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    • 专利摘要:
    The N-(substituted benzyl) imidazoles are selective enzyme inhibitors and thus are useful in the treatment of heart disease, circulatory and vascular problems.
    公开号:SU906374A3
    申请号:SU802872552
    申请日:1980-01-18
    公开日:1982-02-15
    发明作者:Эдвард Кросс Питер；Питер Дикинсон Роджер
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of imidazo derivatives of general formula I with o-t-hydrogen; (a) alkyl group; (C-C-alkoxy group or halogen; - (Qlrjjn where n is a whole number from 1 to or groups of the formula -en.  Z -, CONHR, CON (R) i, CN or tetrazolyl; hydrogen or (alkyl group; R is hydrogen, (C / 1-C4) alkyl group or (CL-C) alkanoyl group; R is ()) alkyl group or to their pharmaceutically acceptable additive salts.  The novel compounds of Formula I are used to inhibit the action of the enzyme thromboxane synthetase in the body of animals, including the human body, without substantially inhibiting the action of the enzymes of prostacyclin synthetase or cyclo-oxygenase.  A known method for producing carboxylic esters by reacting alcohols with acid chlorides with a pretreatment with an alkali metal hydride, such as sodium l.  The purpose of the invention is the synthesis of new compounds with valuable physiological properties.  This goal is achieved by the fact that according to the method of producing compounds of general formula 1, a phenol of general formula P-L, K-Ch.  Where R has the meanings indicated above, is reacted with an alkali metal hydride and then introduced into the action with a halide of the formula Hal-yz where y and Z are as defined above and Hal means chlorine, bromine or iodine, preferably using an alkali metal hydride sodium with the selection of the target product in free form or in the form of a salt.  Pharmaceutically acceptable acid compound salts of the compounds of formulas I are salts with acids containing pharmaceutically acceptable anions, for example hydrochloride, hydra bromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate gluconate , auctioneed and p-toluenesulfonate. Research has shown that in most tissues the main product of arachidonic acid metabolism is one of two unstable substances, thromboxane LfJ (. a) prostacyclin (PG1f).  In most cases, the prostaglandins PGEQ,, and PGDQ are comparatively secondary by-products in this biosynthesis.  The discovery of thromboxane A (and prostacyclin has significantly increased our understanding of vascular homeostasis; prostacyclin is a powerful vasodilator and inhibitor of platelet aggregation and the most active sidogennym substance.  The prostacyclin synthetase enzyme is localized in the endothelial layer of the vessel and is fed by endoperoxides released by blood thrombocytes coming into contact with the vessel wall.  Prostatecycline produced in this way is important for protecting against platelet deposition on vessel walls.  Thromboxane AQ is synthesized by the enzyme synthase of thromboxane, which is localized, for example, in blood rotocytes.  Thromboxane AO is a powerful vasoconstrictor and proaggregant.  Its effects are opposite to those of prostacyclin.  If, for any reason, the formation of prostacyclin by vessels is impaired, the endoperoxides produced by platelets coming into contact with the walls of the vessel are converted into thromboxane and are practically not transformed into prostacyclin.  A shift in the balance of prostacyclin - thromboxane to the side of the last substance can lead to platelet aggregation, vascular spasm and increase susceptibility to atherothrombosis.  It is experimentally known that the atherosclerotic prostacyclin generation is suppressed and the formation of An thromboxane is enhanced.  Thus, An thromboxane is an agent that causes various diseases, such as angina, myocardial infarction, cardiac arrest, and paralysis.  Studies in rabbits showed that ECG changes typical of these conditions were obtained when freshly prepared An thromboxane An was introduced directly into the heart of the animal.  