EP0420953A1 - Ergolines 8-beta-substituees, leur procede de fabrication et leur utilisation - Google Patents

Ergolines 8-beta-substituees, leur procede de fabrication et leur utilisation

Info

Publication number
EP0420953A1
EP0420953A1 EP90905438A EP90905438A EP0420953A1 EP 0420953 A1 EP0420953 A1 EP 0420953A1 EP 90905438 A EP90905438 A EP 90905438A EP 90905438 A EP90905438 A EP 90905438A EP 0420953 A1 EP0420953 A1 EP 0420953A1
Authority
EP
European Patent Office
Prior art keywords
ergoline
propyl
ethyl
methyl
vinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90905438A
Other languages
German (de)
English (en)
Inventor
Gerhard Sauer
Thomas Brumby
Helmut Wachtel
Jonathan Turner
Peter Andreas LÖSCHMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0420953A1 publication Critical patent/EP0420953A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
    • C07D457/06—Lysergic acid amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8

Definitions

  • the invention relates to ergolines substituted in the 2-, 6- and 8 ⁇ -position, their production and their use as medicaments.
  • the ergoline derivatives substituted according to the invention have a longer-chain hydrocarbon radical in the 6-position, which increases the dopamine-agonistic activity in comparison to the 6-methyl-ergoline derivatives. At the same time, the metabolic stability of the compounds is maintained or improved.
  • the invention relates to compounds of the formula I.
  • R 2 optionally substituted C 1-7 alkyl, C 2-7 alkenyl, CH 2 -SC 1-4 -
  • R 6 is C 2-6 alkyl, C 3 - 6 alkenyl or C 3 - 5 cycloalkyl-C 1 - 2 alkyl and
  • R 8 is CH 2 -X, CO-NH- or CO-NR 3 -CO-NHR 4 ,
  • R 1 is hydrogen, halogen, methyl or methoxy
  • R 3 and R 4 are each C 1-4 alkyl or
  • alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, hexyl, heptyl, 2, 2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl and others.
  • the alkyl radical R 2 can in particular be substituted in the 1-position with a hydroxy, C 1-4 alkoxy or C 2-5 acyloxy group corresponding to the
  • R ''R' '' in which R '' and R '' 'each represent hydrogen or alkyl radicals having a maximum of 6 carbon atoms and R' is in particular hydrogen or acetyl.
  • Aliphatic carboxylic acids such as, for example, acetic acid, propionic acid, butyric acid, caproic acid and trimethyl acetic acid and others are suitable as acyl groups.
  • R 2 or R 6 are an alkenyl radical, this preferably contains only one double bond, it being possible for the double bond in the R 6 radical not to be adjacent to the nitrogen atom.
  • suitable alkenyl radicals are: vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, methallyl.
  • R 6 is a cycloalkyl-alkyl group, cyclopropylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl is meant, for example.
  • the carboxylic acid anilide radical R 8 can be mono- or disubstituted in the o-, m- or p-position, with halogen being fluorine, chlorine, bromine or
  • Iodine is understood.
  • the radicals R 3 and R 4 are preferably alternating.
  • R 6 C 2-5 alkyls, C 3-4 alkenyls or cycloalkylalkyls with up to 5 carbon atoms are to be considered.
  • the compounds of formula I can occur as E- or% - I somers or, if a chiral% entrum is present in the radical R 2 , as diastereomers and as mixtures thereof.
  • the isomers and mixtures of isomers are also encompassed by the present invention.
  • the physiologically compatible acid addition salts are derived from the known inorganic and organic acids such as, for example, hydrochloric acid, sulfuric acid, hydrobromic acid,% citric acid, maleic acid, fumaric acid, tartaric acid and others.
  • the compounds of formula I and their acid addition salts have, in particular, central dopaminergic activity and can therefore be used as medicaments.
  • the dopamine agonistic effect was determined using the method of automatic stereotype registration in rats described by Horowski (Pharm. Forsch. 12, 2281-2286, 1978): Immediately after intraperitoneal test substance or vehicle administration, male Wistar rats (90-120 g) individually placed in% cheek cages made of acrylic glass. Via an electrodynamic recording system in front of the head of the animals, the% of the contacts on a steel cup with a central metal rod is as a result of the stereotypical chewing,
