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    • 专利摘要:
    …<CHEM>… R1 = H, CH3… R2 = H, halogen, CH3, CN, lower alkylthio, phenylthio …<CHEM>… R4 = C1-C4 hydrocarbon… R5 = H, C1-C4 hydrocarbon, phenyl… A = CHR6, CH2CHR6, CH = CR6… R6 = H, lower alkyl… n = 0, 1, 2… X = O,S,NH B=CN, COOalK, CONH2… R9 = H or B and R9 = -C=W… W = O,NH… and their pharmaceutically acceptable salts are antiprolactinic and antihypertensive agents. Their preparation and pharmaceutical compositions containing them are also described.
    公开号:SU1327788A3
    申请号:SU843728545
    申请日:1984-04-24
    公开日:1987-07-30
    发明作者:Бернарди Луиджи；Чиодини Лаура；Мантегани Серджио；Руджиери Даниела；Темперилли Альдемио；Салвати Патриция
    申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new ergol derivatives of general formula (I):
    X
    II
    R7%, N-Rs
     A-in RS
    VScN-K f N R, 4-
    R is hydrogen or methyl
    Group;
    R, is hydrogen or bromine, or a methyl, cyano, methylthio group,
    K is hydrogen and R is hydrogen or methoxy, or R is hydrogen, and RJ
    and RV
    together
    taken to form a bond, or RJ — hydrogen or methoxy, and R and R, taken together, form a bond; R, is methyl, propyl, or allyl group j Rf is hydrogen or C —C alkyl;
    X is oxygen or sulfur, RJ is hydrogen, and B is a methoxycarbonyl or ethoxycarbonyl group, or Rg and B, taken together, are the XC O group; A is a group of formula -,
    - CHg-CHg - or - CH CHP is an integer O, 1 or 2, with improved pharmacological properties.
    Example 1. 6-Methyl-8 - (1H, 3N) -2,4-dioxo-dihydro-1-pyrimidinylmethyl-zrgoline.
    A mixture of 5.1 g of nomethyl-6-methyl-zrgoline and 1.8 ml of methyl acrylate in 100 ml of methanol is heated to boiling for 4 hours using a reflux condenser. The solvent is evaporated under reduced pressure, and crystallization of the residue from distil ether gives
    6 g 6-methyl-8g- m- (2-methoxycarbo 1
    nilmethyl) -aminomethyl-ergoline, melted at 130-132 C.
    To a solution of 2.86 g of potassium cyanate in 30 ml of water is added 35 ml of 1N. hydrochloric acid and a solution of 6 g of 6-methyl-8 | - s- (2-methoxycarbonylethyl) - -aminomethyl-ergoline in 120 ml of water
    0
    five
    Reaction mixture for 4 h. they are warmed up and then left overnight at room temperature. The precipitated solid is filtered and recrystallized from ethanol gives 4.5 g of the title compound, melting with decomposition at
    Example 2. 6-Methyl-86- n- (2-methoxycarbonylethyl) -H-carbomoyl-aminomethyl-ergoline.
    A mixture consisting of 8.5 g of 6-methyl-8J5-N- (2-methoxycarbonyl ethyl) -amino-5 methyl ergoline prepared as in Example 1, 2.86 g of cyanate. potassium in 120 ml of water and 35 ml 1 and. hydrochloric acid, heated for 1 h to, then the solution is neutralized with 1 N, sodium hydroxide and extracted with chloroform. The organic layer is evaporated and the residue is purified on a silica gel chromatography column to obtain 6.5 g of the title compound.
    Rf in ethyl acetate - dimethylformamide - butanol - pyridine (4: 3: 3: 1 by volume) 0.45.
    MS (F.D) 384 (M), 352 (M-CHjOH).
    Example 3. 6-Methyl-8 - (2,4-Q -dioxo-1-imidazolidinyl-methyl) -ergoline.
    A solution of 1.3 ml of ethyl bromoacetate in 30 ml of dimethylformamide is added to a heated solution of 5 g of 8-aminomethyl-6-methylergoline in 90 ml of dimethylformamide. Upon completion of the reaction, the solution is evaporated in vacuo, then placed in ice-cooled water and extracted with chloroform.
