Method of producing derivatives of dichloroaniline, or their pharmaceutically acceptable salts, or s

专利摘要:
Compounds of the general formula (I> …<IMAGE>… [wherein… X is a bond or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain, and… Y is a bond, or a C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene chain (with the proviso that the sum total of carbon atoms in X and Y is not more than 8);… Py is a pyridyl group optionally substituted by one or two substituents selected from halogen, hydroxy, C1-3 alkyl and C1-3 alkoxy; and… R<1> and R<2> are independently hydrogen or C1-3 alkyl (with the proviso that the sum total of carbon atoms in R<1> and R<2> is not more than 4)]… and physiologically acceptable salts and solvates (e.g. hydrates) thereof,… have a stimulant action at beta 2-adreno-receptors and may be used in the treatment of diseases associated with reversible airways obstruction (such as asthma and chronic bronchitis), inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and gastric or peptic ulceration.
公开号:SU1590042A3
申请号:SU874202054
申请日:1987-02-11
公开日:1990-08-30
发明作者:Генри Чарльз Лантс Лоренс
申请人:Глэксо Груп Лимитед (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of novel biologically active chemical compounds, namely, derivatives of dichloraniline or their physiologically acceptable salts or solvates, which have a stimulating effect on 1-adrenoreceptors.
The purpose of the invention is to obtain new dichloraniline derivatives having a higher stimulating effect on i-adrenoreceptors.
The following examples illustrate the invention.
Temperatures are given in C. The term dehydrate refers to dehydration using magnesium sulphate or sodium sulphate, unless otherwise indicated. Thin-layer chromatography (TLC) is carried out on SiOj, and evaporation column chromatography (ICH) is carried out on silica (Merck 9385), using
 s
ten
20
25
the following solvent system: A - toluene: ethanol: O, 88 ammonia; B - hexane: ethyl acetate: triethylamine; C - then luol: ethanol: triethylamine,
The following abbreviations are used: THF - tetrahydrofuran, DMF - dimethylformamide, BTPH - bis (triphenylphosphine) palladium (II) chloride, DEA N, N-diisopropylethylamine DMSO - dimethyl-tilsul foksid, TAB - tetra-N -butilam- mony bisulfate.
Intermediate 1 is 1- (4-amino-3,5-dichlorophenyl) -2-bromo-ethanone.
Intermediate 2 is 4-amino-I-o (aminoethyl) -3,5-dichloro-beisolmeth 1 NOL.
Intermediate 3 is N-6- and 3- - (2-pyridinyl) -2-propynyl / oxy / hexyl.
benzenemethanamine.
A mixture of 2-bromopyridine (2.0 g),: s (b - / (2-propynyl) oxy / hexyl / benZol methanamine (3.2 g), HGHP (0.07 g) with a copper diet (0.007 g) and diethylamine: (20 ml) was stirred under nitrogen for 18 hours, treated with aqueous sodium bicarbonate (W, 50 ml :) and extracted with diethyl ether (2 x 100 ml). The dehydrated extract was evaporated and the residue was purified using ICH-elution prost diethyl ether. Get the specified connection as a yellow oil (3.0 g), TLC (diethyl ether) - Rf 0.05,
The intermediate is 4 2- / 2- / (5-bromgexyl) oxy / ethyl / pyridine.
A mixture of 2-pyridine ethanol (1 g) of 1,6-dibromhexane (20 ml), 50% (volume / mass) sodium hydroxide (20 ml) and TAB (500 mg) is stirred at room temperature for 6 hours. Water (100 ml) is added. ml) and the mixture is extracted with simple ethyl ether (2x100 ml). The organic extracts are washed with water and brine, dehydrated and the end of the mixture: 7yut. An oil is obtained which is obtained by ICH - elution with hexane, then with a mixture of hexane-ether (1: 1). The title compound is obtained as a colorless oil (6.6 g) by TLC (hexane-ethyl ether 1: 1) - R 0.19.
Intermediate 5 is prepared similarly from the corresponding alcohol and bromine compound.
Intermediate 5., / Z / 4- / (6-bromine35
45
ten-1-ol (2.74 g) and 1,6-dibromhexane (10.03 g) with a reaction time of 18 hours and using ethyl acetate for extraction. ICH elution with cyclohexane-ethyl acetate (100: 95: 5) gave the title compound as a yellow oil (1.74 g). TLC (ethyl acetate - cyclohexane 5:95) Rf 0.17.
Intermediate 6 K- / 6- 2- (2-pyridinyl) ethoxy hexyl} benzene methanamine.
2- [2- (6-Bromhexyl) oxy / ethyl / pyridine (6.3 g) was added to benzylamine (20 ml) at 140 ° C under nitrogen. After 1 h at 140 ° C, the reaction mixture is cooled and divided into parts between 2 K sodium hydroxide (100 ml) and ethyl ether. The organic layer is washed with water and brine, dried and concentrated to a yellow oil. Excess benzylamine is removed by distillation at low pressure to give the title compound as a yellow oil (6.8 g), TLC (System A 80: 20: 2), R 0.44.
Intermediate 7 is obtained similarly. Intermediate 7 - N- / 6- / 4- (3-hydroxy-2-pyridinyl) butoxy / hexyl / benzenemethanamine.
Intermediate 7 is prepared from 2- (4- (6- -bromhexyl) oxy) butyl / -3-oxypyridine (1 g) and benzylamine (3 ml) by separating the reaction mixture after 4 hours between T 8% sodium bicarbonate (10 ml) and ethyl acetate (10 ml). The final product is purified by ICH-elution at System C (95: 5: 1) and the indicated compound is obtained as a yellow oil (0.8 g), those (System C 95: 5: 1) Rf 0.25.
Intermediate 8 - 4 amino-3, chloro-eb // (phenylmethyl) (2-pyrL - dinyl) ethoxy / hexyl / amino / methyl / benzenemethanol.
