• 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:
    Disubstituted N,N'-piperazinyl derivatives are disclosed wherein one substituent is heteroaryl and the other is alkylene attached to the ring nitrogen of substituted 2,5-pyrrolidinedion-1-yl moieties. The substitution pattern of the pyrrolidinedione ring involves either geminal disubstitution, including spiro ring fusion, or 3,4-phenyl ring fusion to give phthalimide derivatives. Heteroaryl substitution on the other piperazine nitrogen comprises pyridine, pyrimidine, and benzisothiazole ring systems. Representative examples of these compounds demonstrate useful central nervous system effects.
    公开号:SU1384199A3
    申请号:SU843796451
    申请日:1984-09-11
    公开日:1988-03-23
    发明作者:Стюарт Нью Джеймс；П.Йевич Джозеф
    申请人:Бристоль-Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

     CM
    . 113841
    This invention relates to the field of the preparation of novel 1,4-substituted piperazine derivatives of the general Formula.
    R
    |) - (CH2) pk () to.
     . where R, is phenyl, unsubstituted or substituted by halogen; R is phenyl or C, -C alkyl, or R and R together form 1- (1,2,3,4-tetrahydrnaphthalyl) or 1-indanyl, provided that H or together form a fused phenyl ring, unsubstituted or substituted by halogen or nitro; B is pyrimidinyl-2 or its 5-fluoro (chloro) - or 5-fluoro-4-methylthio-substituted, 3-cyanopyridyl-2, benzisothiazolyl-3; .n 2-4, with psychotropic properties,
    The aim of the invention is to develop, on the basis of known methods, a method of obtaining new compounds with valuable pharmacological properties with low toxicity.
    Example 1. 2-4-t4- (5-Fluoro-4-methylthio-2-pyrimidinyl) -1-piperazinyl butylT-1H-isoindole-1,3 (2H) -dione.
    A mixture of 8- 5-fluoro-4- (methylthio-2-pyrimidinyl)} -8-aza-5-azonium-spiro- (4,5) decanbromide (9.76 kg, 0.027 mol and phthalimide potassium salt (5.0 g, 0.027 mol) is refluxed in dimethylformamide (100 ml for 16 hours. The volatile compounds are removed under vacuum, the mixture is dissolved in chloroform (100 ml) and extracted with water (2 x 50 ml). The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to a resinous compound, which is dissolved in ethanol (50 ml) and processed with ethanolic hydrochloric acid After cooling, the product crystallizes and 12.9 g (93.0%) of the product are obtained in the form of a white solid hydrochloride salt, mp 235-237 ° C.
    Calculated,%: C 54.14 H 5.41; N 15.03.
    C ,,, SHCl
    Found,%: C 54.25; H 5.34; N 15.06.
    five
    Jq 5 20 25
    thirty
    -zs) 0 d
    0
    five
    992
    NMR spectrum (DMSO - dg): 1.73 (4, m) G 2.51 (3, c) i 3.09 (4, m) | 3.58 (6, m) 4.59 (2, m); 7.86 (4, m); 8.19 (1, D,; 1.8 Hz); 11.63. (1, schs).
    IR spectrum (KBr), 725, 1440, 1500, 1550, 1585, 1715, 1770, 2500 and 2940.
    EXAMPLE 2: 3,3-Difensh1-1-G4- and (2-pyrimidinyl) -1-piperazinyl1-bu-, 5-pyrrolidinedione.
    A mixture of 1- (4-brymbutsh1) -3,3-diphenyl-2,5-pyrrolidinedione with 1,4-dibrobutane and potassium carbonate in acetonitrile at reflux (4.1 g, 0 , 01 mol), 1- (2-pyrimidinyl) piperazine (1.75 g, 0.01 mol) and potassium carbonate (2.94 g, 0.02 mol) are refluxed in acetonitrile (300 ml) within 12 hours. The solution is filtered and concentrated under vacuum to an oil, which is treated with a mixture of water and chloroform. The organic phase is separated, dried over anhydrous sodium sulfate, filtered and concentrated to an oil, which is dissolved in isopropanol. Treatment of this solution with an ethanolic solution of hydrochloric acid leads to the crystallization of a white hydrochloride salt (4.2 g, 83%) so pl. 201.5-203.5 ° C.
    Calculated,%: C, 66.46; H, 6.38J; N, 13.84.
    C ,, Hj, N, 0, HC1.
    Found,%: C 66.31; H 6.42; IN 13.64.
