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    • 专利摘要:
    Neue heterocyclische Oxypropanolamin-Derivate der allgemeinen Formel in welcher die Reste R1-R10 außer Wasserstoff eine oder mehrere der folgenden zusätzlichen Bedeutungen haben können: Niederes Alkyl (gegebenenfalls substituiert, ungesättigt oder durch Sauerstoff oder Schwefel unterbrochen), Alkanoyl, Aroyl, Alkoxycarbonyl, Hydroxyl, Halogen, Aminocarbonyl, Aminosulfonyl oder Alkanoylamino, wobei R8 und R9 bzw. R8 und R, gegebenenfalls gemeinsam eine Niederalkylendioxy- bzw. eine -CH2-0-Brücke bilden und Z einen Valenzstrich, eine Methylengruppe, ein Sauerstoff-oder Schwefelatom, Ar einen carbocyclischen Arylrest oder einen Pyridylrest und A die Gruppe -X1-Y1-, in der X1 eine Gruppe -CH2- oder eine gegebenenfalls alkylsubstituierte -NH-Gruppe und Y1 eine -CH2-, eine -CO- oder eine -CS-Gruppe bedeuten, eine Gruppe -X2 =y2-, in derX2 undY2 gleich oder verschieden sein können und jeweils Stickstoff oder eine gegebenenfalls alkyl- oder alkoxycarbonylsubstituierte Gruppe =CH- bedeuten, darstellt, mit der Maßgabe, daß jeweils Y1 bzw. Y2 mit dem Rest -NR4- der allgemeinen Formel verbunden ist, deren pharmakologisch unbedenkliche Salze, Verfahren zu ihrer Herstellung sowie Arzneimittel zur Bekämpfung von Herz- und Kreislauferkrankungen, die diese Verbindungen enthalten.
    公开号:SU1243622A3
    申请号:SU802878004
    申请日:1980-02-11
    公开日:1986-07-07
    发明作者:Фрибе Вальтер-Гунар；Михель Хельмут；Хайнц Росс Карл；Видеманн Фритц；Барч Вольфганг；Дитманн Карл
    申请人:Берингер Маннхайм ГмбХ；
    IPC主号:
    专利说明:

    -CH is a CII group, and Z is a valence bond, or in the case when X - YI is a -0-group, and Z is an oxygen atom or a valence bond, 11 cannot be hydrogen, or R and RT must together form -CH -O-bridge, or them. salts, excluding him- with. the fact that the compound of General formula II:
    R and A have the indicated
    where R is the value
    subjected to interaction with the compound of General formula III:
    .X
    E
    CH-Z- (Ar} -Rfl I V
    N
    6
    R9
    where Kd have the indicated values, at a temperature of from room temperature to 100 ° C, followed by the fission of the target product in free form or as a salt.
    f
    The invention relates to the field of the preparation of novel aminopropanol derivatives or their pharmacologically acceptable salts with pronounced vasodilating properties, which mainly manifest themselves in lowering blood pressure. .
    The aim of the invention is to develop, on the basis of a known method, a method for the preparation of new compounds with valuable pharmacological properties.
    Example 1.4-: 2-Hydroxy-3- (1- -methyl-3-phenyl) -propylamino-Propoxy-6-methylindol benzoate.
    4.9 g of 4- (2,3-epoxypropoxy) -6- -methylindole and 3, -7 g (1-methyl-3-phenyl) -propylamine are stirred in 50 ml of N-butanol for 18 h, evaporated in vacuo and shake with 1N. a solution of lactic acid and simple ether. After precipitation of the base with a dilute solution of sodium hydroxide, it is extracted with a mixture of ether and ethyl acetate 1: 1 and purified by chromatography over silica gel using methylene chloride with Methanol 9: 1. The resulting base is dissolved in ethyl acetate, mixed with an equivalent amount of benzoic acid and sucked off. 2.0 g of 4- - 2-hydroxy-3- (1-methyl-3-fe Nile) -11g are obtained; sp; un; 1 J propoxy 6-me
    tilindol-benzoate (18% of theory), so pl. 119-122 C.
    Example 2. According to the method similar to that described in example 1, receive:
    a) 4 2-hydroxy-3- 2- (3,4-dimethoxyphenyl) ethylamino-propoxy-6-methylindolben-zoate from 4- (2,3-epoxypropoxy) -6-methylindole and 2- (3 , 4-dimethoxyphenyl) ethylamine, yield 27% of theory, so pl. 147-148 C, the solvent is ethyl acetate;
    b) 4- 2-hydroxy-3-2- (2-pyridinyl) ethylamino-propoxy 6-methylindole-di-h-nitrobenzoate from 4- (2,3-epoxy-propoxy) -6-methylindole and 2- (2- pyr and-dinyl) ethylamine, yield 16% of theory, so pl. , solvent - methanol f
    c) 4-L2-oxy-3- (2-phenoxy-ethylamino) propoxy, -b-methylindol benzoate
    from 4 (2,3-epoxypropoxy) -6-methylin-dol and 2-phenoxy-thylamine, yield 16% of theory, m.p. 123-125 C, solvent - simple ether;
    d) 4-; 2-hydroxy-3- 1-methyl-2-phenyl) -ethylamino-propoxy-6-methylidol benzoate from 4- (2,3-epoxypropoxy) -60-methylindol benzoate from 4- (2, 3-epoxypropoxy) -6-methylindole and (1-methyl--2-phenyl) -ethylamine, yield 20% of theory, m.p. 125 128 s, the solvent is ethyl acetate.
