• 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:
    Compounds of formula <CHEM> (wherein R, R1, R2, R3 and n have the meanings reported in the specification), their salts with pharmaceutically acceptable acids, process for their preparation and pharmaceutical compositions containing them are described. The compounds of formula I have a remarkable analgesic activity.
    公开号:SU1727531A3
    申请号:SU894614156
    申请日:1989-05-19
    公开日:1992-04-15
    发明作者:Карензи Анджело；Чиарино Дарио；Делла Белла Давиде；Карло Гранчини Джан；Венециани Карло
    申请人:Дзамбон Груп С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    -2- (2R, 2 P) -divor. Butylamino-ethanol (compound 1).
    A solution of 9.5 g (0.03774 mol) of (5.2 P) -1- (2-chlorophenyl) methyl-5-oxiranyl-2-pyrrole dinone and 6.34 g (0.04906 mol) (P, P -divor.butylamine in 19.5 ml of n-butanol is maintained at reflux for 70 hours. After evaporation of the solvent, the residue is dissolved in 50 ml of cooled 5% hydrochloric acid and subjected to extraction treatment with 2x50 ml diethyl ether. The aqueous phase is alkalinized by the addition of potassium carbonate and extracted with diethyl ether, then the extract is washed with water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel using a mixture of chloroform and 1N methanolic ammonia solution in a ratio of 93: 2 as eluent, resulting in a yield of 7.2 g (50% yield) of compound 1. Melting point 71-73 ° C (n.hexane), -6.4.6 ° (with 1%, methanol).
    The absolute configuration is refined during X-ray analysis.
    Compound 1 is obtained in a similar way using dioxane or toluene instead of N. butanol,
    The following compounds are prepared analogously:
    (1P) -1- (53) -1- (2-chlorophenyl) -methyl -2-о-ксо-5-pyrrolidinyl -2- (2Р, 2 Р) -divor.butylamino-ethanol (compound 2) , melting point 9b-98 ° C (n.hexane), 73% yield, and about 20 + 20.0 ° (with 1%, methanol);
    (13) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl-2- (2P, 2UR) -div.-butyl but-ethanol (compound 3), melting point 58-60 ° C (n Hexane), 66% yield, -47.9 ° (m, 1% methanol);
    (1P) -1- (5P) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl} -2- (2P, 2 P} -divor.butylamino-ethanol (compound 4), melting point 59-61 ° C (n.hexane), 40% yield, -27.8 ° (with 1%, methanol);
    (1P) -H (53) -1- (2-chlorophenyl) -methyl -2-ox-with-5-pyrrolidinyl -2- (23.23) -divor. But-thylamino-ethanol (compound 5), temperature melting 58-60 ° C (n.hexane), 70% yield, and L20 + 49.0 ° (with 1%, methanol);
    (13)) - 1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (23.2, 3) -divor. butylamino-ethanol (compound 6), melting point 64-65 ° C (n.hexane), 56% yield, + 24.8 ° (with 1%, methanol);
    (1P)) - 1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2,3) -divor. butylamino-ethanol (compound 7), melting point 63-70 ° C (N. Hexane), 70% yield, + 16.5 ° (with 1%, methanol);
    (13) -1- (5P) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2 P) -div-tor. Butylamino-ethanol (compound 8), oil-like product, 80% yield, -27.1 ° (with 1%, methanol);
    (13) -1- (5P) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (23.2,3) -divor. butylamino-ethanol (compound 9), melting point 96-99 ° C (n.hexane), 6% yield, + 18.4 ° (with 1%, methanol);
    (15) -1- (5H) -1- (2-chlorophenyl) -methyl -2-oxo-b-pyrolidinyl - P3 divtor.b- utilamino-ethanol (compound 10), melting point (N. hexane), 68% yield, -15.0 ° (with 1%, methanol);
    (1H) -1- (5P) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (25.25) -divor. butylamino-ethanol (compound 11), melting point 72-73 ° C (N. Hexane), yield 45%, + 65.8 ° (with 1%, methanol);
