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    • 专利摘要:
    The diaphragm-type expansion vessel is intended for a central heating system, the diaphragm forming a chamber accommodating the expansion water, so as to equalise pressure. The diaphragm (9) is a metal foil, secured by a seal (17) to the inside of the vessel (2). The vessel preferably comprises a cylindrical central portion (1) and top and bottom domes (3, 4) the diaphragm being secured to the bottom dome. The diaphragm may be in the form of a cylindrical bellows with a rigid cowl (11) of cup shape curved towards the cylinder outer surface at one end, and a foot (16) at the other one, by which it is secured to the vessel.
    公开号:SU1277889A3
    申请号:SU813248455
    申请日:1981-02-23
    公开日:1986-12-15
    发明作者:Фрибе Вальтер-Гунар；Михель Хельмут；Хайнц Росс Карл；Видеманн Фритц；Барч Вольфганг；Дитманн Карл
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of new aminopropane derivatives of the general formula 0-CH2-CH-CH2-CH1-CH- & H-1 @ -NB, hydrogen, lower alkyl or collectively denote an alkylen residue; R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; Z is a valence bond, a meleno group, or oxygen; phenyl or pyridyl residue; R., R. and R are the same or different, hydrogen, lower alkyl, lower alkoxy of the allyloxy group R is —CH — O-group 4. 2 pa; the group X is Y, the methylene residue or -NH, the methylene residue or a group, oxygen or sulfur, or the group -,, or (CH) - or their pharmaceutically acceptable 1.1.1 X halides with vasodilating properties. The aim of the invention is to develop, on the basis of a known method, a method of producing new compounds possessing pharmacologically valuable properties with reduced toxic properties. PRI mme R-1. 4- 2-Oxy-3- 2- (2-methoxyphenoxy) propylamino-pro-coxy-7-methyl-2-benzimidazolinone hydrochloride. 12.3 g of 2,3-diamino-1 2-hydroxy-3- (2- (2-methoxy-fenoxy) propylamino-pro-4-methyl 4-methylbenzene-trihydrochloride is dissolved in 500 ml of water. Pass A5 min into this solution-phosgene pr at room temperature, rinsed with nitrogen and sucked in. Crystallized acid is recrystallized from a mixture of 300 ethanol and 200 ml of methanol at an extra 9 pct carbon. Semi-theory) the product is 5.0 s tl. 228-230 ° C. The initial score is obtained in this way. 30.5 g of 2,3-dipitro-1 (2,3-epoxypropoxy) -4 methyl () enzene and 32.6 g of 1-benzyl-2- (2-methoxyphenoxy) propylamine are boiled in 500 ml of ethanol for 3 h. under the action of a downward-facing refrigerator. The reaction mixture is hydrogenated over 10 g of 10% palladium on carbon in 1 liter of ethanol at a pressure of 30.6 atm (30 bar). Free from catalyst, acidified with 2n. with hydrochloric acid solution, clarified with activated carbon and evaporated to dryness. 59 g of 2, 3-diamino-1-2-c1Xi-3- 2- (2-mgtoxyphenoxy) propylamino71-propoxy-Amethylbenzene-trihydrochloride are obtained. II p m m e r 2. In the same way as in example 1 from phosgene and correspondingly, the cradle of the substituted 1-propoxy-2, 3-diami-yu derivative (benzene gives the trace of the compound) w. but. 4- 2-Oxy-3- (3,4-dimethoxyphenethylamino j-propoxy 1-7-methyl-2-6enzimidazolinium hydrochloride chloride from 2,3-diamrt- - 2-hydroxy-3- (3, 4-dimethoxy phenethyl amipo) -pro 10oxi 1-4-methylbenzene-hydrochloride. 42% of theory, mp. 204-206С, solvent isopropanol / methanol, 4-2-hydroxy-3-1,2- {2-hydroxyphenoxy) ethylamino-propox-1 -7-methyl-2-benzimidazolin-1H-guide: Soil chloride from 2,3-diamino-1-2-hydroxy-3- 2- (2-oxyphenoxy) ethylamino-p-oopoxy-4-methylbenzene tri-hydrochloride, yield 67% of theory; mp, 262-263C, solvent methanol / water. at . 