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    • 专利摘要:
    Novel D-6-n-propylergolines of the formula: …<CHEM>… wherein Y is O or S and R<1> is n-propyl, and pharmaceutically-acceptable acid addition salts thereof can be used to lower the prolactin level in mammals or for treating symptoms of Parkinson's syndrome in humans. A process of preparing the compounds is described which comprises reacting D-6-n-propyl-8 alpha - mesyloxymethylergoline with the sodium salt of methylmercaptan or sodium methylate.
    公开号:SU976851A3
    申请号:SU802984351
    申请日:1980-10-01
    公开日:1982-11-23
    发明作者:Карл Корнфельд Эдмунд；Джеймс Бэк Николас
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    397 branched 0-6-methyl-8p-carboxyergoline. Esterification with acidic methanol gives the corresponding derivative of 8) B-methoxycarbonyl. This compound is then N-demethylated with cyanium bromide (which replaces methyl with the CN group) with subsequent reduction of the 6-cyano-derived zinc obtained in acetic acid. Then, 8 / L-methoxycarbonyl-ergoline is alkylated at the 6th position with iodide propyl to obtain the corresponding 0-6-H-propyl-I methoxycarbonyl-ergoline. The D-6-H-propyl-8; 4-methoxycarbonyl-ergoline obtained in this way is then reacted with w-chloroperbenzoic acid, the intermediate obtained is treated with a mixture of acetic anhydride- and triethylamine to give 0-6-n-propyl-8c3-methoxycarbonyl- 7 ergolen Reduction of the 7,8-double bond with hydrogen in the presence of a heavy metal catalyst such as a platinum catalyst gives the corresponding D-6-H-propyl-8 methoxycarbonyl ergoline. The methoxycarbonyl group is reduced to the rxymethyl group by lithium aluminum hydride. Then oxymethyl
    权利要求:
    Claims (2)
    [1]
    a new group is esterified with methane sulfo-30 JieHa. nyl chloride to obtain the corresponding mesilate. Example 1. Preparation of D-6-H-propyl-8 | &amp; methoxycarbonyl ergoline. 10 g of 0-6-n-methyl 8-methoxycarbonyl ergoline (methyldihydrolyzer) is dissolved in 300 ml of methylene dichloride. 10 g of cyanium bromide was added and the mixture was left overnight with stirring at room temperature. The organic layer is first washed with dilute water with hydrochloric acid to remove unreacted starting material, and then with water. The organic layer is dried. the evaporator is removed from it by evaporation. Preparing) -6-cyano-8 (L-methoxycarbonyl ergoline, melting at 205-20b ° C. J Mix 10 g of the obtained 6-cyano ergoline, 50 g of zinc powder, 00 ml of glacial acetic acid and 80 ml of water is heated at reflux temperature under nitrogen atmosphere for 16.5 hours. Then the reaction mixture is filtered and the filtrate is poured onto ice.Dilute the filtrate is alkalified under the addition of ammonium hydroxide and water several times extracted chloroform extracts o (5-ed and combined the extracts are washed with a saturated aqueous solution of sodium chloride, then dried. After evaporation of chloroform, 0-8 mg methoxycarbonyl ergoline is obtained. This product is dissolved in 25 P ml of dimethylformamide without further purification. 7 g of potassium carbonate is added, then 8.8 ml of n-propyl iodide. The reaction mixture is stirred at room temperature for about 21 hours, then diluted with water. The diluted reaction mixture is extracted several times with ethyl acetate. The ethyl acetate extracts are combined and the combined extract is washed with a saturated aqueous solution of sodium chloride, then dried. After evaporation of the solvent, 0-6-H-propyl-8-methoxycarbonyl ergoline is obtained as a crystalline residue. The crystals are washed with a mixture of ether and hexane. In this way, 5.6 g of D-6-n-propyl-8 (1-methoxycarbonyl ergoline, mp 206-L08C) are obtained. P – p and m R 2 methoxycarbonyl-7-ergo3 g of 0-6-n-propyl-8 / methoxycarbonyl ergoline is dissolved in 150 ml of methylene dichloride and the solution is cooled to a temperature of -25 to -35 ° C. To this is added 3 g of chloro-benzoic acid in 15 ml of methylene dichloride is added dropwise. The reaction mixture is stirred in the same temperature range for 20 minutes, after which 1.0 