  • Treatment groups each populated with 12 animals, are calculated and the significance of the differences between the mean values of the different test substance doses compared to the artificially treated control group is determined using the simple analysis of variance in conjunction with the Dunnett test. The results are shown in Table 1:
  • Test substance dose [mg / kg]
  • the compounds according to the invention are suitable for the treatment of dopamine deficiency states in living beings and in particular for the treatment of Parkinson's disease.
  • a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • the compounds according to the invention are introduced in a dose of 0.001 to 10 mg of active substance into a physiologically compatible carrier.
  • the compounds according to the invention are used in a dose of 0.00001 to 0.1 mg / kg / day, preferably 0.001 to 0.1 mg / kg / day, analogously to the known bromocryptine agent.
  • the compounds of the formula I according to the invention can be prepared by methods known per se.
  • R 2 and R 6 have the above meaning and R represents a C 1-4 alkyl group with an aniline of the formula VI
  • R 1 has the meaning given above, converted to compounds according to
  • R 6 and R 8 have the above meaning, converted into a compound according to claim 1 with R 2 in the above meaning and, if desired, then forms the acid addition salts.
  • reaction of the compounds of formula II by process a) can be carried out, for example, by the process described in EP-A-185 491, by using a reactive derivative such as tosylate, mesylate or iodide with an alkali metal salt (such as sodium or potassium salt) Reacts methyl mercaptids or cyanides in a polar solvent such as dimethylacetamide, dimethylformamide or alcohols at room temperature or elevated temperature.
  • a reactive derivative such as tosylate, mesylate or iodide with an alkali metal salt (such as sodium or potassium salt) Reacts methyl mercaptids or cyanides in a polar solvent such as dimethylacetamide, dimethylformamide or alcohols at room temperature or elevated temperature.
  • the optional subsequent conversion of the CH-CN group into the CH 2 -CONH 2 group takes place according to the usual hydrolysis methods such as acid treatment, for example with HBr / glacial acetic acid, basic treatment, for example with sodium hydroxide solution, 30% hydrogen peroxide, tetrabutylammonium hydrogen sulfate or in dichloromethane oxidizing treatment such as MnO 2 on silica gel in aqueous acetone, where appropriate also a suitable inert
  • Solvents such as chlorinated hydrocarbons, ethers or aprotic polar solvents can be added.
  • reaction of the compounds of formula III with carbodiimides by process b) can, for example, in aprotic solvents such as tetrahydrofuran, dimethylformamide, dichloroethane or dio ⁇ ane, optionally in the presence of an organic base such as pyridine or triethylamine at temperatures up to the boiling point of the solvent in 5-24 hours .
  • aprotic solvents such as tetrahydrofuran, dimethylformamide, dichloroethane or dio ⁇ ane
  • organic base such as pyridine or triethylamine
  • the preparation of anilides by process c) can be carried out, for example, by the methods described in DPS-3150918, by the ester of the formula V with the corresponding aniline in the presence of trimethylaluminum, dimethylaluminium chloride or aluminum chloride in inert solvents such as toluene, benzene, hexane or methylene chloride, optionally with cooling.
  • the introduction of the substituents in the 6-position by method d) can be carried out, for example, according to A. Cerny et al. Coll. Czech. Chem. Comm. 49, 2828 (1984) or by the process described in EP-21206, by reacting the 6H compound of the formula VII with the corresponding R 6 halides (bromides, chlorides, iodides).
  • the reaction is expediently carried out in an inert solvent such as dimethyl sulfoxide, dimethylformamide, acetonitrile or nitromethane in the presence of bases such as alkali metal hydroxides or carbonates.
  • the introduction of the substituent R 2 can, for example, according to the in
  • the Mannich base of formula VIII or its quaternary salt can be substituted nucleophilically or via the 2-aldehyde derivative as
