• 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 invention relates to heterocyclic compounds, in particular to the preparation of isoindolinone derivatives @ where R 1 is 4-phenyl-1, 2, 3, 6-tetrahydro-1-pyridyl, or 4- (4-fluorophenyl) -1, 2, 3, 6-tetrahydro-1-pyridyl, or 4-phenyl-1-piperazinyl, the phenyl ring of which is substituted in position 4 by a halogen atom or a hydroxy group R 2 - C 1 - C 2 - CNS radical, or their salts, possessing the antigonistic properties of serotonin. The goal is to develop a method for producing compounds with a specified action. The preparation is carried out by alkylation of the corresponding isoindolinone derivative with an aliphatic alcohol of f-ly R 2 OH, where R 2 is indicated above, in the presence of an inorganic acid, followed by isolation of the desired product in free form or in the form of a salt.
    公开号:SU1660579A3
    申请号:SU894613666
    申请日:1989-03-07
    公开日:1991-06-30
    发明作者:Комт Мари-Терез；Гереми Клод；Понсине Жерар
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing new isoindolinone derivatives of the general formula O
    HR, where Ri is 4-phenyl-1,2,3,6-tetrahydro-1-pyridyl or 4- (4-fluorophenyl) -1,2,3,6-tetrahydro1-pyridyl or 4-phenyl-1- piperazinyl, the phenyl ring of which is substituted at position 4 by a halogen atom or an oxy group;
    Pr-Su-Cr-alkoxyl radical, or their salts, possessing the antagonistic properties of serotonin (receptors
    5HT 2 ).
    where Ri is 4-phenyl-1,2,3,6-tetrahydro-1-pyridyl or 4- (4-fluorophenyl) -1,2,3,6-tetrahydro1-pyridyl or 4-phenyl-1-piperazinyl, the phenyl ring of which is substituted at position 4 by a halogen atom or an oxy group; P2 ~ C1 ~ C2-alkoxyl radical, or their salts, possessing antagonistic properties of serotonin. The goal is to develop a method for producing compounds having the indicated action. The preparation is carried out by alkylation of the corresponding isoindolinone derivative with an aliphatic alcohol of the form R2OH, where R2 is indicated above, in the presence of an inorganic acid, followed by isolation of the desired product in free form or in the form of a salt. 1 tab.
    The purpose of the invention is the development on the basis of well-known techniques of a method for producing new derivatives of isoindolinone with valuable pharmacological properties.
    For example. To a stirred * solution of 5.7 g of 2- {3- [4- (4-fluoro-phenyl) -1,2,3,6tetrahydro-1-pyridyl2-propyl} -Z-hydroxy-1isoindolinone in 145 cm 3 '. '· Methanol is added at a temperature of about 20 ° C for 10 min 28.5 CM d ; concentrated sulfuric acid. Stirring is continued for 5 hours at a temperature of about 65 ° C. After cooling the solution to a temperature of about 0 ° C, add over! h 70 · cm 3 aqueous 33% aqueous solution of ammonium hydroxide. The precipitate formed is filtered off and washed with 50
    SU. „, 1660579 AZ
    Q about cm methanol. The filtrate is diluted with 200 cm of distilled water and 50 cm 3 of an aqueous 33% solution of ammonium hydroxide and extracted 3 times with 200 cm 3 of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg,
    2.7 kPa) at 40 ° C. The resulting residue was dissolved in 10 cm 3 of methylene chloride and the solution was poured onto 550 g of silicon dioxide contained in an 8 cm diameter column. Elute with a mixture of methylene chloride and methanol (90:10 by volume), the first 900 cm 3 were removed and the next 200 cm 3 were evaporated to dryness at reduced pressure (50 mm RT. Art., 2.7 kPa) at 50 ° C. The resulting residue was dissolved in 10 cm 3 of methyl ethyl ketone. A solution of 0.6 g of oxalic acid in 5 cm3 of methsethyl ketone is added and stirring is continued for 1 h at a temperature of about 20 ° C. The precipitate formed is filtered off. Thus, 2.4 g of Z-methoxy-2 oxalate} 3- | 4- (4-fluoro-phenyl) -1,2,3,6-tetrahydro-1-pyr and d and l J are obtained at once about p and lu - G- isoindolino-. on, melting at 139 ° C.