    0
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    e) 4- 2-hydroxy-3-2- (2-methoxyphenoxy) ethylamino-propoxy-6-methylindole from 4- (2,3-epoxy propoxy) -6-methylindole and 2- (2- methoxyphenoxy) ethylamine, yield 19% of theory so pl. 5 123-125 0, solvent - ethyl ester of acetic acid;
    e) 4- 2-hydroxy-3-2- (4-carbamidophenoxy) ethylaminoJ-propoxy-6-methylindole from 4- (2,3-epoxypropoxy) -6-methylindole and 2- (4-carbamido - phenoxy) ethylamine, yield 19% of theory, so pl. 128-130 s, solvent is methanol;
     g) 4- 2-hydroxy-3- (benzo / b / -1,4-di-5 oxane-2-yl-methylamino) -propoxy-6-methylindol-U1-chlorobenzoate from 4- (2.3 - -epoxypropoxy) -6-methylindole and 2- .- (aminomethyl) -1,4-benzo / b / dioxane, yield 14% of theory, so pl. 168-170 C, 20 solvent - ethyl acetate;
    h) 4-X2 hydroxy-3- (2-phenoxy-K-benzylpropylamino) propoxy-6-methylindole from 4- (2,3-epoxypropoxy) -6-methylindole and 2-phenoxy-L- benzylpropyl-amine, yield 95% of theory, oil;
    i) 4- 2-hydroxy-3- .2- (2-methoxy-phenyl-noxy) -N-benzyl-propylamino-3 propoxy-6-methylindole from 4- (2,3-epoxy-3O propoxy) -6-methylindole and 2- (methoxy-phenoxy) -N-benzyl-propylamino, yield; 95% of theory, oil;
    k) 4- 2-hydroxy-3- 2- (5-urea theory, mp. 60 ° C (amorphous substance);
    o) 4- 2-hydroxy-3-z- (2-allyloxy-phenoxy) ethylamino-propoxy-6-m tilindole from 4- (2,3-epoxy-ipoxy) methylindole and 2- (aplyloxyphenoxy) ethylamine, 36% of theory , mp 125 s, solvent methanol.
    Example 3. 2-Ethoxycarbonyl-4-G2-oxy-3- (3-phenylpropyl rano) I
    propoxyJ-6-methylindole.
    36.2 g of 2-ethoxycarbonyl-4- (2,3- -epoxypropoxy) -6-methylindole and 1.76 P of 3-phenylpropylamine in 5 ml of three amides of hexamethylphosphoric acid are stirred until the exchange reaction is completely complete at room temperature is absorbed by water and ether, ethereal extract phase that 1 n. a solution of tartaric acid and the base is released with a solution of potassium carbonate. After shaking with ether, drying and evaporation, 2.0 g of 2-ethoxycarbonyl-4-2-hydroxy-3- (3-phenylpro-25 pilamino) propoxy-b-methylindole, m.p. 127 C (33% of theory).
    Getting acetate.
    1.4 g of 2-ethoxycarbonyl-4- 2-hydroxy-3- (3-phenylpropylamino) -propoxy-6-methylindol is dissolved in 10 ml of ethyl acetate and mixed with a small amount of warming; after cooling, suction is performed. Get 1.3 g
     -2-pyridoxy) -H-benzylethylamino pro-2-ethoxycarbonyl-4-2-hydroxy-3- (3-fepoxy-6 methylindole from 4- (2,3-epoxy-propoxy) -6-methylindole and 2- ( 5- -carbamido-2-pyroxy) -N-benzylethylamine, 76% yield of theory, oil;
    l) 4- 2-hydroxy-3- 2- (2-benzsh10-xyphenoxy) ethylamino-propoxy-6- -methylindole from 4- (2,3-epoxy-propoxy) -6-methylindole and 2- (2-benzyloxy - phenoxy) ethylamine, yield 16% of theory, oil;
    m) 4-: 2-hydroxy-3- 2- (3,4-dimethoxyphenyl) ethylamino-propoxy-6-me tocarbonylindole from 4- (2,3-epoxy-propoxy) -6-methoxycarbonylindole and
    40
    45
    nilpropylamino) -propoxy-6-methylinol in the form of acetate with so pl. 155 ° C.
    Example 4. According to a method similar to that described in Example 3, the following is obtained:
    a) 2-ethoxycarbonyl 4- 2-hydroxy-3- 1 (1-methyl-3-phenyl) -propylamino-propoxy-6-methylindole from 2-ethoxy carbonyl-4- (2,3-epoxypropoxy) -6- -methylindole and (1-methyl-3-phenyl) -propanolamine, yield 28% of theory, m.p.
    133-134 C solvent - ethyl acetate.
    b) 2-ethoxycarbonyl-4; 2-hydroxy2- (3,4-dimethoxyphenyl) ethylamine, you -3-2- (2-pyridinyl) ethylamino pass 59% of theory, so pl. 145-147 C, the solvent is isopropanol / ether;
    i) 4- 2-hydroxy-3- 2- (3,4-dimethoxy-diphenyl) ethylamino-propoxy-6-oxymethyl dinol from 4- (2,3-epoxy propoxy) -6-hydroxymethyl indole and 2- ( 3,4-dimethoxyphenyl) ethylamine, yield 35%
    55
    coxy-6-methylindolbenzoate from 2-etoc of sicarbonyl-4- (2,3-epoxypropoxy) -6- -methylindole and 2- (2-pyridinyl) ethyl amine, yield 20% of theory, m.p. 129-131 C, the solvent is ethyl acetate;
    c) 2-ethoxycarbonyl-4 2-hydroxy-3- - 2- (4-pyridinyl) ethylamino;
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    50
    ABOUT
    from theory, so pl. 60 ° C (amorphous substance);
    o) 4- 2-hydroxy-3-z- (2-allyloxyphenoxy) ethylamino-propoxy-6-methylindole from 4- (2,3-epoxy-iropoxy) 6-methylindole and 2- (aplyloxyphenoxy) ethylamine, 36% of theory, so pl. 125 seconds, the solvent is methanol.