This method allows us to present a unique model of the heart affected by a coronary disease, and allows us to show that the administration of a compound that has resistance to thromboxane A "prevents rabbits from the effects of administering thromboxane Ajj.  Another area where the PPIn / TxAQ imbalance is considered as a causative factor is migraine.  Head migraine is associated with changes in intra-extracerebral blood flow, in particular, pre-head decrease in cerebral blood flow, followed by the spread of the phenomenon in both hemispheres during the headache phase.  Prior to the development of headache, the level of hydroxytryptamine in the blood decreases and this implies the implementation of in vivo aggregation and release of the amine from the reserve blood platelets.  It is known that blood platelets of migraine patients are more prone to aggregation than platelets of normal individuals.  In addition, it is assumed that not only the abnormal function of the platelets is a major factor in the pathogenesis of migraine, but. she is the root cause of it.  Thus, a drug that selectively modifies the function of blood platelets in the direction of inhibiting the formation of AQ boxing can significantly improve migraine therapy.  The abnormal behavior of blood thrombiocytes is also described for patients with diabetes.  Patients with diabetes are particularly sensitive to microvascular complications, atherosclerosis and thrombosis, and the hyper-activity of blood platelets is the cause of such angiopathy.  Platelet excretion in diabetes has reduced the amount of TxBQ and malondialdehyde.  It was also shown experimentally that in rats with diabetes, the excretion in the vessels of prostagacycline worsened and the synthesis of AhAg from blood platelets increased.  Thus, the imbalance between prostacyclin and TxA. -j, leads to microvascular complication of diabetes.  The synthetase inhibitor could find clinical application in the prevention of these vascular complications.  Aspirin and the majority of non-steriodal anti-inflammatory drugs inhibit the cyclo-oxygenase enzyme.  This effect is to stop the formation of PGGn / H endoperoxides, reducing the levels of both prostacyclin and thromboxane Aij.  Aspirin and aspirin-like medications are used clinically to prevent paralysis and heart attack.  Although some encouraging results were obtained with these drugs, compounds that specifically inhibit the formation of thromboxane L | 2 without compromising the prostacyclin biosynthesis would be of greater importance in these clinical conditions.  The effect of compounds of formula I on thromboxane synthetase enzyme and prostacyclin synthetase and cycloxy genase synthetase enzymes was measured as follows in vitro.  one .  Cyclo-oxygenase.  Drum seed microsomes were incubated with arachidonic acid (100 mM: 1 min 22 ° C) in order to obtain PCH 0 and aliquots of the reaction mixture were injected into Krebs bicarbonate stream at 37 ° C, which was injected into the rabbit's spiral-cut aorta.  The ability of a compound to inhibit an enzyme was measured by comparing the increase in isometric tension produced by PCH In the absence of the test compound, and such a strain after preincubating the enzyme with the test compound for 5 minutes.  2 Prostacyclin () synthetase.  Microsomes of the aorta of the piglet were incubated (30 s: 22 ° C) with PCHо, as produced in the first case and tested as described above.  GH excretion (j was assessed indirectly by measuring the decrease in PGM i) - induced tension (PGHg itself does not contact with the aorta.  This reduction can be completely eliminated by preincubating the enzyme with a selective PC8l synthetase inhibitor, 15 hydroperoxy-arachidonic acid.  The test compound is then pre-incubated with the enzyme for 5 minutes and its ability to prevent a decrease in tension I is measured.  3 Thromboxane A (2 (TxA2) synthetase.  Indomethacin microsomes were pre-treated with human platelets incubated (2 min:) with PGll (prepared as in the first case and aliquots of the reaction mixture were introduced into two rabbit aortic helixes, which were separated by a separating ring (2 min). I the more unstable thromboxane Aj, thereby making it possible to separately measure increased isometric tension due to the formation of TxAo and the remaining PGH.  