• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Ergoline derivatives of formula (I) …<CHEM>… wherein R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom or a methoxy group, X represents an oxygen or sulphur atom or a NH or NCH3 group, R3 represents a hydrogen atom, a trifluoromethyl or phenyl group or an alkyl group having from 1 to 4 carbon atoms, R4 represents a hydrogen atom, a methyl or acetyl group or an alkyl group having from 1 to 4 carbon atoms, or R3 and R4 together represent a 3 or 4 membered carbon atom chain, Y represents an electron withdrawing group such as a cyano, nitro, alkylsulphonyl or alkylsulphinyl group or a group of the formula COR5 wherein R5 represents an alkyl group having from 1 to 4 carbon atoms or a phenyl, alkoxy, amino or N-substituted amino group or R5 an R3 together represent a 2 or 3 membered carbon atom chain, R6 represents a hydrocarbon group having from 1 to 4 carbon atoms or a benzyl or phenethyl group, and R7 represents a hydrogen or halogen atom or a methyl or formyl group or a group of the formula SR8 wherein R8 represents an alkyl group having from 1 to 4 carbon atoms or a phenyl group. The pharmaceutically acceptable addition salts and their preparation are disclosed. In form of therapeutical compositions the compounds exhibit useful pharmacological properties.
    公开号:SU1034606A3
    申请号:SU803212054
    申请日:1980-12-05
    公开日:1983-08-07
    发明作者:Бернарди Луиджи；Босисио Джермано；Мантегани Серджо；Росси Алессандро；Темперилли Альдемино
    申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to methods for producing new ergoline derivatives of the general formula
    (5H2-X-C -Y
    (I)
    TO
    Bflff where k. Is hydrogen or methyl}. ; % hydrogen or methoxy, X - oxygen, NH-rpynna; Rj is hydrogen, methyl or phenyl; RJ, - Hydrogen, silt Together,., D - means 3-4-membered hydrocarbon saturated uenbj
    Y cyano group, COR, where Rjmethyl, g phenyl, ethoxy or KB and P3 together mean a 2-3-membered saturated carbon chain f Rg is methyl, propyl, isopropyl
    or allyl; R -, - hydrogen, chlorine, bromine, methyl
    group ZSNe,
    possessing valuable pharmacological properties.
    A known method for producing 8-pyridyl-substituted ergolium derivatives by reacting an ergoline tosyl-derivative with the sodium salt of the corresponding pyridine derivative in a polar aprotic solvent in an inert atmosphere at 50-100 ° C 1.
    The purpose of the invention is to obtain new ergoline derivatives. Possessing valuable pharmacological properties.
    This is achieved by the fact that according to the method of obtaining ergoline derivatives of general formula I, based on the known reaction 1, the compound of general formula
    50
    ir-jl,
    (P)
    55
    2. fife and r
    Where
    have indicated
    meanings
    condense in hexamethylphosphorus
    amide with sodium salt of the compound
    general formula
    , four
    (Iii)
    Tfa-: 3C - (} (J-T
    65
    where R5,, RA, X and Y have the indicated
    cheni
    followed by highlighting the target
    product known methods.
    The process is preferably carried out at 50-100 ° C for 2-10 hours.
    Example 1. 6-Methyl-8-C {3-butene-2-one-4-methyl) -4-hydroxymethyl J-ergoline.
    A mixture of 4.1 g of 6-methyl-8B-tolylsulfonyl-oxymethylergoline and 2.44 g of sodium acetate of acetylacetone in 30 ml of hexamethylphospho-triamide is heated to and kept at this temperature for 3 hours. The resulting solution is poured into 500 ml of water, the precipitate is filtered off and purified by crystallization from acetone, yielding 2.3 of the title compound, m.p., 247,249 ° C.
    Example 2. 6-Methyl-8-C (2-cycl. Lexenone) -3-hydroxymethyl-ergoline.
    Example 1 is repeated, but using sodium 1, 3-cyclohexanedione sodium salt instead of ace- sodium salt. tylaCeton, and get the target compound with a yield of 65%, so pl. 224226 s.
