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    • 专利摘要:
    Compounds of the formufa: wherein R1, which is attached to a carbon atom of ring "B", is hydrogen, halo, C,-C, alkyl, or -S(C1-C4 alkyl); Y. which is attached to ring "A", is -CN, -COOH, -COO(C1-C4 aikyl) or -CONH2: X is O, S. NH, N(C,-C, alkyl) or -CH=CH; and R. which is attached to a carbon atom of ring "8", is a group of the formula: where Z is -CH2-, -CH=CH-, -OCH2-, -CO- or -S-: and the pharmaceuticaliv. acceptable salts thereof. The compounds in which Y is -COOH, -CCO(C1-C4 alkyl) and -CONH2 are pharmaceutical agents being selective thromboxane synthetase inhibitors. Those in which Y is -CN are useful intermediates.
    公开号:SU1217256A3
    申请号:SU823486394
    申请日:1982-08-25
    公开日:1986-03-07
    发明作者:Эдвард Кросс Питер；Питер Дикинсон Роджер
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    I
    This invention relates to a process for the preparation of new benzofuranbenzo (c) thiophene or naphthalenecarbonose 1 systems of the general formula.
    where Y, which is attached to the ring And means-COOH or
    X - O, 5 or,
    E, is attached to the carbon atom of ring B, means hydrogen, halogen, alkyl C, -C4 or-5 (C -C-alkyl) i
    K, which is attached to the carbon atom of ring B, means
     N N-CHr
    or (3-pyridyl) -Z,
    where Z is a group, CO or 5, or their pharmaceutically acceptable salts, which can be used as therapeutic agents, for example, in the treatment of thrombosis, ischemic heart disease, heart attacks, transitional attack, migraine, peripheral vascular diseases, vascular diseases . , complications of diabetes, cancer and endoxin shock.
    The purpose of the invention is the synthesis of new compounds with valuable properties.
    The preparation of new compounds of formulas (1) is illustrated by the following examples. All temperatures are in p.
    Example 1. 2- (1-imidazolyl-methyl) -3-methylbenzo (c) thiophen-6-carbox nova acid, (i) 6-bromo-2-hydroxymethyl-3-methylbenzo c) thiophene
    A solution of n-butyl lithium in hexane (13.2 ml of a 1.55 M solution) is added dropwise to a stirred solution of 2,6-dibromo-3-methylbenzo (c) thiophene (6.60 g) in dry ether (150 g ml) at 0 ° C under a dry nitrogen atmosphere and the mixture is stirred at 0 ° C for 30 minutes. Paraformal dehyd (0.71 g) is then added in portions and the mixture is stirred at 0 ° C for 3 hours. Water and separate the layers. The ether layer is washed with water, dried () and evaporated to give an oil, which is chromatographed on silica gel. Elution with chloroform initially gives a certain amount of impurities, and then the pure product. Evaporation
    2172562
    containing product fractions gives a solid which is recrystallized from ethyl acetate / gasoline (so kip. 60-80 C) to obtain 6-bromo-5 2-hydroxymethyl-3-methylbenzo (c) thiophene (3.20 g ), so pl. 95-9b with.
    Found,%: С 46,97; H 3.49
    С, „Н, Вг.05
    Calculated,%: C, 46.70, H, 3.53. 10 (ii) 6-bromo-2-chloromethyl-3-methyl-benzo (c) tiophene
    Thionyl chloride (2.0 ml) was added dropwise to a stirred solution of 6-bromo-2-hydroxymethyl-3-methylbenzo- (5 (c) thiophene (3.60 g) and pyridine (3 drops) in chloroform (80 ml) The solution is stirred at room temperature for 1 hour, then washed with water, sodium bicarbonate solution 20 and dried (). Evaporation of the solvent gives a quantitative yield of 6-bromo-2-chloromethyl-3-methylbenzo (c) thiophene. A sample recrystallized from gasoline (bp. 40-60 s), 25 has a mp of 92-93.
    Found%: C 43.51 H 3.00
    C gHgBrCeS
    Calculated,%: C 43.58, H 2.92
    (i i i) 6-bromo-2- (1-imidazolyl-30 tb1) -3-methylbenzo (c) thiophene
    Treatment with 6-bromo-2-chloromethyl-3-metobenzo (c) thiophene with imidazole and sodium bicarbonate by the method of example 4 (p) gives 6-bromo-2- (1-im-, dazolylmethyl) -3-methylbenzo (c) thiophene. M.p. 138-139 (from ethyl acetate) gasoline, so pl. 60-80.
    Found%: C 50.49, H 3.57, N9.19
    C ,,, 5
    Calculated,%: C 50.82, H 3.61, N 9.12
    (11) 2- (1-imidazolylmethyl) -3-methylbenzo (c) thiophene-6-carbonitrile
    A mixture of 6-bromo-2- (1-imidazolylmethyl) -3-methylbenzo (c) thiophene (1.01 g) and copper (I) cyanide (1.80 g) in N, M-dimethylformamide (20 ml) is heated at reflux for 22 h and then cooled and poured into water. The solid is filtered off, washed with water and then suspended in a mixture of concentrated aqueous
    ammonia solution (100 ml) and ethyl acetate (150 ml) and the mixture is stirred until the solid disappears. Separate the organic layer by washing.
    water, dried () and evaporated; wow. The residue is recrystallized from ethyl acetate / gasoline (t, bp 60-80 ° C) to give 2- (1-imkdazolylmethyl) -3-methylbenzo (c) thiophene-6-carbonitrile (0.58), mp . 154-155 °.
    Found,%: C 66.04; H 4.50; N 16.61
    Snn., 5
    Calculated,%: C, 66.37; H, 4.38j; N, 16.59
    (y) 2- (1-imidazolylmethyl) -3-methyl-benzo (c) thiophene 6-carboxylic acid
    A mixture of 2- (1-imidazolylmethyl) -3-methylbenzo (c) thiophene-carbonitrile (0.40 g), sodium hydroxide (0.20 g) ethanol (2 ml) and water (20 ml) is heated at boiling point reflux for 24 hours. The solution is evaporated and the residue is dissolved in water and the solution is acidified with acetic acid. The solid is filtered off and purified by re-dissolving in dilute sodium hydroxide solution, filtering and acidifying the filtrate with acetic acid. The solid is filtered off, washed with water and dried to give 2- (1-imidazolylmethyl) -3-methylbenzo (c) -thiophene-6-carboxylic acid (0.35 g) so pl. 254-255 °.
    Found,%: C, 61.37; H, 4.60; By 10.19. ,.,,five
    Calculated,%: C, 61.74; H 4.44; - M 10.20
    Example 2. 3-methyl-2- (3-pyridylmethyl / benzo (c) thiophene-6-carboxylic acid (1) 6-bromo-3-methylbenzo (c) thien-2-yl-pyrid-3-yl -Keton
    A solution of n-butyl lithium in hexane (16.3 ml of a 1.55 M solution) is added to a stirred solution of 2,6-dibromo-3-methylbenzothiophene (7.65 g) in dry ether (159 ml) with 70 in a dry nitrogen atmosphere. The mixture was stirred for 30 minutes at -70 °, after which 3-cyanopyridine (2.60 g) in dry ether (50 ml) was added dropwise over 5 minutes. The resulting mixture was stirred at -70 ° for 3 hours and then at room temperature for another 2 hours. Concentrated hydrochloric acid (40 ml) was added with stirring and the layers were separated. The ether layer is extracted with concentrated hydrochloric acid
    6 s
    (20 ml), the acid extracts are combined and heated to complete the hydrolysis of the ketimine intermediate. The solution is cooled and basified with sodium hydroxide solution. The mixture is extracted several times with ethyl acetate and the combined extracts are washed with water and dried (). Distilling off the solvent gives
    a solid which chromatographs on silica gel. Elution with chloroform with gasoline (so Kip. 40-60 (2: 1) gives a solid, which is recrystallized from ethyl acetate / gasoline (t, Kip 40-60) to obtain 6-bromo-3-methylbenzo (c) tien-2 - yl-pyrid-3-yl-ketone (4.70 g), mp 110-G11 °.
