• 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:
    Novel 3-(1-Imidazolylalkyl)indoles and the pharmaceutically acceptable acid addition salts thereof are disclosed. The novel compounds are useful in selectively inhibiting the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacycline synthetase or cyclooxygenase enzymes and are thus of value as therapeutic agents for the treatment of ischaemic heart disease, stroke, transient ischaemic attack, thrombosis, migraine and the vascular complications of diabetes.
    公开号:SU1277894A3
    申请号:SU802891745
    申请日:1980-03-05
    公开日:1986-12-15
    发明作者:Эдвард Кросс Питер；Питер Дикинсон Роджер
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to new 3- (1-imidazolylapkyl) indoles or their pharmaceutically acceptable acid addition salts, which have physiological activity and can be used in medicine.
    The purpose of the invention is the synthesis of new compounds in the series of 3- (1-imidazolylalkyl) indoles with valuable properties.
    Example 1. 1- (2-Cyanoethyl) -3 (1-imidazolylmethyl) indole fumarate.
    A 40% solution of benzyltrimethyl ammonium oxide in methanol (0.5 ml) was added to a suspension of 3- (1-imidazolidmethyl) indole (1.97 g) in 25 ml of dioxane containing 2.0 mp acrylonitrile to obtain a clear solution. This solution is heated to 50-60 ° C for 30 minutes, then allowed to cool and kept overnight at room temperature. Then it is poured into water and the mixture is extracted with ethyl acetate (3x50 ml). The combined extracts are washed with water and dried over sodium sulfate. By evaporation of the solvent,
    2.5 g of 1-cyanoethyl-3- (1-imidaeolylmethyl) indole as an oil.
    The oil is dissolved in a few milliliters of ethanol and a slight excess of a saturated solution of fumaric acid in ether is added. The precipitate is filtered off and crystallized from a mixture of 2-butanol and petroleum ether (bp 60-80 ° C) to obtain | - (2cyanoethyl) -3- (1-imidazolylmethyl) indole fumarate, mp 167-169 ° C ...
    Found,%: C 61.93; H 4.99; N 15, 14.
    C Η N -C N.O.
    f5 M 4 4 4 4
    Calculated,%: C 62.28; H 4.95; N 15.29.
    Example p 2, 1- (2-Cyanoethyl) 3- [1- (1-imidazolyl) ethyl] indole fumarate.
    Treatment of 3 “U- (1-imidazolyl) ethyl] indole with acrylonitrile according to the procedure of Example 1 gave an oil which was purified by chromatography on silica gel. After elution with chloroform, the product is obtained as an oil. Part of the product was treated with fumaric acid as described in Example 1 and the resulting solid crystallized from ethyl acetate to give 1- (2-cyanoethyl) -3- [1 (1-imidazolyl) ethyl] indole fumarate, m.p. 128-129 ° C.
    Found,%: C 62.80; H 5.33;
    N 14.48.
    C Η N -C N.O.
    * 16 1 b 4 4 4 I
    Calculated,%: C 63.15; H 5.30; N 14.73.
    Example 3. 1 - (2-Cyanoethyl) - 3- (1-imidazolylmethyl) -5-methoxyin
    Treatment of 3- (1-imidazolylmethyl) 5-methoxyindole with acrylonitrile and purification of the crude product as described in Example 2 gives 1 - (2-cyanoethyl) -3 (1-imidazolylmethyl) -5-methoxyindole, m.p. 130 ° C (from chloroform / petroleum ether b.p. 60-80 ° C).
    Found,%: C 63.22; H 5.72; N 19.99.
    C Η N O b 16 p 16 and 4
    Calculated,%: C 68.55; H 5.72; N 19.99.
    Other 1 ~ (2 ~ cyanoethyl) indole analogs were obtained in a similar way25 from the corresponding 3- (1-imidazolylmethyl) indoles. In all cases, the crude product was partially purified by chromatography on silica gel using chloroform as eluent and was used without further specification as starting material for examples 12-22 and 28-37.
    Preparation of 3- (1-imidazolylmethyl) indole starting materials as described in European patent application 0,003,901, with the exception of 5chloro-3- (1-imidazolylmethyl) indole, which was prepared as follows. A solution of 5-chlororamine (3.73 g) and imidazole (1.22 g) in xylene (20 ml) was refluxed for 3 hours and cooled. The solid is filtered off, washed with toluene 4 $ and then with petroleum ether and then crystallized from a mixture of isoprspilol and petroleum ether (bp 60-80 ° C) to obtain 5-chloro-8 (1-imidazolylmethyl) indole (3, 50 g), 50 m.p. 195-197 d S.
    Found,%: C 62.48; H4.31;
    N 18.09.
    s <2 n 1a 01¾
    Calculated,%: C 62.20; H 4.35;
    55 KG 18.14.
    PRI me R 4.1 - (4-Cyanobenzyl) 3- (1-imidazolylmethyl) indole.
    3- (1-Imidazolylmethyl) indole (4.93 g) is dissolved in 25 ml of dry Ν, Ν-dimethylformamide, the solution is cooled to 0 ° C. Was added portionwise 1.2 g of sodium hydride (50% dispersion in oil) with stirring, the mixture was stirred for 30 minutes at 0 e C. While stirring with a solution of (bromo-p-tolunitrile (4.9 g) in Ν , Dimethylformamide (10 ml) for 2 min, the mixture is stirred at room temperature for 2 h and then poured into water.The mixture is extracted with ethyl acetate (3 times 50 mp each), the combined extracts are washed with water and dried with sodium sulfate. evaporation of the solvent gives an oil which is chromatographed on silica gel First, the column is eluted with a mixture of chloroform and petroleum ether (bp 60 80 s C, 1: 1) in order to remove some impurities and mineral oil, then the purified product is eluted using a mixture of chloroform and methanol (95: 5). Evaporation of the eluate gave an oil (7.25 g), which crystallized on standing. The solid was recrystallized from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C) to give 1- (4cyanobenzyl ) -3- (1-imidazolylmethyl) indole, mp 127 -129 * 0.
    Found,%: C 76.55; H 5.15;
    N, 17.80.
    C £ 0 H 16 W 4
    Calculated,%: C 76.90; H 5.16;
    N 17.94.
    PRI me R 5. 1- (2-Cyanobenzyl) 3- (1-imidazolylmethyl) indole.
    The compound was prepared as described in Example 4, using & -bromo-o-tolunitrile instead of c-bromo-p-tolunitrile. The product has a mp 135 136.5 ° C (from ethyl acetate / petroleum ether b.p. 60-80 ° C).
    Found,%: C 77.10; H5.22;
    N 17.92.
    C A N 4
    Calculated,%: C 76.90; H 5.16;
    N 17.94.
    PRI me R 6. 1- (3-Cyanobenzyl) 3- (1-imidazolylmethyl) indole fumarate. The compound was prepared as described in Example 4, using oi-bromo-mtolunitrile instead of bromo-p-tolunitrile. The fumaric acid salt has m.p. 156-158 ° C (from isopropanol petroleum ether bp 60 to 80 ° C).
    has a melting point, 120 isopropanol and πέτο melting point 60-80 ° C).