6, 7-Dimethyl-4-12-hydroxy-3- 2 (2-methylphenoxy): eth-amino-propoxy 2 5 3-diamino-4, 3-dimethyl-1 -2-oxy-3- 2- (2- methylphenoxy, 1 ethylamino-propoxy-benzene trihydrochloride, yield 34% of theory, m.p., 273274 C, p will vaporize methanol / water 4-2-Oxy-3- 2- (2-ketoxyphenoxy) ethylamino n ;-) ogloxy-7-methpl-2-benzimidazhcholno-hydrochloride from 2; 3-diamino-2-pxy-3-t2- (2-methylphenoxy) ethylamino-propox-4-methylbenzol-trihydropcJ chloro, yield 62% 02-203С., solution of the theory, m.p., ritel ethanol / met. ictl. D. 4-; C2-hydroxy-3- (benzo (b) -1, 4-dioxan-2-yl-methylamino) -propoxy} -2-benzimidazolinone hydrochloride from 2, diamine-1-12-hydroxy 3-benzo (b) -1,4-diox-2-yl-methylamino) propoxy-5-benzene-trihydrochloride. e, 4- 12-hydroxy-3- (2-phenoxyethylamine but) -propoxy-7-methyl-2-benzmidato linon-hydrochloride from 2,3-diamino-1-C2-hydroxy-3- (2-phenoxyethylamino) - about. Coxy-4-methylbenzene-trihydrochloride, 56% of theory, so pl. 231232 ° C, the solvent is ethanol / methanol. W.4- -Oxy-3- (2 phenoxyethyla but) -propoxy-6-methyl-2-benzimidazo-linon-hydrochloride from 2,3-diamino-1-H2-hydroxy-3- (2-phenoxyethylamino) -proxi } -5-methylbenzol-trihydrochloride, yield 52% of theory, so pl. 250252 ° C, the solvent is ethanol / methanol. h, 4- 2-Oxy-3- 2- {2-methoxyphenoxy) zylamino1-propoxy-6-methyl-2-benzimidazolinone hydrochloride from 2,3-diamino-1 - 2-hydroxy-3- T.2- ( 2-methoxyphenoxy) ztilamino-propoxy-5-metstbenzene-trihydrochloride, yield, 87% of theory, so pl. 213-215 C, solvent ethanol. and. 4-C2-hydroxy-3- (3,4-dimethoxyphenethylamine) -propoxy-6-methyl-2-benzimidazolinone hydrochloride from 2,3-diamino-1-2-hydroxy-3- {3,4-dime oxyphenylamino) propoxy-5-methylbenzene-trihydrochloride, yield 15% of theory, so pl. 260-262 ° C, the solvent is ethanol. K. 4- 2-Oxy-3- 2- (2-allyloxyphenoxy) ethylamino-propoxy-7-methyl-2-benzimidazolidinone-hydrochloride from 2,3-diamino-2-hydroxy-3-12- (2-allyloxyphenoxy ) ethylamino-pro poxy-4-methylbenzene-trihydrochloride, yield 24%, so pl. 195-198c (methanol). EXAMPLE 3 4-: 2-Oxy-g3-C2- (2-methoxyphenoxy) propylamino-propoxy-7-methylbenzimidazole hydrochloride, 14.7 g of 2,3-diamino-1-G2-OXI- 3- 2- {2-methoxyphenoxy) propylamino7-propoxy-4-methylbenzene-trihydrochloride is boiled in 80 ml of formic acid for 3 hours under the action of a downward-facing refrigerator. Lighten with charcoal and evaporate to dryness. The formyl compound formed is washed in 50 ml of 2N. hydrochloric acid solution at boiling point. After evaporation to dryness, the residue with the addition of activated carbon is recrystallized from 50 ml of ethanol. 5.6 g (41% of theory) of the title compound are obtained with a mp. 103105С. EXAMPLE 4 Analogously to Example 3, the following compounds were prepared from formic acid and suitably substituted with 1-propoxy-2,3-diaminobenzene derivative. a.4-C2-Oxy-3- (3,4-dimethoxyphenethylamino) -propoxy-benzoimidazole hydrochloride from 2,3-diamino-1-C2-Oxy-3-C 3,4-dimethoxyphenylthylamino-propoxy-benzene- trihydrochloride, yield 50% of theory, so pl. 255-256Cj solvent ethanol. b.4-2-Oxy-3 (3,4-dimethoxyphenethylamino) -proproxy-7-methylbenzimidazol-hydrochloride of 2,3-diamino-1-C2-hydroxy- (3,4-dimethoxyphenethylamino-propoxy-4-methylbeneleol trihydrochloride, yield 20% of theory, so pl. 254-256 ° C, the solvent is ethanol / water. c.4- 2-hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino-propoxy-7-methylbenzimidazole hydrochloride from 2,3-diamino-1-12 hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino7- propoxy-4-methylbenzene-trihydrochloride, yield 92% of theory, mp .- 229-231 ° C, solvent is water. 6,7-Dimethyl-4-2-hydroxy-3-C2- (2-methylphenoxy) ethylamino-propoxy-benzimidazole hydrochloride and 2,3-diamino-4, 5-dimethyl-1 -.2-hydroxy- 3- 2- (2-methylphenoxy) ethylamino-propoxy-benzo-trihydrochloride, yield 17% of theory, so pl. 106-109 ° C, solvent ethanol / ethyl acetate 4.4-2-hydroxy-3-C2-methoxyphenoxy) ethylamino-propoxy-7-methylbenzimidazole hydrochloride from 2,3-diamino-1-2-hydroxy-3-E2-methoxyphenoxy ethylamino-propoxy-4-methylbenzene-trihydrochloride , yield 62%, so pl. 219-221C, solvent ethanol / methanol. e.4- 2-Oxy-3-E2- (2-methoxyphenxy) ethylamino-propoxy-benzimidazole-hydrochloride from 2,3-diamino-1 2-hydroxy-3- (2-methoxyphenoxy) ethylamino-propoxy-bvnzol- trihydrochloride, yield 17%, so pl. 115-118 C, solvent ethanol. 