    The organic layer was removed in vacuo, and by purifying the residue on a silica gel chromatography column using ethyl acetate: methanol (9: 1 by volume) to elute, g 3.5 g of 6-methyl-8 - (N-ethoxycarbonylmethyl) were obtained. aminomethyl) ergoline, having after crystallization from diethyl ether, so pl. 174-176 ° C.
    3.5 g of 6-methyl-8 - (N-ethoxycarbonylmethyl-aminomethyl) -ergoline is mixed with 1.75 g of potassium cyanate, as in Example 1, and the title
    yield 72%
    five
    0
    0
    five
    the compound is obtained with m. pl. . 300 ° C.
    Example 4, 6-Methyl-8 - y- (2-.-Methoxycarbonylethyl) -H-methylcarbamoyl-aminomethyl-ergoline.
    A mixture consisting of 8.5 g of 6-methyl-86-N- (2-methoxycarbonyl-aminomethyl) -ergoline, prepared as in Example 1, and 2.95 ml of methyl isocyanate in 100 ml of pyridine, is heated within 1 h to 60 ° C. After evaporation of the solvent by crystallization of the precipitate from methanol, 8.5 g of the title compound are obtained with an mp. 140-142 C.
    Example 5. 6-Metsh1-8y- (1H, ZN) -2,4-dioxo-3-metsh1-dihydro-1-pyrimidinyl-methyl ergoline.
    Heated in vacuo for 1 hour to 145 from 6-methyl-8 - y- (2-methoxycarbonylethyl) -K-methylcarbamoyl-aminomethyl) -ergoline, prepared as in Example 4, gives 6.5 g of this in the title of the compound having, after crystallization from methanol, m.p. 118-120 C,
    Example 6. 6-Metrtl-8jS- N- -ethoxycarbonylmethyl-K-methylcarbamoyl-aminomethyl-ergoline,
    In example 4, but using 6-methyl-86 - (N-etoxycarbonyl-methyl-aminomethyl) -ergulin, prepared as in example 3, instead of 6-methyl-8-y- (2- -methoxycarbonylethyl) -aminomethyl - ergoline , receive specified in the title compound with so pl. 165-167 s
    Example 7. 6-Metsh1-8y- (2,4-Dioxo-3-methyl-imidazolidinyl-methyl) -ergoline.
    From heated in vacuo for 1 h to 140 ° C with 6-methyl-8 / - (S-ethoxycarbonylmethyl) -K-methyl-carbamoylamine nomethyl) -ergoline, the title compound is obtained in a yield of 77%, and so on. 250 C, with decomposition.
    Example 8. 6-MeTmi-86- N- - (2-methoxycarbonnethyl) -Y-propyl-β-carbamoyl-aminomethyl-ergoline.
    The title compound is obtained as in Example 4, but propyl isocyanate is used instead of methyl isocyanate.
    Output 85%, so pl. 130-132 C.
    P. and mera 9. 6-Metsh1-8 - (1H, ZN) -2,4-dioxo-3-propyl-dihydro-1-pyrimidinyl-methyl ergoline.
    I act like. in example 5, but applying. 6-methyl-8 - y- (2-methoxy-carboxylic-ethyl) -N-semi-I-carbamate-aminomethyl-ergoline, prepared as in example 8, instead of 6-methyl (2-methoxycarbamoyl-aminomethyl) -ergoline get specified in
    titles Compound; output with a yield of 70%; and so on. pl. 201-202 ° C.
    I'll try it on. 6-Methyl-8 - k- - (2-methoxycarbonylethyl) -K-isopropylcarbamoyl-aminomethyl-ergoline.
    In Example 4, using isopropyl isocyanate instead of methyl isocyanate, the title compound is obtained, having a mp. 112-115 C.
    Example 11. 6-Methyl-8 - (1H5
    3H) -2,4-dioxo-3-isopropyl-dihydro-1-pyrimidinyl-methyl-ergoline.
