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GB2185743A - 8 alpha -Acylaminoergoline's - Google Patents

8 alpha -Acylaminoergoline's Download PDF

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GB2185743A
GB2185743A GB08701274A GB8701274A GB2185743A GB 2185743 A GB2185743 A GB 2185743A GB 08701274 A GB08701274 A GB 08701274A GB 8701274 A GB8701274 A GB 8701274A GB 2185743 A GB2185743 A GB 2185743A
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compound
alkyl
acid addition
ergoline
methyl
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Rene Ziegler
Peter Neumann
Walter Haefliger
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
    • C07D457/12—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Novel compounds of the formula I <IMAGE> wherein R1 is hydrogen or (C1-4)alkyl, R2 is CN, COOH, COOR5, CONH2, CONHR5, CON(R5)R6, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2R7', CH(OH)R5, CH2CF3, iodine, C IDENTICAL CR8, CH=CHR8, (C2-12)alkyl, NO2, NH2 or NHCOR9,wherein R5 and R6 are independently (C1-4)alkyl, R7 is (C1-4)alkyl, CF3, phenyl or phenyl(C1-5)alkyl, R7' is phenyl or phenyl(C1-5)alkyl, R8 is hydrogen, (C1-10)alkyl or phenyl and R9 is (C1-6)alkyl, R3 is (C1-5)alkyl or (C3-5)alkenyl, in which the double bond is not at the carbon atom adjacent to the nitrogen atom, and R4 is (C1-12)alkyl, (C3-7)cycloalkyl or adamantyl, or acid addition salts thereof, are useful as neuroleptic and antidepressant agents. Some of the compounds possess prolactin secretion inhibiting activity.

Description

SPECIFICATION 8a-Acylaminoergolines, their production and pharmaceutical compositions containing them The present invention relates to novel 8a-acylamino-ergolines, processes fortheir production, pharmaceutical compositions containing them and their use as pharmaceuticals.
More particularly the present invention relates to compounds offormula I,
wherein R1 is hydrogen or (C1 4)alkyl, R2 is CN, COOH, COOR5, CONH2, CONHR5, CON(R5)R6, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2R7', CH(OH)R5, CH2CF3, iodine, C#CR8, CH=CHR8, (C2 12)alkyl, NO2, NH2 or NHCOR9, wherein R5 and R6 are independently (C1 4)alkyl, R7 is (C1-4)alkyl, CF3, phenyl or phenyl(C1.5)allyl, R7' is phenyl or phenyl(C1-5) alkyl, R8 is hydrogen, (C1.10)alkyl or phenyl and Rg is (C1-6)alkyl, R3 is (Ca 5)alkyl or (C3.5)alkenyl, in which the double bond is not at the carbon atom adjacent to the nitrogen atom, and R4 is (Ca 12)alkyl, (C3 7)cycloalkyl or adamantyl, as well as the acid addition salts thereof.
In one group of compounds R1 is hydrogen or (C1-4)alkyl, R2 is CN, COOH, COOR5, CONH2, CONHR5, CON(R5)R6, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2R7,, CH(OH)R5, CH2CF3, iodine,C#CR8, CH=CHR8 or (C2-5)alkyl,wherein R5 and R6 are independently (C1.4)alkyl, R7 is (C1.4)alkyl or CF3, R7' is phenylmethyl and R8 is hydrogen, (C1 3)alkyl or phenyl;; R3 is (C1.5)alkyl or (C3.5)alkenyl in which the double bond is not at the carbon atom adjacent to the nitrogen atom, and R4 is (C1-12)alkyl, (C3-7) cycloalkyl or adamantyl or an acid addition salt thereof.
In another group of compounds offormula I, R1 is hydrogen; R2 is CN, COOH, COOR5, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2CF3, iodine, OCR8, CH=CHR8, (C2.12)alkyl, NO2 or NHCOR9, wherein R5 is (C1-4)alkyl, R7 is (C1-4)alkyl or CF3, R8 is hydrogen and R9 is C1-12)alkyl; R3 is (C1-5)alkyl and Rq is C1-12)alkyl or an acid addition salt thereof.
Alkyl groups and moieties in the compounds of formula I may bestraight- orbranched-chain.
For the above formula I the following significances, as well as combinations thereof, are preferred: 1. R1 is hydrogen or methyl, especially hydrogen.
2. R3 is (C1.5)alkyl, especially (C1.3)alkyl.
3. R4 is (C1.12)alkyl, especially (C3.7)alkyl, in particular branched-chain (C3.7)alkyl.
Compounds offormula , wherein R2 is SOR5 or CH(OH)R5, have one additional chiral centre and can thus appear as diastereoisomers. Wherein alkenyl groups are present, cis and trans isomers occur. The present invention extends to the individual diastereoisomers and cis/trans isomers as well as to mixturesthereof.
The present invention also provides a process for the production of the compounds of formula I and their acid addition salts, which comprises: a) reacting a compound offormula II,
wherein R1, R3 and R4 are as defined above, with chlorosulfonyl isocyanateto obtain a compound offormula I, wherein R2 is CN and optionally converting the cyano group into COOH, COOR5, CONH2, CONHR5 or CON(R5)R6;; b) reacting a compound offormula II with a compound offormula Ill, R5SCI Ill wherein R5 is as defined above, to obtain a compound offormula 1, wherein R2 is SR5, and optionally converting the SR5 group into SOR5 or SO2R5, c) reacting a compound offormula II with a compound offormula IV, R7CO-Y IV wherein R7 is as defined above and is a leaving group, in the presence of a Lewis acid to obtain a compound offormula I, wherein R2 is COR7 and optionally converting a COR7 group, wherein R7 is phenyl or phenyl(C1.5)alkyl, into CH2R7' or converting a COR7 group, wherein R7 is (C1.4)alkyl, into CH(OH)R5 or into (C3 12)alkyl, d) reacting a compound offormula II with N,N-dimethylformamide and phosphorous oxychloride to obtain a compound offormula I, wherein R2 is CHO and optionally converting the CHO group into CH2OH, e) introducing into the position 2 of a compound offormula II an iodine atom or the CH2CF3 group orthe C(CH3)3 group to obtain a compound offormula I, wherein R2 is iodine, CH2CF3 or C(CH3)3, f) nitrating a compound offormula II to obtain a compound offormula I, wherein R2 is NO2 and optionally converting the NO2 group into NH2 or NHCOR9, g) reacting a compound offormula V,
wherein R1, R3 and R4 are as defined above and Xis bromine or iodine, with a compound offormula VI orVII, CH2=CHR5, VI CH-CR8 VII wherein R8' has the meaning of R8 except hydrogen but additionally can also be a protecting group, and as appropriate removing any protecting group present, to obtain a compound offormula I, wherein R2 is CH=CHR8 or Ce0R5 and optionally reducing a CH=CHR8or Ce0R8 groupto CH2CH2R8, and recovering the obtained compound offormula I as such or as an acid addition saltthereof.