4-4-2-Oxy-3- (4-phenyl-2-butylmino) -propoxy J-benzimidazol hydrochloride from 2,3-diamino-1--1 2-hydroxy 3- (4-phenyl-butylamino) -propoxy -benzene-trihydrochloride, 77% yield of theory, amorphous product, 3. 4- 2-Oxy-3- (2-phenoxy-ethylamino) -pro-xy -b Enimidazole-hydrochloride from 2,3-Aiamino-1-oxy-3 - (2-phenoxyethylamino) -propoxy-benzene-trihydrochloride, yield 10% of theory, amorphous product. and. 4-Y-Oxy-3- (benzo (b) -1, 4-diocan-2-yl-methyl-amino) propane J-benzimidazole hydrochloride from 2,3-diamino-1 - 2-hydroxy-3- (benzo (b) .- 1, 4-di oxane-2-yl-methylamino) -pr6poxy-7-benzene-trihydrochloride, yield 19% of theory, m.p. 105-107 ° C, solvent iso: propanol / methanol. K. 4-g 2-hydroxy-3- 2- (2-methoxyphenoxy) propyl amino} -propoxy-benzimylazole-hydrochloride from 2,3-diamino-1 -: 2-hydroxy-3 - 2-methoxyphenoxy propyl amino | -propoxy-benzene-trihydrochloride, yield 59% of theory, so pl. 1 5-118 C, the solvent is ethanol. Example 5. 4-G2-Oxy-3- (3,4-dimethoxyphenethylamino) -propoxy -2, 7-dimethylbenzimidazole-hydrochloride 14, 6 g of 2,3-diamino-1-2-hydroxy-3- (3,4- dimethoxyphenylamino) - propoxy - 4-methylbenzene-trihydrochloride, heated in 50 ml of acetic acid for 3 hours under the action of a cooled down refrigerator. Clear with activated charcoal and evaporate completely. The residue in 40 ml of 2N hydrochloric acid solution is boiled under the action of a downward-facing refrigerator, and then evaporated to dryness. Purify, pass through the column: with silica gel, using chloroformmethanol (8: 2) as a solvent. In conclusion, the crystal is lysed from 100 ml of ethanol 2.2 g (19% of theory) of the compound mentioned in the preparation with m.p. 167-1b9 C „The diamine used as the starting product is prepared as follows: 26.0 g N-benzyl-3, 4 dimethoxyphenethyl-amine and 24.3 g 2,3-O2 1- (2,3-epoxypropoxy) -4- methylbenzene in 300 ml of ethanol is boiled for 4 hours under the action of a downward-facing refrigerator. The reaction mixture is diluted with 300 ml of ethanol and hydrogenated at a pressure of 30.6 atm (30 bar) over 7.0 g of 10% palladium applied to G 96 on coal. Free from catalyst, acidified with 2N. hydrochloric acid solution and get after evaporation of the amorphous salt of iamine. EXAMPLE 6 Analogously to Example 5, compounds are obtained from acetic acid and a correspondingly substituted 1-propoxy-2,3-diaminobenzene derivative, and 4- (2: Oxy-3- 2- 2-propoxyphenoxy) ethylamino Propoxy -2,7-dimethylbenzimidazole hydrochloride from 2, 3-diamino-4-methyl-1 -2-hydroxy-3-C2- (2-propoxyphenoxy) ethylamino-propoxy-benzene-trihydrochloride, 44% yield from theory, m.p. 143-45 ° C, the solvent is ethanol / ethyl acetate. b.4- 2-hydroxy-3- 2- (2-methoxy-4-methylphenoxy) ethylamino-propoxy -2, 7-dimethylbenzimidazole hydrochloride from 2, 3-diamino-4-methyl-1 - 2-hydroxy-3 - 2- (2-methoxy-4-methylphenoxy) ethylamino J-propoxy-benzene-trihydrochloride, yield 62% of theory, so pl. 165167 C, the solvent is ethanol. EXAMPLE 7, 4- 2-Oxy-3- (3,4-dimethoxyphenethylamino) -propoxy-benzotriazole hydrochloride. 14.1 g of 2, 3-diamino-1-2-hydroxy-3- (3,4-dimethoxyphenylamino) -propoxy-benzene-trihydrochloride are dissolved in 10 ml of water and 3.5 ml of glacial acetic acid, cooled to 5 ° C and mixed with 2.07 g of sodium nitrite in 5.0 ml of water. Stir for 2.5 hours at room temperature. The resulting sodium chloride is precipitated by the addition of 480 ml of isopropanol. After filtration, it is evaporated, purified through a column of silica gel (solvent: methanol / ethyl acetate 2: 1), mixed with hydrochloric acid; in ether and crystallized from ethanol. 