    63.61; H 5.37;
    Found,%: C 67.01; H 4.70;
    12.95.
    С Η N 'С Η О 11 10 4 А 4 4
    Calculated,%: · C 67.28; H 4.71; 13.08.
    Example 7. 1- (4-Ethoxycarbonylbenzyl) -3- (1-imidazolylmethyl) indole hemi-fumarate.
    The compound was prepared as described in example 4 using ethyl ether <7. -bromo-p-toluic acid together with ol-bromo-p-tolunitrile. Semi-fumarate salt 122 ° C (from a mixture of roll ether
    Found,%: C N 9.76.
    C i2 H 2) N 3 0 2 1/2 SD0 4
    Calculated, ^: C 69.05; H 5.55; N 10.07.
    Example 8. 1- (4-Ethoxycarbonylbenzyl) -3- (1-imidazolylmethyl) -5meto to syindole.
    The compound was prepared as described in Example 4 using 3- (1-imidazolylmethyl) -5-methoxyindole and ethyl ester d. -bromine-p-toluic acid as starting materials. The fumaric acid salt hemihydrate has m.p. 113-114 ° C.
    Found,%: C 63.10; H 5.29; N 7.32.
    C 23 H 23 N 5 ° 3 СД0 <1 / 2Н g О
    Calculated,%: C 63.02; H 5.48;
    N 8.16.
    PRI me R 9. 1-Ethoxycarbonylmethyl-3- (1-imidaz olylmethyl) indole.
    The compound was prepared as described in example 4 using ethyl bromoacetic acid instead of oί bromo-p-tolunitrile. The product has a m.p. 123-124 ° C tat / petroleum 80 0 C).
    Found,%: С
    14.68.
    C 16 H 47 Ν30 2
    Calculated%: 14.83%.
    Example 10 1- (2-Carboxyethyl) -3- (1-imidazolylmethyl) indole fumarate monohydrate.
    A mixture of 1.0 g of 1- (2-cyanoethyl) ~ 3 (1-imidazolylmethyl) indole and a 10% aqueous solution of potassium hydroxide (10 mp) is refluxed for 2 h to obtain a clear solution. The solution is slightly acidified with acetic acid and then evaporated.
    (from a mixture of ethyl acetate with bp 50 67.51; Η 6.02;
    C 67.82; Η 6.05;
    The residue is chromatographed on silica gel. When eluted with a mixture of chloroform and methanol (1: 1), a small amount of impurity is first obtained, followed by pure product. Evaporation of the eluate containing the product gives an oil, which is dissolved in a minimum volume of ethanol. A small excess of a saturated solution of fumaric acid in ethanol is added, and the mixture is diluted with ether. The precipitate was separated by filtration and crystallized from methanol to give 1- (2-carboxyethyl) -3- (I imidazolylmethyl) indole fumarate monohydrate (0.45 g), m.p. 161-163 ° C.
    Found 7: C 56.67; H 4.82;
    N 9.97.
    c, s H 1s N 5 q> · c 4 n, o 4 -n r o Calculated, 7: C 56.57; H 5.25;
    N 10.42.
    Examples 11-21., Other analogs of 1- (2-carboxyethyl) indole, obtained in a similar manner from the corresponding 1- (2-cyanoethyl) indoles, are shown in table. 1. In some cases, the crude product crystallizes after acidification and there is no need for chromatography. The substance of example 20 is purified by dissolution in aqueous sodium hydroxide, filtration and re-precipitation of the product with acetic acid.
    Example 22 1-Carboxymethyl-
    3- (1-imidazolylmethyl) indole.
    1-Ethoxycarbonylmethyl-3- (1-imidazole and l methyl) in to l (0.98 g) was dissolved in ethanol (10 ml) and a solution of sodium hydroxide (0.25 g) in 2 ml of water was added. The mixture was heated under reflux for 2 hours and then evaporated. The residue is dissolved in 5 megapixels of water and the solution is slightly acidified with acetic acid. The solution is evaporated to dryness, and the residue is stirred with a little water, the mixture is filtered to give 1-carboxymethyl
    3- (1-imidazolylmethyl) indole (0.65 g), m.p. 2.18-220 th C, mp increases up to 223-224 C under crystallization from water.
    Found, 7: C, 65.47; And 5 N 16.19.
    С Н x Ni0 o <О 3 s
    Calculated, 7: C 65.87; H 5.13;
    N 16.46.
    PRI me R 23. 1- (4-Carboxybenzyl) -3- (1-imidazolylmethyl) indole.
    1- (4-Ethoxycarbonylbenzyl) -3 (1-imidazolylmethyl) indole (1.53 g) is dissolved in 25 ml of ethanol and a solution of 0.2 g of sodium hydroxide in 5 ml of water is added. The reactor is heated under reflux for 2 hours and then evaporated. The residue is taken up in water and the solution is slightly acidified with acetic acid. A sticky residue forms which hardens when scratched. The solid was filtered off, washed with water and crystallized from ethanol to give 1 - (4-carboxybenzyl) -3- (1imidazolylmethyl) indole (0.76 g), m.p. 234-235 ° C.
    Found, 7: C, 72.32; H 4.96; N 12.67.
    ' C. o H n N 3 O 2
    Calculated, 7: C 72.49; H 5.17; N 12.68.
    Example 24 1- (3-Carboxybenzyl) -3- (1-imidazolylmethyl) indole.
    1- (3-Cyanobenzyl) -3- (1-imidazolyl methyl) indole (1.0 g) is dissolved in 5 ml of ethanol and a solution of 0.5 g of potassium hydroxide in 5 mp of water is added. The mixture was heated under reflux for 6 h and then worked up to give 0.70 g of 1- (3-carboxybenzyl) -
    3- (1-imidazolylmethyl) indole, m.p. 201.5-203.5 ° C (from ethanol).
    Found, 7: C, 72.16; H 5.19; N 12.66.
    C 2ff H i7 N 3 0 2
    Calculated, 7: C 72.49; H 5.17;
    N 12.68.
    PRI me R 25. 1 - (4-Carboxybenzyl) -3- (1-imidazolylmethyl) -5-methoxyindole.
    The compound was prepared as described in Example 23 using 1- (4-ethoxycarbonylbenzyl) -3- (1-imidazolylmethyl) -5methoxyindole as starting material. The crude product is purified 'by dissolving in a minimum volume of 1 N sodium hydroxide solution, filtration and re-precipitation with acetic acid. The pure product has so pl. 232-233 ° C.
    Found 7: C 69.79; H 5.30; N 11.63.
    С С1 Η N 0
    Calculated, 7: C 69.41; H 5.43;
    N 11.36.
    Example 26. 1 - [2- (5-Ethoxycarbonyl) thienylmethyl] -3- (1-imidazolemethyl) indole hemi-fumarate,
    Ί
    The compound was prepared as described in Example 4 using ethyl 5-bromomethylthenoate instead of d-bromo-p-tolunitrile. The fumaric acid half salt has m.p. 119-121 ° C (from water).
    Found: 62.41; H 5.10; N 9.91.
    C 2o H 13 N d O 2 S 1/2 C, H 4 0.
