• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A quinolone inotropic agent of the formula: or a pharmaceutically acceptable salt thereof, wherein «Het» is an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group attached by a carbon atom to the 5-, 6-, 7- or 8- position of said quinolone; R, which is attached to the 5-, 6-, 7- or 8- position, is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulphinyl, C1-C4 alkylsulphonyl, halo, CF3, hydroxy, hydroxymethyl, or cyano; R1 is hydrogen, cyano (C1-C4 alkoxy)carbonyl, C1-C4 alkyl, nitro, halo, -NR3R4 or -CONR3R4 where R3 and R4 are each independently H or C1-C4 alkyl or together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic group optionally containing a further heteroatom or group selected from 0, S and N-R5 where R5 is H or C1-C4 alkyl; R2 is H, C1-C4 alkyl, or 2-hydroxyethyl; Y is H or C1-C4 alkyl; and the dotted line between the 3- and 4- positions represents an optional bond.
    公开号:SU1407397A3
    申请号:SU843826174
    申请日:1984-12-21
    公开日:1988-06-30
    发明作者:Энтони Робертс Дэвид；Фразер Кемпбелл Симон
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:


    cm
    This invention relates to a method for producing new quinolone. derivatives that selectively increase the force of contraction of the myocardium without significantly increasing the heart rate.
    The purpose of the invention is the synthesis of new compounds with valuable properties that allow their use in medicine in the treatment of heart failure.
    Example 1. Getting 6- (3- -pyridyl) -2- (1H) -quinolone.,
    A mixed solution of 2-methoxy-6- - (3-pyridyl) -quinoline (1.83 g) in an i48% -HOM aqueous solution of bromo-boric acid (6 cm) is heated at -100 ° C for 1.5 h. The mixture is cooled in an ice bath, mixed with 5 M sodium hydroxide solution and adjusted to pH 8 and continuously extracted with chloroform for 6 hours. Dried (MgS04) The organic extract is extracted with a solid, which is recrystallized from meta-iol and ethyl acetate to form 6- (3 pyridyl) -2- (1H) -quinolone, mp 217-218 C (0.62 g).
    Found,%: C 75.9; H 4.8; N 12.2.
    , N ,, 0
    Calculated
    N
    f C 75.7j H 4.5 i 12.6.
    Examples 2-11. The following Compounds were prepared analogously to Example 1, with the starting material being the Corresponding 6-substituted 2-tags of Sikhinolin and a 48% aqueous solution of IVH (Table 1). Het
    Examples 12 and 13. The following compounds were prepared analogously to Example 1, but the corresponding 3.6-disubstituted-2-methoxy-quinoline and Single 5 M hydrochloric acid solution are used as starting materials. Instead of a 48% aqueous solution of hydrobromic acid (see Table 2).
    Hettl
    0
    S
    0
    five
    0
    five
    0
    five
    0
    Example 14. Hemihydrate of 3-Methocarbonyl-6- (3-pyridyl) -2- (1H) -quinolone.
    A solution of 2-methoxy-3-methoxycarbonyl-6- (3-pyridyl) quinoline (0.50 g) in a 5 M hydrochloric acid solution (30 cm) is heated under reflux for 20 minutes. The cooled mixture is filtered, and the solid is washed with methanol, and the resulting 6- (3-pyIridyl) -2- (1H) -quinolone-3-carboxylic acid intermediate hydrochloride, m.p. 35C-352 s (0.45 g); This material is placed in methanol (50 cm) and heated under reflux in concentrated sulfuric acid (1 cm) for 1 hour. The mixture is concentrated under vacuum and the residue is divided between chloroform (100 cm) and an aqueous solution of sodium bicarbonate. The aqueous phase is extracted with chloroform (3 X 25 cm), the combined organic extracts are dried and
    evaporated, as a result of which 3-methoxycarbonyl-6- (3-pyridyl) -2- (1H) -quinolone hemihydrate is applied to the floor, mp. 223 - 225 C (0.32 g).
    Calculated,%: C, 66.9; H 4.3J N 9.4 ...
    C, H ,, N20, 0., 5Н20
    Found,%: C 66.5; H A, 5j N 9.7.
    Example 15. 3-to -carbonyl-6- (4-pyridyl) -2- (1H) - -quinolone hemihydrate, m.p. 246-248 C, prepared analogously to the previous example, using 2-methoxy-3-methoxy-carboNYL-3- (4-pyridyl) quinoline as the starting material.
    Found, -%: C 66.7; H 4.2; N 9.4.
    CffeH N Oj-
    Calculated,%: C 66.4, H 4.5J N 9.7.
    Example 16. Preparation of 8-methyl-6- (3-pyridyl) -2- (1H) -quinoline.
    A mixed solution of 2-methoxy- -8-methyl-6- (3-pyridyl) quinoline (1.07 g) in a 5 M solution of hydrochloric acid (10 cm) is heated. under reflux for 2.5 hours and then cooled. The cooled solution is basified with a pH of 9 with an aqueous solution of sodium hydroxide, an extruded mixture of chloroform and methanol with a ratio of 9: 1 (4 x 100 cm), after which the combined and dried (MgSO4) extracts are concentrated under vacuum conditions. purpose of obtaining solids. Recrystallization of the solid from a mixture of ethyl acetate and methanol afforded 8-methyl-6- (3-pyridyl) -2- (1H) -quinolone, m.p. 235.5-236.5 ° C (0.63 g).
    Found,%: C 76.0; H 5.1; N 11.6.
    C, 5H ,,,
    N
    %: C 76.2; H 5.1;
    some
    -CONH, j.
    Calculated 11.9.
    Examples 17-56. The following compounds were prepared analogously to example 16 using an appropriately substituted 2-methoxy-noline and / or 10% by volume of a 48% aqueous solution of HBg in ethanol (examples 37, 42, 46 and 51) or a 5 M aqueous solution of HC1 examples) (see table. 3).
    In Example 43, the starting material 2- -methoxy-6- (1-tributylstannyl tetrazol-5-yl) quinoline, the tributyl-stannyl group is removed under acidic reaction conditions.
    In Example 37, the groups are hydrolyzed, FROM -CN to the resulting product mixture is separated by chromatography on silica gel (Merck MK 60.9385), eluted at a volume ratio of 94: 5: 1: The carbamoyl compound is determined as in Example 51.
    Example 57. 6- (1-Methyl-1,2,4-tripiazol-5-yl) -4,8-dimethyl-2- (1H) -quinolone. 0.75; mp; 327 ° C, prepared analogously to example 16 using 6- (1-methyl-1,2,4-triazol-5- -yl) -2-methoxy-4,8-dimethylquinoline and 5 M HC1 solution as starting materials .
    Found,%: C 62.8; H 5.3; N 20.6.
     0.75H40
    Calculated,%: C, 62.8; H 3.8; N 20.9.
    Example 58. Preparation of 8-methyl-6- (2,6-dimethylpyrid-3-yl) -2- (1H) -quinolone sodium salt.
    8-Methyl-6- (2,6-dimethylpyrid-Z-yl) -2- (1H) -quinolone (94.7 g) is stirred with a 5 M aqueous solution of sodium hydroxide (379 cm) for 4 hours. Solid filtered and washed with water (380 cm), added
    (600 cm) and distilled le1407397
    isopropanol are fatty substances, resulting in a solid, which is dissolved in boiling methanol (1620 cm). Hot filter solution
    five
    they are concentrated ma (volume 270 cm) O. The precipitate is filtered and dried 50 °
    vacuum at bO C compound, live) (60.4 g). Found,% 7.9.
    under vacuum conditions, they cool to
    at
    to obtain the indicated - so pl. (splitN
    C 59.8; H 5.5;
    15
    C, N ,, Calculated%: C
    60.0; H 6.2;
    N 8.2.
    0
    0
    five
    0
    five
    0
    five
    The following examples illustrate the synthesis of new starting materials.
    Example 1. Preparation of 2-methoxy-6-bromoquinoline.
    A mixture of 6-bromo-2- (1H) -quinolone (2.90 g) and trimethyloxy tetrafluoroborate (2.10 g) is stirred in dichloro-5 methane (50 cm) under nitrogen atmosphere for 48 hours. Add 10 The solution is sodium hydroxide (20 cm), after which the aqueous phase is extracted with dichloromethane (2 x 40 cm). The dried (MgSO4) extracts are evaporated and the residue is crystallized from petroleum ether (mp. 60-80 ° C) to give 2-methoxy-6-bromoquinoline, mp. 90-944 (2.16 g).
    Found,%: C 50.7; H 3.5, N 6.0.
    C, HgNOBr
    Calculated,%: C 30.4; H 3.4; N 5.9.
    Example 2. Preparation of 2-methoxy-6-bromoquinoline.
