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    • 专利摘要:
    The invention relates to heterocyclic compounds, in particular, spartein derivatives of the general formula 1 @ where N = 0 or 1, A-2-furyl, with N = 0 2-pyridyl, 4-pyridyl or substituted phenyl of formula 2 -C 6 H 3 R 1 R 3 is a pair of -R 2 where R 1 -C 1 -C 4 is alkyl, C 1 -C 4 alkoxy, OH, F, CL, BR, CF 3 , CH (O) R 2 -H, C 1 -C 4 - alkyl, C 1 -C 4 - alkoxy, CL, F or R 1 and R 2 together form a 1,3-dioxolan-2-ilen group R 3 -H or R 1 , R 2 and R 3 -C 1 -C 4 -alkoxy, or their pharmacologically acceptable acid additive salts, which can be used in medicine, coronary heart disease and arrhythmias. The goal is to create substances with activity not characteristic of this class. The synthesis is carried out by the interaction of 17-oxiparteine or 17-dehydrosparteine perchlorate with the Grignard reagent of the formula 3 A 1 - (CH 2 ) N MGHAL, where N = 0 or 1, A 1 has the values indicated for A, except for phenyl, substituted hydroxy or CH (O) -group or phenyl substituted with a 1,3-dioxolan-2-yl group. The resulting compound is isolated in free form or in the form of salts. If necessary, the compound of formula 2, where R 1 -C 1 -C 4 -alkoxy, 2- or 4-bromine, is metallized with alkylate and then treated with dimethylformamide to obtain R 1 -CH (O), or where R 1 -OCH 3 , is treated HI to obtain R 1 -OH, or where R 1 -1,3-dioxolan-2-yl group is subjected to acid hydrolysis to obtain R 1 -CH (O), followed by isolation of the target compounds in free form or in the form of pharmacologically acceptable acid addition salts. The new compounds reduce the heart rate, lengthen the functional reflex period, and reduce the force of contraction of the heart muscle at the minimum toxic dose of * 98,100-300 mg / kg. 6 tab.
    公开号:SU1491340A3
    申请号:SU864027569
    申请日:1986-06-04
    公开日:1989-06-30
    发明作者:Шен Уве；Кербах Вольфганг；Хахмайстер Бернд；Бушманн Герд；Готтфрид Кюль Ульрих
    申请人:Кали-Хеми Фарма Гмбх (Фирма)；
    IPC主号:
    专利说明:

    3
    Izobrep eiinc ogositg. to the c-synthesis of new lromine compounds of the snarthein series, namely, snlrtein derivatives of the general formula I
    N
    N
    ) Mr. A
    1 de p-0 go 1;
    L - 2-Luril when
    2-pyridyl, 4-11 YRIDIL, HJ: H substituted phenyl of the general formula la g.- RI
    -Kg Kz
    where K (- C, -C4-l, C, -C-adkoxy, hydroxy, fluorine, chlorine, bromine, trifluoromethyl, CHO group; K. is hydrogen, C, -C-adyl, alkoxy, chlorine, fluorine, or RI and K together form a 1,3-di oxolan-2-ilen group; H, is a hydrogen, or each R ,, R
    and R, | -C-Sc.-alkoxy, or their pharmacologically acceptable acid addition salts, possessing valuable pharmacological properties. The purpose of the invention is to obtain new derivatives of spartein with a modified profile of action in comparison with well-known structural analogues of a similar action.
    The following abbreviations are used in the examples and in the tables: LSM - solvent; THF is tetrahydrofuran; Et is cyethyl ether; T is the temperature (C); Kat is a catalyst; P - ne chlorate 1-dehydroparthen; H - 17-hydroxys partin; TWO - 1,2-dibromo-ethane; WS is a salt of tartaric acid; HFu salt of fumaric acid.
    II p and mep 1. 0.1 mol of magnesium chips are placed in 50 ml of solvent (absolute). If necessary, the catalyst (iodine) is added. After instillation of 0.1 mol of A- (GH) n-Hal in 50 ml of solvent, the initial mixture is kept until the magnesium is dissolved under reflux.
