• 专利附录
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    • 专利摘要:
    The invention relates to heterocyclic compounds, in particular, to the preparation of pyrrolo-benzimidazoles of the formula @ where R 1 is H, a lower alkyl group, a lower cycloalkyl R 2 is hydrogen, a lower alkyl group or a carboxyl group substituted by a lower alkoxy or hydrazino group, or together with R 1 a lower cycloalkylene group or a lower alkylidene group X is a valence bond, a lower C 1 - C 4 is an alkylene group and a vanilla group. T is oxygen or sulfur and Py is 2,3 = or 4 is a pyridyl residue which, if necessary, carries an oxygen atom on the ring hetero atom and / or may be replaced by one or more lower alkyl, lower alkoxy or hydroxyl group or halogen atom, or their physiologically compatible salts with inorganic acids that exhibit pharmacological properties. The goal is to create new compounds of the indicated class with biological activity that are not typical for this series. Obtaining the target compounds is carried out by the interaction of 5,6-diaminoindolin-2-one (at T is oxygen) with a compound of the formula Py-X-Co-Y, where Py and X have the indicated value, Y is a hydrogen atom, a halogen atom, an ester group or anhydride. The resulting compound is cyclized in an acidic medium and the target product is isolated in free form or reacted with an inorganic acid and the target product is isolated as a physiologically compatible salt. 5 tab.
    公开号:SU1480770A3
    申请号:SU853894709
    申请日:1985-05-10
    公开日:1989-05-15
    发明作者:Хельк Йенс-Петер；Мертенс Альфред；Кампе Вольфганг；Мюллер-Бекманн Бернд；Шпонер Гисберт；Штрайн Клаус
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to a method for the preparation of pyrrolobenzimidazoles exhibiting pharmacological properties, in particular, increases cardiac activity and / or decreases blood pressure, and / or is affected
    platelet accumulation and improve microcirculation.
    The purpose of the invention is to obtain new compounds in the range of pyrrolo-benz-imidazoles with biological activity, which is not characteristic of this series of compounds.
    Example 1. 7,7-Dimethyl-2- (A-pyridyl) -6, 7-dihydro-3H, 511-pyro-, 3-g-benzimidazol-6-one x A.
    To a solution of 5,6 diamino-3,3-dimethylindolin-2-oia (2.9 g, 0.015 mol) in methylene chloride (30 ml) with triethylamine (4.4 ml, 0.032 mol) is added gat portions of isonocotene acid chloride-hydrochloride (3 g, 0, mol) and leave overnight with further stirring. Concentrate in vacuum to dryness, stir the residue several times with water, suck off, prepared in a solution of ethanol (IOO ml) with concentrated IIC1 (10 ml) is heated for about 12 hours to reflux. The resulting mixture was concentrated in vacuo to dryness, stirred with water (20 ml) and brought to neutral with an aqueous solution of NH $. Then suction is performed, washed with additional water, dried and recrystallized from water with 30% ethanol.
    Output 1.9 g (36% of theory), t.plav. 215 ° C.
    Analogously to Example 1, compounds are obtained, the characteristics of which are listed in Table. one.
    The starting materials for the compounds described in Example 1 can be prepared as follows.
    4,4-Dnometl 2H, 4P-isoquinoln--1,3-dione.
    but. To a solution of cyan-o-tolunitrile (142 g, 1 mol) together with benzltributylammonium bromide (10.8 g, 0.03 mol) in a concentrated solution of NaOH (700 ml) are added dropwise with ice cooling with methyl iodide (185 ml, 2 mol). Stir for 2 hours, suck off crystallized water, wash with water and dry. Obtain 170 g (100% of theory) of the nitrile o-cyano-cr,: dimethylpheno-mm-acetic acid. , SABS C. The resulting product is introduced into 90% IIZS04 (1500 ml), stirred for 3 hours, poured onto ice, washed with crystallized water and dried. 167 g (88% of theory) of the main point are obtained. T. melt. 119-120 ° C.
    b.COP (17.73 g, 0.32 mol) was dissolved in 26.5 ml of water and. 106 ml of ethanol. 1.3- (2H, 4H) -isoquinolin-dione (25.55 g, 0.16 mol) is dissolved in this solution by heating. R cooled to room temperature rast thief instilled with methyl iodide
    (45, AA g, 0.32 mol).
    After 1 h at room temperature, the mixture is stirred for 1 h at 80 ° C. The largest part of the ethanol is distilled off, the residue is mixed with 300 ml of hot water, cooled and the crystals are sucked off. The latter are dissolved in a small amount of 2N. NaOH, precipitated with a saturated solution of NH4C1 and sucked off. By treatment with activated carbon and recrystallization from ethanol, 17 g of pure product (57%) are obtained.
    Similarly, according to method a or b, you can get the connection:
    Spiro cyclopentane-1,4 -2 n, A II- -isoquinolyG -, 3 -dione from cyan-o-tolunitrile and 1,4-dibromobutane (yield 90%, mp. 136-138 ° C).
    c.A, A-Dimethyl-7-nitro-2H, AP-isoquinoline-1,3-dione.
    In solution A, A-dimethyl-2H, AN-Isoquinoline-1,3-dione (195 g, 1 mol) in concentrated H2SO4 (1000 ml), a solution of fuming nitric acid 11NO (A6.2 ml, 1, 1 mol) in concentrated H2SO4 at 20 ° C. Stir for 1 hour at room temperature, pour on ice, suction off the crystals., Wash well with water and dry. Recrystallized from ethanol. Output 206 g (85% of theory), t. Melt. 211-21 ° C.