    Example 3. 2-Ethoxycarbonyl-4-G2-oxy-3- (3-phenylpropane Hano) I
    propoxyJ-6-methylindole.
    36.2 g of 2-ethoxycarbonyl-4- (2,3-epoxypropoxy) -6-methylindole and 1.76 P of 3-phenylpropylamine in 5 ml of hexamethylphosphoric triamide are stirred until the exchange reaction is complete at room temperature, absorbed in water and ether, ethereal extract phase that 1 n. a solution of tartaric acid and the base is released with a solution of potassium carbonate. After shaking with ether, drying and evaporation, 2.0 g of 2-ethoxycarbonyl-4-2-hydroxy-3- (3-phenylpro-5 pilamino) propoxy-b-methylindole, m.p. 127 C (33% of theory).
    Getting acetate.
    1.4 g of 2-ethoxycarbonyl-4- 2-hydroxy-3- (3-phenylpropylamino) -propoxy-6-methylindol is dissolved in 10 ml of ethyl acetate with mild heating, and mixed with 0.2 ml of acetic acid and after cooling, suction is performed. Get 1.3 g
    2-ethoxycarbonyl-4- 2-hydroxy-3- (3-fe2-ethoxycarbonyl-4- 2-hydroxy-3- (3-fe
    nilpropylamino) -propoxy-6-methylindole in the form of acetate with so pl. 155 ° C.
    Example 4. By the method similar to that described in example 3, receive:
    a) 2-ethoxycarbonyl 4- 2-hydroxy-3, -1 (1-methyl-3-phenyl) -propylamino-propoxy-6-methylindole from 2-ethoxycarbonyl-4- (2,3-epoxypropoxy) - 6-methylindole and (1-methyl-3-phenyl) -propylamine, yield 28% of theory, m.p.
    133-134 C solvent - ethyl acetate.
    b) 2-ethoxycarbonyl-4; 2-hydroxy-3- 2- (2-pyridinyl) ethylamino pro
    coxy-6-methylindolbenzoate from 2-ethoxycarbonyl-4- (2,3-epoxypropoxy) -6- -methylindole and 2- (2-pyridinyl) ethyl amine, yield 20% of theory, m.p. 129-131 C, the solvent is ethyl acetate;
    c) 2-ethoxycarbonyl-4 2-hydroxy-3- - 2- (4-pyridinyl) ethylamino-propoxy-6-methylindole from 2-ethoxycarbonyl-4- (2,3-epoxypropoxy) -b-methylindole and 2- (4-pyridinyl) ethylamine, yield 32% of theory, so pl. 133-134 s, the solvent is ether;
    d) 2-ethoxycarbranyl-4- 2-hydroxy-3- - (2-phenoxyethylamino) -propoxy-6-methylindole benzoate from 2-ethoxycarbonyl-4- (2, 3-epoxypropoxy) -6-methylindole and 2 - phenoxyethylamine. Yield 24%, mp. 147 ° C, the solvent is ethyl acetate;
    d) 2-ethoxycarbon-4-2-hydroxy-3-g (1-methyl-2-phenoxy) -ethylamine propoxy-6-methylindol benzoate from 2-e toHycarbonyl-4- (2, 3-epoxypropoxy) -6 -methylindole and 1-metsh1-2-phenoxyethylamine, yield 23% of theory, so pl. ISS-IST C, solvent - ether
    e) 2-ethoxycarbonyl-4- 2-hydroxy- (2-methoxyphenoxy) ethylamino-propoxy-6-methylindole from 2-ethoxycarbonyl-4- (2,3-epoxypropoxy 6-methylindole and 2- (2- methoxyphenoxy) ethylamine, yield 21% of theory, mp 145-147 C, the solvent is ethyl acetate;
    g) 2-ethoxycarbonyl-4-i2-oxy-3-2- (4-carbamidof-Oxoxy) ethylamino-1 propoxy-6-methylindole acetate from 2-ethoxycarbonyl-4- (2, 3-epoxypropoxy) -6-methylindole and 2- (4-carbamidophenoxy) -ethylamine, yield 18% of theory, so pl. 160-165 C, solvent-ethyl acetate;
    . 3) 2-ethoxycarbonyl-4-2-hydroxy-3 (benzo / b / -1,4-dioxan-2-ylmethyl-amino) propoxy-6-methylindole from 2-ethoxycarboxy 1-4-C2, 3-epoxypropoxy ) -6-methylindole and 2- (aminomesh1) - -1,4-benzo / b / dioxane. 25% yield of theory, so pl. 135-137 C, solvent - ether. (
    Example 5. 4- 2-Oxy-3- (3-phenylpropyl-amine) propoxy | indazole
    5 g of 4- (2, 3-epoxypropoxy) indazole and 25 g of 3-phenylpropylamine are stirred for 20 h at. The excess amine is distilled off in vacuo, the residue is triturated with ether, sucked off and recrystallized from ethyl acetate. 4.3 g of 4- 2-hydroxy-3- (3-phenylpropylamino) are obtained for a p-indazol, m.p. 122-124 С (50% of theory).
    Example 6.4- 42-Oxy-3- (1- -methyl-2-phenoxy) -ethylamino-prok-Si indazod.
    5 g of 4- (2, 3-epoxypropoxy) indazole and 4.17 g of 1-methyl-2-phenoxyethyl) amine are heated in 10 ml of 1,2-dimethoxy ethane for 20 hours at. After trituration with acetone, suction and recrystallization from isopropanol, 3.7 g of 4-2-hydroxy-3- (1-methyl-2-phenoxy) -ethyl amino-propoxy ind-0 ash with mp. 175-177 C (41% of theory).
