WO1982000463A1 - Ergoline derivatives,method for their preparation,pharmaceutical compositions containing them and their therapeutic application - Google Patents
Ergoline derivatives,method for their preparation,pharmaceutical compositions containing them and their therapeutic application Download PDFInfo
- Publication number
- WO1982000463A1 WO1982000463A1 PCT/CH1981/000080 CH8100080W WO8200463A1 WO 1982000463 A1 WO1982000463 A1 WO 1982000463A1 CH 8100080 W CH8100080 W CH 8100080W WO 8200463 A1 WO8200463 A1 WO 8200463A1
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- WIPO (PCT)
- Prior art keywords
- hydrogen
- formula
- compounds
- alkyl group
- carbon atoms
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 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 description 11
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 230000028327 secretion Effects 0.000 claims abstract description 5
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 230000001430 anti-depressive effect Effects 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- -1 N-diethylsulfamoylamino Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 239000002243 precursor Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 102000003946 Prolactin Human genes 0.000 claims description 4
- 108010057464 Prolactin Proteins 0.000 claims description 4
- 239000000935 antidepressant agent Substances 0.000 claims description 4
- 229940005513 antidepressants Drugs 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 229940097325 prolactin Drugs 0.000 claims description 4
- 239000007859 condensation product Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 3
- 230000000648 anti-parkinson Effects 0.000 claims 1
- 239000000939 antiparkinson agent Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- OXBOABAOQWBSIV-UHFFFAOYSA-N [N]S(N)(=O)=O Chemical compound [N]S(N)(=O)=O OXBOABAOQWBSIV-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 230000003291 dopaminomimetic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KGUBZNRUCSWDAU-ZKYQVNSYSA-N (6ar,9s,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-amine Chemical compound C1=CC([C@H]2C[C@H](N)CN([C@@H]2C2)C)=C3C2=CNC3=C1 KGUBZNRUCSWDAU-ZKYQVNSYSA-N 0.000 description 2
- RYVRSQTXYQBZDI-JGGQBBKZSA-N (6ar,9s,10ar)-7-propyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-amine Chemical compound C1=CC([C@H]2C[C@H](N)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 RYVRSQTXYQBZDI-JGGQBBKZSA-N 0.000 description 2
- NNDATQSUZGLGQT-BXUZGUMPSA-N 6-methylergoline Chemical class C1=CC([C@H]2CCCN([C@@H]2C2)C)=C3C2=CNC3=C1 NNDATQSUZGLGQT-BXUZGUMPSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 0 C*C(C1)(CN(*)[C@@](C2)[C@@]1c1cccc3c1c2c[n]3*)N* Chemical compound C*C(C1)(CN(*)[C@@](C2)[C@@]1c1cccc3c1c2c[n]3*)N* 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 208000001287 Galactorrhea Diseases 0.000 description 1
- 206010017600 Galactorrhoea Diseases 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- 206010026889 Mastitis postpartum Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 238000007281 aminoalkylation reaction Methods 0.000 description 1
- 206010003883 azoospermia Diseases 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000009027 insemination Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- NDYAAZRKZRTLQC-UHFFFAOYSA-N n,n-diethylsulfamoyl chloride Chemical compound CCN(CC)S(Cl)(=O)=O NDYAAZRKZRTLQC-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 208000008634 oligospermia Diseases 0.000 description 1
- 230000036616 oligospermia Effects 0.000 description 1
- 231100000528 oligospermia Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
-
- 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
- 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
-
- 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
Definitions
- Ergoline derivatives processes for their preparation, pharmaceutical compositions containing them and their use in therapeutic treatment
- the present invention relates to ergoline derivatives, processes for their preparation, pharmaceutical compositions which contain these ergoline derivatives and the use of these ergoline derivatives in therapeutic treatment.
- the invention relates in particular to the compounds of the formula I,
- R 1 is a straight chain alkyl group with 2 or
- R 2 represents hydrogen or an alkyl group
- R 3 represents an alkyl group with 1 to 3 carbon atoms and R 4 represents hydrogen or methyl, and their acid addition salts.
- the ergoline scaffold in the 6-position is preferably a methyl or branched in et
- Alkyl group such as isopropyl. Only 6-methyl-ergolines are listed in the examples.
- DOS No. 2656344 also describes a broad class of ergoline compounds with the properties mentioned above, comprising the compounds of the formula I, in which R 1 is ethyl and R 4 is methyl.
- the preferred 6-position substituent is said to be the methyl group and all examples relate to 6-methyl-ergolines.
- R 1 is preferably n-propyl.
- R 2 and R 3 are preferably identical and each represent methyl or ethyl.
