• 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 derivatives of N aminoalkylindole of the general formula ES. R is unsubstituted alkyl with 1-4 carbon atoms or a substituted phenyl residue, or an acetyl residue R, is an alkoxycarbenyl group with 1-4 carbon atoms or cyan; A-C, -C5 -alkylene group j are identical or different and mean water-. genus or alkyl with 1-4 carbon atoms, or alkylene groups that, together with the nitrogen atom, form a cyclic group with 5-6 members in the chain Rg and are the same or different and mean hydrogen, halogen alkyl or alkoxy group with 1-3 carbon atoms or one of Rj and R (denotes a nitro group, and the other is hydrogen, or their salts, from the fact that an alkali metal salt of an д ndol of the general formula Rp. OPj g is indicated by R, which values are treated with a dihaloalkane in an inert solvent formulas - X - A. - X2 where A has The mean values of i X and X, j may be identical or different and mean halogen, with an amine of the formula t jf 3 HN (CD Od R4 O E where Rg and R have the indicated values, or with one, halogenoalkylamine of the formula / X-L-1 where A has the indicated values} RJ and R have the indicated values besides hydrogen} X is halogen, at a temperature from to the boiling point of the solvent, followed by separation of the target product in free form or as a salt.
    公开号:SU1119606A3
    申请号:SU802936511
    申请日:1980-06-25
    公开日:1984-10-15
    发明作者:Хайнеманн Хеннинг；Вильхельм Олендорф Хайнрих；Вольф Клаус-Ульрих
    申请人:Кали-Хеми Фарма Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of novel N-aminoalkylindole derivatives having an effect on gastric motility. The known reaction of alkylation of amines with alkyl halides. The purpose of the invention is to develop a process for the preparation of new compounds with valuable pharmacological properties. This goal is achieved by the method of obtaining N-aminoalkylindole derivatives of the general formula Be .. And J is an unsubstituted alkyl with 1-4 carbon atoms or substituted by a phenyl residue, or an acetyl residue i 2 is an alkoxycarbonyl group with 1-4 carbon atoms or cyan; AC, -C5 alkylene group; R and R are the same or different and are hydrogen or alkyl with 1-4 carbon atoms or alkylene groups, which together with the nitrogen atom form a cyclic group with 5-6 members in the chain; 5 6 are the same or different and denote hydrogen halide, alkyl or alkoxy group with 1-3 carbon atoms or one of Rj and R means a nitro group, and the other is hydrogen, or their salts, the conclusion is that the alkali metal salt of the indole of the common indole formulas. -i where R, Rg, Rj and R - have the indicated values in an environment of an inert solvent after 62 are treated with a dihaloalkane of the formula Xi-A and have the indicated values; X and X may be the same or different and mean halogen, with an amine of the formula where R, and Hl. have the indicated meanings, or with one haloalkylamine of the formula, where. have the indicated values of j R- and Kc. - have the indicated values except hydrogen; X - halogen, at a temperature from 0 ° C to the boiling point of the solvent. Under the action of a dihalogenoalkane (III), a derivative of N- (haloalkyl) -indole is formed, which can be removed from the reaction medium before subsequent transformation with ammonia or with alkylamines and in this case recrystallize. The reaction with the amine of formula (IV) can be carried out in an inert solvent, such as dimethylformamide, sulfolane, tetrahydrofuran, 154-dioxane, toluene, dimethyl sulfoxide, or mixtures thereof under normal or elevated pressure. The temperatures lie between room temperature and the boiling point of the solvent, preferably between 40 and 60 ° C. Alkali or alkaline earth carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate, as well as tertiary amines, like triethyl n or pyridine, can also serve as acid binding agents, but also amines of formula (IV) used in excess. The latter are used in excess, may also be used as a solvent.
    3
    In the second case, a haloalkylamine of formula (V) is added to a solution of the alkaline salt of the indole derivative of formula (II) and the transformation is carried out at temperatures between room temperature and the boiling point of the solvent, preferably between 60 and 90 ° C, and under normal or elevated pressure.
    Target products are available in free form or in the form of salts. They show a pronounced effect on motility disorders in the gastrointestinal canal,
    In the experiment with animals, under their influence, the peristaltic waves of the stomach are amplified, and the frequency of movements in favor of stronger, deeply churned waves decreases, resulting in an improved emptying of the stomach,
    Pharmacological research methods.