    Example 6. 6-Methyl-8- (2-cyclopentenone) -3-hydroxymethyl-3-ergo.
    Example 1 is repeated, but using the sodium salt of 1,3-cyclopentadione instead of the sodium salt of acetylacetone and heating to give the desired compound c. yield 70%, so pl. 215-2170С.
    Example 4. 6-Methyl-8-C (1-phenyl-3-methyl-2-propen-1-one) -3-hydroxymethyl ergoline,
    Example 1 is repeated, but using the sodium salt of benzoyl acetone instead of the sodium salt of acetylacetone. Obtain the target compound with a yield of 75%, so pl. . 195-1E7S.
    Example 5. 6-Methyl-8-C 3-buten-2-one) -4-o, xymethyl ergoline.
    Example 1 is repeated, but using formylacetone sodium salt instead of acetylacetone-sodium salt. Heated to and get the target compound with. 55% yield, so pl. 156-159 ° C.
    Example 6. b-Methyl-8-C (1-acetyl-1-cyclohexem-2-hydroxymethyl-3-ergoline.
    Reproduce Example 1, but using 2-acetylcyclohexanone sodium salt instead of acetylacetate sodium salt. Get the target compound with a yield of 65%, so pl. 147150 C.
    Example 7, 6-Methyl-8-C (1,3-diphenyl-2-propen-1-bn) -3-hydroxymethyl 3-ergoline.
    Example 1 is reproduced, but using dibenzoylmethane sodium salt instead of acetylacetone sodium salt. Get the target compound with so pl. 182-184 ° C and 75% yield. Example 8. 6-Methyl-8 (3-m tilacrylic acid ethyl complex) -3-hydroxymethyl-3-ergoline. Example 1 is repeated, but with the use of the sodium etselacetoate salt instead of the acetylacetone sodium salt. Obtain the target compound with a yield of 50% and t, pl. 215-217 Pr im im 9. 1,6-Dimethyl-8-Cf 3-butene-2-one-4-methyl) -4-hydroxymethyl-3-ergoline-. . ,; Example 1 is repeated, but using 1,6-dimethyl-8B-trillylsulfur Nyloxymethyl-ergoline instead of 6-methi-8i-tolylsulfonyloxy-ergoline. The target compound is obtained with a yield of 70% and so pl. 161-163 C. For example 10. 1,6-Dimetsh1-8-: (2-cyclopentenone) -3-hydroxymethyl-, -ergoline. Example 3 is repeated, but using 1,6-dimethyl-8 (5-tolylsulfonyloxymethyl ergoline instead of 6-methyl-8y-tolylsulfonyloxymethyl ergolene. The desired compound is obtained in 80% yield and so on. 139-141C. Pp and measures 11 „1,6-Dimethyl-8- {3-buten-2-one-4-methyl-4-hydroxymethyl)} r-10-methoxy-ergopin. Example 1 is repeated, but using 1 6-dimethyl-8B-tolylsulfonyloxymethyl-10-methoxyergoline instead of 6-methyl-8B-tolylsulfonyloxymethylsrgoline, the compound is obtained with a yield of 60% and so on. 147-149 ° C. Note 12. 1,6-Dimethyl-8-t (2-cyclopenteyl 6n) -3-hydroxymethyl-1-1-methoxy erg. Example 3 is repeated, but using 1,6-dimethyl-815-tLylsulfonyloxymethyl-10-methoxyergoline instead of 6-methyl-8B-tolylsulfonyl simethylene-ergoline. Obtain the target compound with a yield of 45%, and so pl. 158-160 0. EXAMPLE 13. 6-Methyl-8-C {3-butene-2-one-4-methyl) -4-hydroxymethyl 1-10-methoxy-ergoline. Example 1 is repeated, but using 6-methyl-8B-tolylsulfonyloxymethyl-10-methoxyergoline instead of 6-meth-L-8B-tolylsulfonyl simethylergolium. Obtain the target {connection with the release of 55%, and so pl. 178-1800 C. Example 14. 