The test compound was preincubated with the enzyme for 5 min and its ability to inhibit the thromboxane enzyme synthetase was measured as a decrease in isometric tension due to the TxAj component.  The proposed compounds tested in this way have been shown to exhibit the ability to selectively inhibit the thromboxane synthetase enzyme. .  The table shows the molar concentration causing inhibition of enzymes.  The results presented in the table show that all the tested compounds caused 50 | -e inhibition of the thromboxane synthetase enzyme at a molar concentration of 1.0 x 10 or less and some caused inhibition at concentrations or less.  Of the compounds tested to inhibit cyclooxygenase enzyme, none caused inhibition at a molar concentration of 10 ° or less, and their ability to inhibit this enzyme was at least 2100 times less than their ability to inhibit the enzyme synthase trsboxbox.  Of the compounds tested to inhibit prostacyclin, none caused inhibition at a molar concentration 2000 times greater than the concentration at which they (compounds) inhibited the enzyme synthetase, thromboxane, i.e., all of them were at least 2000 times more with. : Flax-active as inhibitors of thrombotic xanta synthetase, compared with inhibition of prostacyclin synthetase.  It is expected that all proposed compounds tested in this way will give results within the limits of the results of compounds already tested.  In addition to the above, tests have been described for measuring the inhibition of human platelet aggregation and this can serve as confirmation of anti-thrombolytic efficacy in clinical use.  Both clinically effective agents aspirin and sulfinpyrazone show in vitro inhibitory activity against various aggregating agents in this trial.  A number of animal tests in vivo have also been described for the evaluation of potential antithrombolytic drugs.  An intravenous injection of arachidonic acid causes the death of rabbits due to grouping of platelets and pulmonary embolism.  Both clinically effective agents aspirin and sulfinpyrazone protect the rabbit from the lethal effects of the injection.  It was also shown that sulfinpirazon prevents platelet aggregation in the extracorporeal node 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 excipients such as maize starch, calcium carbonate, dicalcium phosphate, alginic acid.  9 7 lactose, magnesium stearate, I iimogel (trade mark) or talc.  Tablets are usually prepared by granulating the ingredients together and packaging them into appropriately sized hard gelatin capsules, depending on the content of the ingredients.  The compounds may also be administered parenterally, for example intramuscularly, intravenously or subcutaneously.  For parenteral administration, they are best used in the form of sterile.  an aqueous solution that may contain others.  soluble substances such as tonic and buffer solutions.  The compounds can be added to distilled water and the pH is adjusted to 3-6 with an acid, such as citric, lactone or hydrochloric acid.  Suitable soluble substances such as dextrose or saline may be added to render the solution isotonic.  The resulting solution can then be sterilized and packaged in sterile glass ampoules of a suitable size, taking into account the required volume of solution.  The proposed compounds may also be administered by injection of a parenteral form, as described above, into a vein.  For oral administration to sick people, the daily dose level of the proposed compound is from 0.1 to 20 mg / kg per day for a typical average patient (70 kg).  For parenteral administration, the daily dosage level of the compound of formula I is from 0.01 to 0.5 mg / kg per day for a typical average patient.  Thus, tablets or capsules may contain from 5 to 150 mg of active compound for oral administration up to 3 times per day.  Dose of drugs for couples. Enteral administration may contain from 0.5 mg to 35 mg of active compound.  A typical 10 ml vial may contain 5 mg of active compound in a 6-10 ml solution.  