    Heated for 2 hours to 150 ° C, 6-methyl-8 p- (2-methoxycarbonylethyl) -Y-isopropylcarbamoace-amino-metr-zrgoline prepared in Example 10 gives the title compound vigho; om 60 %, so pl. 175-177 C.
    Example 12, 6-Methyl-8-CK-ethoxycarbonylmethyl-K-propylcarbamoyl-aminomethyl) -ergoline.
    In Example 6, using propyl isocyanate instead of methyl isocyanate, the title compound is obtained, in a yield of 80%, having a melting point of mp. 109 - 110 ° C.
    Example 13. 6-Methyl-8 2,4-α-dioxo-3-propyl-1-imidazolidinyl-methyl-ergoline.
    From heated in vacuo for 1 h to 6-methyl-8 / - (H-ztoxy-carboxymethyl-N-propyl carpamoyl-am nomethyl) -ergoline, prepared
    in Example 12, the title compound is obtained with a yield of 68%, and so on. 188-190 ° C.
    Example 14. 6-Methyl-8 - (N- -ethoxycarbonylmethyl-L-isopropylcarbamoyl-aminomethyl) -ergoline.
    For example 6, using isopropyl isocyanate instead of methyl isocyanate, the title compound is obtained, having mp. 118-120 ° C.
    Pp. M. 15. 6-Metsh1-8 p- (2,4- -dioxo-3-isopropyl-1-imidazolidinyl-methyl) -ergoline.
    Heated in vacuo for 2 hours to 160 ° C of initial 6-metsh1-8 - - (N-etoxycarbonylmethyl-N-isopropylcarbamoyl-aminomethyl) -ergoline, prepared as in Example 1, is given in the title connection with a yield of 75%, t. Pieces - 210-212 ° C. : Example 16. 6-Methyl-8 p-2- - (1H, 3N) -2,4-dioxo-dihydro-1-pyrimidinyl-ethyl-ergoline.
    0
    five
    five
    In example 1, using 8-amino-etip-6-methyl-ergoline instead of nomethyl-6-methyl-ergoline, get specified in the title compound with
    the title compound yield 74%, so pl, 140-142 ° C.
    Example 17. 6-Methyl-8 - 2- - (2,4-dioxo-1-imidazolidinyl) -ethyl-ergoline.
    In Example 3, using 8-amino-ethyl-6-methyl-ergoline instead of BA-aminomethyl-6-methyl-ergoline, the title compound is obtained in 68% yield, mp. 242-244 ° C.
    Example 18. 6-Methyl-8) - (1 H ZN) -2,4-dioxo-dihydro-T-pyrimidinyl-ergoline.
    In example 1, apply 8 | α-amino-6-methyl-zrgoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in 79% yield, mp. Zi Zi S.
    Example 19. 6-Methyl-8 - (2,4-dioxco-1-imidazolidinyl) -ergulin.
     In Example 3, using 8-amino-6-methyl-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained with an yield of 80%, t. square 295-297 ° C. .




    Example 27. 6-Allyl-8 -2-tioxo-4-oco-3-methyl-tetra
    PRI me R 20. 1,6-Dimetsh1-8y - hl t
    r / itr oo o / h JO -1-pyrimidinyl-metsh1-ergoline.
    - (1H, ZN) -2,4-dioxo-dihydro-1-pyri-i m j i-
    midinyl-methyl ergoline.
    In example 1., using 8-amino-methyl-1,6-dimethyl-ergoline instead of 8-α-aminomethyl-6-methyl-ergoline, semi-example 25, using 8 methyl-6-allyl-ergoline instead of 8 nomethyl-6- methyl ergoline, the floor indicated in the title of compound 35 in 77% yield.
    The title compound in 75% yield, mp, 314-31b ° C.
    Example 21, 1,6-Dimethyl-8b- - (2,4-dioxo-1-imidazolidinyl-methyl) -ergoline.
    In Example 3, use 8-amino-methyl-1,6-diethyl-ergoline-instead of -aminomethyl-b-methyl-ergoline, semi-. indicated in the title compound with a yield of 65%, so pl. 292-294 ° C.