    Similarly, in the method with you can get the connection;
    7-Litro-spiro cyclopentan-1,4 - -2 II, A 1 -isoquinoline -1 3-dione from spiro (cyclopeitan-1, A -2 P-isoquinoline) -1 -1 pion (yield 90% , t.p. 225-227 ° C, the solvent is ethanol).
    d.3, 3-Dimethyl-6-nitroindolin--2-one.
    In a solution of NaOH (210 g, 5.25 mol) in water (1700 ml), bromine (54 ml, 1.05 mol) is instilled at O and then A, 4-dimethyl-7-nitro-2H, AN- isoquinolin-1,3-dione (81.7 g, 0.35 mol). After 1 hour of stirring at room temperature, about 1 hour is heated to 80 ° C and, after cooling with acetic acid, the acid is set
    51
    Wednesday Suction is performed, washed well with water and dried.
    Output 49 g (68% of theory), so pl. 241-242 ° C.
    By analogy with d, you can synthesize the compound
    6 -Nitro-spiro-cyclopentane-1,3-indoline -2 —one from 7 -nitro-spiro-diclopenentane-1,4 -2H, 4II1-isoquinoline - -1, 3 -dione (yield 82%, melting point 226-228 C, the solvent is ethanol).
    e.6-Amino-3, 3-dimethylindolin-2-one.
    A suspension of 6-nitro-3, 3-dimethylindol-2-one (146 g, 0.71 mol) in methanol (3.5 l) with glacial acetic acid (300 ml) is hydrogenated with 10% Pd / C at 40 ° C with good mixing. The resulting clear solution is sucked off from the catalyst and dried. Yield 125 g (100% of theory), t. Melt. 185-190 ° C.
    By analogy with e, you can get a connection.
    b -Amino-spiro-cyclopentane-1,3-indoline | -2 -one from 6 -nitro-spiro-cyclopentan-1,3-indolshG-2 -one (yield 98%, melt 165 165 ° C, plant viortel - vinegar ether).
    f.6-Acetamido-3, 3-dimethylindol-2-one.
    In a suspension of 6-amino-3,3-dimethyl-indolin-2-one (32 g, 0.18 mol) in acetic ester (500 ml), acetic anhydride (20.4 g, 0.2 mol ) and additionally stirred for about 1 h at room temperature. The formed product is sucked off, washed well with ethyl acetate and dried. The output of 37.8 g (96% of theory), t. Melt. 275-277 ° C.
    According to f, a compound is obtained in a similar manner.
    6 -Acetamido-spiro cyclopentan-1, 3 -indolshG -2 -one from 6-amino-spiro- Ј cyclope ntan-1,3 (-indoline -2 -one (75% yield, t.p. mel. 263-265 С solvent - ethanol).
    g.6-Acetamido-3,3-dimethyl-5-nitroindolin-2-one.
    To a solution of 6-acetamido-3,3-dimethyl-indolin-2-one (35 g, 0.16 mol) in concentrated H.SO4 (200 ml) drop a cooling solution of HN03 (7.6 ml, 0.18 mol) in concentrated (7.6 mol). Stir for 1 h, poured onto ice,
    706
    the crystals are sucked off, washed well with water and dried.
    Yield 39 g (92% of theory), t. Pl. 2 / 6-280 ° C.
    Similarly, g can be obtained compound
    b -Acetamido-5 -nitro-spiro-cyclopentan-1, 3 -indolin-2 -one from b-acetamido-5 -nitro-spiro-cyclopentane-1,3-indoleshG--one (yield 83%, t Melting point: 290-292 ° С, solvent - ethanol).
    h, 6-Amino-3, 3-dimethyl-5-nitroin-dol-2-one.
    A solution of 6-acetamido-3, 3-dimethyl-5-nitroindolin-2-one (36.2 g, 0.14 mol) in ethanol (180 ml) with concentrated NaOH (18 ml) is heated for about 2 hours under reflux, then concentrated in vacuo, set to pi b and cooled in an ice bath. The resulting crystals are sucked off, washed with water and dried. Yield 29.5 g (97% of theory), t. Melt. 247-248 ° C.
    By analogy with h, you can get a connectioni
    6 -amnno-5 -nitro-spiro-cyclopentane-1,3-indindin-2 -one of b-acetamido-5-nitro-spiro Zdloplo-1-1,3-α-richolsG-2 (yield 87% , melting point 300-303 ° С, solvent - ethanol).
    i. 5, 6-Diamino-3,3-dimeshshndolin--2-one.
    A solution of 6-amino-3, 3-dnmethyl-5- -nitroindolin-2-one (18.7 g, 0.085 mol) in methanol (200 ml) is hydrogenated with 10% Pd (C) 1.9 g at 40 ° s Sucked off from the catalyst, concentrated and crystallized from ethanol.
    Yield 15.6 g (96% of theory), t. Melt. 245-247 ° C. By n.i, a connection can be similarly obtained;
    5, 6-iHaMHrio-cnHpo-jitHKnoneHTaH- -1,3 -indolin-2 -one from b -amino-5 - -nitro-spiro-cyclopentane-1,3-indo--one (yield 100%, t. melt 255-256 ° C).
    Example 2. 7,7-Dimethyl-2-- (4 pyridylmethyl) -6,7-dihydro-3H, 5H-pyrrolo 2,3-f-benzimidazol-6-one x 1 NgO.
