CH628895A5 - Process for the preparation of ergoline compounds - Google Patents
Process for the preparation of ergoline compounds Download PDFInfo
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- CH628895A5 CH628895A5 CH697480A CH697480A CH628895A5 CH 628895 A5 CH628895 A5 CH 628895A5 CH 697480 A CH697480 A CH 697480A CH 697480 A CH697480 A CH 697480A CH 628895 A5 CH628895 A5 CH 628895A5
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- ergoline
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- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 abstract description 18
- 229910052801 chlorine Inorganic materials 0.000 abstract description 9
- 239000000460 chlorine Substances 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 8
- 150000003839 salts Chemical class 0.000 abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 230000003291 dopaminomimetic effect Effects 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 125000000217 alkyl group Chemical group 0.000 description 16
- 102000003946 Prolactin Human genes 0.000 description 12
- 108010057464 Prolactin Proteins 0.000 description 12
- 229940097325 prolactin Drugs 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 150000002367 halogens Chemical group 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- -1 monosubstituted phenyl Chemical group 0.000 description 4
- 229910052757 nitrogen Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Chemical group 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical class 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- JHWDWUPYEQIICX-HRBVQNPCSA-N (6ar,10ar)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-amine Chemical class C1=CC([C@@H]2[C@H](NCC(C2)N)C2)=C3C2=CNC3=C1 JHWDWUPYEQIICX-HRBVQNPCSA-N 0.000 description 1
- JHWDWUPYEQIICX-UFGOTCBOSA-N (6ar,9s,10ar)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-amine Chemical compound C1=CC([C@@H]2[C@H](NC[C@H](C2)N)C2)=C3C2=CNC3=C1 JHWDWUPYEQIICX-UFGOTCBOSA-N 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000001287 Galactorrhea Diseases 0.000 description 1
- 206010017600 Galactorrhoea Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010023424 Kidney infection Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- C07D457/10—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
628895 628895
PATENTANSPRUCH Verfahren zur Herstellung von neuen Ergolin-Verbin-dungen der Formel I, PATENT CLAIM Process for the production of new ergoline compounds of formula I,
HR MR
worin wherein
X Chlor oder Brom bedeutet, X represents chlorine or bromine,
Ri Methyl oder Äthyl bedeutet, Ri means methyl or ethyl,
R2 Alkyl mit 1 bis 4 Kohlenstoffatomen oder Allyl bedeutet und R2 means alkyl with 1 to 4 carbon atoms or allyl and
Rs für CH2-CN oder eine Gruppe NR4R5 steht, in der R4 Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen und Rs Alkanoyl mit 1 bis 5 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 5 Kohlenstoffatomen oder monobis tri-Halogen-alkoxycarbonyl mit 3 bis 5 Kohlenstoffatomen, dessen Alk-oxyrest nicht in a-Stellung zum Sauerstoff substituiert sein kann, bedeuten oder Rs den Rest SChRc. bedeutet, in der Rh Alkyl mit 1 bis 4 Kohlenstoffatomen, mono- bis tri-Halo-genaikyl mit ! bis 4 Kohlenstoffatomen, Phenyl, Pyridyl, durch Halogen oder Alkoxy mit 1 bis 4 Kohlenstoffatomen moiiosubstituiertes Phenyl darstellt oder Rt> eine Gruppe NR-Rs darstellt, in der Rs represents CH2-CN or a group NR4R5 in which R4 is hydrogen or alkyl having 1 to 4 carbon atoms and Rs alkanoyl having 1 to 5 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms or monobis tri-haloalkoxycarbonyl having 3 to 5 carbon atoms, whose alkoxy radical cannot be substituted in the a position to the oxygen, or Rs represent the remainder SChRc. means in the Rh alkyl with 1 to 4 carbon atoms, mono- to tri-halo-genaikyl with! represents up to 4 carbon atoms, phenyl, pyridyl, phenyl moiiosubstituted by halogen or alkoxy having 1 to 4 carbon atoms or Rt> represents a group NR-Rs in which
R - und Rs unabhängig voneinander je Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen bedeuten oder R? und Rs zusammen eine der Gruppen (CHjJn oder (CH:):-A-(CH2)2 darstellen, wobei n eine Zahl von 3 bis 7 und R - and Rs each independently represent hydrogen or alkyl having 1 to 4 carbon atoms or R? and Rs together represent one of the groups (CHjJn or (CH:): - A- (CH2) 2, where n is a number from 3 to 7 and
A Sauerstoff, Schwefel oder durch Alkyl mit 1 bis 4 Kohlenstoffatomen oder Phenyl substituierter Stickstoff bedeuten, A is oxygen, sulfur or nitrogen substituted by alkyl having 1 to 4 carbon atoms or phenyl,
und ihrer Säureadditionssalze, dadurch gekennzeichnet, dass man in Verbindungen der Formel II, and their acid addition salts, characterized in that in compounds of the formula II,
R R
worin Ri, R: und R3 obige Bedeutung besitzen, einen Chloroder Brom-Rest in 2-Stellung einführt und die so erhaltenen Verbindungen der Formel I in Form der Basen oder von Säureadditionssalzen gewinnt. wherein R 1, R 3 and R 3 have the above meaning, introduces a chlorine or bromine radical in the 2-position and the compounds of the formula I thus obtained are obtained in the form of the bases or of acid addition salts.
