IE51341B1 - Heterocyclic compounds,their preparation and pharmaceutical compositions containing them - Google Patents
Heterocyclic compounds,their preparation and pharmaceutical compositions containing themInfo
- Publication number
- IE51341B1 IE51341B1 IE1421/81A IE142181A IE51341B1 IE 51341 B1 IE51341 B1 IE 51341B1 IE 1421/81 A IE1421/81 A IE 1421/81A IE 142181 A IE142181 A IE 142181A IE 51341 B1 IE51341 B1 IE 51341B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- indole
- dibenz
- propyl
- formula
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 11
- 125000001033 ether group Chemical group 0.000 claims abstract description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 52
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 25
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 25
- -1 propionyloxy Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical group 0.000 claims description 9
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 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 3
- NGEVMZJCGSABFB-LSDHHAIUSA-N (9R,11S)-10,11-diethyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),2(7),3,5,12,14-hexaene-3,4-diol Chemical compound C(C)[C@@H]1N([C@@H]2CC3=C(C4=C2C1=CC=C4)C(=C(C=C3)O)O)CC NGEVMZJCGSABFB-LSDHHAIUSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- RFMNLPNQJKDVDJ-UHFFFAOYSA-N 11-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1,3,5,7,9(16),10,12,14-octaene-3,4-diol Chemical compound OC=1C=CC=2C(=C3C=4C(C(=NC=4C=2)CCC)=CC=C3)C=1O RFMNLPNQJKDVDJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- AZNXBNYSBPNDEN-FCHUYYIVSA-N [(9R,11S)-10-ethyl-3-(2-methylpropanoyloxy)-11-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),2(7),3,5,12,14-hexaen-4-yl] 2-methylpropanoate Chemical compound C(C)N1[C@H](C=2C3=C(C4=C(C[C@@H]13)C=CC(=C4OC(C(C)C)=O)OC(C(C)C)=O)C=CC2)CCC AZNXBNYSBPNDEN-FCHUYYIVSA-N 0.000 claims 1
- MZXQWBJGSQDALU-VQTJNVASSA-N [(9R,11S)-3-acetyloxy-10-ethyl-11-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),2(7),3,5,12,14-hexaen-4-yl] acetate Chemical compound C(C)(=O)OC=1C=CC2=C(C3=C4C([C@@H](N([C@@H]4C2)CC)CCC)=CC=C3)C=1OC(C)=O MZXQWBJGSQDALU-VQTJNVASSA-N 0.000 claims 1
- JHJWWQDOZZKDOZ-FCHUYYIVSA-N [(9R,11S)-3-butanoyloxy-10-ethyl-11-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),2(7),3,5,12,14-hexaen-4-yl] butanoate Chemical compound C(CCC)(=O)OC=1C=CC2=C(C3=C4C([C@@H](N([C@@H]4C2)CC)CCC)=CC=C3)C=1OC(CCC)=O JHJWWQDOZZKDOZ-FCHUYYIVSA-N 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- RJTZUHVCZIGJMB-UHFFFAOYSA-N hydron;1h-indole;chloride Chemical compound Cl.C1=CC=C2NC=CC2=C1 RJTZUHVCZIGJMB-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000003291 dopaminomimetic effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000155 melt Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 102000003946 Prolactin Human genes 0.000 description 4
- 108010057464 Prolactin Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000002425 crystallisation 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
- 239000002552 dosage form Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229940097325 prolactin Drugs 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ILWGYWSBUWKROZ-UHFFFAOYSA-N 1h-indole;hydrobromide Chemical compound Br.C1=CC=C2NC=CC2=C1 ILWGYWSBUWKROZ-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- UARUVPSHLDRXIZ-UHFFFAOYSA-N 10-ethyl-3,4-dimethoxy-11-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1,3,5,7,9(16),12,14-heptaen-11-ol Chemical compound C(C)N1C(C=2C=3C(=C4C(=CC13)C=CC(=C4OC)OC)C=CC2)(CCC)O UARUVPSHLDRXIZ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- PKZXKYOUTNKIMK-UHFFFAOYSA-N 3,4-dimethoxyphenanthren-9-amine Chemical compound C1=CC=C2C3=C(OC)C(OC)=CC=C3C=C(N)C2=C1 PKZXKYOUTNKIMK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000009132 Catalepsy Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 102000004659 Presynaptic Receptors Human genes 0.000 description 2
- 108010003717 Presynaptic Receptors Proteins 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 206010047853 Waxy flexibility Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
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- 238000001727 in vivo Methods 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- DRHKAJZMZVLERV-UHFFFAOYSA-N n-(3,4-dimethoxyphenanthren-9-yl)acetamide Chemical compound C1=CC=C2C3=C(OC)C(OC)=CC=C3C=C(NC(C)=O)C2=C1 DRHKAJZMZVLERV-UHFFFAOYSA-N 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