    NMR spectrum (DMSO-d): 1.64 (4, m), 3.05 (4, m), 3.50 (6, m), 3.60 (2 s), 3.68 (2, m), 6.74 (1, t,; 4.4 Hz), 7.34 (10, s); 8.45 (2, d, 4.4 Hz), 11.78 (1, bs). . , IR spectrum (KBV), cm: 700, 765, 1445, 1495, 1550, 1585, 1700, 1775, 2450 and 2940. Example: 1 - 4-G4- (2-Pyrimidinyl ) -1-piperazinyl butyl-spiro; (1,2,3,4-tetrahydronaphthalen-2,3-pyrrolidin-2, 5-dione).
    A mixture of -G4-bromobutyl) spiro (1,2, 3,4-tetrahydronaph; 7H-2,3-pyrrolidine-2,5-dione, (3.9 g 0,6l1 mol) and 1- (2- pyrimidinyl) piperazine (1.82 g 0.011 mol) is heated in acetonitrile (100 ml) for 24 hours with 2.76 g (0.02 mol) of potassium carbonate. The hot solution is filtered and concentrated under vacuum to a solid residue, which is solution are in chloroform
    (100 ml) and extracted with water (2x 100 ml). The organic phase is separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to a solid residue, which is dissolved in acetonitrile (40 ml) and treated with 1.62 ml 7 and ethanolic hydrochloric acid solution. Cooling leads to crystallization 3.5 g (yield 68.6%) of a white solid, which is recrystallized from acetonitrile: ethanol (2: 1) and the product is obtained in the form of the hydrochloride salt, m.p. 241-243 ,.
    Calculated,%: C 63.89; H 6.86, N 14.90.
     HC1.
    Found,%: C 63.76; H 6.79; N 14.68.
    NMR spectrum (DMSO - dg): 1.76 (6, m), 2.36 (1, d $ 17.6 Hz) 2.72 (1, d, 17.6 Hz); 3.00 (8, M) j 3.44 (6, m); 4.67 (2, m), 6.72 (1, t, 4.5 Hz); 7.09 (4, m); 8.42 (2, d, 4.5 Hz), 11.75 (1, bs).
    IR spectrum (KBG), cm: 750, 1440, 1550, 1585, 1700, 1770, 2500 and 2930.
    Similarly, the compounds listed in Table 1 can be prepared.
    The compounds have psychotropic properties. From this point of view they

    possess tranquilizing activity when used in non-toxic doses and are of particular interest as sedative and / or antipsychotic agents. The compounds are also active when the cataleptic condition is removed. Selected animal tests in vivo in vitro confirm that preferred compounds of the formula in which B is a 2-pyrimidyl residue, have a sedative and / or antipsychotic effect. The presented in vivo screening tests are used as a basis for determining the tranquilizing effect and possible side effects of the proposed compounds.
    The method of conducting pharmacological studies is carried out as follows: protection against the porepinephrine lethal outcome.
    1. Substances in a volume of water O, 1 cm are orally administered to groups of 20 mol. (19-21 g were not given without food, both sexes). After 2 hrs inside
    0
    five
    0
    five
    0
    five
    0
    five
    14.4 mg / kg epinephrine hydrochloride (equivalent to 12.0 mg / kg epinephrine in base form) was administered peritoneally, which is enough to kill 67.0 t 1.53% in 40 groups of 20 control mice (which are administered saline). In smaller pretreated non-toxic doses of substances, a reduction in mortality indicates antagonism of the action of epinephrine. Substances are considered effective if the mortality in the treated group is significantly reduced compared with the mortality in a group of 20 saline-treated control mice. If the substance manifests its efficacy, then the test dose is successively reduced by 50% until one or more doses cease to have a significant effect on mortality. Commonly used oral doses are 50–25; 12; 5; -6,0; 3.0 and 1.5 mg / kg.
    Values of increasing with decreasing doses of mortality are plotted on a logarithmic dose schedule, from which an estimate is made of the effective dose for each substance and its standard deviation. An effective dose is a prophylactic dose protecting 50% of the animals that would otherwise die after an injection of epinephrine, i.e. estimated dose reduces mortality from 67.0 + 1.53% (control) to 33.5%. Analysis of the mortality data obtained for 40 groups of 20 control mice using the Chi Square homogeneity test shows that the groups were taken from a homogeneous population (, 50).
    The choice of the two-hour interval between oral administration of the substance and the injection of epinephrine is based on several known or established facts. In addition to the time required to assimilate the test compound, it is necessary to take into account the fact that the characteristic compounds from several chemical series covered by the study do not develop, as is known, maximum activity when reversing the pressor response to epinephrine and blocking the adrenergic nerve effect for 10 -30 min. And more, even with intravenous administration to dogs. Conduct
    experiments with several adrenergic blocking agents to obtain important information regarding the onset and duration of action on mice. The data obtained show that from the point of view of convenience and simplicity in the mass selection of compounds, the interval of 2 hours between the administration of the substance and the injection of epinephry is most suitable for determining the activity of the compounds, regardless of whether the effect of the substance begins somewhat later or earlier. Even a compound such as dibenamine (N, N-dibenzyl-α-chloroethylamine PNS) J, which has a slow onset of action, is active 2 hours after administration and gives a sufficiently high dose (50.0 mg / kg or more). The choice of a two-hour interval after oral administration is also suitable for testing compounds with a fast action.