    (1H) -1- (5H) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 25) -divor. butylamino-ethanol (compound 12), butter-like product, 70% yield, and o20 + 25.8 ° (with 1%, methanol); (1 P) -1- (55) -2-oxo-1- (phenylmethyl) -5-pyrrolidinyl -2- (2P, 2 P) -divator. Butyl - mino-ethanol (compound 13), melting point 103- 104 ° C (isopropyl ether), 73% yield, -15.3 ° (with 1%, methanol);
    (13) -1- (55) -2-oxo-1- (phenylmethyl) -5-pyrrolidinyl -2- (2P, 2 P) -divator. Butyl amino-ethanol (compound 14), melting point 53- 55 ° C (n.hexane), 51% yield, "L20 - -57.6 ° (with 2%, ethanol);
    (1P) -1- (55) -1- (2-fluorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2 P) divider. butylamino-ethanol (compound 15), melting point 115-116 ° C (isopropyl ether), 72% yield, -20.8 ° (with 1%, methanol);
    (15) -1- (53) -1- (2-fluorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2 P) divider. butylamino-ethanol (compound 16), melting point 50-52 ° C (n.hexane), 40% yield, -53.9 ° (with 2%, ethanol);
    (1 P) AND- (5S) -1- (3-methoxyphenyl) -methyl 2-oxo-5-pyrrolidinyl -2- (2P, 2 P) divider.
    butylamino-ethanol (compound 17), melting point 74-76 ° C (n.hexane), 60% yield, -9.3 ° (with 1%, methanol);
    (15)) - 1- 3-methoxyphenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2P) -divor. butylamino-ethanol (compound 18), an oil-like product, 70% yield, and 20 -51.1 ° (with 1%, methanol);
    (1P) -1- (55) -1- (3,4-dichlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2P) -divator. Butylamino-ethanol (compound 19), temperature melting 116-117 ° C (isoprolyl ether), 69% yield, -10.0 ° (with 2%, methanol);
    (13) -1- (55) -1- (3,4-dichlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (2P, 2 P} -divor, butylamino-ethanol (compound 29), oil-like product, 59% yield, a Dza -48.9 ° (s - 2%, ethanol);
    (1P) -1- (53) -1- (3-bromo-5-isoxazolylmethyl) -2-oxo-5-pyrrolidinyl -2- (2P, 2 P) -di or sec-butylamino-ethanol (compound 21 ), melting point 111-112.5 ° C (isopropyl ether), 55% yield, -42.2 ° (with 1%, methanol);
    (1) -1- (55) -1- (3-bromo-5-isoxazolylmethyl) -2-oxo-5-pyrrolidinyl -2- (2P, 2 P) -div-tor. Butylamino-ethanol (compound 22), butter-like product, 58% yield, -46.1 ° (with 1%, methanol);
    (1P) -1- (55) -2-oxo-1- (3-trifluoromethyl-phenyl) -methyl-5-pyrrolidinyl -2- (2P, 2P) -div.butylamino-ethanol (compound 23), temperature melting 86.5-87.5 ° C (isopropyl ether), 77% yield, -26.4 ° (with 1%, methanol);
    (15) -1- (55) -2-oxo-1- (3-trifluoromethyl-phenyl) -methyl-5-pyrrolidinyl -2- (2P, 2 P) -di-sec. Butyl amine o-ethanol (compound 24), butter-like product, 54% yield, -50.6 ° (with 1%, methanol);
    (1P) -1- (55) -1- (4-bromophenyl) -methyl 2-oxo-5-pyrrolidinyl -2- (2P, 2 P) -divor.b- utilamino-ethanol (compound 25), oil similar product, 81% yield,. -10.2 ° (with 1%, methanol);
    (15) -1- (55) -1- (4-bromophenyl) -methyl 2-oxo-5-pyrrolidinyl -2- (2P, 2 P) divalent. B - utamino-ethanol (compound 26), melting point 132-133 ° C (isopropyl ether), 55% yield, -53.6 ° (with 1%, methanol);
    (1 P) -1- (5) -1- (diphenylmethyl) -2-oxo-5-p-yrrolidinyl -2- (2P, 2 P) -divator. Butyls but-ethanol (compound 27), amorphous solid , 71% yield, or 20 75.4 ° (with 1%, methanol);
    (15) -1- (55) -1- (diphenylmethyl) -2-oxo-5-pyrrolidinyl -2- (2P, 2 P) -divator. Butyl foreign ethanol (compound 28), melting point 84-85 ° (isopropyl ether), yield 39.4%;
    (1 R) -1 - (55) -2-oxo-1 - {2-thienylmethyl) -5pyrrolidinyl} -2- (2P, 2 P) -divator. Butyl-yno-ethanol (compound 29), melting point 78 -79 ° С (n.hexane), yield 74.3%, «L20 -19.2 ° (with 1%, methanol);
    (15) -1- (55) -2-oxo-1- {2-thienylmethyl 5-pyrrolidinyl -2- {(2P, 2 P) -divator. Butylamino-ethanol (compound 30), melting point 65.5- 67 ° C (isopropyl ether), yield 73.5% -48.6 ° (with 1%, methanol);
    Example2. The resulting (15) -1- (55) -1- (3-bromo-5-isoxazolylmethyl) -2-oxo-5-pyrrolidinyl -2- (2P, 2 V) -divor. Butylamino-ethanol (compound 22).