1.62 g (10% of theory) of the title compound are obtained ... mp. 123-124C. Example 8, Analogously to Example 7, a trace of lean compounds is obtained from sodium nitrite and a suitably substituted 1-propoxy-2,3-diaminobenzene derivative. but. 4- 2-Oxy-3- (3,4-dimethoxyphenethylamino) -props) xi-7-methylbenzotriazole hydrochloride from 2,3-diamino G2-oxy-3- (3,4-dimethoxyphenethylamino) -propoxy-4-methylbenzene trihydrochloride, yield 16% of theory, so pl. 184-1, solvent solvent b.4- 2-Oxy-3- 2 (2-methoxyphenyl6-oxy) ethylamino-propoxy-benzotriazole-hydrochloride from 2,3-diamino-1-12-oxy-3-12- (2-methoxyphenoxy) ethylamino-propoxy-benzene trihydrochloride, yield 25% of theory, so pl. PZ-MZ S, solvent meta, nol / ether. 4-2-hydroxy-3-C2- (2-methoxyphenoxy) ztilamino-propoxy-7-methylbenzotriazole hydrochloride from 2,3-diamino-1-2-hydroxy-3-G2- (2-methoxyphenoxy) ethylamino propoxy-4-methylbenzene-trihydrochloride, yield 48% of theory, so pl. 109-111C, solvent isopropanol / methanol. 4- 2-hydroxy-3- 2- (2-hydroxyphenoxy ztilamino-propoxy-benzotriazole-hydrochloride from 2,3-diamino-1-2-oxa-3- 2- (2-hydroxyphenoxy) ethylamino-7-propoxy - b Enzol-trihydrochloride, yield 14%, mp 200-203G, solvent ethanol / methanol, 4.4-2-Oxy-3- (2-methoxyphenethyl amino) -propoxy 3-benzotriazole hydrochloride of 2, 3- diamino-1-, 2-hydroxy-3- (2-methoxyphenethylamino) -propoxy t | -6 it gels rigid hydrochloride, yield 21% of theory, mp 82-85 ° C, alcohol / ethyl solvent acetic acid. a. 4- 2-hydroxy-3-C2- (2-methoxyphenoxy) pro pylamino-propoxy benzotriazole hydrochloride from 2,3-diamino-1 - 2-hydroxy-3-G2- (2-methoxyphenoxy) propylamino} -propoxy-benzene-trihydrochloride, yield 62%, amorphous product. 4- (2-Oxy-3- 2- (2-allyloxyphenoxy) grapylamino - Propoxy-benzene triazole-hydrochloride from 2,3-diamino-1- (2-hydroxy-3- 2- (2-allyloxyphenoxy-propylamino-propoxy-benzo-trichlo hydrate, 15% of theory, mp. 143145 with ( ethanol / acetic ether). EXAMPLE 9 4- 2-Oxy-3- (3,4-dimethoxyphenethylamino) propoxy -2-benzimidazolin-hydrochloride. 17.4 g of 2,3-diamino-1-2-hydroxy-3- (3,4-dimethoxyphenethylamino) -prop-C-benzene-trihydrochloride is dissolved in 450 ml of chloroform and 50 ml of ethanol and dropwise at room temperature m with 3.2 ml of thiophosgene in 30 ml of chloroform. After 2 h, about 898 are treated with activated carbon and evaporated to dryness. The mixture is purified through a silica gel column (chloroform / methanol 8: 2) and 10 g (62% of theory) of a homogeneous product are obtained. After being taken up in isopropanol and mixed with a solution of hydrochloric acid in sephira, the title compound is precipitated by means of ethyl acetate, m.p. 108-1 0С. Example 10: Analogously to Example 9, the following compounds were prepared from thiophosgene and an appropriately substituted I-prostoxy-2,3-diaminobenzene derivative. but. 4-C2-hydroxy-3- (3,4-dimethoxyphenethylamino) -propoxy-7-methyl-2-benzimidazolinium hydrochloride from 2,3-diamino-1-G2-OXI-3- (3,4-dimethoxyphenethylamio) - propoxyZ-4-methylbenzene-trihydrochloride. b. 4- 2-Oxy-3-G2- (2-methoxyphenoxy) propylamino-propoxy) -7-methyl-2-benzimidazoline thionobenzoate from 2,3-diamino-1-hS-oxy-3-C 2- (2-methoxyphenoxy) propylamino-propoxy-4-methylbenzene-trihydrochloride, yield 14% of theory, so pl. 169-170 ° C, the solvent is ethanol / ether. at. 4-: 2-Oxy-3- 2- (2-methylphenoxy) ethylamino-propoxy -2-benzimidazolition-hydrochloride from 2, 3-diamino-1-; 2-hydroxy-3- 2- (2-methylphenoxy) ethylamino propoxy-benzene-trihydrochloride. Example 11: 4- 2-hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino} propoxy-6, 7-cyclopenten-2-benzimidazolinone hydrochloride. In a solution of 6.5 g (0,0175 mol) of 4, 5-diamino-6- 2-hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino-propoxy-indan hydrochloride, phosgene is passed through in 10 ml of water and 10 ml of tetrahydrofuran. 1 hour, then thoroughly flushed with nitrogen through the solution, filter, transfer the precipitate to a dilute solution of sodium hydroxide, rinse with methylene chloride, adjust the aqueous phase to extract with methylene chloride, evaporate, transfer to acetone and precipitate the hydrochloride salt in ether with the hydrochloride salt. 2.8 g of the title compound (36% of theory) are obtained in the form of an amorphous salt, m.p. .