    A solution of 2-chloro-6-bromoquinoline (4.0 g) in methanol (20 cm) is heated under reflux with sodium methyl acetate made of sodium (0.3 g) and methanol (20 for 16 h. Solvent removed under vacuum, the residue is partitioned between water (20 cm) and chloroform (100 cm). The aqueous phase is extracted with chloroform (2 X 30 cm), the dried extracts (MgSO4) are evaporated to form a solid, which is recrystallized from petroleum - ester (bp 60-80 0), the result is 2-methoxy-6-bromoquinoline, mp 93-96 0 (3.0 g),
    Found,%: C 50.4 {H 3.4 -, N 6.0.
    cm,
    c, o RgNOBr
    Calculated,%: C 50.4; H 3.4; N 5.9.
    The following compounds were prepared analogously to example 2 using the appropriately substituted 2-chloroquinoline and sodium methyl in methanol as the starting materials (see, Table 4),
    Example 10. 6-Bromo-4,8-dimethyl-2-methoxy-quinolin-O., Mp, 105 C was prepared in a manner similar to Preparation 2 using 6-bromo-2 chloro-4,8-dimethyl-chloro as starting materials. quinol and sodium methylate in met-anole.
    Found%: C 53.1; H-4.4-, N 5.2.
    C ,,, H, .j BrNO 0,25HjO
    Calculated,%: C 53.2; H 4.6; N5,2.
    Example 11. 2-Methoxy-8-methyl-6- (3-pyridyl) quinoline,
    Tert-Butyl lithium (8.0 cm, 2.0 M solution in pentane) is added dropwise to a stirred solution of 6- -brom-2-methoxy-8-methylquinoline (2.0 g) in tetrahydrofuran (20 cm) in nitrogen atmosphere at minus 70 ° C. After 10 minutes, this mixture is exposed to a solution of anhydrous zinc chloride (1.09 g) in tetrahydrofuran (10 cm) and the resulting solution is heated to 0 °. A solution containing 3-bromopyridine (1.26 g) and tetrakis (triphenylphosphine) palladium (0) (0.05 g) in tetrahydrofuran (10 cm) is added, and the mixture is heated under reflux for 2 hours. The reaction mixture cooled, concentrated under vacuum and exposed to chloroform (100 cm) and a solution of ethylenediaminetetraacetic acid, disodium salt (6 g), in water (100 cm). The aqueous phase is extracted with chloroform (3 x X 50 cm), the combined and dried (MgSO4) extracts are concentrated under vacuum to form a gel. This oil is chromatographed on silica gel (Merck MK 60.9385 s., Eluted with ethyl acetate. The fractions containing the product are combined and evaporated to give a solid, which is recrystallized. Lysing from hexane to form 2- methoxy-8-methyl-6 - (3-pyridyl) quinodane, mp 117-118.5 ° C (1.12 g).
    407397 6
    Found,%: C 76.5-, H 5.7,
    N
    , 0,
    C ,, H ,,
    f Calculated,%: C 76.8, H 5.6
     N11.2.
    Examples 12-40. The following compounds were prepared analogously to the previous method of preparation using the bromo-substituted heterocycle and the appropriately substituted 2-methoxyquinoline as the starting materials (see Table 5). Example 41 (alternate
    5 method for preparing example 20). 8-Methyl-6- (2,6-dimethylpyridin-3-yl) -2--methoxy-quinolin-O, 33.
    Solution of 3-bromo-2,6-dimethylpyridine (0.935 g) in tetrahydrofuran (THF)
    0 (5 cm) is added dropwise to a stirred suspension of magnesium chips (0.133 g) and iodine (0.005 g), in tetrahydrofuran under heating with reflux. Magnesium is completely absorbed after heating for 1 hour, after which the solution is cooled to O during the addition of a solution of anhydrous zinc chloride (0.680 g) in tetrahydrofuran (4 cm).
    0 After half an hour, add a bt solution of 6-bromo-8-methyl-2-methoxy-quinoline (1.25 g) and tetrakis (t-riphenylphosphine) palladium (0) (0.05 g) in tetratidrofuran (10 cm), a mixture heat under reflux for 4 hours. The cooled mixture is partitioned between chloroform (100 cm) and ethylenediaminetetraacetic acid disodium salt (4 g) in water (80 cm). Waterway
    The phase is extracted with chloroform (2 x X 50 cm) and the combined and dried (MgSO4) extracts are evaporated under vacuum to give an oil, which is chromatographed on silica gel (Merck MK 60.9385), eluting with chloroform. Compounding and evaporating the corresponding fractions allows an oil (1.04 g) to be obtained which crystallizes during the trituration with hexane to form 8-methyl-6- (2,6-dimethyl-pyrid-3-yl) -2-marks of chiolinoline 0.33, so pl. 74-7b with.
    gg Found,%: C 76.5; H 6.4; N 9.7.
    C, BE-g, 33H20
    Calculated,%: C 76.0 :, H 6.6, N 9.8.
    35
    five
    0
    one
    Example A2 (alternative to the production method of Example 12). 2-Methisi-6- (3-pyridyl) -quinoline.
    tert-Butyl lithium (7.7 cm of a 2.6 M solution in pentane) is added dropwise over 5 minutes to a stirred solution of 3-bromopyridine (1.44 cm) in tetrahydrofuran (25 cm) in a nitrogen atmosphere at minus 100 ° C. After stirring for 10 minutes, a solution of anhydrous zinc chloride (2.05 g) in tetrahydrofuran was slowly added, the mixture was allowed to warm to room temperature over 1 hour. A solution of 2-methoxy-b-bromoquinoline (2 , 38 g) and tetrakis (triphenylphosphine) palladium (O) (0.08 g in tetrahydrofuran) (10 cm), the mixture is heated under reflux for 9 hours. Then a solution of ammonium chloride (20 cm) is added, It is concentrated under vacuum and the aqueous phase is extracted with chloroform (Ex. X 50 cm). The dried iMgSO) extracts are evaporated in vacuo to form a solid, which is subjected to chromatographic on silica gel (Merck MK 60.9385) with elution with a mixture of ethyl acetate and hexane in the ratio 1: 1, resulting in a residue, recrystallized from petroleum ether ( so kip. 60-80 C) and a simple ether with the formation of 2-methoxy-6- (3-pyridyl) quinoline, so pl. 89-91 C (0.35 g)
    Found,%: C 76.4, H 5.1; N 11.6.
    C.sHaNjO
    Calculated,%: C 76.2; H 5.1-, N 11.9.
    Examples 43-46. The following compounds were prepared according to the procedure of the previous preparation method, using the appropriate bromopyridine and 6-bromo-3-cyano-2-methoxy-quinoline (examples 43 and 44) or 6-bromo-2-methoxy-3 as starting materials. -methoxycarbonyl- quinoline (examples 45 and 46). The data are summarized in table. 6
    Example 47. 2-Methoxy-6- (4-pyrimidine 1) quinoline.
    n-Butyl lithium (2.7 cm 1.5 M solution in hexane) is added dropwise to a stirred suspension of 2-methoxy-6-bromoquinoline (0.95 g in ether) (5 cm) under a nitrogen atmosphere
    073978
    at 5 ° C 70 ° C. After all the solid was dissolved, pyrimidine (0.32 g) in ether (1 cm) was added dropwise, and the solution was allowed to warm to room temperature. A saturated solution of ammonium chloride (5 cm) is added, the aqueous phase is extracted with
    10 Rut with chloroform (3 x 10 cm) and the dried (MgSO4) extracts are concentrated under vacuum to give an oil. This residue is placed in acetone and added dropwise
    15 calcium permanganate solution
    (O, 63, g) in acetone until a persistent purple color is formed. This mixture is filtered through a solka-flock (trademark) and concentrated in
    20 vacuum conditions, an oil is obtained, which is chromatographed on silica gel (Merck MK. 60.9385), eluting with a mixture of ethyl acetate and hexane in relation to
    25 1: 1 with the formation of solids. Recrystallization from ethyl acetate affords 2-methoxy-6- (4-pyri-1 "1-dynyl) honoline, m.p. 164-165 С
    (0.54 g).
    Detected%; N 17.9.
    C 70.5) H 5.0
    C, 4H ,, NjO
    N
    five
    0
    five
    0
    five
    Calculated,%: C 70.9} H 4.7; 17.7.
    Examples 48 and 49. The following compounds were prepared analogously to the previous method of preparation using pyridazine and 2-methoxy-6-lithium quinoline as starting materials. In this case, a mixture of 2-methoxy-6- (4-pyridazinyl) -quinoline and 2-methoxy-6- (3-pyridazi-, nip-quinoline) is obtained, which is separated by chromatography on silica gel (Merck J. 60.9386) with elution ethyl acetate (see tab. 7) ..
    Example 50 1/4-l-Metoxy-6- (pyrazin-2-yl) quinoline hydrate.
    tert-Butyl lithium (4.6 Dec of a 2.6 M solution in pentane) are added to Coplilla to a stirred solution of 2-methoxy-6-bromoquinoline (1.43 g) in tetrahydrofuran (10 cm) under nitrogen atmosphere at minus 70 . After 20 minutes, a solution of pyrazine (0.48 g) in tetrahydrofurline (5 cm) is added, after stirring, in an EPP. 20 minutes through the solution for a period of 0.3 hours and at Miius 70 C a stream of dry is bubbled
    9
    chloroform (50 cm) is added, the solution is washed with water (10 cm), dried (MgSO4) and concentrated under vacuum to form a residue, which is subjected to chromatography on silica gel (Merck MK. 60.9385) with elution with a mixture of ethyl acetate and hexane in the ratio 1: 1, the result is a solid. Recrystallization of ethyl acetate yields 2-to-to-6- (2-pyrazinyl) quinoline 1/4 H, Ti pcs. 130-132 ° C (0.22 g).
