• 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:
    Ergolinyl compounds which are nitrogen-substituted in the 8-position and have Formula (I) <CHEM> and physiologically compatible salts thereof, wherein (a) R<1> is hydrogen, the 8-substituent can be in the alpha - or beta -position and <CHEM> represents a single or double bond. R<2> is hydrogen, C1 4-alkyl or C1 7-acyl, R<3> is hydrogen, chlorine or bromine, and R<4> is C1-6-alkyl, C3-6-cycloalkyl-C1-3-alkyl, C3 6-alkenyl, or C3-6-alkynyl; or (b) R<1> is -@-NR<5>R<6>, and the 8-substituent can be in the alpha - or beta -position, <CHEM> represents a single or double bond, R<2>, R<3> are as defined above, R<4>, is C1-6-alkyl, C3-6-cycloalkyl-C1-3-alkyl, C3-6-alkenyl, or C3-6-alkynyl; and R<5> is hydrogen, C1-10-alkyl, C3 10-alkenyl, or C3 10-alkynyl, and R<6> is C1-10-alkyl, C3-10-alkenyl, C3-10-alkynyl, or aryl, or R<5> and R<6> together with the connecting N-atom form a 5- to 10-membered heterocyclic ring, preferably 5- or 6-membered, which optionally can contain further heteroatoms.
    公开号:SU1313348A3
    申请号:SU823519900
    申请日:1982-12-09
    公开日:1987-05-23
    发明作者:Хаффер Грегор；Зауер Герхард；Вахтель Хельмут；Шнайдер Херберт；Эдер Ульрих；Лоренц Ханс-Петер
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    1131
    The invention relates to a method for producing new ergoline derivatives of the general formula:
    ns-id., n
    S
    (I)
    R, -N
    where the substituent in the o-th position can be of the o (, or p-configuration; RI is a hydrogen atom, methyl,
    a 1n H - - / means simple or double
    communication; Rj, - C C-alkyl, cyclopropylmethyl, allyl; R and R are the same and mean alkyl.
    possessing valuable pharmacological properties.
    The purpose of the invention is to obtain new derivatives of ergoline, which have pharmacological advantages over known structural compounds with similar effects.
    Example 1. 359 mg of 9,10-dihydro-6-metip-ergolin-8-6-amine (1.5 mmol) are suspended, by passing nitrogen, in 7.5 ml of anhydrous methylene chloride. 294 mg of 1,1 - thiocarbonyl diimidazole (1, -65 mmol), dissolved in 7.5 ml of anhydrous methylene chloride within 3 minutes, are added dropwise at room temperature. After stirring for one hour, the mixture is heated to 50 ° C and dimethylamine is passed for 1 hour. Then, the cooled reaction solution was vigorously stirred with 10 ml of distilled water for 90 minutes, the aqueous phase was separated, extracted twice with 25 ml each of methylene chloride.
    The combined organic phases are washed once with 20 ml of a saturated solution of sodium chloride, dried over sodium sulfate and evaporated at 30 ° C. in vacuo. 495 mg of 3- (9, U-didehydro-b-methyl-wob-ergolinyl) - 1,1-dimethylthiocarbamide are obtained in the form of an oil, or 491 mg of the compound in the form of a hydroxylate with mp. 186 ° C (decomposition).
      +271.2 (s- 0.5, pyridine) o Example 2. Under the reaction conditions given in example 1, and
    82
    1 ,, 5 mmol of 9.1 O-didehydro-6-methyl-ergolin-8-amine get 3- (9,10-didehydro-6-methyl-8/9-ergolinyl) -1,1-dimethylthiocarbamide with t. square 195 ° С i
    (decomposition). A yield of 91% of theory, or from this thiocarbamide, a hydromaleate with a melting point of 166 ° C (decomposition) is obtained with a 73% yield (counting on the reacted 8/5-amine).