It should of course be borne in mind that in each case the actual dose will be determined as the most appropriate for the particular patient and will vary greatly with the age, weight and characteristics of the patient.  The above doses are exemplary for the average patient and in individual cases higher or lower doses are used.  99 The preparation of the proposed compounds is illustrated by the following examples.  Example 1 L.  1- (2-hydroxy - 5 methyl) denzylimidazole. A solution of 2-dimethylaminoethyl-4-methyl phenol (, 95 g) and imidazole (2.04 g) in xylene (30 ml) is heated under reflux for 3 m and then cooled on standing.  The solid is filtered and crystallized from ethyl acetate to give 1 - (2-hydroxy-5-methyl) benzylimidazole (L, 36 g) t.  square  1b6-1b7 ° C.  C, 70.19; H 6.50; Found,%.  N, k.  WITH-,.   from: 70.19; H 6, (3; Calculated, N T4,83.  AT.  2- (1-imidazolylmethyl) -4-methyl-phenoxyacetic acid ethyl ester.  (2-Hydroxy-5 methyl) benzylimidazole (5, g) is dissolved in dry N, N dimethylformamide (50 ml) and sodium hydride (1.50 g of dispersion in mineral oil) is added.  The mixture was stirred at room temperature for 1 hour and then for 10.  min ethyl ethyl bromoacetate (5.04 g) was added.  The mixture was stirred at room temperature for 2 hours and then allowed to stand overnight before being poured into water.  The mixture was extracted with chloroform (2 times 150 ml each) and the combined chloroform extracts were washed well with water and dried over sodium sulfate.  The solvent is distilled off and the mixture is triturated with gasoline (t.  kip  60-80 ° C) to obtain a solid (5.3 g), which is crystallized twice from ethyl acetate-gasoline t.  (t.  kip  B-BO C) to obtain 2- (1-imidazolylmethyl) - (- methylphenoxyacetic acid ethyl ester t.  square  86-88 ° C.  Found,%; B5.3b; H 6.63; N 10.15.  from 5 1g H-2 | Calculated,%: C b5, b7; N b, b1; N 10.21.  Example 2  2- (1-imidazolylmethyl) -methyl-phenoxyacetic acid hemihydrate.  A mixture of 2- (1-imidazolylmethyl) -methyl-phenoxyacetic acid ethyl ester (1.0 g) and 10 ml of 2.5 and.  410 sodium hydroxide solution is stirred overnight at room temperature.  The solution is acidified with dilute hydrochloric acid and evaporated.  The stack is extracted with boiling ethanol (2 x 50 ml) and the extracts are evaporated to give a solid, which is crystallized from the mixture ethanol ester to give 2- (1-imidazolylmethyl) -h-methyl-phenoxyacetic acid hemihydrate hydrochloride (0.50 gu, t.  square  198-201 S.  Found,%: C 53, b9; H 5.2b; N 9.5.  , HC1 1/2 H9p Calculated,%: C 53.62; n 5.53; N 9.60.  Example 3   1-amidazolylmethyl} -4-methyl-phenoxy butyric acid ethyl ester hydrochloride.  This compound was prepared as described in Example 1B using bromobutyrate instead of bromoacetate and a catalytic amount of potassium iodide.  Hydrochloride salt has t.  square  101-103 ° C (from ethyl acetate).  Found,%: C 59.87; H 6, N 8,17.   H2. M, OzNS1 Calculated, -S: C 60.35; H 6.79; N 8.27.  Example 4  (1-imidazolylmethyl) -4-methyl-phenoxy-butyramide.  A mixture of A- (2) -1-imidazolylmethyl- (,. , „,„ „„ „„ W. . . , , ,,. , v  -methyl-phenoxy) butyric acid ethyl ester ester (1.0 g) and 0.880 of ammonia solution are stirred for 6 hours and left to stand for 36 hours further.  The solid is filtered and crystallized from water to give; 4-chloro-2- (1-imidazolylmethyl) - (- methylphenoxy butyramide (0.30 g) C. T.  square  1Y-1 16C.  Found,%: C 65.31; H 7.23; N 15.13.  Calculated,%: C b5.91; H 7.01; N 15.37.  Example 5  (l-imidazolylmethyl) -4-methyl-phenoxymethyl benzoic acid.  Treatment of (2-hydroxy-5-methyl) benzylmidazole with ethyl (A-bromomethyl) benzoate, as in Example 1 B, results in (l-imidazolylmethyl) -4-phenocoxy benzoic acid and ethyl ester.  A solution of the ester (", 17 g) in ethanol (0 br) 119 o Is treated with a solution of sodium hydroxide (2.0 g) in water (80 ml).  The solution is heated under reflux for 1 hour and then allowed to stand at room temperature for 18 hours. The solution is evaporated to approximately half the volume and acidified with acetic acid.  