    Found,%: C 53.93, H 3.17;
    N 4.29
    C, 5H,
    Calculated,%: C 54.22; H 3.03; N 4.22
    (() 6-bromo-3-methyl-3- (3-pyridylmethyl) benzo (c) thiophene
    A mixture of 6-bromo-3-methylbenzo (c) thien-2-yl-pyrid-3-yl-ketone (4.30 g) and hydrazine hydrate (2.60 g) in ethylene glycol (30 ml) is heated with reflux for 2 hours and then cool. Potassium hydroxide (2.80 g) is added and the temperature is gradually raised to reflux. After heating under reflux for another 3 hours, the solution is cooled and poured into water. The mixture is extracted several times with ethyl acetate and the combined extracts are washed with water and dried (). Distillation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform / benzine (so kip. 40-60) (3: 1) gives 6bromo-3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene (3.20 g). Sample recrystallized from gasoline (bp. 40-60 °). has 69-70 °.
    Found,%: C 56.65; H 3.86; N 4.48.
    C, BM g 5.
    Calculated,%: C 56.61, H 3.80 N 4.40
    (iii) 3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene-6-carbonentryl
    Treatment with 6-bromo-3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene with copper cyanide (1) in M, N-dimethylformamide
    according to the method of example 1 (; y) gives 3-methyl-2- (3-pyridylmethyl) -benzoene) thiophene-6-carbonitrile, so pl. 115-116 (from ethyl acetate / gasoline, t, kip, 40-60 °).
    Found,%: C 72.66; H 4.60; N 10.80
    C, H, 2N25
    Calculated,%: C 82.59; H 4.58; N 10.60
    (1Y) 3-methyl-2- (3-pyridylmethyl) (benzo (c) thiophene-b-carboxylic acid
    Hydrolysis of 3-methyl (2) 3-pyridylmethyl / benzo (c) thiophene-6-carbonitrile using the procedure of example 1 (v) gives 3-methyl-2- (3 pyridylmethyl) benzo (c) thiophene-6 carboxylic acid, m.p. 248-249 °. .
    Found,%: C 68,12; H 4.63; N 4.96
    C, H ,, NO,
    Calculated,%: C, 67.82; H 4.6g2; N 4.94
    Example 3. 2-methyl-2- (3-pyridylmethyl) benzo (c) thiophene-5-carboxylic acid.
    (i) 2,5-dibromo-3-methylbenzo (c) thio phene
    A solution of bromine (3.20 g) - in chloroform (10 ml) is added dropwise to a stirred solution of 5-bromo-3-methylbenzo (c) thiophene (4.54 g) in chloroform (40 ml) and the solution is stirred at room temperature. temperature for 1.5 hours. Then I wash it with a dilute sodium hydroxide solution, water, and dry (. Distillation of the solvent gives a solid, which is recrystallized from gasoline (b.p. 80-100) to obtain 2,5-dibromo- H-methylbenzo (c) thiophene (5.45 g), mp 118-122 °
    Found%: C 35.53 N 1.91
    Calculated,%: C, 35.32; H 1.98
    (ii) 5-bromo-3-methylbenzo (c) thien-2 yl-pyrid-3-yl-ketone
    Sequential treatment of 2,5-dibromo-3-methylbenzo (c) thiophene with n-butyl lithium and 3-cyanopyridine according to the procedure of Example 2 (It gives 5 bromo-3-methylbenzo (c) thien-2-yl-pyrid-3 -yl- ketone, characterized as the hydrochloride salt, mp, 193-195 °.
    Found,%: C 48.50; H 3.00; N 3.94
    C, 5H | Br -tt55HCe
    5. Calculated,%: C 48.86; H 3.01; N 3.80
    (til) 5-bromo-3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene
    Sequential treatment of 5-bromo-0 methylbenzo (c) thien-2-yl-pyrid-3-yl-ketone with hydrazine hydrate and potassium hydroxide in ethylene glycol according to the method of example 2 (J} -) gives 5-bromo-3-methyl- 2- (3-pyridylmethyl) benzo (c) thiophene, 5 characterized as the hydrochloride salt, so pl. 201-203.
    Found,%: C 60.89; H 3.46; N 4.23
    Ci H Bt / fSHCE
    0 Calculated,%: C 50.79, H 3.69; N 3.95
    (y) 3-methyl-2- (3-pyridylmethyl) Senzo (c) thiophene-5-carbonitrile
    Treatment with 5-bromo-3-methyl-2- (3-pyri-5 dilmethyl) benzo (c) thiophene with copper (1) cyanide in N, M Dimethylformamide according to the method of example 1 (p) gives 3-methyl-2- (3 -pyridylmethyl) benzo (c) thiophene-5-carbonitrile, m.p. 149-152 ° of ethyl acetate and gasoline, bp. 60-80.
    Found,%: C 72.56-, H 4.52; M 10.61
    C ,, H ,, N, 5
    Calculated,%: C, 72.69; H 4.58; 5 N 10.60.
    (v) 3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene-5-carboxylic acid
    Hydrolysis of 3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene-5-carbonitrile by the procedure of Example 1 (V) gives 3-methyl-2- (3-pyridylmethyl) benzo (c) thio-phenyl 5-carbonic acid, m.p. 230-223 °.
    Found,%: C 67.69; H 4.62; 5 N 4.90
    C, Hj, NOjS
    Calculated,%: C, 67.82; H, 4.62; N 4.94
    Example 4. 2- (3-pyridylmethyl) benzo (c) thiophene-5-carboxylic acid
    (i) 5-bromobenzo (c) thien-2-yl-pyrid-3-yl-ketone
    A solution of n-butyl lithium in hexane (25.8 ml of a 1.55 M solution) is added dropwise to a stirred solution of 3-bromobenzo (c) thiophene (8.50 g) in dry ether (120 ml) at -20 under nitrogen atmosphere and the mixture is stirred at
    five
    0 for 30 min. Treatment of the resulting lithium compound with 3-cyanopyridine (4.50 g) at -70 according to the procedure of Example 2 (O-5-bromobenzo (c) thien-2-yl-pyrid-3-Sh1-ketone (4.73 g) mp 147-148 (from ethyl acetate) gasoline, bp 60-80 °.
    Found,%: C 53.07, H 2.55, N4.49
    C HjBrNOS
    Calculated,%: C, 52.84; H 2.53; N 4.40
    (i) 5-bromo-2- (3-pyridylmethyl) benzo (c) thiophene
    Sequential treatment of 5-brobenzo (c) thien-2-yl-pyrid-3-yl ketone with hydrazine hydrate and potassium hydroxide in ethylene glycol according to the method of example 2 (p) gives 5-bromo-2- (3-pyridylmethyl ) benzo (c) thiophene, so pl. 102-103 (from ethyl acetate / benzine, bp 60-80 °).
    Found,%: C 55.61; H 3.25; N 4.75
    BrNS.
    . Calculated,%: C 55.27; H 3.31; K 4.60
    (ii i) 2- (3-pyridylmethyl) benzo (c) thiophene-5-carbonitrile 30
    Treatment with 5-bromo-2- (3-pyridylmethyl) benzo (c) thiophene with copper cyanide (p B fi, M-dimethylformamide according to the method of example 1 (iv) gives 2- (3-pyridylmethyl) benzo (c) thiophene-5-carbo-35-nitrile, mp 59-62.
    Found,%: C 71.54; H 3.99; K 10.65
    Calculated,%: C, 71.97; H 4.03; 40 N11.19%
    (iv) 2- (3-pyridylmethyl) benzo (c) thiophene-5-carboxylic acid
    Hydrolysis of 2- (3-pyridylmethyl) benzo (c) thiophene-5-carbonitrile according to the procedure of Example 1 (v) gives 2- (3-pyridylmethyl) benzo (c) thiophene-5-carboxylic acid, m.p. 246-249 ° (from ethanol).
    Found,%: C 66.84 H H 4.24; N5,13 50
    C ,, H,
    Calculated,%: C, 66.89; H, 4.12; To 5.20
    Example 5. 3-methyl-2- (3-py-solution of n-butyl-lithium in hexane (10.3 ml of 1.55 M solution) is added dropwise to a stirred solution of 2 J 5-dibromo-3-methylbenzo (c) thiophene ( the product of example 3 (h) (4.90 g) in dry ether (175 ml) at O under a nitrogen atmosphere. The mixture was stirred at O for 30 minutes and then cooled to -70. For 3 minutes, with stirring a solution of 3,3-dipyridyl disulfide (3.50 g) in dry ether (25 ml). The cooling bath is removed and the mixture is allowed to warm to room temperature with stirring. Then, excess water is added and a partition is added. layers. The aqueous layer is extracted several times with ether and the combined organic layer and the extracts are washed with water and dried (,). The solvent is distilled off and the oil is chromatographed on silica gel. Elution with toluene gives first a certain amount of impurities and then the pure product. - Holding 1x the product of the fractions gives 5- bromo-3-methyl-2- (3-pyridylthio) -benzo (c) thiophene (1.80 g), sufficiently pure for the subsequent reaction. Curry out the gassed gasoline (bp.40-60) sample has bunk. 86-87.