    Suspension 5,6-flnaMiiHo-3,3-AHMeTHn-nndolin-2-one (7.3 g, 0.038 mol) in methyl 4-pyridylacetic acid ester (11, 6 g, 0.077 mol)
    heated under N atmosphere for about 16 hours to 180 ° C with stirring,
    the excess ester is distilled off in vacuo, the resulting residue is separated on silica gel (solvent: D3 dichlorometap and saturated methanol 20: 1). Output 1.8 g (16% of theory) t. Melt. 333-337 C (water and methanol 10: 1).
    .II p and m 3. 3. 7.7-2- (3-Methox-6-metshirishO-6, 7-digdro-3N, 5I- -mippoJio {J2,3-f1 bepzimidazole 6-one.
    A solution of 5, 6-diammy-3,3-dimetll-ppdolin-2-oiia (3.8 g, 0.02 mol) with 2-methoxy-6 methylpnridine - 3-aldehyde (3 g, 0.02 mol ) and toluenesulfonic acid (O, A g, 0.002 mol) in ethanol (50 ml) are heated for about 1 hour to reflux, and after 30 minutes, air is passed through the flow tube through the reaction mixture, after cooling it is sucked off from the precipitated substance and concentrated the filtrate in vacuo, stirred with water and extracted with dichloromethane. The organic phase is concentrated and the residue is crystallized from ether. The combined crude products are recrystallized once more from ethyl acetate. Output 1.2 g (19% of theory), t. Melt. 296-298 ° C.
    Analogously to Example 3, compounds are obtained, the characteristics of which are given in Table. 2
     Example 4. 7.7 Dimethyl-2-- (4-H-hydroxy-pyridyl-6,7-dihydro-3H, 5H-pyrrolo 2,3-fJ-benzimidaeol-6-one x 3 NgO.
    A solution of 7,7-dimethyl-2- (4-pyridinn) - -6,7-dihydro-3H, 5H-pnrrolo 2,3-ЈJ-benzimidaeol-6 it (3.9 g, 0.014 mol) in icy acetic acid (50 ml) with 30% IIjO (20 ml) was stirred for 2 days at 50 ° C, and then the leaves were diluted. The precipitated substance is sucked off and non-recrystallized from dioxane and water 1: 1. Output 1.40g (34% of theory), t. Melt. 260-262 C.
    Analogously to Example 4, compounds are obtained whose characteristics are shown in Table 3.
    14807708
    ethylamine (8.4 ml) is added frequently — With an isonicotinic acid chloride-hydrochloride chloride (5.4 g, 0.03 mol), glacial acetic acid is added after approximately 2 hours and the resulting crystals are sucked off, washed and dried, then heated in a mixture of ethanol (100 ml) and concentrated JQ HCl (20 ml) for approximately 20 hours to reflux, evaporated in vacuo, the residue is drawn with NH 3 solution, sucked off and dried. It is then purified on snigel (solvent: chloride
    15
    20
    25
    thirty
    35
    40
    45
    50
    methylene (NI-C and saturated methanol 15: 1) and crystallized from methanol.
    Output 2.4 g (35% of theory), t. Melt. 216-219 ° C.
    Analogously to example 5 receive the connection:
    7,7-Dimethyl-2- (4-pyridyl) -6,7- -dihydro-3N, 5H-pyrrolo 2,3-G-benzp-midazol-6-one x 4 out of 5,6-dipromol-3, 3-dimethylindolin-2-one and isonicotinic acid chloride - hydrochloride (yield 41%, melting point 215 ° C, solvent - ethanol and water).
    The starting materials for the compounds described in example 5 can be obtained as follows.
    a.5,6-Diamino-3,3-diethylenindin-2-one.
    A solution of 5-amino-3, 3-diztil-6-nitroindolin-2-one (10 g, 0.041 mol) in ethanol (150 ml) is hydrogenated with 10% - nom Pd / C (0.6 g) at room temperature. temperature The catalyst is sucked off, concentrated and recrystallized from ethanol.
    Output 8.5 g (97% of theory), t. Melt. 167-173 ° C.
    In a similar way (according to claim. A) you can get the connection
    5, 6-Diamino-3,3-dimeshshndolin--2-one from 5-amino-3, 3-dimethyl-6-nitro-indolin-2-one (yield 98%, mp. 255-256 ° C, the solvent is ethanol).
    b.5-Amino-3,3-diethyl-6-nitroindolin-2-one.
    A solution of 5-acetamido-3,3-diethyl-6-nitroindolin-2-one (72 g, 0.25 mol) in ethanol (500 ml) with concentrated HCl (100 ml) is heated for about 3 hours under reflux, diluted water (1000 ml), sucked off and the crystals obtained are washed with an aqueous solution of ethanol and dried.
    Example 5. 7,7-Diethyl 2 (4- -pridyl) -6,7-dipshro-3N, 511-pyrrolo JJ2.3-1G-benzyl1azhazol-6-one x CH3OH.
    To a solution of 5,6-dmino-3, 3-diethyl-indolin-2-one (4.4 g, 0.02 mol) in methylene chloride (100 ml) with three
    0
    five
    0
    five
    0
    five
    0
    five
    methylene (NI-C and saturated methanol 15: 1) and crystallized from methanol.
    Output 2.4 g (35% of theory), t. Melt. 216-219 ° C.