    Example 2. The process is carried out as in example 1 based on a stirred solution of 6.8 g of 2- ^ 3- [4- (4-fluoro-phenyl) -1-piperazinyl} -propyl} -Z-hydroxy-1-isoindolinone in 170 cm 3 of methanol, to which 33.5 cm 3 of concentrated, sulfuric acid is added at a temperature of about 20 ° C over 15 minutes. Stirring is continued for 5 hours at a temperature of about 65 ° C. After cooling the solution to a temperature of about 0 ° C. over 1 h, 83 cm 3 of an aqueous 33% solution of ammonium hydrate are added. The precipitate formed is filtered off and washed with 50 cm 3 of methanol. The filtrate is diluted with 200 cm 3 of distilled water and 50 cm 3 of an aqueous 33% solution of ammonium oxide hydrate and extracted 3 times with 200 cm 3 of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 40 ° C. The resulting residue was dissolved in 20 cm 3 of methylene chloride and the solution was poured onto 50 g of silica contained in a column with a diameter of 8 cm. Elute with a mixture of methylene chloride and methanol (99: 1 by volume). The first 300 cm j are removed and the next 3500 cm 3 are evaporated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 50 ° C. The resulting residue was dissolved in 50 cm 3 of acetonitrile. A solution of 1.1 g of oxalic acid in cm 3 of acetonitrile is added and stirring is continued for 1 h at a temperature of about 20 ° C. The precipitate formed is filtered off. Thus, 4.1 g of 3-methoxy-2- {3-G4- (4-fluorophenyl) -1-piperazinyl} propyl} -1-isoindolinone oxalate melting at 177 ° C. are obtained.
    Example 3. The process is carried out as in example 1 based on a stirred solution of 4.8 g of 2- {3- [4- (4-chlorophenyl) -1-piperazinyl} propyl} 3-hydroxy-1-isoindolinone in 115 cm 3 methanol, to which 22.6 cm 3 of concentrated sulfuric acid is added at a temperature of about 20 ° C over 10 minutes. Stirring is continued for 5 hours at a temperature of about 65 ° C. After cooling the solution to a temperature of about 0 ° C, 55 cm 3 of an aqueous 33% ammonium hydroxide solution are added over 1 hour. The precipitate formed is filtered off and washed with 50 cm 3 of methanol. The filtrate is diluted with 200 cm 3 of distilled water and 50 cm 3 of an aqueous 33% solution of ammonium hydroxide and extracted 3 times with 200 cm 3 of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 40 ° C. The resulting residue was dissolved in 20 cm 3 of methylene chloride and the solution was poured onto 500 g of silicon dioxide contained in a column with a diameter of 8 cm. · Elute with a mixture of methylene chloride and methanol (98.5: 1.5 by volume). The first 100 cm 3 are removed and the next 630 cm 3 are evaporated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 50 ° C. The resulting residue was dissolved in 30 cm 3 of acetonitrile; A solution of 0.63 g of oxalic acid in 15 cm 3 of acetonitrile is added and stirring is continued for 1 h at a temperature of about 20 ° C. The precipitate formed is separated by filtration. Thus, 2.9 g of 3-methoxy-2-} 3- [4- (4-chlorophenyl) -1-piperazinyl} propyl} -1-isoindolinone oxalate melting at 200 ° C. are obtained.
    Example 4. The process is carried out as in example 1 based on a stirred solution of 7 g of 2- [3- (4-phenyl-1,2,3,6-tetrahydro1 - pyridyl) -prop and l £ -3-hydroxy- 1-isoindolinone in 265 cm 3 of ethanol, to which 37 cm 3 of concentrated sulfuric acid is added at a temperature of about 20 ° C over 15 minutes. Stirring is continued for 4 hours at a temperature of about 65 ° C. After cooling the solution to a temperature of about 0 ° C, 90 cm 3 of an aqueous 33% ammonium hydroxide solution are added over 1 hour. The precipitate formed is filtered off, washed with 50 cm 3 of methanol. The filtrate is diluted with 200 cm 3 of distilled water and 70 cm 3 of aqueous 33% ammonia solution and extracted 3 times with 250 cm 3 of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm RT. Art., 2.7 kPa) at 40 ° C. The resulting residue was dissolved in 30 cm 3 of methylene chloride and the solution was poured onto 500 g of silica contained in a column with a diameter of 8 cm. Elute with a mixture of methylene chloride and methanol (95: 5 by volume). The first 100 cm 3 are removed, the next 900 cm 3 are evaporated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 50 ° C. The resulting residue was dissolved in 50 cm 3 of methyl ethyl ketone. A solution of 2.2 g of oxalic acid in 20 cm 3 of methyl ethyl ketone is added and stirring is continued for 1 h at a temperature of about 20 ° C. The precipitate formed is filtered off. Thus, 4.9 g of 3-ethoxy-2-C3- (4-phenyl-1,2,3,6-tetrahydro-1-pyridyl) -propyl] -1-isoindoleinone oxalate, melting at 150 ° C, are obtained.
