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    • 专利摘要:
    A carbostyril compound of the formula (I) wherein R1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group; R2 represents a hydrogen atom, a lower alkyi group, a lower alkoxy group, a halogen atom, or a hydroxy group; R3 represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group which may be substituted with a lower alkyl group, a lower alkanoylamino group, a N.N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group, or a carboxymethyl group; R4 and R5, which may be the same or different, each represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, or a nitro group; the bonding between the 3- and 4-positions of the carbostyril nucleus is a single bond or a double bond; and the position at which the imidazopyridyl group of the formula is attached to the carbostyril nucleus is the 5- or 6-position; with the proviso that when the imidazopyridyl group is attached to the 5-position of the carbostyril nucleus, R2 should not be a hydrogen atom, a lower alkyl group, or a halogen atom; or its pharmaceutically acceptable salt, and a composition containing the compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient, and process for preparing same. The Compound of the formula (I) and its pharmaceutically acceptable salts have cardiotonic effects.
    公开号:SU1215621A3
    申请号:SU823466402
    申请日:1982-07-11
    公开日:1986-02-28
    发明作者:Михиаки Янг-Инг-Ксиунг Томинага；Хиденори ОГАВА；Кацуиуки Накагава
    申请人:Оцука Фармасьютикал Ко,Лтд；
    IPC主号:
    专利说明:

    N
    where Rj have the indicated values using at least an equimolar ph the amount of a compound of the general formula (III) per 1 mol, a compound of the general formula (II) in the presence of a dehydrohalogenating agent at a temperature from room temperature to 150 ° C for 1-10 hours .
    Priority on the grounds: A.11. HE - hydrogen, lower alkyl; Rj is hydrogen, lower alkyl,
    lower alkoxy or halogen; R, is hydrogen or lower alkyl; R and Rj each, hydrogen; the imidazopyridyl group is attached to the carbostyril group in position 6.
    12/18/80 with K (- hydrogen, lower alkyl, phenyl-lower alkyl, lower alkenyl or lower alkynyl Rj - hydrogen or lower alkylJ Rj - hydrogen or lower alkyl R and R - each hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy or a nitro; imidazopyridyl group is attached to the carbostyryl group in position 5.

    This invention relates to a process for the preparation of new carbostyril derivatives of the general formula.
    (one)
    de K is hydrogen, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl (lower) alkyl group;
    RJ is hydrogen, lower alkyl group, lower alkoxy group, halogen or hydroxy group,
    EZ is hydrogen or lower alkyl group
    R and RJ are the same or different, each hydrogen, halogen, lower alkyl group, hydroxy group, lower alkoxy group or nitro group {
    the relationship between positions 3 and 4 in the boiling water is single or double /
    the position in which the imidazopyridyl group of the general formula
    Я5
    connected to the carbostyril core — 5 or 6;
    with the proviso that when the imidazopyridyl group is connected to the 5 styrene styrene styrene, R must not be hydrogen, a lower alkyl group or a halo J gene
    or their pharmaceutically acceptable salts.
    The compound of formula (I), as well as the pharmaceutically acceptable salts of these compounds, have an activity that stimulates the contraction of the heart and has a positive effect on muscle contractility, and also has an effect that increases coronary blood flow, and are suitable as cardiac stimulants for the treatment of such heart diseases. how congestive heart failure. They have the advantage of not increasing or, if increasing, only a little heart rate.
    Example 1.6- (y-Bromopropionyl:) - 1-methyl-3,4-dihydrocarbostyryl
    (5 g), 2-aminopyridine (4.77 g) and acetonitrile (20 bp) are refluxed for 1.5 hours. The reaction mixture is cooled with ice water and the precipitated crystals are collected by filtration. The crystals are dissolved in acetone and the solution is adjusted to pH 1 approximately by addition of 48% hydrobromic acid. The resulting crystals are collected by filtration, recrystallized from water, and 5.68 g of 6- (3-methyl-imidase o) -1,2-a- (pyridin-2-yl) -1-me-, 4-dihydrocarbostyryl monohydrobromide are obtained. . M.p. above, colorless powder.
    NMR (DMSO b), S (ppm): 8.85 (doublet, 3 2H, 1H), 8.13-7.20 (multiplet, 6H), 3.33 (singlet, 3N) 3 , 15-2.87 (multiplet, 2H) 2.73 (singlet, 3N), 2.68-2.37 (multiplet, 2H).
    Example 2. 8-Hpor-6- (ob-bromopropionyl) -3,4-dihydrocarbostyryl (4 g), 2-aminopyridine (3.57 g) and acetonitrile (20 ml) are boiled under reflux. for 3 hours. The reaction mixture is concentrated to a dry residue and the latter (an oily product) is washed with water. The residue is then dissolved in acetone, the solution is adjusted to approximately pH 1 by adding 48% hydrobromic acid and the resulting crystals are filtered. The crude crystals thus obtained were recrystallized from water and 2.74 g of the hemihydrate of 8-chloro-6- (3-methylimidazo) monobromic hydrogen salt of 8-chloro-3,4-dihydrocarboxyryl were obtained. .Т.Ш1. above 300 ° C, pale yellow powder.
    NMR (DMSO), (ppm): 9.78 (s. 1H), 8.83 (d., 3 7 H2, 1H), 8.03-7.43 (m, 5H) , 3.23-2.97 (m, 2H), 2.74 (s., 3N), 2.70-2.43 (m, 2H).
