• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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    • 专利摘要:
    There are provided ergoline derivatives of formula <IMAGE> wherein R1=H, CH3; R2=H or halogen atom, or CH3,CN, alkyl- or phenyl-thio; R3=H, OCH3; R4=C1-C4 hydrocarbon group; X=O, S, NH; A=CO, SO2; B=C1-C4 hydrocarbon group, aryl, aralkyl, heterocyclic ring group, alkoxy, aryloxy; n=0, 1, 2; and pharmaceutically acceptable salts thereof. A process for preparing said compounds is also provided. The compounds show anti-hypertensive activity and are active on the gastroenteric system.
    公开号:SU1189347A3
    申请号:SU823506255
    申请日:1982-11-01
    公开日:1985-10-30
    发明作者:Бернарди Луиджи；Темперилли Альдемио；Руджиери Даньела；Аркари Джулиана；Сальвати Патриция
    申请人:Фармиталиа Карло Эрба С.П.А.(Фирма)；
    IPC主号:
    专利说明:

    1 The invention relates to a process for the preparation of new ergoline derivatives of general formula I, CH2-MH-C-Sh-C-B O O. N-R 1H where R is a lower alkyl group; . X is an oxygen or sulfur atom; B is lower alkyl or fensch1, possessing valuable pharmacological properties. A known method for producing 8-substituted zrgolenes of a similar structure by reacting the isocyanate production of aqueous ergolenes with secondary amines in an inert organic solvent, such as toluene, at elevated temperatures. Target products have a hypotensive effect to. The purpose of the invention is to obtain new ergoline derivatives of the general structural formula 1, which possess novel pharmacological properties for this group of compounds. The objective is achieved in that according to the proposed method, the ergolinamine of the general formula P, where R) has the indicated values, is reacted in acetonitrile, dioxane or toluene at the boiling point of the solvent with the isocyanate or isothiocyanate of the general formula W XC NCB II O where X and H have these values, with subsequent selection of target products by known methods. Example 1. 6-Methyl-8o - (3-ben zoyl-thioureidomethyl) -10 / J-ergoline (K ,, R, CH ,,,,). 7 1.05 ml of benzoyl thiocyanate is added to a suspension of 2 g of 8 g-aminomethyl-6-methyl-10/3-ergoline in 2 ml of acetonitrile, with shaking. The solution was heated under reflux for 30 minutes and then evaporated in vacuo to dry. The residue is chromatographed on silica gel (elution solution — chloroform with 2% methanol). 2.2 g of the expected compound are obtained, m.p. 153-155 ° C, after crystallization from diethyl ether. PRI mme R 2. 6-Methyl-8 / E- (3-benzoyl-thioureidomethyl) -ergoline (S;) is prepared as in Example 1, using 8 aminomers 1-6-methyl-croline instead of 8l-aminomethyl- 6-metsh1-10 / -ergolin. M.p. 236-237 ° C. Yield .70%, EXAMPLE 3. 6-Methyl-8 - (3-acetyl-thioureidomethyl) -ergoline () is prepared as in Example 2, using acetylisothiocyanate instead of beoylisothiocyanate and toluene instead of acetonitrile. M.p. 209-2U C. Yield 55%. EXAMPLE 4, 6-Methyl-8y- (3-propionyl-thioureidomethyl) -ergoline (R, R, CH.5;) is prepared in the same manner as in Example 2, using propionyl isothiocyanate instead of benzoyl isothiocyanate and dioxane instead of acetonitrile. M.p. 225-226 C. Yield 58%. EXAMPLE 5. 6-Methyl-8 (- (3-benzoyl-thioureidomethyl) -ergoline (R.;) Is prepared in the same manner as in Example 1, using 8o-aminomethyl-6-methyl-ergoline instead of 8 -aminomesh1-6-methyl-10uZ-ergoline, mp 155-15b C. Yield 65%. EXAMPLE 6 6-Methyl-8use3- (3-benzonl-thioureido) ergoline (,) was prepared in the same manner as in Example 1, using 8 amino 6-methyl-ergoline instead of 8 about-aminomethyl-6-methyl 3-10 U-3-ergoline, mp 224225 ° C. Yield / 0%. Example 7, 6-Methyl 8a ;-( 3-benzoyl-ureidomethyl) -10y} -ergoline (R ,, H;,; В is prepared in the same way as in Example 1, using beisoyl isocyanate instead of 142-144C. Benzoyl isothiocyanate. So pl. B A yield of 64%. EXAMPLE 8. 