• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention provides trans-3,4 1-substituted-3-substituted-4-methyl-4-(3-substituted phenyl)piperidines as opioid antagonists capable of blocking the mu or kappa receptors in the brain, of the formula <CHEM> wherein: R<1> is hydrogen or C1-C4 alkanoyl; R<2> is hydrogen, C1-C4 alkyl or C2-C6 alkenyl; R<3> is C4-C8 cycloalkyl, C4-C8 cycloalkenyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C4 alkyl substituted C4-C8 cycloalkyl, C1-C4 alkyl substituted C4-C8 cycloalkenyl or thiophene; Z is <CHEM> - @- or a bond; R<4> is hydrogen, C1-C6 alkyl, <CHEM> or - @-R<5>; R<5> is C1-C4 alkyl or <CHEM> n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
    公开号:SU1598869A3
    申请号:SU884355530
    申请日:1988-04-14
    公开日:1990-10-07
    发明作者:Говард МИТЧ Чарльз；Майкл Циммерман Деннис
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of production of new heterocyclic compounds, in particular, trans-3,4-isomers of 4- (3-hydroxyphenyl) -piperidine derivatives, possessing the property of blocking mu or kappa receptors, which can be used in medicine.
    The aim of the invention is to create, based on known methods, a method of producing new piperidine derivatives - kyu and kappa receptor blockers, which have high activity with low toxicity.
    Example. Trans- (t) -1- (R, S) - (1-cyclopentyl-propanol-3-yl) -3,4-dimethyl-4- (3-hydroxyphenyl) -piperidine hydrochloride.
    2.0 MP is added to a solution of trans- (t) -l- (l-cyclopentsh1propanol-3-yl) -3,4-dimesh1-4- (3-hydroxyphenyl) -piperidine in -100 yu dry diethyl ether 1 M lithium apyumohydride in tetrahydrofur is not. The mixture was heated under reflux for 90 minutes and cooled to 0 ° C. To the mixture was added 5.0 ml of ethyl acetate, followed by the addition of sufficient water to induce crystallization. The liquid phase is drained and the resulting filtrate is dried over anhydrous potassium carbonate. The filtrate is concentrated in vacuo and converted to the hydrochloric acid salt to give the title compound.
    Calculated,%: 4.23.
    C 76.09; H 10.03;
    C ,, H, NO.
    %: C, 76.07; H 10.09;
    Found 4.01. Spectrum H-NMR (CDClj):
    0.54 (MN,
     Hz); 1.20 (3N, s); 3.62 (1H, Hz); 6.6 (1H, l,. Hz), - (1H,
    ten
    D.
    KB, ,
    6.71 (2H, t, Hz); 7.1. . Hz); 7.47 (1H, broad singlet). The compounds of examples 2-6 are prepared according to the procedure described in
    example 1..
    PRI mme R 2. Trans - (+) - 1- (5) - (3- 15
    hydroxy-3-diclohexylpropyl) -3,4-dimethyl, (3-hydroxyphenyl) -piperidine, m.p.
    142-14a S.
    Calculated,%: C, 76.48; H 10.21;
    4.05.
    C iHjyNO. Found,%: C 76.64; H 10.48;
    4.17.
    PRI me R 3. TpaHC - (-) - (S) - (3-, hydroxy-3-cyclohexylpropyl) -3,4-dimethyl g5
    4- (3-hydroxyphenyl) -piperidine, m.p. 15115 С
     с a (:, -...- 64.9655, Ы 36 -211.655 Calculated,%: C 76.48; H 10.21; 4.05.
    N
     N
    20
    N
    thirty
    C jHjffNO.
    Found,%: C 76.71; H 10.43;
    4.05. PRI me R 4. Trans - (+) - 1- (PO- (3Found,%: C 68.97; H 9.37; 3.70.
    Pharmacological testing; The ability of compounds to block mu- or kappa-receptors (in vitro). Male Spraque Dawley rats for on-site experiments with mu and delta cells and male Hartley guinea pigs for kappa receptor studies were killed by decapitation and the brain was removed. The brain tissue, the whole brain of the rat cerebellum to study the site of application of the mu and delta cells and the cerebral cortex to study kappa perienTopoB, was homogenized in a teflon and glass cloth homogenizer. The fraction of the sediment layer 1, the precipitate after settling IV, was frozen in a nitrogen cooler at a concentration of 1.33 g / ml and kept for no more than five weeks prior to use. Tissue was rehydrated with physiological buffer before use.
