• 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:
    The method of obtaining indolysin derivatives of the general formula i f W-N-c-A-o-cHz-icHiVi mj about where. N is 1 or 2; . . R is unbranched or branched C (-C4-alksh1 or phenyl; R. is unbranched or branched .nкшl, hydrogen, chlorine or bromine A is a radical of the formula OR where Xg. Hydrogen, chlorine, bromine m-methoxy- or their salts with organic or an inorganic acid, characterized in that bromoalkoxibene. nzoyl of the general formula. n C-A-0-CH2- (CH2) p-VG O where E, X |, A and p - have the indicated meanings, are reacted with the primary an amine of the general formula H.JN-R, where RI - has the indicated values, at 50-75 ° C, followed by injecting the desired product in free form or as salts with organic or inorganic acid.
    公开号:SU1194272A3
    申请号:SU833606051
    申请日:1983-06-16
    公开日:1985-11-23
    发明作者:Россель Жильбер；Польстер Петер
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the production of new derivatives of indolysin of the general formula
    OR
    where Xg is hydrogen, chlorine, bromine or methoxy,
    exhibiting properties of calcium antagonists that can be used in the treatment of angina.
    The purpose of the invention is to develop, on the basis of a known method, a method for producing new compounds with valuable pharmacological properties.
    Example 1 Preparation of acid oxalate 2-ethyl-3- 4- (3-tert-butilla shnopropil) oksibenzoylJindolizin.
    In a flask, a solution consisting of 4.2 g {0, OP mol) 2-ethyl-3- 4- (3-bromopropyl) oxybenzoyl indolizine and 2.4 g (0.033 mol) tert is heated for 50 hours at 50 ° C. -butylamine in 40ml toluene. At the end of the reaction, the reaction mixture is allowed to cool, then it is poured into 40 ml of water and is made alkaline with a 10% aqueous solution of sodium hydroxide. The organic phase is separated, the aqueous solution is extracted with toluene, the organic phase is combined and washed with water until neutral. The oily residue is evaporated to dryness and purified by chromatography on alumina using 1,2-dichloroethane as eluent. The purified oily product is dissolved in diethyl ether, to which an ethereal solution of anhydrous oxalic acid is added, and the resulting solid is crystallized from methanol,
    3.9 g (75% yield) of 2-ethyl-3-4- (3-tert.-butylaminopropyl) oxybenzoyl acid oxalate are obtained. indolysin, so pl. 207-208 S.
    The following compounds are prepared analogously.
    Acid oxalate 2-eth1-3-4- (3-ethylaminopropyl) oxybenzoyl indolizine, m.p. 184 ° C (ethanol)
    Acid oxalate 2-ethyl-3-4- (3-n-butylaminopropyl) oxybenzoyl-indolizine, so pl. 155C (ethyl acetate / methanol).
    Sour oxalate 2-n-butyl-3- 4- (3-tert-butshtaminopropil) oxybenzoyl indolizina, so pl. ON and 143145 ° C (methanol / diethyl ether).
    Acid oxalate 2-ethyl-3-t4- (3-n-butylaminopropyl) oxybenzoyl-in-; dolisin, m.p. 172-173 C (isopropanol).
    Acid oxalate 2-isopropyl-3- - 4- (3-n-butylaminopropyl) oxybenzoyl indolizine, so pl. 168-170 C (ethanol).
    Acid oxalate 2-isopropyl-3- - 4- (3-tert-butyl-aminopropyl) oxybenzoyl indolysine, m.p. 195-19 / 7 C (ethyl acetate / methanol). R
    2-Isopropyl-3-4- (3-tert-butylaminopropyl oxybenzosht indolizine hydrochloride, mp. (Ethyl acetate / methanol).
    Acid oxalate of 2-phenyl-3-4- (3-n-butylaminopropyl) oxybenzoyl-indolizine, m.p. 210-211 C (dimethylformamide).