    1. Acute toxicity
    Acute 7-day toxicity is determined after a single intraperitoneal administration on white fed NMRI mice. The calculation of the LD of the 0-values should be done using a probitan analysis
    L.Cavalli-Sj arra. I
    2. Checking the peristalsis of the stomach.
    To determine gastric motility, ketamine hydrochloride / xylazine anesthetized to rats weighing about 200 g, a vascular catheter is introduced into the vein, and a tracheal catheter is inserted into the trachea. A stomach valve is injected into the stomach, which is connected via a three-way valve to the Statham pressure sensor (P 23 V). The stomach in Pylorus and Cardta is closed with a ligature. The stomach is filled with 3 ml of a 059% aqueous solution of NaCI. The shock waves produced by the stomach are recorded uninterruptedly using Watanabe-Multicorder (MC 641). To sense the effect of the test substances, they are dissolved in physiological sodium chloride solution or suspended in Tulose MH50, administered intraperitoneally at a dose of 20 mg / kg. Amplitudes are compared to oscillations
    them shock waves of the stomach, coming before and after the substances.
    Data processing has shown that soon after the application of substances 5 according to the invention, a noticeable increase in amplitude occurs. This effect, in conjunction with a differently perceptible decrease in frequency, leads to an improved gastric transmission.
    According to the described methods, investigative substances were investigated,
    A.1 - (/ i-dimethylaminoethyl) -2-labels „Sicarbonyl-3-methoxy-indole hydro15 chloride,
    B. Hydrochloride 1- ((5-dimethylamino-ethane 1) -2-methoxycarbonyl-3-methoxy-6-methyl-indole,
    C. Hydrochloride 1- (p-dimethylamide 20 noethyl) -2-methoxycarbonyl-3-ethoxy
    si-5-chloro-indole,
    D. Hydrochloride 1 - (/ 3-dimethylaminoethyl) -2-methoxycarbonyl-3-isopropyloxy-5-methyl-indole.
    25E „1 - (- dimethylaminoethyl) -2-methoxycarbonyl- | -benzyloxy-5-chloropridole-toluene | -4-calfonat.
    F, 1 - (; 1-dimethylaminoethyl) -2-ethoxycarboxy-3-ethoxy-6-chloro30 indoltoluene-A-sulfonate.
    G. T-Cy-isopropylaminopropyl) -2-methoxycarbonyl-3-methoxyindole hydrochloride.
    N. 1- (cL) -dimethylaminobutyl) -22 methoxycarbonyl-3-methoxy-indoltoluene-4-sulfonate.
    I, Maleinate 1- (H-piperidinopropyl) -methoxycarbonyl-3-methoxyindole,
    40 So far, no indole compounds have been known to have an effect on mobility and contraction of the gastrointestinal tract. Therefore, for comparison, the table shows the data for metoclopramide (K-diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide) known as Paspertin and used to eliminate feelings of overcrowding and nausea.
    From the data of the table it follows that even small doses of the proposed substances and their acid addition salts cause a significant increase in the peristaltic waves of the stomach, and the high efficiency and low toxicity of the substances indicates a good compatibility.
    such. A further advantage is the observed rapid onset of action.
    The pharmacologically observable effects may be that the proposed substances eliminate in humans disorders of the gastrointestinal function, such as pyloric stenosis, duodenogastric reflex, as well as atonic conditions. Further, an advantageous therapeutic effect can be expected for various functional ailments that lead to pain in the epigastric region, nausea, a feeling of fullness and other unpleasant sensations. These include symptoms of gastric and duodenal ulcers, gastritis and nervous irritation. stomach. An increased gastric patency of the con- is also desired in r.entgenodiagnosis. trust substance.
    Example 1. 20.5 g of 2-methoxycarbonyl-3-methoxy-indole. dissolve in 100 ml of dimethylformamide and, with stirring and with OC, are batchwise mixed with 3 g of sodium hydride (80%). After warming to room temperature, 20 g of 1-bromo-3-chloropropene are added, the mixture is heated to 80 ° C for another 12 hours and the solvent is removed. Treat with a mixture of ethyl acetate / water. The resulting crude product is distilled in a spherical expansion tube. 24.7 g of oil precipitated as 1 - (3-chloropropyl) -2-methoxycarbonyl-3-methoxyindole are obtained. It is dissolved in 100 ml of dimethylformamide and heated with 20 g of diethylamine for 5 hours. After removing the solvent and mixing the residue with 10% hydrochloric acid, it is extracted with ethyl acetate. Then the aqueous phase is made alkaline with a solution of water, extracted with ethyl acetate, The organic phase is dried over sodium sulphate, filtered and evaporated to a hydroxy residue under reduced pressure. As a residue, 25.8 g of 81% of the theoretical) 1- (j-diethylaminopropyl) -2-methoxycarboxylic acid-3-methoxyindole are obtained in the form of an oil. The substance precipitates in the form of maleate in a crystalline form with m.p. 110-112 C.