A solution of intermediate 1 (1.0 g) N-16- / 2- (2-pyridinyl) ethoxy / hexyl / benzenemethanamine (1.01 g) and DEA (460 mg) in THF (10 ml) is left at room temperature for -2 hours. The resulting precipitate is removed by filtration, the solvent is evaporated and the residue in methanol (10 ml) is cooled in an ice bath and treated in portions with caustic soda (300 mg) under nitrogen. After 30 min, the heating solution is 1R 1.
hexyl) oxy / -1-butenyl / -3- (phenylme- 55 to room temperature, its petoxy) pyridine. Stir for another 30 minutes, and then Intermediate 5 is obtained from (E / Z) -4-centered in vacuum and light-3- (Fensch1methoxy) -2-pyridinyl) -3-yellow-yellow foam is obtained. This foam is separated
0
0
five

th
35
45
ten-1-ol (2.74 g) and 1,6-dibromhexane (10.03 g) with a reaction time of 18 hours and using ethyl acetate for extraction. ICH elution with cyclohexane-ethyl acetate (100: 95: 5) gave the title compound as a yellow oil (1.74 g). TLC (ethyl acetate - cyclohexane 5:95) Rf 0.17.
Intermediate 6 K- / 6- 2- (2-pyridinyl) ethoxy hexyl} benzene methanamine.
2- [2- (6-Bromhexyl) oxy / ethyl / pyridine (6.3 g) was added to benzylamine (20 ml) at 140 ° C under nitrogen. After 1 h at 140 ° C, the reaction mixture is cooled and divided into parts between 2 K sodium hydroxide (100 ml) and ethyl ether. The organic layer is washed with water and brine, dried and concentrated to a yellow oil. Excess benzylamine is removed by distillation at low pressure to give the title compound as a yellow oil (6.8 g), TLC (System A 80: 20: 2), R 0.44.
Intermediate 7 is obtained similarly. Intermediate 7 - N- / 6- / 4- (3-hydroxy-2-pyridinyl) butoxy / hexyl / benzenemethanamine.
Intermediate 7 is prepared from 2- (4- (6- -bromhexyl) oxy) butyl / -3-oxypyridine (1 g) and benzylamine (3 ml) by separating the reaction mixture after 4 hours between T 8% sodium bicarbonate (10 ml) and ethyl acetate (10 ml). The final product is purified by ICH-elution at System C (95: 5: 1) and the indicated compound is obtained as a yellow oil (0.8 g), those (System C 95: 5: 1) Rf 0.25.
Intermediate 8 - 4 amino-3, chloro-eb // (phenylmethyl) (2-pyrL - dinyl) ethoxy / hexyl / amino / methyl / benzenemethanol.
A solution of intermediate 1 (1.0 g) N-16- / 2- (2-pyridinyl) ethoxy / hexyl / benzenemethanamine (1.01 g) and DEA (460 mg) in THF (10 ml) is left at room temperature for -2 hours. The resulting precipitate is removed by filtration, the solvent is evaporated and the residue in methanol (10 ml) is cooled in an ice bath and treated in portions with caustic soda (300 mg) under nitrogen. After 30 min, the heating solution 15900426
water (25 ml) and ethyl acetate. The following compounds (intermediates U5 ml; and the organic layer is washed 12-14) are obtained from the corresponding brine, dried and the concentrated starting materials are usually followed by a yellow oil, which is purified by reaction. as described by ICH, by elution with system B (50: 5 d of intermediate 4, then for inter-, and the indicated compound 6 is obtained and then for intermediate 8. as a pale yellow oil 12 — 4-amino-3,5- di-
(1.15 g), those (system B 50: 50: 1), chloro - // (phenylmethyl) / 6- / 3- (3 pyri-t 10 and no-P ropoxy / hexyl / amino / methyl /
Intermediates 9–11 are prepared by analogy-benefolmethanol, TLC (system B 50–50- from the intermediate 1 and correspondingly: l), Kg O 28.
This is followed by the intermediate 13 - 4-amino-3 5-diode. reduction with sodium borohydride. Chloro-o / - /// - 2- (6-methyl-2-pyrndinyl) Intermediates 9-11 receive ano-, 5-ethoxy / -hexyl / (phenylmethyl) amino / metered from intermediate 1 and corresponding / benzenemethanol , TLC (System A of the Incoming Amine, followed by 92: 8: 1) RP O 17 reduction with sodium borohydride. Intermediate 14 - 4-amino-3,5-di-intermediate 9 - (Z) -4-amino-3, 5-chloro-o /// (fvnilme ™ l) (4-pyridi-dichloro-o - // ( Fensch1methyl) / 6- // 3- (2-20 nyl) propoxy / hexyl / amino / methyl / benz-pyridin-yl) -2-propenyl / oxy / hexyl / zolmethanol, TLC (System B 80: 20-1 ) amino-methyl / benzenemethanol. Kr O 04.
Intermediate 9 is obtained from the intermediate Intermediate 15 (E, g) -4- / 3- (phenolate 1 (1.06 g) and H- / 6 - // 3- (2-pyrimethoxy) -2-pyridinyl (-Z-butene-1-ol dinyl) -prop-2-inn / oxy / hex.t / ben-25 Mixture H- (Phenylmethoxy) pyrvdin-2-. Solmethanamine (0.68 g) at time -carboxaldegvd ( 3.9 g), (3-hydroxy reactions for 16 h for both stages and isopropyl) triphenylphosphonium bromide using methanol (20 ml) and THF (8.38 g) and potassium carbonate (3.3 g) dioxane (30 ml), containing water of laziness .. NIKH elution at a ratio of 30 (0.27 ml), heated at a temperature cyclohexane - simple diethyl ether p reflux for 18 hours. Ohlaaden-C1: 1) gives the indicated compound in a diluted mixture and dilute the prostate. ethyl de. light yellow oil (0.7 g), TLC ether, filtered and the filtrate. (idle time diethyl ether), R. 0.5. vsharyvayut. The residue is purified ICH eshgintermedia 10.- 4-amino-3, 5-dichlorine at a ratio of simple // 6- / 4- (3-hydroxy-2-pyridinyl) -butyl ether - hexane (3: 2) - simple tox / hexyl / (phenylmethyl) amino / methyl / ethyl ether and get the specified benzenemethanol connection in the form of a yellow oil
Intermediate 10 is obtained from interme- (3.5 g), TLC (ethyl ether). diat 1 (0.6 g); and K- / 6- / 4 -. (3-hydroxy-2- R.f 0.23.
