• 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:
    This invention provides (8 beta )-N-cycloalkyl-1-alkyl-6-(substituted)ergoline-8-carboxamides of the formula <CHEM> wherein: R<1> is C1-C4 alkyl; R<2> is allyl or C1-C4 straight chain alkyl; R<3> is hydrogen or C1-C4 straight chain alkyl; R<4> is hydrogen, C1-C4 alkyl, hydroxy or C1-C4 alkoxy; m is 0, 1, 2 or 3; or a pharmaceutically acceptable acid addition salt thereof. The compounds are useful for blocking 5HT2 receptors in mammals having an excess of serotonin centrally or peripherally.
    公开号:SU1597103A3
    申请号:SU884355904
    申请日:1988-06-14
    公开日:1990-09-30
    发明作者:Мортенсен Форман Марк；Ли Гарбрехт Вилльям；Пурнелл Марзони Джиффорд；Роуз Виттен Кэтлин
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The purpose of the invention is to obtain new derivatives of cycloalkylamines (8) ergolins, which have pharmacological advantages over known analogues.
    Example 1 (8 p) -N-Cyclohexyl-1-isopropyl-b-methylergoline-B-carboxamide.
    In ZSO-T HanHMeTpOByro three-necked count. 10.0 g (32.01 mmol) (8p) -1-isopropyl-methyl ergoline-8-carboxylic acid, 4.43 g (31.1 mmol) of potassium carbonate and 200 ml of N, N-dimethylformamide . The mixture is under a reflux condenser and 25 ml of distillate are taken. The remaining solution is cooled in an ice bath and then in a bath of acetonitrile carbon dioxide, which reduces the temperature of the reaction mixture to -45 °. To this mixture, 4.59 g (33.62 mmol) of isobutyl chloroformate are added dropwise. The resulting mixture was stirred for about 5 minutes and 3.49 g (35.21 mmol) of cyclohexylamine was added. The reaction mixture is warmed to room temperature and stirred for approximately 19 hours. Ice water (500 ml) containing 25 ml of concentrated ammonium hydroxide is added to the mixture. The mixture is cooled and the precipitated solid is collected by vacuum filtration. The resulting solid is washed with water, dried under vacuum, and 10.13 of the desired compound are obtained having a purity of 92.3%. The yield was 76.8%.
    I ..
    The resulting solid mixture ™
    They were prepared with three other portions of the target compound, previously synthesized to obtain a total mass of 33.6 g. This material was dissolved in 1200 ml of hot methanol and the resulting TpyioT fil solution. The filtrate is cooled to room temperature and 600 ml of water are added dropwise. The mixture is cooled in a refrigerator and the precipitated crystals are collected by vacuum filtration. The crystals are rinsed with methanol, dried in vacuo and 26.95 g of the title compound are obtained having a purity of 96.5% as determined by high performance liquid chromatography. Vysu. The solid is dissolved in 1100 ml of hot methanol and the resulting solution is filtered hot and cooled. 600 ml is added to this mixture.
    water and the precipitated solid are collected by vacuum filtration. This solid was washed with water, dried under vacuum, and 25.82 g of compound were obtained. Purified material I1.1 clearness 98.7%, so pl.
    Calculated,%: C, 76.29; H 8.96; N 10.60.
    CesH-jgN O.
    Nayzno,%: C 76.26; H 8.75; N 10.50.
    ha / e 393; eot) -83,6931.
    Following the general method described in example 1, the compounds mentioned in examples 2 and 3 are synthesized.
    Example 2. Maleate (8p) -cyclohexyl-N-methyl-1-isopropyl-6-methylergoline -8 carboxamide, .., so pl. 1 49154 0.
    Calculated,%: C 68.81; H 7.89; N 8.02.
    C3oH4,
    Found,%: d 68.62; H 7.61; N 7.81.
    m / e 407; (w) p -76.0396.
    Example 3. (8p) -N-Cyclohexyl-l-isopropyl-6-n-propylergolin-8 carboxamide, so pl. 235-237 S.