    A solution of 2.6 g (0.009 mol) (5S, 2; R) -1- (3-bromo-5-isoxazolylmethyl-5-oxiranyl-2-pyrrolidinone and 1.52 g (0.0118 mol) (K, H) - divider butylamine in 4.75 ml of n. butanol is kept at reflux for 64 hours.
    After evaporation of the solvent, the residue is dissolved in 20 ml of chilled 5% hydrochloric acid and extracted with 4x20 ml of diethyl ether. The aqueous phase is alkalinized.
    by adding potassium carbonate and extracting with diethyl ether, and then the extract is washed with water, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture of toluene and diethylamine in a ratio of 95: 5, resulting in 2.2 g (58% yield) of compound 22 with the same analytical characteristics as in Example 22. one.
    Example Preparation of (1R) - (5S) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl - -2-piperidinoethanol (compound 31),
    A solution of 4 g (0.016 mol) of (5S, 2 S) -1- (2chlorophenyl) -methyl-5-oxiranyl-2-pyrrole-dinone and 2.72 g (0.032 mol) of piperidine in 8.3 ml of ethanol is maintained at a temperature reflux for 20 h. After evaporation of the solvent, the residue is dissolved in 5% hydrochloric acid and subjected to extraction with diethyl ether. The aqueous phase is made alkaline by adding potassium carbonate and extracted with diethyl ether, and then the extract is washed with water, dried over sodium sulfate and evaporated. 4.84 g of a thick oil-like product is obtained, which
    crystallized from 75 ml of n-hexane to obtain 3.45 g (64% yield) of compound 31 as a white crystalline solid. Melting point 65-67 ° C, + 43.7 ° (with 1%, methanol).
    The following compounds are prepared analogously:
    (13) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2-piperidinoethanol (compound 32), an oil-like product, 88% yield, -7.3 ° (with 1%, methanol);
    (1 R) - (5S) -1 - (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2-diisopropylaminoethane ol (compound 33), melting point 113.5-114.5 ° C (isopropyl ether), 72% yield, + 29.2 ° (with 1%, methanol);
    (13) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2-diisopropylaminoethanol (compound 34), melting point 73-75 ° C (isopropyl ether), yield 54.6%, -21.1 ° (with 1%, methanol);
    (1H) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2-dicyclopentylamine-ethanol (compound 35), melting point 79-80 ° C (isopropyl ether), 60% yield, and about 20 + 29.7 ° (with 1%, methanol);
    (1 S) -1 - (5S) -1 - (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2-dicyclopentylamine-ethanol (compound 36), oil-like product, 68% yield, -29 , 4 ° (with 1%, methanol).
    (1H) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (P) -v.butyl-isopropylamino-ethanol (compound 37), melting point 116-117 ° С, yield 74.5%, + 3.5 ° (with 5%, methanol).
    (13) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (P) -the second. butyl and zopropylamino-ethanol (compound 38), melting point 44-46 ° C, yield 58.4%, -47.7 ° (with 1%, methanol).