  • % wipe compound of the desired substituent R 2 are introduced.
  • the nucleophilic exchange takes place after quaternization of the
  • Aminomethylene group in an inert solvent such as alcohols, polar, aprotic solvents, ethers or chlorinated hydrocarbons at room temperature or elevated temperature being used as nucleophilic anions
  • Alcoholates can be used, which if desired can then be converted into the CH 2 -OH group. % ur production of the 2-methyl
  • the compound of formula VIII can be reduced in polar solvents such as alcohols such as with sodium borohydride.
  • the oxidation to a 2-CHO compound can be carried out analogously to that in RA Jones et al. Synthetic Communications 16, 1799 (1986) described methods with manganese dioxide or tert. Butyl hypochlorite in inert solvents at room temperature.
  • the conversion of the 2-formyl compounds to compounds of the formula I in which R 2 denotes an alkenyl radical can be carried out in one
  • Wittigction take place, such as with alkyl triphenylphosphonium halide in polar solvents such as cyclic and acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethyl sulfoxide are carried out at temperatures from -50 ° C. to the boiling point of the reaction mixture, strong bases such as alkali metal alcoholates, lithium organyl and others being added to produce the ylene.
  • Substituents R 2 which are hydroxylated in the 1-position can be prepared, for example, by Grignardation or lithium alkylation of the 2-aldehydes or ketones. Grignardation can be carried out with the usual Grignard reagents such as alkylmagnesium-halogen in an aprotic
  • Solvents such as cyclic and acyclic ethers are carried out at low temperatures (-70 ° C to 0 ° C). The reaction with alkyl lithium takes place under analogous conditions.
  • the acetylation of a hydroxyl group can be carried out by the customary methods, for example by reaction with acid anhydrides or acid chlorides. If the substituent R 2 contains a hydroxyl group, this can be reduced to the corresponding 2-alkyl derivative, for example by reaction with Na BH in glacial acetic acid, or oxidized with manganese dioxide to the ketone or dehydrated with the introduction of a double bond. If the substituent R 2 contains a double bond, this can be catalytically reduced, for example.
  • the introduction of the substituent R 2 -C (OH) R "" R "" can be carried out as described above by Grignardation or lithium alkylation of the ketone. To form salts, a compound of formula I is dissolved, for example, in a little methanol or methylene chloride and a concentrated solution of the desired acid is added.
  • the isomer mixtures can be separated into the diastereomers or E / Z isomers by conventional methods such as, for example, crystallization, chromatography or salt formation.
  • the invention also includes compounds of the general formula IX
  • R 9 is CH 2 OH or COOR, with R as C 1-4 alkyl; these compounds are valuable intermediates for the preparation of the pharmacologically active compounds.
  • the intermediate products are converted into the active substances by the methods described above for introducing the desired substituents in the 8-, 6- or 2-position.
  • 6-alkyl-8 ⁇ -hydroxymethyl-2-morpholinomethyl-ergoline can be used
  • 6-Cyan-8 ⁇ hydroxymethyl-2-morpholinomethyl-ergoline also by the route described above 2) by reduction and alkylation.
  • the compound can be prepared by reducing the above ester with sodium borohydride or by reducing the quaternary salt of the ester (in methanol) or the 8 ⁇ -hydroxymethyl compound.
  • the non-crystalline compound can be prepared from 54-yield from 6-cyan-2-methyl-8 ⁇ -ergoline carboxylic acid methyl ester as described above by reduction and alkylation with n-propyl iodide.
  • the allyl compound is obtained in 63% yield by alkylation with allyl bromide.
  • the 6-ethyl compound is obtained in 46% yield by alkylation with ethyl iodide.
  • the 6-alkyl-8 ⁇ -hydroxymethyl-2-methyl-ergoline can be carried out as described above by reducing the above-described esters with sodium borohydride in methanol or by reducing and alkylating the 6-cyan-8 ⁇ -hydro ⁇ ymethyl-2-methyl-ergoline.