    The diamine used as starting material can be prepared as follows.
    Condensation of 5-amino-6- (2,3-epoxypropoxy) -A-nitroindan with N-benzyl-2- (2-benzyloxyphenoxy) ethylamine gives 5-amino-6- 3-H-benzyl-2 (2-benzyloxyphenoxy) ethylamino -2-hydroxy) -4-nitrodane in the form of oil.
    By hydrogenation and hydrogenolytic debenzylation of this compound in the form of hydrochloride in a methanol solution over 10% palladium on charcoal, 4,5-diamino-2-hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino-propoxy -, -indan- hydrochloride with so pl. 193-195 C,
    Example 12 (3,, 4-dimethoxyphenyl) ethylamino-3-2-hydroxypropoxy-6,7-cyclopenteno-2-benzimidazolinone hydrochloride.
    Analogously to Example 1, from phosgene and 4,5 diamino-6-O-t2- (3,4-dimethoxyphenyl) ztilamino -2-oxy-x-indan hydrochloride, the title compound is obtained, so pl. 193-195С.
    The diamino compound used as starting material can be obtained as follows.
    Conducting the reaction of 5-amino-6- (2,3-epoxypropoxy) -4 nitroindan with 3.4 gdimethoxyphenethylamine, 5-amino-6- 3- 2- (3,4-dimethoxyphenyl) ethylamino -2-oxypropoxy-4-nitroindane, t .pl. 230U23BS as hydrochloride. Hydrogenation of this compound in a methanol solution over platinum dioxide gives 4,5-diamino-6- 3- 2- (3,4-dimethoxyphenyl) ethylamino | -2-hydroxypropoxy / -Idane, which is liberated as amorphous hydrochloride.
    Example 13. 4-G2-Oxy-3- (2-phenoxy-propylamino) -propoxy-6,7-cyclopenteno-2-benzamidozolinone-hydrochloride.
     In example 1, the compound obtained from phosgene and, 4,5-diamino-6- 2-hydroxy-3 (2-phenoxypropylamino) -propoxy-indan-hydrochloride is listed in the title, in the form of hydrochloride with g, pl. 26-263 pp.
    The diamino compound used as starting material can be prepared as follows.
    Condensation of 5-amino-6- (2,3-epoxypropoxy) 4-nitroindan and N-6sn zip-3-fanoxypropylamine gives 5-amino-6-3. (, M-benzyl - 2-phenoxpropylamino) -2- hydroxypropoxy-4-nitroindane, so pl. 70-80 ° C in the form of amorphous hydrochloride.
    By hydrogenation and idrogenolytic debenzylation of this compound in methanol solution over I0% palladium applied to coal, they reach 4,5-diamino-6-112-hydroxy-3- (2-phenoxypropylamino) -propoxy-indan hydrochloride , m.p. 153-155 p.
    Example 14. 4-C2-Oxy-3-C2- (2-hydroxyphenoxy) ethylamino-propok5, 7-cyclopenteno-benzimidazole. A mixture of 4J g (0.01 mol) of 4,5-di-amino-6- 2-hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino-nponoKCH-indan hydrochloride and 35 ml of formamide is heated
    0 40 min under the action of the converted
    down the fridge, evaporated. The mixture is stirred with water and extracted with methylene chloride. The extract is evaporated and triturated with ethyl acetate
     acid. 1.3 g of the title compound are obtained (34% of theory), mp 182-183 C.
    EXAMPLE 15: Similarly to the example of RU 3, formic acid and the corresponding substituted 1-propoxy-2-methyl-3-aminobenzene derivative produce the following compounds.