    Analogously to example 5 receive the connection:
    7,7-Dimethyl-2- (4-pyridyl) -6,7- -dihydro-3N, 5H-pyrrolo 2,3-G-benzp-midazol-6-one x 4 out of 5,6-dipromol-3, 3-dimethylindolin-2-one and isonicotinic acid chloride - hydrochloride (yield 41%, melting point 215 ° C, solvent - ethanol and water).
    The starting materials for the compounds described in example 5 can be obtained as follows.
    a.5,6-Diamino-3,3-diethylenindin-2-one.
    A solution of 5-amino-3, 3-diztil-6-nitroindolin-2-one (10 g, 0.041 mol) in ethanol (150 ml) is hydrogenated with 10% - nom Pd / C (0.6 g) at room temperature. temperature The catalyst is sucked off, concentrated and recrystallized from ethanol.
    Output 8.5 g (97% of theory), t. Melt. 167-173 ° C.
    In a similar way (according to claim. A) you can get the connection
    5, 6-Diamino-3,3-dimeshshndolin--2-one from 5-amino-3, 3-dimethyl-6-nitro-indolin-2-one (yield 98%, mp. 255-256 ° C, the solvent is ethanol).
    b.5-Amino-3,3-diethyl-6-nitroindolin-2-one.
    A solution of 5-acetamido-3,3-diethyl-6-nitroindolin-2-one (72 g, 0.25 mol) in ethanol (500 ml) with concentrated HCl (100 ml) is heated for about 3 hours under reflux, diluted water (1000 ml), sucked off and the crystals obtained are washed with an aqueous solution of ethanol and dried.
    Output 54.7 g (89% of theory), t.plav. 267-272 ° C.
    Similarly to p. B, a compound can be obtained;
    5-amino-3,3-dimethyl-6-nitroindolin-2-one from 5-acetamido-3,3-dimethyl-6-nitroindolin-2-one (yield 82%, mp. 247- 250 С, solvent - ethanol and water).
    c.5-Acetamido-3,3-diethyl-6-β-nitroindolin-2-one.
    To a solution of 5-a-cetamido-3,3-diethyl-indolin-2-one (84 g, 0.34 mol) in acetic anhydride (800 ml) is instilled with cooling fusing HNO (24 ml) and stirred for about 2 hours at room temperature. Carefully introduced into ice water, the resulting crystals are sucked off, washed with water and dried. Yield 72 g (72% of theory), t. Melt. 182-184 ° C.
    Similarly, according to the instructions in p.
    5. Acetamido-3,3-dimethyl-6-nitro indolin-2-one from 5-acetamido-3,3-dimethylindolin-2-one (yield 73%, mp 225-228 C, solvent - dichloro - methane).
    d.5-Acetamido 3,3-diethylindolin-2-one.
    A suspension of 3,3-dimethyl-5 - nitro indolin-2-one (86 g, 0.372 mol) in ethanol (700 ml) is hydrogenated with 10% Pd / C (4 g) with good stirring. Then a clear solution is sucked off and the sample is crystallized from ethanol (t.p. 188-190 C), the main amount of the solution is carefully mixed with acetic anhydride (50 ml) and evaporated in vacuo. The residue is drawn with ethyl acetate, sucked off, washed and dried. Crystallization from ethyl acetate.
    Output 85 g (94% of theory), t. Melt. 196-197 ° C.
    By d), the compound is prepared in a similar way;
    5-Acetamido-3, 3-dimethylindolin-2-one from 5-nitro-3,3-dimethylindolin--2-one (yield 92%, melting point. 265-266 ° C, solvent - ethyl acetate)
    e. 3,3-Diet tyl-5-nitroindolin-2- -one.
    To a solution of 3, 3-diethylindolin-2- -one (86 g, 0.462 mol) in 80% 11.50 (500 ml), the HM05 smoke solution (17 ml) in 80% H2SO4 (200 ml), stirred for about 30 minutes, poured onto ice, sucked off, washed with water and dried.
    8077010
    Output 86 g (79% of theory), so melt. 174-17b S.
    Similarly, according to claim f, it is possible to obtain 5
    3,3-Dnmethyl-5-yitroindolin-2-one of 3, 3-dimethylindolin-2-one (yield 78%, the solvent is ethanol).
    Example 6. 7-Isopropylidene-10 -2- (4-pyridyl) -6,7-dihydro-3N, 5H-β-nrrolo 2, 3-fJ-benzimidazol-6-one.
    In suspension 2- (4-nricyl) -6,7- -dihydro-3N, 5H-pyrrolo 2, 3-fJ -benzimidaeol-6-one (0.4 g, 1.6 mmol) in 15 ethanol ( 20 ml) with acetone (10 ml) are added to saturation with ammonia and stirred for 2 hours at 60 ° C, then acetone (10 ml) is added one more time and stirred for 4 hours at 60 ° C, then 20 are concentrated and injected into ethanol , acidify and suck off the precipitate. The resulting residue is dissolved in water, brought to neutral, sucked off from the crystals and recrystallized from an isopropanol / ethyl acetate.
    Yield 40 mg (9% of theory), so melt. 300 C.
    Example 7. 7-Hydrazinocarbonyl-7-methyl-2- (4-pyridyl) -6,7-dihyd-30 ro-ZN, 5H-pyrrolo 2,3-Ј benzimidazol-6-one
    A solution of 7-ethoxycarbonyl-7-methyl--2- (4-pyridyl) -6,7-dphydro-3N, 5H-pyrrolo 2,3-fJ-benzimidazol-6-one-5-hydrochloride (1 g, 2 , 7 mmol) in ethanol (30 ml) is stirred with hydrazine hydrate (6 ml) for about 8 hours at 80 ° C, then sucked off, boiled with methanol solution (1000 ml) with methylene chloride (500 ml), slightly thickened and the crystals are sucked off. washed with methanol and dried.