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Ergolin-Verbindungen der Formel I, The invention relates to a process for the preparation of new ergoline compounds of the formula I,
worin wherein
X Chlor oder Brom bedeutet, X represents chlorine or bromine,
Ri Methyl oder Äthyl bedeutet, Ri means methyl or ethyl,
R2 Alkyl mit 1 bis 4 Kohlenstoffatomen oder Allyl bedeutet und R2 means alkyl with 1 to 4 carbon atoms or allyl and
R3 für CH2-CN oder eine Gruppe NR4R5 steht, in der R4 Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen und Rs Alkanoyl mit 1 bis 5 Kohlenstoffatomen, Alkoxycarbonyl mit 2 bis 5 Kohlenstoffatomen oder mono- bis tri-Halogen-allcoxycarbonyl mit 3 bis 5 Kohlenstoffatomen, dessen Allc-oxyrest nicht in a-Stellung zum Sauerstoff substituiert sein kann, bedeuten oder Rs den Rest SO2R6 bedeutet, in der Rö Alkyl mit 1 bis 4 Kohlenstoffatomen, mono- bis tri-Halo-genalkyl mit 1 bis 4 Kohlenstoffatomen, Phenyl, Pyridyl, durch Halogen oder Alkoxy mit 1 bis 4 Kohlenstoffatomen monosubstituiertes Phenyl darstellt oder Rö eine Gruppe NR7R8 darstellt, in der R3 represents CH2-CN or a group NR4R5 in which R4 is hydrogen or alkyl having 1 to 4 carbon atoms and Rs alkanoyl having 1 to 5 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms or mono- to tri-halogeno-alloxycarbonyl having 3 to 5 Carbon atoms, the Allc-oxyrest can not be substituted in the a-position to oxygen, or Rs represents the radical SO2R6, in which Rö alkyl with 1 to 4 carbon atoms, mono- to tri-halo-genalkyl with 1 to 4 carbon atoms, phenyl , Pyridyl, phenyl monosubstituted by halogen or alkoxy having 1 to 4 carbon atoms or Rö represents a group NR7R8 in which
R7 und Rs unabhängig voneinander je Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen bedeuten oder R7 und Rs zusammen eine der Gruppen (CH2)n oder (CH2)2-A-(CH2)2 darstellen, wobei n eine Zahl von 3 bis 7 und R7 and Rs each independently represent hydrogen or alkyl having 1 to 4 carbon atoms or R7 and Rs together represent one of the groups (CH2) n or (CH2) 2-A- (CH2) 2, where n is a number from 3 to 7 and
A Sauerstoff, Schwefel oder durch Alkyl mit 1 bis 4 Kohlenstoffatomen oder Phenyl substituierter Stickstoff bedeuten, A is oxygen, sulfur or nitrogen substituted by alkyl having 1 to 4 carbon atoms or phenyl,
und ihrer Säureadditionssalze, dadurch gekennzeichnet, dass man in Verbindungen der Formel II, and their acid addition salts, characterized in that in compounds of the formula II,
R R
worin Ri, R2 und R3 obige Bedeutung besitzen, einen Chloroder Brom-Rest in 2-Stellung einführt und die so erhaltenen Verbindungen der Formel I in Form der Basen oder von Säureadditionssalzen gewinnt. wherein R 1, R 2 and R 3 have the meaning given above, introduces a chlorine or bromine radical in the 2-position and the compounds of the formula I thus obtained are obtained in the form of the bases or of acid addition salts.