    Calculated,%: C 76.92; H 9.32; N 9.96.
    Cu7H, 9N ,, 0;
    m - .50;
    HCH W J J /
    m / e 421; (ci) p -76,7791.
    Example 4. (8B) -Cys-K- (4-methoxycyclohexyl) - -isopropyl-6-methylergoline-8-carboxamide.
    A round-bottom 50-mm flask was charged with 1.71 g (3.49 mmol) (8p) -1 -isopropyl-6-methylergoline-8-carboxylic acid, g (11.01 mmol) of potassium carbonate and 25 ml of N, N-dimethylformamide. The mixture is heated under reflux and 3 ml of distillate are collected. The mixture is cooled to room temperature and then to approximately -38 ° C by means of a cooling bath on acetonitrile-carbon dioxide mixture. To the mixture is added 0.79 g (5.76 mmol) of isobutyl chloroformate in one portion. The mixture is stirred for about 10 minutes and 1.0 g (6.03 mmol) of cis-4-methoxycyclohexylamine hydrochloride is added to the reaction mixture. The mixture was stirred at -35 ° C for 3 h and 100 ml of water containing 10 ml of ammonium hydroxide was added. The precipitated solid is collected by vacuum filters and washed with water. The solvent was dried in vacuo and 1.9 g of c. Of the left compound, having a purity of 99.57 °, were obtained. 220-2210С. Calculated,%: C 73.72; H 8.80; 9.92. C.2bNu7MzO “; Found,%: C 73.49; H 8.60; m / e 423; W -81,8546. Example 5. (8p) -TpaHc N- (4 Methoxycyclohexyl) -1-isopropyl-6-methylergoline-8-carboxamide. Following the general procedure described in example 4, 2.32 g of compound are obtained using 1.71 g (5.49 mmol) of (8) -1-isopropyl-6-methylargoline-8-carboxylic acid and 10.0 g, (6 , 03 mmol) trans-4-methoxycyclogoglymine. M.p. above 230 ° C. Calculated,%: C 73.72; H 8.80; N 9.92. C-zbH N Oe. Found,%: C 73.97; H 8.59; N9.93. m / e 423; (ut) j -79,6284. Following the general procedure outlined in Example 4 B, the compounds are prepared according to examples 6-8. Example 6. Maleate (8p) -cis -N- (4-methoxycyclohexyl) -l, 6-dime tyergoline-8-carboxylic acid, so pl. 144-14bS Calculated,%: C 65.73; H 7.29; N 8.21. .SsaNzt aO; Found,%: C 65.46; H 7.27; N 8.05. . Example 7. Maleate C8p) -cis -Y- (4-methoxycyclohexyl) -1-ethyl-6 methylergoline-8-carboxamide, m.p. PZ-Pb C. Calculated,%: C, 66.26; H 7.48; N 7.99. C-29H39N., Ob; Found:% C 66.49; H 7.50; 8.16. Example 8. (8p) -K-iiklohek sil-1,6-dimethylergoline-8-carb0xam m.p.260-261 S.%: C 75.58; H 8.55; Calculated 11.50. ; Found,%; C, 75.72; H 8.73. 11.75. 3 Example 9. (8p) -Y-Cyclopentyl-1-isopropyl-6-methylergoline-8-carboxamide .. To a solution of 3.26 g (0.01 mol) (8p |) -1-isopropyl-6-methylergoline- 8 hydrazide in 25 ml of hydrochloric acid and 100 ml of water at a temperature of about 25 ml of 0.2 N sodium nitrate are added dropwise over about 5 minutes. The resulting mixture is stirred at room temperature for about 5 minutes and a sufficiently dilute sodium bicarbonate solution is added dropwise to it until the pH of the mixture is alkaline. The mixture was extracted with three portions of distil ether, 200 ml each. The organic extracts are mixed, dried over anhydrous magnesium sulphate and filtered. To the resulting filtrate is added a solution of 2.55 g (0.03 mol) of cyclopentylamine in 50 ml of dimethylformamide. The mixture was left overnight at. The solvent is drained from the resulting oil. The oil is suspended in acetonitrile and the solvent is again drained. The resulting solid is crystallized from. acetonitrile and receive 1.23 g of compound, m / e 379.