    Found,%: C 49.96; H 2.92; N 4.03 C H ,, 5
    Calculated,%: C 50.01; H 3.00, N 4.17
    (i |) 3-methyl-2- (3-pyridylthio) benzo (c) thiophene-5-carbonitrile
    Treatment with 5-bromo-3-methyl-2- (3-pyridylthio) benzo (c) thiophene with copper cyanide (1) in N, N-dimethylformamide according to the method of example 1 dv) gives 3-methyl 2- (3-pyridyl methyl ) benzo (c) thiophene-5-carbonitrile, so pl. 125-128 (from MeOH / H O).
    Found,%: C 63.72; H 3.71; N 9.64
    Ci HioNzSa
    Calculated,%: C 63.80; H 3.57;
    N 9.92
    () 3-methyl-2- (3-pyridylthio) benzo (c) thiophene-5-carboxylic acid.
    Hydrolysis of 3-methyl-3- (2-pyridylthio)
     - x J-ibi i JTi JJU / Jll J-J-ETC 1 fiJl- J- .llrlJ J J, rlJl 1 rHJ
    Rimedylmethyl) benzo (c) thiophene-5-carbobenzo (c) thiophene-5-carbonitrile is a permenic acid.
    (O 5-bromo-3-methyl-2- (3) -pyridyl-thio) benzo (c) thiophene
    Example 1 (v) gives 3-methyl-2- (3-pyridylthio) benzo (c) thiophene-5-carboxylic acid, m.p. 220-222.
    five
    0
    five
    0
    five
    0
    A solution of n-butyl lithium in hexane (10.3 ml of a 1.55 M solution) is added dropwise to a stirred solution of 2 J 5-dibromo-3-methylbenzo (c) thiophene (product of example 3 (h) (4.90 g) in dry ether (175 ml) at O under nitrogen atmosphere. The mixture was stirred at O for 30 minutes and then cooled to -70. A solution of 3,3-dipyridyl disulfide (3.50 d) in dry ether (25 ml). The cooling bath is removed and the mixture is allowed to warm to room temperature with stirring. Then excess water is added and the layers are separated. The aqueous layer is not extracted several times with ether and the combined organic layer and the extracts are washed with water and dried (,). Distillation of the solvent gives an oil which is chromatographed on silica gel. Elution with toluene gives first a certain amount of impurities and then the pure product. Evaporation containing 1x product fractions gives 5-bromo-3-methyl-2- (3-pyridylthio) -benzo (c) thiophene (1.80 g), sufficiently pure for subsequent reaction. The sample recrystallized from gasoline (bp.40-60) has a batch. 86-87.
    Found,%: C 49.96; H 2.92; N 4.03 C H ,, 5
    Calculated,%: C 50.01; H 3.00, N 4.17
    (i |) 3-methyl-2- (3-pyridylthio) benzo (c) thiophene-5-carbonitrile
    Treatment with 5-bromo-3-methyl-2- (3-pyridylthio) benzo (c) thiophene with copper (1) cyanide in N, N-dimethylformamide according to the procedure of example 1 dv) gives 3-methyl- 2- (3- pyridyltil) benzo (c) thiophene-5-carbonitrile, so pl. 125-128 (from MeOH / H O).
    Found,%: C 63.72; H 3.71; N 9.64
    Ci HioNzSa
    Calculated,%: C 63.80; H 3.57;
    N 9.92
    () 3-methyl-2- (3-pyridylthio) benzo (c) thiophene-5-carboxylic acid.
    Hydrolysis of 3-methyl-3- (2-pyridylthio)
    i JTi JJU / Jll J -J-ETS 1 fiJl- J- .llrlJ J J, rlJl 1 rHJ
    benzo (c) thiophene-5-carbonitrile by mebenzo (c) thiophene-5-carbonitrile according to the method of example 1 (v) gives 3-methyl-2- (3-pyridylthio) benzo (c) thiophene-5-carboxylic acid m.p. 220-222.
    Found,%: C 59.94; H 3.83 - N 4.80,
    WITH,
    Calculated,%: C 59.78, H 3.68; N 4.65
    Example 6, 3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene-5-carboxyMID.
    Hydrogen peroxide {1.6 ml of a 30% w / v% solution) is added to a stirred solution of 3-methyl-2- (3-pyridylmethyl) benzothiophene-5-carbonitrile (product of example 5 (/) 0.30 g in ethanol (3.5 ml) followed by (by the addition of 6% sodium hydroxide solution (1.6 ml). The resulting mixture is heated at 50-55 ° with stirring for 2 hours, then cooled and drunk in water.The solid is filtered off, washed with water, and recrystallized from ethanol / water to obtain 3-methyl-2- (3-pyridylmethyl) benzo (c) thiophene-5-carboximide E (-0.21 g), mp. 194-195
    Found,%: C 67.91 H 5.04, 9.66
    Calculated, /;: C 68, Ob, H 5.00; 9.22.
    Example 7. 3-methyl-2- (3-pyri, dilmethyl) benzofuran-5-carboxylic acid (1) 5-bromo-3-methylbenzofuran-2-yl pyrid-3-yl ketone hydrochloride.
    A mixture of 3-bromoacetylpyridine hydrobromide (1.50 g) and fine ground anhydrous potassium carbonate (2.20 g) was added to a stirred solution of 5-bromo-2-hydroxyacetophenone (1.10 g) in dry acetone (50 ml) at 5. The mixture was stirred at 5 ° for 30 minutes and then at room temperature for 24 hours. It was then filtered and the solid was washed with acetone. The combined filtrate and wash was evaporated and the residue was extracted several times with ether. The combined ether extracts are filtered and an excess of ethereal hydrogen chloride is added. The solid is filtered off, washed with ether and dried to give 4-5-bromo-methylbenzofuran-2-yl pyrid 3-yl ketone hydrochloride (1.07 g), t, pl.193-197 °.
    five
    About 5,
    0
    five

    five
    0
    Found,%: C 50.99; H 3.09; N 4.22
    C, H.BhNO, HCCI
    . Calculated,%: C 51.09; H 3.15; K 3.97
    (rl-) 5-bromo-3-methyl-2- (3-pyridylmethyl) benzofuran
    A mixture of 5-bromo-3-methylbenzofuran-2-yl pyrid-3-yl-ketone as a free base (2.67 g) and hydrazine hydrate (1.80 g) in ethylene glycol (30 ml) is heated at 120 for 2.5 hours. The mixture is cooled, potassium hydroxide (1.80 g) is added. The temperature is increased to 120 again, keeping it at this level for 1 hour. Dilution with water and extraction with ether gives an oil which is chromatographed on silica gel. Elution with chloroform gives a solid, which is recrystallized from benzine (so kip. 80-100 °) to obtain 6-bromo-3-methyl-2- (3-pyridylmethyl) benzofuran (2.00 g), so pl . 57-58.
    Found,%: C, 59.81; H 4.0lj N 4.74: 1.
    WITH
    Calculated,%: C 59.62, H 4.00, K 4.64
    (i); ) 3-methyl-2- (3-pyridylmethyl) benzofuran-5-carbonitrile
    Treatment with 5-bromo-3-methyl-2- (3-pyrimylmethyl) benzofuran with copper cyanide (1) according to the method of example 1 (“v) gives 3-methyl-2- (3-pyridylmethyl) benzofuran-5-carbonitrile, which is directly used in the next stage, di. .
    Accurate mass measurement: found 248.0960, - calculated 248.09489.
    (tv) 3-methyl-2- (3-pyridylmethyl) benzofuran-5-carboxylic acid
    Hydrolysis of 3-metsh1-2- (3-pyridylmethyl) benzofuran-5-carbonitrile according to the method of example 1 (y) gives D, -methyl-2- (3-pyridylmetesh1) benzofuran-5-carbonic acid, so pl. 219-221,
    Found,%: C 71, B1; H 4.65; N 5.12
    C, gH, jN03
    Calculated,%: C 71.90; H 4.90; N 5.24
    Example 8. 3-chloro-2- (1-imidazolylmethyl) benzofuran-5-carbonic acid (i) 3-chloro-2-methylbenzofuran-5-carbonitrile,
    A solution of 2-methylbenzofuran-5-carbonitrile (1.52 g) and sulphuryl chloride (1.49 g) in chloroform (25 ml) is heated at reflux for 9 h, then cooled. The solution is washed successively with water, a dilute sodium hydroxide solution, water, and then dried (). Evaporation of the solvent gave a solid, which was recrystallized twice from methanol to give 3-chloro 2-methylbenzofuran-5-carbonitrile (0.45 g), mp. 131.5-133.5 °.