- the compounds of formula I and their salts are obtained by using compounds of formula II or their precursors
- R 2 and R 4 have the above meaning and R 5
- R 6 is hydrogen or an alkyl group having 1 to 3 carbon atoms and one of the two substituents X and Y is -SO 2 Z, in which Z is a cleavable group, and the other Means hydrogen.
- the condensation is preferably carried out by reacting the compounds of the formula II in which X is hydrogen with compounds of the formula IV
- the reaction can be carried out according to methods known per se.
- the reactive or functional derivative of the acid of formula IV is preferably chloride or bromide.
- Suitable solvents are, for example, chlorinated, aliphatic hydrocarbons such as methylene chloride or chloroform, or cyclic or open-chain ethers such as dioxane.
- the reaction temperature can vary between - 10 to 80 ° C.
- the compound of formula II and / or III can also be used in the form of a precursor, e.g. in a protected form.
- a nitrogen can be protected by an amino protective group and the protective group can be split off after the condensation.
- R 5 and / or R 6 are hydrogen, the condensation product must of course still be alkylated.
- the compounds of the formula I in which R 2 and / or R 4 are hydrogen can also be alkylated to give further compounds of the formula I in which R 2 and / or R 4 is alkyl.
- the alkylation can be carried out in a manner known per se.
- the type and amount of the alkylating agent and / or the reaction conditions can of course vary depending on whether only alkylation in position 1 or 6 or also mono- or dialkylation on the sulfamoyl nitrogen is desired.
- the alkylation in position 1 or 6 is carried out, for example, by reacting the corresponding compounds which are unsubstituted in position 1 or 6 with compounds of the formula CH 3 -Z 1 or R 1 -Z 1 , in which R 1 has the above meaning and Z 1 represents the acid residue of a reactive ester, preferably halogen or an organic sulfonic acid residue such as tosyloxy.
- the reaction is preferably carried out in an inert organic solvent, at temperatures between about 10 and 100 ° C, in the presence of a base.
- the alkylation in position 6 can also be carried out reductively, for example by catalytic hydrogenation under mild reaction conditions.
- the alkylation on the sulfamoyl nitrogen can be carried out by conventional methods for aminoalkylation. Of course, care must be taken to ensure that if R 1 or R 4 in the starting products is hydrogen, the corresponding nitrogen is primarily alkylated in an alkylation reaction.
- the reaction is preferably carried out using alkyl halides, in acetone, dimethylformamide or a hydrogen halide and in the presence of a base. If a monoalkylation on the sulfamoyl nitrogen (and optionally one
- alkylation is to be achieved in position 1 or 6
- the alkyl halide is expediently used in at most equivalent amounts. If dialkylation is to be achieved on the sulfamoyl nitrogen, the alkyl halide is expediently used in excess.
- the compounds of formula I obtained can be isolated and purified from the reaction mixture in a manner known per se.
- Acid addition salts can be prepared in a known manner from the free bases of the compounds of the formula I and vice versa.
- Acids suitable for salt formation are e.g. Hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid.
- Compounds of formula II in which X is -SO 2 Z can be prepared by introducing the group -SO 2 Z into the corresponding compounds of formula II in which X is hydrogen.
- the compounds of the formula II in which X is hydrogen can be reacted with sulfuryl chloride, it being possible to temporarily protect a nitrogen atom in position 1 or 6 of the ergoline skeleton if R 4 or R 1 is hydrogen.
- Some of the starting products of the formula II in which X is hydrogen are known. Among these compounds, those in which R 4 is hydrogen or methyl and R 5 is hydrogen, and those in which R 4 is methyl and R 5 is n-propyl are new. All compounds of the formula II in which X is hydrogen can be prepared by methods known per se, starting from 8 ⁇ -amino-6-methylergoline. The 8 ⁇ -amino group can be protected, for example, by a benzyloxycarbonyl group, the 6-methyl group can be replaced by an R 1 group and a methyl group can be introduced in position 1. Insofar as the production of the starting products is not described, they are known or can be produced by processes known per se or analogously to processes known per se.
- the compounds of the formula I and their pharmacologically acceptable acid addition salts are distinguished by superior pharmacodynamic properties and good tolerability in comparison to the above compounds known from the literature and can therefore be used as medicaments.
- these substances show a surprisingly strong prolactin secretion-inhibiting effect.
- they inhibit the nidation of the fertilized eggs in the uterine mucosa after subcutaneous application on day 5 after insemination, at doses between 0.001 and 0.1 mg / kg s.c. [Method: Experientia 34, 1330 (1978)].