%: C 75.95; H 8.76; Calculated N 11.09. . C 76.21; H 8.54; Nay ;; ano,% N 10,68. Following the procedure described in Example 9, the compound of Example 10 is synthesized. Pr and m in p 10. (8p) -Y-Cyclohexyl-1-ethyl-6-methylergoline-8-carboxyamide, m / e 379. Calculated,% : C 75.55; H 8.76; N I 1, 07. C 75.68; H 8.46; Found N, 10.98. Example 11 (8)) - TpaHc-N- (4-Oxycyclohexyl) -1 -and yupropil-6 methylergoline-8-carboxam1. A mixture of 3.12 g (0.01 mol) (8) - isopropyl-6-methylergoline-8-carboxylic acid, 6.0 g (0.04 mol) of 4-amino-cyclohexanol hydrochloride, 4.44 g (6.0 ml , 0.04 mol) of triztilamine and 3.0 g (0.012 mol) of K-ethoxycarbonsh-1-2-ZTOXI-1, 2-dihydroquinolin p 100 ml of dichloromethane are heated at about 4 hours. The mixture is cooled. The organic phase is separated and concentrated in vacuo. The resulting residue is suspended in hot acetonitrile and the insoluble solid fractions are collected by vacuum filtration. The collected solid is recrystallized 7 from a solvent mixture consisting of 75 ml of methanol and 45 ml. water, and receive 1, 18 compounds, m / e 409. Computed,%: C 73.31; H 8.61; N 10.26. C sHggNgOe. Found,%: C 73.58; H 8.71; N 10.41. The procedures described in example 11 were synthesized for compounds in examples 12-14. 1 Example 12. {8p) -K-Cycloheptyl-1 isopropyl-6-methylergoline 8-cage boxamide, t / e 407.. Calculated,%: C 76.62; H 9.15; N 10.31. SybNet eO. Found,%: C 76.48; H 8.85; N 10.23. Example 13. (8.p) -K-4-Methylcyclohexyl) -1-isopropyl-b-methylergoline-8-carboxamide, m / e 407. Calculated,%: C 76.62; H 9.15; M 10.31. CebH-jyN O. Found,%: C 76.31; H 8.91; N 10.16. Example 14. (8p) -N- (2-Oxycyclohexyl) -1-nzopropyl-6-methylerg lin-8-carboxamide, m / e 409., Calculated,%: C 73.31; H 8.61; N 10.26. CftsHagN O. Found,%: C 73.09; H 8.45; N 10.04. An additional aspect of the invention is the use of compounds of formula (I) for blocking the receptor receptors in mammals. These agents are useful for the treatment of disease states, mainly due to an excess of circulating serotonin. These conditions include hypertension, thrombosis, migraine, vascular spasm (coronary and cerebral), ischemia, derescence, pain, insomnia and anorexia. The proposed compounds exhibit relatively weak affinity with other receptors, such as (s ,, o (, i, rhistamine, carbachol, and similar receptors), and thus are highly selective in their action. In a single hesitant hypegate, mediated through 5HT receptors. Therefore, the proposed compounds lower blood pressure in humans, like ketanserin, another 5HT blocker, but without the side effects caused by ketanserin during blockade of adrenergic alpha receptors. Injections are administered orally or parenterally to a mammal if there is an excess of circulating serotonin and this mammal wants to block the 5HT receptors in order to alleviate the symptoms caused by excessive serotonin levels, such as high blood pressure and migraine. dissolved in an isotonic saline solution and administered intravenously. For oral administration, the pharmaceutical salt of the drug is mixed with the usual pharmaceutical excipiens, Kimi, as starch, and loaded into capsules or compressed into tablets, each of which contains 0.1-100 mg of active ingredient. Dose-dose levels of 0.01-1000 mg / kg are effective in blocking 5HT4 receptors, i.e. The oral dose can be administered 2-4 times per day, bringing the daily dose range from Oj003 to 10.0 mg / kg of body weight. To show that the proposed compounds have a high affinity for 5HT (r-receptors, true dissociation constants were determined ( (Cd) as a measure of affinity for 5HTo receptors, expressed as negative logarithm, according to the following method: Male Wistar rats (weighing approximately 150-300 g) were killed and their external strap veins and thoracic aorta were freed from connective tissue, cannulated in situ placed in a modified bica Krebs bonate buffer in a suitable tissue bath. Two 30-gauge stainless steel L-shaped needles were inserted into each cannula and the excised vessels were gently pushed onto the needles. One needle was attached to the stationary glass wand, and the other to The modified bicarbonate buf