• 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:
    A process for the preparation of indole derivatives of the general formula CHj-N -NHCOUHCORj RE where RI is hydrogen, 5-OXI-, 5- (C4-Mn) alkoxy, 7-C | -C |, -alkyl; Rj is hydrogen, C 4 -C alkyl; Rj is phenyl, 3-C;, - C |, alkoxyfesch, 4-C4-Cif-alkoxyphenyl, 4-halophenyl, thieyl; or addition salts thereof, characterized in that the indole derivative of the formula where R4 and R; have the indicated values, are reacted with a compound of the formula (L RjCOWHCONHa with where RJ has the indicated values, orbore rates during addition) inert solvent, and the target product is isolated in free form or in the form of an additive salt.
    公开号:SU1110380A3
    申请号:SU802862505
    申请日:1980-01-04
    公开日:1984-08-23
    发明作者:Лихеуп Арчибальд Джон；Джеймс Вард Теренс
    申请人:Джон Вайс Энд Бразер Лимитед (Фирма)；
    IPC主号:
    专利说明:

    1.2 f of product (67.5%) with m. pl. 231232 C. Found,%; C, 56.78; H 5.59; N 13.57. СGO HiiNi OiS НС1 Calculated,%: С 57.34; H 5.53; N 13.37. Example 4-. 1- (4-chlorobenzoyl) (INDOLIL-.3-methyl) -piperidyl-4-urea. A mixture of 1.5 g (6.5 mmol) of 4-amino-1- (indols-3-methyl) -piperidine, 1.0 g (5 mmol) of 4-chloro-benzoyl urea and 4 ml of piperidine is boiled for 3 h. The mixture is then poured into water and the precipitated product is collected by filtration, washed with water and dried to give the title compound as a free base. The base is then suspended in warm ethanol and acidified with an ethanolic solution of hydrogen chloride, resulting in a clear solution, which, on standing in an ice bath, absorbs crystals of 0.9 g (40.5%) of the hydrochloride of this compound, the crystallization of which methanol allows to obtain a product with so pl. 269-271 C. Found,%: C 58.74; H 5.65; N 12.68 Ssc.H.jClNiOa HC1 Calculated,%: C 59.07; H 5.18; N 12.52. Example 5. (Indolyl-3-methyl) piperidyl-4 -3- (4-and-propyl-x-enzo-Itl) -wheels on. A mixture of 0.58 g (2.5 mmol) of 4-amino-1- (HI-3-methyl) -piperidine, 0.58 g (2.5 mmol) of 4-n-propyloxybenzoyl urea and 5 ml of chlorobenzene is boiled at stirring under reflux for 2.5 hours. The solution is then cooled in an ice bath and the precipitated product is collected by filtration to give 0.95 g of the indicated compound as its free base. The suspension is suspended in a stanol (5 ml) and acidified by adding ethanolic solution of hydrogen chloride, with the result that when cooled, 0.9 g of hydrochloride precipitates. This product is recrystallized from a mixture of ethanol and methanol in a 1: 1 ratio (10 ml) to give 0.7 g (59.5%) of the indicated compound hydrochloride as its hydrate with m.p. 167-168C. Found,%: C 61.52; H 6.61; N 11.30Cjs HCl Calculated,%: C, 61.40; H 6.80; N 11.46 Example 6. 1- (4-Fluorobenzoyl-3- 1- (indoli L-3-methyl) -piperidyl-4-urea. Analogously to Example 4, but using 0.9 g (5 mmol) 4- instead of 4-chlorobenzoylurea instead of 4-chloroform urea, this compound is obtained in the form of a free base, which is then converted into hydrochloride to obtain 1.55 g (72%) of the product with mp, respectively, 210 and 260 C. Found: C, 61.40; , 70; N 12.95. Cga Hj, HCl. Calculated,%: C 61.32; H 5.61; N 13.00 Example 7. 1-beisoyl-3-l (2-methyl-indols-3-methyl a) percidyl-4-urea. 0.82 g (5 mmol) of benzoyl urea and 1.2 g (5 mmol) of 4-amino-1- (2-methylene-1-dolyl-3-methyl) -pip The idine is boiled under reflux in toluene as in Example 5, resulting in 1 g (53%) of the indicated compound to be obtained in the form of free hydration, mp 209-211 ° C. Found: C 71, 04; H 6.75; N 14.48 C2iHy, Nj, Oi,%: C 70.74; H 6.71; N 14.35 Example 8. 1-benzoyl-3-l- (5-oxoxylolyl) 3-methyl-piperidyl-4I-urea. 0.82 g (5 mmol) of benzoyl urea and 1.2 g (5 mmol) of 4-amino-1- (5-OXIIINDOLSH13-methyl) -piperidine are refluxed. in dioxane, as a result of which the said compound is obtained, which is further transformed into hydrochloride, 0.8 g (37%) of hydrochloride is obtained. T. pl. popuhydrate 200C. Found,%: C 60.24; H 6.10; N 12.70 CrgNgcy Oz HC1 1/2 HjO Calculated,%: C 60.34; H 4,984; N 12.7 Example 9. 3- (4-methoxy-isoyl) -1-1- (and scholyl-3-methyl) -piperidyl-41-urea. - 0.97 g (5 mmol) -4-methoxybenzoyloyl urea H 1.14 g (5 mmol) of 4-amino-1- (indolyl-3-methyl) -piperidine are boiled with xylene in reverse refrigerant until the indicated compound is formed. which is then converted into the hydrochloride (1.8 g, 81%) with so pl. 220-222 0. Found,%: C, 62.28; H 6.30; N 12.38 Cr H HM Calculated,%: C 62.37; H 6.14; N 12.65. Example 10. 