6-Methyl-8- (2-cyclopentene) -3-oximethyl-10-methoxy-rislin. Example 3 is repeated, but using 6-methyl-8B-tolylsulfonyloxymethyl-10-methoxyergoline instead of 6-methyl-8B-tolylsulfonyl simethylergoline. Obtain the target compound with a yield of 63%, and so pl. 239-241С. Example 15. 1,6-Dimethyl-8-C (3-buten-2-one) -4-hydroxymethyl-3-ergoline. Example 5 is repeated, but using 1,6-dimethyl-8D-tolylsulfonyloxymethyl ergoline instead of 6-methyl-8B-tali lsulfonyloxymethyl ergoline. Obtain the target compound with a yield of 45%, and so pl. 120-122 C. EXAMPLE 16. 6-Methyl-8- (3-methacrylonitrile) -8-hydroxymethyl-erGalin. Example 1 is repeated, but using sodium cyanacetone instead of acetylacetone sodium. Obtain the target compound with a yield of 60%, and so pl. 210 212C. Example 17. 1,6-Dimethyl-8-G (8-methacrylonitrile) -3-hydroxymethyl ergoline. Example 16 is repeated, but using 1 6-dimethyl-8Й-tolylsylphonyloxymethyl ergoline instead of 6-fetil-BB-tolylsulfonyloxymethylergolAn. Obtain the target compound with a yield of 70%, and so pl. 162-164 C. Example 18. 2 6-Dimethyl-8- (3-butene-t2-one-4-methyl) -4-hydroxymethyl-ergoline. A mixture of 3.18 g of 2,6-dimethyl-8B-tolyl sulfonyloxymethyl ergoline and 1.65 g of sodium acetate of acetylacetone in 30 ml of hexdimethylphosphate of rtriamide is heated to and kept at this temperature for 3 hours. The resulting solution is poured into SCO ml of water, the precipitate is filtered and purified by crystallization from ethanol. Chorus 1.3 g of the title compound with m.p. 224-225C. Example 19. 21,6-Dimethyl-8- (2-cyclopentenone) -3-oxymethyl ergopene. Example 18 is repeated, but the sodium salt of 1,3-cyclopene adion is used instead of the sodium salt of acetylacetone. The title compound is obtained in a yield (50% and mp. 221-223 ° C. Example 20. 6-Propyl-8-c H-buten-2-one-4-methyl) -4-oxomethyl 3-ergoline. . Example 18 is repeated, but 6-propyl-8B-tolylsulfonyloxymethyl ergoline is used instead of 2,6-dimethyl-86-tolylsulfonyloxymethyl ergoline. - Obtain the target compound with a yield of 75%, and so pl. 198-201 ° C. Example 21. 6-Propyl-8- (2-cyclopentenone) -3-hydroxymethyl-ergspin. Example 20 is repeated, but using the 1; 3-cyclopentanedione sodium salt instead of the acetyl-acetone sodium salt. Obtain the target compound with a yield of 70%, and so pl. 180-183 p.
    Example 22. 2-Bromo-6-methyl-8- (3-buten-2-one-4-methyl) -4 oxymethyl ergoline.
    Example 18 is repeated, but using 2-bromo-b-methyl-8 (3-tolylsulfonyloxymethyl ergoline instead of 2,6-di-. Methyl-8B-TOLsylsyloxymethylergoline. The target compound is obtained with a yield of 68% and so on. 250-251C,
    Example 23, 2-Chloro-b-methyl-8-tf3-butene-2-one-4-methyl) -4-hydroxymethyl - er gol ..
    Example 18 is repeated, but 2-chloro-6-methyl-8y-tolylsulfruxyloxymethyl ergoline is used. Obtain the target compound with a yield of 70% and. m.p. 257-260RS.
    Example 24. 2-Thiomethyl-6-methyl-8- (3-butene-2-one-4-methyl) g 4-hydroxyethyl-EH. GOLY.
    . Example 18 is repeated, but using 2-iometi l-B fS tols l sul lphonyl-g oxymethylergol .. Obtain the title compound with so pl. 196-198 C. Yield 65%.
    Example 25. 2-Bromo-6-methyl-8- (3-buten-2-one) -4-hydroxymethyl-ergo and n. .