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- 239000012071 phase Substances 0.000 description 2
- 150000002987 phenanthrenes Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
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- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- 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
- GGPBYYIINHBLOR-JKSUJKDBSA-N (9R,11S)-11-ethyl-10-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),2(7),3,5,12,14-hexaene-3,4-diol Chemical compound C(C)[C@@H]1N([C@@H]2CC3=C(C4=C2C1=CC=C4)C(=C(C=C3)O)O)CCC GGPBYYIINHBLOR-JKSUJKDBSA-N 0.000 description 1
- QLMDBQBZWJCDLT-UHFFFAOYSA-N 1,2-dimethoxyphenanthrene Chemical compound C1=CC=C2C3=CC=C(OC)C(OC)=C3C=CC2=C1 QLMDBQBZWJCDLT-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- CGUWCLGCJCLJOK-UHFFFAOYSA-N 10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(15),2,4,6,12(16),13-hexaene Chemical class C1C2=CC=CC=C2C2=CC=CC3=C2C1NC3 CGUWCLGCJCLJOK-UHFFFAOYSA-N 0.000 description 1
- KMDJVZQFYPQGNF-UHFFFAOYSA-N 10-ethyl-3,4-dimethoxy-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1,3,5,7,9(16),12,14-heptaen-11-one Chemical compound O=C1N(CC)C2=CC3=CC=C(OC)C(OC)=C3C3=C2C1=CC=C3 KMDJVZQFYPQGNF-UHFFFAOYSA-N 0.000 description 1
- UGDOHIHUJVNQST-UHFFFAOYSA-N 11-propyl-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1,3,5,7,9(16),10-hexaene-3,4-diol Chemical compound OC=1C=CC=2C(=C3C=4C(C(=NC=4C=2)CCC)CCC3)C=1O UGDOHIHUJVNQST-UHFFFAOYSA-N 0.000 description 1
- UUAIGYUJQOIJQK-UHFFFAOYSA-N 1h-phenanthro[9,10-b]pyrrole Chemical compound C12=CC=CC=C2C2=CC=CC=C2C2=C1NC=C2 UUAIGYUJQOIJQK-UHFFFAOYSA-N 0.000 description 1
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- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 1
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012505 colouration Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229940005501 dopaminergic agent Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- BQPIGGFYSBELGY-UHFFFAOYSA-N mercury(2+) Chemical class [Hg+2] BQPIGGFYSBELGY-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- NYFMUOLWACUBDV-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyphenanthren-9-amine Chemical compound C1=CC=C2C(NCC)=CC3=CC=C(OC)C(OC)=C3C2=C1 NYFMUOLWACUBDV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation 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
- 239000012047 saturated solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000028838 turning behavior Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
Abstract
The compounds of formula <IMAGE> wherein Z is a splittable ether group, R1 and R2 independently are ethyl and n-propyl radicals, in racemic form having the relative configuration 4aR*, 5aS* or an optically active form having the absolute configuration 4S, 5aR, are useful as intermedients for the preparation of pharmaceuticals.
[GB2136418A]
Description
Heterocyclic compounds, their preparation and pharmaceutical compositions containing them The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical 5 compositions containing them.
British Patent Specification No. 2 024 818 describes a class of 4,5,5a,6-tetrahydro-dibenz[cd,f]indole derivatives having stimulant activity on central dopaminergic receptors. All the compounds specifically exemplified which have alkyl groups attached to positions 4 and 5, contain as one alkyl group a methyl group. It has been now surprisingly found that a group of (4R*,5aS*)4,5,5a,6-tetrahydro-dibenz[cd,f]indole derivatives having ethyl and n-propyl groups in the 4 and 5 positions, which are nowhere specifically described or suggested in this patent, possess a particularly interesting pharmacological profile, inter alia, long duration of action and/or notable potency as central dopaminergic agents and good tolerability.
In accordance with the invention there are provided compounds of formula I, wherein Rx and R2 independently, are ethyl or jy-prcgyl radicals, 5 and the Rj substituents are the same and are hydroxy or acyloxy radicals, in racemic form having the relative configuration 4R*,5aS*, or in optically active isomer form having the absolute configuration 4S,5aR.
The acyloxy radicals are conveniently radicals of formula R - CO - 0 a in which R is an alkyl radical, (C, „)cycloalkyl, a phenyl radical or a 5- or 6-membexed heterocyclic ring.