    ... Calculated,! : C 62.40; H 5.00; N 9.92.
    PRI me R 27. 1- [2- (5-methoxycarbonyl) -furanylmethyl] -3- (1-imidazolylmethyl) indole.
    The compound was prepared as described in Example 4 using methyl 5-chloromethyl furoate in place of ot-bromo-p-tolunitrile. The product has a m.p. 97-99 ° C (from toluene / petroleum ether bp 60-80 ° C).
    Found: 67.97; H 5.04; N 12.15.
    s 73 n 17 n 3 o 3
    Calculated, Ζ: C 68.05; H 5.11; N 12.53.
    Example 28 1- [2- (5-Carboxy) thienylmethyl} -3- (1-imidazolylmethyl) indole.
    The compound was prepared from 1-12- (5ethoxycarbonyl) thienylmethyl)] -3- (1 imidazolylmethyl) indole as described in Example 24. The crude product was dissolved in a slight excess of 2N sodium hydroxide solution, filtered and the product precipitated by adding acetic acid. m.p. 228-229 ° C.
    Found,%: C 63.87; H 4.47; N 12.21.
    WITH ALA '
    Calculated, X: C 64.09; H 4.48; N 12.46.
    The compounds of formula (1) have been found to selectively inhibit the action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclooxygenase enzymes. Thus, these compounds are of importance in the treatment of various clinical conditions characterized by an imbalance in prostacyclin thromboxane Aβ. For the reasons listed below, these conditions can include thrombosis, ischemic heart disease, systolic, transient ischemic attack, migraine, and diabetic vascular degeneration.
    The effect of the compounds of formula (1) on the thromboxane synthetase enzyme, prostacyclin synthetase and cyclooxygenase enzymes was determined using the following enzyme tests in the body.
    Cyclooxygenase. The microsomes of the ram seminal vesicle were incubated with arachidonic acid (100 mmol, 10 1 min, 22 ° C) in order to obtain PGH, and aliquots of the reaction mixture were injected into a stream of Krebs bicarbonate at 37 ° C containing a mixture of antagonists and indomethacin, 15 which was perfused through a coil cut into the strip of the rabbit aorta.
    The ability of a compound to inhibit the enzyme was measured 20 by comparing the increase in isometric pressure due to FGH 2 and the absence of the test compound, followed by pre-incubation of the enzyme with test compound 25 for 5 minutes.
    Prostacyclin (PG / 2) synthetase. Porcine aortic microsomes are incubated (30 s, 22 ° C) with PGHiH and bioassay of aliquots. The formation of PG / „30 was determined indirectly by measuring the pressure reduction induced by PGH (PG /, Z itself has no compressive effect on the aorta). This decrease can be completely prevented by preliminary exposure of the enzyme to a selective inhibitor of PG / N-synthetase, 15-hydroxy-arachidonic acid. The test substance is then pre-conditioned with en40 winter for 5 min and its ability to prevent a decrease in pressure is measured.
    Thromboxane A 2 (TxA 2 ) -synthetase. Microcircuits of human platelets, pretreated with indomet45 tation, are kept (2 min, O ' 7 C) with PGH and aliquots of the reaction mixture were perfused through 2 loops inserted into the rabbit aorta and separated by a retention coil (2 min). The last is necessary in order to effect a selective decomposition of the unstable thromboxane A 2, 55 thereby providing the opportunity to separate measurement of increased isometric pressure due forming TxA "and remaining PGH . Test compound pre-soaked 1277894
    IO was added to the enzyme for 5 min, and its ability to inhibit the enzyme thromboxane synthetase by reducing the TxAg-component at isometric pressure was measured.
    It has been shown that the compounds according to the invention tested in this way are capable of selectively inhibiting the enzyme thromboxane synthetase.
    In addition to these in-body tests, inhibition of human blood platelet aggregation has been described for measurement, which may serve to predict the clinical efficacy of the compounds against thrombosis. Clinically effective agents - aspirin, as well as sulfinpyrazole, have shown inhibitory activity against various aggregating agents when tested in the body.
    In addition, a number of animal trials have been described to evaluate potential anti-thrombotic drugs. Intravenous injection of arachidonic acid in a rabbit was fatal due to clumping of platelets and blockage of blood vessels in the lungs. In this case, the clinically effective aspirin, as well as sulfinpyrazone, prevent the rabbit from dying from this injection. It has also been shown that sulfinpyraeon prevents platelet aggregation in the additional physical turn of the abdominal aorta in rats.
    These compounds can be administered orally as tablets or capsules containing a unit dosage of the compound along with excipients such as maize starch, calcium carbonate, dicalcium phosphate, alginic acid, lactose, magnesium stearate, Primogel, or talc. Typically, tablets are prepared by co-granulating the ingredients, followed by compressing the resulting mixture to obtain tablets of the desired size. Capsules are usually prepared by co-granulating the ingredients and then filling them into hard gelatin capsules of the appropriate size in order to obtain the desired dosage.
    In addition, these compounds can be administered parenterally, for example, intramuscularly, intravenously, or subcutaneously. For parenteral administration, these substances are best used in the form of a sterile aqueous solution that may contain other solutes such as tonic and pH adjusters. These compounds can be added to distilled. water, and the pH is brought to 3-6, using acids such as citric, lactic or hydrochloric. To ensure the isotonicity of the solution, suitable soluble substances such as dextrose or salt can be added thereto. The resulting solution can be sterilized and filled into sterile glass tubes of the appropriate size containing the required amount of solution. The compounds of this invention can also be administered by infusion of the parenteral composition described above into a vein.
    For oral administration to patients, it is believed that the daily dosage level of the compound may range from 0.1 to 20 mg / kg per day for a typical adult patient (70 kg). For parenteral administration, the daily dosage level of the compound of formula (1) is considered to range from 0.01 to 0.5 mg / kg per day for a typical adult patient. 35 Thus, it is contemplated that tablets or capsules may contain 5 x 150 mg of active compound for oral administration up to 3 times a day. Unit dosages for parenteral administration may contain 0.5 to 35 mg of active compound. Typical A test tube can have a volume of 10 ml and contain 5 mg of the active substance in a 6-10 megapixel solution.
    However, the clinician can determine the actual dosage that is most appropriate for the patient and may vary with age, weight and patient response. The above dosages are approximate for the average patient, they, of course, can, in some cases, be more or less than the recommended intervals of up to 55 eras.
    The proposed compounds, tested using the methods described above, are capable of selectively
    1 inhibit the enzyme thromboxane synthetase.
    The results of these tests are shown in Table 2, which gives the molar concentrations of each substance that cause a 50% change in the action of the corresponding enzyme ns isometric pressure, i.e. causes 50% inhibition of the action of this enzyme.
    The materials shown in Table 2 show that all test compounds cause 50% inhibition of the thromboxane synthetase enzyme at a molar concentration of 1.0 * 10 or lower, and some compounds cause 50% inhibition at a concentration of 1O ~ 40 or lower.