    Found,%: C 62.82; H 3.17-, N 7.34
    C gHgCeNO
    Calculated,%: C, 62.68; H 3.16; N 7.31
    (ii) 2-bromomethyl-3-chlorophenzofuran 5-carbonitrile
    Treatment with 3-chloro-2-methylbenzofuran-5-carbonitrile-bromosuccinimide and azobisisobutyronitrile in carbon tetrachloride according to the procedure of Example 3 (I I;) gives 2-bromomethyl-3-chloro-benzofuran-5-carbonitrIiP, t. square 124-127 (from ethyl acetate / gasoline, bk, 80-OO) ..
    Found,%: C 44.71; H 1.94; N 5.49
    qoN SrCeNO
    Calculated,%: C, 44.40; H 1.86; N 5.18
    (iJi) 3-chloro-2- (1-imidazolylmethyl benzofuran-5-carbonitrile
    Treatment of 2-bromomethyl-3-chlorobenzo-furan-5-carbonitrile with imidazole and sodium bicarbonate by the method of Example 4 (lu) gives. 3-chloro-2- (1-imidazolylmethyl (benzofuran-5-carbonitrile, m.p., 231-233 ° (from ethyl acetate / gasoline, bp 60-80),
    Found,%: C 60.65; H 3.11; N 16.42
    C H, 3CEN, 0
    Calculated,%: C, 60.59; H 3.13; N 16.31.
    (iv) 3-chloro-2- (1-imidazolylmethyl) benzofuran-5-carboxylic acid
    A solution of 3-chloro-2- (1-imidazolylmethyl) benzofuran-5-carbonitrile (0.35 g) in concentrated sulfuric acid (5 ml) and water (5 ml) is heated under reflux for 1 h, and then cooled. The solution is diluted with 5 ml of water and
    alkalinized by the addition of 5N sodium hydroxide solution. The solution is filtered and acidified by the addition of acetic acid. The solid, which crystallizes out on standing, is filtered off, washed with water and dried to give 3-chloro-2- (1-imidazolylmethyl) benzofuran-5-carboxylic acid (0.20 g), mp. 248-250.
    %,%: C, 56.27; H, 3.35; N 10.24
    C H CENjOj
    Calculated,%: C 56.43; H 3.28; N 10.13
    Example 9. 3-bromo-2- (1-imidazolylmethyl) benzofuran-5-carboxylic acid
    (1) 3-bromo-2-methylbenzofuran-5-carbonitrile
    Bromine (3.20 g) is added dropwise to a stirred mixture of 2-methylbenzofuran-5-carbonitrile (3.04 g) and anhydrous sodium acetate (2.0 g) in acetic acid (30 ml), and the mixture is stirred at room temperature for 1 hour and then drunk into water (about 200 ml). The mixture is extracted several times with chloroform and the combined extracts are washed successively with water, diluted with sodium hydroxide solution, water and dried (). Distillation of the solvent gave a rubber-like solid, which was triturated with several milliliters of methanol and filtered. The solid is washed with a small amount of methanol and dried to give 3-bromo 3-methylbenzofuran-5-carbonitrile (3.44 g), so pl. 163-165, increasing to 164-166 ° after recrystallization from isopropanol / gasoline (bp 60-80 °).
    Found,%: C 50.98; H 2.62; N 6.09
    C, N O
    Calculated,%: C 50.87 H 2.56, N 5.93
    (h) 3-bromo-2-bromomethbenzofuran-5-carbonitrile
    Treatment of B-bromo-2-methylbenzofuran-5-carbonitrile with bromosuccinimide and azobisbutyronitrile in carbon tetrachloride according to the procedure of Example 3 ((m) gives 3-bromo-2-bromo methyl benzofuran-5-carbonitrile, mp 129- 131 (from ethyl acetate) gasoline, bp 80-100.
    Found%: C 38.31; H 1.57; K A, 60
    C, H
    Calculated,%: C 38.13; H 1.60; K 4.45
    (((O 3-bromo-2- (1himidazolylmethyl) benzofuran-5-carbonitrile
    Treatment of 3-bromo-2-bromomethylbenzo furan-5-carbonitrile with imidazole and sodium bicarbonate by the method of example. 4 (du) gives 3-bromo-2- (1-imidazolylmethyl) benzofuran-5-carbonitrile, t, pl. 119-122 (from ethyl acetate / benzine, bp 80-100).
    Found,%: C 51.59; H 2.69; N 14.09.
    C, HgBr N, 0
    Calculated,%: C, 51.68; H 2.67; N 13.91
    (Iv) 3-bromo-2- (1-imidazolylmethyl) benzofuran-5-carboxylic acid
    Treatment with 3-bromo-2- (1-imidazolylmethyl) benzofuran-5-carbonitrile with sulfuric acid / water (I) according to the method of example 8 (Iv) gives 3-bromo-2- (1-imidazolylmethyl) benzofuran-5 -carboxylic acid, so pl. 249-251.
    Found,%: C 48.58; H 2.80 M 8.72
    C ,, H ,, BrN20,
    Calculated,%: C 48.61; H 2.83; N .8,72
    Example 10. 1-methyl-2- (3-pyridylmethyl) naphthalene-7-carboxylic acid.
    (1) 7-bromo-2- (3-pyridylmethylene) - 1-tvtralon
    A mixture of 7-bromo-1-tetralone (11.25 g), pyridine-3-carboxaldehyde (5.35 g), acetic acid (5 ml) and piperidine (6 ml) is heated on a steam bath for 6 hours and then left cost 18 hours. Volatile material is distilled off. The residue is dissolved in ethyl acetate. The solution is extracted several times with dilute hydrochloric acid and the combined extracts are made alkaline with dilute sodium hydroxide solution. The solid is filtered off, washed with water and recrystallized from methanol to afford 7-bromo 2- (3-pyridylmethylene) -1-tetralone (12.8 g), mp. 124-125.
    Found,%: C 60.87; H 3.86 N 4.46
    C, (. H | jBhN O
    Calculated,%: C, 61.16; H 3.85, - N 4.46
    () 6-bromo-2- (3-pyridylmethyl) -1- 5 te.tralon
    A solution of 7-bromo-2- (3-pyridylmethylene) 1-tetralone (13.9 g) in ethanol (150 ml) containing 5% palladium on carbon (0.50 g) is hydrogenated at
    10 25 ° and a pressure of 4 atm until the selection of the theoretical amount of hydrogen. The catalyst is filtered off and the filtrate is evaporated. The residue is distilled to obtain oil (12.0 g), bp 20015 240 at 1.0 mm Hg, containing about 40% debrominated material. The product is purified by high pressure liquid chromatography using a silica gel column and
    20 hexane / ethyl acetate (45:55) in, as eluent. First, the debrominated product is eluted, and then pure 7-bromo-2- (3-pyridylmethyl) -1-tetralone, m.p. 63-67.
    25 (lii) 7-bromo-1-hydroxy-1-methyl- 2- (3-pyridylmethyl) -1,2,3,4-tetrahyd-, ronaphthalene
    Methyl magnesium bromide (15 ml of ZM solution in ether) is added dropwise per
    30 over 5 minutes to a stirred solution of 6-bromo-2- (3-pyridylmethyl) -1-tetralone (3.20 g) in dry tetrahydrofuran (50 ml). The resulting mixture is heated under reflux with NIKOM with stirring for 10 hours, then cooled. An excess of an aqueous solution of ammonium chloride is added and the mixture is extracted several times with ether. The combined ether extracts dry () and pump. The residue is chromatographed on silica gel. Elution with chloroform gives 7-bromo-1-hydroxy-1-methyl-2- (3-pyridylmethyl) -1,2,3,4-tetrahydro5 naphthalene (2.87 g) as a mixture of isomers, which is directly used in the next stage .