fer of Krebs had the following composition, mmol: sodium chloride 118.2; potassium chloride 4.6; calcium chloride dihydrate 1.6; potassium hydrochloric acid phosphate 1,2; magnesium sulfate 1,2; dextrose 10.0; sodium bicarbonate 24.8; and water to a total weight of 1000 g. Tissue baths were kept at, aerated with a mixture consisting of 95% oxygen and 5% carbon dioxide (by volume). The initial optimal rest force of 1 and 4 g was applied to the belt vein and aorta, respectively. Isometric abbreviations were recorded as changes in grams of force on a Beckmann dinograph with Statham UC-3 sensors and microscale instrumentation. Tissue equilibrium was established 1-2 h before exposure to the drug. Control reactions were obtained for serotonin in Vienna and for norepinephrine in the aorta. The vessels were then incubated with appropriate concentrations of the test compound for 1 hour. The reaction to serotonin or epinephrine was repeated in the presence of the test compound. Narrowing (lumen) from serotonin was evaluated in the strap vein, since this tissue produces noticeable responses to serotonin in the absence of alpha receptors. The antagonistic activity of alpha receptors has been evaluated in the aorta. The true dissociation constants of the antagonist were determined for each concentration of the test compound by the following equation (dose ratio - 1) in which (B) is the concentration of the antagonist and the dose ratio represents the competitor's ED Q in the presence of an antagonist divided by the control ED "l the results are then expressed as negative logarithm. Values - log K, obtained for the corresponding proposed compounds are presented in Table 1. By the way, the two proposed compounds are about three times stronger than the comparison compounds in this in-vitro communication analysis. Thus, an increase in the N-1 alkyl group from methyl to ethyl, or an increase in the cyclopentyl group to the cyclohexyl moiety leads to an unexpected increase in the strength of the compound. All compounds in the analysis were moderately toxic. The ability of the proposed compounds to affect the sexual behavior of male animals was established by conducting the following experiments. Male Sprague Dax-7ley rats were used for these studies. Evaluation of sexual behavior was performed at two-week intervals, starting at 6 months of age and ending at the age of 12 months. In the initial period of the process, male rats with different levels of productivity were selected for testing the proposed compounds. These levels of productivity included male rats that did not exhibit sexual behavior (cages) (not mating): male rats capable of cage, but not able to eject during the test period (not ekuleters) and male rats capable of to ekulyatsii during testing. Before treatment with the drug solution, each male rat required at least two consecutive tests with the carrier. After testing each compound, additional tests were carried out with the carrier. In order to eliminate behavioral reactions during treatment with compounds that may be due to spontaneous changes in mating ability, the behavioral reaction reversibility criterion followed by carrier treatment was used. Thus, the actual behavioral response to drug treatment was arbitrarily set as a response that did not change from the initial control response or changed in a subsequent control test with the carrier. The pairing tests were carried out during my phase of the light cycle. using red light. Each behavioral test was initiated by injecting a ratseptive female rat to a male and ended either 30 minutes or immediately after the first post-breeding set. Indicators of ability to mate, which were evaluated in rats capable of ejaculation, included: delaying of the set (time interval from the introduction