-pyridinyl) butoxy / hexyl / benzenemethane-Intermediate 16 - 2- / 4 - / (6-bromohexamine (0.7 g) at a reaction time of 18 forces) oxn / butyl / -3-oxypyridine. and 2.5 hours for both stages. ICH elui- (g) -2- / 4- / (6-bromohexin 1) oxy M-yyyy brown oil -butenyl / -3- (phenylmethoxy) pyridine (0.6 g), those (system A 80: 20: 1 ), d) hydrogenated over optionally reduced 10% oxide
 // yy 7 / am "no-3,5-dichloropaste on coal (50% water vapor-o (- // (phenylmethyl) / 6- / 2- (3-pyridinyl) one hundred, 300 mg) in ethanol (15 ml). Kata-ethoxy / hexyl / amino / methyl / benzenemetalizer is removed by filtration through 50 iflon, the solvent is evaporated and
Intermediate 11 is obtained from inter- get the indicated compound as mediate 1 (2.98 g) and H- / 6- / 2- (3-pyri-yellow oil (1.18 g). Dinyl) ethoxy / hexyl / benzenemethanamine Found %: C 54.51; H 7 41- (3 g) with reaction time during N 4.3; Br 23 83.
nights and 3 hours for both stages. IHC elu-C, gN., BrNO
Simulation with system C (95: 5: 1) gives Calculated,%: C 54.55; H 7 32- the indicated compound in the form of a light co-N 4.24; Br 24 19
brown oil (3 g), TLC (system. C. Intermediate 17 - N- / 6- / 2-and-pyri-1g -.. Dienyl) ethoxy / hexyl / benzenemethanamine.
A mixture of 3-pyridine ethanol (4 g), 1,6-g-dibromhexane (23.78 g), TAB (0.5 g) and 2N sodium hydroxide (50 ml) is stirred vigorously for 3 hours. The mixture is diluted water (75 ml), extracts from ethyl acetate and the combined (organic extracts are washed with brine (150 ml), dehydrated and sharpened. The resulting oil is purified-1 ICH by elution at a hexane: hexane-e-acetate ratio (19: 1) and get (6-bromhexyl) -oxy ztil / pyridine / (6 g). A solution of this
The solution was diluted with water (100 ml) and extracted with ethyl ether (2x100 ml). The combined organic extracts were washed with water (100 ml), dried, and evaporated in vacuo to give a colorless oil. The first aqueous washes were combined, re-extracted with dichloromethane (2x150 ml), washed with water (100. ml), dried, and evaporated in vacuo to give a brown oil. Then, the initial aqueous washes were buffered to pH 6.5 using phosphate buffer, and
ten
ethyl / pyridine / b g ;, solution is eto.and „aC. This. Our solution is a solution of compound (5 g) and benzylamine (5 ml) with 5 ormethane (2x100 ml),
stirred at 140 sec. under nitrogen atmosphere for 1 hour. The cooled reaction mixture was partitioned between sodium bicarbonate (150 ml) and ethyl acetate 4 i, --...- extracted with dichloromethane (2x100 ml), u) washed with water (100 ml), dehydrated, evaporated in vacuo and a brown oil is obtained. These three oils are combined with sodium nitrate; and ethyl.-elution with volume (50 ml). Organic layers are washed. 20. All hexane - simple ethyl
brine (50 ml), dehydrate, concentrate and get a yellow oil. Excess benzylamine is removed by distillation, the resulting oil is purified by ICC by elution at 25 with System C (95: 5: 1) and the indicated compound is obtained as a yellow oil (4 g), those (System A 80: 20: 1),
 2;:; p „e„ „a. 3 6- / 2Ча .. „„ ri „and„ „„ „0 G.- Gi / Gaa: ;; :
ethoxy / hexanol., carbonyldiimidazole (0.4.1 g)
A mixture of 2- / 2 - / (6-bromhexix) oxy / t / l / o
Hexane: ethyl ether (1: 1), and then methanol, to obtain a yellow oil, which is dissolved in dichloromethane (50 ml), and filtered. The filtrate is evaporated in vacuo to afford the title compound as a green oil (0.55 g).
those (system A 40: 10: 1), Ig Q, 6. Intermediate 20 - K- / 2- (4-aminoethyl / pyrimidine (9.0 g), sodium acetate trihydrate (34.24 g), trioctylpropyl ammonium chloride (1.9 g) and water 35 (25 ml) is stirred at reflux distilled 2 hours. A solution of 2N sodium hydroxide (50 ml) and ethanol (50 ml) is added to the cooled mixture, which is further stirred for 10 minutes at 40 room temperature. The ethanol is stirred in vacuum, the residue is diluted with brine (150 ml and extracted with ethyl ether (2x100 ml). The combined organic extracts were then 45 washed with water (150 ml), brine (100 ml), and the solution was dried. ayut, vacuum under vacuum and a yellow oil is obtained. Purification of ICH by elution with ethyl ether gives the title JQ in the title compound as a colorless oil (4.94 g), TLC (ethyl ether) 5 R 0.31.
Intermediate 19 - 6- / 2- (2-pyridinyl) ethoxy / caproic acid,
A solution of 6- / 2- (2-pyridish) ethoxy /, / hexanol (1.0 g) and pyridine dichromate (5.90 g) in DMF (12 ml) is mixed at room temperature for 24 hours.
partly added to a mixture of 6- / 2 (2- -pyr and No. 1nyl) ethoxy / caproic acid (0.5 g) in acetonitrile (30 ml) at room temperature under nitrogen. The mixture was stirred for 3 hours, then a suspension of intermediate 2 (0.46 g) in aceto-nitrile (10 ml) was added dropwise at room temperature. The mixture was stirred for 2.5 hours at room temperature under nitrogen. The solvent is evaporated in vacuo, the residue is purified by ELC with elution at a ratio of toluene to ethanol - triethyl min – 0.88 ammonia (95: 5: 1: 0–40: 10: 0: 1) and the indicated compound is obtained as a colorless — JHoro oil ( 0.23 g), TLC (system A 40: 10: 1), Rf 0.39.