    The reaction feed was used as such for the conversion in Example 2.
    These reaction conditions are given in table. one .
    9



    And pm. M p. 2. The initial mixture obtained according to an example is introduced with 0.05 mol of 17-hydroxy11 arteine or
    J 17-dehydrospartein perchlorate in 100 SU1 solvent and heated to a complete conversion of phlegm. After careful acidification with dilute hydrochloric acid and subsequent separation of the acid with base and chromatography on neutral alumina or silica gel with a mixture of ether-hexane, the compound (I) as the solvent is added. In one
    In 15 variant, this compound is converted to its acid addition salt. The special reaction conditions and the products obtained are given in table. 2
    Example 2a Getting 17- (320 methoxybenzyl) -spartein-substance No. 218.
    Analogously to example 1 in 0.6 g of magnesium chips in 20 ml of absolute tetrahydrofuran with stirring
    5 slowly add instillation of a solution of 3.4 ml of 3-methoxybenzyl chloride in 5 ml of absolute tetrahydrofuran. At the same time, as soon as the reaction is accelerated, the reaction vessel is cooled so that the internal temperature remains between 20 and 25 ° C. At the end of the addition, the enje is moved for 30 minutes. Then, the thus obtained 3-methoxybenzyl magnesium chloride
    35 holding the reaction of the initial mixture is processed further in the next stage of the reaction.
    Analogously to Example 2, to the resulting starting reaction mixture is added
    40 dropwise a solution of 2.6 g of 17-hydroxypartein in 5 ml of absolute tetrahydrofuran, and then the reaction mixture is stirred for 2 hours at 20-2 ° C.
    45 To treat the reaction mixture containing the resulting 17- (3-methoxybenzyl) -sparteine, add 20 ml of a saturated aqueous solution of ammonium chloride to the latter and separate
    CQ contains the organic phase of the reaction product. The aqueous phase is extracted twice more, respectively, with 10 ml of tertiary butylmethylgene ether and these extracts are combined with the organic phase. The title organic compound containing the title compound was shaken twice, respectively, with 20 ml of an aqueous solution of 0.5N. salt water
    lots. At P (M h, 11 m; I1 Ml H; () ix: unieHMf, as salt of r.styleor and nolgoGg of the salt – acid phase. At that, the combined aqueous phases are basified with a dilute solution of sodium hydroxide (pI 8–9), with the title base it is again released. It is extracted four times with 10 ml of tertiary 1 st simple butyl methyl ether. The combined ether extracts, which contain a free title base, are dried over sodium sulfate and concentrated, 2.65 g of the title compound are obtained as a residue. subject to hro atografii ATsOz to column using simple dietilovog ether as solvent. Pysle OTGONK.I the solvent, the title compound remains as a yellow oil, Ko toroe.medlenno crystallized, mp 51-52 C, yield 2.5 g of the title base.
    If necessary, the resulting free base base is transferred to the dehydrochloride salt. For this, -2.4 g of 17- (3-methoxybenzyl) - Spartein base is dissolved in 2.5 ml of isopropanol and a solution of 2.1 equivalent hydrochloric acid in isopropanol is added to this solution (for example, 1.8 ml of HCl solution in isopropanol, which contains 285 g of gaseous HCl per liter). The solution is stirred overnight and then 20 ml of tertiary butyl methyl ether are added and the precipitated dehydrochloride is filtered and dried at 60 ° C in a vacuum oven. Yield 2 g, melting point of the dehydrochloride of the title compound 230-233 ° C (with decomposition).
    Example 2b Preparation of 17- (3-methoxybenzylpartein) (substance No. 218).
    Analogously to Example 2a, 204 g of magnesium shavings and a few iodine crumbs in 50 ml of absolute diethyl ether are introduced. To this end, 15.6 g of 3-methoxybenzyl chloride are instilled in 50 ml of absolute diethyl ether at such a rate that the reaction mixture is boiled slightly. Once the magnesium is completely dissolved, the containing 3-methoxy1-containing treated (AO6
    PM111 and H1H1111D of the initial mode for pi (B-second mixture further in the next stage.