    Mj, +125.2 (c 0.5, pyridine). Example 3, 359 mg 9., 10-didero-6-methyl-ergolin-8o-amine (1.5 mmol) is translated, as indicated in example i, together with 1,1-thiocarbonyldiimidazole, into the corresponding 8o (, -isothiocyanate. To it, at room temperature, add 0.5 ml of freshly distilled diethylamine at room temperature, leave to react for 2 hours at
    room temperature in an inert gas atmosphere and then finish the job as indicated in example 1, the residue after evaporation with methylene chloride-water (99: 1) is filtered
    .
    Teres silica gel. Yield: 414.8 mg. 3 .- (9, I O-didehydro-6-methyl-Wob-ergolinyl) -, 1-diethylthiocarbamide
    M.p. 157-158 ° C (decomposition).
    Wj, + 377.0 ° (c 0.5, pyridine).
    As a result of the salt formation of diethylthiocarbamide with malonic acid, 468 mg of hydromaleate with a mp. 183 C (decomposition) ..
     MW + 283.8 ° (with 0.5, pyridine),
    Example 4. 1 mmol (241 mg) of 6-metsh1-ergolin-8OC-amine is subjected to an exchange reaction to 3- (6-methyl-8 | y, -ergolinyl) -1, 1 diethylthiocarbamide, similarly to the indications of Example 3.
    Yield: 244 mg (68.4% of theory). Mp 217 C (decomposition); ethyl acetate / ether.
    WD + 35.0 ° (with O, 5, pyridine). By adding piperidine N-methylpiperazine or 4-fluoroaniline instead of diethylamine, the following thiocarbamides in a similar way are obtained in
    in the form of free bases or — by co-dissolving with an equivalent amount of maleic acid and / or L-tartaric acid in methylene chloride and / or methanol — the corresponding hydromaleates or L-hydrateartrates are obtained.
    Piperidine-1-thiocarboxylic acid- (b-methyl-8-6-ergolinyl) -am.id, 68% of theory, mp, C (decomposition).
    31
    oiT d +4,8. (with 0.5,. in methanol).
    - (4-Fluorophenyl) -3- (6-methyl-8 (- ergolinyl) -thiocarbamide, L-tartrate, 81% of theory, m.p., 260 C (decomposition).
    Wp + 17.6 ° (with 0.5% in pyridine). 4-Methylpiperazin-1-thiocarboxylic
    acid- (6-methyl-8-ergominyl) -amide, 74% of theory, m.p. 220 C (decomposition).
      +1.8 (, 5% in pyridine)
    Example 5. 9,10-Didehydro-6-methyl-ergolin-8c-amine (1 mmol) is subjected to an exchange reaction with 1,1-thiocarbonyl-diimidazole and the corresponding amine.
    With diallylamine, 3- (9,10-didehydro-6-methyl-8c (, -argolinyl) -1,1-bis- (2-propen-1 yl) -thiocarbamide) is obtained.
    Yield: 72% of theory.
    L-Hydrotartrate (93% of theory), so pl. 154 C (decomposition).
    HD + 228.2 ° (, 5, methanol). I
    With pyrrolidine, pyrrolidine-1-tylcarboxylic acid- (9,10-didehydro-6-methyl-8-6-ergolinyl) -amide is obtained.
    Output: 78% of theory, so pl. 138 С (decomposition).
      + 247.8 ° (, 5, methanol)
    Morpholine-4-thiocarboxylic acid-9,10-didehydro-6-methyl-8o; .- ergolinyl) -amide is obtained with morpholine.
    Output: 85% of theory, so pl. 120 (decomposition),
    si J-) +235 (, 5 in pyridine).
    C (2) -2-hydroxy-methylpyrrolidine gives (2S) -2-hydroxy-methylpyrrolidine 1-thiocarboxylic acid- (9,10-didero-6-methyl-8c (gergolinyl) -amide.
    Output: 83% of theory, mp, 130 (decomposition).
    I.R. 203.6 ° (, 5, pyridine).
    Hydromaleate: 65% of theory, so pl. 196 ° C (decomposition).
    MD + 175.8 ° (, 5, pyridine).