    Example 22. 6 Methyl-10-methoxy-8 - (2,4-dioxo-1-imidazolidinyl- -methyl) -ergoline.
    In Example 3, using 8-amino-1-6-methyl-10-methoxy-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in 68% yield, mp. 234-236 ° C.
    Example 23. 6-Methyl-8 - (1H, ZN) -2,4-dioxo-1-pyrimidinyl-methyl - -ergoline.
    In Example 1, use 6-methyl--8) - (3-acrylic acid ethyl ester) -3-amino-methyl-1-ergoline instead of 6-methyl-8 p-m- (2-mutoxycarbonylethyl) -aminomethyl-ergoline, get specified in
    the title of the connection with the output of 48%, so pl. 320 C,
    Example 24. 6-Methyl-8 - (1H) - -2-thioxo-4-ox6-tetrahydro-1-pyrimidinyl-methyl-ergoline.
    In Example 1, using potassium thiocyanate instead of potassium dianate, the title compound is obtained in 58% yield, mp. .
    Example 25. 6-Methyl-8 p- (1H) - -2TIOXO-4-OXO-3-methyl-tetrahydro-1-pyrimidinyl-methyl-ergoline.
    In Example 1, using methyl isothiocyanate instead of potassium cyanate, the title compound is obtained, in 74% yield, mp. 266-268 C. Example 26. 6-p-Propyl-8 - - (1H) -2-thioxo-4-oco-3-methyl-tetra-hydro-1-pyrimidinyl-methyl-ergoline.
    In Example 25, using 8 p-amino-methyl-6-p-propyl-ergoline instead of -aminomethyl-6-metnl-ergoline, the title compound is obtained with a yield of 63%.
    Example 27. 6-Allyl-8 - (1H) - -2-tioxo-4-oxy-3-methyl-tetrahydrate
    i m j i-
    In Example 25, using 8 amino-methyl-6-allyl-ergoline instead of 8 with 1-aminomethyl-6-methyl-ergoline, the title compound is obtained in a yield of 77%.
    PRI me R 28. 6-Methyl-8 - (2- -thioxo-4-oxo-3-methyl-1-imidazolidinyl-methyl) -ergoline.
    In Example 3, using methyliso-Thiocyanate instead of potassium cyanate, the title compound is obtained, yield 83%, mp. 263-265 0.
    Example 29. 6-Propyl-8 | - (2- -thioxo-4-oxo-3-methyl-G-imidazolidinyl-methyl) -ergoline.
    In Example 28, using 8-amino-methyl-6-propyl-ergoline instead of 8-aminomethyl-6-metsh-1-ergoline, the title compound is obtained in 88% yield.
    Example 30. 6-Allsh-1-8 - (2- -thioxo-4-oxo-3-methyl-1-imidazolidinyl-methyl) -ergoline.
    In Example 28, using 8-amino-methyl-6-allyl-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in 69% yield.
    71327788
    Example 31. 6-Methyl-8 | - m-, - (2-cyanoethyl) -Y-carbamoyl-aminoethyl-1-ergoline.
    According to example T, using acrylonitrile instead of methyl acrylate, 6-methyl-8 (2-cyano-ethyl) -amino-ethyl-ergoline is obtained with a yield of 80% (mp. 169-17GS).
    As in Example 2, said compound is obtained from this compound.
    ten
    in the title compound, so pl. 252-254 C.
    PRI me R 32. 6-Methyl-8 - (1H, 3N) -2-OXO-4-IMINO-DIHYDRO-1-pyrimidinyl-methyl-ergoline.
    Decomposition in vaciio for 1 hour with the compound prepared as in Example 31 gives the title compound in 45% yield, mp. 248-250 ° C.
    Example 33 2-Bromo-6-methyl- (2,4-dioxo-1-imidazolidinyl-methyl) -ergoline.
    In Example 3, using 8-amino-methyl-2-bromo-6-methyl-ergoline instead of 8 |) -aminomethyl-6-methyl-ergoline, the title compound is obtained with a yield of 64%, so pl. 279-281 s. 34. 2,6-Dimethyl-88-methyl-6-methyl-ergoline, the title compound is obtained in 58% yield, mp. 199-20Gs.