    To study mu and delta cells. At room temperature, polystyrene tubes were mixed with increasing concentrations of the experimental compound (0.1-1000 nmol), Krebs-Hepes buffer pH 7.4, and labeled with three examples., ™ I eat ligand. The reaction was initiated with do-oxy-3-, d..clohexylcrop.-3 4-dime. 35, ,,, dehydrated, tissue.
    4- (3-hydroxyphenyl) -piperidine, m.p. 150151 C.
    Wli ,, -, 6069 °, U33tf. + 238.963 Calculated,%: C, 76.48; H 10.21; 4.05.
    40
    Suppression of rehydrated tissue that was preincubated at 37 ° C for 20 minutes. The reaction mixture was kept in a water bath for 20 minutes.
    The reaction was terminated by rapid filtration (Amecon vacuum collectors) through Whatman GF / C glass filters that were pre-wetted in Krebs-Hepes buffer with a pH of 7.4. Then the filters were washed twice with 5 ml each time with supercooled Krebs-Hepes buffer with a RP of 7.4. Washed filters were placed in scintillation microtubes and 10 ml of PCS (Amersham) was added, and samples were counted on a Searle D-300 beta radiation counter. Mean values and standard deviations are calculated after three times.
     3fNO. Found,%: 4.18. Example
    C 76.24; H 9.92;
    5. Trans - (-) - 1- (J) - (3oxy-3-1shkogeoksilpropyl) -3,4-dimethyl-4g (3-hydroxyphenyl) -piperidine, so pl. 141-1434 :.
    0/3, 3 -68.81% R3efc., 88 Vijisleno,%: C 76.48; H.10,
    N 4.05.
    C Hjsno.
    Found,%: C 76.40; H.10.35; N 4.01.
    Example 6
    45
    50
    Hydrochloride transReaction was terminated by rapid filtration (Amecon vacuum collectors) through Whatman GF / C glass filters that were pre-wetted in Krebs-Hepes buffer with pH 7.4. Then the filters were washed twice with 5 ml each time with supercooled Krebs-Hepes buffer with a RP of 7.4. Washed filters were placed in scintillation microtubes and 10 ml of PCS (Amersham) was added, and samples were counted on a Searle D-300 beta radiation counter. Mean values and standard deviations are calculated after triplicate Ex. 1 hydrochloric acid Definitive determination in concrete (()), (K, 5) - (3-hydroxy-3-cyclohexyl by Rose. Method somewhat modifil) -3,4-dimethyl-4- (3-hydroxyphenyl) -piperidine.
    Calculated,%: C 69.18; H 9.50;
    N 3.67.
    cases. The method is somewhat modified with 1 # 1 for kappa receptors. The tissue was pretreated with 100 nano molar concentrations of blockers.
    0
    15
     g5
    20
    thirty
    C ,,,,. NO ,.
    Found,%: C 68.97; H 9.37; 3.70.
    Pharmacological testing; The ability of compounds to block mu- or kappa-receptors (in vitro). Male Spraque Dawley rats for on-site experiments with mu and delta cells and male Hartley guinea pigs for kappa receptor studies were killed by decapitation and the brain was removed. The brain tissue, the whole brain of the rat cerebellum to study the site of application of the mu and delta cells and the cerebral cortex to study kappa perienTopoB, was homogenized in a teflon and glass cloth homogenizer. The fraction of the bed of the outer layer 1, the precipitate after settling IV, frozen. They were kept in a nitrogen cooler at a concentration of 1.33 g / ml and kept for no more than five weeks prior to use. Tissue was rehydrated with physiological buffer before use.
    To study mu and delta cells. At room temperature, polystyrene tubes were mixed with increasing concentrations of the experimental compound (0.1-1000 nmol), Krebs-Hepes buffer pH 7.4, and a tri-labeled ligand. The reaction was initiated by up to 35 ,,,,, „,,, dehydrated, tissue.
    ™ eat ligand. The reaction was initiated up to-5 ,,,,, „,,, dehydrated, tissue.
    0
    45
    50
    Suppression of rehydrated tissue that was preincubated at 37 ° C for 20 minutes. The reaction mixture was kept in a water bath for 20 minutes.
    The reaction was terminated by rapid filtration (Amecon vacuum collectors) through Whatman GF / C glass filters, which were pre-wetted in Krebs-Hepes buffer pH 7.4. Then the filters were washed twice with 5 ml each time with supercooled Krebs-Hepes buffer with a RP of 7.4. Washed filters were placed in scintillation microtubes and 10 ml of PCS (Amersham) was added, and samples were counted on a Searle D-300 beta radiation counter. Mean values and standard deviations are calculated after a three-fold explicit definition in concrete. The method of several modificomental definitions in concrete. The method of several modifica cases. The method is somewhat modified with 1 # 1 for kappa receptors. The tissue was pretreated with 100 mM concentrations of blockers.
    mu and delta cells. The incubation time of the 7CH reaction mixture was 45 minutes at 37 ° C.