ml of acetic anhydride and 6.9 MP of triethylamine are added. The resulting reaction mixture is stirred in t 90 min in the temperature range from -30 to + 5T. Then the reaction mixture is diluted with aqueous sodium bicarbonate and the resulting mixture is extracted with methylene dichloride. The methylene dichloride extract is washed with a saturated aqueous solution of sodium chloride and then dried. After evaporation of the solvent, a residue is obtained containing 6-H-propyl-8-methoxy-. Carbonyl-7-ergolene, obtained in this way. The chloroform solution of the residue is chromatographed on 150 g of phlorisil using chloroform containing 0-1 methanol, as Noah phase. The fractions containing 5 0-6-n-propyl-B / l-methoxycarbonyl-7-er shin, as shown by thin-layer chromatography, are collected, combined and the solvent is evaporated. About 700 ml of product is obtained, mp. 193-19t ° C, with a disruption. Calculated: C 73.52; And 7, N 9.03. Found, I: C 73.68; H 6.85; N 8.93. Example 3. Preparation of D-6-n-propyl-8/1-methoxycarbonyl-ergoline. About mg of 0-6-n-propyl-8grmethoxycarbonyl-7-ergene is dissolved in 50 ml of a mixture of dimethylformamide and glacial acetic acid in a ratio of 1: 2. The solution is hydrogenated in the Adams apparatus at a hydrogen pressure of about 22 kg / cm over a catalyst of oxide of platinum oxide. After the absorption (calculated) amount of hydrogen, the hydrogenated mixture is filtered and the filtrate is poured onto ice. The aqueous mixture is alkalinized with 14 n. ammonium hydroxide. The resulting alkaline mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with water and saturated aqueous sodium chloride, then. dried After evaporation of the ethyl acetate, a residue is obtained, which contains two main spots on a thin layer chromatogram, including two reaction products, 8oL and 8p isomers. The ether precipitate solution is chromatographed on 30 g of phlorisil using ether as the mobile phase. The first eluent fraction, as indicated by thin layer chromatography, contains two main spots, whereas 2–6 fractions contain only one spot. The first fraction is subjected to thin layer chromatography using ether as eluent and the fractions showing on TLC the content of D-6-npropyl-8c1-methoxycarbonyl-ergoline are combined and the solvent is evaporated. This material moves more slowly on the preparative plate and after separation from the faster layer it is combined with fractions 2-6. By evaporation of the solvent from the o () of the combined fractions, 0-6-H-propyl-8o1-methoxycarbonyl-ergoline is obtained, having the following composition. You are number,%: C 73.05; .H 7, N 8,.:. Found,%; C, 72.80; H 7.81; N 8.72. Vihod is O, T g. 1 Example k. Preparation of D-6-H-propyl-8o {.-Hydroxymethyl ergoline A 1 gram of an intact mixture containing 0-6-H-propyl-8p-methoxycarbonyl-ergoline and its 8-1 isomer obtained by the method of Example 3 is dissolved in 125 ml of tetrahydrofuran. 2 g of lithium aluminum hydride is added to it. parts and the resulting mixture is heated at reflux temperature for 1.5 hours. Then the reaction mixture is cooled and the excess lithium aluminum hydride is decomposed by adding ethyl acetate. The aqueous sodium hydroxide is added to decompose present (their organometallic impurities and the resulting mixture is further diluted with water. The alkaline aqueous mixture is extracted several times with a mixture of chloroform and isopropanol. The organic extracts are combined and the combined extracts are washed with saturated aqueous sodium chloride and then dried. Thin layer chromatography shows the presence in the resulting residue of two materials corresponding to T) -6-n-propyl-8Y-hydroxymethyl ergoline and its 8 (3-isomer. Chloroform solution of the residue chromate 35 g of florizil using chloroform containing 2 methanol as the mobile phase. The fractions showing on the TLC the content of identical materials are combined. 870 mg of 0-6-n-propyl-8p-hydroxyethyl-ergoline with a melting point of 17H 17b ° C are obtained. when combining fractions containing, according to, TLC, this product. The solvent is evaporated from the combined fractions. Well fractions that showed the content of the second component on TLC are also combined and prepared. 