    Example 22 is repeated, but using; formylacetone sodium salt is added. Get the target compound with so pl. 108-110 ° C. Yield 55%.
    Example 26. 2-Chloro-6 methyl-8- (3-buten-2-one) -4-hydroxymethyl-1-ergoline.
    Example 23 is repeated, but formylacetone sodium is used. Get connection with so pl. 117120 ° C. Exit 601.
    Example 27. 2-Thiomethyl-6-methyl-8 (3-buten-2-on) -4-oxymethide-ergoline.
    . Example 24 is repeated, but formylacetone sodium is used. Get the target compound with so pl. 162-165 seconds Yield 70%.
    Example 28. 2-Bromo-6-methyl-8-1, (2-cyclopentenone} -3-hydroxymethyl) -ergoline.
    Example 22 is repeated, but 1,3-cyclopentadion sodium salt is used. Get the target compound with so pl. 216-218 C. Yield 73%. ;
    Example29. 2-Chloro-6-methyl-8-P (2-cyclopentenone) -3-hydroxymethyl 3-, -ergoline.
    ttoB example 23, but using the sodium salt of 1,3-cyclopentanlion. The desired compound is obtained in 65% yield, mp, 230-232 ° C.
    Example. 30, 2-Thiomethyl-6-mvtil-8-E (2-cyclopentenone) -3-ox methD-ergoline,
    Example 24 is repeated, but the 1,3-cc sodium bentant of Lyon soda salt is used. Get the target connection
    from m.p. goz aob with Yield 64%.
    Example 31. b-Propyl-8-f (3-butene-2-one) -4-hydroxymethyl-3-ergoline,
    Example 20 is repeated, but formylacetone sodium is used. Get the target compound with so pl. 5 -122-124C. Yield 55%:
    Example 32. 6-Allyl-8-C (3-butene-2-one-4-methyl) -4-ximethyl} -hergOLIN:
    Example 18 is repeated, but 10 6-allyl-8B-tolylsulfonyloxymethyl ergoline is used. Get the target compound with so pl. 195-199 0. Exit 60.
    Example 33. 6-Allyl-8-C (2-cyclopentenone) -3-hydroxymethyl ergoline. 5 Example 32 is repeated, but using sodium, 1,3-cyclopenan tandione salt. Obtain; the title compound with m.p. . Yield 70%.
    Example 34.:B Allyl-8- {3-buten-2-one) -4-hydroxymethyl erg.olin.
    Example 32 is repeated, but using sodium salt of formyl acetone. Get the target compound with so pl. 118-120 ° C. Yield 60%.
    Example 35. 6-Isolrop L-8-P 3-buten-2-one-4-methyl) -4-hydroxymethyl ergoline.
    Example 18 is repeated, but using 6-isopr, opil-8 (5-tolsulfonyloxymethyl-ergoline). The title compound is obtained with mp 213-215 C. The yield is 73%.
    Example 36. 6-Isopropyl-8-C (2-cyclopentenone) -3-oxymethyl ergoline.
    5 Example 35 is repeated, but using the sodium salt of 1,3-cyclopentanedione. Get the target compound with so pl. 129-132 C. Yield 65%,
    PRI me R 37. 6-Isopropyl-8Q-C (3-butene-2-one) -4-oxymethyl-3-ergoline .-
    Example 35 is repeated, but using formylacetone sodium salt. Get the target connection with so pl. 145-148c. Yield 55%. 5 Example 38. 6-Me | TIL-8- (8-methacrylic acid ethyl ester) -3-aminomethyl-ergoline.
    A mixture of 2 g of 6-methyl-8B-tolylsulfonyloxymethyl ergoline and 1 g of sodium BOY of the B-aminocrotonic acid ethyl ester salt in 20 ml of hexamethylphospho triamide is heated for 7 hours. The reaction mixture is poured into ice water, the precipitate 5 is filtered off and purified by crystallization from methanol to obtain 1.2 g of the title compound with mp. : 160-162 0.
    Example 39. 1, -6-Dimethyl-80 -C (3-methacrylic to slots ethyl complex eff) -8 aminomers of l. -Ergol n.