    To the obtained initial mixture, 16.65 g of 17-dehydroPgErtyep-perchlorate P is added to 100 ml of absolute diethyl ether. The reaction mixture is heated under reflux to iiojiiioro conversion.
    Q For processing at the end of the reaction, a dilute aqueous solution of hydrochloric acid is added to the base compound of the reaction mixture as the base. Water phase
    5 which, as the salt, contains the title compound in dissolved form, is separated and basified again with a dilute aqueous solution of sodium hydroxide. In this case, the title
    The Q compound is again released as a base and extracted four times, respectively, with 40 ml of diethyl ether from the aqueous phase. United essential extracts containing
    5, as a base, the title compound, dilute, dry over magnesium sulphate and thicken. The resulting crude title compound is purified again, as described in Example 2a and analogously to Example
    Q 2a is converted to dehydrochloride. 12.7 g of the dehydrochloride of the title compound are obtained, m.p. 230-233 C (with decomposition).
    I t PRI me R 2c. Obtaining 17-phenylspartein (substance number 201). .
    2.4 g of magnesium in an argon atmosphere are introduced into a three-necked flask with an addition funnel, a stirrer, and a thermometer.
    o Then add 20 ml of chlorobenzene,
    First, 8-10 ml of chlorobenzene is added dropwise to the reaction flask and the reaction mixture is activated by adding 2 drops of 1,2-dibromoethane. Heat up quickly
    5 to ambient temperature C. With vigorous stirring, chlorobenzene boils. Slow onset yellow staining indicates the onset of the reaction. When the contents of the flask become fresh in a mushy form, the rest of the chlorobenzene is quickly added. After 30 minutes, the initial reaction mixture was diluted with 15 ml of absolute xylene and stirred for 12 hours at a solution temperature of 150 ° C, and the magnesium chips were completely dissolved. Then, the initial reaction mixture containing the phenyl magnesium chloride obtained in this way is cooled to 60 ° C and further processed further in the next 1-111 reaction stage.
    Analogously to example 2, to the initial peaKiuioHHoft mixture obtained above, add 10, A g of hydroxispartein in 50 III of absolute tetrahydrofuran. Then the reaction mixture is stirred for 2 h at 60 ° C. Then, the reaction mixture containing the 17-phenylsparteine formed is treated as in Example 2a. Get 3.2 of 17-phenylspartein with so pl. 105-107 S.
    PRI me R 2d. Preparation of 17- (2-methoxyphenyl) -spartein (substance No. 202).
    In a three-necked flask with a thermometer, a dropping funnel and the final condenser, 2.4 g of magnesium shavings are introduced under pressure. In an atmosphere of argon, chips of 5 ml of toluene and 6.8 ml of tetrahydrofuran are layered over. A solution of 13.1 g of 2-methoxybenzene in 70 ml of toluene is added to the addition funnel, 5 ml of this solution is introduced into the reaction flask. The reaction starts by gently heating the reaction mixture to 70 ° C. After that, the remaining solution of 2-methoxybromobenzene is added from the dropping funnel with such a speed that the reaction temperature remains Biuiacb at 40-50 C. After the completion of the reaction, the initial mixture containing 2-methoxyphenylmagnesium bromide is processed further in the next reaction step .
    Analogously to Example 2a, the resulting starting reaction mixture is converted with a solution of 10.4 g of 17-hydroxyspartein in 50 ml of tetrahydrofuran. The resulting 17- (2-methoxyfenxO-Spartein-formed reaction mixture is treated a-taxically to Example 2a. 4.2 g of 17- (2-methoxyphenyl) -spartein is obtained. The latter is analogous to Example 2ac to be converted into its dihydrochloride with mp 220 C.
    PRI me R For. Preparation of 17- (4-formylbenzyl) -spartein.