    Among the compounds tested to inhibit the enzyme prostacyclin synthetase, none produced 50% inhibition at a molar concentration less than 450 times the concentration for 50% inhibition of the enzyme thromboxane synthetase, i. E. they were at least 450 times more potent inhibitors of thromboxane synthetase than inhibitors of prostacyclin synthetase, and for many compounds this ratio is many times higher.
    It is believed that all proposed compounds in this kind of tests will give results in the same range as for already tested compounds.
    The compounds obtained according to the proposed method are at least four times active, and in some cases 1000 times more active, that is, they have an inhibitory effect at concentrations 1000 times lower than 1-butylimidazole, which is a structural analogue.
    Effects of known compounds on thromboxane synthetase, below is the molar concentration of compounds resulting in 50% inhibition of thromboxane synthetase:
    imidazole N O 6.7 ► 10 _ < ;
    N-benzyl imidazole
    I.
    N ^ N-CHz-CsHj,. 10 - "
    N-butyl imidazole "10" /
    The resulting compounds are non-toxic.
    LD 50 data for 1- (2carboxyethyl) -2- [1 (. 1-imidazolyl) ethyl] indole fumarate monohydrate are given in Table 3.
    权利要求:
    Claims (1)
    [1]
    The invention relates to new 3- (1-imidazrilylalkyl) indoles or to their pharmaceutically acceptable acid addition salts, which have physiological activity and can be used in medicine.  The chain of the invention is the synthesis of new compounds in a series of 3- (l-imidazolylalkyl) indols with valuable properties.  Example 1, 1- (2-Cyanoethyl) -3 (1-imidazolylmethyl) indole fumarate.   A 40% solution of benzyltrimethylammonium oxide in methanol (0.5 ml) was added to a suspension of 3- (1-imidazolidomethyl) indole (1.97 g) in 25 ml of dioxane containing 2.0 ml of acrylonitrile, obtaining a clear solution This solution is heated to 50-60 ° C for 30 minutes, then allowed to cool and incubated for a night at room temperature.  Then it is poured into water, and the mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts are washed with water and dried over sodium sulfate. .  By evaporation of the solvent, 2.5 g of 1-cyanoethyl-3- (1-imidazolylmethyl) indole are obtained in the form of an oil.  The oil is dissolved in a few ml of ethanol and a small excess of a saturated solution of fu-maric acid in ether is added.  The precipitate is filtered off and crystallized from a mixture of 2-butanol and petroleum ether (t. kip 60-80 ° C) to give 1- (2-cyanoethyl) -3- (1-imidazolylmethyl) y.  dol fumarate, t. square  167-169 C.  Found,%: C 61.93; H 4.99; N 15.14.  C K N C N.  O, IS Il 4 4 Calculated,%: C 62.28; H 4.95; 15.29.  PRI me R 2.  1- (2-Cyanoethyl) 3- 1- (1-imidazolyl) -tang indole fumrate.  Treatment with (1-imidazolyl) ethyl zindol with acrylonitrile, according to the procedure of example 1, yields an oil, which is purified by chromatography on silica gel.  After elution with chloroform, the product is obtained.  A portion of the product was treated with fumaric acid, as described in Example 1, and the resulting solid was crystallized from ethyl acetate to give 1- (2-cyanoethyl) (1-imidazolyl) -ethyl indole fumarate, t. square  128-129C.  Found,%; C, 62.80; H 5.33; N 14.48.  C, N N with. but. 1 16 1 H C 63.15; H 5.30; Calculated, 14.73.  PRI me R 3.  1- (2-Cyanoethyl) 3- (-imidazolylmethyl) -5-methoxyinol.  Treatment of 3- (1-imidazolylmethyl) 5-methoxyindol, ol by acrylonitrile and purification of the crude product, as described in Example 2, gives 1- (2-cyanoethyl) -3 (1-imidazolylmethyl) -5-methoxyindole, t. square   (from a mixture of chloroform / petroleum ether with t. kip  60-80 ° C).  Found,% ;: C 63.22; H 5.72; N 19.99.  CuH.  Calculated,%: C 68.55; H 5.72; N 19.99.  Other 1- (2-cyanoethyl) indole analogues were obtained in a similar way from the corresponding 3- (1-imidazolylmethyl) indoles.  In all cases, the crude product was partially purified by chromatography on silica gel using chloroform as eluent, and it was used without further refinement as a starting material for examples 12-22 and 28-37.  Preparation of 3 - (- imidazolylmethyl) indole starting materials as described in European patent application O 003 901, with the exception of 5 chloro-3- (1-imidazolylmethyl) indole, which is prepared as follows.  A solution of 5-chlorohramine (3.73 g) and imidazole (1.22 g) in xylene (20 ml) is refluxed for 3 hours and cooled.  The solid is filtered off, washed with toluene and then with petroleum ether and then crystallized from a mixture of isopropyl and petroleum ether (t. kip  60-80 C) to give 5-chloro-8 (1-imidazolylmethyl) indole (3.50 g), ToPL, 195-197 C.  Found D: C 62.48; H 4.31; N 18.09.  C. , H ,, C1N, Calculated,%: C 62.20; H 4.35; N- 18, 14.  PRI me R 4.  1- (4-Cyanobenzyl) 3- (1-imidazolylmethyl) indole.  3- (1-Imidazolylmethyl) indole (4.93 g) is dissolved in 25 ml of dry S, N-dimethylformamide, the solution is cooled to 0 ° C.  1.2 g of sodium hydride (50% dispersion in oil) are added portionwise with stirring and the mixture is stirred for 30 minutes.  With stirring, a solution of o-bromo-p-tolunitrile (4.9 g) in N, N dimethylformamide (10 ml) is added over 2 minutes, the mixture is stirred at a com-natum temperature for 2 hours and then dried in water.  The mixture is extracted with ethyl acetate (3 times 50 mp), the combined extracts are washed with water and the sodium sulfate is dried. Upon evaporation of the solvent, an oil is obtained which is chromatographed on silica gel.  First, the column is eluted with a mixture of chloroform and petroleum ether (t. kip  60 80 C, 1: 1) to remove some impurities and mineral oil, then the purified product is eluted using a mixture of chloroform and methanol (95: 5).  Upon evaporation of the eluate, an oil (7.25 g) is obtained, which crystallizes upon standing.  The solid is recrystallized from a mixture of ethyl acetate and petroleum ether (t. kip  B-B C) to give 1- (4 cyanobenzyl) -3- (1-imidazolylmethyl) and dl, t. square  127-129c.  Found,%: C 76.55; H 5.15} N 17.80.  C ,, n, s, Calculated,%: C 76.90; H 5.16; N 17.94.  PRI me R 5.  1- (2-Cyanobenzyl) 3- (1-imidazolylmethyl) indole.  The compound was prepared as described in Example 4, using d-bromo-o-tolunitrile instead of with -brom-p-tolunitrile.  The product has t. square 135 136, 5 ° C (from ethyl acetate / petroleum ether with m. kip  bo-wO).  