3- (3-methoxy -benzoyl) -1-1-indol-3-methyl) -nperndyl-4-urea. 0.97 g (5 mmol) of 3-methoxybenzoyl urea and 1.14 g (5 mmol) of 4 amino-1- (indol-3-ylmethyl) -shocherdine are boiled in toluene, after which the resulting compound is transformed into hydrochloride. Obtain 1.7 g (71%) of product with so pl. 234-235 C. Found,%: C 62.55; H N 12.67, HCl Calculated,%: C 63.37; H 6.14; N 12.65 Assessment of pharmaceutical properties. Comparison of the pharmacological properties of the proposed compounds of formula (1) with the analogue of the structure - 1-tl (I ndonyl3-zhthyl) -piperdcl-4-13-bereoylmocochevII (compound (11) and the standard compound - il-praminine M- (3-dimethylaminopronyl) - iminodibenzylhydrochloride. The test results showed that 1- (1-indolyl-3-methyl) -piperi-dil-4 -3-6-benzoylurea compound (1) and compound (I) are effective inhibitors of the absorption of 5-oxitriptamine (5- NT), but mild inhibitors of norepinephrine absorption. However, in contrast to compound (11), (i) does not induce a marked depression of CNS when conducting animal studies or does not significantly reduce blood pressure in rats with Hypertension. In addition, compound (1) is not an antagonist of the post-characteristic 5-HT receptor when conducting experiments vitro Inhibition of norepinephrine and 5-hydroxytryptamine intake in brain sections The effect of test compounds on the absorption of norepinephrine nerves in sections of the cerebral system prepared from the brain of a crank was determined according to the method described by Snyder, Green and Hindley (1968). The effect of the tested compounds on the uptake of 5-hydroxy tryptamine was studied in a similar way, excluding that H-oxytryptamine was used instead of H-nor; phenaline. Curves of the relationship between concentration and reaction would be obtained for the substance under study and imipramine. The efficacy of each test compound was expressed in fractions of imipramine. The Tak) ratio of the efficacy of the implied compound is the ratio of the molar concentration of imipramine giving 50% inhibition of norepinephrine uptake (or 5-HT) to the molar concentration of the test substance giving 50% nngabination of noradrenalia absorption. The test results are summarized in the table below. Compounds are effective in inhibiting TopaiviH uptake of 5-hydroxytryptamine and are very weak inhibitors of uptake of noradrenal. Anti-hypertension activity is determined as follows. Female rats were brought to the hypertensive state by unilateral nephrectomy and implantation of s. tablets containing 30 mg of deoxycorticosterone acetate. Drinking water was replaced with a normal physiological solution lib lib during the first four weeks after preparation. Blood pressure stabilized after 6 minutes. The systolic pressure was measured indirectly before the dose of the test compound was administered, using the E and M pneumatic pulse converter and recording devices M X27. Groups of four rats received an oral dose of a suspension or solution of the test compound in a 0.5% solution of hydroxypropyl methylcellulose in 0.9% saline. Blood pressure was recorded after 2.6 and 24 hours, and the results, expressed as a percentage of the values obtained prior to dosing, were compared with the same results for a similar group of rats who received only the medium. The test results are presented in table 2. Compound (11) induces a marked decrease in blood pressure, but compound (I) does not show significant activity. In another method of determining antihypertensive activity, when conducting experiments on rats with increased blood pressure, compound (P) showed significant activity, while compound (1) showed moderate activity. Activity with CNS (effect on the behavior of mice). The test compounds were administered orally to three mice (CF-1, weight from 14 to 24 g) in the form of the following doses: 400,127, 40 and 12.7 mg / kg. The animals were monitored for two hours with the detection of signs of general stimulation during (i.e., monitored for reduced spontaneous activity, hyperactivity), with tactile stimulation by twitching), general depression (i.e., for decreased motor activity, reduced ducking) and autonomous activity (i.e., monitored miosis, midreasis, diarway). The results are presented in table. 3. Compound (11) showed signs of sedation at doses significantly lower than the doses of compound (1) / that required to induce a similar effect. Motor activity (the behavior of the experiment in experiments). The test compounds were injected intraperitoneally to mice (three, groups of four, of the dose) at time taken at 0. Seven minutes later, the animals were transferred to square boxes placed near the detector heads of equipment to keep track of the actographer. The activity of the tests was counted for a subsequent period of 20 ms. The results are presented in table. 4. Compound (11) caused a marked decrease in activity, while compound (1) had almost no effect on Antagonis with respect to 5-HT, in vitro experiments.