    0.013 mol of 17- (4-bromobenzyl) -spartein (substance No. 230) is dissolved in 50 ml of absolute tetrahydrofuran. The initial reaction mixture is cooled to -30 ° C and 0.026 mol of p-butyl lithium is added to the cooled mixture (15% solution in hexane), the reaction mixture is stirred for 1 h at room temperature. Then to containing 17- (4-lithiumbeneyl) -sg1ar

    0 5 d
    O j
    -.
    five
    five
    a theine reaction mixture was added with a solution of 0.04 mol of N, N-dimethylformamide in 0 MF absolute tetrahydrofuran and the mixture was left to react for 4 hours. After that, the mixture was diluted with water. For further processing of the base compound containing the base compound and separating the title compound as described in Example 2a, by separating the aqueous acid solution with dilute hydrochloric acid, separating the aqueous acid phase and then alkalizing the acid phase with a solution of sodium hydroxide and base acid separation. 4 g of the crude title compound are obtained, which, according to Example 2a, is purified by chromatography on ether and hexane 1: 1 as solvent. Obtain 1.2 g of pure 17- (4-formylbenzyl) -sparteine with so pl. .
    EXAMPLE 4. Preparation of 17- (4-formyl-3-methoxybenzyl) -spartein.
    1 7- (4-Bromo-3-methoxybenzyl) -spartain is first converted as described in the example of the Abs method with absolute tetrahydrofuran at O C with the addition of catalytic amounts of tetraethylene diamine with p-butyl lithium and then further with S, S-dimethylformamide . The 17- (4-formyl-3-methoxybenzyl) -parthein containing initial reaction mixture is treated in the same way as in the example of Pro. Then the title compound, similar to that described in Example 2 according to the method, is converted to its wine-acid salt. PL-Avenia point, 1 7- (4-formyl-3-methoxybenzyl) -spartein X 2,3 WS 117-120 s.
    Example 5: Record the subsequent hydroxyl elimination from the methoxy group. Getting 17- (3-hydroxybenzyl) - Sparteina (compound No. 501) in the compound of formula I.
    In 0.017 mol of 17- (3-methoxybenzene1) - Spartein in 14 ml of acetic anhydride, 30 ml of 57% hydroiodic acid are slowly instilled. The initial mixture is heated for 4 hours under reflux. The reaction mixture is carefully placed in ice water and then proceeds as in Example 2.
    The resulting 17- (3-hydroxybenzyl) - spartein has so pl. 74-76 S.
    Analogously to example 5, obtained from 17- (4-methoxyphenyl) -spartein 17- (4
    i-MAllilKCHlb -Hll. l) - SGMRTSYAI and B1.1. SLIP1
    in fiHjio. iMOpi iiioi-o de1 Idrg, x:; orida (compound No. 500).
    And pimer 6, Preparation of (1,3-dioxol-2-yl) -phenyl-sportenone and its further transformation into 17- (3-formylphenyl) -sparteine,
    Analogously to Example 1a, 0.02 moles of magnesium shavings are introduced into 50 ml of absolute tetrahydrofuran and 0.2 ml of 1,2-dibromoethane is added to activate it. A solution of 0.02 mol of 2- (3-bromophenyl) -1,3-dioxolane in 10 ppm of absolute tetrahydrofuran is then added dropwise and the initial reaction mixture is heated under reflux for 1 hour and then diluted with 100 ml. absolute tetrahydrofuran. The 3- (1, 3-dioxolan-2-yl) -phenylmagnesium bromide containing initial reaction mixture is immediately processed further in the next reaction stage.
    To the resulting starting reaction mixture, similarly to Example 2b, 0.01 mol of 17-dehydrosparteine-β-perchlorate was added and the reaction mixture was heated for 5 hours under reflux. The resulting (1, 3-dioxolan-2-yl-phenyl-Sparteine) formed as the base, the initial reaction mixture is further processed without isolation of the title compound.
    Containing the above 17- (3- (1, 3-dioxolan-2-yl) phenyl-J-apartein reaction mixture to convert the 3- (1, 3-dioxolan-2-yl) phenyl substituent to 3-Formylphenio
    The left substituent is mixed with an aqueous solution of dilute hydrochloric acid and stirred for 30 minutes at room temperature. llfiH treatment containing the 17- (3-formylphenyl) -parthein formed as a salt, the aqueous phase of the reaction mixture is washed twice with 30 ml of ether to separate the non-basic parts. The aqueous phase is then made alkaline with a dilute aqueous solution of sodium hydroxide, and the 17- (3-formylphenyl) -party is released again as a base. It is extracted twice, each time with 30 ml of diethyl ether. The combined ether extracts containing 17- (3-formylphenyl) Sparteine free base are dried over magnesium sulfate and concentrated. As a residue, 2.1 g of crude 17- (3-formylphenyl) -spartein is obtained.