    Example .3. Analogously to Example 2, the following compounds are prepared using the corresponding starting materials.
    Monohydrate monohydrochloride salt of 8-methyl-6- (3-methylimidazo) -1,2-aa (pyridin-2-yl) -3,4-dihydrocarbostyryl. M.p. 273-276 C (with decomposition), pale yellow powder.
    Hemihydrate monobromic salt of 6- (3-methylimidazo) -1,2-a (py
    din-2-yl) -3,4-dihydrocarbostyril. M.p. above goiter C, pale yellow needles.
    NMR (DMSO -1): 0), S (ppm): 8.65 (d, Hz, 1H), 8.06-7.73 (m, 2H), 7.67-7, 40 (m, 3N), 7.23-7.03 (m, 1H), 3.20-2.50 (m, 4H),. 2.72 (s., ZN).
    3/2-hydrate of the hydrochloride salt of 8-methyl-6- (imidazo) -1,2-a (pyridine-2-IL) -3,4-dihydrocarboxyethyl. M.p. above 300 ° C, pale brown powder.
    NMR (flMCOotg), S (ppm): 9.64
    (s., 1H), 8.86 (d, O 7 H, 1H),
    8.70 (s., 1H), 8.03-7.30 (m, 5H),
    3.10-2.83 (MO, 2H), 2, -67-2.40 (m,
    2H), 2.32 (s., 3N).
    8-Chloro-6- (imidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbrostyrene monohydrochloride hemihydrate. M.p. above 300 ° C, pale brown cotton crystals.
    NMR (DMSO-yb), B (ppm): 9.70. (s., 1H), 8.82 (d, Jf 7 H, 1H), 8.75 (s., 1H), 8.05-7.23 (m, 5H), 3.20-2 , 90 (m., 2H), 2.73-2.40 (m., 2H).
    Monobromide salt of 8- -methoxy-6- (imidazo) 1,2-a (pyridin-2-yl) -3,4-dihydrocarbostyril. M.p. 294.5-296, (with decomposition), pale yellow flaky crystals.
    6- - (Imidazo) -1,2-a (pyridin-2-yl) -carbostyril monohydrochloride salt. M.p. above, pale yellow flaky crystals.
    NMR (DMSO- "y), S (h // ppm): 8.74 (d,: 7 Hz, 1HI, 8.61 (s., 1H), 8.31 (d. 2.5 N) , 8.17-7.10 (m., 6H), 6.58 (d, 3 9 Hz, 1H).
    Monohydrate monobromic salt of 6- (3-methylimidazo) -1,2-a (pyridine-2-sh1) -carbostyril. M.p. above 300 ° C, colorless flaky crystals.
    NMR (DMSO ale -), S, (ppm): 8.81 (d, 3 7 Hz, 1H), 8.14 (d., 3 10 Hz, 1H), 8.05-7, 45 (m., 6H), 6.69 (d., 3 10 Hz, 1H), 3.45-3.00 (m, 2H), 1.38 (t., D 7.5 Hz, MN ).
    6- (Imidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbostyril. M.p. 230- (with decomposition), colorless powder.
    Example 4. To a suspension of 6- - (imidazo) -1,2-a (pyridin-2-yl) -3,4- -dihydrocarbostyril (5 g) in dioxa-
    2, 3-dichloro-5,6-dicyano--1,4-benzoquinion (6.47 g) was added at 50 ° C under stirring (50 ml). The reaction mixture is heated for 3 hours with stirring. After completion of the reaction, the solvent is evaporated. The residue is extracted with chloroform and 0.5N. Naph. The chloroform layer was washed with 0.55 n. NaOH, with water and drain. After evaporation of the chloroform, the resulting residue is taken up and purified by silica gel column chromatography. The resulting oily product is dissolved in acetone and the solution is adjusted to approximately pH 1 with concentrated hydrochloric acid. The resulting crystals are collected by filtration. The crude crystals thus obtained were recrystallized from water to obtain 2.4 g of 6- (imidazo) -I, 2-a (pyridin-2-yl) -carbostyril monohydrochloride. M.p. Above 300 ° C, pale yellow flaky crystals.
    NMR (daSO-sk b), 5 (ppm): 8.74 (d, Hz, 1H), 8.61 (s., 1H), 8.31 (d, 3 2.5 Hz ), 8., 17-7.10 (m. 6H), 6.58 (d, 3 9 Hz, 1H).
    Example 5. Analogously to Example 4 and using the corresponding starting compounds, foT 6- (3--ethylimidazo) -1,2-a (pyridin-2-yl) -carbostiryl monohydrate monohydrate was obtained. M.p. Above 300 C, no colored flaky crystals.
    NMR (daSO-o6b- 1) 0), 8 (ppm): 8.81 (d, 3 7 Hz, 1H), 8.14 (d. 3. 10 Hz, 1H), 8, 05-7.45 (m., 6H), 6.69 (d., 3 10 Hz, 1H), 3.45-3.00 (m, 2H), 1.38 (t., 3 7, 5 Hz, ЗН). EXAMPLE 6 To a solution of 8-methyl-6- (3-methylimidazo) -1,2-a (pyridin-2-yl) -carbohydrate (2 g) in 40 ml of methanol is added 10% palladium coal (0.2 g) and the mixture is subjected to catalytic reduction for 8 hours at 60 ° C and a hydrogen gas pressure of 2-3 kg / cm. After completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated to a dry residue. The residue is dissolved in acetone and the solution is adjusted to approximately pH 1 with concentrated hydrochloric acid. The crystals precipitated are collected by filtration. The crude crystals thus obtained were recrystallized from ethanol to obtain 1.2 g of 8-methyl 6- (3-methylimidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbatiryl monohydrochloride monohydrate monohydrate. M.p. 273-276 C (with decomposition), pale yellow needles.