110 mg of 0-6-n-propyl-8 ° C-oxymethylergoline with a melting point after recrystallization from a mixture of ether and hexane. Example 5 Preparation of D-6-H-propyl-8o (.-Mesyloxymethyl ergoline. About 0.5 grams. 0-6-n-propyl-8o-1-hydroxymethyl ergoline is dissolved in 20 ml of pyridine. 0, 5 ml of methanesulfonyl chloride and the resulting mixture is stirred at room temperature for 90 minutes. The reaction mixture is then diluted with ammonium hydroxide. The basic layer is extracted with ethyl acetate. The ethyl acetate extract is separated, washed with water and saturated aqueous: sodium chloride, then dried. containing D-6-n-pro saw-8o1.-mesyloxymethyl airpoly as the main ingredient. The fractions that showed the content of D-6-n-propyl-BOC-mesyloxymethylergoline are combined, the solvent is evaporated from the combined extract. Recrystallization 1 of the resulting residue is obtained 500 mg of 0-6-H-propyl-8cA -milox of ergoline, melting point about 95 ° C 1 Calculated,% 1 C b2.9b; H 7.23; N 7.73. Found,: C 62.82; And 7i2A; N. Example B. Preparation of D-6 -n-propyl-8 | 0 -methylmercaptomethyl ergol. The solution is prepared from 470 ml of D-6-H-propyl-8 ° C-methyloxymethyl ergoline and 10 ml of dimethylformamide. This solution is slowly added to a solution of methyl mercaptan sodium salt prepared from 1 ml methyl mercaptan and 520 g sodium hydride in 25 ml dimethylformamide. The reaction mixture is stirred at room / temperature under a nitrogen atmosphere for 4.5 hours. The thin CJ sample chromatography of the reaction mixture sample shows only one with a RP value lower than that of the starting material. The reaction mixture is diluted with water and the aqueous mixture is extracted several times with ethyl acetate. The ethyl acetate extracts were separated, combined, and the combined extruders were washed with water, then with a saturated aqueous solution of sodium chloride. The combined extracts are dried, the solvent is removed from them by evaporation. The resulting residue is dissolved in ether and the ether solution is filtered through florisil. Metaisulfonate salt is obtained by dissolving the residue in 25 ml of methanol. A methanol solution containing an equivalent amount of methanesulfonic acid is added to the first solution and cooled. The mixture is then diluted with simple ether and the methanesulfonic acid salt precipitates. Methanesulfonate D-6-n-propyl-8b-methylmercaptomethylergoline has a melting point of 206208 ° C, with decomposition. The yield is 2Po mg. A second fraction is also obtained with a yield of 220 mg. Calculated,%; C 58.5; H 7.36; N 6.82; S 15.62. Found,%. C, 58.71; H 7.14; N 6.78; S 15.35. 0-6-H-propyl-8c | 1-methoxymethyl ergolyl can be obtained by replacing the sodium salt of methyl mercaptan with sodium methoxide in the example described above. Evidence of the usefulness of the compounds according to the invention in the treatment of Parkinson's syndrome may be that they are effective in a test on cruises that cause motor impairment using 6-oxophenamine. In this experiment, rats with non-striatum damage caused by the method described Ungershtednt and Arbutnott in n Res 24, 485 (1970). A compound with an agonizing dopinin action,. causes the rats to move in a circle opposite to the injured side. After the end of the latent period, which is different for different compounds, count the number of turns for 15 minutes. Methylsulfonate 0-6-I-propyl-8b-methylmercaptomethylergoline causes, on average, 98 rats at a peritoneal dose of 0.1 mg / kg and 90 rotations at a dose of 0.05 mg / kg on an injured rat. 100 rats exhibit a rotational motion at. both doses. The compounds according to the invention can also be useful as prolactin inhibitors and, as such, can be used in lactation disorders, such as postpartum secretion of milk and galactor. Evidence of the usefulness of the compounds according to the invention in the treatment of diseases for which it is desirable to reduce the prolactin level can The following procedure shows