Process step a) may be carried out in known manner. The reaction is suitably carried out in an inert organic solvent, such as N,N-dimethylformamide in an inert atmosphere, e.g. argon. Conveniently a base, such as a tertiary amine, e.g. triethylamine, is present. The optional conversion of the cyano group into the COOH group may be carried out conventionally. The conversion of the cyano group into a COOR5 group can be effected by conventional methods. The conversion of the cyano group into CONH2, CONHR5 or CON(R5)R6 may be carried out in accordance with standard procedures. For example, the conversion may be effected via the carboxylic acid methylester or via the carboxylic acid chloride.
Process step b) may also be carried out in conventional manner. A compound offormula Ill may be prepared in situ from a disulfide and sulfuryl chloride. The reaction is suitably carried out in an inert organic solvent, such as dichloromethane. The optical oxidation of a thioetherto a sulfoxide or sulfone can be carried out in known manner. For example for the preparation of sulfoxides sodium periodateor tetra(n-butyl)ammonium-periodate can be used. Sulfones can be obtained using as oxidizing agents hydrogen peroxide or peracids, e.g. peracetic acid or m-chloroperbenzoic acid.
Process step c) may be performed in conventional manner. Suitable Lewis acids are for example boron trifluoride or aluminium trichloride. As a solvent an excess of a compound offormula IV can be used. The leaving group Y is e.g. halogen, especially chlorine, or -OCOR7, wherein R7 is as defined above. The optional conversion of COR7, wherein R7 is phenyl or phenyl(O1.5)alkyl into CH2R7, may be effected in conventional manner. The reduction may be effected with e.g. lithium aluminium hydride. The optional conversion of COR7, wherein R7 is (C1.4)alkyl into -CH(OH)R5 may be carried out conventionally. The reduction may be effected with e.g. sodium borohydride.The optional conversion of COR7 into an alkyl group may be performed by reaction with an appropriate Grignard reagent or an alkyl lithium, followed by hydrolysis. The resulting compound is dehydrated with acid, followed by hydrogenation.
Process step d) can be carried out in known manner. For example reaction conditions according to Vilsmeier can be applied. The optional conversion of the CHO group into CH2OH may be effected conventionally. The reduction may be performed by catalytic hydrogenation for example using Raney-nickel or with sodium borohydride.
Process step e) may be effected in conventional manner. For example the introduction of an iodine atom can be performed using standard iodinating agents, such as N-iodosuccinimide. The reaction is conveniently effected in the presence of a solvent such as dioxane ortetrahydrofurane. The introduction of CH2CF3 may be effected by reaction with 1 ,2-bis-(2-trifluoromethyl-1 ,3-dithiolan-2-yl)-thioethane under Friedel-Crafts reaction conditions. Titanium tetrachloride may be used as a Friedel-Crafts catalyst. The resulting compound offormula II, which is substituted in 2-position by2-trifluoromethyl-1,3-dithiolan-2-yl is converted by desulfuration into a compound offormula I, wherein R2 is CH2CF3 using Raney-nickel.
The introduction of the C(CH3)3 group may be carried out by reaction with tert. butanol under Friedel-Crafts reaction conditions. Aluminium trichloride may be used as a catalyst.
Process step f) may be carried out in conventional manner. The reaction may be effected in an organic solvent, e.g. dichloromethane. The optional conversion ofthe NO2 group into NH2 may be effected using conventional methods, e.g. catalytic hydrogenation. The optional conversion of NO2 into NHCORg may be carried out conventionally, e.g. by reduction followed by acylation.
Process step g) may be effected in conventional manner. The reaction may be carried out in an organic solvent, e.g. N,N-dimethylformamide or N-methylpyrrolidone, in the presence of an amine, e.g.
triethylamine. Suitabletemperatures rangefrom about400 to the boiling temperature of the reaction mixture.
The reaction is suitably carried out in the presence of a catalyst, e.g. a palladium complex, such as bis(triphenyl-phosphine) palladium (II) chloride or palladium (II) acetate/triphenylphosphine. The reaction is suitably carried out in an inert atmosphere, e.g. argon. In a compound offormula VI or VII R8' is a protecting group, e.g. trimethylsilyl, when compounds offormula I areto be prepared, wherein R2 is CH=CH2 resp.
CZECH. The deprotection can be carried out using conventional procedures, e.g. by alkaline hydrolysis. The optional reduction of CH=CHR8 resp. C-CR5 to CH2CH2R8 may be effected conventionally, e.g. catalytic hydrogenation.
Insofarasthe production of the starting materialsforthe above processes is not particularly described, these may be produced in analogous mannerto known compounds orto processes described herein. The mixtures ofthe diastereoisomers or the cis/trans isomers may be separated in known manner.
The compounds offormula I may be converted into acid addition salts thereof in conventional manner and vice versa. Suitable acids include for example, hydrochloric acid, hydrobromic acid, maleic acid orfumaric acid.
In the following Examples all temperatures are given in degrees centigrade and are uncorrected. The [a]D20 values are also uncorrected.