The precipitate was filtered, washed with water and crystallized from ethanol to obtain (1-imidazolylmethyl) -4-methyl-phenoxymethyl benzoic acid (2.33 g) with m.  square  220-221 ° C.  Found,%: C 70, H 5.57; N 8.59.     J Calculated,%: C, 70.78; H 5, h3; N 8.69.  .  Example 6  4- (1-imidazolylmethyl) phenoxy-acetic ethyl ester fumarate. .  Sodium hydride (. 3.17 g of 50% suspension in mineral oil is added in portions to a stirred mixture of 1- (C-hydroxybenzyl) imidazole (11.50 g) in dry H, M-dimethylforma de (100 ml) at room temperature.  The mixture is stirred at room temperature for 10 minutes and then. heated to 100 ° C for 30 minutes  The mixture is then cooled and ethyl bromoacetate (11, OA g) is added dropwise with stirring.  The resulting mixture is heated on a steam bath for 9 hours and then poured into water.  The mixture is extracted with chloroform and the combined extracts of chloroform are washed well with water and dried over sodium sulfate.  Evaporation of the solvent results in an oil, which is chromatographed on silica gel.  Elution with chloroform first leads to impurities and mineral oil, followed by pure product, the fractions containing the product were combined and evaporated to give an oil (13.90 g).  The part is dissolved in ether and the solution is treated with an excess of ethereal fumaric acid solution.  The solid was filtered and crystallized from ethyl acetate to give {- (1-imidazollylmethyl) phenoxyacetic acid ethyl ester fumarate c.  square  99-101 C.  Found,%: C 57.16; H 5.29; N 7, to.  , Calculated,%: C 57, H 5.36; N l. kh.   Example 7  - (1-ikidazolylmethyl) phenoxyacetic acid hydrochloride.  A solution of (1-imidazolylmethyl) phenoxyacetic acid ethyl ester (6.0 g) in concentrated hydrochloric acid (10 ml) is heated at 100 ° C for 8 hours and then evaporated to give an oil that solidifies upon trituration with ethyl acetate.  The solid is crystallized twice from aqueous acetonitrile to give 4- (1-imidazolylmethyl) phenoxyacetic acid hydrochloride (if, 8 g), t.  square  100-107С.  with S3, Found, H 5.31; N 9, -83.   HCl Calculated,%: C 50.28; H 5.23; N 9.77.  Example 8  4- 1-imidazolylmethyl) phenoxyacetamide.  The solution of A- (1-imidazolylmethyl) phenoxyacetic acid ethyl ester (2.0 g) in ethanol (10 ml) and concentrated aqueous ammonia (SG 0.880) are refluxed for 2 hours and then evaporated.  The residue is crystallized from a mixture of methanol and 2-butanol to give - (1-imidazolylmethyl) phenoxy-acetamide (1.31 g) with m.  square  Ml, -Mk.  Found,%: C 62.2; H 5.76; N 17.40.  Calculated: C 62,32; H 5.67; N 18.17.  Example 9- N-methyl- - (1-imidazolylmethyl) phenoxyacetamide.  A solution of A- (1-imidazolylmethyl) phenoxyacetic acid ethyl ester (1.02 g) in ethanol methylamine is left to stand for 2 hours.  The solution is evaporated, the residue is crystallized from a mixture of ethyl acetate and benzene to obtain N-methyl-A- (1-imidazolylmethyl) phenoxyacetamide (0.61 g; s t.  square  12it-125C.  Found,%: C 63, H 6.21; N 17.25.  С1з1% «ЗО. ,  C, 63.66; H 6.16; Calculated 4 N 17,13.  ten.  (tetrazol-5 Example-methylmetrics) benzyl imidazole.  Sodium hydride (1.92 g of a 50 | dispersion in mineral oil) is added in portions to a stirred solution of 1-C-hydroxybenzyl) imidazole (7.08 g) 139063 in dry S, M-dimethylformamide (100 ml) at O C and the resulting mixture is stirred at room temperature for 1 h.  The mixture is then cooled to OC and chlorine, acetonitrile (2.9 g) is added over 2 minutes with stirring.  The mixture was left to stand overnight and then evaporated.  The residue is dissolved in chloroform and the mixture is filtered.  The filtrate is evaporated and the residue is kept.