    Acid oxalate 2-phenyl-3- 4- (3-tert-butylaminopropyl) oxybenzos) indolizina, so pl. 205 ° C (methanol / diethyl ether).
    Acid oxalate 2-n-butyl-3-1 4- - (3-methylaminopropyl) oxybenzoyl - indolizina, mp. 132 C (methyl methyl ketone / methanol).
    Sulfur oxalate 2-n-butyl-3- 4- (2-tert-butylaminoethyl) oxyben. Zo-ilideylindisine, m.p. 205-208 C (methanol / diethyl ether).
    Acid oxalate 2-ethyl-3- 4- (3- - neopentylaminopropyl) oxybenzoip indolysin, so pl. 210 C (dimethylformamide).
    Acid oxalate 2-n-butyl-3- 4- - (3-n-propylaminopropyl) oxybenzyl indolizine, so pl. (from propanol). Acid oxalate 2 N-butyl 3-4 - (3-ethylaminopropyl) oxybenzoyl indolysine, mp, 7 -} 72 ° C (meta-NOL}). Acid oxalate 2-n-butyl-3- 4- (Z-propyl-aminopropyl hydroxybenzo III indolizina, mp 159-160 ° C (from propanol). Acidic oxalate 2H-1ch3-3-4- (3-neopentylaminopropyl) oxybenzo shpindolizina, mp 190-1191 ° С (I tanol.) Acid oxalate 2-H-butyl-3- 4- (2-neopentylaminoethyl) oxy-bis-1/1 indolizine, mp 197-198 C (methanol). 2-Isopropyl-3 -.- (2- tert-butylaminoethyl) oxybenzosh - indolizina, mp 222 ° C (ethanol / di ethyl ester 2/1). Acidic oxalate 2-isopropyl-3- 4- (2-neopentinite Retol) oxybenzo2 Indolysine, mp 205-207 ° C (methanol). Sour oxalate 2-isopropyl-3-- 4- (3-neopentylaminopropyl) oxybenzoyl thindolysin, mp 206-207 (methanol). Acid 2-methyl-3-G4- (3-tert-butylaminopropyl) oxybenzoyl yl indolizine oxalate, mp 215 C (methanol). Acidic oxalate 2-n-propyl-3- 4- (3-neopentylaminopropyl) hydroxybenzoyl indolizine, mp 190-192 ° C (methanol). Sour oxalate 1-chloro-2-n-butshg-3-4- (3-tert-butylaminopropyl) - indolizine oxybenzosht, so pl. 168 ((ethanol). Sour oxalate 1-chloro-2-n-butyl, - 4- (H-n-butylaminopropyl) -oxibene pcs of indolizine, mp. 164 C (ethanol Acid oxalate 2-n-propyl-3 - 4-tert-butylaminopropyl) oxybenzoyl indolizina, mp 182-184 0 (methanol). Acid oxalate 1-bromo-2-n-butyl-3-4- (2-neopentilaminoethyl) oxybenzoyl | indolysine, mp 195-197 (methanol). Sour oxalate 1-brO1 g 2-n-butyl (2-tert-butylaminostil) oxy benzoyl indolizine, mp 220-22 (methanol). 72 Acid oxalate 1-bron-2- n butyl-3-G4- (3-tert-butylaminopropyl) oxy-sibenzoyl-indindolysin, mp 168170 C (methanol). 1-Bromo-2-n-butsh-1-3-| 4- (3-nepentine-aminoproppohydrate) l) oxybenzoyl | indolisin, mp 184-186 C (methyl ethyl ketone / methanol). Sour oxalate I-bromo-2-phenyl-3-4- (3-n-butylaminopropyl) oxy-3chlorobenzoyl Pindolizina, mp 176- (methanol). 1-Bromo-2-isopropyl-3- - 4- (3-tert-butylaminopropyl) oxybenzoyl indolizine hydrochloride, mp 207-209 C (diethyl ether / metaiol 9/1). Sour 2-n-butyl-3-4 (3-tert-butylaminopropyl) oxy-3-methoxybenzoyl indolysine oxalate, m.p. (ethanol). Acid oxalate 2-isopropyl-3- 4- - (3-tert-butylaminopropyl) oxy-3,5-dimethylbenzoyl indolizine, mp. (methanol). :, 2-isoprosh-3-4- (3-tert-butylaminopropyl) oxy-3-bromo-1-benzoyl1 -indolysine hydrochloride, m.p. 238 C (methanol / diethyl ether). Example 2. Getting 1-bromo--2-n-butyl-3- | 4- (2-tert-butylamino-ethyl) oxyben zoyl) indolysin. A solution consisting of 7.4 g (0.015 mol) of 1-bromo-2-n-butyl-3-4- (3-bromopropyl) -oxybenzoyl2indolysin and 3.3 is heated in a flask for 30 hours at 75 ° C. g (0.045 mol) tert-butylamine in 50 ml of toluene. At the end of the reaction, the reaction mixture is cooled, poured into 50 ml of water and made basic with a 10% aqueous solution of sodium hydroxide. The organic phase is separated, the