• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    The present invention provides (S)-norfluoxetine, pharmaceutically acceptable salts and solvates thereof capable of inhibiting the uptake of serotonin.
    公开号:SU1750417A3
    申请号:SU894742384
    申请日:1989-11-09
    公开日:1992-07-23
    发明作者:Вард Фуллер Рэй；Вэйн Робертсон Дэвид；Тайвай Вонг Дэвид
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing (S) -norfluoxetine, or its pharmaceutically acceptable salts, or their hydrates - new biologically active compounds that may find application in medicine.
    Known norfluoxetine [3 - (4trifluoromethylphenoxy) -3 'phenylpropylamine ^, which is a means of blocking monoamine, in particular serotonin. Norfluoxetine is a racemate. However, it was found that the activity of the (S) enantiomer of norfluoxetine significantly exceeds the activity of the (R) enantiomer.
    The purpose of the invention is a method for producing new derivatives of norfluoxetine with higher biological activity.
    The goal is achieved by the described method for producing (S) norfluoxetine of the formula
    GI 0- © -CF, ζΤ '- ^ -' ΝΗζ
    1750417 AZ
    Τ 750417 or its pharmaceutically acceptable salts or hydrates thereof, which consists in the fact that (S) -3-amino-1-phenyl1-propanol of the formula
    Η ΌΗ
    J · nh 2 is treated with a bimolar sodium hydride, then the sunken anion is subjected to a quantitative .., ____ interaction with a 4-substituted benzotrifluoride of the formula
    where X is a leaving group, when heated, the desired product is isolated in the form of a base, or, if necessary, a pharmaceutically acceptable salt thereof or its hydrate is obtained.
    . PRI me R 1. A. Obtaining (S) -3 “phthalimido-1-phenylpropanol.
    To a solution of 470 mg of (3) - / - / ~ 3-chloro-4-phenylpropanol in 4 ml of dimethylformamide was added 612 mg of potassium phthalamide . The resulting mixture was heated for 6 hours at 100 ° C, then cooled to room temperature and stirred overnight. The mixture was filtered, the filtrate was diluted with water, and the solution was extracted with ethyl acetate. The organic layer is washed once with water, once with 0.2 N sodium hydroxide, then again once with water and once with a saturated solution of sodium chloride, after which it is dried over sodium sulfate and concentrated in vacuo to obtain an opaque oil, which is then solidified. After crystallization from ethyl acetate / hexane 350 mp of the desired intermediate compound in the form of a white powder, the melting point of CO is 82.5 C.
    Analysis for C ^ H ^ MEs.
    Calculated: · C 72.58; H 5.38;
    N 4.9 8.
    I
    Found: C, 72.57; H 5.40; N, 4.96.
    B. Preparation of (S) -3 ~ amino-1-phenyl1-propanol.
    To a solution of 4.046 g of (5) -3-phthalimido-1-phenyl-1-propanol in 100 ml of ethanol was added 2.5 ml of anhydrous hydrazine. The mixture was heated in a flask with a reflux condenser in a nitrogen atmosphere for 3.5 h, cooled to room temperature and stirred overnight. The resulting precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The resulting oily substance is treated with diethyl ether I and 25 ml of 5 N sodium hydroxide. After which the layers are separated, and organic. the layer is dried over sodium sulfate and concentrated in vacuo, resulting in 1.92 g of opaque; oil. 200 mg of this oil is treated with oxalic acid in ethyl acetate and crystallized from ethyl acetate (methanol to obtain 210 mg of the desired intermediate compound as an oxalate salt, melting point 161 - 162 ° C.
    Analysis of oxalate salt StsN 15 -K0 5 . Calculated: C 54.77; H b, 27;
    . N 5.81 '
    Found: C 54.96; H, 6.15; N .5.73. C. Preparation of (S) -norfluoxetine. To a suspension of 484 mg of 60% sodium hydride in oil in 10 ml of dimethylacetamide is added. 1.74 g of (S) -3-amino-1I phenyl-1-propanol in 40 ml of dimethylacetamide. The resulting mixture was heated for 10 min at 70 ° C. Then, 4-fluorobenzotrifluoride (1.54 ml) and a solution were added to the reaction mixture; heated for 3 hours at 100 ° C.