  • the quaternary salt is dissolved in dichloromethane and reacted with a 10-fold excess of sodium methanethiolate at room temperature in 4 hours. After hydrolysis of the nitrile and alkylation, the desired alcohol is obtained in a yield of 63%.
  • the aldehyde is prepared from the 6-cyclopropylmethyl-2-morpholinomethyl-8 ⁇ -ergoline carboxylic acid methyl ester as described above by oxidation with tert-butyl hypochlorite. All ergoline aldehydes alkylated in the 6-position are used as crude products in the Wittig reaction.
  • the aldehyde is obtained in approximately 80% yield by oxidation with trichloroisocyanuric acid in dichloromethane and triethylamine at -78 ° C.
  • the aldehydes are obtained in 35 to 76% yield from the corresponding Mannich bases by oxidation with trichloroisocyanuric acid.
  • the 2-vinyl compounds can be obtained by reducing the esters with sodium borohydride or lithium aluminum hydride or by Wittig reaction with the corresponding 6-alkyl-8 ⁇ -hydroxymethyl-2-ergoline carbaldehyde as described above. 8 ⁇ -hydroxymethyl-6-n-propyl-2-vinyl-ergoline
  • 6-Cyclopropylmethyl-2-ethyl-8 ⁇ -ergolinic carboxylic acid methyl ester is obtained from the 2-vinyl compound by hydrogenation in quantitative yield.
  • 2,6-Diethyl-8 ⁇ -ergoline carboxylic acid methyl ester is obtained from the 2-vinyl compound by hydrogenation and crystallization from ethyl acetate / hexane in 87% yield.
  • 6-alkyl-2-hydroxyxmethyl-8 ⁇ -ergoline carboxylic acid methyl ester can be prepared by reducing the 2-aldehydes with sodium borohydride in acetonitrile or by reducing the 6-cyano-2-hydroxymethyl-carboxylic acid methyl ester with zinc in glacial acetic acid and subsequent alkylation as described above.
  • 2- (1-hydroxypropyl) -8 ⁇ -hydroxymethyl-6-n-propyl-ergoline can be prepared analogously with ethyl magnesium bromide.
  • Example 1 The above compound is hydrogenated as described above in methanol with 10% palladium / carbon at normal pressure and room temperature. The yield is quantitative.
  • Example 1 The above compound is hydrogenated as described above in methanol with 10% palladium / carbon at normal pressure and room temperature. The yield is quantitative.
  • Methanesulfonyl chloride stirred for one hour at room temperature. Ice is added, the mixture is stirred for a further 30 minutes and made alkaline with ammonia. The
  • 6-ethyl-2-methyl-8 ⁇ -methylthiomethylergoline is produced from 6-ethyl-2-methyl-8 ⁇ -ergoline carboxylic acid methyl ester in 38% yield.
  • 6-Cyclopropylmethyl-8 ⁇ -methylthiomethyl-2-vinyl-ergoline from 6-cyclopropylmethyl-2-vinyl-8 ⁇ -ergoline carboxylic acid methyl ester in 34% yield, lot] -131 ° (0.1% in chloroform).
  • 8 ⁇ -Metho ⁇ ymethyl-2-methyl-6-n-propyl-ergoline from 2-methyl-6-n-propyl-8 ⁇ -ergoline carboxylic acid methyl ester by nucleophilic displacement of the mesyl group with sodium methylate, yield 20%, [ ⁇ ] D - 72 ° (0.1% in chloroform).
  • 6-ethyl-2-methoxymethyl-8 ⁇ -methylthiomethyl-ergoline from 6-ethyl-8 ⁇ -hydroxymethyl-2-methoxymethylergoline in 27% yield.
  • 2-isopropenyl-8 ⁇ -methylthiomethyl-6-n-propyl-ergoline from 8 ⁇ -aceto ⁇ ymethyl2-isopropenyl-6-n-propyl-ergoline by saponification with methanolic KOH and subsequent conversion to position 8 in 47% yield.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Des composés ont la formule (I), dans laquelle R2 représente C1-7-alkyle, C2-7-alkényle, CH2-O-C1-4-alkyle ou CH2-S-C1-4-alkyle éventuellement substitués; R6 représente C2-6-alkyle, C3-6-alkényle ou C3-5-cycloalkyle-C1-2-alkyle et R8 représente CH2-X, (1) ou CO-NR3-CO-NH-R4, alors que X représente CN, OCH3, SCH3 ou CONH2 et R1 représente hydrogène, halogène, méthyle ou méthoxy, et R3 et R4 représentent C1-4-alkyle ou (CH2)n-N(CH3)2, et n est compris entre 1 et 4. L'invention concerne également les sels d'addition d'acide de ces composés, leur procédé de production, leur utilisation comme médicaments et des composés intermédiaires.
EP90905438A 1989-04-21 1990-04-06 Ergolines 8-beta-substituees, leur procede de fabrication et leur utilisation Withdrawn EP0420953A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3913756A DE3913756A1 (de) 1989-04-21 1989-04-21 8(beta)-substituierte ergoline, verfahren zu ihrer herstellung und ihre verwendung
DE3913756 1989-04-21