    Example 38. 6-Methyl-8- (1H, ZN) -2,4-dioxo-dihydro-1-pyridinyl-methyl-8,9-didehydro-ergoline.
    In Example 1, using 8-aminomethyl-6-methyl-8,9-didehydro-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in a yield of 63%, mp. 190-192 ° C.
    Example 39. 6-Methyl-8- (2,4- 15 -dio15Co-1-imidazolidinyl-methyl) -8,9- dehydro-ergoline.
    In Example 3, using 8-aminomethyl-6-methyl-8,9-didehydro-ergoline instead of 8-aminomethyl-6 methyl erg-20lin, the title compound is obtained in 72% yield, mp. 204-.
    Example 40. 6-Methyl-8 - (1H, ZN) -2,4-dioxo-dihydro-1-pyridinyl-25-methyl-9,10-didehydro-ergoline.
    In Example 1, -8i-amino-methyl-6-methyl-9,10-didehydro-ergoline-8, instead of 8-aminomethyl-6-methyl-ergoline, is given in the title
    Example
    - (2,4-dioxo-1-imidazolidinyl-methyl) - 30 compounds in 77% yield, so pl. 290- -ergolin.292 S.
    In Example 3, use 8-amino-methyl-2,6-dimethyl-ergoline instead of -amicomethyl-6-methyl-ergoline, semi-.
    35
    indicated in the title compound with a yield of 75%, so pl. 215-217 C,
    Example 35. 2-Thiomethyl-.6- -methyl-8 | - (2,4-dioxo-1-imidazolidinyl-methyl) -ergoline.
    In Example 3, using 8-amino-40-methyl-2-thiomethyl-6-methyl-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in 62% yield, mp. 255-257 ° C. . , 45
    Example 36. 6-p-Propyl-8 - - (2,4-dioxo-1-imidazolidinyl-methyl) - -ergoline.
    In Example 3, using 8-amino-gQ methyl-6-p-propyl-ergoline instead of -aminomethyl-6-methyl-ergoline, the title compound is obtained in a yield of 80%, mp. 168-170 ° C.
    Example 37. 6-Methyl-81 - (2,4- 55 -dioxo-1-imidazolidinyl-methyl) -ergoline.
    In Example 3, use 8-6-amino-methyl-6-methyl-ergoline instead of 8 -amis Example 41. 6-Methyl-8 - (2,4-β-dioxo-1-imidazolidinyl-methyl) -9,10-didehydro ergolin
    In Example 3, using 8-amino-methyl-6-methyl-9,10-didehydro-zrgolin in place of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in 78% yield, mp. . 282-284 ° C.
    Example 42. 2-Cyano-6-methyl- (2,4-dioxo-1-imidazolidinyl-methyl) -ergoline.
    Carrying out the reaction as in example 3, but using 8-aminomethyl-2- -cyano-6-methyl-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the compound indicated in the title is obtained with a yield of 73%, t Sh1. 227-229 s.
    The compounds prepared according to the inventive method and their pharmaceutically suitable salts exhibit pharmacological activity. For example, they are active in suppressing prolactin release, as indicated by delayed engraftment of fertilized eggs on day 5 after fertilization of female rats. In addition, the proposed
    0
    Nomethyl-6-methyl-ergolin, receive specified in the title compound with a yield of 58%, so pl. 199-20Gs.
    Example 38. 6-Methyl-8- (1H, ZN) -2,4-dioxo-dihydro-1-pyridinyl-methyl-8,9-didehydro-ergoline.
    In Example 1, using 8-aminomethyl-6-methyl-8,9-didehydro-ergoline instead of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in a yield of 63%, mp. 190-192 ° C.
    Example 39. 6-Methyl-8- (2,4- 5 -dio15Co-1-imidazolidinyl-methyl) -8,9- dehydro-ergoline.
    In Example 3, using 8-aminomethyl-6-methyl-8,9-didehydro-ergoline instead of 8-aminomethyl-6 methyl ergoglobin, the title compound was obtained in 72% yield, mp. 204-.