    This mixture was poured into ice water and extracted with diethyl ether. The organic extract is washed three times with water, once with saturated sodium chloride solution I, dried over sodium sulfate and concentrated in vacuo, to give 2.96 g of a yellow oily substance. The resulting material was purified by high pressure liquid chromatography on silica gel using a gradient elution technique with a mixture of methylene chloride - 10% methanol in methylene chloride, to which was added ( Ut 0.5% ammonium hydroxide. The desired fractions were combined and concentrated in vacuo, in 5 g of the expected product is obtained in the form of an amber oil.The residue is dissolved in ethyl acetate and then a solution of 451 g of shavelic acid in ethyl acetate is added.The resulting precipitate is crystallized from ethyl acetate / methanol to give 1.67 g of the desired product are obtained in the form of salt of oxalate, melting point 148 - 150 C. In the same way, (S) -norfluoxetine-hydrochloride is obtained, melting point 128 - 130 ° C, (S) -norfluoxetine fumarate (melting point 156 157 ° C) and hemi-hydrogenated (S) -norfluoxetine maleate (melting point 9 ^ “9b ° C) (in this case, the reaction between the acid and the free base is carried out not in ethyl acetate, but in diethyl ether, and the resulting product is crystallized from the reaction · Mixture upon cooling.
    Analysis for C ^ gH (6 F 3 NO · HC1 C (S) ~ norfluoxetine hydrochloride).
    Calculated: C 57.93; H 5.17; N, 4.22. .
    Found: C 57.86; H 4.94; N, 4.15. Analysis for C 2o H Zo I ' 3 N0 5 - ((8) -Norfluoxetine Fumarate).
    Calculated :. C, 58.39; H 4.90;
    N, 3.41.
    Found: C, 58.63; H 4.90; N, 3.57. · 25 Analysis for 0 2o H 2o F ^ NO 5 '(hemi-hydrogenated (c) -norfluosetine maleate, but in dried form).
    Calculated: C 58.39; H 4.90;
    N 3.41
    Found: C, 58.18; H 4.76; N, 3.50.
    The indicated hemihydrate was crystallized from diethyl ether and a water content of 2.2% was found by thermogravimetric analysis carried out before drying.
    Crystallization of (S) norfluoxetine maleate hemihydrate from water leads to the formation of a crystalline (S) -norfluoxetine maleate hydrate (1: 1), melting point 97 ~ 101 ° C, which, as calculated by thermogravimetric analysis, has 3.6% water.
    Drying for ί h in a vacuum oven at 45 ° C gives anhydrous (S) -norfluoxetine maleate (melting point
    - У7 ° С), which contains, in accordance with thermographic analysis, water in an amount of 0.02%.,
    In accordance with these procedures, (R) -. (+) - 3-xnopo1-phenyl-1-propanol and (R) -norfluoxetine are obtained. Maleate (salt.) (SJ-norfluoxetine has a melting point of 95 -
    FROM.
    (S) -Norfluoxetine and its pharmaceutically acceptable salts and solvates are used to inhibit the absorption of serotonin. Therefore, another embodiment of the invention is a $ method of inhibiting the absorption of serotonin in mammals, which is the introduction of mammals requiring increased nonirotra! emissions of serotonin, a pharmaceutically effective amount of (S) -norfluoxetine, or a pharmaceutically acceptable salt thereof.
    The term “pharmaceutically effective amount” means an amount of (8) -norfluoxetine capable of inhibiting the uptake of serotonin. The specific dose of the administered compound of the invention is determined in accordance with the conditions of each particular case, including the route of administration. Щ) -norfluoxetine can be introduced in various ways, namely: by oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or nasal administration. The usual daily dose is about 0.01 mg / kg of 20 mg / kg of (S) -norfluoxetine. The preferred daily dose is about 0.05 ".10 mg / kg, and the most preferred is about 0.1 -. 5 mg / kg.