    Example 7. 2-Benzyl-4- 2-ox-3- (3,4-dimethoxyphenyl) ethylamino-propoxy indazole. 5 17 g of 2-benzyl-4- (2, 3-epoxypropoxy) indazole and 20 g of 2- (3,4-dimethoxy-phenyl) ethylamine are stirred for 20 hours at 70 ° C. Excess amount of amine is separated by stirring with ether 0 and sucking . 19.1 g of the title compound are obtained. Mp. 101-102 C (74% of theory).
    Example 8. According to a method similar to that indicated in Example 7, 2-benzyl-4- 42-hydroxy-3- is obtained. 2- (2-benzyloxyphenoxy) -ethylamino-propoxy indazole to 2-5enzyl-4- (2, 3-epoxypropoxy) indazole and 2- (2-benzyloxyphenoxy) ethylamine, 91% yield from 0 theory, mp, 81-83 s, solvent-ethanol.
    -Example 9. 2-Benzyl-4- (2-oxy-3-3- (2-phenoxyethylamino) propoxy-indazol.
    5 g of 2-benzyl-4- (2, 3-epoxypropoxy) indazole and 2.6 g of 2-phenoxyethylamine are heated in 10 ml of 1,2-dimethoxyethane 48 hours at 50 C. The volume is dissolved and dissolved in methylene chloride Q and purified chromatographically, passing through a silica gel column. The solvent is methylene chloride: ethyl ester of acetic acid 8: 2 and ethyl ester of acetic acid. - After evaporation, 4.2 g of the title compound are obtained in the form of a viscous oil (56% of theory).
    Example 10. According to the method analogous to the one described in Example 9, they emit;
    a) 2-benzyl-4- 2-hydroxy-З- 2- (2- -methoxyphenoxy) ethylamino {propoxy indazole from 2-benzyl-4- (2,3-epoxy-propoxy) indazole and 2- (2-methoxyphenoxy a) ethylamine, yield 52% of theory, oil;
    b) 2-benzsh1-4- i: 2-oKCK-3- 2- (2-methoxyphenoxy). Propylamine propoxy indazole from 2-benzyl-4- (2,3-epok 5
    7
    sipropoxy) -indazole and 2- (2-methoxy-phenoxy) propylamine, yield 83% of theory, oil;
    c) 2-benzyl-A-2-hydroxy-3- 2- (4-pyridyl) ethylamino-propoxy 7 indaeol from 2-benzyl-4- (2, 3-eprxypropoxy) indazole and 2- (4-pyridyl a) ethylamine, yield 51% of theory, oil;
    d) 2-benzyl-4- 2-hydroxy-3- (benzo) (6) -1,4-dioxan-2-yl-methylamino) propoxy j indazole from 2-benzyl-4- (2,3- epoxypropoxy) ) indazole and 2- (amino methyl) -1,4-benzo / b / dioxane, yield 47% of theory, oil;
    d) 2-benzyl-4- 2-hydroxy-3- 2- (3j4-ethylene dioxyphenyl) ethylamino propoxy indazole from 2-benzyl-4- (2,3-epoxypropoxy) indazole and 2- (3,4 - - ethylenedioxyphenyl) ethylamine, yield 76% of theory, so pl. 165-168 C, solvent isopropanol;
    e) 2-benzyl-4- 2-hydroxy-3- 2- (3--ethoxy-4-methoxyphenyl) ethylamino-propoxy indazole from 2-benzyl-4- (2,3-epoxy-propoxy) indazole and 2- (3- ethoxy-4-methoxyphenyl) ethylamine, yield 85% of theory, oil;
    g) 2-benzyl 4- 2-hydroxy-3- 2- (3,4, 5-trimethoxyphenyl) ethylamino propoxy indazole from 2-benzyl-4- (2,3-epoxy-propoxy) indazole and 2- ( 3,4,5-trimethoxyphenyl) ethylamine, yield 88% of theory, oil;
    h) 2-benzyl-4- 2-oxy-3- 2- (4- -benzyloxy-3-methoxyphene) I-ztilami-propoxy indazole from 2-benzyl-4- (2,3-epoxypropoxy) -indazole and 2 - - (4-benzyloxy-3-methoxyphenyl) these | lamina, yield 78% of theory, m.p. ; 96-98 s, the solvent is methanol;
    i) 2-benzyl-4-C2-hydroxy-3- 2- (3-ben zyloxy-4-butoxyphenyl) ethylamino-propoxy indazole from 2-benzyl-4- (2, 3-epoxypropoxy) -indazole and 2- ( 3- -benzyloxy-4-butoxyphenyl) ethylamine, yield 80% of theory, oil;
    k) 2-benzyl-4-X2-hydroxy-3- 2- (3, 4-dibenzyloxyphenyl) -ethi-1-amino 3 proxy indazole from 2-benzyl-4- (2,3-epoxy-propoxy) -indazole and 2- ( 3, 4-dibenzyloxyphenyl) ethylamine, from theory, oil;
    l) 2-benzyl-4- 2-hydroxy-3- 2- (2-pyridyloxy) ethyl-propoxy indazole from 2-benzyl-4- (2,3-epoxypropoxy) indazole and 2- (2-pyrioxy) ethyl - amine, yield 64% of theory, oil.
    43622 .8
    Example 11. 2-Benzyl-4- 2-oxy-3- 2- (2-hydroxyphenoxy) -M-benzyl-propylamino-propoxy indazole,
    4.2 g of 2-benzyl-4- (2,3-epoxy-pro-5 coxy) indazole and 3.85 g of 2- (2-hydroxyphenoxy) -Y-benzylpropylamine in 30 ml of dioxane are boiled for 4 days in an atmosphere nitrogen under the action of a downward-facing refrigerator. I Reduce the volume, dilute in methylene chloride and purify by chromatography, passing through a silica gel column. After evaporation, 5.8 g of the title compound remain as a viscous oil (72% 15 of theory),.