Found,%: C 77.10; H 5.22; N 17.92.  WITH. he. .  N Calculated,%: C 76.90; H 5.16; N 17.94.  PRI me R 6.  1- (3-Cyanobenzyl) 3- (1-imidazolylmethyl) indole fumarate.  The compound was prepared as described in Example 4 using o-bromo-mtolunitrile instead of cf-bromo-p-tolunitrile.  The fumaric acid salt has t. square  156-158 ° C (from a mixture of isopropanol and petroleum ether with t. Kip, 60-80 ° C).  944 Found: C 67.01; H 4.70; N 12.95.  C H N C. .  2 1 1st 4 1 4 Calculated,%: - C, 67.28;; H, 4.71; N 13.08.  Example 7  1- (4-Ethoxycarbonylbenzyl) -3- (1-imidazolylmethyl) indole poly UfuMarat.  The compound was obtained as described in example 4 using ethyl ether ci.  -bromo-p-toluic acid together with C-bromo-p-tolunitrile.  Semi-fumarate salt has t. square 120 (from a mixture of isopropanol and petroleum ether with t. kip 60-80 ° C).  Found,%: C 63.61; H 5.37; N 9.76.  C, 2H ,, N, 1/2 Calculated,%: C 69.05; H 5.55; N 10.07.  Example 8  1- (4-Ethoxycarbonylbenzyl) -3- (1-imidazolylmethyl) -5me then siindol.  A compound was prepared as described in Example 4, using 3- (1-imidazolylmethyl) -5-methoxyindole and of-bromo-p-toluic acid ethyl ester as starting materials.  The fumaric acid salt hemihydrate has t. square  113-P4 ° C.  Found,%: C 63.10; H 5.29; N 7.32.     Calculated,%: C 63.02; H 5.48; N 8.16.  PRI me R 9.  1-Ethoxycarbonylmethyl-3- (1-imidazoylmethyl) indole.  Connection was prepared as described in Example 4 using bromoacetic acid ethyl ester instead of bromo-p-tolunitrile.  The product has t. square  123-124s (from ethyl acetate / petroleum ether t. kip  50 80С).  Found,%: C 67.51; H 6.02; 14.68.  C, C, NjO Calculated,%: C 67.82; H 6.05; 14.83%.  An example.  1- (2-Carboxyethyl) -3- (1-imidazolylmethyl) indole fuarate monohydrate.  A mixture of 1.0 g of 1- (2-cyanostil) -3 (1-imidazolylmethyl) indole and 10% single solution of potassium hydroxide (10 ml) is boiled with a reflux condenser for 2 hours to obtain a clear solution.  The solution is slightly acidified with acetic acid and then evaporated.  The residue is chromatographed on sylkagel.  When elution with a mixture of chloroform and methanol (1: 1) first: a small amount of impurity is obtained, the product is followed by a clean product.  Evaporation of the product containing eluate gives an oil which is dissolved in a minimum volume of ethanol. A small excess of a saturated solution of fumaric acid in this ethanol is added, and the mixture is diluted with ether.  The precipitate was separated by filtration and crystallized from methanol to give 1- (2-carboxyethyl) -3- (Iimidazolylmethyl) monol indole fumarate (0.45 g), m. square  lei-iesc.  Found,%: C 56.67; H 4.82; 9.97.  C, 5H, 5 “L e 56.57; H 5.25; Calculated, N 10,42.  PRI me R s 11-2 ;.  Other analogs of 1- (2-carboxyethyl) indole, obtained in a similar way from the corresponding 1- (2-cyanoethyl) indoles, are listed in Table.  one.  In some cases, the crude product crystallizes after acidification and there is no need for chromatography. The substance of Example 20 is purified by dissolving in aqueous sodium hydroxide, filtering and re-precipitating the product with acetic acid.  Example 22  1-Carboxymethyl3 (1-imidazolylmethyl) indole.  1-Ethoxycarbonylmethyl-3- (1-imide 3 OLYL methyl) indole (0.98 g) was dissolved in ethanol (10 ml) and a solution of sodium hydroxide (0.25 g) was added in 2 ml of water.  The mixture is heated under reflux for 2 hours and then evaporated. .  The residue is dissolved in 5 ml of water, and the solution is slightly acidified with acetic acid.  The solution is evaporated to dryness, and the residue is stirred with a small amount of water. The mixture is filtered to obtain 1-carboxymethyl 3- (1-imidazolylmethyl) indole (0965 gt, nl.  2.18-220 ° C, t. square  increases to 223-224 ° C with crystal lysat-p and from Found,%: C 65.47; H 5 H; N 16.19.  with,. , 1a "ZO.  Calculated,%: C 65.87; H N 16.46.  Example 23.  1- (4 - Carboxibezyl) -3- (1-imidazolylmethyl) indole.  1- (4-Ethoxycarbonylbenzyl) -31-imidazolylmethyl) indole (g) is dissolved in 25 ml of ethanol and a solution of 0.2 g of nati hydroxide B 5 ML of water is added.  The reactor is heated under reflux for 2 hours and the loan is evaporated.  The residue is dissolved in water and the solution is slightly acidified with acetic acid.  An adherent precipitate forms, which hardens when scratched.  The solid substance is filtered off, washed with ode and crystallized from zanol, the catalyst 1- (4-carboxybenzyl) -3- (1midazolylmethyl) indole (0.76 g),. square  234-235 0.  Found,% C 72,32; H 4.96; 12.67.  C ,, H, N, 0, Calculated,%; C, 72.49; H 5.17; 12.68.  1- (3-Carboxy) Example 24.  benzyl) -3- (1-imidazolylmethyl) indole.  1- (3-Cyanobenzyl) -3- (1-imidazolylmethyl) indole (1.0 g) is dissolved in 5 ml of ethanol and a solution of 0.5 g of potassium hydroxide in 5 ml of water is added.  The mixture was heated under reflux for 6 hours and then treated to yield 0.70 g of 1- (3-carboxybenzyl) 3- (1-imidazolylmethyl) indole 5 tons. pl, 20, 5-203, (from ethanol).  Found,%: C 72,16; H 5.19; 32.66.  WITH. N.  C H 5.17; Calculated 5%: N 12.68.  25  1 (4-Carboxyben Example zil) -3- (1-imidazolylmethyl) -5-labels-sindol.  The compound poh-: is studied as described in Example 23s as initial material, 1- (4-ethoxycarbonylbenzyl) -3- (1-imidazolylmethyl) -5 methoxyindole.  The crude product is purified by dissolving in a minimum volume of 1 N, T) sodium hydroxide solution 8 f ½ tf: and FACT PBS using acetic acid.  Chisty t. square  232 233C.  product has Found D: C, 79; H 5.30; 63  CC, H ,,, Calculated,% from 69.41; H 5.43; N 11.36.  1-G2- (5-EthoxyPr and meper 26 carbonyl) -thienesyl-3- (l-and (izolomethyl) indole hemi-fumarate, 7 A compound was prepared as described in example 4, using ethyl-5-bromo methyl tenoate instead of d -brom-p-tolunitrile.  Half salt of fumaric acid has t. square  119-121 C (out of water).  Found,%: C 62.41; H 5.10; N 9.91.   1/2 C, h, 0,.  Calculated,%: C, 62.40; H 5.00; N 9.92.  PRI me R 27.  (5-methoxy carbonyl) -furanylmethyl-3- (1-imide zolylmethyl) indole.  The compound was prepared as described in Example 4 using methyl 5-chloro methyl furoate instead of α-bromo-p-tolunylle.  The product has t. square  97-99 C (from a mixture of toluene / petroleum ether c-t. kip  bo-wO).  Found,%: C 67.97; H 5.04; N 12.15.  