    Found,%: C $ 69.9; H; 4.6; N 17.1.


    SCN „N, 0. 1 / 4H, go
    Calculated,%: C 69.6, H 4.8 {N 17.4.
    Example 51, 3-Cyano-6-bromo-2- (1H) -quinolone.
    Suspension of 3-cyano-2- (1H) quinolo-Ia (13.3 g) in acetic acid (130 cm) at room temperature Exposed to a solution of broth (4, 1 cm) in acetic acid (10 cm), after heating under reflux for 4 h, the mixture is cooled to room temperature, filtered and the solid is washed with ethanol, the result is 3-cyano-6-bromo-2- (1H) -quinolone (14.63 g), a small amount of which is recrystallized from ethanol, pl. 308-311 C,
    Obnarutkno,%; C, 48.6; H 2.1; N 11.4,
    C oHyNjOBr
    Calculated,%: C 48, .-, H 2.00;
    S 11.3. g
    Example 52. 6-Bromo-3-cyano-2-methoxy-quinoline.
    A suspension of 6-bromo-3-cyano-2- (1H) -quinoline (14.6 g) in dichloromethane (150 cm) is stirred under a nitrogen atmosphere with trimetn-oxonium tetrafluoroborate (10.35 g) for two days. A 2 M solution of sodium hydroxide (100 cm) is added, after which the aqueous phase is extracted with dichloromethane (3 x 200 cm). The dried (MgSO4 extracts are concentrated under vacuum, the residue is subjected to silica gel chromatography (Merck MK-60.9385), eluting with a mixture of hexane and ethyl acetate in the ratio 4: 1, to give a solid
    N 5
    0
    five
    0
    five
    0
    0
    five
    ten
    during which the recrystal is lysed from ethyl acetate to form 6-bromo-3-cyano-2-methoxy-quinoline, e.g. 169-172 C (1.96 g).
    Found,%: C 50.4; H 2.8 N 10.8.
    C4
    Calculated,%: C 50.2 H 2.7; 10.7.
    53, 2-Chloro-6-bromo-3; Example: cyano-quinoline,
    6-Bromo-3-cyano-2- (1H) -quinoline (142 g) is heated under reflux to phosphorus oxychloride (500 cm) for 1.5 hours. The volatiles are removed under vacuum, the solid residue is placed in chloroform (400 cm) after which the resulting suspension was poured into ice. This mixture is neutralized with an aqueous solution of ammonia (S, G, 0.880), the aqueous phase is extracted with chloroform (2 X 150 cm). Dried (MgSO4) organic extracts are concentrated in vacuo, the residue is chromatographed on silica gel (Merck MK 60.9385), eluting with toluene to give a solid, which is recrystallized from ethyl acetate to give 2-chloro-6-bromo-3-cyano - quinoline, t, pl. 228- (80 g),
    Found,%: C 44.6, H 1.5; N 10.6,
    Cj HyClBrN,
    Calculated% N 10.5.
    EXAMPLE 54 (alternative production method 52), 6-Bromo-3-cyano-2-methoxyquinoline.
    A solution of 6-bromo-2-chloro-3-cyano-quinoline (1.2 g) in methanol (30 cm) is heated under reflux for 16 h with sodium metipate, 5 obtained from sodium (0.116 g) and methanol (20 cm). This mixture is cooled to 0 °, the solid is filtered, the result is 6-bromo-3-cyano-2-methoxy-quinoline, t, mp, 172-174 ° C (0.60 g),
    C, 49.8; H 2.8; N
    C 44.9-, H 1.5;
    N
    Found 10.4, C 44 H NjOBr
    Calculated, /, 10.7, Example
    C 50.2; H 2.755. Similarly to the preceding method of preparation, using 6-brb-2-chloro-3-methoxycarboxy-1-quinoline as the starting material, 6-bromo-2-synthoxy-3-methoxycarbonyl-quinoline is synthesized, mp. 144-1D5 ° C.
    Detected%; C 49.0-, H 3.5; N5.1.
    C ,,, H, BrNO ,,
    Calculated,%: C 48.7 H 3.4; N 4.7.
    Example 56. 6-Bromo-2- (1H) -quinolone-3-carboxylic acid.
    A mixed solution of 3-ethoxycarbonyl-2- (1H) -quinolone (4.5 g) in acetic acid (50 cm) is exposed to a solution of bromine (16 g) in acetic acid (20 cm) at room temperature. The mixture is heated under reflux for 24 hours, cooled and filtered to form 6-bromo-2- (1H) -quinolone-3-carboxylic acid, mp. 300 ° C (3.42 g) as a crude solid.
    Example 57. 6-Bromo-2-chloro-3-β-methoxycarbonylquinoline.
    A stirred suspension of 6-bromo-2- - (1H) -quinolone-5-carboxylic acid (3.4 g) in phosphorus oxychloride (40 cm) is heated under reflux for 2 hours. This mixture is cooled, evaporated to dry conditions under vacuum, the solid residue is exposed to methanol (50 cm at 0 ° C.) After stirring for 2 hours at room temperature, the mixture is filtered, the solid is washed with methanol, and 6-bromo-2-chloro are obtained. 3-methoxycarbonylquinoline, mp 176-177 C (1.82 g).
    Found,%: C 44.0; H 2.3, N 4.7.
    With „H BrClNOi
    Calculated,%: G 44.0, H 2.3; N 4.7.
    Example 58. 6-Iodine-2- (1H) -quinolone.
    A solution of 2 (1H) -quinolone (2.0 g) and silver sulfate (2.14 g) in concentrated sulfuric acid (15.0 cm) is stirred at room temperature while adding | iodine (3.5 g). After heating at 50 ° C for 24 hours, the mixture was poured into ice, the solution was neutralized with solid sodium carbonate, and the solid was filtered off. This material is subjected to chromatography on silica gel (Merck MK 60.9385
    g
    -
    Yu
    g 20
    25
    zo)
    ) 50 gg oh)
    35
    45
    397. 12
    with elution by chloroform, and the result is a residue which is recrystallized from methanol to form 6-IODE-2 (1H) -quinol1a, mp. 261 ° C (0.8 g).
    Found,%: C 41.0; H 2.4; N 5.5.
    C 9 HgINO
    Calculated: C 39.9; H 2.2; N 5.2.
    Example 59. 6-Bromo-2-chloro-8-β-methylquinoline.
    A mixture of 6-bromo-8-methyl-2- (1H) -xiiHolon (12.0 g) in phosphorus oxychloride (100 cm) is refluxed for 2 hours. The volatiles are removed under vacuum, the residue is dissolved in chloroform (200 cm), and the resulting solution is poured onto ice (200 g). The basicity of this mixture is adjusted to pH 100 with aqueous ammonia (0.88), the aqueous phase is extracted with chloroform (2 x 100 cm). The combined and dried (MgSO.) Extracts are concentrated in vacuo to give a solid (10.7 g), which is recrystallized from ethanol, to give 6-bromo-2-chloro-8-methyl 1-quinoline, t. square
    ti-pb with.
    % Found: C 47.2 N 2.7 {N 5.8.
    C gH BrClN
    Calculated,%: C 46.8J H 2.7, N 5.5.
    Examples 60-65. The following compounds are prepared analogously to the previous method of preparing using as a starting material rials a mixture of 5-bromo-2- (1H) -quinoline and 7-bromo-2- (1H) -quinolone with a ratio of 1.0: 1.7 ( used in production methods 60 and 61) and a mixture of 6- - bromo-5-methyl-2- (1H) -quinolone and 6- -, bromo-7-methyl-2- (1H) -quinolone with a ratio of 1.0: 2,3 (used in production method 63), 6-iodo-7- (prop--2-yl) -2- (1H) -quinolone (used in production method 64) and 6-bromo-8-methoxy-2 (1H) -quinolone (used in production method 65) and phosphorus oxychloride, Table 8).
    Example 66. 6-Bromo-2-chloro-4,8-dimethylquinoline, m.p. 182 C was prepared analogously to example 59 using 6-bromo-4,8-dimethyl-2- (2H) -quinolone and phosphorus phosphorus as starting materials.
    Found%: C 48.3j H 3.3 - N 5.3.
    With „H, BrClN
    Calculated,%: C 48.3 H, 3.3 N 5.2.
    Example 67. 6-Bromo-8-methyl- (1H) -quinolone.