    Example 12. According to a method similar to that described in Example 11, 2-benzyl-4-2-hydroxy-3-2- (4-acetamidophenoxy) -H-benzsh1Ethyl-20 amino propoxy indazole from 2-benzyl-4- ( 2,3-epoxypropoxy) -indazole and 2- (4-acetamidophenoxy) -M-benzyl-ethylamine, yield 67% of theory, mas-, lo.
    25 2-Benzyl-4- (2,3-epoxypropoxy) -indazole, used as the starting material, can be obtained as follows.
    Under cooling and in an atmosphere of nitrogen, 9.2 g of sodium hydride in paraffin (55-60% suspension) are added to a solution of 47.1 g of 2-benzyl-4-hydroxyindazole in 250 ml of dimetformamide. After the evolution of hydrogen is complete, 19 ml of epibromohydrin are added and the mixture is stirred for 16 hours at room temperature. Then mixed in 1.5 l of water, extracted with methylene chloride and purified, passing through a column of silica gel using methylene chloride with methanol 99: 1. After trituration with a mixture of ligroin with ether 1: 1 and suction, 30 g of 2-benzyl-4- (2, 3-epoxypropoxy) -indazole with m.p. 66-68 ° C (51% of theory).
    Example 13. 4- 2-Oxy-3- 2- - (3,4-dimethoxyphenyl) -ethylamino-propoxy-1-formylindoline benzoate.
    2.2 g of 4- (2,3-epoxypropoxy) -1- -formedindoline and 1.8 g of 2- (3,4-dimethoxyphenyl) ethylamine are stirred in 50 ml and-butanol for 18 h at room temperature, reduce the volume in a vacuum and absorb with ether and 1N. solution of lactic acid. The reaction of the aqueous phase is made alkaline with 2N. sodium hydroxide solution solution and extracted with methyl ethyl chloro
    0
    five
    0
    five
    1243622
    house. After drying and evaporation, 4 g of crude npojiyKTa are left. The latter is purified using silica gel column and methylene chloride with methanol 95: 5. 1.8 g of purified base are obtained, KdTopoe is dissolved in 50 ml of ethyl ester of acetic acid and mixed with an equivalent amount of benzoic acid. g 4- 2 hydroxy-3- 2- (3,4-dimethoxy-phenyl) -ethylamino-propoxy -1-formylindrlinbenzoate, m.p. 136-138 with (24% of theory).
    Example 14. According to a method similar to that described in Example 13, the following is obtained:
    a) 4-- 2-hydroxy-3-2- (4-fluorophenoxy) ethylamino-propoxy -1-formylin dolinbenzoate from 4- (2,3-epoxypropoxy) -1-formylindoline and 2- (4 fluorophen- niloxy) ethylamine, yield 20% of theory, so pl. 121-123 s, the solvent is ethyl ester on hydrochloric acid. . b) 4- "2-hydroxy-3- 2 (2-methoxy-phenyl-noxy) ethylamino-propoxy -1-formilindoline benzoate from 4- (2 3-epoxy-1-propoxy) -1-formylinoline and 2- (2-me toxphenoxy) ethylamine, yield 19% of theory, so pl. 78-79 s, solvent - ethyl acetate.
    c) 2-hydroxy-3-2- (2-methoxyphenoxy) -N-benzylpropylamino propoxy -1-formylindoline from 4- (2,3-epoxypropoxy) -1-formylindoline and 2- (2-methoxyphenoxy) - K-benzsh1Propylamine yield 90% of theory, oil;
    d) 4- 2-hydroxy-3- 2- (2-benzyloxy-phenoxy) -Y-benzylethylamino-propoxy-1-formylindoline from 4- (2,3-epoxy-propoxy) -1-formylindoline and 2- (2 - -benzyloxyphenoxy) -N-benzylethylamine, yield 95% of theory, oil;
    d) 4- 2-hydroxy-3- (2-phenylethylamino-Opropoxy -1-formylindoline from 4- (2,3-epoxypropoxy) -1 formylindolin and 2-fensh13-thylamine, 18% yield
    from theory, t., Ш1. 121-123 C, the diluent is ethyl ester of acetic acid;
    e) 4- i2-OKCH-3- 2- (2-chlorophenoxy) ethylamino-propoxy -1-formsh1in valleys from A- (2,3-epoxypropoxy) -1- -formedindoline and 2- (2-chlorophenoxy) ethylamine , yield 15% of theory, mp 104-107 ° C, solvent ethyl ester of acetic acid;
    622
    ten


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    five
    g) 4-: 2-hydroxy-3-2- (2-methylmer-capto-phenoxy) -ethylamino-propoxy-1-formylindoline from 4- (2,3-epoxypropoxy) 1-formylindoline and 2- (methyl-mercapto-phenoxy ) ethylamine, output 20% of theory, so pl. 129-130 C, the solvent is methanol.
    Example 15. Analogously to Example 6, the compounds listed in Table 2 are obtained. one.
    Example 16. By analogy with the method described in Example 1, the compounds listed in Table 2 can be prepared. 2
    Example 17 By analogy with the method described in Example 1, 4- 2-hydroxy-3- 2- (2-ca.-siphenoxy) -ethylamino-propoxy -1-tform-rhyndyndoline acetate from 4- (2,3-epoxy) - coxy) -1-formylindoline and 2- (2-hydroxyphenoxy) ethylamine, followed by 66% acetic acid, yield 40% of theory, m.p. 171-173 C, the solvent is ethyl acetate.
    4- (2,3-Epoxypropoxy) -1-formylindoline, used to prepare this compound, is prepared by the following method.