    (13) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (dicyclobutylamino) -ethanol (compound 38), melting point 44-46 ° C, yield 58.4%, and about -47.7 ° (with 1%, methanol).
    (15) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2- (dicyclobutylamino) -ethanol (compound 39), oil-like product, 82% yield -17.68 ° (with 1%, methanol).
    (13) -1- (53) -1- (2-chlorophenyl) -methyl -2-oxo-5-pyrrolidinyl -2-bis-1-ethyl propyl-amino-ethanol (compound 40), melting point 73- 75 ° C (n.hexane), 25% yield, -37.2 ° (with 1%, methanol).
    The resulting compounds were subjected to pharmacological tests in laboratory conditions.
    Evaluation of competition in the binding of - dihydromorphine (DHM) by opioid receptors of rat brain homogenate.
    In the experiments, rats weighing about 150 g were used. The animals were decapitated and, after removing the cerebellum, the brain was homogenized in 50 nM Tris-HCl buffer (pH 7.4), which contained 0.32 M sucrose. The homogenate was centrifuged at a speed of 1000 rpm for 10 minutes, and the upper layer was centrifuged at a speed of 20,000 rpm for 20 minutes. The precipitate obtained after centrifugation was suspended in a homogenization buffer without sucrose to bring the protein concentration to 2 mg / ml. The incubation system consisted of 500 µl of homogenate (1 mg of proteins), 390 µl of 50 nM Tris-HCl buffer (pH 7.4), 100 µl of a solution of various concentrations of compounds of formula (I) or 10 µM of Naloxone to determine non-specific binding and 10 µl of 3H-DHM (specific activity 87.7 Ci / mol., Final concentration 1 nM). This mixture was incubated at 25 ° C for 30 minutes after the addition of the radioactive binder. Then the samples were filtered through Wattman GF / B filters, washed with 2x3 ml of buffer and dried in an oven at 70 ° C. The filters were placed in scintillation tubes with 15 ml of Filter Count (Packard) scintillation cocktail, and radioactivity was evaluated using a Packard Fricard 4530 scintillation counter with 60% efficiency.
    The activity was expressed as an inhibitory concentration (Ued), providing 50% binding of 3H-DHM.
    The competition (ICso) of compounds 1, T4, 16, 22 and 26 for the specific binding of 3H-DHM to the rat brain homogenate in comparison with morphine is shown below; Connection ICso, nm 10.9
    143.3
    162.5
    229.4
    3610.0
    Morphine1,5
    Assessment of the morphine-like effect on the ileum region of the guinea pig.
    Experiments were carried out in accordance with the method based on the ability of molecules exerting an agonistic effect on opioid receptors to inhibit smooth muscle contractions in the ileal region of guinea pigs caused by electrical stimulation (0.1 Hz, 0.5 μs). The pharmacological effect was expressed as the concentration (MM) required for 50% inhibition (ICso).
    The morphine-like effect on the isolated ileum of some compounds of formula (I), expressed in terms of ICso, in comparison with the effect of morphine is given below:
    Connection ICso, nM
    10.03
    34.6
    48.7
    550.0
    770.0
    844.0 1283.0 140.43
    . 1540.0
    160.29
    180.28
    190.77
    200.23 224.96 242.9 260.04 34 44.71 36 4.06 3821.54 4060.0 Morphine 111.0
    To evaluate the central analgesic effect in laboratory conditions, the obtained compounds were tested with a hot plate in mice. The analgesic effect was expressed as a 50% effective dose (EDso).
    In tab. 1 shows the results of the analgesic action (EDso) of some compounds of formula (I) in comparison with the effect of morphine.
    Compounds were tested in vivo in order to assess their ability to initiate physical dependence. To this end, bouncing tests were conducted. In a two-day period, 7 intraperitoneal injections of compounds of formula (I) and morphine were made in doses that increased exponentially, starting with a dose that corresponded to the value of EDso determined in mice after subcutaneous injections. After 4 hours from the last injection, the naloxone product at a dose of 10 mg / kg was administered intraperitoneally to the animals, and then the number of jumps made by the animals was counted for 15 minutes after the naloxone product was administered. For compounds that did not exhibit the ability to cause withdrawal symptoms, experiments were repeated with
    double the number of procedures (a total of 14).