    (t v) 7-bromo-1-methyl-2- (3-pyridylmethyl) naphthalene
    0 7-bromo-1-hydroxy-1-methyl: -2- (3-pyridylmethyl) -1,2,3,4-tetrahydronaphthalene (2.87 g) is dissolved in formic acid (30 ml) and the solution is left stand for 6 hours after
    5 of which is evaporated at 35. The residue was dissolved in ethyl acetate, and the solution was washed with sodium bicarbonate solution, water, and dried (). Evaporation
    the solvent gives an oil which is chromatographed on silica gel. Elution with chloroform gives the dehydrated product as an oil (2.11 g).
    The mixture of oil (2.00 g) and sulfur (0.35 g) is heated at 200 for 2 hours, then cooled. The residue is taken up in several milliliters of ethyl acetate and the mixture is filtered. The filtrate is evaporated and the residue is chromatographed on silica gel. Elution with chloroform initially gives some impurities and then a clean product. Evaporation of the product-containing fractions gives a solid, which is recrystallized from gasoline (BP. 80-100) to obtain 7-bromo-1-metsh-2- (3-pyridylmethyl) naphthalene (1.42 g), t. square I0l-t04 °.
    Found,%: C 65.52; H 4.60; N 4.42
    C, H |, VGM
    Calculated,%: C, 65.40; H 4.52; N4,49
    (V) 1-methyl-2- (3-pyridylmethyl) naphthalene-7-carbonitrile
    Treatment with 7-bromo-1-methyl-2- (3-pyridylmethyl) naphthalene with copper cyanide (1) according to the method of example 1 (v) gives 1-methyl-2- (3-pyridylmethyl) naphthalene-7-carbonitrile, t .pl. 110-112 (from gasoline, as kip. 80-100).
    Found,%: C 84.05; H 5.56; N 10.93
     N
    Calculated,%: C 83.69; H 5.46; M 10.84
    (: V () 1-methyl-2- (3-pyridylmethyl); naphthalene-7-carboxylic acid
    Hydrolysis of 1-methyl-2- (3-pyridylmethyl) naphthalene-7-carbonitrile according to the procedure of Example 1 () gives 1-metsh-2- (3-pyridylmethyl) naphthalene-7-carboxic acid, so pl. 210-211.
    Found.%: C 77.95; H 5.47; N 5.38.
    C | aH | 5 N Oj.
    Calculated,% C 77.96, H 5.45; N 5.05
    Example 11. 3-chloro-2- (1-imidazolylmethyl) benzo (c) thiophene-6-carboxylic acid.
    (l) Chloride 6-bromo-3-chlorobenzo (c) thiophene-2-carboxylic acid
    A mixture of para-bromocinnamic acid (49.95 g), thionylchloride (79.80 ml), pyridine (1.77 ml) and chlorobenzene
    (220 ml) is heated under reflux for 72 h, then cooled and filtered. The filtrate is evaporated and the residue is triturated with gasoline. The solid is filtered off and recrystallized from toluene / gasoline to give 6-bromo-3-chlorobenzo (c) thiophene-2-carboxylic acid chloride (26.6 g), m.p. 126-127 °.
    Found,%: C 35.00; H 1.15
    C H Br-CE OS Calculated,%: C 34.87; H 0.98
    5 (h) 6-bromo-3-chloro-2-hydroxymethylbenzo (c) thiophene
    The solution of the acid chloride 6-bromo-3-chlorobenzo (c) thiophene-2-carboxylic acid (6.20 g) in dry ether
    0 (50 ml) and dry tetrahydrofuran (50 ml) are added dropwise to a stirred suspension of lithium aluminum hydride (0.58 g) in dry ether (250 ml) at 0 under a dry atmosphere
    5 nitrogen. The mixture was stirred at room temperature for 30 minutes and then at reflux for 2.5 hours to cool and left to stand for 18 hours. Then cooled and the excess lithium-aluminum hydride was decomposed by careful addition of water (1, 0 mm), then 5 n. sodium hydroxide (1.0 ml), water (2.0 ml) with vigorous stirring. The mixture is filtered and the filtrate is evaporated to give a solid, which is chromatographed on silica gel. Elution with chloroform initially gives a certain amount of impurities,
    - and then a pure product. The fractions containing the products are combined and evaporated to give a solid, which is recrystallized from chloroform to obtain 6-bromo-3-chloro-2-hydroxymethylbenzo (c) thiophene (2.22 g), mp. 117-118 °.
    Found,%: C 39.03; H 2.18
    c, HgBr seo5
    Calculated,%: C 38.94} H 2.19. (| 1 () 6-bromo-3-chloro-2-chloromethyl- benzo (c) thiophene.
    five
    five
    0
    Treatment with 6-bromo-3-chloro-2-hydroxymethyl-benzo (B) thiophene with thionyl chloride-R and U, pyridine using the procedure of Example 1 (ii) gives 6-bromo-3-chloro-2-chloromethylbenzo (c) thiophene, m.p.95-9b (from gasoline, kip. 40-60).
    Found,%: C 36.12; H 1.66., 5
    Calculated,%: C, 36.52; H 1.70.
    (iv) 6-bromo-3-chloro-2- (1-imidazolylmethyl) benzo (c) thiophene
    Treatment of 6-bromo-3-chloro-2-chloromethylbenzo (c) thiophene with imidazole and sodium bicarbonate according to the method of example 4 (iv) indicated in the European application gives 6-bromo-3-chloro-2 (1 -imidazolylmethyl) benzo (c) thiophene, so pl. 123-124 (from ethyl acetate / benzine).
    Found,%: C 43.99; H 2.46; IN 8.55
     BrCeNS
    Calculated,%: C, 44.18; H 2.47; N 8.72.
    (V) 3-chloro-2- (1-imidazolylmethyl) (c) thiophene-6-carbonitrile
    Treatment with 6-bromo-3-chloro-2- (1-imidazolylmethyl) benzothiophene with copper (I) cyanide according to the method of example 1 (fl v) gives 3-chloro-2- (1-imidazolylmethyl) beiso (c) thiophenyl 6-carbonitrile, so pl. 158-159 °.
    Found,%: C 56.63; H 2.97; N 15.03
    C, HgCfN, 5 Calculated,%: C 57.04; H 2.95; N 15.35
    (vi) 3-chloro-2- (1-imidazolylmethyl benzo (c) thiophene-6-carboxylic acid
    Hydrolysis of 3-chloro-2- (1-imidazolyl) benzo (c) thiophene-6-carbonitrile according to the procedure of Example 8 (iv) gives 3-chloro 2- (1-imidazolylmethyl) benzo (c) thiophene 6-carboxylic acid, mp 256-257
    Found,%: C 53.24; H 3.15; - tJ 9.70
    Calculated,%: C 53.33; H 3.10; N 9.57
    Example 12. 2- (3-pyridyl- 1methyl) benzofuran-5-carboxylic acid iTa.
    I (i) 5-bromobenzofuran-2-yl pyrid-3-yl ketone
    A mixture of 5-bromosalicylaldehyde (17.7 g), 3-bromoacetylpyridine hydrobromide (25.3 g) and anhydrous potassium carbonate (60: 8 g), is heated under reflux with stirring over 2 times in 2-butanone (200 ml). 5 h. The mixture is filtered and the solid is rinsed with 2-butanone. Combined filtrate and washes
    evaporated and the residue is recrystallized from methanol to “give 5-bromo-benzofuran-2-yl pyryl-3-yl-ketone (19.2 g), m.p. 144-145.
    Found,%: C 55,56; And 2.79; N 4.72
    C | N VGNOG
    Calculated,%: C 56.65, H 2.67; N 4.63
    (ii) 5-bromo-3- (3-pyridylmethyl) benzofuran
    Reduction of 5-bromibersofuran 2-yl pyrid-3-yl ketoyl by the procedure of Example 7 (/ (g) gives 5-bromo-2- (3-pyridmethyl) benzofuran, mp. 72-74 (from gasoline, t .kip. 60-80).
    Found,%: C 58.01; H 3.51; N 5.09
    C ,, H, BrNO
    Calculated,%: C 58.35; .H, 3.50; N 4.86
    (fli) 2- (3-pyridylmetsh1) benzofuran-5-carbonitrile
    Treatment of 5-bromo- (3-pyridylmethyl benzofuran with copper (I) cyanide according to the method of example 1 (iv) gives 2- (3-pyridylmethyl) benzofuran-5-carbonitrile, mp. 59-61.
    Found,%: C 76.44; H 4.27; N 12.38
    С „Н ,, НгО
    Calculated,%: C 76.90; H 4.28; N 11.96.
    (1 y) 2- (3-pyridylmethyl) benzofur 5-carboxylic acid
    Hydrolysis of 2- (3-pyridylmethyl) benzofuran-5-carbonitrile according to the procedure of Example 1 (v) gives 2- (3-pyridylmethyl) benzofuran-5-carboxylic acid, mp. 197-198.