of the female rat to the first saddle); the delay of the intromission (the time interval from the introduction of the female rat to the first intromission); delay of ejaculation (time interval from intromis .159 sy. to eculation); post-emission interval (time from elution to the next charge) j frequency of the charge (total number of charges with or without intromissia) to ejection); the frequency of the intromice (the number of ponds, with the intromissia prior to ekulii); the effectiveness of the inromsii (frequency of the inromsions, divided by the frequency of the tank); the frequency of copulation (the number of ponds before the eculation); the efficiency of copulation (the number of tanks with the syntromissia divided by the total number of tanks), and the intensity of copulation (the number of tanks per minute). Ka: to each other, the male rat was given a solution containing either only the vehicle in water or the compound obtained in Example 1, (8)) N-cyclohexyl-1-isopropyl 6-met1-shergolin-8-carboxamide, in the same vehicle. The support consisted of mmol of acetic acid and 1 mmol of ascorbic acid. The results of these experiments are presented in table 2-7. In TabLo2, 7 N means the number of stomachs used to obtain data, the average values of which are represented by the invention. Formula
    The method of producing cycloalkylamides (8p) -1-alkyl-6- (substituted) ergoline of the general formula
     S N /, f C- N-
    Rt -N
    Ri,
    //
    NHR,
    (cHj) fr,
    where Rj, R; j and m have the indicated meanings,
    in the presence of an acid-binding agent in the case when Y-COOH is a group, followed by, if necessary, the conversion of products I into their salt. 12: where, -C4 is alkyl; | -C4-alksh1 with a straight chain; RJ is hydrogen or C-CA is straight chain alkyl; hydrogen, C | -CA-alkyl, hydroxy - l group or C (-C-alkoxygroup pa; m O, 1 or 2, provided that when RX and Rj each means methyl and each means hydrogen, m does not equals 0; or their pharmacist acceptable acid addition salts, which is a compound of the general formula where Y is COOH-, CON3 group, or COOCO (C-C4 alkyl), and RJ and R have the indicated values , is subjected to interaction with the amine of the formula
    131597103
    True dissociation constants and for 5HT - reactors
    Example
    R СН (СНз), СНССН,), (СН5) СНз СНз) 4 CH (CH,) j СН (СНз), СН «2 СН CHj СН (СН,) 4, а1 (сп5) g СН ( CH5) g CH (CHj) a CH (CHs) 4 Veshchest- (8p) -N-UHiaioreKCHn-1, 6-dimethyl ergopya compared to (8)) - K-Cycpopentyl-1-ethyl-6-meth gperg. ,. ", ..." ..... | - - - Effect of the compound on the ability to cop male rats, Subcutaneous Dose, Response,% ng / kg Not mating 16.3 (1/16) 1028.6 (4/14). 10057.1 (8/14) 100058.3 (7/12) 1000054.5 (6/11)
    14
    t a t5 p n c a 1
    5HT
    - log KB Tab H H H A-OCH ,, trans4-OCH3 cis-A-OCH cis-A-OCHE H H transn-8-carboxamide olin-8-carboxamide -, -, - -. persons 2 about the example of I str. u th e introduction) t Not e-books 11.1 (1/9) 45.0 (9/20) 54.5 (6/11) 56.3 (9/16) 61, 1 (11/18)
    The numbers in parentheses show the part of the reacted rats.
    15
    The effect of the compound of Example 1 on the ability to copulate in male rats, subcutaneous administration
    Note. Control values were obtained for the same rats two weeks after the administration of the vehicle,
    All injections were performed 30 minutes before the test. Statistically significant changes.
    The effect of the compound of Example I on the ability to copulate in male rats, subcutaneous behavior
    p and swords do not. The control ones (at the same time, received the same abdomen and two pedals after “keeping the carrier,
    All injections were performed 30 minutes before the N. Chaplus experiment. statistically significant itmenich.