- the new substances because of their prolaktinsekretionshemmenden properties for the treatment of endocrine indications associated with an abnormal prolactin secretion such as galactorrhea with or without amenorrhea, prolactin-menstrual disorders and subfertility, Laktationshemmung incipient puerperal mastitis, postpartum milk tension, prolactin-, premenstrual complaints, prolaktin occupationaler hypogonadism Man, impotence and oligospermia, and acromegaly.
- the new substances have a dopamine receptor-stimulating effect.
- the dopaminergic properties could be determined in rats in which a unilateral violation of the nigro-neostriatal dopamine web was produced by a 6-hydroxydopamine injection into the substantia nigra, with doses between approximately 0.05 and 2 mg / kg ip [method according to U Ungerstedt, Acta physiol. scand. Suppl. 367, 69-93 (1973)]. After administration of the active substance, a clear activation was recognizable by the fact that the rats made rotational movements in the direction of the undenervated side.
- the new substances can be used to treat Parkinsonism.
- the new substances also have antidepressant properties. They inhibit ptosis and catalepsy caused by reserpine in the rat, with doses between approx. 0.01 and 0.1 mg / kg s.c. Because of these properties, they can be used as antidepressants.
- the invention also relates to pharmaceutical compositions which contain the compounds according to the invention.
- the auxiliaries and carriers customary in pharmacy can be used for their production.
- the invention further relates to the use of the new substances as pharmaceuticals, for example in therapeutic treatment, in particular as prolactin secretion inhibitors, for the treatment of Parkinsonism and as antidepressants.
- Example 1 relates to the preferred compound.
- Example 1 2 g (8.2 mM) of 8 ⁇ -amino-6-n-propyl-ergoline in 50 ml of chloroform and 5 ml of triethylamine is heated to the reflux temperature. A solution of 2.0 ml (approx. 26 mM) of diethylsulfamic acid chloride in 5 ml of chloroform is added dropwise at this temperature. The reaction solution is then heated to boiling temperature for 12 hours. After adding 10 ml
- Example 7 8 ⁇ - (N, N-diethylsulfamoylamino) -1-methyl-6-n-propyl-ergoline
- Mp of the hydrochloride from 180 ° decomposition .
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH572380 | 1980-07-25 | ||
| CH572480 | 1980-07-25 | ||
| CH5724/80 | 1980-07-25 | ||
| CH5723/80 | 1980-07-25 | ||
| CH7360/80 | 1980-10-02 | ||
| CH7358/80801002 | 1980-10-02 | ||
| CH736080 | 1980-10-02 | ||
| CH735980 | 1980-10-02 | ||
| CH735880 | 1980-10-02 | ||
| CH7359/80 | 1980-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1982000463A1 true WO1982000463A1 (en) | 1982-02-18 |
Family
ID=27509257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CH1981/000080 WO1982000463A1 (en) | 1980-07-25 | 1981-07-15 | Ergoline derivatives,method for their preparation,pharmaceutical compositions containing them and their therapeutic application |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US4764517A (en:Method) |
| AT (1) | AT381940B (en:Method) |
| AU (1) | AU550151B2 (en:Method) |
| CA (1) | CA1182816A (en:Method) |
| CH (1) | CH654838A5 (en:Method) |
| CS (1) | CS231988B2 (en:Method) |
| CY (1) | CY1383A (en:Method) |
| DE (1) | DE3127845A1 (en:Method) |
| DK (1) | DK148883C (en:Method) |
| FI (1) | FI71736C (en:Method) |
| FR (1) | FR2487351B1 (en:Method) |
| GB (1) | GB2081262B (en:Method) |
| GR (1) | GR74310B (en:Method) |
| HK (1) | HK83887A (en:Method) |
| HU (1) | HU186417B (en:Method) |
| IE (1) | IE51423B1 (en:Method) |
| IT (1) | IT1171410B (en:Method) |
| KE (1) | KE3727A (en:Method) |
| MY (1) | MY8500686A (en:Method) |
| PH (1) | PH20160A (en:Method) |
| PT (1) | PT73413B (en:Method) |
| SE (1) | SE442869B (en:Method) |
| SG (1) | SG38387G (en:Method) |
| WO (1) | WO1982000463A1 (en:Method) |