    48.6 g of 2-benzyloxy-6-nitrotoluene, dissolved in 670 ml of dimethylformamide, are mixed with 29.9 g of paraformaldehyde, after which 200 ml of 1N are added dropwise to the mixture. solution-, pa tert.-butylate potassium. After stirring for 1 hour at room temperature, the mixture is poured, stirred in 3 l of ice water and extracted with diethyl ether. The ether phase is dried over sodium sulfate and then evaporated in vacuo. In the form of the residue, 62 g of 2-benzyloxy-6-nitrophenyl ethanol are obtained, which is used as a crude product in the next step.
    62 g of 2-benzyloxy-6-nitrophenylethanol is dissolved in 500 ml of anhydrous pyrid1 1a and the solution prepared at about; and the precipitate is mixed at a temperature with 47.7 p-toluene sulfonyl chloride. The temperature of the reaction mixture is allowed to rise to room temperature, then to complete the inter. the mixture was stirred. About an hour. Then the reaction solution was poured into ice water with stirring. After
    filtering, washing the precipitate with water and drying to obtain 74 g of 2- (2-benzyloxy-6-nitrophenyl) ethyl ester AND toluenesulfonic acid with m.p. 96-98 (86% of the theoretically calculated value per 2- benzyloxy-6-nit rotoluene).
    74 g (2- (2-benzyloxy-6-nitrophenyl) -ethyl p-toluenesulfonic ester is dissolved in 2 liters of ethyl ligature monomethyl ether, the solution is mixed with 5 g of 10% palladium-supported carbon catalyst, after which hydrogenation is carried out at room temperature and hydrogen pressure of 1 bar. After separation of the catalyst, evaporation is carried out. The residue is formed with a mixture of 227 ml of acetic anhydride and 91 ml of formic acid. After the reaction, the reaction mass is decomposed with ice and water, after which extrag The organic phase is neutralized, dried over sodium sulphate and evaporated in vacuo. The resulting residue is mixed with 320 ml of epichlorohydrin and then 173 ml of 2N sodium methoxide is added to the mixture. After stirring overnight, the mixture is evaporated , and the residue is dissolved in water and ethyl acetate. From the residue obtained after evaporation of the ethyl acetate solution by trituration with isopropyl alcohol and flux, 15.8 g of 4- (2,3-epoxypropoxy) -1-formylindoline are obtained. pl . 88-89 C (42% of the theoretically calculated value).
    In addition to the compound indicated at the beginning of the example, the compounds listed in Table 2 are also prepared. 3
    The vasodilating effect and the blocking activity of the proposed compounds is tested in rabbits.
    Test for vasodilator action.
    Rabbits are anesthetized with 26% ur: tane, a dose of 5 ml / kg. For a non-adherent determination of arterial blood pressure, a catheter is implanted into the femoral artery of the test animal. Blood pressure is measured using an electromechanical pressure transducer (Statham P. 23 D c). Pulses are recorded on the recorder and after
    . five
     About 15 20 -iS zo.
    five
    0
    ABOUT
    .five
    calibration values are expressed in mmHg.
    After determining the initial value, both cervical arteries are pinched for 2 minutes, as a result of which the blood pressure rises temporarily (Carotis-Sinus - EHtlastungs-Reflex CSE). Then, the minimum dose of 0.125 mg / kg of the test compound is administered intravenously and after 8 minutes the CSE reflex is determined again. Thereafter, every 15 minutes, the test compound is reintroduced, the dosage of which increases logarithmically (factor 2), and the CSE factor is determined again.
    Compounds that, in these conditions, extinguish the increase in blood pressure below CSE, can be considered as vasodilators. To assess the efficacy of test compounds with respect to a decrease in blood pressure, a dose is calculated, with the introduction of which the CSE reflex decreases by 30 mm Hg. (ED-30 mm Hg).
    Tests for 0-blocking activity.
    Rabbits are fixed in wooden cages. The heart rate perceived by needle-shaped electrodes is determined using a counter-frequency meter (measurement time 15 s). After that, 1 µg / kg of isoprenaline is injected intravenously through the ear vein, as a result of which the heart rate rises to l-370 beats per minute. Then, the test compound is administered intravenously in increasing doses and the heart rate is again determined. Inhibition of isoprene-line tachycardia is taken as a measure of the 3-blocking activity. The dose of the test compound is then determined, with the introduction of which the increase in heart rate caused by isoprenaline is reduced by 50% (HDy). The data of both tests are given in Table. 1 Calculation of equieffective doses (ED., 0 Mw.prcT. And HD, .J is carried out on the basis of 4-6 and 6-10 experiments, respectively, after which the ratio of the calculated doses is determined.
    All tested compounds have high and-blocking activity and, in addition, significantly reduce blood pressure.
    The vasodilating effect and / 3-blocking activity of the proposed compounds as compared with the control compound, which uses propranolol-1-isopropyl-amino-3- (1-naphthyloxy) -2-propanol as the control compound, are given in Table. four.