    1597103
    16 3
    Table
    Table
    The effect of the compound of Example 1 on the ability to copulate in male rats is oral administration.
    Note. All solutions were administered with food 90 minutes before the start of the experiment.
    Control reactions were obtained in the same rats two weeks after the administration of the vehicle with feed. Statistically significant changes. The effect of the compound according to the example in male rats, oral
    29.7i 2.9 27,514.4
    19.4 ± 2.4
    18.7t2,1
    21.1 b3.9
    16.81: 1,8
    25.9tl, 6 22.9 ± 1.2
    Table 5
    2.5 ± 0.2 2.3iO, 2
    1.7 ± 0.2
    2,5rO, 4

    2, OiO, 4 2.7 ± 0.4
    2.21 0.2 .3,310.3 Table I for copulation ability introduction
    nineteen
      and n. e. Solutions were injected with feed 90 minutes before the expiration. The control values represent the reactions of the same rats to the oral administration of the carrier two weeks before the experiment with the drug. Statistically significant changes.
    The effect of the compound of example 1 on the ability to copulate in male rats after subcutaneous administration of the compound at a dose of 10 µg / kg in different periods of time
    I Statistically significant and
    20
    1597103 Continuation of the table.
    Table 7
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining cycloalkylamides (8p) -1-alkyl-6- (substituted) ergoline of the General Formula
    About R Λ
    12 'where R ^ -Cf-C ^. -alkyl ’;
    Straight chain Rq-Cf-Cd alkyl;
    Rj is hydrogen or C; -C4- ~ straight chain alkyl;
    R 4 is hydrogen, Ci-C 1 -alkyl, hydroxy -> group or C (-C 4 -alkoxygroup. Pa;
    m is 0.1 or 2, provided that when R; and R { each means methyl, a R 3 h R 4 each means hydrogen, m is not 0; or their pharmaceutically acceptable acid addition salts, wherein the compound of the general formula wherein Y is COOH-, CON is a group, or
    COOCO (C; ~ C 4 ~ alkyl);
    a R T and have the indicated meanings, are reacted with an amine of the formula where R j, R 4 and w have the indicated meanings, in the presence of an acid-binding agent when Y-COOH is a group, followed by, if necessary, converting the products of I into their salts.
    Table 1
    True Dissociation Constants for δΗΤ ^ -ρθπεπτοροΒ
    Example R R Rj R 4 . m 5NT-2,- log q 1 CH (CH 3 SI " n AND 1 9.67 2 CH (CH,) 2sn eChj n 1 9.0 3 CH (CH 3 ) 2(CH in ) 4 CH en n 1 9.1 4 CH (CH, sun 4n 4-0CH 31 9.73 5 CH (CH 3 ) 4sn en trams4-OSDN 1 9.73 6 sn esun 3n CIS-4-0CH i 1 9.57 7 CH 2 CH LChj n cis-4-och- 3 9.64 8 Chj sun 3n N 1 9.70 9Chj and N 0 10.33 10 CH 4 CH bCH }n n 1 9.25 eleven cn (si) gSNZ n trance-4-OH I 8.19 12 SI (SI,) gSNZ n n 2 8.98 thirteen CH (CH & ) inSNE and 4-chj 1 8.19 14 CH (CH,) esn en 2-OH 1 10.56 Substances (8 p) -N-Cyclohexyl-1,6-dimethylergoline-8-carboxamide 9.70 comparable (8 £>) -N-Cyclopentyl-1-ethyl -6-methylergoline-8-carboxamide 9.80 NII
    table 2
    The effect of the compounds of example 1 on the ability to copy in male rats, subcutaneous administration
    Dose, ng / kg Response% Not mating Not ejaculators 1 6.3 (1/16) And, 1 (1/9) 10 28.6 (4/14). 45.0 (9/20) 100 57.1 (8/14) 54.5 (6/11) 1000 58.3 (7/12) 56.3 (9/16) 10,000 54.5 (6/11) 61.1 (11/18)
    The numbers in brackets indicate the portion of the reacted rats.