    the current is chromatographed on silica gel. Eluation with chloroform leads first to mineral oil and impurities, after which the pure product is obtained. Next, the pure product is obtained after exchanging the eluant for chloroform-methanol (9: 1) —The fractions containing the products are evaporated to give 4- (1-imidazolylmethyl) phenoxyacetonitrile 5.2 g) as an oil, Nitrile (2.13 g), sodium azide (3.25 g) and ammonium chloride (2, B7 are heated on the steam bath for A h in S, K dimethyl fluoromamide. The solution is then evaporated to dryness and a few millimeters of water are added to the residue. the substance is collected by filtration and crystallized from ethanol to give 1 - t- (tetrazol-5 ylmethoxy) benzyl imidazole (0.88 g) t, mp, 189 191 ° C, c 56, H 4.73; Found, Z N 33,, Calculated: C 5b, H 4.72; N 32.80, P-p and measure 11, A, 1- (4-hydroxy-3 methoxy) benzylimidazole, Imidazole mixture (20.4 d) and 4-hydroxy-4-methoxybenzyl alcohol (46.25 g) is heated at 1bO ° C for 2 hours, the resulting mixture is cooled and the product is crystallized twice from a mixture of ethanol, benzyl to obtain I- (4-hydroxy-3 methoxy ) benzylimidazole (48.7 g) with m, pl, 159-1BS. C, 64.73; H 5.98; Found; N 13.70; C ,, H ,, C 64.69; H 5.90; N, 13.67. B, 4- (1-imidazolylmethyl) -2-methoxyphenoxyacetic acid ethyl ester. Sodium hydride (3.3 g disperse in mineral oil) is added in portions to a stirred solution of 1- (4-hydroxy-3-methoxy) benzyl-:
    the mixture is evaporated. The residue is chromatographed on silica gel, Eluating with chloroform results in the production of a mineral oil and some impurity, Elu-A14 imidazole (1.3 g) in dry dimethylformamide (150 ml) at 0 ° C. The mixture is stirred at room temperature for 1 hour and then cooled to 0 ° C. Ethyl bromide etatate (11, B9 g) is added over 5 minutes with stirring. The mixture is stirred for k hours at room temperature. To decompose an excess of sodium hydride, add a few milliliters of water and a mixture of chloroform ethanol (20: 1) to produce a solid, which is crystallized from a mixture of vi3 ethyl acetate benzene to give 4- (1I-imidazolylmethyl) 2-methoxyphenoxyacetic acid ethyl ester (9.02 g ) with t, pl, 91 ° С; Found,%: C 61.94; H 6.2b; N 9.69,. Calculated: C 62.05; H 6.25; N 9.65, Example 12, 4- (1-imidazolylmethyl) -2-methoxyphenoxyacetamide, Treatment with 4- (1-imidazolylmethyl) -2-methoxyphenoxyacetic acid ethyl ester with ammonia, as described in Example 8, results in 4- (1-imidazolylmethyl) -2-methoxyphenoxyacetamide with m, mp, 124-125 ° C (from a mixture of chloroform gasoline). C 59.39; H 5.83; Found, K July 16, C 59.75; And 5.78; Calculated, N 16.08, Example 13, 2- (1-imidazolylmethyl) phenoxyacetic acid ethyl ester. Treatment of 2 -. (1-imidazolylmethyl) phenol with sodium hydride in dry N, N-dimethylformamide, followed by the addition of bromoacetate as described in Example 11 B, results in 2- (1-imidazolyl) phenoxyacetic acid ethyl ester as an oil, which is used without further processing. Example 14, 2- (1-imidazolylmethyl) phenoxyacetic acid, 2- (1-imidazolylmethyl) phenoxyacetic acid ethyl ester (1 g) is heated on a steam bath for 30 minutes in a solution of 15 potassium hydroxide Go, 5 g) in water ( 10 ml) and the solution is left to stand at room temperature for 18 hours. Then the solution is evaporated to a small volume and added to pH 5 with acetic acid. The solid is collected by filtration and crystallized from water to give 2- (1-imidazolylmethyl) phenoxy-succinic acid (0.26 g) with m.p. 218-21 ° C 61.83; H 5.2k; Found,%: 12.34. llN.iOj C 62.05; H Calculated, N 12.06. Example 15. A. 1- (5-chloro-2-hydroxy) benzylimidazole. A solution of 4-chloro-2-dimethylaminomethyl phenol (30.0 g) and imidazole (11.75 in xylene (200 ml)) is heated under reflux for 3.5 hours. The solution is evaporated and the residue is triturated with a small the amount of ethyl acetate to induce crystallization. The product is crystallized from ethyl acetate / benzene to obtain 1 - (5-chloro-2-hydroxy) benzylamidazole (G5.91 g) with mp H2-14 ° C. C 57.33; H i, 36; Found, N 13.45. HgClNo 0 C 57.56; H Calculated, N 13.43 B. 4-Chloro-2- (1-imidazolylmethyl) phenoxyacetic acid ethyl ester. Processing 1- ( 5 hl6p-2-hydroxy) benzylimidazole hydride sodium in dry M, N-dimethylformamide, after treatment with ethyl bromoacetate, as described in Example 11 B, results in -chloro-2- (1-imidazolylmethyl) phenoxyacetic acid ethyl ester with mp 108-110 ° (from a mixture of ethyl acetate gasoline). Found,%: C 56.80; H A, 83; 9.16., 5C1N2 0 ". C, H, C 57.06; H Calculated, N 