    Acute toxicity after oral administration of three or four doses of each substance in groups of 20 m, yours (19–21 g were not given without food, both sexes) are evaluated after
    postponing death rate data
    values on a logarithmic dose schedule.
    Suppression of induced evasion response (IRA),
    2. Raised Avoiding Reaction Rats are trained to move through the barrier in a rocking chair for 30 s in a crate (VIR). Placing the animal in the test chamber is a raised stimulus (BC). After 30 seconds, an electric shock is made for another 30 seconds in the half of the chamber that the rat originally occupied. This blow is an unexpected stimulus (HC). After impact, the untreated rat moves to the other safe half of the crate. This avoids the response to surprise (IRN). Blocking VIR without affecting the NRI is regarded as laboratory evidence of a tranquilizing effect.
    The test compounds are administered intraperitoneally and, after 30 minutes, observations are started 5 which continue for 30 minutes. The initial test was performed on four animals at a single dose. If the compound exhibits only weak activity, then
    d g 0
    five
    0
    five
    0
    five
    four more animals are tested at the same dose, and if poor activity is confirmed, the compound is discarded. If the compound is active, then other doses are tested using four animals per dose. Thereafter. R & D is also determined for VIR.
    Amphetamine-aggregation stress. Groups of 20 or more male mice weighing 18-20, g were administered subcutaneously with various doses of the test compound. Then, the mice were planted in separate cells for 60 minutes, after which they were subcutaneously injected with 20 mg of dl-amphetamine sulfate (LD99, d), and planted in two cells in a mouse in a cage. After 23 hours, mortality is recorded. Mortality protection for each dose is plotted on a log plot and the dose (ED) required to protect 50% is determined at a 95% confidence interval.
     3. Receptor binding assay. Dopamine.
    Rat and bovine brain membranes bind (3H) dopamine in a manner that indicates a relationship with postsynaptic dopamine receptors. Regional changes in the distribution of binding sites are parallel to the regional differences in brain dopamine innervation. The relative activity of substances in relation to these binding sites is similar to the relative pharmacological activity of behavior change, which is presumably realized through dopamine receptors.
    The caudal or other part of fresh or frozen calf brains is homogenized in 40 volumes of ice-cold 0 mM Tris buffer, 7 at 25 s using a Brinkmann Polytron RT-10 (with a setting of 6.5 s). The homogenisate is centrifuged twice at 50,000 g for 10 minutes (Sorvall PC2-B, 20,000 rpm, SS-34 or M-24 rotor) while re-homogenizing the precipitate in fresh buffer. The resulting precipitate is homogenized in 90 volumes of cold, freshly prepared 50 mM Tris buffer containing 0.1% ascorbic acid, 10 μM pargyline and the following ions, mM: NaCl 120, HC1 5, CaClj 2 and MgClj1 to give the resultant, 1 at 37 ° WITH. Tissue suspension (11 mg / ml) is placed
    71
    5 minutes in the bath at and return to the ice.
    Freezing tissue for up to 2 weeks does not affect binding or has only a minor effect. Adding approximately physiological concentrations of ions reduces the values for both ligands, but does not change the specific binding.
    Use (ztil-1- H / N /) dopamine 8.4 C / mmolv.
    On the day of use, each radioactive substance is diluted with 0.1% ascorbic acid to a concentration, and 100 nM t (H) dopamine.
    Two or three identical incubation tubes were added to each 100 µl of a solution of the compound in various concentrations, dissolved in 0.1% ascorbic acid and 1.8 ml of tissue suspension. The tubes were incubated at 37 ° C for 10 minutes and quickly filtered under vacuum through a Whatmar GF / B filter and the filter was washed with two portions of 5 ml of ice-cold 50 mM Tris buffer, 7 at 25 ° C. Filters were measured by liquid scintillation spectrometry in 10-12 ml of Hydromix lorktown Research with an efficiency of 37-44%.
    The saturation or specific binding of dopamine (H) is measured as an excess compared to the blank experiment carried out in the presence of 1 µM dopamine 10 µM M (+) - butaclamol. As previously established, the associated radioactivity from (H) dopamine migrates with an auto-authentic dopamine. The total associated membrane radioactivity is less than 3% for (H) dopamine. The specific binding by the caudal membranes is about 40% to about 60% for (D dopamine. The latter value is much more accurate than the previously obtained results using centrifugation.