C, 3Hi7, Calculated,%: C 68.05; H 5.11; N 12.53.  PRI me R 28.  (5-Carboxy) -NITIlmethyl 1-3- (1-imidazolylmethyl) indole.  The compound is obtained from l-l2- (5ethoxycarbonyl) -thienylmethyl-3- (1imidazolylmethyl) indole according to the method of example 24.  The crude product is dissolved in a small excess of 2 N. sodium hydroxide solution, filtered and the product precipitated by adding acetic acid, t. square  228-229c.  Found,%: C 63.87; H 4.47; N 12.21.    .  Calculated,%: C 64.09; H 4.48; N 12.46.  It has been found that the compounds of formula (1) selectively inhibit the activity of the thromboxane synthetase enzyme without significantly inhibiting the action of prostacyclin synthetase or cyclooxygenase enzymes.  Thus, these compounds are important in the treatment of various clinical conditions that are characterized by an imbalance in prostacyclin thromboxane A.  For the reasons listed below, these conditions may include thrombosis, ischemic heart disease, systolic, temporary ischemic attack, migraine, and diabetic vessel degeneration.  4 The effect of compounds ({herma. The potentials (1) on the epzyme of thromboxane synthetase and the enzymes of prostacyclin synthetase and cyclooxygenase were determined using the following enzyme tests in the body.  Cyclooxygenase.  The seminal vesicle microsomes were kept with arachidonic acid (100 mmol, 1 min) to obtain PGH and aliquots of the reaction mixture were injected into a Krebs bicarbonate stream at 37 ° C containing a mixture of antagonists and indomethacin, which was perfused through a coil embedded in the aorta band a rabbit .  The ability of a compound to inhibit an enzyme was measured by comparing the increase in isometric pressure due to FGH and the absence of the test compound, and then pre-incubating the enzyme with the test compound for 5 minutes.  Prostacyclin (PG / 2) synthetase.  Microsomes of porcine aorta are kept (30 s, 22 ° C with PCNsi) and aliquots are biologically tested.  PG formation was determined indirectly by measuring the decrease in pressure induced by PGH 2 (PG itself does not have a compressive effect on the aorta).  This decrease can be completely prevented by pre-exposure of the enzyme with a selective PG / synthase inhibitor, 15-hydroxy-arachidonic acid.  The test substance was then pre-incubated with the enzyme for 5 minutes and its ability to prevent a decrease in pressure was measured.  Thromboxane A (TxA2) synthetase.  Pre-treated indomethation of human platelet chips is maintained (2 minutes, () with PGH and aliquots of the reaction mixture are perfused after 2 turns inserted into the rabbit aorta and which are separated by a retention (2 minutes) spiral.  The latter is necessary in order to carry out the selective decomposition of the more unstable thromboxane A, thereby providing the possibility of separate measurement of the increased isometric pressure caused by the xA g generator and the remaining PGH.  The test compound is preliminarily incubated with the enzyme for 5 min and its ability is measured to inhibit EN zimthromboxane synthetase by reducing TxA-component in isometric pressure.  It has been shown that the proposed compounds thus tested are capable of selectively inhibiting the enzyme tronboxane synthetase.  In addition to these tests in the body, inhibition of human blood platelet aggregation has been described for measurement, which can serve to predict the clinical efficacy of compounds against thrombosis.  Clinically effective drugs, aspirin, as well as sulfinpyrazole, have been shown, when tested in the body, inhibitory activity against various aggregating agents.  In addition, a series of animal tests have been described for evaluating potential anti-thrombosis medications.  Intravenous injection of arachidonic acid to the rabbit resulted in death as a result of grouping of platelets and blockage of blood vessels in the lungs.  In this case, clinically effective aspirin, as well as sulfinpyrazone, prevent the rabbit from dying as a result of such an injection.  It was also shown that sulfinpirazon prevents aggregation of thrombiocytes in the additional physical string of the abdominal aorta in the rat organism.  These compounds may be administered orally in Bi-tablets or capsules containing a unit dosage of the compound along with such excipiens} as maize starch, calcium carbonate and dicalcium phosphate, alginic acid, lactose, magnesium stearate, Primogel or talc.  Typically, tablets are prepared by co-granulating the ingredients, followed by compressing the resulting mixture to obtain tablets of the desired size. Capsules are usually prepared by co-granulating the ingredients, followed by filling the appropriate size of hard gelatin capsules with granules in order to obtain the desired dosage.  In addition, these compounds may be administered parenterally, for example, intramuscularly, intravenously or by subcutaneous injection.  It is best to use these substances in the form of a sterile aqueous solution that may contain other solutes, such as tonic and pH regulators.  These compounds can be added to distilled water, the pH being adjusted to 3-6 using acids such as citric, lactic or hydrochloric.  To ensure that the solution is isotonic, suitable solutes such as dextrose or salt can be added to it.  The resulting solution can be sterilized and filled into sterile glass tubes of the appropriate size containing the required amount of solution.  The compounds of this invention can also be administered by infusing the parenteral composition described above into a vein.  For oral administration to patients, it is considered that the daily dosage level of the compound may vary from 0.1 to 20 mg / kg per day for a typical adult patient (70 kg).  For parenteral administration, the daily dosage level of the compound of formula (1) is considered to vary from 0.01 to 0.5 mg / kg per day for a typical adult patient.  Thus, it is believed that tablets or capsules may contain 5 to 150 mg of active compound for perora, full dose up to 3 times per day.  Unit dosages for parenteral administration may contain 0.5 to 35 mg of active compound.  A typical test tube may have a volume of 10 ml and contain 5 mg of active substance in 6-10 ml of solution.  However, the attending physician can determine the actual dosage that best suits the patient, and it can vary depending on the age, weight, and response of the patient.  