    4-12-Oxy-3- (2 Phenoxypropyl mno BUT) -propoxy-b-methylindole-p-chlorobenzoate, yield 42%, so pl. 134-136C (ethyl acetate).
    4- 2-Oxy-3- 2 - (2-methoxyphenoxy) propylamino-propoxy-6-methylindole, 0 yield 58%. m.p. 104-106 ° C (ethylace-. Tat).
    4- 2-Oxy-3-12 (5-carbamido-2-pyryloxy) ethylamine-propoxy-6-methylindole-di-p-chlorobenzoate, G0% yield, m.p. 141-143C (isopropanol).
    4-- 2-0x04-3-12 - (2-hydroxyphenoxy) ethylamino7-propoxy-6-methylindol benzoate, 72% yield, m.p. 85-90C (methanol).
    4-; 2-hydroxy-3-C2 (3,4-dimethoxyfenyl) ethylamino 1-propoxy-6-oxymethyl-indole, yield 51%, mp. (sintering)
    4- 2-Oxy-3- (1-methyl-3-phenyl) propylamino-7-propoxy-6-methylindol benzoate, m.p. 119-122p.
    4-: 2-Oxy-3- 2- (3,4-dimethoxyphenyl) ethylamino-propoxy-6-methylindol benzoate, m.p. 147-148 C. 4- 2-Oxy-3-C2- (2-pyridnnl) ethyl aminoD-propoxy-6-methylindole-di-p-nitrobenzoate, m.p. 146 ° C, A- 2-Oxy-3- (2-phenoxyethylamino-propoxy 1-6-methylindolbenzoate, mp 123-125s. 4-2-Oxy-3-1-methyl-2-phenyl) these amino -propoxy) -6-methylindolbenzoate, so pl. 125-128p. 4- -Oxy-3- 2- (2-methoxyphenoxy. Ethylamino-propoxy) -6-methyl-nndol, m.p. 123-125 ° C. 4- 2 Oxy-3- 2- (4-carbamidophenok si) ethylamino-propoxy-6-methylindole, so pl. 128-130C. 4- 2-Oxy-3- (be.nzo / b) -1, 4-dioxan-2-yl-methylamino) -propoxy 1-6-methylindole-p-chlorobenzoate, m.p. 168-170С. 4-G2-Oxy-2- (2-phenoxy-I-benzylpropylamino) -propoxy-6-methylindole oil. 4-, 2-Oxy-3-C2- (2-methoxyphenoxy-Y-benzylpropylamino} -propoxy-6-methylindole, oil. 4- 2-Oxy-3- 2- (5-carbamido-2-pyridoxy) - K-benzolethylamino-propoxy-6-methylindole, oil. 4 -; 2-hydroxy-3- 2- (2-benzyloxyphenoxy) ztilamino-propoxy-6-methyline dol, oil. 4- 2-hydroxy-3- 2- (3,4-dimethoxyphenyl) ethylamino 7-propoxy-6-methoxycarbonylindole, mp 145-147 C. 4- 2-Oxy-3-C2- (3,4-dimethoxyphenyl) ethylamino-propoxy 6-hydroxymethylidol, t mp 60 ° C. 4- 2-hydroxy-3- 2- (2-allyloxyfenk si) ethylamino-propoxy 6-methylindole, mp 2-ethoxycarbonyl-4-2-hydroxy-3- (3 - phenylpropylamino) propoxy-6-methylindole, mp 127 ° C. 2-Ethoxycarbonyl-4-2-hydroxy-3-G (1-methyl-3-phenyl) propylamino-propoxy-6-methylindole, mp 133-134 C. 2-Ethoxycarbonyl-4- 2-hydroxy-3-C2- (2-pyridylin) ethylamino-propoxy 6-methylindolbenzoate, mp 12913 p. 2-Ethoxycarbonyl-4-42-hydroxy-3- 2- (4-pyridinyl) ethylamino-propoxy - 6-methylindole, m.p. 133-134 C. 2-Ethoxycarbonyl-4-C2-hydroxy-3- (2-phenoxyethylamino) -propoxy J-6-methylindol benzoate, m.p. . 2-Ethoxycarbonyl-4- 2-hydroxy-3 -. ((1-methyl-2-phenoxy) ethylamino} -propoxy-6-methylindole, mp 135-137 C. 2-Ethoxycar-10-4-2-hydroxy -3- t2- (1-methoxyphenoxy) with ethyls on Lpropo si-6-methylindole, mp 145-147 C. 2-Ethoxycarbonyl-4-2-hydroxy-3- 2- (4-carbamidopepoxy) ethylamino-propoxy -6-methylindol acetate, mp. 160165 ° C. 2-Ethoxycarbonyl-4-2-hydroxy-3- (benzo (b) -1,4-dioxan-2-yl-methylamino) -propoxy 3 6-methylindole, t mp 135137 ° C. Example 16. In analogy to Example 3, the following compounds are prepared from sodium nitrite and, respectively, substituted 1-propoxy-2-methyl-3-aminobenzene derivatives. 4-2-Oxy-3- (3-f nilpropylamino) -propoxy-indazole, yield 50%, mp: 122-124 ° C. 4-2-hydroxy-3- (1-methyl-2-phenoxy) ethylamino-propoxy-indazole, mp. 175- 177 0. 4- 2-hydroxy-3- 2- (3,4-dimethoxyphenyl) ethylamino-propoxy indazole, yield 59%, mp 1 18-119 ° C. 4- 2-hydroxy-3- 2- (2-hydroxyphenoxy) ethylamino-propoxy-indazole, yield 41% of theory, mp. 137-139T, solvent isopropanol. 4- 2-hydroxy-3- (2-phenoxyethylamino) -propoxy-indazole, 88% absorption from theory, so pl. 134-135 ° C, the solvent is ethyl ester of acetic acid. 4- 2-Oxy-3- 2- (2-methoxyphenoxy) ethylamino | -propoxy-indazole, use of 82% of theory, so pl. 106-107С, ethyl acetate solvent. 