    0
    0
    five
    0
    five
    0 5
    For further purification, this crude product was subjected to chromatography on an AljO pa column using diethyl ether and hexane as the solvent. After distilling off the solvent, 0.8 g of 17- (3-formylphenyl) -parthein in oily form is obtained. The latter, similar to that described in Example 2 according to the method, is converted into its tart-and-acid salt with 3 equivalents of tartaric acids. M.p. 126-130 ° C.
    The effect of the substances listed in Table 2, which reduces the heart rate, was determined. 3, in which this dose is indicated in / and mol / kg for intravenous administration, which causes a decrease in heart rate (FRQ) from 25 to 75% of its previous value. The numbers of the examples correspond to the numbers in the following examples or tables.
    Determination of the minimum toxic dose. Male mice weighing 20–25 g are prescribed by mouth maximum doses of 300 mg / kg of the test substance. Animals are closely observed for 3 hours for toxicity symptoms. Over a period of 2 hours after administration, all symptoms and deaths are additionally recorded. Side effects are also observed and recorded. If death or severe toxic symptoms are observed, smaller doses are given to the rest of the mice until more toxic symptoms appear. The lowest dose that causes death or severe toxic symptoms is indicated as the minimum toxic dose.
    Introduced as dihydrochloride. Introduced as tart salt.
    Detection of antiarrhythmic agents with 1 viin active substances was performed experimentally by determining the functional refractory period of the left atrium of the albino I irbright-Wliite female guinea pig weighing 300-400 g using paired electrical stimulation using the Govier method (WCGovier, I.PharmacoL, Exp. Ther, (1965), 148 (1), 100-1 Ob. Kce. The anti-arrhythmic agents of various chemical structures currently used in therapy differ in the | Ts1 = absence of a functional refractory period. additional The effect of contractions on the strength of contraction of the heart mass is therefore B. Table 5 shows a NKR 125% such concentration in Schmol / L, at which, 18 min after the substance was injected, the functional refractory period lengthened by 125% or F 75% indicated concentration and concentration, which causes a decrease in the force of contraction of the heart muscle by 75% of the initial value.
    The direct effect of the active substance on heart rate (FR () was tested on spontaneously beating, isolated right atria of Guinea pigs of the female Albino Pirbright-White weighing 300-400 g. Table 3 shows how KK (75% indicated such mol / l, in which, after 20 minutes after giving the substance, the frequency decreases by 75% of the initial value.
    More specifically, the quotient F 75% (FKQ 75%) of the cardiac muscle contraction force and the heart rate reduction dose is indicated. This quotient provides an explanation of the therapeutic range of substances with respect to the effect of the contraction of the heart rate.
    From the data table. 5 it follows that the new substances do not show any noticeable undesirable negative inotropic effects, however, in very low concentrations, they exhibit a reduced heart rate and a coarrhythmic effect.
    The data table. 5 shows the compounds of peroxidized pentylsparteine-L (+) -tartre;) ta. The comparison clearly shows tremendous therapeutic
    range relative to reducing h;) heart rate of actuation of the compound according to the invention in contrast to the action of a known substance.