    Repeat Example 38, but using 1 6-d 1 dat l-8th-tsch lsulfo (n-oximethylergoline instead) b-meth l5 -86-tolylsulfone loxymethyl ergol. Get the target compound with so pl, 143-145 C. The yield of 55%. Example 40. 6-Methyl-8- (3-buten-2 on-4-methyl) g 4-aminomethyl-er (GrLIN. Example 38 is repeated, in which sodium 4-amino-3-pentene - 2-it instead of sodium coAi and B-aminocrotonic acid of ethyl ester. The desired compound is obtained with mp i93-195 C. Output-B: Example 4: 6-Methyl-8-C ( 2-cyclopeVTenone) -8-aminomethyl3-ergali Example 38 is repeated, yo is used, the sodium salt of 3-amino-2-cyclopeitin-1-one is used instead of the sodium salt of 6-azo-hydrochloric acid of ethyl ethyl ester. 235-Z47c. Yield 45%. If. ROME ep 42; 1, b-Dime tyl-8-1 (2g: cyclopentenone) - 3-aminomethyl-ergr in ,, Povhrr 19T is an example compound, but using 1 6-di-methyl-8B-tolylsulfonyloxymethylergoline BMeqjco- -methyl-86-tolisulfonyloxymethyl-ergoline. 124P26 C. Yield 50%. Example 43 6-Ketil-8- (1,3-diphenyl-2-propyen-1-one) - 3 aminomethyl-ergoline. Example 38 is repeated, but sodium salt 3 is used. -amine-1,3-difennl-2-propen-1-one. Obtain the target compound with so pl.L45-147 C. The output is 45%. . Example44. b-Methyl-8- (2 | -cyclohexenone) -3-aminomethyl3-ergoline. Example 38 is repeated, but the 3-amino-2-cyclo-w-xen-1-one sodium salt is used. Get the target compound with so pl. 280-282C. Yield 65%. Example 45. 6-Methyl-8-f (l-acetyl-l-cyclohexene) -2-amino-methyl 3 -pergulin. Example 38 is repeated, but using the 2-amino-1-a-ethyl-1-cyclohexene sodium salt. Get the target compound with so pl. 212-214 s. Yield 65%. Example 46. 6-Methyl-8- (1-fe NIL-3-methyl-2-propen-1-one) -3-aminomethyl-ergolI. Example 38 is repeated, but the 3-guicino-1-phenyl-3-methyl-2-propen-1-one sodium salt is used. Gender — Target compound with m.p. 150-153C, yield 70%. The compounds obtained by the proposed method are useful antidepressants, sedatives and antipsychotic agents. They manifest Netr. From moderate to good anti-prophylactic and anti-hypertensive activity. Profiles of the main sedative pharmacological activity were obtained by Irwins by observing the behavior of the mouse, which also defines the indicative toxicity after seven days of observation, and by antagonism to central amphetamine-induced hypothermia. Results obtained with some compounds are presented in abl. 1. T a b l and C a 1 To antagonize the central amphetamine-induced hypothermia of the compound, were orally administered to the male in doses of 0.01-10 mg / kg 30 minutes before the intraperitoneal injection of 10 mg / kg d-amphetamine sulfate. Antagonism to hypothermia was assessed after 60 min. After the administration of amphetamine. The compounds were active potential antidepressant agents, as predicted by their antagonism to reperin-induced blepharospasm and hypothermia. Tests were carried out under KOMHaTHHk conditions at a constant ISil C. temperature. Randomly selected groups of male kyloi were treated respectively with the appropriate: O71 dose: 1x doses (from 25 mg / kg and below) of the test compounds suspended in 0.5% solvent (Methocel) , 1 ml / 100 g of live weight), or solvent only. An hour later, the animals received intraperitoneally injection of reserpine (1.5 mg / kg, 1 p / 100 g of live weight). After 3 hours from the start of the test, i.e. 2 h after treatment with reserpine or a solvent, blepharospasm was evaluated according to the scales proposed by Rubin et al. Two hours after the above assessment, the rectal temperature of the animals was measured with the aid of a corresponding probe associated with a finger thermometer (ELLABDU- .3). In tab. Figure 2 shows that the target compounds, g, were very active in preventing the considered reserpine-induced symptoms with an AU in the range of 0.1-10 mg / kg and with a very low estimated acute toxicity. The tricycle antidepress site imipramine, used as a standard drug, prevented reserpine-induced blepharospas and hypothermia with a range of 8.1–18.2 mg / kg and showed higher estimated acute toxicity in mice.