    Table 3
    The effect of the compounds of example 1 on the ability to copy in male rats, subcutaneous administration
    Dose, mcg / kg Delayed ejaculation, s Post-ejaculation interval, s The control0.01 N = 14 602.6 * 47.4530.4 164.6 366.9 + 15.6266.8 + 9.8 The control0.10N = 15 747.9 * 61.8532 * 59.0* 367.1 + 18.7355.9 +13.2 Control ι; ο N = 11 749.5 + 59.1584 * 89.4* 371.2 + 19.8357.3 + 9.5 The control10.0N = 11 850.4+ 99.2454.1 * 78.4* 368.3 i 23.0333.9 * 10.9 The control100.0N = 16 731.8 +44.5463.6 +46.6X 373.3 + 22.8325.6 +16.0
    Note. Control values were obtained for the same rats two weeks after vehicle administration.
    All injections were performed 30 minutes prior to testing.
    L Statistically significant changes.
    Table '4
    The effect of the compounds of example 1 on the ability to copy in male rats, subcutaneous administration Vine, mcg / kg GCadence Frequency Copulation efficiency Copulation rate The control 20.1 1 2.4 0.59 10.05 2.1 ± 0.2 0.01 21, 4 12.0 0.56 10.03 2.4 ± 0.3 N "14 The control 25.0 ± 2.3 0.38 + 0.03 2.0 + 0.2 0.10 22,912.6 0.54 1 0.04 2.7 + 0.3 N "15a. *. The control 23.1 12.4 0.53 10.04 1, 9 +0.2 1.00 21.4 ± 1.7 0.67 ± 0.03 2.4 ± 0.2 N-I1h The control 23.2 12.1 0.49 ± 0.05 1, 71 0.2 10.0 18.5 12.4 0.57 ± 0.04 2.6 + 0.4 N "11N F The control 24.8 + 2.3 0.49 1 0.03 2.1 1 0.2 100.0 21.3 + 1, 4 0.59 i 0.04 2.9 + 0.3 N "164 h
    ’Note. Control values were obtained on the same animals two weeks after vehicle administration.
    All injections were performed 30 minutes before the start of the experiment. ’Statistically significant changes.
    Table 5
    The effect of the compounds of example 1 on the ability to copy in male rats, oral administration
    Dose, mcg / kg Delayed ejaculation, s Post-ejaculation interval, s The controlh 1 713.6 ± 58.1 358.5 ± 23.1 0.01 689.2 * 91.2 370.2 ± 23.7 N = 17 + The control 735.4 * 51, 9 381.9 ± 13.4 0.1 486.5 ± 70.8 313.4 ± 12.0 N = 14 * - * The control 646.3 ± 51.0 384.1+ 23.5 1, about 415.9 ± 62.3 322.1 ± 15.3 N = 8 + m The control 731.0 ± 87.0 345.1 ± 20.3 10.0 434.2 + 37.9 299.7 ± 15.1 N = 12 h X The control 804.6 ± 73.5 417.9 ± 28.4 100.0 366.1 * 52.2 350.6 + 29.5 N = 8 H-
    Note. All solutions were introduced with. food 90 minutes before the start of the experiment.
    Control reactions were obtained on the same rats two weeks after administration of the vehicle with food.
    ^ Statistically significant changes.