6-Methyl-8 - (3-benzoyl-ureidomethyl) ergoline (B) is prepared in the same manner as in Example 2, using benzoyl isocyanate instead of benzoyl isothiocyanate. mp. 180-181 ° C, Yield 73%. EXAMPLE 9. 6-Methyl-8 - (3-acetyl-ureidomethyl) -ergoline (,;) is prepared as in Example 2 using acetyl isocyanate instead of benzoyl isothiocyanate. 256-257c. Yield: 65%. Example 10. 6-Methyl-81J- (3-benzoyl-ureidomethyl) -ergoline (R, H) is prepared in the same manner as in Example 5, using benzoyl isocyanate instead of benzoyl isothio anianate T.Sh1. 19 p-191 ° C. Yield 70%. Example 11. 6-Methyl-8 (3-benzoyl-ureido) -ergoline (C (, V .;)) is prepared in the same manner as in Example 6 using benzoyl isocyanate instead of benzoyl isothio cyanate. Mp. 239-241 0. 74% yield. Example 12. 6-Methyl-8 / 3- (3-acetyl-ureido) -ergoline (R) is obtained in the same manner as in Example 6 using acetyl isocyanate instead of benzoyl isothiocyanate, mp 237-239s. %. EXAMPLE 13. 6-Methyl-8L - (3-benzoyl-thioureido-ethyl) -ergoline (R ,, H;) is obtained in the same manner as in Example 1, using DM-aminoethyl-b- methylergoline instead of 8-amino-ethyl-6-methyl 10 -ergoline, mp 205-207 ° C. Yield 85% Example 14. 6-Methyl-8 / - (3-acetyl-thiou eidostil) -ergoline (R, R2) is prepared in the same manner as in Example 13 using acetyl isocyanate instead of benzoyl isothiocyanate. mp 213-215 c., yield 78%. Example 15. 6-Methyl-8U3- (3-b- 5 Zoyl-ureidoethyl) -ergoline (Rj R CHg;,;) was prepared in the same manner as in Example 13, using benzoyl isocyanate instead of benzoyl isothiocyanate. T. mp 215-217 0, Vcode 72%. Jo Example 16. 6-Methyl -8 - (3-acetyl-thioureido) -ergoline (Rj R, XS; ) is also prepared as in Example 6 using acetyl isothiocyanate instead of benzoyl isothio-jj cyanate. M.p. 240-242 ° C. Yield 68%. Example 17. 6-Methyl-80- (3-benzoyl-guanidino-methyl) -ergoline (R ,, H;,;) is prepared in the same manner as in Example 2, using benzoyl cyanamide instead of benzoyl isothiocyanate. M.p. 19019lc. Yield 64%. Example 18. 6-Methyl-8 / 3- (3-acetyl-guanidinomethyl) -rgoline (R) is prepared in the same manner as in Example 2, using acetyl cyanamide instead of benzoyl isothiocyanate. M.p. 218220 ° C. Yield 58%. Example 19. 1,6-Dimethyl-8 / 3- (3-acetyl-thioureidomethyl) -rgoline () is prepared in the same manner as in Example 3, using 8/3 amino-methyl-1,6-dimethyl-ergoline instead of 8y- aminomethyl-6-methylzrgoline. M.p. 195-197c. Yield 70%. PRI me R 20. 1,6-Dimethyl-8 (3-nicotinoyl-hisidinomethyl) -ergolin (R ,,; B 3-CcH-N;) is prepared in the same way as in Example 19, using nicotinoyl cyanamide instead of acetylisothiocyanate. M.p. 207-209 ° C. Yield 48%. PRI me R 21. 1,6-Dimethyl-8L 3- (5-bromniknicotinoyl) -guanidinomethyl1 ergoline (R, B 5Br-3-CjH2N;) is prepared in the same manner as in Example 19, using 5-bromonicotinoyl cyanamide instead acetylisothiocyanate. M.p. 140-142 0. Yield 55%. Example 22. 6-Metsh1-8Я- (3-g toluensulfonyl-ureidomethyl) -ergoline (.H; B 4-CH5-CgH;) is obtained in the same way as in example 2, using P-toluensulfonyl isocyanate instead of benzoyl isothiocyanate. M.p. 234-236 0; Yield 73%. For example 23. 10-Methoxy-6-methyl-8D- (3-acetyl-thioureidomethyl) -ergoline (R,.;,;) Is prepared in the same manner as in Example 3, using 8D-aminomethyl1O-methoxy -6-methyl-ergolin instead of 8J-aminomethyl-6-methyl-ergolin. M.p. 212-214 about. 75% yield. EXAMPLE 24 10-Methoxy-1,6-dimethyl-8 - (3-acetyl-thioureidomethyl) ergoline (R, R 4.) is prepared in the same manner as in Example 3 using 83-aminomethyl 1-methoxy- 1, 6-dimethyl-ergoline instead of 8 p-aminomethyl-6-methyl-ergolin. : M.p. 170-172 0. Yield 73%. EXAMPLE 25. 