    Butyrophenone and similar compounds are dissolved in a minimum volume of glacial acetic acid (the resulting volume is less than 1%) and added to a concentration of 2 mM k-hot 0.1% ascorbic acid solution. Other substances are dissolved in a 0.1% solution of ascorbic acid and all substances are further diluted.
    Q
    five
    0 5 o
    „
    five
    0
    five
    998
    0.1% ascorbic acid. Proteins are determined by the method of Lowry,
    Regional distribution in the binding (H) of dopamine with brains.
    Zones of the brains of the brain, kept frozen for 1 week, are analyzed with the help of 5 nM (N) dopamin.
    The results are expressed as the mean ± standard error for three experiments (with the exception of the hindbrain). It should be noted that the presented data reflect the actually observed binding, and not the total number of binding centers in each region (zone). Nonspecific binding is approximately the same in all regions and is approximately 200-250 mol (mg of protein for binding (H) dopamine. As a rule, it is not possible to determine specific binding that is less than 10% of these control values.
    Regional variations in the competition of a substance with respect to dopamine binding (H).
    Regions of fresh or frozen calf brains are analyzed using three or more concentrations of the compounds, wire For each case two or three experiments. The concentration of the compound required to inhibit specific binding by 50% (HKjt) is determined from logarithmic graphs and converted to K values; by equation; K (1 + s) KB, where the concentration of the radioactive ligand (5 nM for d (H) dopamine), and K- - | their dissociation constant (taken as 20 nM for (H) dopamine). The results are presented as the average value of i standard error for the number of experiments indicated in brackets. The values of K, for individual drugs, are the same for used concentrations of 1 or 2 nM / (H) haloperidol,
    Inhibition of dopamine binding compounds (H).
    Each substance was tested in three or more concentrations twice or three times for a specified number of experiments.
    Pharmacological data of some compounds covered by the formula are listed in table 2,
    913841
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derived 1-heteroaryl-4- (2,5-pyrrolidinedione-1-yl-alkyl) piperazii of the general formula
    "L °
    (CIS1 „-OUT
    ten
    de R, is phenyl, unsubstituted or
    substituted with halogen; R is phenyl or C-C-alkyl, or R 1 and R together form 1- (1,2,3,4-tetrahydronaphthyl) or 1-indanyl, provided that R3 - Hj, or R, - RjBMecTe form a condensed phenyl ring unsubstituted or substituted by halogen or nitro;
    B - pyrimidinyl-2 or its 5-fluorine (chlorine) - or 5-FTOR-420
    25
    methylthio-substituted, 3-cyano99
    ten
    pyridyl-2, benzisothiazolyl-3; n 2-4,
    characterized in that the compound of the general formula
    RI O
    RO-H:
    .: E
    where R, -Rj - above;
    W - / NH or N - (CHj) -Q, where Q is halogen,
    subjected to interaction with the compound of the General formula
    Y-N (N-B
    where B is indicated above;
    . Y is hydrogen or a group Q- (CH,), where pyr is indicated above, provided that if W is -) W, then Y is a group of Q- (CH ,,) „-, or if W (CH) Q, then Y is hydrogen.
    Rt (CHi tT-NQN-B 1
    9 Phenyl
    Trifluoro-Hj 4 methyl
    ten
    Phenyl Hj 4
    eleven
    Table 1
    H, 4
    3-Benzisothiazolyl
    188-189,5
    2-pyrimidinyl
    185-186
    2- (3-Cyanopyri-179-182 dil).
    N.
    3-Benzisothiazo- 188-189,5 lil
    eleven
     Ethyl
    131- (1,2,3,4-tetrahydronaphthalene)
    141- (1,2,3,4-tetrahydronaphthalene)
    15 1- (1,2,3,4-Tetrahydronaphthalene) H,
    1-indanyl
    1-indanyl
    Benzo
    2,3-Dichlorboneo
    1,2,3,4-tetrachlorobenzo
    2-Nitrobenzo
    1,4,5,6-Tetrahydrobenzo
    2-Nitrobenzo
    Benzo
    Benzo
    1384199
    12 Continuation of table 1
    but
    but
    ,
    a a
    , four
    4 4 4 4 4 4
    5-Fluoro-2-pyrimidinyl
    2-pyrimidinyl
    2- (3-Cyanopyridil)
    Z-Benzizotiya-- Zolil
    2-11irimidinism
    5-Fluoro-2-pyrimidinyl
    2-pyrimidins1
    241-196207 241
    247 198
    -212 -248
    2- (3-Cyanopyridyl
    5-Fluoro-2-pyrimidinyl
    5-Chloro-2-pyrimidinyl
    137-145-154-130-209-205139, 5,146.5,156, 133,210,208
    Table 2
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    申请号 | 申请日 | 专利标题
    US06/531,519|US4524206A|1983-09-12|1983-09-12|1-Heteroaryl-4-alkyl)piperazine derivatives|
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