    Found,%: C 71.3t; H 4.51-, N 5.58
    C, 5H ,, N05
    Calculated,%: C 71, H 4.38; N 5.32.
    Example 13. 5-carboxy-3-methylbenzo (c) thien-2-yl pyrid 3-yl keto
    (1) 5-cyano-3-methylbenzo (c) thien-2-yl-pyrid-2-yl ketone
    Treatment with 5-bromo-3-methylbenzo (c) thien-2-yl-pyrid-3-yl ketone (product of example 2 (JO copper cyanide (T) according to the procedure of example. 1 (IV) gives 5-cyan 3 methylbenzo (in ) thien-2-yl pyrid-3-yl ketone, mp 138-139 ° (from ethyl acetate and gasoline, bp 6Q-80 °).
    Found,%: C 69.08 H 3.70; N 9.87.
    C, gH, Calculated,%: C 69.04; H 3.62;
    : N 10.07
    () 5-carboxy-3-methylbenzo (c) thien-2-yl pyrid-3-yl ketone
    1 Hydrolysis of 5-cyano-3-methylbenzo (c) thien-2-yl pyrid-3-yl ketone according to the method of example 8 (IV) gives 5-carboxy-3-methylbenzothien-2-yl-pyrid-3-sh1 ketone, J.pl. 253-265.
    Found,%: C b4,00; H 3.81; C. 4.60
    C ,, H ,, NO, 5
    Calculated,%: C 64.63; H 3.73; N 4.71
    Example 14. 3-methyl-2- (1-them
    DazoliLmetil) benzofuran-.5-K | p | boic acid 1) 5-b rum-3-ethylbenzofuran-2-carbonitrile.
    A mixture of 5-bromo-2-hydroxypropiophenone (t3.74 g), chloroacetonitrile (4.62 ml) of anhydrous potassium carbonate (49.8 g) in anhydrous dimethylformamide (140 ml was heated at reflux temperature for 1 h with stirring. The solvent was evaporated and the residue was separated between water and diethyl ether. The layers were separated from each other and the aqueous layer was extracted several times with diethyl ether. The mixture of the organic layer and the extract was thoroughly washed with water and dried (over Na, SO). After evaporating the solvent, a solid residue was obtained which subjected and chromatography on silica gel. Elution with chloroform and benzine (3: 1) gave 5-bromo-3-ethylbenzofuran-2-carbonitrile (8.90 g) with mp 68-69 after crystallization from methanol / water mixtures.
    Found,%: C 53.14 j H 3.24; N 5.71
    C ,, HgBrNO
    Calculated,%: C, 52.83 H, 3.22; N 5.60
    Ii) 5-bromo-3-ethylbenzofuran-2-carboxylic acid
    A mixture of 5-bromo-3-ethylbenzofuran-2 carbonitrile (2.00 g), potassium hydroxide (1.00 g), water (10 ml) and ethanol (0.5 ml) was heated at reflux temperature for 48 h. and then solvent was added. The residue was dissolved in water and the filter solution5
    ABOUT
    five
    0
    0

    were added and acidified with 2N hydrochloric acid. The solids were filtered, washed with water, dried, and obtained 5-6 ppm-3-ethylbenzofuran-2-carboxylic acid (2.01 g) with mp. 240-242 after crystallization from a mixture of methanol and water.
    Found,%: C 49.27; W C, 51 S „n; Br O,
    Calculated,%: C 49.10; H 3.37
    fll) 5-bromo-3-ethyl-2-hydroxymethyl-benzofuran
    In a stirred solution of 5-bromo-3-ethylbenzofuran-2-carboxylic acid (1.91 g) in anhydrous tetrahydrofuran-70 (70 ml) at O in a dry atmosphere (nitrogen was added a borane-tetrahydrofuran complex (25 ml 1M solution. The solution was stirred at 0 for one hour and then at room temperature for 24 hours. In order to decompose the excess of the borane complex, methanol was added continuously and then the solution was evaporated. The residue was dissolved in diethyl ether, washed with water and dried (over). The ether was evaporated and a solid residue was obtained. the current was chromatographed on silica gel by elution with chloroform to obtain a solid which was crystallized from a mixture of ethyl acetate and gasoline to give 5-bromo-3-ethyl-2-hydroxymethylbenzofuran (1.05 g) mp 93 -94 °.
    Found,%: C 51.71; And 4.36 С ,, Н „ВгОг
    Calculated,%: C, 51.79; And 4.35
    V) 5-bromo-2-chloromethyl-3-etsh1-benzofuran
    Treatment with 5-bromo-3-etch1-2-hydroxy-methylbenzofuran with thionyl chloride and pyridine according to the method described in Example 1 (P) gave 5-bromo-2-chloromethyl-3-ethylbenzofuran, mp. 58-60.
    Found,%: C 48.41; - H 3.89 C ,, HjgBrCeo
    Calculated,%: C, 48.30; And 3.68
    V) 5-bromo-3-ethyl-2- (1-imidazolylmethyl) benzofuran
    After treating with 5-bromo-3-eth1-2-oximethylbenzofuran with imidazole and sodium bicarbonate using the method described in Example 4 (14) of this European patent application, 5-bromo-3 ethyl-2- (1-imidazolylmethyl) benzofu was obtained. - wounds, m.p. 140-141.
    x
    Found,%: C 55.10; H 4.29, W 9.18
    SCN „ВгНр
    Calculated,%: C 55.12; H 4.45; N 9.29
    Vr) 3-ethyl-2- (1-nmidazolylmethyl) benzofuran-5 carbonitrile
    After treating 5 - bromo-3-eti.n-2- (1-imidazolylmethyl) benzofuran with copper cyanide (1) according to the method described in example G (IV), 3-ethyl-2 - (dazolyl) benzofuran is obtained -5-carbonitrile, TL1L. 88-89 °,
    Found,%: C, 70.99; H 5.28; N 16.46
    c ,, n, o
    Calculated,%: C, 71.70; H, 5.21; N16.72
    11G) 3-ethyl-2 (1-imidazolylmethyl) benzofuran-5-carboxylic acid
    By hydrolyzing 3-ethyl-2- (1-imidazolylmethyl) benzofuran-5-car bonitrile using the method described in example iCV), 3-ethyl-2- {1-imidazolyl) benzofuran 5-carboxylic acid was obtained. 215-217 °.
    Found,%: C 66.05; H 5.29; H 10.31
    C, 5 iNgOe Calculated,%: C 66.66; H 5.22;
    To 10.36,
    Example 15, - 2- (1-imidazolylmethyl) -1-methyl naphthalene-7-carboxylic acid.
    1) 7 bromo-2-dimethylamine, omethyl-1 - tetralone
    A mixture of 7-bromo 1-tetralone (4.50 g dimethylamine hydrochloride (2.50 g) „paraformaldehyde (1.0 g) ethanol (6 ml) and concentrated hydrochloric acid (4 drops) was heated at reflux temperature for 2 h. and cooled. The mixture was diluted with several milliliters of acetone, the solids were filtered, washed with a small amount of acetone, dried, and 7-bromo-2-dimethylaminomethyl-1-tetralone hydrochloride was obtained, having a mp of 169-171 and pure enough for use in the next reaction.
    A sample crystallized from cm 2 methanol with ethyl acetate had so pl. 176-178 °.
    Found,%: C 48.99 H 5.26; N 4.72
    gBrNOHC
    Calculated,%: C 49.00, - H 5.38; N 4.40
    Hydrochloride turned into free
    the base by dissolving in a small volume of water and adding a slight excess of a saturated aqueous solution of sodium bicarbonate. After extraction with simple diethyl
    ether obtained free base in the form of oil.
    II) 7-bromo-2- (1-imidazolylmethyl) -1-tetralone
    A solution of 7-bromo-2-dimethylaminomethyl-1-tetralone free base (6,, 0 g) and imidazole (2.5 g) in xylene (30 ml) was heated at reflux for 1.5 hours and then evaporated. The residue was dissolved
    in a simple dithyl ether solution and a solution of (-Nose with water and then dilute hydrochloric acid. The acid extract was made alkaline with dilute sodium hydroxide solution. The mixture was extracted with chloroform, the extract was washed with water and dried (over Na2S04). After evaporation of the solvent, a solid residue was obtained, crystallized from ethyl acetate, and
    Got 7-bromo 2- (1-imidazolylmethyl) - - tetralone 3 m.p. 129-131.