Wenn nicht anders angegeben, enthält eine Alkyl- oder Alkoxygruppe vorzugsweise 2, insbesondere 1, Kohlenstoffatom. Unless otherwise stated, an alkyl or alkoxy group preferably contains 2, in particular 1, carbon atom.
2 2nd
5 5
10 10th
IS IS
20 20th
25 25th
30 30th
35 35
40 40
45 45
50 50
55 55
60 60
65 65
Ri bedeutet vorzugsweise Methyl. Ri preferably means methyl.
R2 bedeutet vorzugsweise Alkyl. R2 is preferably alkyl.
Rj bedeutet vorzugsweise einen Rest NR4R5. Rj preferably represents a residue NR4R5.
R4 bedeutet vorzugsweise Wasserstoff. R4 is preferably hydrogen.
Bedeutet Rs Alkanoyl oder Alkoxycarbonyl, so enthält dieses vorzugsweise 3 oder 2 Kohlenstoffatome. Trägt der Rest Rs oder Ra einen Halogensubstituenten, so bedeutet dieser Fluor, Chlor oder Brom und insbesondere Chlor oder Fluor. Enthalten Rs oder Rs mehr als einen Halogensubstituenten, dann sind diese Rest vorzugsweise identisch. If Rs is alkanoyl or alkoxycarbonyl, this preferably contains 3 or 2 carbon atoms. If the radical Rs or Ra carries a halogen substituent, this means fluorine, chlorine or bromine and in particular chlorine or fluorine. If Rs or Rs contain more than one halogen substituent, these residues are preferably identical.
Rs bedeutet vorzugsweise den Rest SO2R6. Rs preferably denotes the remainder SO2R6.
Steht Rö für Alkyl oder mono-, di- oder tri-Halogenalkyl, so enthält dieses vorzugsweise 1 bis 3 Kohlenstoffatome. If Rö stands for alkyl or mono-, di- or tri-haloalkyl, this preferably contains 1 to 3 carbon atoms.
Steht Rö für monosubstituiertes Phenyl, dann bedeutet dieser Substituent vorzugsweise Halogen, und insbesondere Chlor oder Fluor. If Rö stands for monosubstituted phenyl, this substituent preferably means halogen, and in particular chlorine or fluorine.
Rò bedeutet vorzugsweise Alkyl, Phenyl, monosubstituiertes Phenyl, Pyridyl oder eine Gruppe NR7R8. Rò is preferably alkyl, phenyl, monosubstituted phenyl, pyridyl or a group NR7R8.
Stehen R7 und/oder Rs für Alkyl, so enthält dieses vorzugsweise 1 bis 3 Kohlenstoffatome, und insbesondere 2 oder 1 Kohlenstoffatom. If R7 and / or Rs are alkyl, this preferably contains 1 to 3 carbon atoms, and in particular 2 or 1 carbon atom.
R7 und Rs sind vorzugsweise identisch, n ist vorzugsweise eine Zahl 4 oder 5. A bedeutet vorzugsweise Sauerstoff. R7 and Rs are preferably identical, n is preferably a number 4 or 5. A is preferably oxygen.
Eine bevorzugte Ausgangsverbindung umfasst Verbindungen der Formel I, worin X Wasserstoff, Ri und R2 je Methyl, und R3 NH-S02R'6 bedeuten, wobei R'6 für Alkyl, Phenyl, durch Halogen monosubstituiertes Phenyl, Pyridyl oder 1-Morpholino steht. A preferred starting compound comprises compounds of the formula I in which X is hydrogen, R 1 and R 2 are each methyl and R 3 is NH-S02R'6, where R'6 is alkyl, phenyl, phenyl monosubstituted by halogen, pyridyl or 1-morpholino.
Die Einführung des Chlor- oder Brom-Restes kann analog zu bekannten Methoden erfolgen. The chlorine or bromine residue can be introduced analogously to known methods.
Geeignete Halogenierungsmittel sind N-X-Succinimid oder N-X-Phtalsäureimid, in denen X obige Bedeutung besitzt. Als Lösungsmittel wählt man dann ein inertes Lösungsmittel wie Dioxan oder Chloroform. Die Umsetzung kann in einem Temperaturbereich von 10 bis 100° erfolgen. Suitable halogenating agents are N-X-succinimide or N-X-phthalimide, in which X has the above meaning. An inert solvent such as dioxane or chloroform is then chosen as the solvent. The reaction can take place in a temperature range from 10 to 100 °.