    Yield 0.6 g (70% of theory), T. melt. 300 ° C.
    I
    45Exampler. 7- (2-Methylpropyl) -2- (4-pyridyl) -6,7-dngydro-3N, 5H- -pyrrolo 2,3-1G-benzimyAazol-6 -on x x 1.5 H20.
    To a solution of 5,6-diamino-3- (2-Me2Q tylpropyl) -indolin-2-one (1.3 g, 0.006 mol) in methylene chloride (40 ml) with trnetilamine (3 ml) is added with parts of isococti chloride - new acid - hydrochloride (1.6 g
    0.009 mol), extracted after approximately 2 hours with water and the organic phase is concentrated. The solid residue is heated in ethanol (70 ml) with concentrated HCl (10 ml) overnight under reflux, concentrated and stirred with aqueous ammonia solution and extracted with methylene chloride / methanol. The organic phase is concentrated and purified on silica gel (solvent: methylene chloride and saturated NHj methanol 9: 1).
    The output of 0.65 g (35% of theory), so melt. 200-202 ° C.
    The starting materials for Example 8 were prepared as follows.
    a.5,6-Diamio 3- (2 methylpropyl) -inind-2-one.
    A solution of b-ammonium-3- (2-methyl derivative) 5-nitroindolin-2-one (1.5 g, 0.006 mol) in methanol (50 ml) is hydrogenated with 10% Pd / C (0.3 g ). The catalyst is sucked off, concentrated and perekrystallny from ethanol.
    The output of 1.3 g (99% of theory).
    b.6-Amshu-3- (2-methyl1 ro1 1sh) -5- -nitroindolin-2-one.
     A solution of 6-acetamido-3 (2-metsh1-propyl) -5-nitroivdolin-2-one (2.9 g, 0.01 mol) in ethanol (50 ml) with concentrated IS1 (3 ml) is heated for approximately 30 minutes at phlegm, concentrated and purified on silica gel (solvent: methylene chloride and saturated N11 e methanol 20: 1). Yield 1.5 g (60% of theory).
    c.6-Acetamido-3- (2-methylpropyl) -5-nitroindolin-2-one.
    A solution of 6-acetamido-3- (2-metnl-propnl) -indolin-2-one (4.2 g, 0.017 mol) in acetic anhydride (50 ml) is mixed while cooling with a flue gas reflux gas} (0.8 ml, 0.019 mol) and additionally stirred for about 30 minutes. Then carefully drink on ice and suck off the crystals, washed with water and dried. Yield 3.2 g (66% of theory), t. Melt. 192-197 ° C.
    d.6-Lcetamido-3- (2-methylpropyl) - -Sh1DOLIN-2-OH.
    A solution of 6-acetamido-3-Ioyl-iphenidenidolin-2-one (6.4 g, 0.026 mol in methanol (100 ml) is hydrogenated with 10% Pd / C (0.6 g). Then sucked off from the catalyst and concentrated the solution is dry.
    Output 5.5 g (84% of theory), t. Melt. 214-216 ° C.
    e.b-Acetachscho-3-isopropyl- - -Sh1DOLSH1-2-OH.
    To a suspension of 6-acetamidoindoline - -2-opa (9 g, 0.047 mol) in ethanol (50 ml) with isobutyraldehyde
    (3.4 g, 0.047 mol) drop a solution of NaOH (1.9 g) in water (2 ml). After about 5 hours, it is concentrated in vacuo to dryness and purified on silica gel (solvent: methylene chloride and saturated метан methanol). - Yield 7.6 g (65% of theory), foam, t. Melt. 93 C.
    Example 9. 7,7-Dimethyl-2- (4-pyridyl) -6,7-dihydro-3H, 5H-pyrrolo-2,3- / -benzimidazole-6-thione x x 2 HZ0.
    The solution of 7,7-dimethyl-2- (4-pyridyl)
    5 -6, 7-dihydro-3N, 5H-pyrrolo 2, -benzimidazole-b-she (2.0 g, 7.2 mmol). Pyridine (35 ml) is heated with, 0 (4 g) with good stirring. about 5 hours to 100 ° C, then dissolve with ice water, establish an alkaline reaction, extract the desired substance and purify on silica gel (solvent: methylene chloride and saturated NH3
    5 methanol 20: 1).
    Output 1.7 g (72% of theory), so melt. 205-220 ° C.
    Example 10. 7,7-Dimethyl-2- (3-hydroxypyridyl) -b, 7-dihydro0N, 5H-pyrrolo 2,3-tJ-benzimidazol-6-one.
    To a mixture of 3-hydroxypyridine-4-carboxylic acid (2.8 g, 0.02 mol) in dimethylformamide (30 ml) with anhydrous acid (CaSO4 (3 g) and hydroxybenzotriazole (3.4 g, 0.025 mol) with a stirring at 0 ° C, a solution of DCC (5.2 g, 0.025 mol) in DMF (20 ml) is introduced, then mixed with 5,6-diamino-3.30-dimethylindolin-2-one (2.8 g,
    0.015 mol) and, after a short stirring, are concentrated, infused with water and sucked off. The residue is heated with ethanol (200 ml) and a concentric HC1 (40 ml) for 2 hours under reflux, after cooling aspirated and the filtrate is concentrated in vacuo, infused with ammonia water and sucked off. Purified by chromatography on a column of silica gel (solvent: chloride
    0
    five
    methylene, methanol and acetic acid 10: 1: 1).