    At the concentration of compound (11), inddodar blocking of reactions to isolated ileum of rats with respect to 5-hydroxytrypta 1 «Inu. At the same concentration, compound (1) caused a relax preparation of the drug, but the reaction to the subsequent administration of the drug substance 5-HT was not affected.
    Thus, the compounds of the T1s (1) form have psychotropic activity, determined by inhibition of the absorption of 5-hydroxytryptamine in the brain, with significantly reduced hypotensive and anti-hypertensive activity compared with the known compounds.
    Table 1
    formulas
    2 6
    (11) 10
    24
    25
    2
    b
    24
    50
    2
    6
    24
    Table
    权利要求:
    Claims (1)
    [1]
    (E4) METHOD FOR PRODUCING INDOLE DERIVATIVES OR THEIR ADDITIVE SALTS.
    (57) A method for producing indole derivatives of the general formula * 1 ^ Y-NNSOINSO3 where Ri is hydrogen, 5-hydroxy, 5- (C <—Cz) -alkoxy, 7-C <-C4 (-alkyl;
    R 2 is hydrogen, C4-Cc alkyl;
    Rj is phenyl, 3-C ^ -Ci, alkoxyphenyl,
    4-C, <- Ci-alkoxyphenyl, 4-halo phenyl, thienyl; or their additive salts, characterized in that the indole derivative of the formula
    NR 2 Η where R <and R 2 have the indicated meanings, Q is reacted with a compound S of the formula
    RjCONHCONHg
    I where R 3 has the indicated meanings, if necessary in the presence of an inert solvent, and the target product is isolated in free form or in the form of an addition salt.
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    同族专利:
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    引用文献:
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    RU2500677C2|2008-02-22|2013-12-10|Грюненталь Гмбх|Substituted indole derivatives|GB1425354A|1973-10-10|1976-02-18|Wyeth John & Brother Ltd|Indole derivatives|
    US4061641A|1973-10-10|1977-12-06|John Wyeth & Brother Limited|Ureidopiperidino-ketoalkyl indoles|
    ZA76475B|1975-03-10|1977-08-31|Ciba Geigy Ag|Indolyalkylpiperidines|
    GB1494805A|1975-07-17|1977-12-14|Wyeth John & Brother Ltd|Indole derivatives|US4806552A|1980-03-01|1989-02-21|John Wyeth & Brother, Limited|Pyridyl- and/or pyridoyl- ureas and analogues thereof|
    PL135545B1|1980-03-01|1985-11-30|Wyeth John & Brother Ltd|Process for preparing novel derivatives of piperidine|
    US4722930A|1980-03-01|1988-02-02|John Wyeth And Brother Limited|3-benzoyl-1-[-piperid-4-yl]ureas and derivatives|
    US4808601A|1984-09-19|1989-02-28|Pfizer Inc.|Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds|
    US4752609A|1985-06-20|1988-06-21|Pfizer Inc.|Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds|
    GB8528234D0|1985-11-15|1985-12-18|Wyeth John & Brother Ltd|Heterocyclic compounds|
    EP1629841A1|2003-05-29|2006-03-01|Kyowa Medex Co., Ltd.|Antidepressants or food and drinks for antidepression|
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    法律状态:
    优先权:
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