    Trans-K- (4-Brom-2-methylphenyl) -3-ethoxypropenamide (2.0 g) is added in portions to 98% sulfuric acid (15 cm) while stirring at room temperature. After 16 h, the solution was poured into ice (100 cm), the resulting precipitate was filtered and dried (1.5 g). Re- (crystallization from a mixture of ethyl acetate and methanol allows to obtain 6- -bromo-9-methyl-2- (1H) -quinolone, mp 272-274 C.
    Found,%: C 50.4j H 3.4; N 6.1.
    C, 0 Hg NOBr
    Calculated,% s C 50.4, H 3.4; N 5.9.
    Examples 68-75. The following Compounds are prepared analogously to the pre- (1–3-bromo-phenyl) -3-ethoxypropenamide (in Preparation Methods 68 and 69), TpaHC-N- (4-6poM- -3-methylphenyl) -3-ethoxy-propenamide (in production methods 70 and 71), Trans-H- (4-iodophenyl) -3-ethoxypropene amide (in production method 72), trans-N- (4- iodo-2-ethylphenyl) -3-ethoxypropanamide (in the production method 73), trans-N- (4-iodo-2-) prop-2-yl (- -phenyl) -3-ethoxypropenamide (in the production method 74 ) and trans-H- (4-bromo-2-methoxyphenyl) -3-ethoxypropanoamide (in the process of preparing or 75) and 98% sulfuric acid (see. Table. 9)
    An alternative example to Preparation 58. 6-iodo-4-methyl-2- - (1H) -quinolone is a known compound.
    Example 76. 6-Bromo-4,8-dime-2- (1H) -quinolone.
    H- (4-Bromo-2-methylphenyl) acetoacetamide (18 g) is heated at 100 ° C for 5 hours in 98% sulfuric acid (50 cm) with constant stirring. The cooled в mixture is poured into ice (200 g), the solid is filtered off and dried under vacuum at 100 ° C for 2 U, the result is a crude 5 product (15.0 g). A small part (1.5 g) of this material recrystallized from a mixture of ethyl acetate and methanol to form 6-; bromo-4,8-dimethyl-2- (1H) -quinolone, m.p. 10 300 ° C (1.1 g).
    Found,%: C 52.0 H 4.1; N 5.5.
    With „H, oBrNO
    Calculated,%: C 52.4, H 4.0, 15 N 5.6.
    Example 77 H- (4-Bromo-2-methylphenip) -acetoacetamide.
    A mixture of 4-bromo-2-methipaniline (25 g) and diketene (11.8 cm) in toluene 20 (100 cm) is heated under reflux with constant stirring for 5 hours. After cooling to room temperature, the precipitated solid is filtered off 25 wate and recrystallize from mixture
    hexane in ethyl acetate to form .N- (4-bromo-2-methylphenyl) -atsetoacetate-amide, m.p. 109 ° C (14.0 g). Found,%: C 48.5; H 4.4, 30 N 5.4.
    C ,, H, 2 BrNO
    Calculated,%: C 48.9; H 4.5; N 5.2.
    Example 78. trans-H- (4-Bromo-2g -2-methylphenyl) -3-toxypropenamide.
    Trans-3-ethoxypropenoyl chloride (0.74 g), at O, is added to a stirring solution of 4-bromo-2-methylaniline (0.93 g) in pyridine (10 cm). 40 After 0.5 h, water (40 cm) is added, the solid is filtered, washed with water (30 cm) and dried. The resulting product is recrystallized from ethyl acetate to form g trans-N- (4-6poM-2-methylphenyl) 3-ethoxypropenamide, mp. 163-164 ° C (1.3 g).
    Found,%: C 50.7, H 5.0; N 5.1.
    CnH NOgBr
    Calculated,% C 50.7; H 5.0j N 4.9.
    Examples 79-85. The following compounds were prepared in a manner similar to the preceding method of preparation using the appropriately substituted aniline and trans-3-ethoxypropenoyl as the starting materials (see Table 10).
    1A07397
    (prop-2
    a) to g p-2-yl-sodium (250 cm), separate section cm and sodium by organization of 15 sol-5-yl quinoline.
    6-Cyano-2-metho And tri-n-buty azide jointly heating for 18 h, into a 2-methoxy-6-1-tr-tetrazol-5-yl chemical oil, which was directly prepared from 6-2- (1H) -quinolone
    Example 9 -butyl- (1H) -tetra and 2-methoxy-6-26-cyano-2-metho and azide tri-n-buty jointly heating for 18 h. Then to 100 ° С, add til (0.42 g ), alternating mixture for 3 hours. The residue was separated by nitrile (20 cm) and a layer of acetonitrile vacuum conditions. Chromatography of le (Merck MK 60.9 em dichloromethane chit (Rf 0.75 v c methane with a ratio of si-6-2 butyl- (2H quinoline in the form of sy and rf 0.62 in a mixture of thanol with a ratio of -6-1 -butyl (1H) -t lin as crude These compounds are for further purification and 45.
    oil, which is subjected to chromatography on silica gel (Merck MK 60. 9385) with elution with hexane. Combining and evaporating the product fractions affords the product as a crude, dark, unstable oil (38 g), which is not fully characterized, but is used in preparation method 84.
    Example 87. 4-Iodine-2-etipanine-LI (cfu oil) is prepared similarly to the previous preparation method using 2-ethylaniline as the starting material (4-bromo-2-methoxyaniline is a known compound).
    Example 88 6-Cyano-2-methoxy-quinoline.
    A mixture of 6-bromo-2-methoxyquinoline (0.476 g), potassium cyanide (0.26 g) potassium hydroxide (0.05 mg) and palladium (II) acetate (0.067 g) in dimethylformamide (2.0 cm) is heated at 135 ° C for 3 hours. The cooled solution is then partitioned between water (20 cm) and chloroform (50 cm), the aqueous phase is extracted with chloroform (2 x 25 cm). The combined and dried (MgSO4) extracts are evaporated in vacuo, the residue is chromatographed on silica gel (Merck G 60.9385), eluting with toluene, and 6-cyano-2-methoxy-quinoline is obtained after assembly and evaporation of the corresponding fractions. . 163-165 С (0,216 g)
    C, 71.7; H 4.4;
    Found, N 14,8.
    CnHgN o
    Calculated,%: C 71.4; H 4.4; N 15.2.
    An example is tributylstanyl- (1H) -tetrazol-5-yl-quinoline.
    89, 2-Methoxy-6-1

    sixteen
    ash-5-yl quinoline.
    6-Cyano-2-methoxyquinoline (0.368 And tri-n-butyltin azide (g) are heated together at 110 ° C for 18 h, the result is 2-methoxy-6-1-tributylstanyl (1H) - tetrazole-5 yl-quinoline in the form of crude oil, which is not further purified, and is directly used in production method 6 (tetra: - "ol-5-yl) - -2- (1H) -quinolone (see Example 43).
    Example 90. 2-Methoxy-6- 1- -butyl- (1H) -tetrazol-5-yl quinoline and 2-methoxy-6-2butyl- (2H) -tetra5 sol-5-yl quinoline.
    0
    50
    g 0
    6-Cyano-2-methoxyquinolic (0.368 g) and tri-n-butyltin azide (0.73 g) are heated together at 120 ° C for 18 hours. The mixture is then cooled to 100 ° C, n-butyl iodide is added. (0.42 g), then the reaction mixture is stirred for 3 hours. The residue is partitioned between acetonitrile (20 cm) and hexane (20 cm) and the acetonitrile layer is concentrated under vacuum to form an oil. Chromatography of oil on sipicagele (Merck MK 60.9385) with elution with dichloromethane allows to obtain (Rf 0.75 in a mixture of chloroform and methane with a ratio of 19: 1) 2-methoxy-6-2-butyl- (2H) -tetrazol-5-yl-quinoline as a crude oil (0.087 g) and (Rf 0.62 in a mixture of chloroform and methanol with a ratio of 19: 1) 2-methoxy- -6-1-butyl (1H) -tetrazol-5 -il) quinoline in the form of crude oil (0.30 g). These compounds are used without further purification in Examples 44 and 45.
    Example 91. 6-Bromo-4-methyl-3,4-DIHIDRO-2- (1H) -quinolone.
    A solution of bromine (0.08 cm) in vinegar
    0
    Acidic acid (1 cm) is added at 5 room temperature to a stirred solution of 4-methyl-3,4-dihydro-2- - (1H) -quinolone (0.5 g) in acetic acid (4.0 cm). After 2 hours, the volatile substances are removed under vacuum, the residue is partitioned between chloroform (50 cm) and water (20 cm), the organic phase is extracted with chloroform (2 x 20 cm). The combined and dried (MgSO4) organic extracts g are evaporated in vacuo, the solid residue is recrystallized from ethyl acetate to form 6-bromo-4-methyl-3.4-dihydro-2- (1H) -quinolone, i.e. . 190 ° C (0.35 g).
    1714
    Found,%: C 50.2} H 4.2; N 6.0.
    C, oH, BrNO
    Calculated,%: C 50.0, H 4.2, N 5.8.
    6-Bromo-3,4-dihydro-2- (1H) -quinolone is a known compound.
    Example 92. 6-Iodine-3-nitro-2- - (1H) -quinolone.