| YU (1) | YU182381A (en:Method) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3151912A1 (de) * | 1981-12-23 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue ergolin-aminoderivate, verfahren zu ihrer herstellung und deren verwendung als arzneimittel |
| NL8400333A (nl) * | 1983-02-16 | 1984-09-17 | Sandoz Ag | Moederkoornalkaloiden, hun bereiding en hun toepassing. |
| DE3915950A1 (de) * | 1989-05-12 | 1990-11-15 | Schering Ag | 8(alpha)-acylamino-ergoline, ihre herstellung und verwendung als arzneimittel |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2656344A1 (de) * | 1975-12-23 | 1977-07-07 | Sandoz Ag | Ergolinderivate, ihre verwendung und herstellung |
| DE2657770A1 (de) * | 1976-01-02 | 1977-07-14 | Sandoz Ag | In 8-stellung aminocarbonyl- und -sulfonylsubstituierte ergoline, ihre verwendung und herstellung |
| CH605938A5 (en) * | 1974-08-13 | 1978-10-13 | Sandoz Ag | 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1517971A (en) * | 1974-07-19 | 1978-07-19 | Sandoz Ltd | 8alpha-substituted ergoline i derivatives |
| US4348392A (en) * | 1974-07-19 | 1982-09-07 | Sandoz Ltd. | 8α-Substituted ergoline-I derivatives |
| US4202279A (en) * | 1977-09-12 | 1980-05-13 | The Unites States Of America As Represented By The United States Department Of Energy | Sticky foam |
| US4180582A (en) * | 1978-02-08 | 1979-12-25 | Eli Lilly And Company | 6-n-Propyl-8-methoxy-methyl or methylmercaptomethylergolines and related compounds as prolactin inhibitors and to treat Parkinson's syndrome |
| EP0021206B1 (de) * | 1979-06-13 | 1983-06-22 | Schering Aktiengesellschaft | Neue (Ergolin-yl)-N', N'-diäthylharnstoff-Derivate, ihre Herstellung und sie enthaltende Arzneimittel |
-
1981
- 1981-07-15 DE DE19813127845 patent/DE3127845A1/de not_active Withdrawn
- 1981-07-15 WO PCT/CH1981/000080 patent/WO1982000463A1/en unknown
- 1981-07-15 CH CH2003/82A patent/CH654838A5/de not_active IP Right Cessation
- 1981-07-17 FI FI812253A patent/FI71736C/fi not_active IP Right Cessation
- 1981-07-17 FR FR8114129A patent/FR2487351B1/fr not_active Expired
- 1981-07-22 CY CY138381A patent/CY1383A/en unknown
- 1981-07-22 AU AU73182/81A patent/AU550151B2/en not_active Ceased
- 1981-07-22 PH PH25949A patent/PH20160A/en unknown
- 1981-07-22 GB GB8122547A patent/GB2081262B/en not_active Expired
- 1981-07-22 YU YU01823/81A patent/YU182381A/xx unknown
- 1981-07-22 IT IT48951/81A patent/IT1171410B/it active
- 1981-07-23 DK DK329781A patent/DK148883C/da active
- 1981-07-23 SE SE8104508A patent/SE442869B/sv not_active IP Right Cessation
- 1981-07-23 PT PT73413A patent/PT73413B/pt unknown
- 1981-07-23 IE IE1665/81A patent/IE51423B1/en unknown
- 1981-07-23 CA CA000382311A patent/CA1182816A/en not_active Expired
- 1981-07-23 GR GR65606A patent/GR74310B/el unknown
- 1981-07-24 CS CS815679A patent/CS231988B2/cs unknown
- 1981-07-24 AT AT0326881A patent/AT381940B/de not_active IP Right Cessation
- 1981-07-24 HU HU812179A patent/HU186417B/hu not_active IP Right Cessation
-
1985
- 1985-12-30 MY MY686/85A patent/MY8500686A/xx unknown
-
1987
- 1987-04-25 SG SG383/87A patent/SG38387G/en unknown
- 1987-05-05 KE KE3727A patent/KE3727A/xx unknown
- 1987-08-25 US US07/089,299 patent/US4764517A/en not_active Expired - Fee Related
- 1987-11-12 HK HK838/87A patent/HK83887A/xx unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH605938A5 (en) * | 1974-08-13 | 1978-10-13 | Sandoz Ag | 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs |
| DE2656344A1 (de) * | 1975-12-23 | 1977-07-07 | Sandoz Ag | Ergolinderivate, ihre verwendung und herstellung |
| DE2657770A1 (de) * | 1976-01-02 | 1977-07-14 | Sandoz Ag | In 8-stellung aminocarbonyl- und -sulfonylsubstituierte ergoline, ihre verwendung und herstellung |
Non-Patent Citations (2)
| Title |
|---|
| Experientia, 34/10 (1978), Basel, (CH) E. Fl}ckiger u.a: "Prolactin secretion inhibition by a new 8alpha-amino-ergoline, CH 29-717, Seiten 1330-2 * |
| Experientia, 35 (1979), Birkh{user-Verlag Basel, (CH), E. Fl}ckiger u.a:, "Two novel prolactin release-inhibiting 8alpha-amino-ergolines", Seiten 1677-8 * |
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