6-Methyl-8 |) g- (3-acehygly-tnouridomethyl) -ergoline (Ri R) is prepared in the same manner as in Example 5, using acetyl eothiocyanate instead of benzoyl isothiocyanate. M.p. 20A-205 C. Yield 71%,. EXAMPLE 26. 6-Methyl-8 (x ;-( 3-acetyl-ureidomethyl) -ergoline () is prepared in the same manner as in Example 5, using acetyl isocyanate instead of benzoyl isothio cyanate. 182-183s. Yield 70% Example 27. 6-Propyl-8 (3benzoyl-ureidoethyl) -ergoline (,;) is prepared in the same manner as in Example 8, using 8B-amino.ethyl-6-propyl-ergoline instead of 8 (-aminomethyl-6-methylergoline), mp: 194-196 ° C. Yield: 71% EXAMPLE 28: 6-Allyl-8A- (3-benzoyl-ureidoethyl) -ergoline (, Cl CH CH -Nl 5) is obtained in the same way as in example 8, using 8 /} - aminoethyl-6-allyl-ergoline instead of 8A-aminomethyl-6-methyl-ergoline. So pl. 173-175 C, Out od 64%. Example 29.2,6-Dimethyl-8-UZ (3-acetyl-ureidometsh1) -ergoline (R, R.) is prepared in the same manner as in Example 9, using 8I-aminonethyl-2,6-dimethyl-ergoline instead 8 / -aminomethyl-6-methyl-ergoline, mp 275-277 C. Yield 69%. EXAMPLE 30 2-Brom-6-methyl-8 /:} - (3-acetylureidomethyl) ergoline (K, Cs H;) is obtained in the same manner as in Example 9, using 8H-aminomethyl-2-bromo-6-methy-ergoline instead of 8 / -aminomethyl-6-methyl-ergoline. M.p. 210-212 C. Yield 73%. Ergoline derivatives obtained according to the proposed method exhibit an antihypertensive effect (moderate to good) and are active in relation to the gastrointestinal system (in particular, they have anti-ulcer, antisecretory and very slight anticholinergic activity, therefore they are used in therapy, for example, for prevent and treat peptic ulcers, such as duodenal gastric and esophagus, and inhibit gastric acid secretion). Compounds 1 and their non-toxic pharmaceutically acceptable acid addition salts, or mixtures thereof, can be administered parenterally or orally, usually in combination with a suitable pharmaceutical carrier. Pharmaceutical carriers may be solid or liquid depending on the method of administration. Solid carriers include lactose, sucrose, gelatin, agar-agar, and the like, and liquid carriers include water, syrup, peanut butter, olive oil, and the like. The compound of formula 1 can be produced in the form of various dosage forms, such as tablets, capsules, suppositories, solutions, emulsions, powders and syrups. Action on the gastrointestinal system. The compounds of formula 1 exhibit an anti-ulcer effect: inhibit limited ulcers in rats according to the Bonfils method. In accordance with this method, test compounds were administered orally one hour before immobilization. For the experiment, six male Sprague-Dawley rats (100-120 g), starving for 24 hours, were used. For immobilization, a square flexible wire net with small cells was used. Four hours after immobilization, the rats were killed, their stomachs were removed and the lesions were counted under an analytical microscope. The compounds of formula 1 also have a gastric antisecretory effect: they were active after administration to the duodenum, suppressing gastric secretion in rats according to the method of H. Shay. In accordance with this method, the test compounds were injected into the duodenum during dressing. Six male Sprague-Dawley rats were used for each group. 24 hours before testing, the rats were deprived of food, but continued to give water. On the day of the operation, the gatekeeper (pylorus) was placed under light ether anesthesia. 