Die Verbindungen der Formel I können in freier Form als Base, oder in Form ihrer Additionssalze mit Säuren vorliegen. Aus den freien Basen lassen sich in bekannter Weise Säureadditionssalze herstellen und umgekehrt. The compounds of the formula I can be in free form as a base or in the form of their addition salts with acids. Acid addition salts can be prepared from the free bases in a known manner and vice versa.
Die Verbindungen der Formel II sind neu. Ihre Herstellung wird im CH-Patent Nr. 620 441 beschrieben. The compounds of formula II are new. Their manufacture is described in Swiss Patent No. 620 441.
Die Verbindungen der Formel I in freier Form oder in Form von physiologisch verträglichen Additionssalzen mit Säuren zeichnen sich durch interessante pharmakodyna-mische Eigenschaften aus. Sie können als Heilmittel verwendet werden. The compounds of the formula I in free form or in the form of physiologically tolerable addition salts with acids are distinguished by interesting pharmacodynamic properties. They can be used as a remedy.
Aus der schweizerischen Patentschrift Nr. 418 660 sind ähnliche 8-Amino-ergoline bekannt, welche in Stellung 8 eine Carbamidsäurealkylestergruppe aufweisen und sero-tonin-antagonistische und analeptische Wirkungen zeigen. Von diesen vorbekannten Verbindungen unterscheiden sich die erfindungsgemäss hergestellten Verbindungen durch den verschiedenartigen Substituenten in Stellung 8 sowie durch ihre andersartige pharmakodynamische Wirkung. Similar 8-amino-ergolines are known from Swiss Patent No. 418 660, which have a carbamic acid alkyl ester group in position 8 and show serotonin antagonistic and analeptic effects. The compounds prepared according to the invention differ from these previously known compounds by the different substituents in position 8 and by their different pharmacodynamic action.
So zeichnen sie sich durch eine ausgeprägte prolactinsekre-tionshemmende Wirkung aus. Sie sind daher geeignet zur Prophylaxe oder Behandlung von prolactinabhängigen Funktionsstörungen wie z.B. physiologischer Lactation und So they are characterized by a pronounced prolactin secretion-inhibiting effect. They are therefore suitable for the prophylaxis or treatment of prolactin-dependent functional disorders such as physiological lactation and
628 895 628 895
Galactorrhoe, von Prostatahypertrophie, von Prostata- und Mammacarcinomen; des weiteren können sie bei Nephropathien und chronischen Nierenentzündungen, zur Regulierung des Wasser- und Elektrolythaushaltes, bei Ödemen, zur Behandlung von essentiellen und renalen Hypertonieformen sowie bei akuten Zuständen wie vor Migräneattacken und beim prämenstruellen Syndrom Anwendung finden. Galactorrhea, prostate hypertrophy, prostate and breast carcinomas; Furthermore, they can be used for nephropathies and chronic kidney infections, for regulating the water and electrolyte balance, for edema, for the treatment of essential and renal forms of hypertension as well as for acute conditions such as before migraine attacks and premenstrual syndrome.
Die Prolactin-Sekretionshemmung konnte an Ratten deutlich gemacht werden. Bei lädierenden Ratten, die zeitweilig von ihren Jungen getrennt waren, kommt es bei erneuter Kontaktaufnahme zu einer massiven Prolactin-Aus-schüttung, die z.B. als Depletion des hypophysären Prolactin-Gehaltes erfasst werden kann. Dieses Phänomen (beschrieben von Grosvenor und Mena in J. Endoer. 52,11 [1972]) ergibt eine reproduzierbare Versuchsanordnung, um die Prolactin-Sekretionshemmung pharmakologisch zu erfassen. Es zeigte sich, dass 1 bis 5 mg/kg s.c. einer Verbindung der Formel I nicht nur signifikant die durch sensorische Reize ausgelöste Prolactin-Freisetzung hemmen, sondern gleichzeitig zu einem leichten Anstieg des Prolactin-Gehaltes führen, wodurch deutlich gemacht wird, dass die Verbindungen die physiologisch stimulierte Prolactin-Sekretion zu hemmen vermögen. The inhibition of prolactin secretion could be demonstrated in rats. In contacting rats, which were temporarily separated from their pups, a massive prolactin release occurs when they are contacted again. can be recorded as a depletion of the pituitary prolactin content. This phenomenon (described by Grosvenor and Mena in J. Endoer. 52.11 [1972]) results in a reproducible experimental set-up for pharmacologically recording the prolactin secretion inhibition. It was found that 1 to 5 mg / kg s.c. a compound of formula I not only significantly inhibit the prolactin release triggered by sensory stimuli, but at the same time lead to a slight increase in the prolactin content, which makes it clear that the compounds are able to inhibit the physiologically stimulated prolactin secretion.