The above dosages are approximate for the average patient; they may, of course, in some cases be more or less than the recommended dosage intervals.  The proposed compounds, tested using the methods described above, can selectively 111 inhibit the enzyme thromboxane synthetase.  The results of these tests are shown in Table. 2, in which the molar concentrations of each substance are given, which cause a 50% change in the action of the corresponding enzyme ng isometric pressure, t. e.  causes a 50% inhibition of this enzyme.  Given in Table. 2 shows that all test compounds cause a 50% inhibition of the thromboxane synthetase enzyme at a molar concentration of 1.0 10 or lower, and some compounds cause a 50% inhibition at a concentration or lower.  Among the compounds tested to inhibit the enzyme of prostacyclin-synthetase, none has caused 50% inhibition at a molar concentration less than 450 times the concentration for 50% inhibition of the enzyme thromboxane synthetase, PG. e.  they were at least 450 times more potent thromboxane synthetase inhibitors than prostacyclin synthetase inhibitors, and for many compounds this ratio is many times greater.  It is believed that all the proposed compounds with such tests will give results in the same range as for the compounds already tested.  The compounds prepared according to the inventive method are at least four times as active, and in some cases c. 1000 times more active, t. e.  they have a suppressive effect at concentrations 1000 times lower than 1-butylimidazole, which is a structural analogue.  The effect on the thromboxane synthese of known compounds, below is the molar concentration of the compounds leading to a 50% inhibition of thromboxane synthetase: imidazole N. NH 6.7 N-benzyl-imidazole-N-CH-CEHs 4 N-butyl-imidazole N H The compounds obtained are not toxic LDJ for 1- (2-carboxyethyl) -2-11 (1-2-carboxyethyl) -2-11 monohydrate (, 1-imidazo-yl) ethyl indone-muparate are given in Table 3  The claims of the method for producing 3- (I-imidazolylalkyl indoles of the general formula where R is hydrogen or -alkyl; R is hydrogen, C-C-alkyl, Cj-C-cycloalkyl or phenyl substituted by C-C-alkyl; Rj hydrogen, C -C-alkyl, C, -C -, alkoxy, trifluoromethyl, di- (C -C-diapkyl) -amino, chlorine or bromine; X is a group of the formula - (CHjV-CHi -c «. -O CHg-Or, where n. 1 and 2, or their pharmaceutically acceptable acid addition salts, characterized in that the compounds of the formula de R - R are reacted with the indicated values, with acrylonitrile in the presence of osnanoane or with a strong base, c.  by the subsequent reaction of the resulting anion with an alkylating agent of the formula Br - x - y de X has the indicated values; Y -, 3 where () is alkyl or CN, the resulting compound is heated by heating with an aqueous solution and hydrochloric acid at a temperature of 70-100 ° C, with the desired product being isolated in free form or as a salt.  127789414
    Table 2
    15
    Primary Molar Concentration, Amount of Viable 50% Inhibition
    Thromboxane Prostacyclo Synthase Synthase
    Mice
    the males
    females
    Male rats
    female mouse rat
    1277894 I Continued table. 2
    Table 3
    520 575
    850 1060
    No mortality up to a dose of 3 g / kg
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1277894A3|1986-12-15|Method of producing 3-|indoles or their pharmaceutically acceptable acid-additive salts
    CA1126272A|1982-06-22|Imidazole compound and anti-depressing agentcontaining the same
    US4532331A|1985-07-30|1-Benzyl-2-aminomethyl imidazole derivatives
    US4217357A|1980-08-12|Inhibition of thromboxane synthetase with 3-|indoles
    PL192029B1|2006-08-31|Heterocyclic vinyl ethers efefctive as agents against neurological disorders
    IE49318B1|1985-09-18|Imidazole derivatives
    SK301992A3|1995-10-11|Acyl imidazole -5-carboxylic acid derivatives, method of production and pharmaceutical agents with their contents
    US4835154A|1989-05-30|1-aralykyl-5-piperazinylmethyl-2-mercaptoimidazoles and 2-alkylthioimidazoles and their use as dopamine-βhydroxylase inhibitors
    EP0302603A1|1989-02-08|Dopamine-beta-hydroxylase inhibitors
    US4230714A|1980-10-28|Imidazole therapeutic agents
    US4634711A|1987-01-06|Pyridylalkyl imidazole-2-thiols
    US3982020A|1976-09-21|Substituted benzylidene hydrazines for treating hyperglycemia, obesity and inflammation
    US4743613A|1988-05-10|Ester prodrugs of dopamine-β-hydroxylase, inhibitors, composition containing them, and method of using them to inhibit dopamine-β-hydroxylase activity
    US5155123A|1992-10-13|Pyridine derivatives and pharmaceutical compositions containing them
    US4882348A|1989-11-21|2-|imidazoles as dopamine-β-hydroxylase inhibitors
    US4783467A|1988-11-08|Tetrahydroimidazoquinazolinone inotropic agents
    US4093725A|1978-06-06|-1-hydrazinophthalazines
    US4762850A|1988-08-09|Dopamine-beta-hydroxylase inhibitors
    US4761415A|1988-08-02|Dopamine-β-hydroxylase inhibitors
    US4152440A|1979-05-01|Novel derivatives of imidazole, and pharmaceutical compositions containing them
    EP0246888A2|1987-11-25|Dopamine-beta-hydroxylase inhibitors
    US4213986A|1980-07-22|Novel derivatives of imidazole and pharmaceutical compositions containing them and method of use
    US4421754A|1983-12-20|Syndonimine derivatives, process for production thereof, and use thereof
    US4581460A|1986-04-08|Substituted 1-benzoyl-2-phenyliminoimidazolidine derivatives
    GB2102795A|1983-02-09|Indole derivatives
    同族专利:
    公开号 | 公开日
    HU184727B|1984-10-29|
    DK151884C|1988-06-13|
    SG67284G|1985-03-15|
    LU82224A1|1980-06-06|
    IE49542B1|1985-10-30|
    NO800650L|1980-09-08|
    BE882113A|1980-09-08|
    CS253702B2|1987-12-17|
    FR2450832A1|1980-10-03|
    AT375366B|1984-07-25|
    IL59524A|1982-11-30|
    KE3467A|1984-11-09|
    GR67237B|1981-06-25|
    US4273782A|1981-06-16|
    CH649546A5|1985-05-31|
    HK89884A|1984-11-23|
    NO152217C|1985-08-21|
    FI800672A|1980-09-08|
    SE440778B|1985-08-19|
    PT70914A|1980-04-01|
    FR2450832B1|1983-04-22|
    NL8001351A|1980-09-09|
    IL59524D0|1980-06-30|
    PL222470A1|1980-12-01|
    KR850000760B1|1985-05-25|
    PH15198A|1982-09-17|
    NO152217B|1985-05-13|
    DE3008632A1|1980-10-16|
    ES8104278A1|1981-04-01|
    FI66860C|1984-12-10|
    NZ193052A|1984-07-06|