When R is an alkyl radical,this may A conveniently contain 1-17 carbon atoms, preferably 1 to 7 carbon atoms, and may be straight chain or branched chain. 51341' R may be a substituted alkyl radical, con£L taining in the alkyl chain conveniently 1-5 carbon atoms. Conveniently it is a monosubstituted alkyl radical. The substituents may be, e.g., carboxy, hydroxy, amino, (C^^) alkylamino, (C.^) alkoxy, di-alkylamino, halogen, alkylthio, phenoxy, a phenyl radical, 1-pyrrolidinyl, piperidino or morpholino, and conveniently a phenyl radical.
Rfl may also be e.g. an alkyl radical containing in the alkyl chain 1-4 carbon atoms and substituted by cycloalkyl.
When R is a phenyl radical or alkyl substituted by a phenyl radical, the phenyl radical may be unsubstituted or contain 1, 2 or 3 identical or diffe15 rent substituents, selected,for example, from halogen, trifluoromethyl, (C^_4)alkyl, (C^_4)alkoxy, (C^) alkylthio and di- (C^p alkylamino, or a methylene dioxy group. Preferably the phenyl ring is mono- or disubstituted.
When R^ is an alkyl substituted by a phenyl radical, Rfi is preferably a benzyl radical. The phenyl ring may bear substituents selected,for example, from halogen, (C.^)alkyl, (C^)alkoxy or (C.^)alkylthio.
When R is a heterocyclic ring, this is A suitably a heterocycle containing oxygen, nitrogen or sulfur as sole heteroatom, e.g. pyridine, thiophene or furan.
Preferably R& is (Cj_7)alkyl; {C3_g)cycloalkylj unsubstituted phenyl; phenyl mono- or disubstituted by chlorine, fluorine, trifluoromethyl, (Cj_4Jalkyl or alkoxy; unsubstituted benzyl; or benzyl mono- or disubstituted by chlorine, fluorine, (cl-4^al,tyl or (0χ_4) alkoxy.
Halogen may signify chlorine, bromine or fluorine, preferably chlorine or fluorine.
In a group of compounds, R^ is n-propyl and R2 is ethyl. In another group of compounds, R^ and R2 15 are the same and signify ethyl or n-propyl. Preferably in the compounds of formula I the R^ substituents are hydroxy. The preferred compounds are the (4S,5aR) optical isomers.
More particularly the invention provides a process for the production of compounds of formula I, which comprises a) producing a compound of formula Ia la wherein and R^ are as-defined above, by splitting the ether groups Z of a compound of formula II II wherein R^ and R2 are defined above and Z is a splittable ether group, in racemic form having the relative configuration 4R*,5aS*,cr in critically active isomer form having the absolute configuration 4S,5aR, or Ib wherein R^ and R2 are defined above and the radicals R^ are identical acyloxy radicals,by acylating a compound of formula Ia in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR.
The ether splitting process according process a) may be effected in conventional manner for splitting ether groups. For example the reaction may be carried out by treatment of the starting materials with a strong mineral acid,e.g. hydrobromic or hydroiodic acid, at a temperature of at least 1OO°C, preferably from 100eC to the boiling point of the reaction mixture, especially at about 130’C.The ether group Z i3 preferably a methoxy radical.
The acylation process according to process b), may be effected in conventional manner for the selective acylation of phenolic groups in the presence of an amine function. For example there may be used, as acylating agent, a functional derivative of an aeid such an acid chloride, acid bromide or the acid anhydride. Conveniently the reaction is carried out by reacting an acid chloride in the presence of trifluoroacetic acid at temperatures from 20°C to the boiling point of the reaction mixture or in the presence of pyridine at temperature from 0°C to room temperature.
The resulting compounds of fonnula I may be isolated from the reaction mixture and purified in known manner. The free base forms of compounds of formula I may be converted into acid addition salt - 51341 forms in conventional manner and vice versa. Suitable acids for salt formation are, for example, hydrochloric acid,tartaric acid, di-0,0-p-toluoyl-D-or L-tartaric acid, and hydrobromic acid..
Racemic compounds of formula I may be obtained from racemic starting materials. Optically active isomers of formula I may be obtained from optically active precursors with the configuration (4S,5aR) or from the racemate. The 4S,5aR enantiomer may be obtained from racemate by known methods, for example by fractional crystallization of diastereoisomeric salts, e.g. their salts with (+)-di-O,O-ptoluoy1-D-tartaric acid or (-)-di-0,0-p-toluoyl-Ltartaric acid. Racemic resolution into the optically active isomers may be effected preferably at an early stage in the synthesis, e.g. before splitting of the ether groups.
The starting materials of formula II are described and claimed in British Divisional Application No. 8 325 760 and may be prepared by reducing compounds of formula III wherein R^, R2 and R3 are as defined above.