9.51. Example 16. -chlorine -2- (1-dazolylmethyl-phenoxy-acetic acid) Hydrolysis of -chloro-2- (1-imidazolylmethyl) phenoxy-acetic acid ethyl ester, as described in Example 1A, results in -chloro-2- (1-imidazolylmethyl) phenoxyacetic acid with t. square 222-22 ° C (out of water). H 4.10; Found, C 53.95; 10.52. .. Calculated, C, H it, 16; N 10.50. Example 17. -chloro-2- (1-imidazolylmethyl) phenoxyacetamide. Treatment with A-chloro-2- (1-imdazolylmethyl) phenoxyacetic acid ethyl ester with ammonia, as described in Example 8, results in 4-chloro-2- (1-imidazolyl) phenoxyacetamide with m.p. 1b2-1b With (from a mixture of isopropanol-gasoline). Ktaiden, 2: C, 53.91; H A, 51; N 15.79. . q H riClNjOfj. Example 18. (1-Imidazolylmethyl) phenoxy butyric acid ethyl ester. Treatment of 1- (2-hydrobeibenzyl) imidazole with sodium hydride followed by treatment with ethyl-β-bromobutyrate, as described in Example 3, results in {-I 2- (1-imidazolylmethyl) phenoxy-butyl acid on ethyl ester as an oil . A portion of the product was dissolved in a small amount of ethanol and the solution was treated with an excess of a saturated solution of oxalic acid in diethyl ether. The solid is filtered off and crystallized from ethyl acetate-gasoline to obtain A-H2- (1-imidazolylmethyl) phenoxy-butyl acid of ethyl oxalate ester with m, pl. 7b-8. C 56.76; H 5.88; Found,; 7.43. C (, (0, Calculated;%: C 57.13; H 5.86; N 7.41. Example 19. (1-imidazolylmethyl) phenoxy butyric acid. Hydrolysis of (1-imidazolylmethyl) phenoxy butyric acid ethyl ethyl ether, as described in Example H, results in 2- (1-ymidazolylmethyl) phenoxy-butyric acid with mp 150-152 ° C (from water. Found: C 64.27; H 6.29; N 10, 71. CHNO, Calculated, Z: C 6.39; H 6.19; N 10.76. Example 20. (1-Imidazolylmethyl) phenoxymethyl-benzonitrile, Treatment of 2- (1-ymidazolylmethyl) phenol with sodium hydride, and 4-bromomethyl 17E benzonitrile in dry NN-dimethylformamide, as described in example 1, results to obtain (1-imidazolylmethyl) phenoxymethylbenzonitrile with t, melting point 11b-118 ° C (from a mixture of ethyl acetate and gasoline). Found,% C 7, H 5.16; N 14.65. Calculated,%: C , 68; H 5.22; NU; 52. Example 21. (1-Imidazolylmethyl) phenoxymethyl benzamide (1-imidazolylmethyl) phenoxymethyl 1 benzonitrile (1.0 g) is dissolved in ethanol (10 ml) and hydrogen peroxide (5 ml) , is added to the solution after which 6 n is added. sodium hydroxide solution (5 ml). The mixture is heated at A5 for 1 hour and then evaporated to a small volume. The solid is filtered and crystallized from ethanol-benzim to give 4-f2- (1-imidazolylmethyl-phenoxy-1-ethylenebenzamide (0.60 g) with mp 209-21 ° C. Found, I: C b 9.97; H 5.70 ; N 13.28. QgH.NjO Calc-,%: C 70, H 5.57; N 13.67. Example 22. (2-Imidazole -1-ylmethyl) phenoxymethyl phenyl-tetrazole Treatment (1-imidazolylmethyl-phenoxymethyl-benzonitrile sodium azide and ammonium chloride, as described in Example 10, results in 5- (2-imidazol-1-ylmethyl) phenoximethyl phenyl tetrazole with mp 232–23 ° C (from methanol-ethyl acetate). %: C, H 4, N 25.69. Qg Calculated,%: C 65 , On; H, 82; N 25.30. PRI mper 23. A, 1- (2-hydroxy benzyl) imidazole hydrobromide. A solution of 1- (3-methoxybenzyl) imidazole (18.1 g) in saline acid (150 ml) is refluxed for 2 hours and then boiled to form a thick oil. Trituration with diethyl ether gives a solid which is crystallized from isopropanol C to give 1- (3 hydroxybenzyl) dazole hydrobromide (19-25 g) with t. Pl. 12b-128-C. C, 4b; H i 4,27; Found, N 11.17. C, O, O Calculated, I: C, 7.07; H 4.35; N 10.98. B. 3 (1-imidazolylmethyl) phenoxyacetic acid ethyl ester OPMarath. Sodium hydride (3.2 g of dispersion in mineral oil) is added in portions to a stirred solution of T- (2-hydroxybenzyl) imidazole hydrobromide (9.0 g) in dry, N-dimethylformamide at. After the addition is complete, the mixture is quickly heated to 100 ° C and cooled to room temperature. Ethyl bromoacetate (5.50 g) was added over 2 minutes with stirring, and the resulting mixture was heated at / for 1.5 hours and then evaporated. The residue is partitioned between water and chloroform. Water layer