    Example 7. Analogously to Example 6 and using the corresponding starting compounds, the following compounds are obtained.
    Hemihydrate of monohydrobromide 6- - (3-methylimidazo) -1,2-a (pyridin-2- -yl) -3., 4-dihydrocarbostyryl.-T.sh1. above, pale yellow needles.
    NMR (DMSO dg- 1) O), 5 (ppm): 8.65 (d, 3 7 Hz, 1H), 8.06-7.73 (m, 2H), 7.67- 7.40 (m., ZN), 7.23- 7., 03 (m., 1H), 3.20-2.50 (m., 4H), 2.72 (s., ZN).
    3/2-Hydrate monohydrochloride 8- -methyl-6- (imidazo) -1,2-a (pyridin-2- -yl) -3,4-dihydrocarbostyryl. M.p. Over 300 ° C, pale brown powder.
    NMR (DMSO - “b), 8 (ppm): 9.64 (s., 1H), 8.86 (d., 3 7 Hz, 1H), 8.70 (s., 1H) , 8.03-7.30 (m., 5H), 3.10-2.83 (m., 2H), 2.67-2.40 (m, 2H), 2.32 (s., ZN).
    Hemihydrate of monohydrochloride 8- - xx (or-6- (imidazo) -1,2-a (pyridin-2- -sh: () - 3,4-dihydrocarbostyril. So pl. 300 ° C, pale brown flaky crystals .
    NMR (DMSO-l), S (ppm): 9.70 (s, 1H), 8.82 (d., 3 7 Hz, 1H), 8.75 (s., 1H), 8 , 05-7.23 (m., 5H), 3.20-2.90 (m. 2H), 2.73-2.40 (m., 2H).
    6- (3-methyl-imidazo) -1,3-a (pyridin-2-sh1) -1-methyl-3,4-dihydrocarbostyril monohydrobromide. M.p. Above 300 ° C, colorless powder.
    NMR (DMSO-otg), 8 (ppm): 8.85 (d, 3 7 Hz, 1H), 8.13-7.20 (m, 6H), 3.33 (s, ZN) 3.15-2.87 (m, 2H), 2.73 (s, ZN), 2.68-2.37 (m, 2H).
    8-methoxy-6- - (imidazo) -1,2-a (pyridin-2-yl) -3,4--dihydrocarbostyril monohydrobromide. M.p. 294.5- 29 & 0 ° C (with decomposition), pale yellow flaky crystals.
    Example 8. To a solution of 6- (3- -methylimidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbostyril (3 g) in
    7
    dimethylformamide (50 ml) was added 50% sodium hydride in oil (580 mg) and the mixture was allowed to react for 2 hours at room temperature. Then, after adding methyl iodide (1.85 g), the mixture is reacted for an additional 3 hours at room temperature. After completion of the reaction, dimethylformamide is evaporated. Dn of extraction, chloroform and 0.5N are added to the residue. NaOH. The chloroform layer is washed thoroughly with water, dried and then the chloroform is evaporated. The residue is purified using silica gel column chromatography. The oily product thus obtained is dissolved in acetone. The solution is adjusted to about pH 1 by addition of 48% hydrobromic acid, and the crystals formed are collected by filtration. The crude crystals thus obtained were recrystallized from water to obtain 2.9 g of monohydrobromide b- (3-methylimidazo) -1,2-a (pyridin-2-yl) -1-methyl-3,4-dihydrocarbostyryl. M.p. above, colorless powder.
    NMR (DMSO -otg), S (ppm): 8.85 (d, 3 7 Hz, 1H), 8.13-7.20 (m, 6H), 3.33 (s. , ZN), 3.15-2.87 (m., 2H), 2.73 (s., ZN), 2.68-2.37 (m, 2H).
    Example 9. 5- (c6-Bromobutyryl) -8-methoxy-3,4-dihydrocarbostyryl (5 g), 2-aminopyridine (4.33 g) and acetonitrile (20 ml) react with boiling with reflux for 6 hours. The reaction mixture is concentrated to a dry residue, which is crystallized by the addition of water. The crystals are collected by filtration, injected with water and dissolved in acetone. The solution is adjusted to a pH of about 1-2 by adding 48% hydrobromic acid. The resulting crystals are collected by filtration. The crude crystals thus obtained were recrystallized {from a mixture of methanol and sulfuric ether, and 3.73 g of 5- (3-ethyl-imidazo) -1,2-a (pyridin-2-yl) -8-methoxy- monohydrobromide was obtained. 3,4-dihydrocarbostyr. M.p. 254-256 ,, colorless powder.
    Example 10. 5-Chloroacesh 1-8-methoxycarbostyryl (5 g), 2-amino-picoline (6.45 g) and acetonitrile
    156218
    (40 ml) is reacted for 3 h under reflux, after which the reaction mixture is cooled with ice water. The resulting 5 crystals are collected by filtration, suspended in a mixture of acetone and methanol, and the suspension is adjusted to approximately pH 1 by the addition of concentrated hydrochloric acid. The crystals formed are collected by filtration, recrystallized from methanol, and 4.0 g of 3/2-hydrate of 5- (7-methylimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarboxyryl monohydrochloride are obtained. M.p. 269.5-271.5 C (with decomposition), colorless powder.