Example 1: 2-Cyano-6-methyl-8a-pivaloylamino-ergoline To a solution of 12.3 g 6-methyl-8-pivaloylamino-ergoline in 250 ml acetonitrile is added dropwise over a period of 10 minutes, under cooling in an ice bath, a solution of 3.6 ml chlorosulfonyl isocyanate in 30 ml acetonitrile. The reaction mixture is then stirred for 30 minutes at room temperature and treated dropwise over a 10 minutes period with 12.5 ml N,N-dimethylformamide in 30 ml acetonitrile. The mixture is stirred for 2 hours at room temperature and then treated with CH2CI2 and 2N Na2CO3 solution. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel (500 g) using CH2Cl2/CH3OH (95:5).
On crystallisation from ether the title compound, m.p. 195-200 , [aiD20 = + 290 (c = 1.0 in CH2C12), is obtained.
Example 2: 2-Carbomethoxy-6-methyl-8(x-pivaloylamino-ergoline 0.3 g 2-Cyano-6-methyl-8a-pivaloylamino-ergoline and 8.6 ml H2SO4/CH3OH 1 N are heated at reflux under nitrogen for about 100 hours. The reaction is followed bythin layer chromatography. CH2Cl2and 2N aqueous Na2CO3 are added, the organic layer dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel (10g) usingCH2CI2/CH3OH (97:3) to yield the title compound, m.p. 133 .
Example 3: 6-Methyl-2-methylthio-8e-pivaloylamino-ergoline To a stirred solution of 2.35 g dimethyldisulfide in 90 ml CH2Cl2 at -20' to -25" under nitrogen are added 2.42 g sulfurylchloride. The reaction mixture is warmed to room temperature and stirring continued for 2 hours. The mixture is then added dropwise at 0 to 1 00to a solution of 9.76 g 6-methyl-8a-pivaloylamino-ergoline in 300 ml CH2Cl2. The mixture is broughtto room temperature and stirred forfurther 2 hours. After adding 100 ml H20 and 100 ml 2N Na2C03 solution, it is extracted with CH2C12.
The organic layer is dried (Na2SO4), evaporated and chromatographed on silica gel using ethyl acetate.
Crystallisation from CH2Cl2/diethyl ether gives the title compound, m.p. 1830, [a]ID20 = + 13.10 (c = 1.069 in CH2C12).
Example 4: 6-Methyl-2-methylsulfinyl-8e-pivaloylamino-ergoline To 4.5 g 6-methyl-2-methyithio-8&alpha;-pivaloylamino-ergoline in 130 ml 2N acetic acid are added portionwise within 15 minutes3.87 g sodium periodate. The reaction mixture is stirred at room temperature for 24 hours and then evaporated. After adding water to the residue, the mixture is rendered alkaline with 2N KOH solution and extracted several times with CH2Cl2. The organic layer is evaporated to give a mixture.This mixture is then separated by chromatography on silica gel using chloroform/methanol/glacial acetic acid (8:1 :1 ) as eluant. The first eluted component is a diastereoisomer of the title compound, obtained upon crystallisation from CH2C12, m.p. 262-267", [(u]D20 = - 108.6' (c = 0.8165 in CH2C12). The second eluted component is a diastereoisomer of the title compound, obtained as a hydrochloride upon crystallisation from methanol/diethyl ether, m.p. of the hydrochloride 258-260", [a]D20 = - 11.9' (c = 0.52 in H2O).
Example 5: 6-Methyl-2-meth ylsulfon yl-8a-pivalo ylamino-ergollne Asolution of 185 mg 6-methyl-2-methyltbio-8a-pivaloylamino-ergoline inS ml glacial acetic acid istreated at room temperature with a 30% aqueous H202 and the mixture left at room temperature for 2 days.
Thereafter 200 mg of 5% Pt/C are added and the mixture stirred. After the reaction is completed (KJ-starch reaction for peroxides is negative), the mixture is filtered and evaporated. The oily residue is dissolved in CH3OH and hydrogenated over Pd/C during 2 hours in order to reduce eventually present N-oxides. Afterthe catalyst is filtered off, the solvent is evaporated in vacuo to give the title compound, which is crystal lised from CH2CI2/diethyl ether, m.p. 205-210".
Example 6: 2-Acetyl-6-methyl-80L-pivalo ylamin o-ergoline For a pre-cooled (-25") solution of 3.25 g 6-methyl-8a-pivaloylamino-ergoline in 60 ml acetanhydride are added 20 ml boron trifluoride etherate. The mixture is keptfor 25 minutes at -25", then cooled to -35' and treated with 200 ml CH30H. The mixture is then warmed to room temperature, evaporated to dryness, rendered alkaline with 2N Na20O3 and 2N NH3 solutions, diluted with water and extracted several times witch CH2Cl2.The organic phase is dried (Na2SO4), evaporated and the residue chromatographed on silica gel using CH2Cl2/CH3OH (97:3), to yield the title compound which is crystallised from CH2C12/diethyl ether, m.p.
123-127", [lYlD20 = +19.15 (c = 0.945 in CH2C12).
Example 7: 2-Formyl-6-methyl-Ba-pivaloylamino-ergollne To a precooled (5 ) solution of 1.6 g N,N-dimethylformamide and 5 ml 1 ,2-dichloroethane under nitrogen are added 3.38 g phosphorus-oxychlonde in 10 ml 1 ,2-dichloroethane. The mixture is stirred for 1 hour and then treated at a temperature not superating 20" with a suspension of 6.51 g 6-methyl-8a-pivaloylamino-ergoline in 130 ml 1 2-dichloroethane. The obtained suspension is stirred during 1 hour at 0', then for a further hour at reflux. The mixture is cooled to room temperature, treated with a solution of g sodium acetate in 50 ml H2O and heated at refluxfor 75 minutes.After cooling to room temperature, a little of conc. NaOH and conc. NH3 solutions are added and the mixture extracted several times with CH2Cl2. The organic layer is washed with H2O, dried (Na2SO4) and evaporated to the title compound as an oil. The oil is dissolved in acetone and treated with the equivalent amount of maleic acid to give the maleinate ofthe title compound as colourless crystalls, m.p. 147-150'. The free base can be obtained as an oil by dissolving the maleinate in H2O, adding an equivalent amount of conc. NH3 and extracting with diethyl ether. After removal ofthe solvent in vacuo the title compound is obtained, which is used in Example 8 as starting material.