    ES496889A0|1982-08-01|
    IE800453L|1980-09-07|
    ATA125780A|1983-12-15|
    CA1120479A|1982-03-23|
    IT1218420B|1990-04-19|
    DD149525A5|1981-07-15|
    JPS55133380A|1980-10-17|
    FI66860B|1984-08-31|
    MY8500285A|1985-12-31|
    YU41911B|1988-02-29|
    DE3008632C2|1988-02-25|
    DK151884B|1988-01-11|
    DK42580A|1980-09-08|
    AR227015A1|1982-09-15|
    ZA801328B|1981-03-25|
    ES489220A0|1981-04-01|
    NL182959C|1988-06-16|
    SE8001736L|1980-09-08|
    IT8020399D0|1980-03-06|
    AU516957B2|1981-07-02|
    PL128296B1|1984-01-31|
    ES8205789A1|1982-08-01|
    AU5623180A|1980-09-11|
    KR830001928A|1983-05-19|
    YU61480A|1983-12-31|
    JPS6141513B2|1986-09-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR3986M|1963-06-06|
    US3370063A|1964-10-05|1968-02-20|Mcneilab Inc|Substituted dimethoxy indoles and method of making the same|
    US3621027A|1968-03-18|1971-11-16|Endo Lab|1-aminoalkyl-2,6-diaryl 4,5,6,7 tetrahydro-4-oxindales|
    US3931229A|1973-08-23|1976-01-06|Warner-Lambert Company|3-Thiomethyl-2[2-ethyl]indoles|
    US4059583A|1975-11-13|1977-11-22|Mcneil Laboratories, Incorporated|Substituted indoles|
    AU523536B2|1977-08-26|1982-08-05|Wellcome Foundation Limited, The|Imidazoles and methods of preparing them|
    US4140858A|1977-12-19|1979-02-20|Warner-Lambert Company|3--2-indoles and a method for their production|
    DE2960547D1|1978-02-24|1981-11-05|Pfizer Ltd|3-indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them|US4414159A|1980-09-26|1983-11-08|E. I. Du Pont De Nemours & Co.|Vinyl ether monomers and polymers therefrom|
    US4444775A|1981-06-22|1984-04-24|Ciba-Geigy Corporation|Substituted imidazo[1,5-A]pyridines|
    KR840000529A|1981-07-07|1984-02-25|콘스탄틴 루이스 클레멘트|Method for preparing indole derivative|
    ZA825413B|1981-08-26|1983-06-29|Pfizer|Thromboxane synthetase inhibitors, processes for their production, and pharmaceutical compositions comprising them|
    US4460777A|1981-11-19|1984-07-17|Ciba-Geigy Corporation|N-Substituted-2-pyridylindoles|
    US4478842A|1981-11-19|1984-10-23|Ciba-Geigy Corporation|N-Substituted-2-pyridylindoles|
    US4436746A|1982-09-30|1984-03-13|Ciba-Geigy Corporation|Thromboxane synthetase inhibitory N-substituted-2-indoles|
    US4539410A|1982-09-30|1985-09-03|Ciba-Geigy Corporation|N-Substituted-2-indoles|
    AT376436B|1982-11-05|1984-11-26|Laevosan Gmbh & Co Kg|METHOD FOR PRODUCING NEW THIOPHENE-2CARBONS [UREDERIVATIVES AND PHARMACEUTICALLY COMPATIBLE ACID OR BASE ADDITION SALTS THEREOF|
    US4511573A|1983-05-17|1985-04-16|Ciba-Geigy Corporation|3-Substituted-2- indoles|
    EP0239306B1|1986-03-27|1993-06-02|Merck Frosst Canada Inc.|Tetrahydrocarbazole esters|
    JPH0832679B2|1986-09-05|1996-03-29|理化学研究所|N-phthalicide derivative and method for producing the same|
    GR871809B|1986-11-28|1988-03-07|Glaxo Group Ltd|Process for the preparation of tricyclic ketones|
    WO1990012009A1|1989-03-31|1990-10-18|Kyoto Pharmaceutical Industries, Ltd.|New imidazole derivatives, production thereof, and uses thereof as medicines|
    DE4023215A1|1990-07-21|1992-01-23|Hoechst Ag|New substd. azole derivs. angiotensin II antagonists - for treating hypertension, coronary insufficiency, myocardial infarct, coronary hypertrophy, arteriosclerosis etc.|
    EP0550507A1|1990-09-13|1993-07-14|Beecham Group p.l.c.|Indole ureas as 5 ht receptor antagonist|
    US5162337A|1990-10-05|1992-11-10|Merck & Co., Inc.|Animal growth promotion|
    US5120749A|1991-02-20|1992-06-09|Abbott Laboratories|Platelet activating antagonists|
    TW268950B|1991-12-18|1996-01-21|Schering Corp|
    US5538973A|1992-03-27|1996-07-23|Kyoto Pharmaceutical Industries, Ltd.|Imidazole derivative, pharmaceutical use thereof, and intermediate therefor|
    CA2109931A1|1992-03-27|1993-10-14|Hiroshi Matsui|Novel imidazole derivative, pharmaceutical use thereof, and intermediate therefor|
    JPH0632913U|1992-09-18|1994-04-28|三洋電機株式会社|Floor heating panel|
    DE69918278T2|1998-03-31|2005-07-14|The Institutes for Pharmaceutical Discovery, Inc., Branford|SUBSTITUTED INDOLALCANIC ACID|
    CA2509170A1|2002-12-10|2004-06-24|Wyeth|Substituted 3-alkyl and 3-arylalkyl 1h-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 |
    GB0324763D0|2003-10-23|2003-11-26|Oxagen Ltd|Use of compounds in therapy|
    NZ554491A|2004-10-12|2009-07-31|Decode Genetics Ehf|Sulfonamide peri-substituted bicyclics for occlusive artery disease|
    EP1945626B1|2005-08-25|2011-07-27|Schering Corporation|Imidazole derivatives as functionally selective alpha2c adrenoreceptor agonists|
    GB2431927B|2005-11-04|2010-03-17|Amira Pharmaceuticals Inc|5-Lipoxygenase-activating proteininhibitors|
    US8399666B2|2005-11-04|2013-03-19|Panmira Pharmaceuticals, Llc|5-lipoxygenase-activating proteininhibitors|
    US7977359B2|2005-11-04|2011-07-12|Amira Pharmaceuticals, Inc.|5-lipdxygenase-activating proteininhibitors|
    US7579483B2|2006-05-16|2009-08-25|Decode Genetics, Ehf.|Process for preparing 7-indoles|
    ES2391671T3|2006-07-22|2012-11-28|Oxagen Limited|Compounds with CRTH2 antagonist activity|
    TW200920369A|2007-10-26|2009-05-16|Amira Pharmaceuticals Inc|5-lipoxygenase activating proteininhibitor|
    US20110015158A1|2007-12-11|2011-01-20|Viamet Pharmaceuticals, Inc.|Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties|
    US7750027B2|2008-01-18|2010-07-06|Oxagen Limited|Compounds having CRTH2 antagonist activity|
    ES2442717T3|2008-01-18|2014-02-13|Atopix Therapeutics Limited|Compounds that have CRTH2 antagonistic activity|
    WO2009093029A1|2008-01-22|2009-07-30|Oxagen Limited|Compounds having crth2 antagonist activity|
    WO2009093026A1|2008-01-22|2009-07-30|Oxagen Limited|Compounds having crth2 antagonist activity|
    EP2285803A4|2008-05-23|2011-10-05|Amira Pharmaceuticals Inc|5-lipoxygenase-activating protein inhibitor|
    US8546431B2|2008-10-01|2013-10-01|Panmira Pharmaceuticals, Llc|5-lipoxygenase-activating proteininhibitors|
    JP2014518223A|2011-06-20|2014-07-28|アルツハイマーズ・インスティテュート・オブ・アメリカ・インコーポレイテッド|Compounds and their therapeutic uses|
    GB201322273D0|2013-12-17|2014-01-29|Atopix Therapeutics Ltd|Process|
    GB201407807D0|2014-05-02|2014-06-18|Atopix Therapeutics Ltd|Polymorphic form|
    GB201407820D0|2014-05-02|2014-06-18|Atopix Therapeutics Ltd|Polymorphic form|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7908123|1979-03-07|
    [返回顶部]