    table 2
    35S / 1228
    0.14 example3) ZD
    355/1296 {example 4)
    355/1301
    0.46 (example 19}
    355/1311 1.5 (example 16)
    355/1335 0,2 (example 29)
    600
    0.39
    7.7
    800
    0.57
    300
    300
    200
    权利要求:
    Claims (2)
    [1]
    1. METHOD FOR PRODUCING ·
    WATER ERGOTINE general formula • * I "
    R3r4
    K-6 K 7 used a compound of general formula in hexamethylphosphorotriamide condensed with the sodium salt of the compound of general formula wherein R 4 - hydrogen or methyl; R a is hydrogen or methoxy; X is oxygen, an NH group; R ^ is hydrogen, methyl or phenyl; R4 is hydrogen or R e and R ^ together mean a 3-4 membered hydrocarbon saturated chain; Y is a cyano group, COR ^ where R ^ methyl, phenyl, ethoxy or R 5 hR ^ together mean 2-3 membered saturated carbon chain;
    : sa-x-C = C-Y where R ^, R4 "X and Y> have the indicated meanings, with the subsequent isolation of the target product.
    [2]
    2. The method according to p.
    Priority on 12/06/79.
    05/29/80 at
    03/01/80 with hours
    for 2-10 signs: Nd-methyl,)) - »- hydrogen, X - oxygen,
    X is an NH group;
    all other meanings of the radicals.
    1034606.
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    同族专利:
    公开号 | 公开日
    EP0030351A2|1981-06-17|
    US4382940A|1983-05-10|
    DE3068911D1|1984-09-13|
    CA1153367A|1983-09-06|
    HU185020B|1984-11-28|
    AU6495880A|1981-06-11|
    IT1196411B|1988-11-16|
    IT8026488D0|1980-12-05|
    IL61614D0|1981-01-30|
    AU537581B2|1984-07-05|
    FI67081B|1984-09-28|
    EP0030351A3|1981-12-02|
    FI803736L|1981-06-07|
    DK518580A|1981-06-07|
    EP0030351B1|1984-08-08|
    FR2471381A1|1981-06-19|
    IE802558L|1981-06-06|
    FR2471381B1|1983-01-07|
    IE51187B1|1986-10-29|
    YU309080A|1983-02-28|
    IL61614A|1984-04-30|
    FI67081C|1985-01-10|
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    GB8427536D0|1984-10-31|1984-12-05|Lilly Industries Ltd|Ergoline derivatives|
    US4675322A|1984-12-10|1987-06-23|Eli Lilly And Company|1-Substituted-6-n-propyl-8β-methylthio-methylergolines|
    US4683313A|1985-06-24|1987-07-28|Eli Lilly And Company|2-alkylthio-6-N alkyl ergolines and 4-dialkylaminotetrahydrobenz[c,d]indoles|
    US4801712A|1985-06-24|1989-01-31|Eli Lilly And Company|2-Alkylthio-6-n-alkylergolines are dopamine D-1 antagonists without D-2 agonist activity|
    DE3535930A1|1985-10-04|1987-04-09|Schering Ag|NEW 2-SUBSTITUTED ERGOL DERIVATIVES|
    GB8615471D0|1986-06-25|1986-07-30|Erba Farmitalia|T-butyl ergoline derivatives|
    DE3938701A1|1989-11-20|1991-05-23|Schering Ag|NEW AGROCLAVIN AND ELYMOCLAVIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS|
    DK0628042T3|1992-12-24|2001-11-12|Pharmacia & Upjohn Spa|Serotoninergic ergoline derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7942079|1979-12-06|
    GB8007029|1980-03-01|
    GB8017518|1980-05-29|
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