    Under appropriate reaction conditions, 1- (t-chloropropyl) -2-methoxycarbonyl-3-methoxy-indole can be converted with methylamine or ammonia, and in this case, the following compounds can be obtained with an acid
    1 - (3-methylamino-propyl) -2-methoxycarbonyl-3-methoxy-indole,
    1- (3-chloropropyl) -2-methoxycarbonyl-3-methoxyindole was prepared as in Example 1, and dissolved in dimethylformamide. Methylamine is passed into the solution, and the reaction mixture is then stirred for three hours at this temperature. Directly thereafter, the reaction mixture is heated to room temperature and treated in a known manner, thereby obtaining 1- (3-methyl-aminopropsh1) -2-methoxycarbonyl-3-methoxy-indole as an oil. IR: 1695, 3300 cm-- (CO / NH).
    Yield 73%.
    1- (3-aminopropyl) -2-methoxycarbonyl-3-methoxy-indole.
    The test was carried out according to the indicated method, but ammonia was used instead of methylamine. The desired compound obtained as an oil is converted in a known manner into its dihydrochloride salt. M.p. dihydrochloride 184-186 ° C.
    Yield 71%.
    1- (3-piperidinopropyl) -2-methoxycarbonyl-3-methoxy-indole.
    Analogously to Example 1, 24.7 g of 1- (3-chloropropyl) -2-methoxycarbonyl-3-meth6xy-indole in LLP ml of dimethylformamide is obtained. This solution is mixed with 25 g of piperidine and heated for 90 minutes to b. phlegm. Immediately thereafter, the reaction mixture is processed as in Example 1, and the resulting 1- (3-piperidinopropyl) -2-methoxycarbonyl-3-methoxy-indole is converted into its maleate. Exit 67%. T.pl. maleate 104-106 s.
    Example 2 In analogy to Example 1, 20.5 g of 2-methoxycarboxy-3-methoxy-indo a dissolved in 100 ml of dinethylformamide with 3 g of sodium hydride (30%) and 22 g of 1-bromo-4 -chlorobutane get 25.1 g of 1- (chloro-butyl) -2-methoxycarbonyl-3-methoxyindole in the form of oil. It is dissolved in 100 ml of dimethylformamide at, converted with dimethylamine 7 and obtained in crystalline form as toluenesulfonate. 29.4 g (62% of theory) of toluene-4-sulfonate 1 - (cH-dimethylamine nobutyl) -2-methoxycarbonyl-3-methoxindole are obtained, mp. PZ-PZ C. Example 3. 20.5 g of 2 methoxy carbonyl-3-methoxy-indole are dissolved; in 60 ml of dimethylformamide. With stirring and ice-dripping, portionwise add-3 g of sodium hydride - (80%). After 15 minutes, 12 g of 1-dimethylamino-chloroethane was added and then heated for 2 hours and then evaporated under reduced pressure. . The residue is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The aqueous phase is then made alkaline with soda solution, extracted with ethyl acetate. The organic phase is dried over sulfate. The sodium is filtered and evaporated under reduced pressure. 23.7 g of 1- (p-dimethylaminoethyl) -2-methoxycarbonyl-3 is obtained as a residue. -methoxyindole in the form of an oil (86% of theoretical). To form a salt, the oil is dissolved in: 100 ml of methanol and hydrogen chloride gas is passed into the solution. The precipitated salt is sucked off, washed with methanol and ether and sugars. The title compound is obtained as monohydrochloride, m.p. 202-203 ° С (with decomposition). Example 4. According to examples 1-3, proceeding from the alkaline salts of the corresponding indole derivatives, the following compound can be obtained: maleate 1- (p-diethylamino-amino) 2-e-toxicarbonyl-3-e-toxi-indole, mp 110 -112 ° C. 1- (p-Dimetsh1aminoetnl) -2-isopropyloxycarbonyl-3-methoxyindole, IR: 1685 cm (carbonyl) J 1- (y1-dimethylaminoethyl hydrochloride) -2-methoxycarbonyl-3-isoproth shoxy-5-methyl-indole, t. w1. 