    Example 11. Analogously to example 2 and using the corresponding starting compounds receive
    20
    the following compounds, I
    Monohydrate monohydrate of 5- - (imidazo) -1,2-a (pyridin-2-yl) -3-methoxycarbostyril. M.p. 256-257, (with decomposition), colorless flaky crystals (water).
    Hemihydrate of monohydrochloride 5- - (imidazo) -, 2-a (pyridin-2-yl) -8- -methoxy-3,4-dihydrocarbostyril.
    M.p. 260-261 ° C (with decomposition), colorless needles (methanol).
    3/2-Hydrate monohydrobromide 5- (3- -methylimidazo) -1,2-a (pyridin-2-yl) -.
    -5-methoxycarbosteryl. M.p. 207.5-210.0 C, pale yellow scaly crystals (methanol-distil ether).
    5- (3-Methylimidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3,4-degiArocarbostiril monohydrobromide. M.p. 263- 264.5 ° C, pale yellow needles (methanol - diethyl ether).
    1/4-Hydrate monohydrobromide 5- (3- -ethylimidazo) -1,2-a (pyridin-2-yl) g -8-methoxycarbostyril. M.p. 229- 231.5 ° С, colorless powder (methanol - diethyl ether).
    Monohydrochloride monohydrate 1-methyl-5- (imidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3, 4-dihydrocarbostyril. . 259-260,5 С (with decomposition), colorless needles (methanol - diethyl ether).
    Dihydrate monohydrochloride 5- (6-chloroimidazo) -, 2-a (pyridin-2-W1) -8-methoxycarbostyril.T.pl. 270272, 5 ° С (with decomposition), colorless powder (methanol - diethyl ether). Monohydrate monohydrochloride 5- (3- -methylimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril, T. pl ,, 255- 258.0 С (with decomposition), pale yellow flaky crystals (water)
    Monohydrobromide monohydrate 5- - (3,7-dimethylimidazo) -1,2-a (pyridin--2-yl) -8-methoxycarbostyril, m.p. 249-251 0, colorless prismatic crystals (methanol - diethyl ether
    1/4-Hydrate monohydrochloride 5- - (imidazo) -1,2-a (pyridin-2-yl) -8- -oxycarbostyril. M.p. above 300 C, pale yellow cotton crystals (water).
    Found 7; C 60.55; H 3.80; N 13.23.
    C ,, H,
    Calculated,%: C 60.38; H 3.96, ° N 13.21,
    NMR (DMSO - 1) 0), (ppm): 8.82 (d, 3 7.0, 1H), 8.43 (s, 1H), 8.18 (d. 3 10 , 0, 1H), 8.06-7.90 (m, 2H), 7.63-7.43 (m, 1H), 7.44 (d, 3 8.0, 1H), 7 , 23 (d., 3 8.0, 1H), 6.73 (d, v1 10.0.1H
    3/2-Hydrate monohydrochloride 5- - (imidazo) -1,2-a (pyridin-2-yl) -8- -oxy-3,4-dihydrocarbostyryl. M.p. Above 300 ° C, colorless cotton crystals (water).
    Found,%: C 55.82; H 4.91; N 12.34.
    C, 6 H 02N3 HCe-3/2 Calculated,%: C 56.06; H 5.00; N 12.26.
    NMR (DMSO), S (ppm): 9.02 (s, 1H), 8.93 (d., 3 7.0, 1H), 8.47 (s, 1H), 8, 10-7.80 (m., 2H), 7.60-7.40 (m., 1H), 7.23 (d., 3 8.0, 1H), 7.01 (d., 3 8 , 0, 1H), 3.26-2.97 (m, 2H), 2.63-2.36 (m, ZN),
    5- (3-Methyl-6- -nitroimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril monohydrobromide. M.p. 247.5 250 ° C (with decomposition), yellow needles (methanol - diethyl ether).
    5- (8-hydroxyimidazo -1,2-a (pyridin-2-yl) -8-methoxycarbo-steryl monohydrochloride. T. mp. 266-268 with (decomposed), colorless powder (methanol - diethyl ether).
    5/2-Hydrate monohydrochloride 5- - (8-methoxyimidazo) 1,2-a (pyridine.
    121562110
    -2-yl) -8-methoxycarbostyril .T. an, 215-216,5 C (with decomposition), colorless flaky crystals (water).
    5 5- (3-Methyl-6,8-dibromimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril monohydrobromide. M.p. 246
    five
    five
    0
    247 C (with decomposition), pale yellow needles (methanol).
    1-Allyl-5- (imidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride. So pl.250-252 C (with decomposition), colorless needles (methanol - diethyl ether).
    Monohydrochloride monohydrate of 1- -benzyl-5- (imidazo) -1,2-a (pyridin--2-yl) -8-methoxy-3,4-dihydrocarboctipryl. M.p. 243.5-245, (with decomposition), colorless needles (ethanol).
    Hemihydrate of monohydrochloride 1 - -propargyl-5- (imidazo) -1,2-a (liridin-2-yl) -8-methoxy-3, 4-dihydrocarbostyril. M.p. 241.5-242.5 ° С (with decomposition), colorless needles (ethanol).
