine-2,4-dione-6-yl-amino) propyl min1 propane-2ola, mp 132-133 ° C. Neutral fumarate 1- (4-hydroxyphenoxy) -3-C 2- (2,6-dimethylphenylamino-propan-2-ol, mp 193-195 ° C 1- (4-Fluorophenoxy) -3-C2- (2,6-dimethylphenylamino) ethylamino} propan-2ol, mp benzoate 105-106 ° C. Oxalate 1-phenoxy-3- 2- (2-methyl4 -oxymethylthiophene-3-ylamino) ethylamino-propan-2-ol, mp.117-120 ° C. 1-phenoxy-3- 2- (6-chloropyridazin-3-yl-amino) ethylamino-propan-2-ol, t mp 147-149 ° C. 1-phenoxy-3- 2- (2-aminoquinazolin-4-yl-amino) ethylamino-propan-2-ol, m.p. furarate 204-206 ° C. 1-phenoxy-3- 2- (3-methylinoksalin-2-yl-amino) ethylamino-propan-2-ol, mp. 152-153 C (fumarate neutral hydrate), 1-phenoxy-3- 2- (1,2 , 3,4-tetrahydroacridin-9-yl-amino) ethylamino-propan-2-ol, mp 99-100 ° C. . Seskvi acidic fumarate 1-phenoxy-2- (1,3-dimethyl-5-H-butylpyrimidine 2, 4-dione-6-yl-amino) ethylamino-propan-2-ol, 76 ° C sintering, mp. 7880 C (blistering). 1-phenoxy-3-21, 3-dimethyl-5-phenylpyrimidine-2,4-diene-5-yl-amino) ethylamino-propan-2 .ol, T.SH1 acid fumarate. 181-183 ° C. Hydrochloride 1-phenoxy-3- 2- (1,3-dimethyl-5-cyanopyrimidin-2, 4-dione-6yl-amino) ethylamino-7-propan-2-ol, mp 202-204 ° С. 1-phenoxy-3- 3- (1,3,5-trimetsh1 pyrimidin-2, 4-dione-6-yl-amino 2,2-dimethylpropylamino propan-2-ol, mp 1P-112c. Acid fumarate 1-phenoxy -3-C2 (I, 3,5-trimethylpyrimidin-2-one-4-thion-6-yl-amino) ethylamino1-propan-2-ol, mp 151-153 ° C (during the formation of bubbles). examples 2-5. PRI mme R 2. Cesqui sour fumarate 1-phenoxy-3- 2- (1,3-dimethyl-5H-butyl-pyrimidine-2, 4-dione-6-yl-amino) ethylamino propan-2-ol. 5.5 g 4-chloro-1,3-dimethyl-5-n-butylpyrimidine-2, 6- (lH, 3H) -dione and 5.0 g 1-phenoxy-3- (2 -amine ethylamino propan-2-ol is stirred in 20 mp of dimethylformamide for 4 days at. the solution is dissolved, the residue is dissolved in methylene chloride, shaken with water, dried and purified by chromatography through a column of silica gel with an eluting solution of methylene chloride - methanol 9: 1. By evaporation of the pure fractions, 4.4 g of a yellowish oil is obtained. and mixed with a solution of 1.3 g of fumaric acid in ethyl acetate. After crystallization, the precipitate is filtered off with suction and washed with ethyl acetate. Yield 2.4 g (17% of theory), colorless crystals, with speka78-80С (formation of puny, T.Sh1. Zyrey). Froze The acid fumarate of 1-phenoxy-3- 2- (1,3-dimethyl-5-phenylpyrimidium-2, 4-dione-6-yl-amino) ethylamino JnponaH-2-ol. 5.0 g 4-chloro-1,3-dimethyl-5-fensch-pyrimidine-2, 6- (W, 3N) -dione, 4.2 g 1-phenoxy-3- (2-amino-ethylamino) pro pan-2- Ola and 3.5 ml of N-ethyldiisopropylamine are heated in 20 ml of acetonitrile for 48 hours with reverse flow. The mixture is evaporated in vacuo, the residue is taken up in methylene chloride, the solution is shaken with 2N sodium hydroxide solution, dried and separated by chromatography on a column of silica gel with an eluting mixture of methylene chloride-methanol and ammonia saturated with methanol 40: 1: 1. The oil (5.3 g) obtained by evaporation of the pure fractions is dissolved in 10 ml of ethyl acetate, and then mixed with a solution of 2 g of fumaric acid in 20 ml of ethanol. After crystallization, the precipitate is stripped off and rinsed with ethyl acetate. Yield 6.7 g. (62% of theory), colorless crystals, mp.181-183 C. Example 9 4. 