206208С; 1 - (- dimethylaminopropyl) hydrochloride - (2-methoxycarbonyl-3-methoxy-6-methyl) indole hydrochloride, m.p. 198-200C, 1 - (/ 3-drshetilakinoethyl) -2-methoxycarbonyl-3-ethoxy-5-chloroindole hydrochloride, m.p. 175-177 C; 6 toluene-4-sulfonate 1- (| 3-dimethylaminoethyl) -2-methoxycarbonyl-3-benzyloxy-5-chloro-indole, m.p. 175177 ° C; tolyuol-4-cyJ7-phosphonate 1- (u-dimethylaminoethyl) -2-ethoxycarbonyl-3-toxy-6-chloro-indole, m.p. 152-154 ° C; hydrochloride of 1- (p-dimethylaminoEgsh1) -2-methoxycarbonyl-3-methoxy-5-bromo-indole, so pl. 190-19lC; 1 (p-Dinetilaminoethyl) -2-methoxycarbonyl-3-methoxy-5-nitroindole, IR; 1690 cm- (), oil; hydrochloride of 1- (| -dim8Tyla i-ethyl) -2-methoxycarbonyl-3,5-dimethoxyindole, so pl. 182-184 ° C; 1 - (/ 3-dimethylaminoethyl) -2-methoxycarbonyl-3,5,6-trimethoxy-indole hydrochloride, m.p. 203-204 C, 1 - (- dimethylaminoethyl) -2-methoxycarbonyl-3-methoxy-5-bromo-6-methyl-indole hydrochloride, m.p. 200202 C-, 1 - (/ 1-Dimethylaminoethyl) -2-cyano-3-methoxy-indole, IR: 2230 cm (nitrile), oil, 1- (y-dimethylaminopropyl) -2-methoxycarbonyl-3-methoxyindole hydrochloride m.p. 154-155 ° C; 1 - ((1-dimethylaminopropyl) -2-methoxycarbonyl-3-methoxyindole hydrochloride, m.p. 186-188 seconds; 1 - (- di1 | zopropylaminopropsh1) -2-methoxycarbonyl-3-methoxyindole, IR: 1700 cm (carbonyl), oil; 1- (y-pyrrolidinopropyl) -2-methoxycarbonyl-3-methoxyindole, IR: 1700 cm (carbonyl), oil maleate 1 - (- (p-piperidinopropyl) -2-methoxycarbonyl-3-methoxyindole, mp 104- 106C, 1- (2g-isopropylaminopropyl) -2-methoxycarbonyl-3-methoxyindole hydrochloride, mp 148-149 C. Example 5. 23.3 g of 2-methoxycarbonyl-3-acetoxy-indole, dissolved in dimethylformamide, respectively Example 2 is converted from 3 g of sodium hydroxide and then from 1-dimethylamino-chloroethane to 1- (1-dimethylaminoethyl) -2-methoxycarbonyl-3-acetoxyindole with mp 165-167 C. The product is dissolved in 150 mp of methanol, mix up With a solution of 10 g of sodium carbonate in 100 ml of water, the mixture is stirred for 1 hour at room temperature, the pH is then set to 8 with dilute hydrochloric acid, the solvent is distilled off and the residue is treated with a mixture of ethyl acetate / water. -2-methoxy-carbonyl-3-hydroxy-indole crystallizes as maleate from ethyl acetate / ether mixture, mp 156-158 C. The code is 26.8 g (71% of the theoretical). five
    权利要求:
    Claims (1)
    [1]
    A method of producing derivatives of N-aminoalkylindole of the general formula where R 1 is unsubstituted alkyl with
    1-4 carbon atoms or substituted by a phenyl radical, or an acetyl radical;
    R 2 is an alkoxycarbonyl group with 1-4 carbon atoms or cyan;
    A-C 2 -C 5 is an alkylene group;
    R 3 hR4 ~ identical or different and mean water. genus or alkyl with 1-4 carbon atoms, or alkylene groups, which together with the nitrogen atom form a cyclic group with 5-6 members in the chain;
    R g and R fc - are the same or different and mean hydrogen, a halogen alkyl or an alkoxy group with 1-3 carbon atoms or one of R 5 and R b means a nitro group, and the other hydrogen, or their salts, characterized in that common indole alkali metal salt
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    DK96884C|1959-09-14|1963-09-16|Dumex Ltd As|Process for the preparation of indole derivatives or their salts.|
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    TR199700334T1|1995-09-01|1997-08-21|Lilly Co Eli|Indolyl neuropeptide y receptor antagonists.|
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    SG183699A1|2007-08-10|2012-09-27|Lundbeck & Co As H|Heteroaryl amide analogues|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792931323|DE2931323A1|1979-08-02|1979-08-02|NEW N-AMINOALKYLINDOL DERIVATIVES AND THEIR SALTS|
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