    Example 40. 6-Methyl-8 - (1H, 3N) -2,4-dioxo-dihydro-1-pyridinyl-5-methyl-9,10-didehydro-ergoline.
    In Example 1, -8i-amino-methyl-6-methyl-9,10-didehydro-ergoline-8, instead of 8-aminomethyl-6-methyl-ergoline, is given in the title
    Example 41. 6-Methyl-8 - (2,4-Dioxo-1-imidazolidinyl-methyl) -9,10-dihydro-ergoline.
    In Example 3, using 8-amino-methyl-6-methyl-9,10-didehydro-zrgoline in place of 8-aminomethyl-6-methyl-ergoline, the title compound is obtained in 78% yield, mp. . 282-284 ° C.
    Example 42. 2-Cyano-6-methyl- (2,4-dioxo-1-imidazolidinyl-methyl) -ergoline.
    Carrying out the reaction as in example 3, but using 8-aminomethyl-2-β-cyano-6-methyl-ergoline instead of nomethyl-6-methyl-ergoline, the compound indicated in the title was obtained with a yield of 73%, t. Ш1. 227-229 s.
    The compounds prepared according to the inventive method and their pharmaceutically suitable salts exhibit pharmacological activity. For example, they are active in suppressing prolactin release, as indicated by delayed engraftment of fertilized eggs on day 5 after fertilization of female rats. In addition, the proposed
    the compounds and their salts are active as antihypertensive agents.
    Antihypertensive activity. An indirect measurement of systolic blood pressure was performed in 4 groups of rats with spontaneous increased blood pressure at the age of 8-10 weeks. Animals were kept for 10-15 minutes in the environment at. 36 ° C in order to register the pulse pressure, and then the streamer was measured
    by using the caudal cuff using the W + W BP Recorder Model 8005, the systolic blood pressure and the number of heartbeats.
    The compounds were administered via the esophagus as a suspension of 5% gum arabic, once a day for 4 days. Changes were made before starting treatment at the 1st and 5th hours after taking the dose of the drug for four days. Dosage doses refer to the free base. Control animals received only a binder (0.2 ml / 100 g body weight).
    Also, as reference ones, they were subjected to hydrolase tests (1–5 mg kg per day) and (methyldopa (30–100 mg days)). The changes in systolic blood pressure and the number of strokes caused by the drug, the hearts were calculated as differences from pretreated values and as mean values obtained from 4 rats.
    In tab. 1 summarizes the results of the effect of compounds on rats KDF.
    In tab. 2 shows the results of the effect of the compounds on the HOS of the rats.
    In tab. 3 summarizes the toxicity data.
    The systolic blood pressure (KDF and the number of heartbeats (HOS)) remained stable throughout the experiment in rats exposed to a binder, while all compounds were active in doses of 1-20 mg kg per day. This effect was not accompanied by a reflex increase in HOS.
    Antihypertensive activity was observed immediately after the application of the proposed compounds and throughout the experiment. Wherein



    tachyphylaxis was not observed. In particular, the compounds prepared in Examples 1 and 3 were well and the long-acting active HOS remained stable.
    Comparison with standards showed that the compounds in examples 4, 5, 8, 9, 12, 13, 16, 19, 23, 24 and 28 (at doses of 1-7.5 mg. Kg per day) were more active than hydrolazine (1–5 mg kg per day) and B6-methyl-Dopa (30–100 mg-kg per day), without causing a reflex increase in HOS, in which
    given in other medicines.
    Thus, the test compounds have a better therapeutic index than b6-methyl-dopa.