    Table 6 The effect of the compounds of example I on the ability to copy in male rats, oral administration
    •Dose, mcg / kg Cadence Frequency Copulation efficiency Intensity copulations, to the cage in number of minutes 1 2 3 4 The control0.01N = 17 29.7 + 2.927.5 ± 4.4* 0.43 ± 0.040.46 ± 0.05 2.5 ± 0.22,3 '± 0,2 The control0.1N = 14 1 9.4 ± 2.418.7 t 2.1 0.60 ± 0.050.60 ± 0.05 1, 7 ± 0.22.5 GO, 4* The control1,0N = 8 21.1 ± 3.916.8 ± 1.8 0.59 ± 0.060.58 ± 0.04 2.0 ± 0.42.7 + 0.4 The control10.0 25.9 ± 1.622.9 ± 1.2 0.43 ± 0.030.49 ± 0.04 2,210,23.3 ± 0.3
    4 ------------------- 1 ---------: --------- Continuation of tlbp A m 2 1 —----- | G— ---------- -. N = 12 The control100.0N = 8 1 9.4 ± 1, 714.4 ± 1.34- 0.51 +0.050.69 ± 0.04* · 1.4U, 12.6 10.4* * Note. The solutions were introduced with food 90 minutes before the ect. Control values represent the reactions of the same rats to the administration of an oral carrier two weeks before the drug experiment.^ Statistically significant changes,
    Table 7
    The effect of the compound of example 1 on the ability to copy in male rats after subcutaneous administration of the compound. in a dose
    10 mcg / k g at different time periodss1 1 Delayed ejaculation, s Post-ejaculation interval, s Copulation rate, number of cages per minute The control0.5 N = 11850.4 ± 99.2454.1 ± 78.4 368.3 123.0333.9 1 10.9 1, 7 ± 0.22.6 ± 0.4* The control8.0 N = 11653.5 1 61.7402.3 ± 59.7• ί 349.5 ± 16.8 320 ± 17.0* 2.6 1 0.23.9 1 0.5* The control24N = 15815.5 ί 64.6604.1 ± 68.4* - 422.4 ± 25.5391, 7 118.7 2.0 ί 0.32.8 ± 0.4 The control48N = 11591,0133.8531.8 * 60.6 364.8 ± 27.8365.4 1 20.2* 2.4 ± 0.22.5 1'0.2*
    * Statistically significant changes.
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    同族专利:
    公开号 | 公开日
    ES2054806T3|1994-08-16|
    IE61884B1|1994-11-30|
    JPS6416781A|1989-01-20|
    EP0296748B1|1993-04-07|
    MX11866A|1993-12-01|
    EP0296748A1|1988-12-28|
    KR890000482A|1989-03-14|
    DE3880022T2|1993-08-19|
    DK322588A|1989-02-01|
    IL86725D0|1988-11-30|
    HK77693A|1993-08-13|
    HU203344B|1991-07-29|
    KR960010454B1|1996-08-01|
    CN1019451B|1992-12-16|
    DE3880022D1|1993-05-13|
    UA6022A1|1994-12-29|
    IL86725A|1993-01-14|
    AT87921T|1993-04-15|
    DK322588D0|1988-06-14|
    CA1339661C|1998-02-10|
    ZA884222B|1990-02-28|
    EG18586A|1993-08-30|
    AU1765288A|1988-12-15|
    IE881788L|1988-12-15|
    HUT47271A|1989-02-28|
    PT87716A|1988-07-01|
    JP2653835B2|1997-09-17|
    AU613641B2|1991-08-08|
    PH24309A|1990-05-29|
    PT87716B|1992-10-30|
    NZ225022A|1990-07-26|
    CN1030586A|1989-01-25|
    HU211235A9|1995-11-28|
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    GB996062A|1961-07-13|1965-06-23|Westminster Bank Ltd|Improvements in or relating to lysergic acid compounds|US4902691A|1988-12-19|1990-02-20|Eli Lilly And Company|Heteroalkylamides of -1-alkyl-6-ergolines useful for blocking 5HT2 receptors|
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    AU2012355982A1|2011-12-19|2014-07-10|Map Pharmaceuticals, Inc.|Novel iso-ergoline derivatives|
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    US9012640B2|2012-06-22|2015-04-21|Map Pharmaceuticals, Inc.|Cabergoline derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US6228587A| true| 1987-06-15|1987-06-15|
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