Example 8: 2-Hydroxymethyl-6-methyl-8a-pivaloylamino-ergoline 2.34 g ofthe Example 7 compound in 250 ml ethanol are hydrogenated in the presence of Raney nickel at room temperature and normal pressure. After up-take ofthe calculated amount of hydrogen, the reaction mixture is filtered and evaporated. The residue is chromatographed on silica gel using ethyl acetate/methanol (5:1). On crystallisation from CH2CI2 the title compound, m.p. 239-246", [(ll]D20 = +8.8 (c = 0.9225 in DMF) is obtained.
Example 9: 2-(2,Z2- Trifluoroethyl)-6-methyl-8a-pivaloylamino-ergollne To a stirred mixture of 40 g Raney nickel in 200 ml ethanol under nitrogen is added at room temperature a solution of 1.9 g 2-(2-trifluoromethyl-1,3-dithiolan-2-yl)-6-methyl-8&alpha;-pivaloylamino-ergoline in 150 ml of methanol/acetone (1:1). After stirring for 30 minutes at room temperature, the catalyst is filtered off,the filtrate evaporated, the residue treated with water and conc. NaOH solution and extracted several times with CH2Cl2. The organic phase is evaporated and the residue chromatographed on silica gel using chloroform/cyclohexane/diethylamine as eluant.The title compound is obtained on crystallisation from ether/petroleum ether as colourless prisms, m.p. 116-120 , [aiD20 = + 22.9 (c = 0.895 in CH2C12).
The starting material may be obtained asfollows: 2.19 g 6-Methyl-8a-pivaloylamino-ergoline and 1.62 g 1 ,2-bis-(2-trifluoromethyl-1, 3-dithiolan-2-yl)-thioethane [prepared according to P. Stütz + P.A. Stadler, Helv. chim. Acta 55,75 (1972] are dissolved under nitrogen in 125 ml CH2Cl2andtreated at room temperature with 2.3 ml titanium tetrachloride. The mixture is held at room temperature for 24 hours and then diluted with 50 ml CH2C12. Water is added and the mixture rendered alkaline with conc. NH3 solution. After filtration over Hyflo, the organic phase is separated, washed with H20, dried (Na2SO4) and evaporated.The residue is chromatographed on silica gel using chloroform/methanoi/glacial aceticacid (8:1 :I)solvent mixturefor elution. The purefractions are treated with conc. NH3 solution, extracted with CH2C12 and the organic layer evaporated to give 2-(2-trif luoromethyl-l ,3-dithiolan-2-yl)-6-methyl-8a-pivaloylamino-ergoline, which cristallizesfrom dichloromethane/diethyl ether as colourless crystals, m.p. 260-262" (decomp.).
Example 10: 6-Methyl-8a-pivaloylamino-2-tert.butyl-ergoline To a mixture of 15 g 6-methyl-801-pivaloylamino-ergoline in 200 ml CH2C12 and 3.7 ml tert. butanol are added portionwise under stirring 18 g AiCI3. The mixture is stirred 18 hours at room temperature, then treated with 400 ml 5% aqueous NaHCO3 and extracted with CH2C12 (3 x 300 ml). The combined extracts are dried (Na2SO4), evaporated and the residue chromatographed on silica gel with toluene/isopropanol (97.5:2.5)to give the title compound, m.p. 238-240".
Example 11:2-lodo-6-methyl-8ce-pivaloylamino-ergoline To a stirred solution of 10 g 6-methyl-8a-pivaloylamino-ergoline in 200 ml dioxane is added dropwise at room temperature a solution of 8.49 N-iodosuccinimide in 150 ml dioxane within 30 minutes. The mixture is stirred for 1 hour and then added under stirring to 500 ml saturated NaHCO3 solution. Stirring is continued for 1 hour, the precipitate filtered off and the filtrate treated with CH2Cl2/H2O. The organic phase is separated, dried (Na2SO4) and evaporated to give 2-iodo-6-methyl-8a-pivaloylamino-ergoline, m.p. 200-203" (from isopropanol).
Example 12: 6-Methyl-2-ethinyl-8a-pivaloylamino-ergoline To a solution of 3.6 g 2-iodo-6-methyl-8(x-pivaloylamino-ergoline in 18 ml abs. N,N-dimethylformamide and 36 ml triethylamine under argon are added 2.45 ml ethinyltrimethylsilane, 0.072 g copper (I) iodide and 0.17 g bis(triphenylphosphine)palladium(ll)chloride. The mixture is heated 3 hours at 60' and then evaporated. The residue is extracted with ethyl acetate, the extract dried and evaporated to give 2-trimethylsilylethinyl-6-methyl-8a-pivaloylamino-ergoline, which is used without further purification.
To a suspension of 4.1 g 2-trimethylsilylethinyl-6-methyl-8a-pivaloyiamino-ergoline in 140 ml ethanol and 16 ml H20 are added under stirring 1.7 g K2CO3. After 30 minutes the reaction mixture turns dark and stirring is continued overnight. After removal of the solvent by distillation, the residue is dissolved in ethyl acetate and chromatographed on Kieselgel 60to yield thetitle compound, recrystallised from ethanol, m.p. > 180" (decomp.), [o]D20 = + 46 (c = 0.5 in CHO3).
Example 13: 6-Methyl-2-ethin y1-8a-(Z2-dieth yl- 1-oxopropyl)amino-ergoline In manner analogous to that described in Example 1 2the title compound is obtained, m.p. 200-201'.
Example 14: 6-Methyl-2-ethyl-8a-pivaloylamino-ergoline 2 g 6-Methyl-2-ethinyl-8c-pivaloylamino-ergoline in 100 ml ethanol and 3 g Raney nickel are hydrogenated at room temperature and normal pressure. After completion of the reaction, the catalyst is filtered off and the filtrate evaporated to yield the title compound, m.p. 197-198' (sintering at 175 ).