    rmula of invention
    Method for preparing general ergoline derivatives of formula (I)
    X 11
    R.M-CHaVT - “5
    v JC I
    R3-.r A-BRg
    ,one
    five
    0
    five
    (
    RX, 0
    where R is hydrogen or methyl group; hydrogen or bromine or methyl, cyano or methylthio;
    R and R is hydrogen and RJ is hydrogen or
    the methoxy group, or R, is hydrogen, and RJ and R, taken together form a bond, or Rj are hydrogen or methoxy, and
    R and R,
    taken
    five
    RX Rj X R. together form a bond
    methyl, propyl or allyl;
    hydrogen or C-Cx alkyl;
    oxygen or sulfur;
    hydrogen, and B is methoxycarbonyl- or ethoxycarbonyl, or R
    g and B taken together with the group,. are
    sing A is a group of the formula -CHj-, -CHj-CHg-, or n is an integer O, 1 or 2, characterized in that the compound of general formula (II) is condensed
    11 W CCH2lir H-A-B
      -R H
     Sr
    where R ,, Rj, R, R, R, R ,, A, B and
    n have the indicated meanings
    with a compound of general formula III
    If necessary, cyclization of the resulting compound of the general formula (I), where Rg is hydrogen, is carried out to obtain the compound of the general formula (I), where R and B taken together are a CO-group, by heating in vacuum at 140 - 160 ° C, 10
      N-Rj,
    The priority featured on 04/28/83 - B and RJ, taken together, is a C 0 group,
    05/27/83 - B - methoxycarbonyl
    where RJ and X have the indicated values, 15 or toxycarbonyl, and Rg is an atom of water or pyridine at 60-80 ° C, its hydrogen.
    Table 1
    1327788
    12
    If necessary, cyclization of the resulting compound of the general formula (I), where Rg is hydrogen, is carried out to obtain the compound of the general formula (I), where R and B taken together are a CO-group, by heating in vacuum at 140 - 160 ° C
    权利要求:
    Claims (1)
    [1]
    Claim
    A method for producing derivatives of ergoline of the general formula (I) wherein R ( is hydrogen or a methyl group;
    R 2 is hydrogen or bromo or methyl, cyano or methylthio group;
    R 6 and Rj are hydrogen and Rj is hydrogen or a methoxy group, or R fe is hydrogen, and Rj and R taken together form a bond, or R 3 is hydrogen or a methoxy group, a and R taken together form a bond, '
    - methyl, propyl or allyl group;
    Rj is hydrogen or C 4 -C 4 alkyl; X is oxygen or sulfur;
    R a is hydrogen, and B is a methoxycarbonyl or ethoxycarbonyl group, or Rg and B, taken together,. are 'at C = 0 group';
    A is a group of the formula —CH -, -CH I -CH 2 - or -CH = CH-, η is an integer of 0, 1 or 2, characterized in that the compound of the general formula (II) is condensed
    eleven
    Pi Χ'ΎΊ ΤΎ N
    1327788 12 if necessary, cyclize the resulting compound of general formula (I), where Rg is hydrogen, to obtain a compound of general formula (I), where R e and B taken together represent a ^ CO group by heating in vacuum at 140 160 e S.
    10 Priority by signs 04/28/83 - B and Rj, taken together, are a C = 0 group,
    05.27.83 - B - methoxycarbonyl 15 or ^ toxicarbonyl, and Rg - hydrogen atom.
    Table 1 where R, R g , R j, R ^, 9 R7, A, 8 and n have the indicated meanings, with a compound of the general formula III