Auch an männlichen Ratten konnte eine Wirkung auf den Prolactin-Spiegel festgestellt werden; die Verbindungen der Formel I hemmen die tonische Prolactin-Sekretion mit EDso-Werten zwischen 0,005 und 1,0 mg/kg s.c. (durch Prolactin-Bestimmungen der Rattenseren mittels Radioimmuno-assay). An effect on the prolactin level was also found in male rats; the compounds of the formula I inhibit the tonic prolactin secretion with ED 50 values between 0.005 and 1.0 mg / kg s.c. (by prolactin determinations of rat sera using radioimmunoassay).
Für oben genannte Anwendung variiert die zu verwendende Dosis selbstverständlich je nach verwendeter Substanz, Art der Administration und der gewünschten Behandlung. Im allgemeinen werden aber befriedigende Resultate mit Dosen von ungefähr 0,005 bis 1,0 mg/kg Körpergewicht erreicht; die Administration kann mit einer Dosis täglich vorgenommen werden oder nötigenfalls in mehreren beispielsweise 2 bis 4 Teildosen erfolgen. Für grössere Säugetiere liegt die Tagesdosis im Bereich von etwa 0,5 bis 50 mg der Substanz, geeignete Dosierungsformen für z.B. orale Anwendungen enthalten im allgemeinen ungefähr 0,1 bis 100 mg wirksame Substanz neben festen oder flüssigen Trägersubstanzen oder Verdünnungsmitteln. For the above-mentioned application, the dose to be used naturally varies depending on the substance used, the type of administration and the desired treatment. In general, however, satisfactory results are achieved with doses of approximately 0.005 to 1.0 mg / kg body weight; administration can be carried out with one dose daily or, if necessary, in several, for example 2 to 4, partial doses. For larger mammals, the daily dose is in the range of about 0.5 to 50 mg of the substance, suitable dosage forms for e.g. Oral applications generally contain about 0.1 to 100 mg of active substance in addition to solid or liquid carriers or diluents.
Die Erfindung ist im experimentellen Teil erläutert. The invention is explained in the experimental part.
Die Verbindungen der Formel I werden hierin als 8a-Ergolin I-Verbindungen bezeichnet. Sie können auch als (5R,8S,10R)-8-Amino-ergolin I-Verbindungen bezeichnet werden. Die Temperaturangaben erfolgen in Celsiusgraden. The compounds of formula I are referred to herein as 8a-ergoline I compounds. They can also be referred to as (5R, 8S, 10R) -8-amino-ergoline I compounds. The temperatures are given in degrees Celsius.
Beispiel l,6-Dimethyl-2-brom-8a-(N,N-dimethylsulfamoylamino)-ergolin I Example 1, 6-Dimethyl-2-bromo-8a- (N, N-dimethylsulfamoylamino) -ergoline I
1,5 g l,6-Dimethyl-8a-(N,N-dimethylsulfamoylamino)-ergolin I werden in 125 ml Dioxan (abs.) vorgelegt. Man tropft 1,2 g N-Brom-succinimid in 100 ml Dioxan zu, unter Rühren, und rührt die so erhaltene braune Lösung noch 2 Stunden bei Raumtemperatur weiter. Das Reaktionsgemisch wird eingedampft, in Methylenchlorid gelöst, mit Aktivkohle behandelt und in üblicher Weise aufgearbeitet. Der Rückstand wird 30 Minuten unter Hochvakuum bei 60° 1.5 g l, 6-dimethyl-8a- (N, N-dimethylsulfamoylamino) -ergoline I are placed in 125 ml of dioxane (abs.). 1.2 g of N-bromosuccinimide in 100 ml of dioxane are added dropwise, with stirring, and the brown solution thus obtained is stirred for a further 2 hours at room temperature. The reaction mixture is evaporated, dissolved in methylene chloride, treated with activated carbon and worked up in the usual way. The residue is 30 minutes under high vacuum at 60 °
getrocknet. Das Hydrochlorid der Titelverbindung (aus Äthanol) schmilzt bei 252-254° (unter Zersetzung). Die optische Drehung beträgt [a]gJ = +10° (c = 1 in Dimethyl-formamid). dried. The hydrochloride of the title compound (from ethanol) melts at 252-254 ° (with decomposition). The optical rotation is [a] gJ = + 10 ° (c = 1 in dimethylformamide).