    (S) -Norfluoxetine 35 is intended for the treatment of various diseases associated with dysfunction of the serotonergic system, such as obesity, bulimia, obsessive syndrome, depression, alcoholism, pain, 40 premenstrual syndrome, memory loss, anxiety, smoking, insomnia and migraine. The compound of the invention can be used to increase the rate of recanalization after thrombolytic or angioplastic therapy or to prevent restenosis or vasospasm after thrombolytic or angioplastic therapy. (S) -Norfluoxetine also has a small effect on metabolism when administered simultaneously with drugs, such as barbiturates or tricyclic antidepressants, unlike fluoxetine. (S) -Norfluoxetine is relatively non-toxic and has an excellent therapeutic index.
    The following is an experiment conducted to demonstrate the ability of (s) -norfluoxstin to inhibit serotonin uptake in mammals.
    The following is an experiment conducted to demonstrate the ability of (S) -norfluoxetine to inhibit ~ absorption of serotonin compared to its related enantiomer, racemate, or comparable analogues. The experimental procedure was proposed by Wong etai.
    Three days before the study, male Sprague Dawley rats (110-150 g) from Harlan Industries (Cumberland, IN) were fed Rurina Chow, if desired, and then rats were decanted. The whole brain was removed and opened. The cerebral cortex was homogenized in 9 volumes of medium containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal preparations were isolated after differential centrifugation at 1000 g for 10 minutes and 17000 g for 28 minutes. The precipitate was suspended in the same medium and kept in ice until the day of its use.
    The synaptosomal uptake of ^ H-serotonin Pn ~ 5 ~ hydroxytryptamine, ^ H-5HT) was determined as follows.
    Cortical synaptosomes (equivalent to 1 mg protein) were incubated at 37 ° C for 5 min in 1 ml of Krebs bicarbonate medium containing 10 mM glucose, 0.1 mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50 nM E H-5NT. Then the reaction mixture was immediately diluted with 2 ml of ice-cold Krebs bicarbonate buffer, and the cells were collected by vacuum filtration (using Brandel Caitherburg, MD). The filters were washed twice with approximately 5 ml of ice-cold 0.9% saline, and then transferred to a counter containing 10 ml of scintillation fluid (PCS, Amers ham, Arlington Heights IL). Radioactivity was measured using liquid scintillation spectrophotometry. Background values representing the accumulation of ^ H ~ 5HT at 4 ° C were subtracted from all samples.
    compounds obtained from two experiments, where it contains the estimated second column — concentration. The table shows the results of the evaluation of (S) -norfluoxetine and related compounds through the first column of compounds, the traction of the test compound at 10 ~ e M / nM, necessary for 50% inhibition the absorption of serotonin (5HT), which is indicated in the table as: In the first experiment, we used the older artifact of 5HT labeled with tritium, while in the second experiment a new batch H-5NT.
    It can be seen from the table that (S) -norfluoxetine has a higher activity in inhibiting the absorption of serotonin than the known analog compounds: (R, S) -norfluoxetine, (R) -norfluoxetine and (R, S), (R) , ^ -fluoxetines.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining (S) -norfluoxetine of the formula
    ABOUT
    CF 3
    I or its pharmaceutically acceptable salts or hydrates thereof, characterized in that (S) 73 is aMHno-1-phenyl-1-propanol of the formula
    ОН .ННн 2 is treated with a two-molar amount of sodium hydride, then the formed anion is reacted with 4 substituted benzotrifluoride of the formula '
    CF 3
    X is a leaving group, heating and the target is isolated where, when the product is in the form of a base, or, if necessary, its pharmaceutically acceptable salt or its hydrate is obtained.
    9 1750417
    Compound 6 NT ic ^ Chm) Experiment 1 Experiment 2 (R.S) -norfluox-tin 202 55, 8 (R) -norfluoxetine 1051 484.1 (S) - norfluoxetine 69 29.8 (R. S) -fluoxetine 79 34,4 (R) -fluoxetine ί27 39.7 (S) -fluoxetine 93 25.0
    - Compiled by V. Volkova a Editor N. Khimchuk Tehred M. Morgenthal Corrector M, Keretsman Order 2606 Circulation Subscribed VNIIIPI State113035, Committee for Inventions and Discoveries at the State Committee for Science and Technology of the USSR Moscow, Zh-35, Raushskaya nab., 4/5
    Production and Publishing Plant Patent, Uzhgorod, st. Gagarina, 101
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    法律状态:
    优先权:
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