    1598869
    The K values were calculated using the statistical mini-program according to the following
    K, - S where is a concentration in which 50% of the tritiated ligands are replaced by the test compound.
    dissociation constant for tritium-labeled ligands at the site of the action of the torus receptor.
    The results of the evaluation of some compounds in the experiment on the binding of an opiate receptor are presented in Table 1. Compounds A - F are known compounds and are: Compound A - hydrochloride 4; 9- (3-hydroxyphenip) -3 / 3- 4o-dimetsh1-o / -phenyl-1-piperidinepropanol; Compound B — hydrochloride of 3- (1, 4/3-trimethyl-4o-piperidyl) -phenol; Compound C — maleate 3-. G4 pr (3-hydroxyphenyl) -3, 4o-dimesh1-piperidino J-propiophenone; Compound D is 3- (3o / hydrochloride, 4yl-dimethyl-1-phenethyl-4b / -piperidyl) phenyl hydrochloride; Compound E is naloxone -4,5-epoxy-3, 14-dioxy-17- (2-propenyl) morphinan-6-one; Compound F Naltrexone - 17-Cyclopropyl-methyl-4,5-epoxy-3, 14-dioximorphyl-: nan-6-one.
    1 + K2 Centering of tritiated ligands, Cr
    They were given within 10 minutes after the letter reaction, which began 5 minutes after the introduction of acetic acid. Percent inhibition of the reaction
    25
    thirty
    35
    letters were determined from an average of 15 scratches in the control group.
    Each combination dose was administered to pympyam.
    Each test compound entered. The dose of morphine, the prototypical competitor of the opiate mu-receptor, and the analgesic dose of I-50, 488H, the prototype of the opiate receptor kappa receptor, were given in various doses. (I-50, 488N is a well-known diagnostic substance. Trans-3,4-dichloro-methyl-N-H 2- (1-pyrrolidinyl) cyclohexyl 35 benzene-acetamomethane-methane sulfonate). The corresponding lean doses were 1.25 and 2.5 mg / kg body weight. These doses cause approximately .90-100% inhibition of the letter reaction. Each potential antagonist tested at a dose of 1.25 mg / kg with morphine and I-50, 488H. If a significant antagonism of either analgesic or morphine or .I-50, 488H was observed, then a series of consecutive doses of antagonist was taken to get the full. dose-response curve - effect and calculate the anta-40 gonistic dose of 50 (). Blood pressure was calculated from the linear regression equations of the experimental data obtained on the recorder and it means an approximate dose that reduces the analgesic effect of a competitor to 50% inhibition of the letter reaction. Injectable test drugs and prototypical competitors were subcutaneously administered 20 minutes before the injection of uksuu acid.
    Tests in vivo. The compounds of the invention also showed high activity in in vivo experiments in mice as antagonists of the mu and kappa receptor opiates. This activity was established as follows.
    / The opioid receptor antagonism in vivo determinations used a letter reaction commonly used in younger to measure analgesia. Letter responses in mice were defined as contraction of the abdominal muscles, followed by extension of the lower limbs. The letter reaction was caused by the intraperitoneal injection of 0.6% acetic acid in a volume of 1 ml / 100 g of weight. Five male OF-1 mice (Charles River, Portage, ML), weighing approximately 20-22 g each, after fixing them overnight, continuously monitor
    SO
    .
    They were given within 10 minutes after the letter reaction, which began 5 minutes after the introduction of acetic acid. Percent inhibition of the reaction
    25
    thirty
    35
    five
    letters were determined from an average of 15 scratches in the control group.
    Each combination dose was administered to pympyam.
    Each test compound entered. The dose of morphine, the prototypical competitor of the opiate mu-receptor, and the analgesic dose of I-50, 488H, the prototype of the opiate receptor kappa receptor, were given in various doses. (I-50, 488N is a well-known diagnostic substance. Trans-3,4-dichloro-methyl-N-H 2- (1-pyrrolidinyl) cyclohexyl 35 benzene-acetamomethane-methane sulfonate). The corresponding lean doses were 1.25 and 2.5 mg / kg body weight. These doses cause approximately .90-100% inhibition of the letter reaction. Each potential antagonist tested at a dose of 1.25 mg / kg with morphine and I-50, 488H. If a significant antagonism of either analgesic or morphine or .I-50, 488H was observed, then a series of consecutive doses of antagonist was taken to get the full. dose-response curve - effect and calculate the anta-40 gonistic dose of 50 (). Blood pressure was calculated from the linear regression equations of the experimental data obtained on the recorder and it means an approximate dose that reduces the analgesic effect of a competitor to 50% inhibition of the letter reaction. Injectable test drugs and prototypical competitors were subcutaneously administered 20 minutes before the injection of uksuu acid.