    The action of the invention according to the invention is characterized by a combination of the effect of oxygen saving, the effect of forming a rhythm and the effect on the heart rate, which is used in the search for heart disease, for example, angina pectoris, and myocardial infarction, as well as in life-threatening arrhythmias.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The way to get) 1 and derivatives of spratein of general formula I:
    -N
    25
    .N
    TO
    SSNg) yy-A
    0
    five
    0
    five
    where or 1;
    A - 2-furyl, with
    2 pyridyl, 4 pyridi, p, shsh substituted phenyl of the general formula 1a
    RI
    -Kg
    C - (- alkyl, C | -C-alkoxy, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl, CHO group; hydrogen, C-C-alkyl, C, alkoxy, chlorine, fluorine, or U and K- together form 1 , 3-dioxolan-2-ileny group; hydrogen, or K ,, IL and Kg - C) -C4-alkoxy,
    or their pharmacologically acceptable salts of acid addition salts, characterized in that, 17-ox; sparteine (formula II
    where K, K, R,
    ABOUT
    or 17-dehydrochloride1 arteine perechlorate of the formula III.
    © ClOf
    introduced into interaction with the Grignard reagent of formula IV A - (Crf,) n -MgHal, where either 1;
    A has the indicated; UIH A values, in addition to phenyl, substituted by hydroxy or CHO group, or phenyl, substituted by 1,3-dioxolan-2-yl group, to obtain the compound of formula 1a
    -N
    -N.
    sen,} p.-A
    (la)
    where p and A have the indicated value, which is isolated in free form or in the form of salt, or, if necessary, with a compound of formula 1a, where K, is alkoxy or 2-, or 4-bromo, is metallized with alkyl lithium with a subsequent reaction with dimethylformamide to form a compound
    0 mules ia, where R is a CHO group, or, if necessary, a compound of general formula 1a, where R is a methoxy group, are treated with HJ to obtain a compound of formula I, where K is hydroxyl 5 per group, or if necessary, a compound of formula ia, where R, - The 1,3-dioxalan-2-yl group is subjected to acid hydrolysis to form a compound of formula 1a, where the XO group is 10, followed by isolation of the desired compounds in free form or as pharmacologically acceptable acid addition salts.
    Preparation of A- (CHj) n-MgHal from A- (CH4) p-H1
    Table 1
    llll JU M l PHHfI: l. l. one
    T a b l and C a 3
    The effect on heart rate (FRQ), systolic blood pressure (PS) and double product (DR) under
    anesthetized rats
    used as a dehydrochloride.
    Continued tabl, 2
    Table4
    nineteen
    Table3
    The effect on heart rate (FRQ) of spontaneously beating right atria of guinea pigs, as well as on the force of contraction of the heart muscle (F) and on the functional refractory period (FRP) of irritated left guinea pig atria
    1491340
    20 Continuation of table 4
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2360475C3|1973-12-05|1980-11-20|Kali-Chemie Pharma Gmbh, 3000 Hannover|medicines for the treatment of irregular heartbeat|
    EP0025069B1|1979-09-06|1982-06-16|Kali-Chemie Pharma GmbH|Pentylsparteine salt, medicament containing it and process for the preparation of this medicament|
    DE3032219A1|1980-08-27|1982-04-15|Kali-Chemie Pharma Gmbh, 3000 Hannover|NEW SPECIAL DERIVATIVE, METHOD FOR THE PRODUCTION THEREOF, THE DERIVATIVE-CONTAINING MEDICINAL PRODUCT AND METHOD FOR THE PRODUCTION OF THE MEDICINAL PRODUCTS|US4879299A|1985-06-22|1989-11-07|Kali-Chemie Pharma Gmbh|Treatment of heart conditions with spartein compounds|
    DE3643402A1|1986-12-19|1988-06-30|Kali Chemie Pharma Gmbh|17-BENZYL SPARTEIN DERIVATIVES CONTAINING POSITIVE INOTROP EFFECTIVE PHARMACEUTICAL PREPARATIONS|
    US5912343A|1996-12-31|1999-06-15|Bridgestone Corporation|Tertiary amines containing side-chain organolithium structures and method for the preparation thereof|
    PT2067775E|2001-07-16|2012-07-16|Genzyme Corp|A n-acylsphingosine glucosyltransferase inhibitor|
    DK2796457T3|2009-11-27|2016-08-29|Genzyme Corp|Genz 112 638 for the treatment of Gaucher disease or Fabry of combination therapy|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19853522475|DE3522475A1|1985-06-22|1985-06-22|NEW AROMATIC COMPOUNDS, THEIR PRODUCTION AND USE|
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