Publications (1)

Publication Number Publication Date
EP0420953A1 true EP0420953A1 (fr) 1991-04-10

Family

ID=6379506

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90905438A Withdrawn EP0420953A1 (fr) 1989-04-21 1990-04-06 Ergolines 8-beta-substituees, leur procede de fabrication et leur utilisation

Country Status (6)

Country Link
US (1) US5219862A (fr)
EP (1) EP0420953A1 (fr)
JP (1) JPH03505587A (fr)
CA (1) CA2031510A1 (fr)
DE (1) DE3913756A1 (fr)
WO (1) WO1990012796A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT628042E (pt) * 1992-12-24 2002-01-30 Pharmacia & Upjohn Spa Derivados de ergolina serotoninergicos
US6388079B1 (en) * 2000-08-29 2002-05-14 Scinopharm Singapore Pte Ltd. Process for preparing pergolide
CA2688265C (fr) 2007-06-08 2021-02-16 Wake Forest University Health Sciences Therapie cellulaire selective pour le traitement de l'insuffisance renale
US9580688B2 (en) 2007-06-08 2017-02-28 Wake Forest University Health Sciences Kidney structures and methods of forming the same
US10590391B2 (en) 2007-06-08 2020-03-17 Wake Forest University Health Sciences Selective cell therapy for the treatment of renal failure
CN104822264A (zh) * 2012-06-22 2015-08-05 Map药物公司 新的卡麦角林衍生物

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4054660A (en) * 1975-04-14 1977-10-18 Eli Lilly And Company Method of inhibiting prolactin
US4246285A (en) * 1975-10-20 1981-01-20 The Procter & Gamble Company Skin conditioning compositions containing guanidine inorganic salts
CS188414B1 (en) * 1975-12-12 1979-03-30 Antonin Cerny New d-6-alkyl-8-cyanmethyl ergolines,their salts and method of producing
US4166182A (en) * 1978-02-08 1979-08-28 Eli Lilly And Company 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds
US4246265A (en) * 1979-10-01 1981-01-20 Eli Lilly And Company 6-n-Propyl-8α-methoxymethyl or methylmercaptomethylergolines and related compounds
GB2074566B (en) * 1980-04-03 1983-11-02 Erba Farmitalia Ergoline derivatives
GB2103603B (en) * 1981-08-11 1985-04-11 Erba Farmitalia Ergoline derivatives
DE3150918C1 (de) * 1981-12-18 1983-04-21 Schering Ag, 1000 Berlin Und 4619 Bergkamen Verfahren zur Herstellung von Aniliden in der Ergolinreihe
CH649998A5 (de) * 1982-08-09 1985-06-28 Sandoz Ag Ergolinderivate, ein verfahren zu ihrer herstellung und heilmittel, enthaltend diese ergolinderivate als wirkstoff.
CH657366A5 (en) * 1983-08-05 1986-08-29 Sandoz Ag Ergot alkaloids, their preparation and use
ATE107647T1 (de) * 1984-04-09 1994-07-15 Schering Ag 2-substituierte ergolin-derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9012796A1 *

Also Published As

Publication number Publication date
JPH03505587A (ja) 1991-12-05
US5219862A (en) 1993-06-15
CA2031510A1 (fr) 1990-10-22
WO1990012796A1 (fr) 1990-11-01
DE3913756A1 (de) 1990-10-25

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