    X = C = N-Rj, where Rj and X have the indicated meanings, in water or pyridine at 60-80 C, ec- <
    Connection example Dose mg · kg ” 4 per day Changes in KFOR, .mm Hg, after taking the medicine 1st day 4th day 1st h 5th h 1st h 5th hBinder •+2.5 | -7.5 -6.4 -5.0 1 20 -90.0. -62.5 -62.5 -46.2 ' 3 20 -60.0 -72.5 -90.0 -62.5 4 20 -53.3 45.0 -42.5 -50.0 4- 5 -35.0 -40.0 -43.7 -45.0 5 7.5 -55.0 -56.2 -55.0 -53.7 8 20 -30.0 -10.0 -36.2 -37.5 9 7.5 -5S2 -65.0 -82.5 -55.0 12 7.5 -52.5 -38.7 -37.5 -41.2 thirteen 7.5 -37.5 -26.2 -50.0 -31.7 16 1 -20.0 -28.7 -43.7 -52.5 19 fifteen -50.0 -33.7 -62.5 -23.7 23 20 “51.2 -60.0 -85.0 -72.5 24 5 -38.7 -66.7 -41.7 -38.3 28 1 -27.5 -3Ϊ, 2 -70.0 -30.0
    13 1327788 14
    Continuation of the table. 1
    Compound Dose as Example μγ · κγ _ < per day Changes in KFOR, mm Hg, after drug admission 1st day1st h 5th h 4th day 1st h I 5th h Binder+2.5. | -7.5 | -6.4 | -5.0 Hydrolazine 1 -5.1 -15.7 -5.0 ' -0.3 5 -40.2 -20.0 -20.4 -7.0 oC-methyl -Dopa thirty -10.4 -20.1 -10.0 +0.5 100 -10.0 -25.4 -20.2 -25.0 20 Λ5 -17.5 -25.0 -20.0 -30.0 21 1 -18.7 -11.2 -21.2 -20.0 22 20 -10.0 -13.7 -21.2 -40.0 38 20 -60.0 -66.2 -35.0 -30.0 eleven 5 -32.5 -48.7 -10.0 -38.7 ’40 20 -115.0 -126.2 -35.0 -37.7 41 1 -55.0 -63.7 -37.5. -23.7 sz 20 -80.5 -50.7 -45.5 -50.7 34 20 -75.6 -40.5 -80.3 -60.5 35 20 -93.4 -77.4 -75.5 -65.4 26 5 -28.5 -19.7 -30.5 -17.4 ' 36 1 -15.2 -10.5 -19.7 12.3 27 5 . -21.5 -14.4 -16.5 -10.2 42 20 -25.7 -20.4 -30.2 -20.5
    fifteen
    table 2
    Compound The dose of mg "kg’ per day Changes in ChUS beats / min after taking the medicine 1- th day 4th day 1st h | 5th h 1st h | 5th h Binder substance -5.0 + 12.0 -10.0 | -19.0 1 20 +470 -40.0 -33.0 -8.0 3 20 -20 -10.0 -25.0 -7.0 4 20 + 13.0 +23.0 -11.0 -40.0 4 5 -fifteen -30.0 -40.0 -23.0 5 7.5 -37.0 -20.0 -42.0 -10.0 8 20 -13.0 +0.4 +40.0 -20.0 9 7.5 -60.0 -32.0 -75.0 -28.0 12 7.5 -40.0 -28.0 +8.0 +2.0 thirteen 7.5 + 13.0 -55.0 +37.0 -20.0 16 1 -28.0 -8.0 -60.0 -35.0 19 fifteen -18.0 -32.0 -35.0 + 15.0 23 20 -8.0 + 17 +42.0 -18.0 24 5 -23.0 + 17.0 +30.0 -27.0 28 1 -13.0 -23.0 + 15.0 -15.0 Hydrolazine 1 + 30., 0 +35.0 +25.0 + 15.0 5 +40.0 +45.0 + 18.0 + 15.0 4-methyl-Dopa thirty +35.0 +40.0 +45.0 +30.0 100 +70.0 +40.0 +50.0 + 10.0
    17 1327788. 18
    Table 3 Continuation of table.Z Connection by LD 5o for rats,I 2 24 . . · - - · an example mg / kg 5 > 800 1 228 ’ 400 1 > 800 10 38 800 3 > 800eleven 800 4 > 80040 > 800 5 400 fifteen 41 > 800 8 > 80033 400 9 400 20 34 800 12 40035 400 thirteen 40026 > 800 16 800 25 36 800 19 80027 > 800 20 , 400 thirty 42 400 21 400Hydralazine 122 22 800oC-Meth-Dopa At 800 23 > 800 35
    Compiled by I. Fedoseev Editor M. Nedoluzhenko Tehred L. Oliinyk Corrector N.Korol
    Order 3398/58 Circulation 371 Subscription
    VNIIIPI of the USSR State Committee for Inventions and Discoveries 113035, Moscow, Zh-35, Raushskaya nab., 4/5. Production and printing company, Uzhgorod, st. Project, 4
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    优先权:
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    GB838311679A|GB8311679D0|1983-04-28|1983-04-28|Ergoline derivatives|
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