1-Phenoxy-3-C3 (1,3,5-trimethylpyrimidine-2 , 4-dione-6yl-amino-2, 2-dimethylpropylamino propan-2-ol. 4.5 g 4-chloro-1,3,5-trimethyl pimidin-2, 6- (lH, 3H) -dione and 6 , 1 g of 1-phenoxy-3- (3-amino-2,2-dimethylpropyl. Amino) propan-2-ol (Cr c, 159-161 C, from phenylglyciphenyl ether and 2,2-dimethyl-1, 3- diaminopropane) in 8 ml of pyridine is stirred for 50 hours at 80 ° C. The mixture is then introduced into methylene chloride, shaken with water, dried, evaporated and chromatographed over silica gel. 2.3 g (24% of theory), colorless crystals, mp 1 1 1-1 12С (from ethyl acetate). EXAMPLE 5 Acid Iphenoxy-3-2- (1,3,5-Trimethyl-pyrimidin-2-one-4-thion-6-yl-amino) ethylamino-propyn-2-ol fumarate 5.0 g of 1-fecoxy-3- (2-aminoethylamino) propan-2-ol and 5.2 g of 4-methylmercapto-1, 3,5-trimethylpyrimidine-2 (3N) -one-6- (H) α-thion is heated in 150 MP of isopropanol for 22 hours under reflux. The reaction mixture is chromatographed. The resulting slightly yellowish oil (7.5 g) is dissolved in ethyl acetate. Add a solution of 2.3 g of fumaric acid in ethyl acetate – standard mixture, suck out the precipitated crystals and recrystallize it from ethanol. Yield 5.8 g (49% of theory) of yellow crystals, mp 151-153 ° C (during puffing). Used as starting compound 4-methylmercapto-1,3,5-triethespshrimidin-2- (3N) -one-6- (1H) -ti51
    it is yellow crystals, mp 93-94 ° C (from ethyl acetate), is obtained in good yield by methylation of 4-mercapto1, 3,5-trimethylpyrimidine-2- (3N) -6-th (H) -thion.
    The following compounds are prepared in a similar manner.
    Oxalate 1-phenoxy-3- 2- (1,2,4-trimethyl-5-pyrazolone-3-yl-amino-ethylamino-3-propan-2-ol, mp 41-142 ° C. (dec).
    1-phenoxy-3- 2- (2,4,5-trimethylpyrimidin-6-yl-amino) -ethylamino} propan-2-ol, t, pl. 1 19-121 C.
    1- (4-Benzyloxyphenoxy) (2,6-dimethylphenylamino) ethylamino-propane-2ol, maly.
    1- (4-Propoxyphenoxy) (2,6-dimethylphenylamino) -ethylamino-propan2-ol, mp. 51-54 ° C.
    Neutral fumarate, so pl. .
    1- (3,4-Dimethoxyphenoxy) -3 2 (1,3,5-trimethylpyrimidine-2,4-dione-6yl-amino) ethylamino-propan-2-ol, mp. 103-104 ° C
    Neutral fumarate 1-phenoxy-3L3- (1,3,5-trimethylpyrimidine-2,4-dione 6-yl-amino) propylamino propan-2ola, i.e. 132-133 C.
    Benzoate 1-phenoxy-3- 2- (4-indazolylamino) -ethylamino-propan-2-ol, mp 156-157 ° C.
    Neutral fumarate 1- (4-hydroxyphenoxy) -3-H2- (2,6-dimethylphenyl) amino propan-2-ol, mp 193-195 ° C.
    1- (4-Fluorophenoxy-Z-2- (2,6-dimethylphenyl amino) ethylamino-propan-2-ol; mp. SW-Yub C.
    Oxalate 1-phenoxy-3-2- (2-methyl 4-hydroxymethylthiophene-3-yl-amino) ethylamino-propan-2-ol, mp 117-120 ° C. 1-phenoxy-3- 2- (6 chloropyridazn-3-yl-amino) ethylamino-propan-2-ol; mp 147-149 ° C.
    1-phenoxy-3- 2- (2-a "noxinazolin-4-yl-amino) ethylamino-2-ol, mp. Fumarate 204-206 ° C.
    1-phenoxy-3- 2- (3-methylquinoxalin-2-yl-amino) ethylamino-propan-2ol, oil, so pl. (neutral fumarate hydrate).
    1-phenoxy-3- 2- (1,2,3,4-tetrahydroacridin-9 yl-amino) ethylamino-propan-2-ol, mp 99-100 ° C (from isopropanol).
    Biological testing of the proposed compounds is carried out.
    6 6
    In the experiments using crossbreed dogs
    both sexes with an implanted artery and femoral vein, as well as into the left ventricle through the myocardium catheters. Experiments begin no earlier than 10 days after surgery, after complete recovery of the dogs.