    Output 1.4 g (24% of theory), t. Melt. 300 ° C.
    Analogously to example 10 receive the connection
    but. 7,7-Dimethyl-2- 4- (2-hydroxypyridyl D-6,7-dihydro-3H, 5H-pyrrolo
    13
    2,3-Ј -benzimidazol-6-one x 2 NO of, 5,6-diamno-3, 3-dimethylindolin-2-one and 2-oxypyridine-4-carboxylic acid (yield 22%, t.pl. 360 ° C, solvent - water).
    Example 11. 7-Ethoxycarbonyl-7-methyl-2- (4-pyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2,3-f-benzimidazole-6-oi x HC1.
    A solution of 5-amino-3-ethoxycarbosh-3-methyl-6- (4-pyridino-amino-lino) -indolin-2-one (10.85 g, 32.2 mmol) in ethereal (700 ml) with concentrated HC1 ( 50 ml) is heated for about 12 hours under reflux, then cooled, slightly thickened, sucked off from the crystals and recrystallized from ethanol.
    Output 9.6 g (79% of theory), t. Melt. 288-290 ° C.
    The starting materials for the compounds described in example 8 can be obtained as follows.
    a.5-Amino-3-ethoxycarbonyl-3-methyl-6- (4-pyridino-amino) -indolin -2-one.
    A solution of 3-ethoxycarbonyl-3-methyl-5-nitro-6- (4-pyridinoimyla) -indolin-2-one (12.4 g, 32.2 mmol) in ethanol (500 ml) is hydrogenated to 10% - nom Pd / C (1 g) at room temperature. Suction is carried out from the catalyst, concentrated and the resulting substance is immediately applied further.
    b.H-Ethoxycarbonyl-3-methyl-5- -nitro-6 - (4-pyridino-amino-amino) -indolin-2-one.
    In a solution of 3-ethoxycarbonyl-3- -methyl-6- (4-pyridinoyl amino) iido-. Lin-2-one (13 g, 0.038 mol) in concentrated H2SO4 (90 ml) is instilled with cooling a solution of potassium nitrate (3.9 g, 0.038 mol) in concentrated H1SO4 (30 ml). The mixture is stirred for about 1 h, poured onto ice, the pH is adjusted to 8 with concentrated NH3 solution with cooling, the crystals are filtered off with suction and recrystallized from ethanol and methylene chloride.
    Output 12,81 g (82% of theory), so melt. 217-219 ° C.
    c.H-Ethoxycarbonyl-3-methyl-6- - (4-pyridino-amine) -indolin-2-one.
    In a cooled solution of 6-amino-3-α-ethoxycarbonyl-3-methylindolin-2-one (13 g, 0.048 mmol) in methylene chloride (500 ml), triethylamine is added.
    148077014
    (22.1 ml) and iiricin-4-carboxylic acid chloride - yy; rochloride
    (9.4 g, 0.053 mol) and pgmeshivayut p. about 2 h at room temperature, then concentrated to dryness, stirred with water, sucked off and the residue is recrystallized from ethanol and methylene chloride. Yield 11.9 g (73% 0 of theory), t. Melt. 222-224 ° C.
    with. 6-Amino-3-ztokpascarbonyl-3-methylindvoln-2-one
    A solution of methylt-methyl ester of methyl- (2.4 d shptrofonnl) -malonic acid (27 g-, 0.079 mol) in ethanol (800 ml) is hydrogenated with 10% Pd / C (1 g) at room temperature. Then the catalyst is sucked off, acidified with a solution of HCl in ethanol, concentrated and crystallized by the addition of isopropanol.
    Output 13,19 g (71% of theory), t. Melt. 248 ° C.
    According to Example 1, compounds are obtained, the characteristics of which are given in Table. four.
    Experiment Protocol. Male Sprague-Dawley rats weighing about 350-450 g were anesthetized by intraperitoneal barbiturate injection and instrumented to conduct the study as follows
    through the right carotid artery, a catheter was inserted into the left ventricle of the heart to measure pressure (Millos Microtop), 0.5 mm in diameter, using this measuring sensor, the pressure in the left ventricle of the heart is continuously recorded,
    a polypropylene catheter is introduced into the strap vein for intravenous injection of the test substances
    through the femoral artery, another polypropylene catheter is inserted into the abdominal aorta for direct measurement of arterial blood pressure,
    using subcutaneous puncturing electrodes, card-Q grams are removed.
    During the preparation and the entire period of subsequent experiments. rats are fixed on a heat-resistant operating table with electrically heated.
    The use of the tested substances is carried out continuously by intravenous injection, the injection volume is with each injection
    1 ml per 1 kg of body weight. At intervals of 10 minutes, an intravenous injection of doses increasing from 0.01 to 30 mg is made. Thus, dose curves are obtained for the parameters of the test substances.
    On the basis of regression calculus measurement data, equipotential doses were obtained for the positin shutropic effect (dp / dt). Moreover, the corresponding maximum effect values reached (relative to dp / dt) and the doses related to them as a criterion of the force of the effects of substances were determined. Table 5 presents the data comparing the equipotential doses (DE | i5 dose, mg / kg, resulting in an increase in the force of contractions of the heart by 1.5mHg / c) and the maximum effect force (WM & C) CC — the maximum contraction force (dp / dt) relative to one or the other initial value).