    A mixed mixture of 2-amino-5-iodo-benzaldehyde (2.0 g) of ethyl nitrate (4.2 g) and piperidine (0.7 g) is refluxed in ortho-xylene (100 cm) for 1, 5 h. The cooled solution is concentrated, under vacuum, the solid residue is recrystallized from a mixture of chloroform and isopropanol to form 6-iodo-3-nitro-2- (1H) -quinolone, mp. 279-282 ° C. (1.14 g).
    Found,%: C 34.6 {H 1.7-; N 8.6.
    WITH,
    Calculated,%: C 34.2; H 1.6; N 8.9.
    Example 93. Hemihydrate of 2-amyo-5-iodobenzaldehyde,
    Magnesium dioxide (0.044 g) is added to a stirred solution of 2-amio-5-iodobenzyl alcohol (0.125 g) 8 dichloromethane (10 cm) after which the mixture is stirred for 6 hours. Then add another portion of the bottom magnesium oxide (0.044 g) and stirring is continued for 16 hours. The mixture is filtered, the filtrate is evaporated under vacuum, the residue is subjected to silica gel chromatography (Merck ME 60.9385) with elution with ethyl acetate, the necessary fractions are collected and concentrated under vacuum with . the formation of 2-amino-5-iodobenzaldehyde 0,5 in the form of a solid, so pl. 105 C (0.1 g).
    Found,%: C 3,0} H 2.4; N 6,1
    C HgINO.0,5 HjG
    Calculated,%: C 32.8; H 2.5; N 5.5.
    Example 94. 2-Amino-3-yodbenyl alcohol.
    A solution of diisobutylaluminum hydrate (210 cm of a 1.5 M solution of tetrahydrofuran) is added at minus 30 ° C to a mixed solution of methyl 2-amino-5-iodobenzoate (28.0 g) in tetrahydrofuran (100 cm) in nitrogen atmosphere. This mixture is warmed to room temperature. 718
    The mixture is stirred for 16 hours and exposed to methanol (35 cm). Ethyl acetate (50 cm) was added, the mixture was filtered to remove inorganic material. The filtrate is concentrated under vacuum to form a solid, which is subjected to chromatography on silica gel (Merck MK 60.9385) with elution with a mixture of chloroform and methanol in a ratio of 49: 1 (by volume), after which the necessary fractions are collected and evaporated under vacuum, which allowed us to obtain 2-amino-5-yodobenzipovogo alcohol, so pl.
    (19.0 g);
    Found,%: C 34.4; H 3.2; N 6.0.
    With ,, HgINO
    Calculated,%: C 33.8; H 3.2; N 5.6.
    Note t p 95, 2-methoxyquinoline-6-carboxylic acid.
    n-Butyl lithium (63 cm of a 1.6 M solution in hexane) is added dropwise to a stirred solution of 6-bromo-2-methoxyquinoline (20 g) in tetragon and hydrogenofuran (250 cm) under nitrogen at minus. After 0.5 tj, solid carbon dioxide (50 g) is added, the solution is allowed to warm to room temperature, and the volatiles are removed under vacuum. The residue is partitioned between dichloromethane (100 cm) and water (100 cm), the aqueous phase is separated and acidified to pH 3.5 with a 5 M hydrochloric acid solution. The precipitated solid is filtered and dried (14.2 g). Recrystallization of a small part from isopropanol allowed to obtain 2-methoxy-quinoline-6-acetic acid, m.p. 220-222 ° C.
    Found,%: C 65.1 H 4.5j N 7.0.
    C, H, NO,
    Calculated,%: C 65.0; H 4.5; N 6.9.
    Examples 96-100. The following compounds were prepared analogously to the previous method using the appropriately substituted 6-bromo- or 6-iodo-2-methoxy-quinoline (see Table 11) as starting materials.
    Example 101. Amide 2-methoxy-quinoline b-carboxylic acid.
    Oxalyl chloride (10.3 cm) is added dropwise to a stirred solution of 2-methoxyquinoline-6-carboxylic acid (12.0 g) in dichloromethane (1.00 cm) and dimethylformamide (0.1 g). When O, the mixture is heated to at room temperature and after 2 hours, volatiles are removed under vacuum. The residue is placed in dichloromethane (100 cm), cooled to O and carefully exposed to an aqueous solution of ammonia (30 cm S.G.0.880). After 2 hours, the mixture is concentrated under vacuum, the solid residue is recrystallized from isopropanol to give the amide 2-methoxyquinoline-6-carboxylic acid, mp 212-214 (7.9 g).
    Found,%: C 65.0; H 5.0 N 13.8.
    C ,, H,
    Calculated,%: C 65.3, -H 5.0, N 13.9.
    Examples 102-106. The following compounds were prepared analogously to the previous method of preparation using oxalyl chloride as the starting materials, respectively, substituted 2-methoxy-quinoline-6-carboxylic acid and ammonia (see Table 12).
    Example 107. 2-methoxy-quinoline-b- (H) -dimethylaminomethylene-carboxylic acid amide.
    A mixture of amide-2-methoxyquinoline-6-carboxylic acid (3.0 g), dimetipacetal N-dimethylformamide (6.0 cm) is heated at 120 ° C for 1.5 w. After standing at room temperature for 16 hours, the crystalline product is filtered, washed with hexane (10 cm) and dried, and the result is 2-methoxyquinoline-6- - (H) -dimethylaminomethylene-carboxylic acid amide, m.p. 192-195 ° C (3.78 g).
    Found,%: C 65.0; H 5.9, N16.2.
    C ,, H, 5N, 02
    Calculated,%: C65,4; H5.8; N 16.3.
    Examples 108-112. The following compounds were prepared analogously to the previous method using the appropriately substituted amide 2-methoxyquinoline-6-, carboxylic acid and dimethyl acetal M, N-dimeth: shformamide as the starting materials (Table 13).
    Example 113. 2-Methoxy-6- (1H) -1,2.4-triazol-5-yl quinoline.
    A mixture of 2-methoxyquinoline-6- - (N-) dimethylaminomethylene-carboxylic acid amide (1.0 g) and hydrazine hydrate (0.208 cm) is stirred in glacial acetic acid (10 cm) for 1.5 hours at 90 ° C . The volatiles are removed in vacuo, the residue is chromatographed on silica gel (Merck MK 60.9385), eluting with a mixture of ethyl acetate and methanol at a ratio of 49: 1 (by volume), after which the necessary fractions are combined and evaporated to give 2- methoxy-6 - (1H) -1,2,4-triazol-5-ylZquinoline, m.p. 198-200 ° C (0.811 g).
    Found,%: C 63.8; H 4.5j N 24.8.
    C, H,
    Calculated,%: C 63.7) H 4.4; N 24.8.
    Example 114-122, The follow up of the compound was prepared analogously to the previous method using the appropriately substituted amide 2-methoxyquinolin-6- (L) -dimethylaminomethylene carboxylic acid and hydrazine hydrate (in the production method 114) or methyl hydraZINa (in methods of obtaining 115-122) (see table. 14).
    Compounds 116 and 117 are obtained as a mixture of isomers, which are separated by chromatography on silica gel with elution with simple ether. The main isomer is eluted first, Rf 0.8 in ethyl acetate (Preparation Method 116). The minor isomer, Rf, 0.28 in ethyl acetate (Preparation Method 117),
    Compounds 118 and 119 were obtained in a similar way as mixtures of isomers, which were separated by silica gel chromatography. Elution with a mixture of hexa.a and ether with a 1: 1 ratio affords the main isomer (production method 118), while the minor isomer (production method 119) is eluted from the column with ethyl acetate.
    Example 123. 2-Methoxy-6- - (1,2, 4-6xadiazol-5- Il) H-quinments,
    An aqueous 5 M solution of sodium hydroxide (0.94 cm) is added to rast21
    Thief hydroxyamine hydrochloride (0.325 g) In water (3 cm) and acetic acid (7 cm). 2-methoxy-: quinolin-6-K- (dimethylaminomethylene) carboxylic acid amide (1.0 g) is added, the mixture is stirred for 10 minutes, water (10 cm) is added, and the solution is held for 1 hour. The precipitate is filtered off, placed in dioxane (5 cm) and acetic acid (5 cm) n heated at 90 ° C for 1.5 h. Water (10 cm) is poured into the cooled solution, the precipitate is filtered off and chromatographed on silica gel (Merck G 60.9385) with elution with Nium dichloromethane. The desired fractions are combined and evaporated under vacuum conditions, yielding a solid (0.537 g). A small portion of this substance is recrystallized from ethyl acetate to form 2-methoxy-6- (1,2,4-oxydiazole-5-yl) -quinoline, m.p. 150-152 С
    Found% C 63,3 j N 4,0; N 18.6.
    C, H, N, Oj
    Calculated,%: C 63.4; H 4.0; N. 18.5.