    Since both this and the other actions of the compounds are desirable, then
    a) 4- 2-Oxy-3-2- (2-allyl phenoxy) ethylamino-propoxy-indazole from 4- (2,3-epoxypropoxy) -indazole
    and 2- (2-allylphenoxy) ethylamine
    b) 4- 2-Oxy-3-2- (2-allylloxyphenoxy) ethylamino-propoxy indazole from 4- (2, 3-epoxypropoxy) -indazole and 2- (2-allyloxyphenoxy) ethylamine
    ) 4- 2-hydroxy-3 (2-phenoxypropyl-40 amino) -propoxy-6-methylindole-h-chlorobenzoate from 4- (2,3-zpoxy-propoxy) -6-methylindole and 2- -phenoxypropylamine followed by treatment P-chlorobenzoic acid
    ) 4-c2-Oxy-3- 2- (2-methoxyphenok-. 60 si) propylamino-3-propoxy-6- -methylindole from 4- (2,3-epoxypropoxy) -6-methylindole and 2- (2 -metoxyphenoxy) -propylamine
    ) 4-i2-OKCH- (5-carbamido-2-11 pyridoxy) ethylamino-propoxy-6-methylindole-di-p-chlorobenzoate
    from 4- (2,3-epoxypropoxy) -6-methylindole and 2- (5-carbamido-2-puridoxy) ethylamine followed by treatment with AND-chlorobenzoic acid
    The effects of both effects should be observed at almost the same doses, as with an insufficient dose, the second effect may not occur. Optimal from the theoretical point of view is exaggeration, equal to 1.
    one
    Table
    Yield,% m.p.
    from theory (solvent)
    . 47125-126
    (ethyl acetate)
    45137-139
    (from ethyl acetate)
    table 2
    132 - 134 (ethyl acetate)
    105 - 106 (ethyl (Acetic acid ester
    141 - 143 (isopropyl alcohol) (g) 4-: 2-Oxy-3- 2- (2-hydroxyphenoxy) ethylamino-propoxy-6-methylin-dolbene-ester from 4- (2,3-epoxy-propoxy) -6- methylindole and 2- (2-hydroxy-phenoxy) -ethylamine followed by treatment with benzoic acid
    e) 4-: 2-hydroxy-3- 2- (3,4-dimethoxy-phenyl) -ethylamino) -propoxy-6-oxymethylindole from 4- (2,3-epoxy-propoxy) -6-hydroxymethylindole and
    2- (3,4-dimethoxyphenol) -ethylamine
    e) 4-. 2-Oxy-3- 2- (3,4-dimethoxyphenyl) -ethylamino-2-propoxy-indazole from 4- (2,3-zpoxy-propoxy) -indazole and 2- (3 D-methoxyphenyl) -ethylamine.
    g) 4- 2-hydroxy-3- 2- (2-hydroxyphenoxy) - ztilamino-propoxy-indazole from 4- (2,3-zpoxypropoxy) -indazole and
    2- (2-hydroxyphenoxy) -ethylamine
    h) 4-c2-hydroxy-3- (2-phenoxy-ethylamino) -propoxy-indazolysis of 4- (2,3-epo-cipropoxy) -indazole and 2- (2-oxyphenoxy) -ethylamine
    i) 4- 2-Oxy-3- 2- (2-methoxyphenoxy) -ethyl-amino-propoxy-indazole from 4- (2,3-epoxy-propoxy) -indazole and 2-X2-methoxyphenoxy) -ethylamine
    a) 4- 2-Oxy-3- 2- (2-methoxyphenoxyl) -propylamino1-propoxy.-u51-dazole from 4- (2,3-epoxypropoxy) - -indazole and 2- (2-methoxyphenoxy -propalamin
    l) 4- 2-Oxy-3-G2- (4-pyridyl) ethyl amino} -propoxy-indazole from 4- (2,3-zpoxypropvpoxy) -indazole and 2- (4-pyridyl) -ethylamine
    m) 4- / 2-Oxy-3-Tbenzo7v / -1.5. . dioxan-2-Sh1methylamino) -propoxy-indazole from 4- (2,3-epoxy-propoxy) -indazole and benzo / in / - -1,4-dioxan-2-yl-methylamine
    Continued table. 2
    Izi
     82 - 86 (methanol)
    60 (t. Sintering)
    116 - 118 (ethyl acetate)
    135 - 137 (isopropyl alcohol)
    136 - 137 ethyl acetate (acid)
    85
    104 - 106 (ethyl acetate)
    126 - 128 (ethyl ester (acetic acid)
    75
    50
    122 - 124 (acetic acid ethyl ester
    141 - 143 (ethyl acetate)
    n) 4-: 2-hydroxy-3- 2- (2-hydroxyphenox) - 50 propylamino-propoxy-indazole from 4- (2,3-epoxypropoxy) -indazole and 2- {2-hydroxyphenoxy) propyl-amine
    o) 4- 2 Oxy-3- 2- (4 acets: midofenoxy) -ethylamino1-propoxy-indazole from 4- (2j3-epoxypropoxy) -indazole and 2- (4-acetamidofeioxy) ethylamine
    p) 4 - 2-hydroxy-3- 2- (3 94-ethylenedioxphenyl) ethylamino-propoxy-indazole from 4- (253-epoxypropoxy) -indazole and 2- (3, 4-ethylenedioxyphenyl ethylamine
    p) 4- "2-hydroxy-3-- 2- (3-ethoxy-4-methoxyphenyl) etclamio-propoxy-indazole from 4- (2, 3-zpoxypropoxy) -indaol and 2- ( 3-ethoxy-4-methoxyphenyl)
    c) 4-i2-OKCH-3 G2- (354e5 Trimethoxy-phenyl) ethylamino-propoxy-indadazole from 4- (2 3-epoxy-1p proxy:) -indaeol and 2- (354 p5 triketoxyfenyl-ethylamine
    ) 4: 2-Oxy-3- 2 (4 Oxy - 3-labels - 57 139-141
    Siphenyl) -ethylamino-3-propoxy: (isopropanol). Indazole of 4 (2d3-epoxypropy1K-si) -indazole: a and 2 (4-hydroxy-3-methoxyphenyl) -ethylamine
    ) 4- 2-Oxy-3- 2- (4-butoxy-3-ca-55 cyphenyl) ethyl s; noJ-propoxy-indazole from 4- (2 s3-3noKCH: nponoK-si) -indazole and 2- (3 ™ hydroxy-4-buto-. syphenyl) -ethylamine
    ethyl ester of acetic acid)
    94-97
    (ethyl acetate)
    f) 4- -: 2-Oxy-3-G2- (354-dioxyphenyl) -3,13-amino 3 -propoxy-indazole acetate from D- (253-epoxy-propo-si) -indazole and 2 (354-dioxype- Nile) -ethylamine followed by (acetic acid treatment
    x) 4 i2-Oxy-3- 2- (2-pyridoxi) -ethyl-amino-propoxy-indazole from 4- (2, 3-epoxy-propoxy) -inda ash, and 2- (2-pyridoxi) ETSh1amnna
    Continued table, 2
    III
    94 - 95 (ethyl acetate
    49
    130 - 133
    (ethanol - water)
    125 - 126 (ethyl acetate)
    118 - 119 (ethyl acetate)
    63
    171 - 172 (ethyl ether)
    (isopropanol).
