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    • 专利摘要:
    METHOD OF OBTAINING
    公开号:SU1128837A3
    申请号:SU813241694
    申请日:1981-02-02
    公开日:1984-12-07
    发明作者:Боурн Чаплео Кристофер
    申请人:Рекитт Энд Колман Продакте Лимитед (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing a new compound of formulas. K-1 with biological activity. The reaction of the formation of a dipole ring by the interaction of diamines with derivatives of acids lj is known. The purpose of the invention is the synthesis of new compounds with valuable microphysical properties. The goal is achieved by a method of preparing a compound of the above formula by reacting a compound of the general formula. V -Hti where R is methyl or ethyl, with 1-1.25 mol / eq of ethylene diamine when in methanol or ethanol. PRI me R 1. A. Hydrochloride (1,4-benzodioxanyl) -imidoate. A steady stream of gaseous hydrogen chloride is bubbled through a stirred cooling solution of 2-c; early-1,4-benzodiaxane (88 g) in anhydrous diethyl ether (1. l) and ethanol (30.8 ml) for 4.5 h, maintaining the reaction temperature. Yu-s. After a further 24 hours at OO-10 ° C, the solid fraction is collected, washed with anhydrous ether, and dried to obtain the target product as hydrochloride (110 g, 83%), HK: - fAaKo (petroleum jelly) 1670, 1595 cm% B. Hydrochloride (1,4-benzodioxanyl) -2-imidazoline. A solution of ethylenediamine (16.7 g) in ethanol (50 ml) was added over 1 hour to a stirred and cooled (0-10 ° C) solution of etsh - (1,4-beisodioxanyl) hydrochloride 3-imidoate (50 g) in ethanol (200 ml). After a further 24 hours at 0–10 ° C, all precipitated ethylene diamine dihydrochloride is removed and the filtrate volume is reduced to approximately 59 ml. Then, an additional portion of ethylenediamine dihydrochloride is removed by filtration 372 and the remaining filtrate is treated with an excess amount of a solution of hydrogen chloride in diethyl ether. An additional amount of diethyl ether gives a precipitate of crude product (44 g), which is recrystallized from isopropanol to obtain a white crystalline product (34 g, 68%), mp. 207-208 C, (liquid paraffin) 1625, 1590 cm mass spectrogram t / e 204 (), 174 (100%), NMR: L (DMSO) 1.4 (2H, S, NH, and HC1 is exchangeable), 3.05 ( 4H, 8, -aryl-H), 4.4 (1C, t, I 4H, -OCH-), 5.4 (2C, d, I 4H2, -00%), 6.1 (4H, S, N-CHjCH -N). Found,%: C 54.98, H 5.67, N 11.68. C, H, 2N202 HC1. Calculated,%: C 54.89, H 5.44, N 11.64. The following thin layer chromatography systems show that the product is homogeneous: Alumina -..., nor - chloroform RO, 5 Silicon dioxide - chloroform. Methanol 4: 1 R / 0.1 Silicon dioxide chloroform: methanol 1: 1 .R 0, 2 Silicon dioxide, chloroform: MetaNOL 1: 4R 0.3 HPLC analysis showed that. the degree of the number of the sample is 99%. 2-Methyl-2- 2- (1 ,, 3-benzodioxolyl) -2-imidazoline and Y- (2-aminoethyl5-, 4-benzodioxan-2-carboxamide cannot be determined (content of both: 0.1%) in this product Example 2: 2-methyl hydrochloride 2- 2- (1,3-benzodioxolyl) -2-imidg zoline., A mixture consisting of 1,4-benzodiox. An-2-carboxylic acid ( 39 g) and tylenediamine (69 ml) are heated under reflux for 18 hours. 15 ml of distillate are removed, collected to remove water, and then tylenediamine (15 ml) is added. The mixture is heated in a reflux tank. 8 more hours and then concentrated and Till tion. The residue was rectified to obtain a colorless product 13.2 g), m. bales. 