Example 15: 6-Meth yl-2-vin yl-Ba-pivalo ylamino-ergoline Amixture of 0.59 2-iodo-6-methyl-8a-pivaloylamino-ergoline, 10 ml abs. N,N-dimethylformamide, 0.2 ml triethylamine, 0.010 g palladium(ll)acetate, 0.020 g triphenylphosphine and 0.4 ml vinyltrimethylsilane is heated at 80" under nitrogen and stirring for 11/2 hours. The reaction mixture is then poured into H2O and extracted with CH2C12. The organic phase is dried (NA2SO4) and evaporated. The residue is dissolved in ethyl acetate and chromatographed on Kieselgel 60.Upon recrystallisation from diisopropyl etherthetitle compound is obtained, m.p. 185-200" (decomp.), m.p. of the fumarate > 240 (decomp.). [aiD20 = + 70 (c = 0.5 in pyridine).
Example 16: 6-Methvl-Satpivalo ylamin o-2-trffluoroacetyl-ergoline 15 g 6-Methyl-8a-pivaloylamino-ergoline, 45 ml trifluoroacetanhydride and 300 ml CH2C12 are heated at refluxfor8 hours. Afteradding 200 ml CH3OH, the mixture is evaporated. The residue is taken up with H2O and 2N Na2CO3 solution and extracted with CH2C12. The extracts are dried and evaporated. The residue is chromatographed on silica gel using dichloromethane/ethyl acetate (7:1) as eluant. Recrystallisationfrom diethyl ether/petroleum ether gives the title compound, m.p. 225-227', [&alpha;]D20 = + 7' (c = 1.203 in CH2Cl2).
Example 17: 6-Methyl-2-nitro-8a-pivaloylamino-ergol ine To a pre-cooled (0 ) suspension of 10 g 6-methyl-8a-pivaloylamino-ergoline in 100 ml acetanhydride are added under stirring dropwise 4.2 ml 100% no3 (d = 1.52). The mixture is stirred at 0" for 3 hours, then poured into 500 ml saturated NaHCO3solution and extracted thoroughly with ethyl acetate. The organic phase is dried (Na2SO4) and evaporated. The residue is chromatographed on aluminium oxide using toluene/ethyl acetate (2:1) as eluant, to give the title compound, m.p. 160"(decomp.).
Example 18: 6-Methyl-2-acetylamino-8X-pivaloylamino-ergoline To a solution of 400 mg 6-methyl-2-nitro-8a-pivaloylamino-ergoline in 30 ml acetanhydride are added under argon 50 mg 10% Pd/C. The mixture is hydrogenated 18 hours under normal pressure at room temperature, then filtered and evaporated. The residue is treated with 100 ml 5% aqueous NaHCO3 and then extracted with ethyl acetate (3 x 100 ml). The combined extracts are dried (Na2SO4) and evaporated. The residue istriturated with diethyl ether to yield the title compound, m.p. 190' (decomp.).
Example 19 In manner analogous to that described in Example 14the following compounds are obtained: a) 6-methyl-2-ethyl-8e-(2,2-diethyl-1 -oxopropyl )a mino-ergoline, m.p. 177", b) 6-methyl-2-ethyl-8a-(2,2-diethyl-1 -oxobutyl)amino-ergoline, amorphous.
NMR (ODOl3, MHz): 0.78 (t, 9H, C[CH2CH313); 1.31 (t, 3H,2-CH2CH3); 1.5-1.7 (m,6H, C[CH2CH3i3); 2.44 (s, 3H, N6-CH3); 6.77 (d, 1H,CONH); 7.72 (s, IH, N1-H).
Example 20:2-Form yl-6-methyl-8or-(2,2-diethyl- 1-oxoprop yl)amino-ergollne In manner analogous to that described in Example 7 the title compound is obtained, m.p. 110-115'.
Example 1: 2-Hydroxymeth yl-6-meth yl-8a-(2,2-diethyl- 1-oxoprop yl)amino-ergoline In a manner analogous to that described in Example 8the title compound is obtained, m.p. 125-128".
Example22: 2-lodo-6-methyl-8a-62,2-diethyl- 1-oxopropylJamino-ergoline In manner analogous to that described in Example 11 the title compound is obtained, m.p. 198".
Example 23: 2-Cyano-6-methyl-8or-(2,2-diethyl- 1-oxopropylJamino-ergoline In manner analogous to that described in Example 1 the title compound is obtained, m.p. 142-145".
Example 24:2-Ca rb oxy-6-meth yl-8a-(2,2-dieth yl- 1-oxoprop yl)amino-ergollne In manner analogous to that described in Example 2 there is obtained 2-carbomethoxy-6-methyl-8a-(2,2-diethyl-1 -oxopropyl)amino-ergoline, which hydrolyzed with 1 N NaOH yields thetitle compound, m.p. 262' (decomp.).
The compounds offormula land their pharmaceutically acceptable acid addition salts possess pharmacological activity as can be shown in standard animal test methods, and are accordingly indicated for use as pharmaceuticals.
In particular compounds offormula I and their pharmaceutically acceptable acid addition salts, possess apomorphine antagonistic activity as demonstrated e.g. in the test method described by Janssen et al., Arzneim.-Forsch. 10,1003, (1960). Thus compounds offormula I inhibit apomorphine (2 mg/kg i.v.) induced, stereotyped gnawing in rats at dosages of from 0.032 to 3.2 mg/kg i.p.
In view oftheirapmorphine antagonistic activity the compounds offormula land their pharmaceutically acceptable acid addition salts are indicated for use as neuroleptic agents, for example for the treatment of schizophrenia. Forthis use, an indicated daily dosage is in the rangefrom about 1 to about 40 mg ofthe compound, conveniently administered in divided doses 2to 4x/day in unit dosage form or in sustained release form. Suitable unit dosage forms comprise for example from about 0.25 to about 20 mg ofthe compound offormula I together with one or more pharmaceutically acceptable diluents or carriers therefore.