3 3rd
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1569976A CH622518A5 (en) | 1976-12-14 | 1976-12-14 | Process for the preparation of novel ergoline compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH628895A5 true CH628895A5 (en) | 1982-03-31 |
Family
ID=4411193
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1569976A CH622518A5 (en) | 1976-12-14 | 1976-12-14 | Process for the preparation of novel ergoline compounds |
| CH697480A CH628895A5 (en) | 1976-12-14 | 1980-09-17 | Process for the preparation of ergoline compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1569976A CH622518A5 (en) | 1976-12-14 | 1976-12-14 | Process for the preparation of novel ergoline compounds |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH622518A5 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4657914A (en) * | 1982-04-30 | 1987-04-14 | Farmitalia Carlo Erba S.P.A. | Ergoline derivatives |
| US4675322A (en) * | 1984-12-10 | 1987-06-23 | Eli Lilly And Company | 1-Substituted-6-n-propyl-8β-methylthio-methylergolines |
| US4791116A (en) * | 1983-02-16 | 1988-12-13 | Sandoz Ltd. | N,N-diethyl-N'-[(8α)-1-ethyl-6-methyl-ergolin-8-yl]-sulfamide useful as prolactin secretion inhibitor, anti-parkinson agents and anti-depressant agents |
| US4874768A (en) * | 1985-10-04 | 1989-10-17 | Schering Aktiengesellschaft | 1,2-disubstituted ergolines useful for producing central antidopanminergic or α2-receptor-blocking activity |
| US4950672A (en) * | 1984-01-12 | 1990-08-21 | Sandoz Ltd. | 2-substituted-8α-branched chain acylaminoergolines |
| AT392945B (en) * | 1988-06-27 | 1991-07-10 | Gerhard Mader Ges M B H Ing | STORAGE AND TRANSPORTATION CONTAINERS FOR Bulk goods and loose materials |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3151912A1 (en) * | 1981-12-23 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW ERGOLIN AMINO DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| CH666035A5 (en) * | 1984-12-24 | 1988-06-30 | Sandoz Ag | 8-ALPHA ACYLAMINOERGOLENE. |
-
1976
- 1976-12-14 CH CH1569976A patent/CH622518A5/en not_active IP Right Cessation
-
1980
- 1980-09-17 CH CH697480A patent/CH628895A5/en not_active IP Right Cessation
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4657914A (en) * | 1982-04-30 | 1987-04-14 | Farmitalia Carlo Erba S.P.A. | Ergoline derivatives |
| US4791116A (en) * | 1983-02-16 | 1988-12-13 | Sandoz Ltd. | N,N-diethyl-N'-[(8α)-1-ethyl-6-methyl-ergolin-8-yl]-sulfamide useful as prolactin secretion inhibitor, anti-parkinson agents and anti-depressant agents |
| US4950672A (en) * | 1984-01-12 | 1990-08-21 | Sandoz Ltd. | 2-substituted-8α-branched chain acylaminoergolines |
| US5077298A (en) * | 1984-01-12 | 1991-12-31 | Sandoz Ltd. | Novel 8α-acylaminoergolines |
| US4675322A (en) * | 1984-12-10 | 1987-06-23 | Eli Lilly And Company | 1-Substituted-6-n-propyl-8β-methylthio-methylergolines |
| US4874768A (en) * | 1985-10-04 | 1989-10-17 | Schering Aktiengesellschaft | 1,2-disubstituted ergolines useful for producing central antidopanminergic or α2-receptor-blocking activity |
| AT392945B (en) * | 1988-06-27 | 1991-07-10 | Gerhard Mader Ges M B H Ing | STORAGE AND TRANSPORTATION CONTAINERS FOR Bulk goods and loose materials |
Also Published As
| Publication number | Publication date |
|---|---|
| CH622518A5 (en) | 1981-04-15 |
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