15b160s / 1 mmHg Thin layer chromatography shows that the main component of the reaction together with catechin forms at this stage of distillation. Analysis H.P.L.C. indicates the presence of the following compounds,%: 2-methyl- {2- 2- (1,3-benzodioxolyl) -2-imidazoline, catechin, H- (2-aminoeth -1,4-benzodioxan-2-carboxamide - «vl 1 ( , 4-benzodioxanyl) -2-imidase LIN. The catechin is removed by separation of the distillate with ethyl acetate and 2N aqueous sodium hydroxide solution, the organic phase is dried and evaporated, so that a semi-solid remains, which is dissolved in ethanol and treated with an ethanolic solution of hydrogen chloride.Dilution with diethyl ether gives a semi-solid substance from which a solid is obtained Growing into a powder with acetonitrile. Recrystallization from isopropanol gives a slightly contaminated sample of the product in the form of its hydrochloride salt. An improved purification procedure consists in filtering the distillate solution (in a mixture of chlorine methylene: petroleum ether 40-60 through an oxide column The aluminum to form the hydrochloride salt removes the catechin that is the contaminant. The sought salt in the nail is recrystallized from izopropanol to give a colorless solid (0.9 g, 2%) with m.p. 245 C (decomposed), IR: max (zeline oil) 1620., 1590 cm, mass spectrogram m / e 204 (Mb, 161 (100%), NMRg (LMSO) 1.2 (2H, S, No. and HC .T - exchanged in VLO), 3.0 (4H, S, aryl-H), 6.05 (4 S, N-CHjCHj-N), 7.85 (GH, S, CH). G Found,% : C 54.75, H 5.51, li 11.53 ./ HC1. Calculated,%: C 54.89, H 5.44, N 11.64. The following thin layer chromatography systems show that the product is homogeneous: Dioxide silicon - chloroform: meR 0.3 tanol 4: 1 silica silica chloroform: methanol 1: 1 Rf 0.4 silica silica chloroform: methanol 1: 4RI 0.5 HPLC analysis, indicates the presence of M- (2-aminoethyl) -1 , 4-benzodioxan-2-carboxamide (0.6%). 2- (G2- (1,4-Ba Zodioxanil) | -2-1 Vdidazoline cannot be determined (content of .0.3%) in this product. EXAMPLE 3 Hydrochloride 2-. l2- (1,4-benzodioxanyl) 1 -2-imidazoline., A solution of sodium methoxide (1.45 g) in methanol (20 ml) was added over 1 min to a stirred solution of 2-cyano-1,4-benzodioxane (145 g) in methanol (870 ml) at room temperature. After stirring for the next 4 hours at room temperature, the solution is cooled and ethylene diamine (64.7 g) is added dropwise at 5 ° C. A solution of hydrogen chloride in methanol (134 g of a solution containing 34.8 g of hydrogen chloride) is added to the stirred solution for more than 2 hours at. After a further 20 hours at 0-10 ° C, the precipitated ethylene diamine dihydrochloride is removed by filtration and the filter volume is reduced in vacuum to 300 g at 40 ° C. Next, the ethylene diamine dihydrochloride is removed and the remaining filtrate is evaporated in vacuum at 40 ° C until dry. neither The solid residue (225 g) is mixed with dichloromethane (1.1 l) and dry hydrogen chloride is bubbled through this mixture at 510 C. to a slight excess. The crude product is then removed by filtration (172 g) and combined with a 2 nd portion (24 g), obtained by concentrating the filtrate in vacuo at 4Q ° C. Cris-, tallization of these two portions from ethanol with hot filtration and concentration of the filtrate in vacuum to 384 yields not quite white crystalline product (175.5 g, 81%) i st. square 207-208 C. The resulting product is identical to that described in Example 1 (NMR, mass spectroscopy,. IR spectrum. If you reverse the addition of ethylene diamine and hydrogen chloride to methanol, the same yield is obtained. Table 1 compares some of the physical characteristics of the two compounds. Examples 1 and 2; both compounds are hydrochlorides recrystallized from isopropanol.
    Table 1
    Melting point, C
    Thin-layer chronography alumina - chloroform
    silica - chloroform: methanol 4: 1
    aluminum dioxide - chloroform: methanol 1: 1.