    Found, I: C 54.86; H 4.30; N 9.34
    Calculated,%: C 55.10, H 4.29 N 9.13
    (in) 7 - bromo-1-oxo-1-methyl 2- (1-imidazolylmethyl) -1,2,354-tetra-gibrophthalene
    After treatment with 7-bromo-2- (1-imidazolylmethyl) -1-tetradone with magnesium magnesium according to the method described in Example 10 (iri) j, 7-bromoxy-1-methyl-2- (1 -:; - 1-imidazopylmethyl) -1 , 54-tetrahydronaphthalene as a mixture of isomers, which is directly used in the next stage,
    ly) 7 bromo-2- (1-imidazolylmethyl) - 1 methylnaphthalene
    A solution of 7-bromo-1-hydroxy-1-methyl-2- (1 imidazolylmethyl) -1,2,3 54-tetrahydronaphthalene (1.95 g) and triphenyl methanol (2.37 g) in trifluoroacetic acid ( 30 ml) was heated at the reflux temperature for 4 days, then another 2.37 g of triphenylmethanol was added and the solution was heated at the reflux temperature for another 5 days. The solution was evaporated and the residue was basified with a dilute sodium hydroxide solution. The mixture was extracted several times with ethyl acetate, the extract was washed with water and dried (over). After evaporation of the solvent, an oil was obtained, which was then chromatographed on silica gel. By elution with chloroform, triphenylmethane was obtained, some triphenylmethanol and a pure product. The fractions containing the product were evaporated and 7-bromo-2- (1-imidazolylmethyl) -1-methylnaphthalene (1.38 g) was obtained. A sample crystallized from a mixture of ethyl acetate and gasoline (since 70-80), had so pl. 112-113.
    Found,%: C 59.82; H 4.32; N 9,10
    C H, Br N 2
    Calculated,%: C 59.8.2; H 4.35, - N 9,30С
     U) 2- (1-imidazolylmethyl) -1-methyl-naphthalene-7-carbonitrile
    After treatment with 7-bromo-2- (1-imidazolylmethyl) -1-methylnaphthalene with copper cyanide according to the method described in Example 1 (tV), 2- (1-imidazolylmethyl) -1-methylnaphthalene-7-carboxyphenyl, t. square 141-143, sufficiently pure for use in the next reaction.
    VI) 2- (1-imidazolylmethyl) -1-methyl naphthalene-7-carboxylic acid
    By hydrolysis of 2- (1-imidazolylmethyl) -1-methylnaphthalene-7-carbonone by the method described in Example 1 (V), 2- (1-imidazolylmethyl) 1-methylnaphthalene-7-carboxylic acid t was obtained. square 300
    Found,%: C 71.77; H 5.27; N 10.44
    C, H,
    Calculated,%: C, 72.17; H 5.30; N 10.52
    The compounds of formula (1) and their pharmaceutically acceptable salts selectively inhibit the action of the enzyme thromboxane synthetase, without significantly adversely affecting the action of the enzymes prostatcycline synthetase or cycloxygenase. Thus, the compounds are of value for the treatment of many clinical conditions that are characterized by an imbalance of prostacyclin / thromboxan A. For the reasons considered 1, these conditions include thrombosis, coronary heart disease, heart attacks, transient ischemic attacks, migraine, peripheral vascular diseases, cancer, vascular complications of diabetes and endotoxin shock.
    Studies have shown that in the majority of tissues, the main product of Mtabolism of arazidonic acid is one of two unstable substances, thromboxane Aj (TxAj) or prostacyclin (PGIj)
    In most cases, prostaglan DGE PGEg, PGD are relatively less important by-products in this direction of biosynthesis processes. The detection of thromboxane Aj and prostacyclin significantly broadened the understanding of the processes of vascular homeostasis. For example, prostacyclin is a powerful vasodilator and inhibitor of platelet aggregation, and in this respect is the most potent endogenous substance found so far. The enzyme prostacyclin synthetase is located in the endothelial layer of the vascular network, and can be supplied with endoperaciums released by blood platelets in contact with vascular walls. The prostacyclin produced in this way is very important in preventing the deposition of platelets on the walls of blood vessels.
    Thromboxane A is synthesized by the enzyme thromboxane synthetase, which is found, for example, in blood platelets. Thromboxane A is a vasoconstrictor and a pro-aggregating agent. Its action, as such, is directly opposite to that of prostacyclin. If, for any reason, the production of prostacyclin is worsened by the vasculature, the endoperexis produced by the platelets contacting the vascular wall are converted to thromboxane and not converted to prostacyclin effectively. A change in the equilibrium of prostacyclin / thromboxane in the direction of the latter substance can lead to platelet aggregation, i.e. vasospasis and hypersensitivity to atherothrombosis. It is also known that in experimental atherosclerosis, the production of prostacyclin is suppressed and the production of ALS thrombox is enhanced. Thus, Aj thromboxane is recognized as the main causative agent in various types of angina pectoris, myocardial infarction due to heart failure and seizures. Studies in rabbits have shown that ECG changes characteristic of E1 of their conditions occur in the case of freshly prepared thromboxane A, j injection: they are wound directly in the animal sardgle. This methodology is considered to be a unique animal model of heart attacks in patients with coronary insufficiency and is used to demonstrate that the administration of a compound, presumably antagonist to the effects of thromboxane A, protects rabbits from the fatal consequences of injection, thromboxane Aj, "
    Another area where the imbalance PG1, / TxA is considered an important component factor is migraine.
    Migraine headache is associated with changes in intra- and extra-cerebral blood flow5, in particular, the precursor of 1 tin pain and a decrease in cerebral blood flow, followed by a spread to both vascular areas during tin pain stage 1 ,
    Prior to the development of headache, the level of 5-hydroxytripamine in the blood rises, and this indicates the existence of an ag regaia in vivo and the release of the amine from tp (7mg cells reserves. It is known that the blood platelets of patients 5 are more prone to migraine, more susceptible - ng; aggregation 3 than in normal individuals "In addition, 5 it has been postulated that anomalies of function; and platelet count is not just an eye factor in autogenesis of a migraine device, but in fact it is their main cause drug to Second, it selectively iodifies the platelet function; and, in the direction of inhibiting the formation of thromboxane, could have a significant positive effect in the treatment of migraine.
    Abnormalities in platelet behavior found in patients with sugar
    diabetes. Diabetes patients are known to be particularly sensitive to microvascular complications, atherosclerosis and thrombosis, and platelet hyperreactivity is considered to be the cause of such angiopathy. Diabetic platelets produce increased amounts of TxB and malondialdehyde. In addition, it has been shown that in rats with experimental diabetes, vascular prostacyclin production is impaired and TxA synthesis from platelets is enhanced. Thus, it is believed that the imbalance between prostacyclin and TxA is responsible for the microvascular complications of diabetes. Therefore, the TxA synthetase inhibitor would be very clinically
    useful for the prevention of these complications.
    Aspirin and most other nonsteroidal anti-inflammatory drugs inhibit the cyclooxygenase enzyme. The effect of this turns out to be. cessation of production of peroxides and a decrease in the resultant. this level of prostacyclin and thromboxane A. Ac
    Pcrin and aspirin-like drugs were evaluated clinically from the point of view of preventing heart attacks.
    While using these drugs, some encouraging results were obtained, for treating such clinical conditions it was more valuable
    a compound that specifically inhibits the formation of thromboxane A, leaving the biosynthesis of prostacyclin intact.
    The ability of primary tumors to metastasize is the main cause of failure in treatment and cancer in humans. It was assumed that metastatic tumors cells can
    change the critical balance of PGI TxA., thrombosis benefit. Prostacyclin is a potent antimetastatic agent due to its platelet-antiaggregative effect. This result suggests that the inhibitor TxA, synthetase, can act as an antimetastatic agent.
    Shock caused by bacterial endotoxins is associated with thrombocytopenia, disseminated intravascular coagulation, lysosomal labilization and high-constriction of the pulmonary and mesenteric arteries. In addition, plasma thromboxane levels significantly increase. The administration of imidazole inhibitors of TxAg synthetase to experimental animals before endotoxin led to a reduction in the symptoms of shock and a significant increase in the rate of survival. i
    The effects of the compounds of formula (I) on thromboxane synthetase enzyme and the enzymes of prostacyclin synthetase and cyclooxygenase are measured using the following enzyme assays.