Intermediate 21 - 6- / 2- (2-pyridinyl) ethoxy / hexanamine.
A solution of N- / 6- / 2- (2-pyridinyl) ethoxy / hexyl / benzenemethanamine (2.00 g) in ethanol (10 ml) is added to a preliminary hydrogenated suspension of 10% palladium on carbon (50% pasta, 800 mg) in ethanol (120 ml) and hydroge nated at room temperature and pressure. The catalyst is removed.

2
The solution was diluted with water (100 ml) and extracted with ethyl ether (2x100 ml). The combined organic extracts were washed with water (100 ml), dried, and evaporated in vacuo to give a colorless oil. The first aqueous washes were combined, re-extracted with dichloromethane (2x150 ml), washed with water (100. ml), dried, and evaporated in vacuo to give a brown oil. Then, the initial aqueous washes were buffered to pH 6.5 using phosphate buffer, and
 „Au. This. nashe, enn solution .oromethane (2x100 ml),
 „Au. This. nashe, enn solution .oromethane (2x100 ml),
4 i, --... ----- extracted with dichloromethane (2x100 ml), sp) washed with water (100 ml), dried, evaporated in vacuo and a brown oil was obtained. These three oils are combined by elution with hexane — simple ethyl.
  eluting with hexia — simple ethyl
G.- Ki / Gea: ;; :
Hexane: ethyl ether (1: 1), and then methanol, to obtain a yellow oil, which is dissolved in dichloromethane (50 ml), and filtered. The filtrate is evaporated in vacuo to afford the title compound as a green oil (0.55 g).
those (system A 40: 10: 1), Ig Q, 6. Intermediate 20 - K- / 2- (4-amino, carbonyldiimidazole (0.4.1 g)
    t / l / o
partly added to a mixture of 6- / 2 (2- -pyr and No. 1nyl) ethoxy / caproic acid (0.5 g) in acetonitrile (30 ml) at room temperature under nitrogen. The mixture was stirred for 3 hours, then a suspension of intermediate 2 (0.46 g) in aceto-nitrile (10 ml) was added dropwise at room temperature. The mixture is stirred for 2.5 hours at room temperature under nitrogen. The solvent is evaporated in vacuo, the residue is purified by ELC with elution at a ratio of toluene - ethanol - triethyl min - 0.88 ammonia (95: 5: 1: 0-40: 10: 0: 1) and the indicated compound is obtained as a colorless- JHoro oil ( 0.23 g), TLC (system A 40: 10: 1), Rf 0.39.
Intermediate 21 - 6- / 2- (2-pyridinyl) ethoxy / hexanamine.
A solution of N- / 6- / 2- (2-pyridinyl) ethoxy / hexyl / benzenemethanamine (2.00 g) in ethanol (10 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (50% paste, 800 mg) in ethanol (120 ml) and hydrogenated at room temperature and pressure. Catalyst is removed fil159004210
target fumaric acid (51 mg) in methanol (5 ml). The solution is evaporated and the residue is triturated with ether (50 ml) to give the title compound as a white powder (378 mg), those (System A 80: 20: 1), R 0.35.
Example 1. 4- / Amino-3,5-dichlrr-V- /// 6-3 (2-pyrinidyl) propoxy
-dichlorophenyl) -2- (2-pyridinyl) JQ / hexyl / -amino / methyl / benzenemethanol. ethoxy / hexyl / amino / ethanone. The solution of (g) -4-amino-3,5-dichloro-o //
A mixture of intermediate 1 (0.51 g), 6- (phenylmethyl) 6 - // 3- (2-pyridinyl) -2- - / 2- (2-pyridinyl ethoxy / hexanamine-propenyl / oxy / hexylMamino / methyl / ben - (0.40 g), DEA (0.36 ml) and THF - (10 ml) zolmethanol (0.65 g) in ethanol (15 ml)
Traction through Hyflon and the solvent is evaporated in vacuo. The residual oil is purified by ICH by elution with system A (39: 10: 1 - 32: 17: 1) and the title compound is obtained as a colorless liquid (0.99 g), those (System A 39: 10: 1), R Oh, 16. Intermediate 22 - 1- / 4-amino-3,5
The mixture is filtered for 5 hours and the mixture is filtered and evaporated in vacuo. The residual resin was purified by ICH by elution at a ratio of toluene to ethanol (9: 1) and the indicated compound was obtained as a yellow resin (0.45 g) of those (toluene: z-tanol 9: 1), Rf 0.45.
Intermediate 23 - 2- (2 - / (6-bromo-hexyl) oxy / ethyl / pyridine N-oxide.
mt-chloroperbenzoic acid (1.13 g) is added in one portion to a solution of 2- - // (6 bromhexyl) oxy / ethyl / pyridine (1.0 g) in dichloromethane (50 ml). The solution is stirred overnight at room temperature, it is quenched with 10% sodium sulfite solution (50 ml), the organic layer is washed with 8% -Hbw sodium bicarbonate solution. The organic layer is dehydrated.
(E) -Butendioate (salt) (2: 1) - T.Sh1. 103-108 e, benzoate (1: 1) are dyed and the indicated compound is obtained
in the form of a pale yellow oil (980 mg), t.p. 87-89 e, hydrobromide (1: 2) m. 67-72 f.