In addition compounds offormula I and their pharmaceutically acceptable salts possess anti-depressant activity as demonstrated e.g.by an inhibition of tetrabenazine-induced catalepsy and ptosis in rats (modified method of G. Stille, Arzneim.-Forsch. 14,534 [19641).The test was performed as follows: Groups of 6 rats (Sprague-Dawley derivation, females and males, 120-160 9, SüddeutscheTierfarm, Tuttlingen, West Germany) received the test substance in a dosage of ca. 1 to 10 mg/kg i.p. 30 minutes before administration of 10 mg/kg i.p. tetrabenazine. 40 minutes aftertetrabenazine administration the catalepsy of each rat was estimated by placing the forepaws on a 7 cm high wooden block. The time forwhich the animal remained in this unnatural position was measured up to a maximum of 45 seconds. Immediately after determining the catalepsy, the degree of ptosis was scored on a 3-point scale.No ptosis was represented by 0 whereas a score of 3 indicated complete eye-closure. The values from the separately scored eyes were added, so that the maximum score possible was 6. If a catalepsy of 29 seconds or less was observed,the tetrabenazine-induced catalepsywas said to be antagonised. Rats with a ptosis score of less than 3 were said to be protected against the ptotic effect oftetrabenazine. This procedure was repeated 60 minutes after tetrabenazine administration.
The compounds offormula I and their pharmaceutically acceptable acid addition salts aretherefore indicated for use as antidepressant agents, e.g. for the treatment of depression. Forthis use an indicated daily dosage is in the range from about 10 to about 50 mg of the compound conveniently administered in divided doses 2 to 4x/day in unit dosage form or in sustained release form. Suitable unitdosageforms comprise for example from about 2.5 to about 25 mg ofthe compound offormula I together with one or more pharmaceutically acceptable dil uents or carriers therefore.
Furthermore, compounds offormula I wherein R2 is other than CeOR5 and their salts possess prolactin (PRL) secretion inhibiting activity as demonstrated e.g. by inhibition of basal prolactin secretion in male rats in the method described by E. Fluckiger et al., Experientia 34, 1330(1978). These compounds exhibit activity in this test method at dosages of from 0.001 to 0.1 mg/kg s.c.
Compounds offormula I, wherein R2 is Ce0R8, possess prolactin (PRL) secretion enhancing activity as demonstrated in the above mentioned test of E. Flückiger. In this test method the enhancement of prolactin is shown after administration offrom 0.001 to 0.1 mg/kg s.c. of the compound.
As will be appreciated, PRL secretion modulating activity as demonstrable in the relevant test method mentioned above is also demonstrative of dopamine agonist activity. Furthermore apomorphine antagonist activity as demonstrable in the relevant test method mentioned above is also demonstrable of dopamine antagonist activity. Thus compounds offormula I may be characterised as having a dual dopamine agonist/antagonist activity profile.
In view of their PRL secretion inhibiting activity, compounds offormula I, wherein R2 is other than C-CR8 and their pharmaceutically acceptable acid addition salts are indicated for use as PRL secretion inhibitors, e.g. in the treatment of conditions ordisordersforwhich reduction of prolactin levels is indicated, for exampleforthe treatment of galactorrhea including post-partum galactorrhea, for the treatment of prolactin-dependent menstrual disorders including amenorrhea, forthe inhibition of lactation including post-partum lactation and morbid lactation as well as forthe treatment of hyperprolactinaemic hypogonadism in males and females and of prolactinoma.
Furthermore in view of.their inherent dopamine agonist activity compounds offormula I andtheir pharmaceutically acceptable acid addition salts are also indicated for use as dopamine agonists, e.g. forthe treatment of Morbus Parkinson.
For the above uses, an indicated daily dosage is in the range of from about 0.1 to about 10 mg ofthe compound conveniently administered in divided doses 2 to 4x/day in unit dosage form or in sustained releaseform. Suitable unit dosageforms compriseforexamplefrom about0.025to about 5 mg ofthe compound together with one or more pharmaceutically acceptable diluents or carriers therefore.
The Example 12 compound is the preferred compound. The apomorphine antagonistic indication is the preferred indication.
The compounds offormula I may be administered in free base form or in pharmaceutically acceptable acid addition salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free base forms. The present invention also provides a pharmaceutical composition comprising a compound offormula I in free base form or in salt form in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. The compounds of formula I may be administered by any conventional route, in particular enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally e.g. in the form of injectable solutions or suspensions.
In accordance with the foregoing the present invention also provides a compound offormula las hereinbefore defined or pharmaceutically acceptable acid addition salt thereof for use as a pharmaceutical, i.e. for use in therapy, for example: for use as an apomorphine antagonist; or for use as an antidepressant; or for use as a PRL secretion inhibitor or for use as a dopamine agonist, and especially for use in any ofthe specific indications hereinbefore cited in relation to such use; as well as a method of 1 ) effecting neuroleptictreatment, 2) effecting antidepressant treatment, 3) inhibiting PRLsecretion,or 4) treating Morbus Parkinson; e.g. fortreating any of specific conditions hereinbefore cited in relation to such treatment, in a subjectin need of such treatment, which method comprises administering to said subject an effective amount a compound offormula las hereinbefore defined, or a pharmaceutically acceptable acid addition saltthereof.