    alumina - chloroform: methanol 1: 4 NMR data show that the compound of example 1 has two separate multiplets in the L 4,4 range (1 pitch) and 1 5,4 (2 protons), characterized by a 1dl dioxane ring of the formula IV Cyano compound of the formula VI has the same multiplets in the range of 5., (1 proton) and 11 5.7 (2 protons). The spectrum of the compound of Example 2 gives a three-proton singlet in the range of 7.85, which is a characteristic of the methyl group of formula III, and the absence of any signals in the range of about 4.0 - 6.0 indicates the absence of a dioxane ring. The pharmacological activity of the proposed compound is also determined in the form of its hydrochloride (example 1). For convenience, in the subsequent tables, this compound is designated by the letter A, and the isomeric compound (Example 2) is designated by the letter B. 1. Pre- and postsynaptic (, adrenorectal) Tutorial antagonism in experiments on isolated tissue. Initial biological assessment. Presynapt of x-adrenter-receptor antagon carry out the determination of the pA values of PO with respect to the inhibitory effects of clonidine, a well-known presynaptic ob-adrenoreceptor antagonist, on the rat excretory ducts stimulated at a frequency of 0 Hz according to et Doxey, I.C.,
     (different)
    07-208 0.6
    Ri 0.5 0.3
    R 0.1 0.4 R 0.2 0.5 R 0.3 Smith C.F.C. and Walker I.M. (Br. Pharma., 1977, 60.91). This laboratory model is particularly useful as an initial means of studying presynaptic activity in isolation, since the physiological nature of the uterine duct is such that the postsynaptic receptors in it are particularly inaccessible to exogenous agents. In the following, the rat analopchikusum is used as another tissue to establish postsynaptic about -adrenoceptor activity. Antagonism of noradrenaline contractions is used to determine the pA2 values of postsynaptic-adrenoreceptors. The ratio of presynaptic oC -adrenoreceptor gonizma ant (in comparison with the action of clonidine on the rat ducts) to postsynaptic oi -adrenoreceptor antagonism (versus noradrenaline contractions on the action analnokopchikovoy msh1tse rat) was used to assess adrenoceptor selectivity. The pAg values for compounds A and B are given in table. 2, which also includes the results obtained for four standard drugs: (i) a non-selective o4 -adrenoreceptor antagonist, phentolamine, (ii) a selective presynaptic
    , antagonist - yohimbina, (iii) highly selective postsynaptic antagonist - prazosin, (iy) antide, pressant - mianzerin, which is by far. Note.
    From tab. 2, it can be seen that compound A is the most potent pres-: inapticheskoy L-adrenoreceptor antagonist and, in addition, the most selective for presynaptic points. In particular, Compound A is 200 times stronger than Compound B as a presynaptic antagonist.
    2. Presynaptic-adreno-. receptor antagonism in pithed crises
    A. Excretory ducts of a rat - activity when administered intravenously.
    This test model extends the ability to assess presynaptic C-adrenoreceptor antagonism against clonidine on excretory. rat ducts in an in vivo situation. Blood pressure and contractions of the excretory ducts caused by stimulation are monitored in pithed rats with
    It induces non-selective pre- and postsynaptic adrenoreceptor antagonistic properties as part of its pharmacological profile.
    Table 2
    using the method of Brown I., Doxey I.e., Handley S. Virdec N. (Recent Advances in the P, harmacology Cogy of Advenoreceptors, Elveier, Nor-H, Holland, 1978). Clonidine (100 MCH / CG, intravenously) causes a reaction of prolonged overpressure and prolonged inhibition of contractions of the outflow duct. Test drugs are injected intravenously according to a cumulative dosage regimen, and their ability to counteract the inhibition of the stimulation of the hypogastric nerve reflects their Presynaptic antagonism.
    In tab. Figure 3 shows the relative antagonistic potential at presynapt; 1 adrenoreceptors in pithed rats (the results are average for experiments with at least 4 rats). The sign indicates inactivity at a concentration that is given when indicating pA. The results are averages for at least 5 experiments. Intravenous dose Compound of antagonist, causing 50% purulent counteraction against clonidine blocking on high prototype W, MG / KG ka J Yohimbin BS1 Myanzerin HC1 Phentolamine methylsulfonylate Under the experimental conditions, all of the compounds, except for manzanine, have a number of cases and have no weight. clonidine stimulation of the hypogastric nerve. The maximum changes caused by myanserin and Compound B were 36 and 66%, respectively, with cumulative intravenous doses of 4.4 and 14.4 mg / kg, respectively From Table. 