division south. The chloroform layer is dried under sodium sulfate and evaporated to give an oil, which is chromatographed on silica gel. Eluation with chloroform first leads to the production of mineral oil and some impurities, followed by the pure product. Evaporation of the fractions containing the product gives an oil (5.80 t). A portion of the oil is dissolved in a small amount of ethanol and an excess of the fumaric acid solution in diethyl ether is added. The solid is filtered and crystallized from ethyl acetate to give 3 (1 imidazolylmethyl) phenoxyacetic acid ethyl fumarate ester with a m.p. 85-86 ° C. Found,% G C 57.50; H 5.35; N 7.39. C4H404 Calculated,%: C 57, t; H 5.36; N 7.4. Example 2 3 (1 imidazolylmethyl) phenoxyccyclic acid hydrochloride. Hydrolysis of 3 (1-imidazolyl) phenoxyacetic acid ethyl ester of the free base with concentrated hydrochloric acid, as described in Example 7, results in 3- (1-imidazolylmethyl) phenoxy acetic acid hydrochloride st. square 179 l8l ° C (from aqueous acetonitrile, Found, I: C 53.23; H t, 8 +; N 10.65., LN "Oz HC1 VyT), and I, C: 53, H A, 88; N 10.3. Example 25 - (1-Imidazolylmethyl) phenoxyacetic acid hydrochloride (1 g) is added to distilled water (900 ml) and the pH is adjusted to 5 with hydrochloric acid. Sodium chloride is added (18 g and the volume of the solution is up to 5 l. The final solution is sterilized by filtration through a bactericidal filter under aseptic conditions and filled into 10 ml glass bubbles according to the sterility test. 2 8.2 X + 2.4 X 5 it, 7 X 71.0 X 10, 6 X 10®. Invention method half-way method of zilimidazole derivative of the general formula I 1 11 -3 h l and 90
    /
    -Cn, - / +20 where R is hydrogen, (C-C) alkyl,) alkoxy or halogen, y means (CH2} n, where n is an integer from 1 to 4 or a group of the formula -ene Z means CONHR , (R) 2 CN or tetrazolyl, R means hydrogen or () alkyl "am g R means hydrogen, alkyl or () alkanoyl; R4. Means (.C-C 1 alkyl, or their salts, characterized in that the phenol of the general formula Where R is as defined above, is reacted with an alkali metal hydride and then reacted with a halide of the formula Hal-yz where y and Z are as defined above and Hal means chlorine , bromine, or iodine, mainly as the alkali metal hydride use sodium hydride with the release of the target product in free form or in the form of salt. Sources of information taken into account in the examination of K., Pearson A. Organic syntheses. M., Mir, 1973, 2, oy S. / Oy.
    权利要求:
    Claims (1)
    [1]
    claims where hydrogen means, (C <C 4 ) alkyl, (C4 “C 4 ) alkoxy or halogen, y means (CH ^ n, where η is an integer from 1 to 4 or a group of formula ζ means COqR CONHR 3 , CO ^ NfR 4 ) ^ CN or tetrazolyl,
    R ^ · means hydrogen or (C ^ -C 4 ) alkyl;
    means hydrogen, (C ^ -C 4 ) alkyl or (CqjC 4 ) alkanoyl;
    R4 means (C ^ -C 4 ) alkyl, or their salts, characterized in that the phenol of the general formula P where K 1 has the meanings indicated above, is reacted with an alkali metal hydride and then reacted with a halide of the formula
    Hal-y-z where y and ζ have the meanings given above and Hal means chlorine, bromine, or iodine, mainly sodium hydride is used as the alkali metal hydride with the isolation of the target product in free form or in the form
    A method of obtaining derivatives of N-benzylimidazole of General formula I salts.
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    同族专利:
    公开号 | 公开日
    FI800143A|1980-07-20|
    DE3001762A1|1980-07-24|
    AU5474380A|1980-07-24|
    CH646154A5|1984-11-15|
    IE49364B1|1985-09-18|
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    BE881245A|1980-07-18|
    NL8000333A|1980-07-22|
    NO800131L|1980-07-21|
    SE8000435L|1980-07-20|
    AR222204A1|1981-04-30|
    NZ192640A|1984-07-31|
    PL123985B1|1982-12-31|
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    IT1140523B|1986-10-01|
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    法律状态:
    优先权:
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    GB7902114|1979-01-19|
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