4-.2-Oxy-3- 2- (2-methoxyphenoxy) propylamino7 propoxy-indazole, yield 58% of theory, m.p. 127-128c, acetic acid ethyl ester solvent. 4- 2-Oxy-3- 2- (4-pyridyl) ethylamino 7-propoxy u-indazole, yield 72% of theory, m.p. 123-125 0, ethyl acetate solvent K 1 ILO. 4-C2-Oxy-3- (benzene (b) -, 4-dioxan-2-yl-methylamino) -propoxy-7-indazole, yield 54% of theory, so pl. 142143C, acetic acid ethyl ester solvent. 4- 2-hydroxy-3-12- (2-hydroxyphenoxy) propylakino-propoxy-indazole, 57% of the theory, m.p. 92-95 0, solvent is ethyl ester of acetic acid. 131 4- 2-Oxy-3-C2- (4-acetamidophenoxy) ethylamino-propoxyU-indazole, yield 49% of theory, so pl. 130-133 C rast & ethanol / water, 4-2-hydroxy-3-L2- (3,4-ethylenedioxyphenyl) ethylamino-propoxy-indazoz: 1, 59% yield of theory, m.p. 125-126 С acetic acid ethyl acetate solvent. ) xi-3- 2- (3-ethoxy 4-methoxyphenyl) ethylamino-propoxy-indazole, yield 73% of theory, so pl. 118119 C, acetic acid ethyl ester solvent. 1- "G2-Oxy-3- 2- (3,4,5-trim" toxiphenyl) ethylamino-propoxy-indazole, yield 68% of theory, so pl. 1 7 1-1 72 С acetic acid ethyl ester solvent. 4- 2-hydroxy-3-L2- (4-hydroxy-3-methoxyphenyl) ethyl iino-propoxy-indazole, 57% yield from theory, m.p. 139-141 ° C. Solvent isopropanol / ethyl acetate 4- -Oxy-3- 2- (4-butoxy-3-hydroxyphenyl) ethylamino-propoxy indazole, yield 55% of theory, so pl. 9497 C, solvent is ethyl ester of acetic acid. 4- 2-Oxy-3.G2- (3,4-dioxyphenyl) ethylamino-propoxy-indazole acetate9 yield 46% of theory, so pl. 160-162 solvent ethanol. 4- 2-Oxy-3- 2- {2-pyridyloxy) ethyl auger -product-indazol, yield 52% of theory, m.p. 113-115C, ethyl acetate solvent. 4- 2-Oxy-3-G - {3,4-dimethoxyphenyl) -propyl 2-amino1 | -propoxy-indol sol, m.p. Software-P2S. 4 2-Oxy-3- 3- (3,4-dimethoxyphenyl) propyl and 3-propoxy-indazol benzoate. m.p. 131-134 S. i; -Pivaloyl-4-.2-pivaloyloxy-3 - 2- (3 54-diketoxiphenyl) ethyl progl-oxy-indazole hydrochloride, t, pl, 155-158С {69% of theory). 4 2-Pivaloyl-3-C2 - {3,4-dimethoxyphenyl) ethylamino-propoxy indazole, yield 85% of theory, oil. The resulting compounds were tested for their vasodilator-to-blocking activity in rabbits. Since both Properties could not be studied in one experimental mode, various test methods were selected. 9 a. Investigation of vasodilator action. Rabbits were anesthetized using 26% urethane in the amount of 5 ml / kg. A catheter was implanted in A. femorails to continuously measure blood pressure. Blood pressure was measured using an electromechanical pressure transducer (Stathm P23 Bb). The pulses were recorded on a direct recorder and, after calibration, were evaluated with a mercury gauge. After measuring the initial value, both cervical arteries (A, Carotis) were closed for 2 minutes and thus the blood pressure was temporarily maintained (Carotis-simes-Entlaslungs reflex-CSE). Immediately after this, the test substance was injected intravenously at the lowest dose (0.125 mg / kg) and after 8 minutes the CSE reflex was again determined. At intervals of 15 minutes, the test substance was re-injected at logarithmically increasing doses (factor 2) and the CSE was again determined. Substances that, under these conditions, weaken blood pressure below CSE, can be considered as vasodilators. For the evaluation of lower blood pressure, the action blood pressure was calculated for the test substances of the dose, which weaken the SZE-reflex by 30 mm Hg (ED - 30 mm Hg). at. Test for p-blocking action. Rabbits were fixed in wooden cages. The heart rate was determined by the needle electrodes inserted in them, and the readings were taken on a meter-frequency meter device (measurement time 15 s). Through the ear vein, 1 μg / kg of isoprenaline i, v was first injected. that caused the heart rate to increase from approximately 210 to 370 beats per min. Immediately after this, the test