    The compounds obtained are low toxic.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The process for the preparation of pyrrolobenzimidaeol of the general formula
    Hi I
    RU
    de RJ, is hydrogen, lower alkyl group, lower cycloalkyl
    Ra is hydrogen, a lower alkyl group or a carbonyl group substituted by a lower alkoxy or hydrazino group or, together with R, is a lower cycloalkylene group or a lower alkylidene group;
    X is the valence number, lower C, C4 alkylene group or vinylene group, T is oxygen or sulfur;
    Ru - 2,3 - or 4-pyridyl residue, which, if necessary, carries on hetero
    the atom of the ring atom is an oxygen atom and / or may be substituted by one or more lower alkyl, lower alkoxy or hydroxyl group or halogen atom,
    or their physiologically compatible salts with inorganic acids, characterized in that the compound of the general formula
    R wg
    where R and R have the indicated values,
    reacted with a compound of the general formula
    Ru - X - Co - Y,
    Where Py and X are as indicated, Y is hydrogen, halogen, an ester group or anhydride,
    and the resulting compound is cyclized in an acidic medium and the desired product is isolated in free form or reacted with an inorganic acid and the desired product is isolated as a physiologically compatible salt.
    The priority is as follows: 12.05.84 with R, is hydrogen, lower alkyl group, R2 is hydrogen, lower alkyl group or R together with RJ, is a lower cycloalkylene group or lower alkylidene group, X is a valence bond, lower C, -Sp- alkylene group, or vinylene
    group, T is oxygen or sulfur, Ru is a 2,3- or 4-pyridyl residue, which, under certain conditions, carries an oxygen atom on the ring heteroatom and / or may be replaced by one
    or several lower alkyla, lower alkoxy or hydroxyl group or halogen atom at 12.20.84 with R - carbonyl group substituted by lower alkoxy group or hydrazino group, T - sulfur.
    Table 1
    a.7,7-Dimethyl-2- (2-pyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2,3-i-benzimidazol-6-one x 0.3 II O
    from 5,6-diamino-3, 3-dimethylindol-2-one and picnic acid chloride
    b.7,7-Dimethyl-2- (3-pyridyl) -b, 7- -dihydro-3N, 5H-pyrrolo 2, 3-t - -benzim schazol-6-one x 3 BUT from
    5, 6-diammy 3,3-dimethylschcholin--2-one and chlorate nicotinic acid - hydrochloride
    c.7,7-Dimethyl-2- 4- (2-methylpyridilD-6,7-dihydro-ZN, 5H-lirrolo J., 3-f J-benzimidazole-b-on x x 0.6 BUT from 5,6-diamino-3, 3-dimethylindolin-2-one and 2-methylisonicotinic acid chloride
    d.7,7-Dimethyl 2- 4- (2-hydroxy-pyridyl) -6, 7-dihydro-3H, 5H-pyrrol 2,3-fj-bennmidazole-b-x
    x 2 NgO from 5,6-diamino-3, 3-dimethylindolin-2-one and 2-hydroxyisonicotinic acid chloride
    e.7.7-Dimethyl-2- 4- (chloropyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2,3-: Ј -benzimidazol-6-one from 5,6-diamino-3, 3-dime tilindolin- -2-one and 2-chloro-isonicotinic acid chloride
    f.7,7-Dimethyl-2- (3-pyridylvinyl) -6,7-dihydro-3H, 5H-pyrrolo 2,3-f-benzimidaeol-6-one x x 0.75 H20 out of 5.6 -diamino-3, 3-dimethylindolin-2-one and chloroanhydride of 3-pyridylacrylic acid hydrochloride
    g.7,7-Dimethyl-2- (4-pyridyl-ethyl) -6,7-dihydro-3N, 5H-p rrolo {2, 3-fj-benzimidazol-6-one x x 0.6 NgO out of 5 , 6-diamino-3, 3-dimeshshndolin-2-one and chloroanhydride-4-pyridylpropionic acid - hydrochloride
    h. 2- (4-pyridyl) -spiro cyclo-
    Pentane-1,7-6,7-dihydro-3 H 5; H-pyrroloG2, 3-f-benzimide 182-187, water
    331-335, dioxane and water 2: 1
    311-313, acetone
    360, water
    341-344, acetic ether
    203-207, water + 5% СН3ОН
    150-154, water
    365, ethanol
    ash -b-on x 0.3 NgO of 5, b - -diamino-spiro-cyclopentane-1,3-β-indoline -2 -one and nzonicotype acid chloride-hydrochloride
    i. 7,7-Dimethyl-2 3- (6-methyl-pyridyl) 3 -6, 7-dihydro-3N, 511-pyrrolo-2,3-benzimidazol-6-one nz 5,6-diamino-3, 3-dimethylindolin-2-one and 6-methyl nicotinic acid chloride
    k. 7,7-Dimethyl-2- (2-M-oxypyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2, 3-f-benzimidazol-6-one
    -benzimidazol-6-one x 0.3 of 5,6-diamino-3, 3-dimethylindolin-2-one and pyridine-2-aldehyde