    Example 5. The process is carried out as in example 1 based on a stirred solution of 4.6 g of 3-hydroxy-2-p- [4- (4-hydroxyphenyl) -1 piperazinyl] propyl ^ -1-isoindole and nona in 115 cm 3 of methanol to which 22.7 cm 3 of concentrated sulfuric acid is added at a temperature of about 20 ° C over 15 minutes. Stirring is continued for 5 hours at a temperature of about 65 ° C. After cooling the solution to: a temperature of about 0 ° C. over 1 h, add 57 cm 3 of an aqueous 33% solution of ammonium hydroxide. The precipitate formed is filtered off and washed with 50 cm 3 of methanol. The filtrate is diluted with 200 cm 3 of distilled water and 50 cm 3 of an aqueous 33% solution of ammonium hydroxide and extracted 4 times with 100 cm 3 of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm Hg, Art., 2.7 kPa) at 40 ° C. The resulting residue was dissolved in 20 cm 3 of methylene chloride and the solution was poured onto 500 g of silica contained in a 6 cm diameter column. Elute with a mixture of methylene chloride and methanol (97: 3 by volume). The first 800 cm 3 are removed and the next 3000 cm 3 are evaporated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 50 ° C. The resulting residue was dissolved in 35 cm 3 of methyl ethyl ketone. A solution of 0.8 g of oxalic acid in 20 cm 3 of methyl ethyl ketone is added and stirring is continued for 1 h at a temperature of about 20 ° C. The precipitate formed is filtered off and recrystallized from 200 cm 3 of boiling acetonitrile. Thus, 1.4 g of 3-methoxy-2-f 3- (4- (4-hydroxyphenyl) -1-piperazine yl] propyl! -1-isoindolinone melting at 147 ° C. are obtained.
    Example 6. The process is carried out as in example 1 based on the corresponding compounds of formula (I). Get 3-methoxy-2 [3- (4-phenyl-1,2,3,6-tetrahydro-1-pyridyl) phenyl] -1-isoindolinone, so pl. 160 ° C.
    Compounds I possess the antagonistic properties of serotonin (5HTg receptors) and are therefore suitable for the treatment of diseases in which serotonin is involved, especially diseases of the central nervous system, cardiovascular system and gastrointestinal disorders.
    The affinity of the compounds of formula (I) for the central receptor sites with serotonin (type S 2 ) is determined according to the method, which consists in measuring the affinity of the products for the binding sites of tritium-containing ketanserin. In this test, the CI50 of the compounds of formula (1) is below 10 nM.
    The compounds of formula (I) are also antagonists of head tremors caused by mouse mescaline. In this test, the ED50 of the compounds of formula (I), administered orally, is below 5 mg / kg.
    In addition, the compounds of formula (I) have low toxicity. Their LD50 is usually higher than 100 mg / kg orally in mice with a single dose.
    Pharmacological tests.
    1. In vitro affinity test for receptor sites containing serotonin (type 5HT 2 ).
    The experience consists in measuring the affinity of the investigated product to the sites of communication of tritium-containing ketanserin.
    The experiment is as follows: the washed homogenate of the cerebral cortex of a male rat is mixed with a final concentration of 0.15 mg / prot. / Ml in Tris-HCI buffer, 50 mM, pH 7.6, the product under study with various concentrations and tritium-containing ketanserin (final concentration 0 4 nM). Nonspecific fixation is determined in the presence of metisergide (final concentration 1 mM).