    Example 12. 5- (Shidazo) -1, 2- -a (Pyridin-2-yl) -8-methoxy-3,4-dihydrocarbatipyl (1.4 g) and DDQ (3.5 g) are added into dioxane (30 ml) and the mixture is boiled under reflux for 5 hours. The reaction mixture is concentrated under reduced pressure, the residue is extracted by adding chloroform and 0.5N. NaOH. The chloroform layer is washed with 0.5 n. NaOH and then 2 times with water. After drying, the chloroform is evaporated. The residue is isolated and purified by passing through a column of silica gel. The resulting crude crystals are dissolved in acetone and hydrochloric acid is added to the resulting solution. The precipitated crystals are collected by filtration, recrystallized from water, and 410 mg of 5- (imidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril monohydrochloride are obtained. M.p. 256-257.5 C (with decomposition), colorless flaky crystals.
    , -Dirimer 13. To a solution of 5- (3-ethylimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril (2 g) in methanol (50 ml) is added 10% palladium carbon (0.2 g) and catalytic reduction is carried out over 5
    0
    five
    0
    five
    M
    6 hours at 50-60 ° C and a hydrogen gas pressure of 2-3 kg / cm. The catalyst was removed by filtration and the filtrate was concentrated to a dry residue. The residue is dissolved in acetone and hydrobromic acid is added to the solution. The precipitated crystals are collected by filtration, and the crude crystals thus obtained are recrystallized from a mixture of methanol-DIETS1 1 ether and 1.5 g of 5- (3-ethyl-imidazo) -1,2-a (pyridin-2-yl) -8-methoxy monohydrobromide are obtained. si-3,4-dihydrocarbostyril. M.p. 254-256,5 ° C, colorless powder.
    Example 14. To a solution of 5- - (imidazo) -, 2-a (pyridin-2-yl) -8- -methoxy-3,4-dihydrocarbostyril (3 g) in dimethylformamide (100 ml), 50% - sodium hydride in oil (600 ml) and the mixture was stirred at room temperature for 2 hours. After addition of allyl bromide (1.48 g), the mixture is reacted for 3 hours at room temperature. The reaction mixture is concentrated to a dry residue, the latter is extracted by adding chloroform and 0.5 n. NaOH. The chloroform layers are washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel. The oily product is dissolved in acetone and converted to the hydrochloride by addition of hydrochloric acid. The precipitated crystals are collected by filtration, recrystallized from methanol-diethyl ether, and 1.76 g of 1-allyl-5- (imidazo) -1,2-a (pyridin--2-yl) -8-methoxy-3 monohydrochloride are obtained. 4-dihydrocarbostyril. M.p. 250-252 0 (with decomposition), colorless needles.
    Example 15. Analogously to Example 14 and using the corresponding starting compounds, the following compounds are prepared.
    Monohydrate monohydrate of 1- -benzyl-5- (imidazo) -1,2-a (pyridine-2-Sh1) -8-methoxy-3, 4-dihydrocarbostyryl. M.p. 243.5-245.5 ° С (with decomposition), colorless needles (ethanol).
    1- -propargyl-5- (imidazo) -1,2-a (pyricin-2-yl) -8-meth hydroxy-3,4-dihydrocarbostyril hemihydrate monohydrochloride hemihydrate. M.p. 241.5-242.5 С (с
    215621
    12
    decomposition), colorless needles (ethanol) .1
    Monohydrochloride monohydrate 1-methyl-5- (imidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3, 4-dihydrocarbostyril. M.p. 259-260.5 s (with decomposition), colorless needles (methanol - diethyl ether).
    Example 16. Analogously to Example 2 and using the corresponding starting compounds, the following compounds were prepared:
    Hemihydrate of monohydrochloride 6- - (3,7-dimethylimidazo) -1,2-a (pyridin-2-yl) -carbostyril. M.p. above 300 ° C, colorless needles (methanol).
    NMR (DMSO - b), 8 (ppm): 2.56 (s., ZN), 2.67 (s., ZN), 6.58 (d, 3 9 Hz, 1H), 7 , 34 (broad d., 3 7 Hz, 1H), 7.49 (d, Hz, 1H), 7.64-8.11 (m, 4H), 8.59 (d, 3 7 Hz , 1H).
    Monohydrochloride of 6- (5-methylimidazo) -1,2-a (pyridin-2-yl) -carbostyryl. M.p. above, pale yellow powder (methanol). NMR (CFj-COOH), S (ppm): 2.94 (s., 3N), 7.30-7.55 (m, 2H), 7 , 83- 8.17 (m, ZN), 8.23-8.47 (m, 2H), 8.53 (broad, s., 1H), 8.70 (d., 3 9 Hz, 1H).
    3/4-Hydrate monohydrochloride 6- - (imidazo) -, 2-a (pyridin-2-yl) -1- -propargilcarbostyril. M.p. 252- 253 ° С (with decomposition), colorless needles (water).
    Hemihydrate of monohydrobromide 6- (3- -ethylimidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbostyryl.T. pl. 314.5-318 ° C (with decomposition), colorless flaky crystals (water).
    B- (3-ethylimidazo) -1,2-a (pyridin-2-yl) -1-allyl-3,4--dihydrocarbostyril monohydrochloride. M.p. 279-282.5 C (with decomposition), colorless
    needles (ethanol). t
    Monohydrate monohydrochloride 6- (3- -ethylimidazo) -, 2-a (pyridin-2-yl) -1 -1-pro-paragil-3,4-dihydrocarbosteryl. M.p. 264-265 C (with decomposition), colorless flaky crystals (water).