Example 2. 4-Amino-3,5-di-. - chlorine-C - /// 6- / 2- (2-pyridinyl) ethoxy- / hexyl / -amino / methyl / benzenemethanol. 4 4-Amnno-3,5-dizaor-o / (phenylmethyl) / 6- / 2- (2-pyridinyl) ethoxy / hexyl / amino / methyl / benzenemethanol (1.1 g) is subjected to hydrogenation over previously reduced. 10% hydroxy45
which is used without additional purification. A portion (100 mg) was purified by ICH using System A (80: 20: 1) as elute and a pale yellow oil (20 mg) was obtained according to those (System A 80: 20: 1) to give R 0.48 .
Intermediate 24 - 4-amino-3,5-dichlr-o /// 6- (2-pyridinyl) ethoxy / hexyl / amino / methyl / benzenemethanol-1-oxide (E) -butenedioate salt ( 4: 3).
A solution of intermediate 2 (0.74 g), 2- / (6-bromhexyl) oxy / -ethyl / pyridine-N-oxide (0.674 g) and DEA (346 mg) in DMF (15 ml) is heated at over 2 The solvent was removed under high vacuum, the residue was purified by ICH using System A (90: 10: 1) as eluant, and the free base of the title compound was obtained as a pale yellow oil (488 mg). A sample of this free base (388 mg) was dissolved in methanol (20 ml) and added to the mixture.
55
palladium-on-coal house (50% aqueous paste, 200 mg) in ethanol (10 ml) containing hydrochloric acid (conc. Hei) ethanol 1: 9 by volume, 4 ml). The catalyst was removed by filtration, the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (25 ml) and ethyl acetate (25 ml). The organic layer is washed with 8% sodium bicarbonate, water and oil, dehydrated, concentrated and an orange colored oil is obtained, which is purified using ICH, using system e. (95: 5: 1, 90: 10: 1) and get yellow
containing hydrochloric acid (2.7 mmol) is hydrogenated over 10% palladium on activated carbon (0.15 g), filtered and evaporated. The residue is partitioned between aqueous sodium bicarbonate (1 m, 30 ml) and ethyl acetate (150 ml), the dehydrated organic layer is evaporated and a brown gum is obtained, the emolu is purified by means of ICH using System A (93: 7: 1 - 85: 15: 1) as eluent to obtain the indicated compound as a white powder (0.32 g ), t. pl. 38-41 e.
Found,%: e 69.6; H 7.0; N 9.2.
e ,, nz ei.NjG
Calculated,%: e 60.0; H 7.1; N9.5.
(E) -Butendioate (salt) (2: 1) - T.Sh1. 103-108 e, benzoate (1: 1)
palladium-on-coal house (50% aqueous paste, 200 mg) in ethanol (10 ml) containing hydrochloric acid (conc. Hei) ethanol 1: 9 by volume, 4 ml). The catalyst was removed by filtration, the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (25 ml) and ethyl acetate (25 ml). The organic layer is washed with 8% sodium bicarbonate, water and oil, dehydrated, concentrated and an orange colored oil is obtained, which is purified using ICH, using system e. (95: 5: 1, 90: 10: 1) and get yellow
the oil that is triturated with a mixture of ether - hexane, as a result
1590042
Example 5. 4 Amino 3, chlor-h / (3 pyridinyl) propoxy
what is the indicated compound obtained in the form of a white solid (280 mg "- mp. 94-96 0.
Found,%: C 58.89; H 6.93 ;; N 9.55; C1 16.88.
Cj HzsGlzNjQ
Calculated,%:
C 39.16; H 6.86; H 9.86; C1 16.63,
Examples 3 and 4 are carried out by iJHMHo by hydrogenating the corresponding N- (phenylmethyl) compounds,
PRI mme R 3. 4 Amino-3, DI-f10r-h :( U {6- / 2- (6-methyl-2 Pyridinyl) 4toxy / -hexyl / amino / methyl / benzolme-, (E) -Butenedioate (salt) (I: 1). From, 5-dichlorophhHH 6- / 2- 4 (6-methyl-2-pyridinyl) ethoxy / hexyl (Fensch1methyl) amino / methyl / benzolnetan4a (1.66 g) After ICH, using C4 (92; 8; 1), a pale oil (0.9 g) is obtained. Dissolve the Total Oil (870 mg) and fumaric acid (126 mg) in methanol (10 ml) | sonocentrated and an oil is obtained, which is triturated several times with ether and this compound is obtained as a white solid (850 mg), 122-126fc.
Found,%: C 57.48; H 6.59; i 8.07; ei G4,18.
/ С ,, Н „С1, КЗО, / М, 0
6.67;
Calculated,%: C 57.83 H and 8.43; C1 14.23.
Example 4. 4-Amino-3, 5-di-Chloro-o - /// 6- / 3- (4-pyridinyl) pr opoxy / hexyl-amino / methyl / benzenemethanol (E) -butandioate (salt) (2: 1).
From 4-amino-3,5-dichloro-c - // (phenylmetsh1) / 6- / 3- (4-pyridinyl) -propoxy 7 hexyl / amino / methyl / benzenemethanol (690 mg). After concentrating the ethyl acetate extracts, a red oil (500 mg) is obtained. A solution of this oil and fumaric acid (70 mg) in methanol (5 ml) is evaporated and a yellow oil is obtained, which is triturated several times with ether and the title compound is obtained as a cream-colored solid (380 mg), t. square 112-.
Found,%: With 56.49; H 6.52; N 7.89. / CjjH3, Cl2N30j / j / C4H404.0. 6HjO.
Calculated,%: C 56.60; H 6.78; N 8.25.
five
Q 5
0
/ hexyl / -amino / methyl / benzenemethanol. E / - - butandioate (salt) (2: 1).
4-amino-3,5-dichloro-o / - / dphenylmethyl) / 6- (3- (3-pyridinylpropoxy / hexyl / amino-methyl / benzenemethanol (1.5 g) is subjected to hydrogenation over a previously reduced 10% - palladium on carbon (50% aqueous paste, 300 mg) in ethanol (20 ml) containing hydrochloric acid (conc. HCl / EtOH 1: 9 vol., 5 ml). The catalyst was removed by filtration and the solvent was evaporated. The remaining the oil is divided between 8% sodium bicarbonate (50 ml) and ethyl acetate (50 ml), the organic layer is washed with water and brine, dried, concentrated and an oil is obtained, which is purified by ICH, using system C (95: 5: 1, 90: 10: 1) as an eluent, a slightly colored oil (850 mg) is obtained. A solution of this oil in methanol (10 ml) is treated with a solution of fumaric acid (115 mg) in methanol ( 2 ml.) The solvent is evaporated, the residue is triturated with anhydrous ether and the title compound is obtained as a white powder (770 mg), TLC (A 80. 20:20), Rf 0.40.