    After 15 min incubation at 37 ° C, each sample was filtered on a Whatman gF / B glass fiber filter and the radioactivity retained on the filter was measured by liquid scintillation. Field 7 takes into account the value of CJso, i.e., the concentration of the test product, which inhibits 50% of specific ligand fixation.
    2. In vivo test for antagonism of head tremor induced by mescaline.
    Use mice weighing 20-24 g.
    Mice receive an intraperitoneally administered dose of 50 mg / kg of mescaline (a single dose contained in 50 mg of solution per 1 kg of mice). The studied products are administered orally for 45 minutes or 1 hour 30 minutes before the introduction of mescaline, and single doses are contained in a volume of 25 ml per 1 kg of mice.
    Use 6 mice per dose.
    After injection of mescaline, the mice are placed in a chamber divided into 12 cells, a side length of 13 cm, so that each mouse is isolated for the examination period. These chambers are covered with a transparent plastic plate.
    All control mice treated with mescaline at a dose of 50 mg / kg, administered intraperitoneally after 15 minutes after administration, showed sharp jerking of the head, which lasted for 2 min.
    Mice are considered to be protected from head tremor induced by mescaline if no head tremor is observed for a period of 2 minutes.
    The dose of DABO product is the dose at which 50% of the animals are protected (the criterion for protecting the mouse is the absence of twitching, trembling of the head).
    The research results are shown in the table for comparison, the compound 2- | 3- [4- (4-chlorophenyl) -1-piperazinyl ^ propyl} -phthalimide was used).
    Known compound 2- {3- | ^ 4- (4-chlorophenyl) -1-piperazinyl] propyl | -phthalimide <
    studied only in the test for the affinity for serotonin-containing central receptors (test with ketanserin).
    The test results show that the effect of the compound according to the invention is 3-30 times higher compared to the known product.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives of isoindolinone of the General formula
    Oh r 2 where Ri is 4-phenyl-1,2,3,6-tetrahydro-1-pyridyl or 4- {4-fluorophenyl) -1,2,3,6-tetrahydro1-pyridyl, or 4-phenyl- 1-piperazinyl, the phenyl ring of which is substituted at position 4 by a halogen atom or an oxy group;
    Ri-C1-C2-alkoxyl radical, silt and their salts, characterized in that the isoindolinone derivative of the general formula wherein Ri has the indicated meanings, is subjected to alkylation with an aliphatic alcohol of the general formula R2OH, where R2 has the indicated meanings, in the presence of an inorganic acid followed by the selection of the target product in free form or in the form of salt.
    t
    Compound C <nM ketanserin YES G , bp mg / kg, shaking head DL "bp mg / kg mouse Example 1 1,0 1,0 100/300 2 2,3 1,0 100/300 3 6.0 1.7 > 300 4 9.0 le 100/300 5 8.2 2,5 > 300 6 2,8 0.3 ί 300 2 - {s- [4- (4- - - - Chlorophenyl) - 1-piperazinyl] -cut-ft limid thirty
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    同族专利:
    公开号 | 公开日
    NO890969L|1989-09-11|
    FR2628425A1|1989-09-15|
    AU619807B2|1992-02-06|
    AU3102089A|1989-09-14|
    DK106989D0|1989-03-06|
    OA09238A|1992-06-30|
    MA21504A1|1989-10-01|
    MX15184A|1993-10-01|
    FI891073A0|1989-03-07|
    JPH0272158A|1990-03-12|
    HUT51268A|1990-04-28|
    PT89947A|1989-11-10|
    EP0332528A1|1989-09-13|
    KR890014520A|1989-10-24|
    FI891073A|1989-09-09|
    NZ228222A|1991-01-29|
    HU202227B|1991-02-28|
    NO890969D0|1989-03-07|
    US4999355A|1991-03-12|
    IL89517D0|1989-09-10|
    FR2628425B1|1992-04-03|
    SU1739845A3|1992-06-07|
    DK106989A|1989-09-09|
    ZA891694B|1989-11-29|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8802918A|FR2628425B1|1988-03-08|1988-03-08|ISOINDOLINONE DERIVATIVES, THEIR PREPARATION METHODS AND THE MEDICINAL PRODUCTS CONTAINING THEM|
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