Claims (35)

1. A process for the production of a compound offormula I,
wherein R1 is hydrogen or (C1.4)alkyl, R2 is CN, COOH, COOR5, CONH2, COR5, CON(R5)R6, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2R7', CH(OH)R5, CH2CF3, iodine, C=CR8, CH=CHR8, (O2.12)alkyl, NO2, NH2 or COR9, wherein R5 and R6 are indepenently (C1-4)alkyl, R7 is (C1-4)alkyl, 0, phenyl or phenyl (C 5)alkyl, R7' is phenyl or phenyl(C 5)alkyl, R8 is hydrogen, (C1.1o)alkyl or phenyl and Re is (C1-6)alkyl, R3 is (C1 5)alkyl or (C3-5)alkenyl, in which the double bond is not atthe carbon atom adjacent to the nitrogen atom, and R4 is (C1 12)alkyl, (C3 7)cycloalkyl or adamantyl, oran acid addition saltthereof, which comprises a) reacting a compound offormula II,
wherein R1, R3 and R4 are as defined above, with chlorosulfonyl isocyanate to obtain a compound of formula I, wherein R2 is CN and optionally converting thecyano group into COOH, COOR5, CONH2,CONHR5 or CON(R5)R6;; b) reacting a compound offormula II with a compound offormula III, R5SCI Ill wherein R5 is as defined above, to obtain a compound offormula I, wherein R2 is SR5, and optionally converting the SR5 group into SOR5 or SO2R5, c) reacting a compound offormula II with a compound offormula IV, R7CO-Y IV wherein R7 is as defined above and Y is a leaving group, in the presence of a Lewis acid to obtain a compound offormula I, wherein R2 is COR7 and optionally converting a COR7 group, wherein R7 is phenyl or phenyl(Cr 5)alkyl, into CH2R7, or converting a COR7 group, wherein R7 is (C1-4)alkyl, into CH(OH)R5 or into (C3 12)alkyl, d) reacting a compound offormula II with N,N-dimethylformamide and phosphorous oxychloride to obtain a compound offormula I, wherein R2 is CHO and optionally converting the OHO group into CH2OH, e) introducing into the position 2 of a compound offormula II an iodine atom or the CH2CF3 group orthe C(CH3)3groupto obtain a compound offormula 1, wherein R2 is iodine, CH2CF3 or C(CH3)3, f) nitrating a compound offormula II to obtain a compound offormula l,wherein R2is NO2 and optionally converting the NO2 group into NH2 or NHCOR9, g) reacting a compound offormula V
wherein R1, R3 and R4 areas defined above and Xis bromine or iodine, with a compound offormula VI orVII, CH2=CHR8, VI CH-CR8' VII wherein R8' has the meaning of R8 except hydrogen but additionally can also be a protecting group, and as appropriate removing any protecting group present, to obtain a compound offormula I, wherein R2 is CH=CHR8 or CmCR8 and optionally reducing a CH=CHR8 or C=CR8 groupto CH2CH2R8, and recovering the obtained compound offormula I in free base form or acid addition saltform.
2. A process forthe production of a compound offormula loran acid addition salt thereof as hereinbefore described with reference to any ofthe Examples.
3. A compound offormula loran acid addition salt thereof whenever produced by a process according to claim 1 or2.
4. Acompound offormula Koran acid addition saltthereof.
5. A compound of claim 4, wherein R1 is hydrogen or (C1.4)alkyl, R2 is CN, COOH, COOR5, CON H2, CONHR5, CON(R5)R6, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2R7', CH(OH)R5, CH2CF3, iodine, C#CO8, CH=CHR8or (O25)alkyl, wherein R5 and R6 are independently (C14)alkyl, R7 is (C14)alkyl or CF3, R7' is phenylmethyl and Ras is hydrogen, (C1-3)alkyl or phenyl; R3 is (C1-5)alkyl or 5)alkenyl, in which the double bond is not at the carbon atom adjacent to the nitrogen atom, and R4 is (C1 12)alkyl, (C3 7) cycloalkyl or adamantyl or an acid addition salt thereof.
6. A compound of claim 4, wherein R1 is hydrogen; R2 is CN, COOH, COOR5, SR5, SOR5 SO2R5, CHO, CH2OH, COR7, CH2CF3, iodine, C#CR8, CH=CHR8, (C2 12)alkyl, NO2 or NHCOR8, wherein R8 is (Ca 4)alkyl, R7 is (Cla)alkyl or CF3, R8 is hydrogen and Rug is (Cq 12)alkyl; R3 is C1-5)alkyl and R4 is 12)alkyl or an acid addition salt thereof.
7. A compound of claim 4 which is 2-cyano-6-methyl-8a-pivaloylamino-ergoline or an acid addition salt thereof.
8. A compound of claim 4which is 2-carbomethoxy-6-methyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
9. A compound of claim 4which is 6-methyl-2-methylthio-8&alpha;-pivaloylamino-ergoline or an acid addition saltthereof.
10. A compound of claim 4 which is 6-methyl-2-methylsulfinyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
11. A compound of claim 4which is 6-methyl-2methylsulfonyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
12. A compound of claim 4which is 2-acetyl-6-methyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
13. A compound of claim 4which is 2-formyl-6-methyl-8a-pivaloylamino-ergoline or an acid addition salt thereof.
14. A compound of claim 4 which is 2-hydroxymethyl-6-methyl-8a-pivaloylamino-ergoline or an acid addition salt thereof.
15. A compound of claim 4 which is 2-(2,2,2-trifluoroethyl)-6-methyl-8a-pivaloylamino-ergoline or an acid addition salt thereof.
16. A compound of claim 4which is 6-methyl-8a-pivaloylamino-2-tert. butyl-ergoline or an acid addition salt thereof.
17. A compound of claim 4 which is 2-iodo-6-methyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
18. A compound of claim 4which is 6-methyl-2-ethinyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
19. A compound of claim 4which is 6-methyl-2-ethyl-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
20. A compound of claim 4 which is 6-methyl-2-vinyl-8a-pivaloylamino-ergoline or an acid addition salt thereof.
21. A compound of claim 4which is 6-methyl-8a-pivaloylamino-2-trifluoroacetyl-ergoline or an acid addition salt thereof.
22. A compound of claim 4which is 6-methyl-2-nitro-8&alpha;-pivaloylamino-ergoline or an acid addition salt thereof.
23. A compound of claim 4 which is 6-methyl-2-acetylamino-8a-pivaloylamino-ergoline or an acid addition salt thereof.
24. A compound of claim 4which is 6-methyl-2-ethyl-8a-(2,2-diethyl-1 -oxopropyl)amino-ergoline or an acid addition salt thereof.
25. A compound of claim 4which is 6-methyl-2-ethyl-8a-(2,2-diethyl-1 -oxobutyl)amino-ergoline or an acid addition salt thereof.
26. A compound of claim 4 which is 2-formyl-6-methyl-8a-(2,2-diethyl-1 -oxopropyl)amino-ergoline or an acid addition salt thereof.