    The results of the experiment on the reaction in mice are presented b ... Table. 2
    It has been established that the interaction of opti antagonists with kappa receptors leads to a noticeable diuretic effect (Leander. The Journal of Pharmacology and Experimental Therapeutical, 1983, vol 224, No. 1, 89-94).
    45
    50
    letters
    The compounds according to the invention were also evaluated in a rat diuresis experiment carried out according to the method described by Leander et al, in Drug Development Research, 1984, A, 421- 427, to prove the ability of the proposed compounds to block kappa receptors,
    According to this method, 60 male caped rats of the Long Evans line (Charles River Bruding Laboratories, Portage, MI), weighing 300–500 g each, were placed separately or in pairs in a vivarium with controlled temperature (), which was illuminated from .6 h pm to 6 am Rodent food and tap water were continuously available to rats, except for the time when urine bile measurements were made. Animals were reused, but no more than twice a week.
    In determining the antagonistic activity of the compounds according to the invention, each animal was injected with an injection of 0.08 mg / kg bromazocine, a potential competitor to the kappa receptor, to induce urination. The animals were then injected with various doses of the tested compounds. To measure urine excretion, animals were removed from the cabins, weighed, injected, and placed in exchange cells for 5 hours. The isolated urine was withdrawn by a tube into cylinders with divisions. Accumulated urine volumes were determined at set intervals of time (usually 2 and 5 hours after injection).
    The compounds that were tested were in the form of salts dissolved in distilled water. If necessary, the compounds are dissolved in distilled water with a few drops of lactic or hydrochloric acid and lightly heated. All injections were performed subcutaneously in a volume of 1 ml / kg of body weight. In antagonism experiments, two injections were performed, one on each side of the body.
    The results of the study of experimental diuresis in rats are presented in Table. 3
    The proposed compounds have been found to have the ability to increase the amount of food consumed in vivo. The following experiment was conducted to evaluate the ability of compounds.
    In accordance with the invention, increase the intake of feed and water by fatty Zucker rats.
    According to the applied method, obese rats Zucker aged 3-4 months were taught to eat food in the afternoon from 8 am to 4 pm, only so that the weight gain approached that when the rats were fed ad libitum. These rats could consume water at any time. Rats were grouped in four in each group, two females and two males. One group served as a control for the other three groups each day. Each of the other three groups was subcutaneously injected with the test compound to be evaluated. Test compounds were prepared in saline containing 10% by volume of dimethyl sulfoxide.
    Animals were not given medication for 4 days until the next trial. The consumption of food and water by each rat was measured during the first 4 hours. Tests of one compound continued for three consecutive days. The effect of the drug was expressed as a percentage of the control for a particular test day.
    The results of these experiments are presented in Table. 4, where an effective dose of ED.2 is given, which is the amount of compound evaluated (in mg / kg) required to increase food intake by 20% in the first 4 hours of the experiment.
    Thus, the proposed compounds have low toxicity and exhibit only a slightly negative effect on mice at a very high dose of 300 mg / kg.
    权利要求:
    Claims (1)
    [1]
    The invention of the method of producing trans-3,4-isomers of 4- (3-hydroxyphenyl) 7-PXH-yridine derivatives of the general formula
    HE
    CH -CH-CH-R OH
    where R is C5 - C -1.shkloalkil, about tl and h and y. u and with the fact that restore the compound of the general formula
    N About I II
    CH-CHo-C-R
    where R has the specified value
    1598869 12
    , Continuation of table 2
    Compound
    mu receptor
    0.161.38
    -0.081.12
    0.05, 0.06
    Table3
     "G / kg, through g - g
    2hrs 5.h
    e
    0.40. 0.38
    4,092,65
    2,713,49
    -2,172.45
     ------ "" - --- e-toe--, in "in - -
    T a B L I C a 4
    ED ,, mg / kg
    memory stick
    . 0.07
    0.05
    0.12 0.13
    0.35
    . 0.04 e. .
       0.55
    3.99
    3.72
    0.94
     .1.40
    2.05
    spruce I. Bannikova
    Editor S.Pekar
    Tehred L.Oliynyk Order 3076
    Circulation 322
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk iab., 4/5
    AL ,, mg / kg, dpl
    kalpa tseptor
    Proofreader S.Shevkun
    Subscription
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    法律状态:
    优先权:
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    US3912187A| true| 1987-04-16|1987-04-16|
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