    In tab. 2 examples of data on jumping animals for compound 1 and morphine.
    When using compound 1 in conducting with bouncing, the number of bouncing mice is significantly reduced compared with morphine. Similar results were achieved using other compounds of formula I.
    Thus, in contrast to morphine, the compounds of formula (I) do not cause the occurrence of physical dependence.
    Toxicity tests were carried out in mice by subcutaneous administration of increasing doses of 0 compounds of formula (I) in order to assess the level of acute toxicity, which is expressed as LDso. The LDso value for compounds of formula (I) exceeds 300 mg / kg when administered subcutaneously with a fairly high 5 therapeutic value in the range of 100-10000.
    权利要求:
    Claims (1)
    [1]
    Formula
    The method of obtaining 2-amino-ethanol derivatives of the general formula
    0A-fcH2) fi
    ,
    CH-R3R2
    ABOUT
    where with n 1 n
    R is phenyl, unsubstituted or substituted by C1-C4-alkoxy, trifluoromethyl, mono- or dihalo or 0 3-bromo-5-isoxazolyl, or 2-thienyl;
    RI and R2 are the same or different - C1-C4-alkyl, C4-C5-cycloalkyl, or together with the nitrogen atom to which they are attached form piperidine; 5 Yaz - hydrogen or R and R3 - simultaneously unsubstituted phenyl; with n 2
    R is 2-chlorophenyl;
    RI and R2 are each separately secondary 0 butyl;
    R3 is hydrogen;
    characterized in that the compound of the general formula, (CHj) n
    L
    five
    ČSN-CH2
    R
    where R, RS and p have the indicated meanings; subjected to interaction with the amine of the General formula
    NMGN1,
    Ra
    where Ri and R2 are as defined, in an organic solvent medium .5
    Priority featured:
    05/20/88 - R - unsubstituted or substituted phenyl; RS is hydrogen.
    02.17.89- R - 3-bromo-5-isoxazolyl or 2-thienyl;
    R3 is hydrogen, or R and Ra are phenyl at the same time.
    Table 1
    table 2
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2496163A|1948-03-30|1950-01-31|Du Pont|Synthesis of a 2-substituted-5-oxopyrrolidine|
    BE790747A|1971-10-30|1973-02-15|Whitefin Holding Sa|1- -PYRROL-2'-YL) -2-DIBUTYL SEC.-AMINO-ETHANOL STEREO-ISOMERS AND PROCESS FOR THEIR PREPARATION|
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    DE3336024A1|1983-10-04|1985-04-18|Boehringer Ingelheim KG, 6507 Ingelheim|4-AMINO-L-BENZYL-PYRROLIDINONE AND ITS ACID ADDITION SALTS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS|
    DE3420193A1|1984-05-30|1985-12-05|Boehringer Ingelheim KG, 6507 Ingelheim|NEW SUBSTITUTED PYRROLIDINONES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS|FR2653123B1|1989-10-17|1992-01-17|Roussel Uclaf|NEW PYRIDONE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|
    IT1239950B|1990-03-28|1993-11-27|Zambon Spa|PROCESS FOR THE PREPARATION OF COMPOUNDS WITH CENTRAL ANALGESIC ACTIVITY|
    US5208345A|1990-12-17|1993-05-04|Merrell Dow Pharmaceuticals Inc.|Process for the production of -vinyl and allenyl gaba|
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    WO2004069793A2|2003-01-28|2004-08-19|Bristol-Myers Squibb Company|Novel 2-substituted cyclic amines as calcium sensing receptor modulators|
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    EP1993998B1|2005-12-07|2013-08-21|UCB Pharma, S.A.|3-carboxy- 2-oxo-1 -pyrrolidine derivatives and their uses|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT2064888A|IT1217657B|1988-05-20|1988-05-20|New 1-heterocyclyl-2-amino-ethanol cpds.|
    IT1948089A|IT1230754B|1989-02-17|1989-02-17|New 1-heterocyclyl-2-amino-ethanol cpds.|
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