substance was administered intravenously at age-increasing doses (method a) and the frequency of cardiac contractions was determined again after the introduction of isoprenaline. Inhibition of isoprenaline-induced tachycardia was used as a measure of β-blockade. Determine the dose of test substance that attenuated the nsoprenaline elevated 50% increase (HD). The values obtained in two experiments are listed in the table. Calculation of equieffective doses (ED30 mmHg, respectively, HDm) was made on a logarithmic basis 4-6, respectively, 6-10 separate experiments). The doses calculated in both experiments (HD and ED- 30 mmHg were attributed to each other. All studied substances had a strong j9-blocking effect, as well as a clear ability to lower blood pressure, therefore both effects should be caused whenever possible by close doses, since otherwise the usefulness of the second action (due to relative overdose) would be inappropriate. From theoretical x considerations It appears optimal ratio of 1. vasodilator with guide and j3-blocking activity of the substances to the invention in comparison with commercially imeyuschims product RKORVAYOO 1-isopropylamino-3- / 1-naphthyloxy, 2-propanol is given in the table.
    .RS
    0-CH2-9H-CH2-N-jH-g- (-Rb
    and from .ch 1
    i
    RI
    n
    de R / and R- are the same or different, hydrogen, nioi alkyl, or together denote an alkylene residue;
    R is hydrogen or lower alkyl;
    R is hydrogen or lower alkyl;
    Z is a valence bond, a methylene group or an oxygen atom;
    Ar - phenyl or pyri-.
    the remainder;
    ., R, R - identical or different, hydrogen, LOW alkyl, lower alkoxy. an allyloxy group or R - —CH —O. GROUP; A - group X, -U., Where X is a methylene residue5 or NH; Y is a methylene residue or a group), where Q is oxygen or sulfur,. or the group -,, -N 0 N-, or (CH) - or their pharmadeutically acceptable t-halides, which is different. the fact that the compound of the general formula. , 0- J rCH-CH, - -CH-CH-Z-® R y „L in n kk R7 g I, kg g where X is NH or -CR, is reacted with phosgene or thiophosgene, or formamide, or with formic acid, ishtic acid, or nitrous acid, followed by cyclization of the resulting compound and isolation of the desired product in free form or in the form of pharmaceutically acceptable halides.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining aminopropanol derivatives of the general formula
    0
    .RS
    0-CH2-9H-CH2-N-jH-g- (-Rb
    i
    n
    and from .ch 1
    five
    0
    five
    RI
    where R / and R- are the same or different, hydrogen, lower alkyl, or together represent an alkyl residue;
    R is hydrogen or lower alkyl;
    R is hydrogen or lower alkyl;
    Z is a valence bond, a methylene group or an oxygen atom;
    Ar - phenyl or pyri-.
    the remainder;
    R .., R, R - identical or different, hydrogen, LOW alkyl, lower alkoxy.
    allyloxy group
    or R - -CH -O..GRUP-0-J rCH-CH, - -CH-CH-Z-® R
    th „L in n k k R7
    na; g And,
    A - group X, -U., Kg
    where X is the methylene residue5
    or NH; where X is NH or -CR,
    Y, - the methylene residue is subjected to interaction with the phosgeyl group), Mr. or thiophosgene, or the form is: oxygen or sulfur, the house, or, respectively, with formic acid.
    . or the group -,, -N 0 acid, ish acetic acid, or
    N-, or (CH) - or their pharmacid-nitrous acid, followed by
    tantically acceptable cyclic cyclization of the resulting compounds, characterized by the release of the desired product
    by the fact that the compound of the general form is in free form or in the form of farmala.
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    同族专利:
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    法律状态:
    优先权:
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