    ethyl ester of acetic acid)
    94-97
    (ethyl acetate)
    160 - 162
    (ethanol)
    113 - 115 (ethyl
    ester of acetic acid)
    nineteen
    ) 1-Pavaloyl-4-2-py-65-valoyl-3-2- (3,4-dimethoxyphenyl) ethylamino-propoxy-indazole hydrochloride from 1-pivalos 1-4- (2,3-epoxy) sypropoxy) indazole and 2- (3,4-dimethoxyphenyl) ethylamine with an aftertreatment with palvalic anhydride and an equimolar amount of hydrochloric acid
    ) 4- 2-Pivaloyloxy-3- 2- (3,4-DIMo 80 toxiphenyl) ethylamino-propoxy-indazole from 4- (2,3-epoxy-propoxy) -indazole and 2- (3,4- dimethoxyphenyl) ethylamine followed by treatment with pivalinic anhydride
    y) 4- 2-Oxy-3- 2- (2-methoxyphenoxy) -propylamino-propoxy -1- -formedindoline benzoate from 4- (2, 3-epoxy-propoxy) -1-formylindoline and 2- (2- methoxyphenoxy) propyl-amine followed by treatment with benzoic acid
    4-2-hydroxy-3- 2- (2- 60 methoxyphenoxy) -ethylamino -Pr) - coxy-7-methyl-2-benzimidazolinone hydrochloride from 4- (2,3-epoxypropoxy) -7-methyl -2-benzyl1 dazole and 2- (2-methoxyphenoxy) -ethylamine followed by treatment with an equivalent amount of hydrochloric acid
    ..
    ) Hydrochloride 4-: 2-hydroxy-3- 2- (2-25
    -methoxyphenoxy) -ethylamino-propoxy-benzotriazole from 4- (2, 3-epoxypropoxy) -benzotriazole and 2- (2-methoxyphenoxy) -ethylamine followed by treatment with an equimolar amount of hydrochloric acid
    124362220
    Continuation of table 2
    156 - 157 (ethanol)
    Oily substance
    thirty
    130 - 132 (ethanol)
    Table3
    201 - 202
    (ethanol / meta, nol)
    113 - 115 (methanol / diethyl ether)
    c) 4-2-hydroxy-3-1.2- (2-allyloxyfenoxn) -ethylamine hydroxyproxy-benzotriazole hydrochloride from 4- (2, 3-epoxyproioxy) benzotri-2 ol and 2- (2-allyloxyphenoxy) - ethylamine followed by treatment with an equimolar amount of hydrochloric acid.
    d) Hydrochloride 4- 2-hydroxy-3- 2 (2- -methoxyfenk si) - ethylamino-propoxy-7-methyl -2-benzimidazolinone from 4- (253-epoxypropoxy) -7- -methyl-2 -benzimidazolinone and 2- - (2-methoxyphenoxy) -ethylamine followed by treatment with an equimolar amount of hydrochloric acid
    Order 3721/59 Circulation 379. VIDAGSH Subscription of the USSR State Committee
    for inventions and discoveries 113035, Moscow, Z-ZZ, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    149 - 150 (ethanol / ethyl acetic acid)
    62
    201 - 202 (ethanol / methanol)
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of aminopropanol of the General formula I:
    zyloxy radicals, allyloxy radicals, amino.carbonyl groups, acetamino groups, or R 7 together with R fi means —CH 2 -0 group;
    A group X - Y ( where. X, is a methylene group or -NH residue, and Y, a methylene residue or a group>> C = 0, or a group X 2 = Y 2 in which X 2. And U 2 can to be the same or different and mean nitrogen atoms or - a CH group, and in the case when X 2 = Y 2 represents a —CH — N group, and R means a benzyl residue, this group can also be tautomerism due to the ability of indazole localized at the nitrogen atom represented by the symbol y ^, with the proviso that y or y . associated with residual NR f of the general formula I, wherein in the case where X, = y. means
    —CH — CH— group, a Z represents a valence bond or, in the case where Xe - Y, represents —ΝΗ-Ο “
    -0-group, a Ζ - oxygen atom or valence bond, cannot be hydrogen, or R; must together form -CH 2 -0-bridge, or them. salts, characterized in that the compound of the general formula where R <s R ^ and A have the indicated meanings, are reacted with the compound of the general formula III:
    NO- CH- <JH-Z- (Ar) -Rg 1 1 1
    Kb where R 4 - R $ , l and Ar have the indicated meanings, at a temperature from room temperature to 100 ° C, followed by isolation of the target product in free form or in the form of salt.
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    同族专利:
    公开号 | 公开日
    FI66371B|1984-06-29|
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    CA1134827A|1982-11-02|
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    AU531282B2|1983-08-18|
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    FI66371C|1984-10-10|
    HU184719B|1984-10-29|
    AU5541080A|1980-08-21|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792905877|DE2905877A1|1979-02-16|1979-02-16|NEW AMINOPROPANOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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