Found,%: C 57.53; H 6.75; N 8.12; C1 13.90.
five
0
five
0
five
(WITH
U 2 2 3f
CljN30) 2.
6.67;
N
Calculated,%: C 57.83; H 8.43; C1 14.23.
Example 6. 4-Amino-3, 5-dichloro-o - /// 6- (3-hydroxy - 2-pyridinyl) butoxy / hexyl / amino / methyl / benzenemethanol.
4-Amino-3, 5-dichloro (/// 6- / 4- (3- -hydroxy-2-cyridinyl) -butoxy / hexyl / (phenylmethyl) amino / methyl / benzene-methanol (0.49 g) subjected to hydrogenation over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 100 mg) in ethanol (10 ml) containing hydrochloric acid (conc. .HCl / ethanol 1: 9 vol., 1, 6 ml.) The catalyst was removed by filtration through hiflon, the solvent was evaporated, the residue (oil) was separated by meliu with 8% sodium bicarbonate (15 ml) and ethyl acetate (15 ml). The organic layer was washed with 8% sodium bicarbonate (10 ml ), water (10 ml) and brine (10 mL), dried, and yielded a yellow .kontsentriruyut May
which was purified by ICH, using System C (95: 5: 1) as an eluent, yielding a light yellow oil, which was triturated with ether to obtain the title compound as a white solid (215 mg), t. square 95-96 C.
Found,%: C 58,32; H 7.38; N 8., 7; C1 15.21.
. S.zNzzzSH NzOz.
Calculated,%: C, 58.72; H 7.07; N 8.93; C1 15.07.
E / -Butandioate (salt) (2: 1) ,. tgsh | 97-99 with.
Example 7. 4-Amino-3,5-dichloro-g / - /// 6- / 2- (3-pyridinyl) ethoxy / hexyl / -amino / methyl / benzenemethanol / E / -bundioate (salt) ( 2: 1) 4-amino- -3,5-dichloro-o6- // (phenylmethyl) / 6- / 2 (3-pyridinyl) ethoxy / -hexyl / amino / methyl / benzenemethanol (2.98 g) subjected to hydrogenation over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 800 mg) in ethanol (30 ml) containing hydrochloric acid (conc. HC1 / ethanol 1: 9 vol., 10.5 ml) The catalyst was removed by filtration through hiflone, the solvent was then ground, the remaining oil was partitioned between 8% sodium bicarbonate (40 ml) and ethyl acetate (40 ml). The organic layer is washed with sodium bicarbonate (40 ml), water (40 ml) and brine (40 ml) and concentrated to give a brown oil, which is purified by means of ALC using system C (95: 5: 1) as eluent to obtain yellow oil (1.58 g). A solution of the oil (1.57 g) and fumaric acid (216 mg) in methanol (10 ml) is concentrated and an oil is obtained, which is triturated several times with ether and the title compound is obtained as a white solid (1.47 g g), so pl. 103-105 0.
Found,%: C 57.26; H 6.59; N 8.41; C1 14.29.
(C2, H ,, Cl2N302) 2 C4H40 ,.
Calculated,%: C 57.03; K 6.45; N 8.67; C1 14.64.
Example 8. 4-Amino-3,5-di-xjiop-c / - /// 6- / 2- (2-pyridinyl.) Ethoxy / hexyl / -amino / methyl / benzenemethanol, s, c-diphenylbenzene acetate ( 1: 1) (salt).
To a warm solution of the compound of example 2 (100 mg) in isopropanol (2 ml) is added a warm solution of o, e / diphenylbenzenesulfonic acid (67.6 mg) in
five
0
five
0
0
five
0
five
0
five
isopropanol (2 ml). The solution is allowed to cool with stirring for 1 hour, the resulting solid is filtered off, washed with isopropanol (1 ml), dried in vacuo at room temperature and the indicated compound is obtained (128 mg), mp. 125.5-126 ,.
Found,%: C 68.55; H 6.3; N 5.75.
C2, H, C1, NZO,
, fOj
Calculated,%: C 68.9; H 6.35; N 5.9.,
The following salts (Examples 9-18) were obtained by treating 4-amino-3,5-dichloro-of /// 6- / 2- (2-pyridinyl) ethoxy / hexyl / amino / -methyl / benzenemethanol ( free base) (compound of example 2) with the appropriate acid.
Example 9. Fumarate (2: 1).
Free base (100 mg) and fumaric acid (13.6 mg) give the indicated compound fumarate (56.2 mg), so pl. 116-116 ,.
NMR, / (daCO2): 1.25 (4H, m, 2CHj); 1.48 (4H, m, 2CHj); 2.65-2.9 (4H, m, 2CH2 11); 2.95 (2H, t. CH-pyr); 3.38 (2H, t. CHjO); 3.5-4.5 (bs, NH, OH, COjH); 3.71 (2H, t, OCHj,); 4.7 (1H, ds, CH); 5.48 (2H, s, III); 6.45 (1H, s, CH-fumarate); 7.2-7.33 (4H, 2CH ro-: matic., H-3 and H-5 pir.); 7.72 (1H, dt H-4 pir.); 8.5 (1H, d, H-6 pir.).
Example 10. Succinate (2: 1).
The free base (500 mg) and succinic acid (69.2 mg) give the indicated succinate (320 mg), mp. 100 - .
Found,%: C 56.5; H 6.7; N 8.45.
(C ,, H jCl -NjOj) - C4Hi04.
Calculated,%: C 56.9; H 6.65; N8.65;
Example 11. 4-Chlorobenzoate
(1: 1). .