    55
    1/4-Hydrate monohydrochloride 6- (3- -ethylimidazo) -1,2-a (pyridin-2-yl) -1 -1-propargylcarbostyril.T.pl. 26513
    266 ° C (with decomposition), colorless needles (water).
    5- (8-hydroxyimidazo) -1 monohydrochloride, (pyridin-2-yl) -8-methoxycarbostyryl, m.p. 266.5-268, (with decomposition), colorless powder (methanol - diethyl ether).
    Example 17. Analogously to Example 4 and using the corresponding starting compounds, the following compounds were prepared.
    Hemihydrate of monohydrochloride 6- - (3,7-dimethylimidazo) -1,2-a (pyridin--2-yl) carbostyril. M.p. More colorless needles (methanol).
    NMR (flMCO-oig), S (ppm): 2.56 (s., 3N), 2.67 (s., 3N), 6.58 (d., 3, 1H), 7.34 (broad d., 3 7 Hz, 1H), 7.49 (d, 3 8 Hz, 1H) 7.64-8.11 (m, 4H), 8.59 (d, 3. 7 Hz , 1H).
    6- (5-methylimidazo) -1,2-a (pyridin-2-yl) -carbostyryl monohydrochloride. M.p. Vpepe, pale yellow powder (methanol).
    NMR (CH, COOH), S (ppm): 2.94 (s., 3N), 7.30-7.55 (m, 2H), 7.83- 8.17 (m, ZN), 8.23-8.47 (m, 2H), 8.53 (broad s., 1H), 8.70 (d.,.: 9 Hz, 1H).
    3/4-Hydrate of 6- (imidazo) -1,2-a (pyridin-2-yl) -1-propargylcarbostyril hydrochloride. M.p. 252-253 C (with decomposition), colorless needles (water),
    1/4-Hydrate of 6 -. (3-these imidazo) -1,2-a (pyridin-2-yl) -2- -propargylcarbostyryl hydrochloride. M.p. 265- (with decomposition), colorless needles (water).
    5- (8-hydroxyimidazo -1,2-a (pyridin-2-yl) -8-methoxycarbo-steryl monohydrochloride. So pl. 266.5-268, (with decomposition), colorless powder (methanol - diethyl ether ).
    Example 18. Analogously to Example 8 and using the corresponding starting compounds, the following compounds are obtained:
    Monohydrochloride b- (3-ethylimidazo -1,2-a (pyridin-2-yl) -1-allyl-3,4-di hydrocarbostyril. So pl. 279-282,5 (with decomposition), colorless needles ( 3 thanol).
    Monohydrate monohydrochloride 6- - (2-ethylimidazo) -1,2-a (pyridin-2- -yl) -1-proparg1-3,4-dihydrocarbo
    ten
    25
    five
    .
    , 20
    thirty
    35
    - 40
    - 45
    50
    - 55
    14
    steril. M.p. 264- 265 ° С (with decomposition), colorless flaky crystals (water).
    2/4-Hydrate monohydrochloride 6- (3- -ethylimidazo) -, 2-a (pyridin-2-yl) -1- -prolargilcarbostyril. M.p. 265-266 C (with decomposition), colorless needle crystals. 1 (water).
    3/4-Hydrate monohydrochloride 6- - (imidazo) -1,2-a (pyridin-2-yl) -1- -propargilcarbostyril. M.p. 252-253 C (with decomposition), colorless needles (water).
    Example 19. The definition of the pharmacological activity of the compounds according to this invention.
    1. Isolated blood perfused sinoatrial node preparation.
    Experiments were performed on adult mongrel dogs of both sexes. A sinoatrial unit preparation was obtained from dogs weighing 8–13 kg anesthetized with sodium pentobarbital (30 mg / kg, intravenously), administered with sodium heparinate (1000 and / kg, intravenously) and exsanguinated. The preparation consisted mainly of the right atrium and was stored in a cold Tyrode solution. The preparation was placed in a water-jacketed glass vessel maintained at a temperature of about 38 ° C and included in the circulatory system through the right coronary artery with a cannula using blood from a dog donor at a constant pressure of 100 mm Hg. The dogs used as a donor had a weight of 18-27 kg and were anesthetized with sodium pentobarbital (30 mg / kg, intravenously). Heparin sodium was administered at a dose of 1000 and / kg, intravenously.
    The voltage developed by the right atrium was measured with a piezo pressure sensor. Right atrium loading-. A weight of approximately 1.5 g. Sinus velocity was measured by cardiotachoceres triggered by the voltage of the right atrium. Blood flow through the right coronary artery was measured with an electromagnetic flow meter. The recording of the developed voltage, sine velocity, and blood flow was made on paper using a multichannel ink recorder. Compounds in the amount of 10-30 μl were administered intraarterially for 4 s. The inotropic effect of the compounds was expressed as a percentage of
    1-5
    voltage developed before injecting days of compounds. The effect of the compounds on the sinus velocity (beats / min) was expressed as the difference between the values before and after the administration of the compound.
    The results are presented in table 1.
    Test compounds:
    1. Monohydrobromide 6- (3-methyl-azo) -1,2-a (pyridin-2-yl) -methyl-3,4-dihydrocarbostyril,
    2. Monohydrobromide 8-methoxy-6- - (3-methylimidazo) -1,2-a (pyridin-2- -yl) -3,4-dihydrocarbostyril.
    3. Monohydrobromide 5- (3-methyl-6,8-dibromimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril.
    4. Hemihydrochloride hemihydrate
    1-propargyl-5- (imidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3,4-dihydrocarb steryl.