aqueous solution is extracted with toluene, the organic phases are combined and washed with water until neutral. The residue is evaporated to dryness and the oily residue is purified by chromatography by elution from alumina using 1,2-dichloroethane as eluent. Get 1-bromo-2-n-butyl-3- 4- - (2-tert-butylaminoethyl) oxybenzoyl indolysin with a yield of 65%. Example 3. Preparation of 2-ethyl-3-4- (3-ethylamino-1-propyl) oxybenzoyl indolysine acid oxalate. To 22.7 g (0.06 mol) of 2-ethyl-3- 4- (3-bromopropyl) oxybenzene of indolysine in 300 ml of ethanol was added S 48 f-in ethylamine solution in ethanol of 31% concentration, heated in 10 h at 95 ° C in a sealed am pule. The alcohol is distilled off under reduced pressure and dissolved in dichloroethane thick oily residue. It is washed with a 30% aqueous solution of sodium hydroxide and then twice with water. Dry over sodium hydroxide sulfate, filter, and dichloroethane. 20.3 g of an oily residue is dissolved in dry ethyl ether, treated with activated charcoal, filtered, and oxalate is obtained by adding oxalic acid to this ether. Thus, 18 g of 2-ethyl-3- 4- {3-ethylamino-1-propyl) oxybenoyl indolysine acid oxalate are obtained 18 g after recrystallization of ethanol, m.p. 184 C. Indolysin derivatives have been found to exhibit remarkable macroscopic properties, namely, the ability to inhibit calcium translocation at the level of the cell wall. These properties cause the high value of these compounds for the treatment of certain pathological heart disorders, in particular for the treatment of angina pectoris, hypertension, arrhythmia, and circulatory insufficiency of the brain. A derivative of indolysin is known, namely, butoprosine or 2-ethyl-3- - 4- (di-3-n-butylaminopropyl) oxybenzoylPindolizin, which at the same time has anti-on and -I-adrenergic properties (French patent No. 2341578), i.e. . the ability to partially inhibit oi and 0-adrenergic reactions, and the ability to suppress calcium (Biochemical Pharmacology, Vol. 30, No. 8, p. 897-90i, 1981). However, it has been found that the compounds of the proposed formula, as well as their non-toxic additive salts, have the ability to suppress calcium. At the same time, they do not exhibit a significant antiadrenergic effect in doses in which butoprosin already exhibits these properties. The results of the pharmacological tests carried out to determine the cardiovascular properties of the 726 compounds according to the present invention) are as follows. Ability to inhibit calcium. The ability to suppress the advancement of calcium at the level of the cell wall, manifested by the proposed compounds, is shown by measuring their antagonistic effect on the contractile response to depolarization provoked by the action of potassium on the isolated rat aorta. It has been established that depolarization of the sheath of a smooth muscle with potassium makes it permeable to extracellular calcium and causes muscle contraction. Therefore, by measuring the suppression of the contractile response to potassium depolarization or by measuring the decrease in tonus in response to potassium depolarization, the activity of the compound can be evaluated as a membrane permeability inhibitor for Ca ions. Wistar male rats weigh approximately 300 g and cut the aorta about 40 mm long and about 3 mm wide. These strips are placed in a 25 ml bath for an isolated organ with a modified Krebs bicarbonate