Free base (500 mg) and 4-chlorobenzoic acid (183 mg) give fyKajgaHHBrii chlorobenzoate (300 mg), so pl. 85-86 S.
; Found,%: C 57.35; H 5.85; iN 7.0.
С „Н ,, С1, ЫЗО, C.HsClG ..
Calculated,%: C 57.7; H 5.9; N 7.2. Example 12. Benzoate (1: 1).
Free base (50 mg) and benzoic acid (14.3 mg) give the indicated benzoate (31 mg) as a white solid, so pl.
115-117 ° C.
Found,%: C 61.0; H 6.5; N 7, 45.
S. ,, HjgCljNjO ,,.
Calculated,%: C, 61.3; H 6, 45; N 7.65.
Example 13 Benzenesulfonate (1: 1).
The free base (50 mg) and benzenesulfonic acid (19 mg) give the indicated benzenesulfonate as a yellowish-brown substance (20 mg), mp. 110-110,
NMR, G (DMSO): 1.25 (4H, and, 2CH2); 1.4-1.7 (4H, m, 2CE) i 2.8-3., 2 (4H, m, YUN;); 2.95 (2H, t,.); 3.38 (ZN, m, OH); 3.72 (2H, t, OSY); 4.78 (1H, br. CH); 5 „59 (2H, s, NH); 6.13 (1H, br., H); 7.2-7, 4 (7H, m, 2CH aromatic. H-3 and H-5 peer., H-3, H-4, H-5 benzenesulfone g); 7, 6-7.65 (2H, m, H-1 and H-6 benzenesulfonate); 7.72 (1H, dt, 4-H, pyr.); 8.3-8.7 (IH, br. SOgH); 8.5 (1H, d, H-6 pir.). Example 14. Sulfate (3: 3).
The free base (200 mg) and sulfuric acid (93.8 mg, 98 wt.%) Give the indicated sulfate (0.2 g), t „sh1. 55-65 ° C (amorphous).
Found,%: C 44.15; H 5.9; N6.95
(- (HjSO).
Calculated,%: C 44.0; H 5 „6; N 7.3.
Example 15. 1 Hydroxy-2-naphthoate (1: 1).
Free base (500 mg) and 1-, -hydroxy-2-naphthoic acid (220 mg; give the specified hydroxinaftoate (700 mg) as a light brown solid, mp 41-43 ° C (atmospheric).
Found,%: C 62.3; H 6.1 ;; N 6., 5.
C. C „H“ Oz.
Calculated,%: C 62.55; H 6.05; N 6.85.
Example 16. 4-Methylbenzenesulfonate (1: 1).
Free base (50 mg) and p-toluenesulfonic acid (22 mg) give the indicated 4-methylbenzenesulfone in a cream-colored solid (60 mg), mp. 128-GZO ° C.
NMR (D (DMSO): 1.25 (4H, m, 2CH2); 1.4-1.7 (4H, m, 2CH2) 5 2.31 (ZN, s, CHj); 2.8 3.15 (4H, m, 2CHj); 2.95 (2H, t, CHj pir); 3.38 (3N, m, CH ,, 0, OH); 3.71 (2H, t. OCHj); 4, .73 (wd d); 5.59 (2H, s, NHj); 6.12 (1H, shir NH); 7.13 (2H, d, H-3 and H-5 ozene
sulfonate); 7.2-7.35 (4H, mzh, 2CH aromatic. H-3 and H-5 feast); 7.5 (2H, d, H-2 and H-6 benzenesulfonate); 7.72 (1H, dt, H-4 pir); 8.2-8.7 (1H, br., ZOZN); 8.5 (1H, d, H-6 pir).
Example 17. sz-Phenylbenzene-acetate (1: 1).
The free base of 50 mg and o (-phenylbenzeneacetic acid (25 mg) gives the title of α-phenylbenzene acetate as a cream-colored solid (46 mg), mp 105-107 0.
NMR, cH (DMSO): 1.24 (4H, m, 2CH ,,); B45 (4H, m, 2CH,); 2.6; 2.9 (4H, m. 2CH2); 2.95 (2H, t, CH pir); 3.37. (2H, t. CHO); 3.71 (2H, t, OCH); 4.67 (1H, dd, CH); 4.9 (1H, s, CH phenylbenzene acetate); 5.45 (2H, s, III); 7.15-7.4 (14H, m, 2CH aromatic. H-3, H-5 pir, UN phenyl benzene acetate); 7.7 (1H, dt, H-4 pir); 8.49 (1H, d, H-6 pir).
Example 18. Adipat (2: 1).
Free base (100 ml) and adipic acid 17.1 mg give the indicated compound adipate (54 mg), so pl. 94-96 C.
0
five
0
Found,%: C 57.25; H 7.05; N 8.35.
(C.H.jCl.,),, /) ,.
Calculated,%: C 57.7; H 6.8; N 8.4.
Example 19. 4-Amino-3,5-dichloro-c / - // 6- / 2- (2-pyridinyl) ethoxy / hexyl / amino / methyl / benzenemethanol.
A solution of N- / 2- (4-amino-3,5-dichloro-fensh1) -2-hydroxyethyl / -6- / 2- (2-pyridinyl) ethoxy / hexamide (0.166 g) in benzene (5 ml) Add dropwise to a stirred suspension of lithium aluminum hydride (0.065 g) in diethyl ether (5 ml) at room temperature 5 under an atmosphere of nitrogen. The mixture was stirred at room temperature under nitrogen for 3 days. and then carefully quenched in succession with water (Q, 5 ml), 2N sodium hydroxide solution (0.5 ml) and water (2 ml). The mixture was diluted with simple diethyl ether (50 ml), filtered through a hiflon (ppm with the addition of dit ... chloromethane), evaporated in vacuo and an oil was obtained. After purification with the help of ICH, using the system C (95: 5: 1 - 90: 10: 1) as eluent, a colorless oil is obtained, from which when rubbed with a mixture of simple
0
five
17
diethyl ether with hexane, a white solid is obtained (67 mg). Then, two additional columns were re-cleaned on silica (Merck 9385) and silica deactivated with triethylamine (Merck 9385, 10 ml) using system C (98: 2: 1 - 95: 5: 1) and a mixture of toluene and ethanol (98: 2), respectively, and get a colorless oil, which I identify those (system A 39: 10: 1), R 0,44, as the title compound.