    5. Monohydrate monohydrobromide 5- (3,7-dimethylimidazo) -1,2-a (pyridine-2-IL) -8-methoxycarbostyril.
    but. Isoprenaline (comparison) Amrinon (comparison).
    6.1 / 4-hydrate monohydrobromide 5- (3-ethylimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril.
    7. Moiohydrochloride 1-methyl-5- - (imidazo) -1,2-a (pyridin-2-sh1) -8- -methoxy-3,4-dihydrocarbostyril.
    8. Hydrate monohydrochloride 5- (6-chloroimidazo) -1,2-a (pyrcin-2-yl) -8-methoxycarbostyril.
    9.3 / 2-Hydrate of monohydrochloride 5- (7-methylimidazo) -1,2-a (pyridine-2-shl) -8-methoxycarbostyril.
    10. Monohydrochloride 1-Acyl-5- - (imidazo) -1,2-a (pyridin-2-yl) -8- -methoxy-3,4-dihydrocarbostyril.
    11. Monohydrochloride-5- (imidazo) -1,2-a (pyridin-2-yl) -8-hydroxycarbyl reel.
    12. Monohydrochloride of b- (imidazo) -1.2-a (pyridin-2-yl) -carbostyril.
    13. Monohydrate monohydrobromide 6- (3-ethylimidazo) -1,2-a (pyridin-2- -yl) -carbostyril.






    14.5- (3-Methyl-6-nitroimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyryl. .
    15.5- (8-Oxyimidazo) -1,2-a (pididin-2-yl) -8-methoxycarbosteryl.
    16.5 / 2-Hydrate monohydrochloride 5- (8-methoxyimidazo) -1,2-a (pyridin--2-yl) -8-methoxycarbostyril.
    sh
    15
    20
    25
    thirty
    17. Monopodrochloride 5- (imrvdazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyryl.
    18. Monohydrochloride b- (imidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbostyril.
    19. Monohydrochloride monohydrochloride 6 (3-methylimidazo) -1,2-a (pyridin-2-yl) -8-methyl-3,4-dihydrocarbostyril.
    20. Monohydrobromide 5- (3-ethylimidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril.
    21. Monohydrobromide 5- (3-methyl-imidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril.
    22. Hemihydrate of monohydrobromide 5 (3-methylimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril.
    23.3 / 2-Hydrate monohydrochloride 5 (imidazo) -1,2-a (pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyryl.
    24. Monohydrobromide hemihydrate of 6 (3-methylimidazo) -1,2-a (pyridin-2-yl) -3,4-digdrocarbostyril.
    25. Monohydrobromide 6 (3-methylimidazo) -1,2-a (pyridin--1-yl) -8-chloro-3, 4-dihydrocarbostyril hemihydrate.
    Preparative example 1. Tablets
    the following composition, mg: 8-methoxy- (3- -methylimidazo) -1,2- - a (pyridin-2-sh1) -3,4- -dihydrocarbostyril monohydrobromide 5 starch132
    Magnesium stearate 18
    Lactose45
    Preparative example 2. Tablets
    of the following composition, mg: 6- - (3-methylimidazo) monohydrobromide - -1,2-a (pyridin-2-yl) -1 -1 methyl-3,4-dihydrocarbostyril1 O Starch 127 Magnesium stearate 18 Lactose 45 Preparative example 3 . Solution
    l injection.
    Hemihydrate of monohydrobromide 8-chloro-b- (3-methylimidazo) -1,2-a (pyridin-2-yl) -3,4-dihydrocarbostyril, mg 500
    Polyethylene glycol
    (molecular weight 4000), g0.3
    Sodium chloride, g 0.9 Polyoxyethylene
    bitano monooleate, g 0.4 Sodium metabisulfite, g 0.1 Methyl paraben, g 0.18.
    Propyl paraben, g 0,02 Distilled water
    for injection, ml 100
    Said parabens, sodium metabisulphitis and sodium chloride solution in distilled water at 80 ° C and under stirring. The resulting solution is cooled to 40 ° C, polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in it, then brought to final volume with distilled water for injection. The mixture is filtered using a suitable filter paper for sterilization and then filled with 1 ml vials, thus obtaining an injection.
    Preparative example 4. Tablets of the following composition, mg:
    Monohydrobromide monohydrate 1-methyl-5- (imidazo) -1,2-
    -a (pyridin-2-yl) -8-methoxy-3, 4-dihydrocarbostyryl5
    Starch132
    Magnesium stearate 18
    Lactose45
    Formulation 5: Tablets of the following composition, mg:
    Dihydrate monohydrochloride 5- (6-
    -chloroimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyril 10
    Starch127
    Magnesium stearate 18
    Lactose45

    The tablets described in Preparative Examples 1, 2, 4 and 5 are prepared in the usual manner.
    Preparative example 6. Solution for injection.
    Monohydrate monohydrochloride 5- (3,7-dimethylimidazo) -1,2-a (pyridin-2-yl) -8-methoxycarbostyrap, mg 500
    Polyethylene glycol
    (molecular weight
    4000), g0,3
    Sodium chloride, 0.9 g
    Polyoxyethylene sorbitan monooleate, g 0,4
    Metabisulphite
    rub, g0,1
    Methylparaben, 0.18 g
    Propyl paraben, g 0,02
    Distilled
    water for injection, ml 100
    These parabens, sodium metabisulfite, and sodium chloride are dissolved in distilled water at 80 ° C and mixed. The resulting solution is cooled to 46 ° C and polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in it. It is then brought to final volume with distilled water for injection. The mixture is filtered using a suitable filter paper for sterilization and is filled with a 1 ml ampoule with it, thus obtaining an injection preparation.