    Example 124. 5-1-Methyl- (1H) -imidazol-2-yl -2-methoxy-inino.
    n-Butyl lithium (9 cm of a 1.6 M solution in hexane) at minus 45 ° C is added to a stirred solution of 1-methyl- (1H) -imidazole (1.03 cm) in tetrapidrofuran (30 cm) in an atmosphere nitrogen. After 1.25 hours, a solution of anhydrous zinc chloride (1.95 g) in tetrahydrofuran (30 cm) was added dropwise over 5 minutes, resulting in a white precipitate. The mixture is warmed to room temperature, a solution of 6-bromo-2-methoxy necnoline (3 g) and tetrakis (triphenylphosphine) palladium (0) (0.2 g) in tetrahydrofuran (20 cm) is added, followed by the solution is heated under reflux for 16 hours. A complete solution of ammonium chloride (2 cm) is added, the reaction mixture is concentrated under vacuum, the residue is separated between chloroform (100) and a solution of ethylenediaminetetraacetic acid (disodium salt) (10 g) in water ( 100 cm). The aqueous phase is extracted with chloroform (2 X 50 cm), and the combined and dried (MgSO4) extracts
    0739722
    The mixture is evaporated under vacuum to form a solid, which is chromatographed on a silica gel (Merck MK 60.9385), eluted with a mixture of chloroform and methanol in a ratio of 19: 1 (by volume). The required fractions are combined and discharged, - they are evaporated under vacuum conditions, which
    10 is obtained to obtain a foam, which is recrystallized from a mixture of ethyl acetate and hexane to form 6-1-methyl- - (1H) -imidazol-2-yl-2-methoxyquinoline, m.p. 116.5-118.5 ° C (0.517 g).
    15 Found,%: C 70.3; H 5.5, N 17.4.
    C ,, h ,, n, o
    Calculated,%: C 70.3; H 5.5; N 7.5.
    20 Example 125. Similar to the previous method using 1-methyl-3 (1Ы) -imidazole, tetrakis- (triphenylphosphine) palladium (O) and 6-bromo-2-25-methoxy-8-methylquinoline as starting materials. also syn; 6- 1-methyl- (1H) -, -imidazol-2-yl -2-methoxy-8-methylquinoline hemihydrate was synthesized; m.p. 158-161 ° C.
    Found,%: C 68.4; H 5.8 30 N 15.8.
    C, H, fN, 0. Calculated,%: C 68.7 H 6; one; N 16.0.
    Example 126. 6-1-Methyl- (1H) -25-imidazol-5-yl-2-methoxy-8-methylhi nolin.
    tert-Butyl lithium (11.9 cm of a 2.0 M solution in pentane) is added at 70 ° C. under a nitrogen atmosphere to a stirred 40% solution of 1-methyl (1H) -imidazole (0.95 cm) in tetrahydrofuran (8 cm ). After 10 minutes, the mixture is warmed to 0 ° and continued to stir for 1 hour. Then, a solution of anhydrous zinc chloride (6.25 g) in tetrahydrofuran (45 cm) is added and the mixture is stirred for another 1 hour. -bromo-2-methoxy-8-methyl-quinoline (1.0 g) and tetrakis (triphenyl-5Q phosphine) papladium (O) (0.04 g), after which the mixture is heated under reflux for 18 hours. The cooled the mixture is concentrated under vacuum and partitioned between chloroform (200 cm) and a solution of ethylene diamine tetraacetic acid (50 g) disodium salt in water (250 cm). The aqueous phase is extracted with chloroform (2 X 100 cm), combined 23
    The complete and dried (MgSO4) extracts are evaporated to a solid, which is chromatographed on silica gel (Merck MK 60.9385), with elution with chloroform. After combining and evaporating the corresponding fractions, firstly, (Rf 0.32 in chloroform) 6- - l-methyl- (III) -imidazol-2-yl-1-2-methoxy-8-methylquinoline is obtained, t, mp . 160-162 C (0.37 g), identical to the product obtained in method 125; secondly, (Rf 0.26 in chloroform) 6-1-methyl- - (1H) -imidazol-5-yl1-2-methoxy-8-methyl-quinoline, t. 1 A-175 ° C (0 , 05 g).
    Found,%: C 71.2; H 6.0-, N 16.2.
    C, 5H, 5N3
    Calculated,%: C 71.1-, H 6.0; N 16.6.
    Test the biological activity of the compounds obtained.
    0739724
    Oral acute symptomatology. in mice.
    A group of three male mice are given an orally tested compound or an indifferent dry substance. The size of the dose of 10 ml / mg. Animals were observed for at least the next 4 hours and again 2A hours after
    10 processing. The experiment was carried out at 20-24 C. At a dosage of 30 mg / kg, no toxic effect was observed. Dosage 30 mg / kg for an average weight adult patient
    15 70 corresponds to a total of 2.1 g per day. The maximum therapeutic dose in the treatment of people is 1 g daily. So this proves; lack of toxic effect
    20 proposed compounds in therapeutic doses.
    The following compounds showed minor or unpleasant symptoms that occurred after a high oral dose of 30 mg / kg of the test compound:
    Compounds
    Structure
    权利要求:
    Claims (2)
    [1]
    1. A method of producing quinolone P1 derivatives of the general formula
    3
    wherein the Het is attached at the 5th, 6th, 7th or 8th position of the carbon atom and is pyridyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxadiazolyl or thienyl, all of which may be substituted by one or two substituents, each of which is selected from a (| -C-alkyl, cyano or amino groups; R, is hydrogen, -CN or COO C, -C4 alkyl;
    Rj is attached in the 5th, 6th, 7th or 8th position and denotes hydrogen, C-C4-alkyl
    where R ,, R, I, Het have the specified values
    45 is demethylated to isolate the product as a free base or a pharmaceutically acceptable acid addition salt with a reaction with an acceptable acid.
    50 or a metal salt by reacting with an acceptable base.
    [2]
    2. The method of claim 1, wherein t and h so that the demethylation is carried out using an aqueous solution HBg, an aqueous solution
    HC1 or ethanol containing 5-15 vol.% Aqueous solution HBg. Priority featured:
    sn.
    about
    or alkoxy; Y is hydrogen or C -C-alkyl
    or their pharmaceutically acceptable salts, characterized in that the compound of the general formula
    40
    Not
    MAIN
    271A0739728
    12/22/83 with Het - pyridyl, pyridine and is hydrogen, C, -C-Smidinyl, pyrainyl, imidazolyl or thiazolyl, all of which can be substituted by one or two substituents selected from C, -alkyl and amino groups, R, is hydrogen, ON or COO (C) -C4-alknl), R is attached in the 5th, 6th, 7th or 8th poloalkyl or alkoxy group, I is hydrogen or C -C-alkyl,
    07/06/84 - with Het, triazolyl, tetrazolyl, oxadiazolyl, or thienyl, all these groups may be substituted by one or two substituents selected from the cyano group,
    -alkyl or alkoxy, I is hydrogen or C -C-alkyl,
    07/06/84 - with Het, triazolyl, tetrazolyl, oxadiazolyl, or thienyl, all these groups may be substituted by one or two substituents selected from the cyano group,
    .Table 1
    Hel
    Het
    The shape of the extruded and pl., ° C
    12
    -Cn
    0, 355 (decomp.)
    17 -N
    N
    -H-CH,
    18 —H HjC-fV —H
    chl
    -H Free base 74.5 5.7 10.9, hemihydrate, 280-283 (74.1 5.8 10.8)
    SJL
    19 -NLSI -N
    U j
    -H Free base 73.2 5.0 11.5, hemihydrate, 282-284 (73.4 5.3 11.4)
    20 -N
    .sn,. „
    - H Free base 76,4 5,1, 293-295,5 (76,3 5,1 11,9)
    Percentage analysis (theoretical values are given in brackets)
    H
    N
    4.0 3.8
    16.4 16.8)
    Table 3
    Hydrochloride, 350
    66.1 4.7 10.2 (66.1 4.8 10.3)
    - but
    - „НЗС-Н
    Well
    -N
    -N
    but
    0.5 300
    —CH Hydrochloride, 290-292
    -CHj Free base, 256-259
    -NH free base, 235-237
    26 -N -N
    -H Free base 74.0 4.5 12.1, 0.25-Н20 (74.2 4.7 12.4) 237-239
    27 -N -N
    about -
    28
    -N
    29 71 -N
    -N -N free base-75.5 4.512.5
    knowledge, 254-256 (65,64,512,6)
    -N -N Free base-75,34,512,3
    . Knowledge, 259-261 (75,64,512,6)
    A, 614.9) 4, 415.3
    4,415,3)
    6,010.3
    6.110.6)
    4,712,5
    4,512,6)
    Free base 75.4 4.5 12.5, 261-268 (75.6 4.5 12.6)
    39 -N
    N JJ
    /
    -H-CH, Svobodnoe-62,5 4,3 24,1
    knowledge, 0.25 (62.5 4.6 24.3)
    0 -H -.