3, it can be seen that compound A is the most potent presynaptic 4i -adrenoreceptor antagonist of all studied compounds. B. Higher rat ducts - oral activity. The previous test situation (2A) is modified to establish the oral effect of compound A. Animal groups of 5 rats are dosed through the oral cavity with either saline (1.0 ml / 100 g body weight) or compound A (1.0 and 5.0). kg / kg) 30 minutes after the oral administration of the rats were pithed so that the electrically induced contractions of the excretory ducts could be examined locally. Dose-effect curves on clonidine's presynaptic agonistic properties are constructed after 75 minutes. after administration of a physiological solution or compound A. An orally administered compound results in a dose-dependent competitive antagonism of the presynaptic action of clonidine. Cumulative doses of clonidine, which inhibit the vessel-borne reaction of the excretory ducts by 5.p% in rats that received saline, 1.0 and 5.0 mg / kg of compound A, respectively, 6.6, 20.5 and 93.0 µg / kg (intravenously). No inhibition of the postsynaptic action of clonidine (an increase in blood pressure) occurs after 1.0 mg / kg of compound A, although some antagonism is observed at 5.0 mg / kg. In tab. 4 presents presynaptic -adrenoreceptor antago-. next to oral administration. Table 4 Dose of clonidine Treatment of exogenous ducts, µg / kg (intravenously) Physiological solution Compound A, mg / kg (orally) 1. 20.5 93.0 3. Analokopchikov ratum mushroom intravenous activity. Unlike excretory ducts of the wing. both pre- and postsynaptic adrenoreceptors analnopopchikov sy. rat muscles are readily available for exogenous agents, and therefore this test can be used to distinguish selective presynaptic about -adrenoreceptor antagonists from non-selective agents. The rat contractions of the rat, induced by low-frequency (1 Hz) electrical stimulation of the spiral sympathetic outflow, are inhibited by small doses of clonidine. Only selective presynaptic about β-adrenoreceptor antagonists alter the inhibitory effects of clonvdin. So, for example, yohimbin (0.3-1, O kg / kg intravenously) completely suppresses the inhibitory effect of clonidine on the analoclopian muscle. Further studies were conducted using this model, however, instead of clonidine, a stronger, selective presynaptic oi -adrenoreceptor agonist, guanabenz acetate, (30 µg / kg, intravenously) is used. In tab. Figure 5 shows presynapti czech about adrenoreceptor antagonis in the analopchik muscle of a decapitated rat. From tab. 5, it can be seen that the effect of compounds A as an ob-adrenoreceptor antagonist is approximately 14 times greater than that of yohimbine. In this model, phentolamine does not have a presynaptic dose of renoceptor antagonistic activity with a cumulative intravenous dose of 1.4 mg / kg. Based on these results, it can be argued that compound A proves to be the most potent study of the presynaptic ob-adrenoreceptor antagonist and. unlike phentolamine, very selective for presynaptic "6 -adrenoreceptrro" Table 5 Intravenous dose Antagonist compound, causing 50% resistance to guanabenz blocking analcopic, muscles, mg / kg Yohimbine HC1 Methylsulfonylate fentol 4. Effect on blood pressure and heart rate in rats with DOCA (dioxicorticarcionic Acetatum), depressed blood pressure. The effect of 1.0, 5.0, and 20.0 mg / kg of compound A on blood pressure and heart rate is compared with the action of similar doses of compound B and phentolamine when administered orally to rats with DOCA blood pressure. The results, expressed as peak percentages of blood pressure drop, are given in Table. 6. Table 6 Drop in blood pressure at a dose, mg / kg. Drug Compound A (5.0 and 20.0 mg / kg) gives a dose-related drop in mean arterial blood pressure. The lowering effect of these two doses of compound A on the blood pressure is the same as the doses of phentolamine. At a dose of 1.0 mg / kg, compound A slightly increases blood pressure. Thus, the paroral dose of compound A, which selectively inhibits presynaptic ob-adrenoreceptors (2B), does not have a blood pressure lowering activity. In contrast, phentolamine (1.0 mg / kg) lowers blood pressure in DOC rats. Phentolamine in both laboratory and in vivo experiments does not have significant selectivity for pre-or postsynaptic adrenoreceptors. The reflex heart rate rises in response to a decrease in blood pressure, observed at 20 mg / kg phentolamine. Two smaller doses of phentolamine slightly affect the heart rate. The studies did not show a significant effect of three doses of the compound on the heart rate. Unlike Compound A, Compound B has a significant effect of lowering blood pressure at the lowest emitted dose (1 mg / kg orally). Drop in the crown
    权利要求:
    Claims (2)
    [1]
    METHOD FOR PRODUCING 2- [2- (1,4-BENZODIOXANIL)] [2]
    A -2-IMIDAZOLINE HYDROCHLORIDE of the formula characterized in that a compound of the general formula wherein, where R is methyl or ethyl, is reacted with 1-1.25 mol / equiv of ethylenediamine at 0-10 ° C in methanol or ethanol.
    SU .. 1128837
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    同族专利:
    公开号 | 公开日
    ZW2381A1|1981-06-24|
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    EP0033655B1|1984-04-25|
    CS73881A2|1987-07-16|
    DK160092B|1991-01-28|
    DE3163256D1|1984-05-30|
    AU6675881A|1981-08-13|
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    US4818764A|1989-04-04|
    DD155991A5|1982-07-21|
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    NZ196162A|1983-06-17|
    HU187295B|1985-12-28|
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    NO154882B|1986-09-29|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8003636|1980-02-04|
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