27. A compound of claim 4 which is 2-hydroxymethyl-6-methyl-8a- (2,2-diethyl-1 -oxopropyl) amino-ergoline or an acid addition salt thereof.
28. A compound of claim 4which is 2-iodo-6-methyl-8a-(2,2-diethyl-1 -oxopropyl)amino-ergoline or an acid addition saltthereof.
29. A compound of claim 4 which is 6-methyl-2-ethinyl-8a-(2,2-diethyl-1-oxopropyl)amino-ergoline or an acid addition salt thereof.
30. A compound of claim 4which is 2-cyano-6-methyl-8a-(2,2-diethyl-1 -oxopropyl)amino-ergoline or an acid addition salt thereof.
31. A compound of claim 4which is 2-carboxy-6-methyl-8a-(2,2-diethyl-1 -oxopropyl)amino-ergoline or an acid addition salt thereof.
32. A compound according to any one of claims 4to 31 or a pharmaceutically acceptable acid addition salt thereoffor use as a pharmaceutical.
33. A compound according to nay one of claims 4to 31 or a pharmaceutically acceptable acid addition salt thereoffor use as a neuroleptic.
34. A pharmaceutical composition which comprises a compound of any one of claims 4to 31 or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or diluent.
35. A method of effecting neuroleptic or antidepressant treatment which comprises administering a therapeutically effective amount of a compound of any one of claims 4to 31 or a pharmaceutically acceptable acid addition saltthereofto a subject in need of such treatment.
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US4847262A (en) * 1984-04-09 1989-07-11 Schering Aktiengesellschaft 2-substituted ergolines having neuroleptic and antidepressant activities
US4859678A (en) * 1987-06-24 1989-08-22 Farmitalia Carlo Erba N-oxide ergolines as antihypertensive agents
US5037832A (en) * 1988-07-15 1991-08-06 Schering Aktiengesellschaft 2-substituted ergolines
US5547958A (en) * 1989-05-12 1996-08-20 Schering Aktiengesellschaft N-(8α-ergolinyl)-amides
US20140066450A1 (en) * 2011-06-23 2014-03-06 Map Pharmaceuticals, Inc. Novel fluoroergoline analogs
US20140094483A1 (en) * 2011-12-19 2014-04-03 Map Pharmaceuticals, Inc. Novel iso-ergoline derivatives
CN107405346A (en) * 2015-01-20 2017-11-28 Xoc制药股份有限公司 Isergoline compounds and uses thereof
US10246458B2 (en) 2015-01-20 2019-04-02 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10301311B2 (en) 2017-06-01 2019-05-28 Xoc Pharmaceuticals, Inc. Polycyclic compounds and uses thereof

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GB1517971A (en) * 1974-07-19 1978-07-19 Sandoz Ltd 8alpha-substituted ergoline i derivatives
GB2152507A (en) * 1984-01-12 1985-08-07 Sandoz Ltd 8a-acylaminoergolines

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CH615929A5 (en) * 1975-06-02 1980-02-29 Sandoz Ag Process for the preparation of novel ergoline compounds

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GB1517971A (en) * 1974-07-19 1978-07-19 Sandoz Ltd 8alpha-substituted ergoline i derivatives
GB2152507A (en) * 1984-01-12 1985-08-07 Sandoz Ltd 8a-acylaminoergolines

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847262A (en) * 1984-04-09 1989-07-11 Schering Aktiengesellschaft 2-substituted ergolines having neuroleptic and antidepressant activities
US4859678A (en) * 1987-06-24 1989-08-22 Farmitalia Carlo Erba N-oxide ergolines as antihypertensive agents
US5037832A (en) * 1988-07-15 1991-08-06 Schering Aktiengesellschaft 2-substituted ergolines
US5158957A (en) * 1988-07-15 1992-10-27 Schering Aktiengesellschaft 2-substituted ergolines
US5547958A (en) * 1989-05-12 1996-08-20 Schering Aktiengesellschaft N-(8α-ergolinyl)-amides
US20140066450A1 (en) * 2011-06-23 2014-03-06 Map Pharmaceuticals, Inc. Novel fluoroergoline analogs
US20140073647A1 (en) * 2011-06-23 2014-03-13 Map Pharmaceuticals, Inc. Novel fluoroergoline analogs
US9365591B2 (en) 2011-06-23 2016-06-14 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US8927567B2 (en) * 2011-06-23 2015-01-06 Map Pharceuticals, Inc. Fluoroergoline analogs
US8933093B2 (en) * 2011-06-23 2015-01-13 Map Pharmaceuticals, Inc. Fluoroergoline analogs
US8969374B2 (en) * 2011-12-19 2015-03-03 Map Pharmaceuticals, Inc. Iso-ergoline derivatives
EP2793580A4 (en) * 2011-12-19 2015-05-20 Map Pharmaceuticals Inc Novel iso-ergoline derivatives
US20140094483A1 (en) * 2011-12-19 2014-04-03 Map Pharmaceuticals, Inc. Novel iso-ergoline derivatives
CN107405346A (en) * 2015-01-20 2017-11-28 Xoc制药股份有限公司 Isergoline compounds and uses thereof
EP3247357A4 (en) * 2015-01-20 2018-07-11 Xoc Pharmaceuticals, Inc Isoergoline compounds and uses thereof
US10246458B2 (en) 2015-01-20 2019-04-02 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10308651B2 (en) 2015-01-20 2019-06-04 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10464936B2 (en) 2015-01-20 2019-11-05 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
US10703753B2 (en) 2015-01-20 2020-07-07 Xoc Pharmaceuticals, Inc. Ergoline compounds and uses thereof
AU2016209490B2 (en) * 2015-01-20 2020-09-03 Xoc Pharmaceuticals, Inc. Isoergoline compounds and uses thereof
US10301311B2 (en) 2017-06-01 2019-05-28 Xoc Pharmaceuticals, Inc. Polycyclic compounds and uses thereof
US10815235B2 (en) 2017-06-01 2020-10-27 Xoc Pharmaceuticals Polycyclic compounds and uses thereof

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