    CHj
    CH,
    41 -N
    42 -N
    / Nx
    , one
    I-t
    - “n
    -N
    43 -N
    I
    -f
    N1
    R
    -N
    44
    1 H p-Br-and-H
    -H Free base 62.54,424.2 v., 0,
    Stim.) (62,54,624,3
    -H free base-64,95,123,3
    Knowledge, 295-297 (65,05,023,3)
    -N free base-61,63,319,7
    , 228-230 (62,03,319,7) (decomp.)
    -N Free base. , 297-299 (decomp.)
    -N Free base, 212-214
    56,13,332,3
    (56,33,332,9)
    62,05,626,2
    (62,45,626,0)
    45
    46 -N
    47 -H
    48 -N
    G QI
    -N
    -N Free base 76.9 4.8 12.2, 217-218 (75.7 4.5 12.6)
    56,13,332,3
    (56,33,332,9)
    62,05,626,2
    (62,45,626,0)
    55 —H CHj — N — n —CH, N — N CH, —N
    N
    -N
    -E
    Free base 64.3 5.1 23.2
    , 0.25,
    270-272 (64.5 5.1 23.2
    Free base 66.1 5.6 22.2, 252-254 (66.1 5.6 22.0)
    g
    H
    H
    H
    H
    -N
    -Wg
    -N
    -Wg
    -T
    -I
    -N
    -N
    -N
    -Wg
    -sn.
    -sn.
    Loose base, 86-87 Loose base, 89-91 Loose base, 71-72 Loose base, 71-74 Loose base, 40
    -N -SSN, Free base, 64-66
    -N
    -Et
    -N
    -Wg
    -N -QCH,
    Table 4
    Free base, 0.25, 101.5-102.5
    / Nx
    - QСН. -n
    -CHj Free base, 72.5-74.5
    Free base, 4 6.2 10.4, 72.5-74.5 (77.3 6.1 10.6)
    35 -N
    36 -N
    d
    TI -N And
    -N
    -N
    -N
    Free base 76.2, 83-84 (76.2 5.1 11.9)
    Integrated compound- not characterized
    zinc,
    254-257
    -N
    -N
    CHj
    -Nv
    9
    -N
    -N
    -N
    -N
    CH,
    Crude Free Base Oil
    Crude Free Base Oil
    As a result of performing the method of obtaining 36, a stable complex compound containing zinc chloride, whose structure was not exactly characterized, was obtained. This material is used in example 3.
    Het
    Het
    R,
    The selected form and t, pl., C
    43
    -CNComplex connectivity- Not characterized
    zinc content, 266-268
    Table 6
    Percentage analysis (theoretical values are given in brackets)
    H
    N
    Het
    The form is nt, pl., C
    4A
    -CN 0.5, 210-212 71.4
    (71.1
    . eiCOsCHj,
    Complex compound- Not characterized by zinc, 175 (decomp.)
    46 -CO3NG
    Free base 69,5, 129-131 (69.4
    T centr ali: 8 (theoretical values are given in 8 brackets)
    H
    TO
    4.315,8
    4.415,5)
    5.0
    9.2
    4.8 9.5)
    -Br
    -N
    -N
    -N
    -N
    -in
    -N -N Free base, 76-78 Free base 115-116 Free base 121-123
    -Hr -N
    -CH, -N
    -N
    -N
    -one
    -one
    -H -Et free base, 75-76
    -N -CH (CHj) Crude free base, oil
    -N
    -In
    -N -OCHj Free base, 160
    Characterized by NMR spectroscopy H and mass spectroscopy
    44.0 (44.1
    2.55,1
    2.65,1)
    "°
    The ratio determined by an NMR spectroscope and n with a frequency of 250 MTij.
    Table 9.
    Ba
    Kb
    -Br
    -N
    -one
    a
    -one
    -one
    -Br
    -CH, -N Free base-50.7
    tion, 112-115 (50.7
    -Hr -N Free base-49.3
    98-100 (48.9
    -N -H Free base in the form of a crude solid, 181-182
    -N -N Free base-71.3
    I)
    , 201-204 (71.6
    -H -Et free base-45.2
    196.5-199 (45.2
    -H-CH (CH) Free base-47.2
    1b; -163 (46.8
    -N -OCHj Free base-48, .4
    133-136 (48.0
    Table 10
    -yL
    about
    5.0 4.9) 5.4 5.2)
    10.4
    10.4)
    4.1
    4.1)
    4.1
    3.9),
    4.8
    4.7)
    UN,
    (CHjV NCH Tsf
    -N
    -N
    -N
    -sn.
    -Et
    -CH (CH)
    g g
    Free base, 180-182 Free base, 163-164 Free base, 156-159
    Table 13
    Ed
    axes,
    Kb
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1407397A3|1988-06-30|Method of producing quinolonic derivatives or their pharmaceutically acceptable salts
    JP4790703B2|2011-10-12|Cyclic compounds
    EP0498723B1|2001-09-19|Nitrogen containing bicycle compounds, method for their preparation, their use as pharmaceutical and compositions containing them
    TW495504B|2002-07-21|3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators
    JP4764823B2|2011-09-07|Preparation of 1,6-disubstituted azabenzimidazoles as kinase inhibitors
    US10435415B2|2019-10-08|Substituted tetrahydrocarbazole and carbazole carboxamide compounds
    JP3241381B2|2001-12-25|Tricyclic quinoxalinedione compounds
    JPH11505524A|1999-05-21|Imidazo 1,2-A pyridine and imidazo 1,2-A pyrididine derivatives and their use as bone resorption inhibitors
    KR20080076962A|2008-08-20|Nicotinic acid derivatives as modulators of metabotropic glutamate receptors
    HU9902148A2|2000-04-28|Novel 2,3 disubstituted-4|-quinazolinones
    CZ292311B6|2003-09-17|Pyridazine derivatives, process of their preparation and pharmaceutical preparations in which the derivatives are comprised
    PL220721B1|2015-12-31|N-|benzylamines as antagonists of the 5-ht6
    EA001963B1|2001-10-22|Atropisomers of3-aryl-4|-quinazolinones and their use as ampa-receptor antagonists
    US4782055A|1988-11-01|Imidazopyridine compounds useful in the treatment of ulcers
    EP0503349B1|1995-01-04|Hydrazone derivatives, their preparation and use
    JP2011508784A|2011-03-17|TRPA1 antagonist
    EP3270926B1|2021-08-04|Triazolyl pyrimidinone compounds as pde2 inhibitors
    JPH11508267A|1999-07-21|Pyrazole compounds and pharmaceutical compositions
    WO2004022540A2|2004-03-18|Pyridazinone and pyridone derivatives as adenosine antagonists
    JP3351748B2|2002-12-03|Novel atropisomers of 2,3-disubstituted- | -heteroaryl fused-pyrimidin-4-ones
    IE61045B1|1994-09-07|4-aryl-5-carbamoyl-1, 4-dihydropyridines
    EA001961B1|2001-10-22|Atropisomers of 3-heteroaryl-4|-quinazolinones for the treatment of neurodegenerative and cns-trauma related conditions
    WO2010100050A1|2010-09-10|Pyridine-2-yl-carboxylic acid amides
    JP4530663B2|2010-08-25|Imidazoquinoline derivatives
    WO2021164793A1|2021-08-26|Compound used as kinase inhibitor and use thereof
    同族专利:
    公开号 | 公开日
    NZ210670A|1987-03-31|
    GR82511B|1985-04-22|
    PL144816B1|1988-07-30|
    FI845036L|1985-06-23|
    PL251092A1|1985-12-17|
    IL73877D0|1985-03-31|
    AU3701784A|1985-07-04|
    DK619584A|1985-06-23|
    ES8603863A1|1986-01-01|
    HUT36472A|1985-09-30|
    AU556494B2|1986-11-06|
    NO845228L|1985-06-24|
    IL73877A|1988-10-31|
    PT79699A|1985-01-01|
    CS249533B2|1987-03-12|
    KR870000911B1|1987-05-06|
    EP0148623A3|1986-06-04|
    US4710507A|1987-12-01|
    CA1253497A|1989-05-02|
    ES538805A0|1986-01-01|
    PT79699B|1986-12-10|
    DK619584D0|1984-12-21|
    KR850004478A|1985-07-15|
    FI845036A0|1984-12-19|
    EP0148623A2|1985-07-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    RU2695524C2|2013-05-27|2019-07-23|Ф. Хоффманн-Ля Рош Аг|3,4-dihydro-2h-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one derivatives useful as aldosterone synthase inhibitor|US3907808A|1971-05-17|1975-09-23|Sterling Drug Inc|1,4-Dihydro-4-oxo-7-pyridyl-3-quinolinecarboxylic acid derivatives|
    US3962445A|1973-05-19|1976-06-08|Beecham Group Limited|Anti-allergenic carbostyril derivatives|