    1. Cyclo-oxygenase.
    The ram seminal vesicle microsomes are incubated with arazidonic acid (1% μmol, 1 min at 22 ° C) to obtain 7CH and the reaction mixture samples are poured into a Krebs bicarbonate stream at 37 containing a mixture of antagonists and indomethacin, which is used for perfusion of a spiral rabbit aorta strips. The ability of a compound to inhibit an enzyme is measured by comparing the increase in isometric voltage generated by PCH in the absence of the test compound, and following the preincubation of the enzyme with the test compound for 5 minutes.
    2. Prostacyclin (PC12) synthetase
    Pig aortic microsomes are incubated (30 s, -22) with nCHg obtained in step 1, and the reaction is stopped using 5 volumes of ethanol. RFE production is assessed by measuring its stable decay product, 6-keto RSH, using specific immunoassay.
    PC1d-production can be completely inhibited by preincubating the enzyme with a selective PCI-synthase inhibitor, 15-hydroperoxyarachidonic acid. The test compound is preincubated with the enzyme for 5 minutes and its ability to prevent the production of HGH (6-keto HGH,) is measured.
    3.Thromboxane A2. (TxA2) synthetase
    Indomethacin-treated human platelet microsomes are incubated (2 min., O in PCNl, prepared similarly to claim 1) and the reaction is stopped with 5 volumes of ethanol. TxA production is assessed by measuring its stable metabolite, TxB2, using a specific radioimmunoassay.
    The test compound is preincubated with the enzyme for 5 minutes, and its ability to inhibit the thromboxane synthetase enzyme is measured as a decrease in production.
    TxA2 (TxBj).
    It has been shown that the compounds of formula (I), which have been tested by the way considered, are capable of selectively inhibiting the enzyme thromboxane synthase.
    In addition, an assay for measuring inhibition of human platelet aggregation is described.
    blood, and it can be considered predictive for evaluating clinical antitrombic efficacy. In this trial, both clinically effective drugs, aspirin and sulfinpyrazone,
    exhibit inhibitory activity against a variety of aggregating agents.
    In vivo tests are also described.
    "In animals for the evaluation of potential anti-thrombotic drugs."
    The technique of Petrono and co-authors is adapted to study the production of TxB in whole blood samples,
    taken from animals before and after treatment with the drug. Blood samples are taken in glass tubes and allowed to clot at 37. The serum is separated by centrifugation and the samples are stored at prior to analysis on TxBg, when appropriate dilutions of ethanol-deproteinized samples are analyzed with
    using radioimmunoassay. This technique is used in experiments with test compounds to determine the strength of the effect when administered intravenously to anesthetized
    rabbits.
    Anesthetized rabbits. New Lealand white male rabbits (2.6-5.6 kg) were anesthetized with sodium pentobarbitone (30 mg / kg intravenously) and then with urethane (500 mg / kg intraperitoneally). After cannulation of the trachea, the carotid artery is catheterized to collect blood samples. The catheter is left unclosed by slow infusion (0.2 ml / min) of sterile saline. Control samples of carotid arterial blood are taken 30 and 5 minutes before the test compound or medium is injected (0.9% w / v O, - ml / kg) through the marginal vein ,, Use three groups of rabbits. The first group gets 0.03 mg / kg Similarly, the second group receives 0.3 MG / KG, then 1 mg- / kg. The third group receives the carrier medium, followed by another injection of the medium carrier after 1 hour. Samples of carotid arterial blood are taken 15 and 45 minutes after administration of any doses. At the time of collection, 1 ml of KpoBi is taken into the glass tube, without anticoagulant, to determine TxBj. For this purpose, the blood sample is allowed to curtail during two-hour incubation at 37 ° (for this time, preliminary experiments showed the maximum production of TxB, g) and the serum is obtained by centrifugation. Serum samples are then processed by radioimmunoanalysis for TxB, after deprotenisation with ethanol and diluted with Isogel-Tris.
    Intravenous infusion of arachidonic acid causes rabbit death as a result of platelet agglutination and pulmonary embolization. And; again5 clinically effective aspirin and sulfinpyrazone protect the rabbit from the lethal effect of the injection. It is also shown that sulfinpir zones prevents thrombopi LLP 3 from aggregating into the extracorporeal contour of the abdominal aorta of rats.
    The compounds can be administered orally in the form of tablets or capsules containing a single dose of the compound together with indifferent ingredients such as corn starch, calcium carbonate, dicalcium Algphosphate, lactose, magnesium stearate, Primogel (brand name or talc. Tablets are usually prepared
    ,; about 5 С 5 p
    ,
    CS;
    five
    U
    co-granulating the ingredients and pressing the resulting mixture to obtain tablets of the desired size. Capsules are usually prepared by co-granulating the ingredients and filling them; gelatinous capsules of suitable size with filling with the required dose.
    The compounds can also be administered by partial injection, for example, by intramuscular, intravenous or subcutaneous injection. For parenteral administration, they are best used in the form of a sterile aqueous solution, which may contain other solutes, such as tonic pressure reguaches and pH. The compounds may be added to distilled water and the pH adjusted to 3-6 using an acid such as citric, lactic or hydrochloric. Sufficient amounts of solutes, such as dextrose or salt, can be added to ensure the isotonic nature of the solution. The resulting solution can then be sterilized and filled into sterile glass ampoules of a suitable size, containing the required volume of solution. The compounds according to the invention can also be infused with a parenteral infusion as described above into a vein.
    For oral ingestion in humans, the daily dosage of the compound of formula (I) is 0.1-20 mg / kg per day for an typical adult patient (70 kg). For parenteral administration, the daily dosage of the compound of formula (I) is 0.01-0.5 mg / kg per day, for a typical adult and patient. Thus, tablets or capsules contain 5-150 mg of active compound for oral administration up to 3 times 3 days,. Doses for parenteral administration contain O, 5-0.35 mg of active compound. A typical ampoule is a 10 ml ampoule containing 5 mg of active compound in 6; -10 ml of solution.
    Naturally, it should be borne in mind that, in any case, the physician himself determines the actual dosage that is most suitable for the patient, taking into account age, weight and his response. The indicated dosages are averaged by nmi examples: naturally they can
    there are individual cases, in which - or low dosages. In the table there are more effective higher results obtained.
    Order 1007/62 Circulation 379 Subscription VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Branch PGS Patent, Uzhgorod, st. Project, 4
    -
    权利要求:
    Claims (2)
    [1]
    A method of producing benzofuranbenzo (c) thiophene or naphthalene carboxylic acids of the general formula I
    Y where Y, which is attached to ring A, means COOH or SONH g ;
    X is 0, 5 or CH = CH;
    B ( attached to the carbon atom of ring B, means hydrogen, halogen, C ( -C 4 -alkyl or 5 (C ^ -C ^ -alkyl);
    R, which is attached to the carbon atom of ring B, means
    [2]
    2 'or (3-pyridyl) -2, where Ζ is a group of CH 2 , CO or 5, or their pharmaceutically acceptable salts, characterized in that the compound of General formula II where R, R 1 and X have the indicated meanings, and the nitrile group attached to ring A of the compounds of formula 1, are hydrolyzed using sodium hydroxide or sulfuric acid in the form of their aqueous solutions with the release of the target product, where Y is COOH, or using hydrogen peroxide and sodium hydroxide with the release of the target product, where y-C0NH 2 .
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1217256A3|1986-03-07|Method of producing benzofuranbenzo|thiophen- or naphthalenecarbonic acids or their salts which are acceptable in pharmacy
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    同族专利:
    公开号 | 公开日
    CS235023B2|1985-04-16|
    DK378682A|1983-03-25|
    FI822943A0|1982-08-24|
    JPS5852272A|1983-03-28|
    NO160002B|1988-11-21|
    KR870000902B1|1987-05-04|
    JPS611067B2|1986-01-13|
    YU180184A|1985-04-30|
    NO160002C|1989-03-01|
    DD206378A5|1984-01-25|
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    EP0073663A3|1983-04-13|
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    SU1194278A3|1985-11-23|
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    IL66620D0|1982-12-31|
    US4590200A|1986-05-20|
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    NO822882L|1983-02-28|
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    CA1178964A|1984-12-04|
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    IE53739B1|1989-02-01|
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    AU532848B2|1983-10-13|
    FI822943L|1983-02-27|
    KR840001164A|1984-03-28|
    YU191482A|1985-03-20|
    US4496572A|1985-01-29|
    AU8759982A|1983-03-24|
    AT20467T|1986-07-15|
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    法律状态:
    优先权:
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