    With thiomorpholine, 3,4,5,6-tetrahydro-2-H-l54-thiazin-4-thiocarboxylic acid- (9,1O-didehydro-6-methyl-8 ° C-zrgolininyl) -amide is obtained.
    Output: 83% of theory, so pl. 97-108 C (decomposition).
      + 320.4 ° (, 5, pyridine).
    Hydromaleate: 69% of theory, m.p. 148 C (decomposition).
    484
    in + 236.4 ° (, 5, pyridine).
    Example 6.1 mmol of 9,10-dihydro-1, 6-dimethyl-ergolin-8c1.-amine is subjected to an exchange reaction with 1,1-thiocarbonyl diimidazole and diethyl amine, as described in Example 3, to 3- (9, 10-didehydro-1, 6-dimethyl 8 x:, - ergolinyl) -, 1-diethylthiocarbamide. After chromatography, 3- (9,10-didehydro-1, 6-dimethyl-8c-ergolinyl) -1, 1-dimethyl-thiocarbamide is obtained with a 67 D-NHY yield. Combined dissolution with an equivalent amount of L-tartaric acid in methylene chloride and methanol gives 3- (9,10-didehydro-1,6-dimethyl-8c1-zrgolinyl) -1,1-diethylthiocarbamide tartrate. Yield: 226 mg (51% of theory).
     at 296 ° (, 5 in pyridine). Example 7. Conducting the reaction of the exchange of a specific or non-valuable amino compound with 1,1-thiocarbonyldiimidazole followed by the addition of a primary or secondary amine, such as diethylamine, gives the corresponding thiocarbamides, as indicated in Example 3,
    3- (9,10-Dihydro-6-ethyl-8-c1:, - ergolinyl) -1,1-diethyl-thiocarbamide as L-hydrotartrate. Yield: 45% of theory.
    Yves + 209 ° (, 5% in pyridine).
    3- (9,1 0-Didehydro-6-n-propyl-8o - ergolinyl) -, 1-diethylthiocarbamide. Yield: 73% of theory.
    L-tartrate, yield: 80% of theory.
    oi J-, 231 ° (, 5% in pyridine).
    3- (Cyclopropylmethyl-9,10-didegidro-8o-zrgolininyl) -1,1-diethylthio-Jaoba-Mead, yield: 38% of theory.
    L-Tartrate, yield: 65% of theory.
      +266 (, 5 in pyridine).
    T, 1 -Diethyl-3- (6-ethyl-8o-ergolinyl) -thiocabamide. Yield: 57% of theory. WD + 40 ° (, 5% in chloroform).
    1, 1 -Diethyl-3- (6-n-propyl-8th, -ergolinyl) -thiocarbamide.
    Yield: 74% of theory.
    oi. ,, 42 ° (, 5% in chloroform). I
    3- (6-Allyl-8c-zrgolin, w1) -1, 1-di-methylthiocarbamide.
    Yield: 98% of theory. L-tartrate, yield: 70% of theory.
    Md 38 (, 5% in pyridine).
    3- (Cyclopropylmethyl-8-6-zgrolinyl) - 1,1-diethylthiocarbamide.
    Yield: 68% of theory. L-Tartrate, yield 88% of theory.
    oo 42 ° (, 5% in pyridine).
    Example 8. In a similar way to example 3, out of 300 mg of 1, 6-dimethyl-ergolin-8o6 amine, together with 1,1-thiocarbonyl-di-imidazole and diethylamine, 5,274 mg of 1, 1-dieth-1-3- (1,6-dimethyl -8 (/ - ergolinyl) -thiocarbamide.
    Output: 63% of theory,
    ID +38 (, 5% in chloroform),
    1313348
    Efficacy of 8c1 (, - ergolinylthiols by selected parameters of Irvinet-test (methods modified, Irwins Psychopharmacologla 13: 222-257, 1968) after a single intraperitoneal use in mice (given completely low effective dose of at least 2-3 animals in mg / kg) are given in table.1.
    Table 1
    Bn-X
    X
    R.