    US3993656A|1974-11-19|1976-11-23|Merck & Co., Inc.|1,8-Naphthyridine compounds|
    JPS5728710B2|1977-11-15|1982-06-18|
    US4258185A|1978-10-17|1981-03-24|Yoshitomi Pharmaceutical Industries, Ltd.|Pyridazinone compounds|
    FR2439196A1|1978-10-17|1980-05-16|Yoshitomi Pharmaceutical|6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agents|
    JPH0143747B2|1980-10-31|1989-09-22|Otsuka Pharma Co Ltd|
    CA1164459A|1980-11-11|1984-03-27|Yung-Hsiung Yang|Process for preparing -carbostyril or -3,4-dihydrocarbostyrylderivatives|
    EP0102046A1|1982-08-26|1984-03-07|Schering Corporation|Tricyclic lactams, method for making them, pharmaceutical compositions containing them|PT80533B|1984-05-29|1987-04-06|Pfizer|Process for preparing quinolone inotropic agents|
    US4567186A|1985-01-14|1986-01-28|Sterling Drug Inc.|5-Heteryl-1,6-naphthyridin-2-ones, cardiotonic use thereof and intermediates therefor|
    NZ214837A|1985-01-28|1988-10-28|Sterling Drug Inc|5-substituted 1,6 naphthyridin-2-ones|
    GB8502267D0|1985-01-30|1985-02-27|Pfizer Ltd|Quinolone inotropic agents|
    FR2580646A1|1985-04-19|1986-10-24|Synthelabo|2-Quinolinone derivatives, their preparation and their application in therapeutics|
    GB8516573D0|1985-07-01|1985-08-07|Janssen Pharmaceuticaa Nv|Controlling weeds|
    US4666913A|1985-11-22|1987-05-19|William H. Rorer, Inc.|Hydroxy and aminothiazolyl-benzodiazinone compounds, cardiotonic compositions including the same, and their uses|
    GB8529362D0|1985-11-28|1986-01-02|Pfizer Ltd|Quinolone cardiac stimulants|
    DK111387A|1986-03-05|1987-09-06|Otsuka Pharma Co Ltd|CARBOSTYRIL DERIVATIVES AND SALTS THEREOF, MEDICINE CONTAINING SUCH DERIVATIVES AND PROCEDURES FOR THE PREPARATION OF THE DERIVATIVES|
    US5358949A|1986-03-05|1994-10-25|Otsuka Pharmaceutical Co., Ltd.|Carbostyril derivatives and salts thereof and anti-arrhythmic agents containing the carbostyril derivatives|
    US4921862A|1986-05-29|1990-05-01|SyntexInc.|Carbostyril derivatives as combined thromboxane synthetase and cyclic-amp phosphodiesterase inhibitors|
    US4792561A|1986-05-29|1988-12-20|SyntexInc.|Carbostyril derivatives as combined thromboxane synthetase and cyclic-AMP phosphodiesterase inhibitors|
    US4785005A|1986-06-25|1988-11-15|Rorer Pharmaceutical Corporation|6--carbostyril compounds and their cardiotonic uses|
    GB8619902D0|1986-08-15|1986-09-24|Pfizer Ltd|Quinolone cardiac stimulants|
    US5002944A|1986-10-29|1991-03-26|Rhone-Poulenc Rorer Pharmaceuticals Inc.|Compounds having cardiotonic activity|
    US4859672A|1986-10-29|1989-08-22|Rorer Pharmaceutical Corporation|Pyrido[2,3-d]pyrimidinone and imidazo[4,5-b]pyrimidinone|
    US5166160A|1986-12-23|1992-11-24|Burroughs Wellcome Co.|Quinoline compound|
    GB8630702D0|1986-12-23|1987-02-04|Wellcome Found|Quinoline compound|
    GB8709448D0|1987-04-21|1987-05-28|Pfizer Ltd|Heterobicyclic quinoline derivatives|
    DE3935514A1|1989-10-25|1991-05-02|Boehringer Mannheim Gmbh|NEW BICYCLO IMIDAZOLES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    EP0549729B1|1990-09-07|1997-12-17|Schering Corporation|Antiviral compounds and antihypertensive compounds|
    HU207308B|1990-11-09|1993-03-29|Richter Gedeon Vegyeszet|Process for producing 1- /2-/5-/dimethyl-amino-methyl/-2-/furyl-methyl-thio/-ethyl//- -amino-1-/methyl-amino-2-nitro-ethylene|
    US5141931A|1991-01-03|1992-08-25|Sterling Winthrop Inc.|5-Quinolinylpyridinones, cardiotonic compositions and methods|
    GB9200781D0|1992-01-15|1992-03-11|Merck Sharp & Dohme|Therapeutic agents|
    JP2686887B2|1992-08-11|1997-12-08|キッセイ薬品工業株式会社|Piperidino-3,4-dihydrocarbostyril derivative|
    FR2703681B1|1993-04-08|1995-05-12|Bellon Labor Sa Roger|PROCESS FOR PREPARING FLUORO-6-HALOGENO-2 QUINOLEINE|
    JP2000256323A|1999-01-08|2000-09-19|Japan Tobacco Inc|2-oxoquinoline compound and its medicinal use|
    US6566372B1|1999-08-27|2003-05-20|Ligand Pharmaceuticals Incorporated|Bicyclic androgen and progesterone receptor modulator compounds and methods|
    JP2003508397A|1999-08-27|2003-03-04|リガンド・ファーマシューティカルズ・インコーポレイテッド|8-Substituted-6-trifluoromethyl-9-pyrido [3,2-G] quinoline compounds as androgen receptor modulators|
    EP1212330B1|1999-08-27|2006-04-19|Ligand Pharmaceuticals Incorporated|Androgen receptor modulator compounds and methods|
    CO5200852A1|1999-09-14|2002-09-27|Lilly Co Eli|RXR MODULATORS WITH IMPROVED CEPTORS X PHARMACOLOGICAL PROFILE OF RETINOIDS|
    WO2002081728A2|2001-04-06|2002-10-17|Smithkline Beecham Corporation|Quinoline inhibitors of hyak1 and hyak3 kinases|
    GEP20074058B|2002-07-03|2007-03-12|Univ Wayne State|4- linyloxy-phenoxy-propionic acid derivatives as antineoplastic agents|
    WO2004065379A1|2003-01-17|2004-08-05|Warner-Lambert Company Llc|Androgen receptor antagonists|
    PL378111A1|2003-02-14|2006-03-06|Smithkline Beecham Corporation|Novel compounds|
    MXPA06001751A|2003-08-22|2006-05-12|Ligand Pharm Inc|6-cycloamino-2-quinolinone derivatives as androgen receptor modulator compounds.|
    TWI417099B|2007-03-23|2013-12-01|Neuraxon Inc|Quinolone and tetrahydroquinoline and related compounds having nos inhibitory activity|
    DE102008022221A1|2008-05-06|2009-11-12|Universität des Saarlandes|Inhibitors of human aldosterone synthase CYP11B2|
    US8541404B2|2009-11-09|2013-09-24|Elexopharm Gmbh|Inhibitors of the human aldosterone synthase CYP11B2|
    HUE047771T2|2011-09-15|2020-05-28|Hoffmann La Roche|New dihydroquinoline-2-one derivatives|
    BR112014013136B1|2011-11-30|2020-05-26|F. Hoffmann-La Roche Ag|NEW BIOLOGICAL DIHYDROISOQUINOLINE-1-ON DERIVATIVES|
    SG11201502369XA|2012-10-16|2015-05-28|Janssen Pharmaceutica Nv|Methylene linked quinolinyl modulators of ror-gamma-t|
    WO2014062655A1|2012-10-16|2014-04-24|Janssen Pharmaceutica Nv|HETEROARYL LINKED QUINOLINYL MODULATORS OF RORyt|
    JP6251277B2|2012-10-16|2017-12-20|ヤンセン ファーマシューティカ エヌ．ベー．|ROR-gamma-t phenyl-linked quinolinyl modulator|
    EP2964628B1|2013-03-08|2019-09-11|F.Hoffmann-La Roche Ag|New dihydroquinoline-2-one derivatives as aldosterone synthaseinhibitors|
    US9346782B2|2013-10-15|2016-05-24|Janssen Pharmaceutica Nv|Alkyl linked quinolinyl modulators of RORγt|
    US9221804B2|2013-10-15|2015-12-29|Janssen Pharmaceutica Nv|Secondary alcohol quinolinyl modulators of RORγt|
    US9328095B2|2013-10-15|2016-05-03|Janssen Pharmaceutica Nv|Heteroaryl linked quinolinyl modulators of RORgammat|
    BR112016008258A2|2013-10-15|2017-10-10|Janssen Pharmaceutica Nv|quinolinyl ror? t modulators|
    US9284308B2|2013-10-15|2016-03-15|Janssen Pharmaceutica Nv|Methylene linked quinolinyl modulators of RORγt|
    US10555941B2|2013-10-15|2020-02-11|Janssen Pharmaceutica Nv|Alkyl linked quinolinyl modulators of RORγt|
    US9403816B2|2013-10-15|2016-08-02|Janssen Pharmaceutica Nv|Phenyl linked quinolinyl modulators of RORγt|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB838334282A|GB8334282D0|1983-12-22|1983-12-22|Quinolone inotropic agents|
    GB848417340A|GB8417340D0|1984-07-06|1984-07-06|Quinoline inotropic agents|
    [返回顶部]