4 h after ligation, the rats were killed. The secretory contents of the stomach were centrifuged at a speed of 3500 rpm for 10 minutes and the volume of the smaller sediment was determined. The amount of free hydrochloric acid in the gastric juice was determined by titration with 0.01 N, sodium hydroxide to the end point of pH 7. Table. Figure 1 shows the ED (effective dose) values of the compounds obtained by the proposed method for rats, Ta: how many antiulcer agents show, as well as atropine, an undesirable anticholinergic effect, the compounds of formula 1 were also evaluated from the point of view of their effect against the syndrome caused by oxotremorine in mens according to the method of Leszkovszky GP and Tardos L. According to this method, 5 male males (body weight 2025 g) were used for each group. The obtained results show that the compounds of formula 1 do not possess anticholinergic action, at a dose not higher than 100 mg / kg orally. Antihypertensive effect. Nip &amp; le measurements of systolic blood pressure (KFOR) were performed on groups of four rats with spontaneous hypertension (SHR / Kyoto) for 8–10 weeks of age (Charles Reeves, Italy) The animals were kept for 10–15 min, and then recorded bullets and then measured by KDF and heartbeat heart rate using the cuff on the tail using W + W. BP meter, model 8005, Compounds suspended in 5% gum arabic were orally administered once a day AG measurements were carried out before the start of treatment and 1 and 5 hours after dosing, as in The first day and the fourth day of treatment. The mean values of the difference in magnitudes (4 rats per group) are given. Control animals received only an excipient (0.2 ml / 100 g weight) Hydralazine and 0-methyl dioxyphenylalanine were also tested as reference standards. Drug changes in KDF and heart rate 478 Tsebeni were calculated as the difference in magnitudes before and after treatment. The test results are shown in Tables 2 and 3. From the data in Table. 2, it can be seen that the compounds of Formula 1 cause a persistent decrease in SDF in spontaneously hypertensive rats (the fact that a decrease in blood pressure is observed not only on the first day of treatment, but also on the fourth day proves the lack of tolerance). Compared with the action of hydralazine and oi-methyl-d-oxyphenylalanine, new compounds with a dose of 5 mg / kg have a greater hypotensive effect, especially on the fourth day. As can be seen from the data table. 3, the new compounds do not increase the heart rate, like hydralazine and oi-methyl-dioxyphenylalanine, but rather cause moderate bradycardia. Table 1 6-Methyl-8p (3-benzoylthioureidomethyl) -Ergo-. LIN (example 2) 6-Methyl-8 ° C (3-benzoIlthioureidomethyl) -10yZergoline (Example 1) 6-Methyl-8l (3-benzoylureidomethyl) ergoline (Example 10)
    Table 2
    6-Methyl-8y- (Z-acetyl-thioureidomethyl) -ergoline (example 3)
    6-Methyl-8 /} - (3-acetyl-ureidomethyl) ergol. In (example 9)
    6-Methyl-8-o- (3-acetyl-ureidomethyl) 6-Ketil-8 / 3- (3-acetyl-thioureidomethyl) -ergoline (Example 3)
    6-Methyl-8y- (3-acetyl-ureidometan) ergolin (Example 9)
    6-Methyl-8c, - (3-acetyl-ureidomethyl) ergoline (Example 26)
    -22
    -36
    -40
    -sixteen
    -25
    -56
    -17
    -57
    Table3
    -10 -20 -15 -21
    +10 -15 -17 -22
    +5 +8 +9 +10 Note. Cited (4 rats in the mean values of the difference in group values).
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PRODUCTION-
    Ergoline of the general formula where R is a lower alkyl group; X is an oxygen or sulfur atom; B is lower alkyl or phenyl, characterized in that pt ergolinamine of the general formula where R has the indicated meanings is reacted in an acetonitrile, dioxane or toluene medium at the boiling point of the solvent with an isocyanate or isothiocyanate of the general formula
    X = C = N — C ~ B
    II
    About where X and B have the indicated meanings, followed by the isolation of the target products.
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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
    GB8133631|1981-11-06|
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