    In the course of the experiment (the animal is in a waking state) by
    the catheter and the electromechanical sensor continuously measure blood pressure. In addition, using a needle gauge inserted into the ventricular catheter and reaching
    heart, the pressure in the left ventricle is continuously measured, which is differentiated by time and the maximum is found from the dp / dt curve. Heart rate (fcor) is calculated from the data on the number of contractions during fast drawing of paper up to the time of measurement.
    The test compounds were infused at a rate of 0.25 µg / kg per minute for 60 minutes, after which the observation was continued for 30 minutes. Separate compounds are administered in higher doses (10 times), or the studied doses are administered gradually, in logarithmic quantities, in order to investigate as far as possible a dosage interval in this way.
    From the logarithm of the dose introduced at a certain point in time, its action on dp / dt „and, accordingly, the frequency (fcor) calculate the linear regression. From it, the doses of DE + zog + bo7 „(µg / kg) are calculated, causing an increase in the initial values dp / dt d and, respectively, fcor by 30 and 50% (Table 1).
    The results obtained using the proposed compounds and compounds for comparing A and B are shown in Table 1.
    From table 1 it can be seen that although compound A - 1-phenoxy-3- 2- (2,6-dimethylphenyl amino) ethylamino-propan-2-ol has a good cardiotonic effect (an increase in dp / dt), but with the same dose increases and the frequency of contractions, which leads to excessive stress on the heart.
    权利要求:
    Claims (2)
    [1]
    As a quantitative measure of the effectiveness of compounds, doses that increase the contractile force of the heart (dt / dp) and heart rate (fcor) by 30 and 50% are selected. Another criterion for the effectiveness of compounds is the ratio ,, fcor: DE ydp / dt. The most valuable are the compounds for which this ratio is great, because for them as the dose is increased, the contractile force of the heart increases to a greater degree than the frequency of contractions. Thus, the larger the ratio, the more effective the compound. However, one should always take into account the relationship between heart rate and contractility. Compound B — 1-phenoxy-3- 2 (1, 3-dimethylpyrimidine-2,4-dione-6-yl amino) ethylamino-propan-2-ol — does not show a cardiotonic effect. Table 2 shows the characteristics of some compounds. Studies have shown that all the proposed compounds are non-toxic. Claims 1. Method for the preparation of aryloxypropanolamines of the formula gXL / CHgCHCHH-NH-X-NH-. RI 1 l where R - R - are the same or different and denote hydrogen, fluorine, oxygroup, lower alkoxy, benzyloxy; X - alkylene C A - a mono-, bi- or tricyclic five- or six-membered heterocyclic residue containing nitrogen which can be hydrogenated, or thiophene, or in the case that at least one of the residues R - R does not denote hydrogen, is It also contains a phenyl residue, with the restriction that, if A is a residue of ur cyl-6-yl, then the substituent in position 5 of the uracil portion of the molecule is not hydrogen; R - Rg is the same or different and denotes a hydrogen, amino, oxymethyl group, lower alkyl, phenyl, as well as oxygen or sulfur, or their pharmacologically compatible salts, characterized in that the compound of the formula 0-CH2CHCH2-D where R-R have the indicated value; I is chlorine or methyl mercapto group is reacted with a compound of the formula where X, A, have the indicated meanings; with the subsequent selection of the target product in free form or in the form of a pharmacologically compatible salt.
    [2]
    2. A method for producing aryloxypropanolamines of the formula O-CH2CHCH2-NH-X — NH OH where R to R are the same or different and denote hydrogen, fluorine, hydroxy, lower alkoxy, benzyloxy; X -alkylene C, - A - a MONO-, bi- or tricyclic five- or six-membered heterocyclic residue containing nitrogen that can be hydrogenated, or thiophene, or if at least one of the residues R - R does not denote hydrogen is also a phenyl residue, with the limitation that, if A is a uracil-6-yl residue, that the substituent in position 5 of the uracil portion of the molecule is not hydrogen; R g - R is the same or different and denotes a hydrogen, amino, hydroxymethyl group, lower alkyl, phenyl, as well as oxygen or sulfur, or their pharmacologically compatible salts, characterized in that the compound of the formula
    where R - R and X are specified, zn1 4
    cheny;
    subjected to interaction with the compound of the formula
    where Y is chlorine or methyl mercapto group, followed by separation of the target product B in free form or in the form of pharmacologically compatible salts.
    Note.
    Table I
    Tables A2 Pa - mean arterial blood pressure, mm Hg; fcor - heart rate, number of beats per minute; dp / dt — rate of pressure increase in the left ventricle, mm Hg / s; DE and DE, j (correspond to the dose at which the baseline value is increased by 30 and 50%, µg / kg.
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    同族专利:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19803023369|DE3023369A1|1980-06-23|1980-06-23|ARYLOXYPROPANOLAMINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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