Example 20. 4-Amino-3,5-dichloro-c - / 7 / 6- / 2- (2-pyridinyl) ethoxy (hexyl) amino / methyl / benzenemethanol.
4-amino-3,5-dichloro-0-oxobenzene thaldehyde (0.56 g) and 6- (2- (2-pyridinyl) ethoxy / hexamine (0.40 g) are dissolved in benzene (10 ml) and heated at reflux for 1 hour using a Dean-Stark water separator.
The solution is cooled, evaporated in vacuo and the residue is dissolved in methanol (10 ml). Sodium borohydride (0.38 g) is added to the mixture in portions within 0.5 hours while being transferred at 0-5 ° C. The solution is left overnight.
one
and then evaporated in vacuo. The residue was partitioned between water (50 ml) containing 2N sodium carbonate solution (4 ml) and ethyl acetate (60 ml). The organic phase is dehydrated, evaporated in vacuo, the residue is purified by SCI, using System C (90: 10: 1) as eluent, and a gum is obtained. After trituration with hexane, the title compound (85 mg) is obtained as a colorless powder, mp. 93-96 0 of those (system A 39: 10: l) R 0.44.
Example 21. 4-Amino-3, 5-di-xnop-of- /// (2-pyridinyl) ethoxy / hexyl / amino / methyl / benzenemethanol-1-oxide (100 mg) in methanol (10 ml) is subjected hydrogenation on the catalyst Rene (cat. 100 mg) and the reaction is stopped after 1 mol of hydrogen was adsorbed (5 ml). The catalyst was removed by filtration through a hiflon, the filtrate was evaporated and a pink tinge resin was obtained. After purification using ICH, using System A (80: 20: 1) as eluent, the title compound is obtained as a white crystalline solid (20 mg), mp. 94
ten
i
- 25 15
20
35
40
590042 18
95 e ,. those (system A 39: 10: 1), R |, 0.44.
Example 22. 4-Amino-3, 5-dichloro-of-, /// 6- / 2- (2-pyridinyl) ethoxyhexyl / -amino / methyl / benzenemethanol.
Sodium borohydride (0.16 g) is added in portions over 5 minutes in a solution of 1 (4-amino-3,5-dichlorophenyl) -. -2 - // 6-2- (2-pyridinyl ethoxy (hexyl) / amino / ethanone (0.44 g) in methanol (7 ml) with stirring. After 1.5 hours, the solution is evaporated in a vacuum and the residue is divided between water (60 ml) and ethyl acetate (100 ml). The organic phase is dewatered, embedded in a vacuum, a gum is obtained, which is purified by ICH, using system e (90: 10: 1) as eluent and the product is triturated with hexane (2 ml) and the indicated compound was obtained in the form of a colorless powder (47 mg), mp 94.5-96, those (system A 39: 10: 1), Rf 0.44.
Biological test results
The stimulating effect of new dichloroaniline derivatives on e. adrenoceptors was determined on the basis of their ability to cause a decrease in contractions due to electrical stimulation of the prepared guinea pig tracheal strip. Test compounds were compared with isoprenaline, the concentration of which, causing this effect (weakening of contractions), was taken as a unit of activity. The activities of the tested compounds are expressed in equipotential concentrations, i.e. as the ratio of the concentration of the test substance causing this effect to the concentration of isoprenaline causing the same effect (and taken as a unit).
The results are given in the table.
thirty
45
joining by example
Equipotential concentration
As follows from the table, the compounds of the invention cause stimulation.
HE
1 "H2-O - W-CH2HNY2 (CH2) 4CH20CH2-T-P,
P.J
YCHj-, - (2) 2- or (CH2) is well-substituted and 1 and substituted by hydroxyl or methyl pyridyl, attached to the rest of the molecule in 2-, 3-, or 4-position,
NH
X2-Xs-CH20CH2T-R
de x x
R. SNSON) or, the group CHjNH-, or -CHjNR, where a group is converted into hydrogen, such as fensch :: methyl, by catalytic reduction; 35 group -H2 (2) 4 or -COCCHj) -;
has the indicated values or C3-alkenylene;
or their physiologically acceptable salts or solvates, characterized in that the compound of the formula
P has the indicated values or pyridyl-L-oxide, provided that at least one of X ,, Xj, Xj, Y and / or P y is a reducible group,
subjected to reduction and the desired product is isolated in free form or in the form of a physiologically acceptable salt or solvate.

权利要求:
Claims (1)
[1]
The claims The method of obtaining derivatives of dichloroaniline of the formula
-CH ₂ ~, - (CH ₂ ) ₂ - or - (CH ₂ ) ₃ unsubstituted, go substituted with hydroxyl or methyl pyridyl, attached to the remainder of the molecule at the 2-, 3-, or 4-position, or lei and their physiologically acceptable co or solvates, characterized in that the compound is form-
C1 x ₂ -x ₃ -sn ₂ main ₂ tRu where x _g is CH (OH) or) C = 0,
X ₂ is a group —CH ₂ NH ~, or —CH = N — 30 or —CH ₂ NRj, where
R, is a hydrogen convertible group, such as phenylmethyl, by catalytic reduction; 35
X ₃ is a —CH ₂ (CH ₂ ) ₄ - or —CO (CH ₂ ) ₄ - group;
Y has the indicated meanings or C ₂ -alkenylene;
has the indicated meanings or pyridyl — N-oxide, provided that at least one of X ,, X ₂ , X ₃ , Y and / or P _y is a reducible group, is reduced and the target product is isolated in free form or in as a physiologically acceptable salt or solvate.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB868603475A|GB8603475D0|1986-02-12|1986-02-12|Chemical compounds|

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