    B. 7,7-Dimethyl-2- (4-pyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2,3-G benzimidazol-6-one x 4 of 5,6-diamino-3, 3- di-methylindolin-2-one and pyridine-4-aldehyde
    Title
    a.7,7-Dimethyl-2- (3-M-hydroxypyridyl) -6,7-dngydro-3H9 5H-pyrrolo 2,3-Ј | -benzimkaaaol-6-one x
    x 1,25 NgO from 7,7-dimethyl-2- (3- -pyrndyl) -6,7-dngydro-3N, 5H-pyrrol 2,3-Ј 1-beisimidazol-6-one
    b.7-Methyl-2- (4-Y-hydroxypyridyl) - -6,7-dihydro-ZI, 5H-pyrrolo
    L2,3-f J-benzimidazol-6-one from 7-metshg-2- (4-pyridnl) -6, 7-dihydro-3H, 5I-pyrrolo 2, -benzimidazol-6-one
    52
    360, acetic ester
    180-183, acetic acid and
    methanol
    table 2
    22
    215, water and ethanol
    Table 3
    Output, %
    T. melt., C, solvent
    355-358, water
    300, ethyl acetate
    Obtained analogously to the example of 7,7-Dimethyl-2- (4-H-oxypyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2,3-f-benzimidazol-6-one x 3 BUT
    7,7-Dimethyl-2- (3-N-hydroxypyridyl) - -6, 7-dihydro-3N, 5H-pyrrolo 2,3-f-benzimidazol-6-one x 1.25 PO
    7-Methyl-2- (4-M-hydroxypyridyl) -6,7-dihydro-3N, 511-pyrrolo (2,3-fJ-benzimidazole-b-he
    7-Methyl-2- (4-pyridyl) -6,7-dngidro-3N, 5H-pyrrolo 2,3-1G) benzimide sol-6-one
    7-Methyl-2- (3-pyridyl) -6,7-dihydro-3N, 511-pyrrolo 2, 3-fj-benzimide-daeol-6-one
    7-Ethyl-2- (4-pyridyl) -6,7-dihydro-3H, 5H-pyrrolo 2,3-f-benzimida-aola-6-one
    7-Ethyl-2- (3-pyridyl) -6,7-dihydro-3N, 5H-pyrrolo 2,3-Ј-benzimidadol-6-one
    7- (2-Propyl) -2- (4-pyridyl) -6,7- -dihydro-3N, 5H-pyrrolo 2, -benzimidazol-6-one
    7-Cyclopentyl-2- (4-pyridyl) -6,7- -dihydro-3N, 5H-pyrrolo 2, -benzimidazol-6-one
    7-Isopropylidene-2- (4-pyridyl) -6,7-dihydro-3N, 5H-pyrrolo Q, 3-fJ -benzimidazol-6-one (prepared according to example 2)
    7-Ethoxycarbonyl-7-methyl-2- (4-pyridyl) -6,7-dihydro-3H, 5H-pyrrol 2,3-iQ-benzimidazol-6-one HC1 (analogously to example 1)
    7-Hydrazinocarbonyl-7-methyl-2- - (4-pyridyl) -6,7-dihydro-3N, 5H- -pyrrolo 2,3-benzimidazole-6-one (obtained as in Example 2)
    7,7-Dimethyl-2- (4-pyridyl) g 6,7- -dihydro 3N, 5H-pyrrolo 2, -benzimidazol-6-one x 4 H20 (obtained as in Example 3)
    260-262
    355-358, water
    300, ethyl acetate
    315-318, ethanol and water
    300, dioxane and methanol
    270-272, ethyl acetate and methanol
    300, ethanol and water
    215-220, ethanol and water
    200-204, dioxane and methanol
    300, isopropane nol and acetic ester
    288-290
    300
    215
    7,7-Dimethyl-2- (3-pyridyl) -6,7- -digydro-3N, 5H-pyrrolo 2,3-fJ -benzimidazol-6-one x 3 (obtained as in Example 3)
    7.7 Dimetsh1-2- (4-pyr1vdil) -6,7-
    dihydro-ZN, 5H-pyrrolo 2, benzimidazole-6-thione x 2 H20 (obtained analogously to example 1)
    7,7-Dimetnl-2- (4-pyridyl) -6,7- -dihydro-3N, 5H-pyrrolo 2,3-fj- -benzimidazol-6-one (obtained analogously to example 2)
    ,four
    6,6-Dimetnl-1-2- (4-pyrndnl) - -5, b-dlgdro-3N, 4H-pyrroloC2, -6-eneimidaeol-5-one (known jointly).
      6, b-Dnmethyl-2- (4-pyridyl) -4,6- -dihydro-3H, 5H-pnrrolo 3,4-a-benzn-midazol-4-one (known compound).
     6,6-Dimethyl-2- (2 methoxy-5- -metypsulfonylphenyl) -4,6-dihydro-3H, 5H-tfrolo (j3,4-a-benznmidazol-4-one (known compound).
     6,6-Dimetnl-2-feshmetnl-4,6-dihydro-3N, 5H-pyrrolo 3, -benzishadazol-4-one (known compound).
    Continuation of table.4 2 | 3
    EII
    331-335, dioxane and water
    205-220
    285-288
    Table 5
    and
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    同族专利:
    公开号 | 公开日
    FI81351C|1990-10-10|
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    PT80425B|1987-04-16|
    JPH0772185B2|1995-08-02|
    JPH0741474A|1995-02-10|
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    KR850008170A|1985-12-13|
    HU193754B|1987-11-30|
    ES8603178A1|1986-01-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19843417643|DE3417643A1|1984-05-12|1984-05-12|Novel pyrrolobenzimidazoles, process for their preparation, medicaments containing these compounds and intermediates|
    DE19843446417|DE3446417A1|1984-12-20|1984-12-20|Novel pyrrolobenzimidazoles, process for their preparation and medicaments containing these compounds, and novel intermediates|
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