    As described, carbostyryl compounds and their pharmaceutically acceptable salts are suitable as cardiostimulating agents for treating heart diseases such as congestive sephiditis and the like.
    Table 2 shows the data on all the compounds obtained.
    Table
    77.7 128.4
    3.6 1.6
    0.3
    one
    one
    1 -10
    one
    one
    one
    0.3
    0.3
    eleven
    0.1
    0.03
    0.3
    0.3
    0.3
    eleven
    0.1 0.3
    one
    one
    one
    0.3
    one
    -five
    41.2 63.2 09.1 84.68 86.4 61.5 45.8 18.2 14.3 50.0 18.8 40.6 71.4 35.7 38.5 14.5 89, 7
    05 81.2 25
    04.2 84.6 95
    23.3 194.7
    1.8
    2.4
    4.0
    3
    4.8
    2
    1.5
    1.2
    2.6 2.4 1.6 1.8 1.4 0.8
    2.8 3.5 2.0 0.8 1.0 0.4 1.2 2.4 2.0
    21
    1215621
    22 Table 2
    Hydrogen
    -N
    Lower Alkyl Lower Alkenyl Lower Quinil Phenyl Lower
    - CH,
    1 and
     11 -CH-C5CH 11
    "Mr. R,
    -N
    Many test compounds
    11-CH,

    -CH2CHN CH2
    1 and 7
    eleven
    four
    Hydroxy
    -HE
     Position, substitutions on the carbostyril moiety,
    Editor M. Petrov
    Compiled by G.) ukova
    Tehred N.Vonkalo Proofreader A. Obruchar Order 2529 Circulation 379 Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, ul. Project, 4
    f test compound
    eleven
    -HE
    17
    权利要求:
    Claims (1)
    [1]
    A method of producing carbostyryl derivatives of the general formula (I) where R
    - hydrogen, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl (lower) alkyl group;
    R 2 is hydrogen, a lower alkyl group, a lower alkoxyl group, a halogen or hydroxyl group;
    Rg is hydrogen or a lower alkyl group;
    R 4 and R 5 are the same or different, each hydrogen, halogen, lower alkyl group, hydroxyl group, lower alkoxyl group or nitro group;
    the relationship between positions 3 and 4 in the carbostyril core is single or double;
    the position in which the imidazopyridyl group of the general formula is attached to the carbostyril core, 5 or 6;
    with the proviso that when the imidazopyridyl group is attached to the carbostyril core at position 5, R 2 must not be hydrogen, a lower alkyl group or halogen;
    or their pharmaceutically acceptable salts, characterized in that the compound of General formula (II) pine ’where X’ is halogen, ·
    R ,, R 2 , R ^ and the relationship between positions 3 and 4 in the carbostyril core have the indicated meanings, are reacted with a compound of the general formula (III) where R ^ and R5 have the indicated meanings, using at least an equimolar amount of a compound of the general formula ( III) per 1 mol, compounds of the general formula (II) in the presence of a dehydrohalogenating agent at a temperature of from room temperature to 150 Sv for 1-10 hours
    Priority by signs:
    11.11.80 at - hydrogen, lower alkyl; R 2 is hydrogen, lower alkyl, lower alkoxy or halogen; R 3 is hydrogen or lower alkyl; and R 5 is each hydrogen; imidazopyridyl group attached to the carbostyril core in position 6.
    12/18.80 at R ( - hydrogen, lower alkyl, phenyl lower alkyl, lower alkenyl or lower alkynyl; R 2 hydrogen or lower alkyl; R 3 - hydrogen or lower alkyl; R 4 and R 5 - each hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxy or nitro; the imidazopyridyl group is attached to the carbostyryl core at position 5.
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    同族专利:
    公开号 | 公开日
    AT382376B|1987-02-25|
    MX6802E|1986-07-29|
    SE8204237D0|1982-07-08|
    DK307482A|1982-07-08|
    EP0052016A1|1982-05-19|
    PT73959B|1983-04-18|
    SE8204237L|1982-07-08|
    AU547586B2|1985-10-24|
    US4414390A|1983-11-08|
    FI822471A0|1982-07-12|
    IT8149680D0|1981-11-11|
    PH17158A|1984-06-13|
    NO822391L|1982-07-09|
    AU7808581A|1982-06-07|
    CA1164459A|1984-03-27|
    PT73959A|1981-12-01|
    DK157193C|1990-04-09|
    DK157193B|1989-11-20|
    FI71145B|1986-08-14|
    WO1982001706A1|1982-05-27|
    DE3152512T1|1982-11-18|
    NO157819C|1988-05-25|
    KR880001657B1|1988-09-05|
    CH653684A5|1986-01-15|
    NO157819B|1988-02-15|
    FI822471L|1982-07-12|
    FI71145C|1986-11-24|
    ES507545A0|1983-02-01|
    DE3152512C2|1991-01-03|
    SE440653B|1985-08-12|
    ES8301967A1|1983-02-01|
    ATA908381A|1986-07-15|
    EP0052016B1|1984-09-05|
    KR830007644A|1983-11-04|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP55159016A|JPS6411026B2|1980-11-11|1980-11-11|
    JP17995080A|JPS6411027B2|1980-12-18|1980-12-18|
    [返回顶部]