inhibition of prolactin. Adult male Sprague-Douoly rats weighing about 200 grams are placed indoors with air conditioning and controlled light time (lighting from 6 am to 8 pm) and fed with laboratory food and water. Each rat was injected intraperitoneally with a dose of 2.0 mg of resorcinol in an aqueous suspension for 18 hours of administration of the ergoline derivative. The purpose of the introduction of resorcinol is under. Introduction Per os is preferred. If parenteral administration is used, the injection is preferably administered subcutaneously using an appropriate pharmaceutical form. Other types of parenteral administration, such as intraperitoneal, intramuscular, or intravenous, are equally effective. In particular, a water-soluble pharmaceutically acceptable salt is used for intravenous or intramuscular administration. For example, a compound of this formula, especially in the form of an acid addition salt, such as a salt of methanesulfonic acid, for example, can be mixed with a suitable diluent, such as mannitol, sucrose, or the like, in a quantity of 0.5 mg and dissolved in a suitable solvent, such as, for example, 100 "1 saline. Such a formulation can be administered intravenously to an object, for example, dropwise within 2-6 c. Optionally, the active compound of the above formula can be mixed with commonly used diluents and administered intramuscularly in a dose of from 0.01 to 0.5 mg 2 times a day. Formula 1: Method for preparing D-6-n-propyl- &amp; A-methyl- (mercapto or oxf) me-97685112 of tylergoline of the general formula .CHN-t-CH3 where U is an oxygen or sulfur atom; R ,, is H-propyl, its salts., Which is ablating with / that B-6-n-propyl-8o1-mesyloxymethyl ergoline interacts with methyl mercaptan sodium salt or sodium methoxide followed by isolation of the target products in free form or in the form of salts. 2. The method according to claim 1, wherein the process is carried out in dimethylformamide. Sources of information taken into account in the examination 1. US patent number A166182kl. C 07 D 57/02, published 09.28.79.
    [2]
    2. US patent number 39P1894, cl. 260-285.5, publ. 1975.
    Compiled by I. Fedoseeva
    PeflaKTOB I. JexgeQ J. Kastelevich Kovvektod.O.Bilak
    Order902 (TYRAzh 555Subscription
    VNIIPI USSR State Committee for Inventions and Discoveries
    113035i Moscow N: 35x RakhSchska emb. {} / 5 ..
    OilPay Patent, g. Uzhgorod, st. Design, 9976 keeping unevenly elevated prolactin levels. C-6-H-propyl-8s-methyl mercaptomethylergoline is dissolved in ethanol at a concentration of 10 µg / ml and injected intraperitoneally in doses of .5, 5Pi and 500 µg / kg in groups of 1P animals in each. A control group of 10 male rats receives an equivalent amount of 10% ethanol. One hour after the injection, the rats are killed by decapitation and 150 microliter serum samples are evaluated for prolactinHHa content. The results are evaluated statistically using the test with styole -15 to calculate the value, level and p for changing the level of prolactin.
    lactin p. 51 Difference between prolacty content. in rats treated with the compound of the invention, and the content of prolactin in the control rats, divided by the content of prolactin in the control rats, gives the percent inhibition of prolactin secretion that determines the compounds of the invention. These percentages of inhibition for methylsul (U} nata B-6-n-propyl-8o6-methyl mercaptomethylergoline are presented in the table. The table in column 1 shows the dose applied, in columns 2 and 3, the content of prolactin n in serum of control and treated rats in ng is given / ml; column k shows the percentage of inhibition, and column 5 shows the sign of the level
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    KR830003478A|1983-06-20|
    IE802036L|1981-04-01|
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    FR2466465A1|1981-04-10|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/080,768|US4246265A|1979-10-01|1979-10-01|6-n-Propyl-8α-methoxymethyl or methylmercaptomethylergolines and related compounds|
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