solution, mmol: NaCF 112; KCE 5; NaHCO, 25; KH2P04 1; MgSG 1,2; 2.5; glucose P, 5; distilled water up to 1000 mp, through which carbogen flows, at 37 ° C, the Drug is connected to the force micrometer and a contractile reaction is recorded (after it is amplified) using a recording device. A voltage is applied to the drug. for 60 minutes in a modified Krebs bicarbonate solution, then provoked. reduce, replace the Krebs bicarbonate solution with a potassium Krebs solution, mmol: NaCE 17; KCE 100; NaHC03 25; one; MgS04, 1.2; CAC 2.5; glucose 11.5; distilled water up to 1000 ml. After the contractile response of the drug has become reproducible, a certain amount of the proposed compound is introduced into the bath. After 60 minutes, a new spasm is provoked by depolarization with potassium. Results for each aorta tested (expressed as% of
    maximum contractual effect before incubation of the test compound) are given in Table. 1 and 2.
    Hemodynamic properties.
    The compounds according to the invention, in dogs, are administered at doses of 5-10 mg / kg with intravenous administration of a 15-40% decrease in the frequency of heart contractions: as well as a slow and gradual decrease in arterial pressure.
    In addition, experiments conducted also on dogs at a dose of 5 mg / kg when administered intravenously according to a known method (French Patent No. 2341578) show that the compounds according to the invention show, in general, anti-t - adrenergic properties of weak
    intensity, i.e. generally less than 50%, and anti-adrenergic properties of zero or almost zero intensity.
    Meanwhile, butoprosin, under the same conditions, already exhibits anti-o-adrenergic properties well above 50% and anti-ad-allergic properties.
    properties in the order of 50%.
    Consequently, the compounds according to the invention have, as compared with butoprosin, zero antiadrenergic activity or a much more narrow range of antiadrenergic activity, and show anti-calcium properties.
    Table 1
    R
    C- (CH ")
    HE,
    5/3
    .
    С- (СН) СН, -С- (СН) С- {С1Ц), СН СН l /
    s- (sn)
    C- (CH3) C C- (CH3) C
    e With a dose of 10 mol
    eleven
    12,
    1194272 Continuation of the table. I
    Butoprozin
    39
    2
    nn nn nn osn.
    87
    one
    83.4
    2 2 2 2 2 2 2
    78
    76.4
    70
    71.4
    85.2
    80.4
    70.4
    iso-S.N iso-OH
    Table
    sns
    -CH -lCH b-NHRi
    10 26.5 10 68.7
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of indolysin of the General formula
    ЧЛ - “- C-A-O-CHi-iCHiVWj about where.η = 1 or 2;
    R is unbranched or branched C (—Cd — alkyl or phenyl;
    R | - unbranched or branched C ^ -C ^ apkyl;
    Xf is hydrogen, chlorine or bromine; A is a radical of the formula where X 2 is hydrogen, chloro, bromo or methoxy.
    or their salts with an organic or inorganic acid, characterized in that, bromoalkoxy-benzoyl of the General formula
    X | ^ N- ^ C “AO-CH 2 - (CH 2 ) n -Br 0 where R, X ^, A and η - have the indicated meanings, are reacted with a primary amine of the general formula
    H 2 NR, where R ^ - has the indicated meanings, at 50–75 ° C, followed by isolation of the target product in free form or in the form of a salt with an organic or inorganic acid.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8210598A|FR2528845B1|1982-06-17|1982-06-17|
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