    RI
    .Y-ssch
    Known
    Comparative to thioureas (2-4), compared with BOC-ergolinyl urea-lizuride (l), are less toxic in all respects and at least one of the other parameters, which reflect central stimulation of dopamine receptors, is more effective in pamination.
    The effect of intraperitoneal pre-injection of the drug (ZO
    Drug administration, mg / kg
    min) to mice at various doses of 1-methyl transdihydrolizuride (1-Me-TDHL) or € 1 m; thyl-thiotransdihydrolisiside (1-Me-thio-TDHL) for hypothermia caused by clonidine (C 1 OP, 0, 1 mg / kg intraperitoneally) is reflected in the table.2. The temperature of the rectum was measured 30 minutes after administration (modified by Voigtlander P, .F. And al. Neurcipharma-cology 17: 375-381,2978).
    table 2
    Direct temperature
    1-Me-TDHL 6.25 + CLON 1-Me-TDHL 12.5 + CLON
    1-Me-TDHL 25 + CLON
    Indifferent basis of the drug + CLON
    l-Me-THC-TDHL 1.56 + CLON l-Me-THo-TDHL 3.13 + CLON l-Me-THO-TDHL 6.25 + CLOH l-Me-THO-TDHL 12.5 + CLON
    35.0 ± 0.2 34.4 ± 0.6
    36.2 ± 0.2
    34.0 ± 0.2 34.6 ± 0.1
     : 35 .1t 0.1 35.20, 2
    35.3 ± 0.2
    P 0.01 U.S The indifferent basis of the drug + CLON (variant analysis, j test Dunnett a). P 8 animals - per treatment group.
    I-Me-THO-TDHL acts more Effectiveness of 8-tiotranedihydrolisuride derivatives according to the selected parameters of the Irwin-test (method modifyingly blocking for presnayuticheskie central oCj-receptors than. ......
    I-Me-TDHL, thus amplified by Irwin S.Psychopharmacology 13; 222-257, 1968) after a single intraperitoneal administration to mice is given in Table 3 (the smallest fully effective dose is given for an effect on a minimum of 2-3 animals, in mg / kg).
    Table 3
    X
    II
    central noradrenal transmission c. lower dose range. Therefore, l-Me-Tio-TDHL has a potentially more effective antidepressant effect than is Me-T1 HI.
    kn-sg
    n
    X
    II
     h
    N-r
    Well-known
    I
    s, n.
    Missing action ..
    100
    0.05 0.05
    Thiourea derivatives (2,4) are less toxic compared with the corresponding urea derivatives (1,3) in all respects and their agonistic effects on central dopamine receptors (parameter, stereotypes) are less pronounced.
    权利要求:
    Claims (1)
    [1]
    Derivatives (2.4) act as a stimulant - an effect that reflects the stimulation of central noradrenaline receptors. The preferential stimulation of central norepinephrine receptors, compared with the action of central dopamin receptors (2.4) compared with (1.3), is taken as preferred, for example, for geriatric indication, because it allows targeted influence on psychomotor deficiency in old age and reduce the risk of unwanted central dopamine effects (movement disorder, vomiting)
    The method of obtaining ergolin derivatives of the general formula
    , Rit
    ten
    hydrogen atom, methyl;
    - simple or double bond;
     C, 2 -C-alkyl, allyl, or cyclop ropilmethyl;
    and R,
    - the same and mean C, -Slcyl j,
    characterized in that the compound of general formula
    what
     V At 1 at D - p
    where / Kj and Kg have the indicated values, are reacted with 1, - thiocarbonyldiimidazole in anhydrous methylene chloride and then with the amine of the formula
    NHRjR,
    R and R have the indicated meanings, 30 and the obtained target products are allocated where, h,
    Editor V. Danko Order 1983/58
    Tehred I.Popovich
    Proofreader G. Reshet
    Circulation 372Subscribe
    VNYIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, 1-35, Rautpska nab., d.4 / 5
    U production and printing company, Uzhgorod, Projecto st., 4
    Proofreader G. Reshetnik
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813151912|DE3151912A1|1981-12-23|1981-12-23|NEW ERGOLIN AMINO DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
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