The reduction may be effected conveniently tuider acidic conditions suitable for the acidic reduction of enamines or imines, for example with 5 zinc in an aqueous mineral acid, preferably hydrochloric acid, conveniently in the presence of a mercury (II) salt, for example mercury(II) chloride. The reaction may suitably be effected for example in ethanol, and at temperatures from 50®C to the boiling point of the reaction mixture.
Starting materials of formula III may be prepared, for example, according the following reaction scheme: ο συ (VII) butyllithium (VIII) (IX) (X) (XI) Xn the reaction scheme the radicals Rjy R2 and Z are as defined above and R2 is methyl or ethyl.
The reactions may be carried out in conventional manner and the products of the above reactions may be isolated and purified in known manner.
In the above intermediates the ether groups Z are conveniently methoxy.
Insofar the preparation or any particular starting material is not particularly described, this Iq may be effected in conventional manner.
For example the phenanthrene derivatives which are starting materials of fonnula XI, are described in the Elsevier's Encyclopaedia of Organic Chemistry, vol. 13, Tricyclic compounds, Elsevier Publishing Company Inc.
New York (1946).
In the following Examples all temperatures are given in degrees Celsius and are uncorrected.
EXAMPLE 1 : Β2£222£2££Ξ2 [compound of formula IV] A solution of 50 g (133 mM) 9-ethylamino-3bromo-3,4-dimethoxy-phenanthrene in 57.5 ml (333 mM) N-ethyl-diisopropylamine and 420 ml methylene chloride Is added dropwise, with stirring, under a nitrogen atmosphere over a period of 20 minutes -to a solution of 28.8 ml (276 mM) butyryl chloride in 420 ml methylene chloride. During the addition the reaction mixture is maintained at room temperature by cooling in a water bath. The resultant yellow-red solution is then worked un in known manner to afford 9- (M-ethylN-butyry1-amino)-8-bromo-3,4-dimethoxy-phenanthrene; M.pt 102-104°. b) JdRSJ-S-ethjzl^^S-dih^dro-d-hydroxy^.r.lOiiH'SS.thoxyT lo Jl{!lE£2Ey2L^i5S25iES'.£Ii2^2l£_[con!Poun^ °f fonnula III] g (58.14 mM) of 9-(H-ethyl-H-butyrylamino)-8-bromo-3,4-dimethoxy phenanthrene are dissolved with stirring in 450 ml anhydrous tetrahydrofuran and the solution obtained is cooled to -25° with a bath of methylene chloride and dry ice. 73 ml (116.28 mM) of a 1.7 molar solution of tert.-butyl-lithium in pentane are then added dropwise over 4 minutes. Then the temperature of the reaction mixture is allowed to increase to +5° over a period of 30 minutes, the reaction mixture is poured onto 500 ml of a mixture water and ice, extracted three times with, each time, 500 ml methylene chloride,and the organic phases are washed with water, dried and evaporated. After the product is dried in high vacuum, there is obtained (4RS) -5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy4-n-propyl-dibenz [cd, f] indole in the form of a yellow green foam. dime thoxy-4-η-ρΓοργί-άϊο6ηζ [cd, f] indole [compound of formula II] A suspension of 40.6 g (116 mM) of (4RS)-5ethy1-4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propy1dibenz[cd,f]indole in 1060 ml ethanol is added with stirring to a suspension of 140 g of zinc dust and 31.6 g (116 mM) of mercury (111 chloride in 1060 ml distilled water ( alternatively the zinc dust/mercury chloride may be added to the dibenzindole).The reaction mixture is refluxed, 360 ml of 18% hydrochloric acid are added dropwise over a period of 15 to 20 minutes and the mixture is refluxed overnight with stirring. The reaction mixture Is cooled to room temperature, filtered and the zinc amalgam is washed wi th 500 ml methylene chloride. The filtrate is made alkaline with 1 litre of concentrated NH4OH and the alkaline phase is extracted once with 1 litre methylene chloride and twice with, each time, 500 ml methylene chloride. The combined organic phases are washed with water, dried and evaporated. The resultant oil is chromatographicd on silicagel using methylene chloride with 2% methanol as eluant.to give {-)-(4R*,5aS*)-5-ethyl-4,5,5a,6tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz[cd,f) indole in form of an oil.
EXAMPLE 2: The (4RS)-5-ethyl-4,5-dihydro-4-hydroxy9,10-dimethoxy-4-n-propyldibenz[cd,f]indole obtained in the Example lb), may also be prepared as follows : a3 ^famino^l^A-dimethoxy-gherianthrene [compound of formula X) A mixture of 430 ml (3.03 moles) trifluoroacetic anhydride and 430 ml (5.62 moles) trifluoroacetic acid is added at room temperature under a nitrogen atmosphere to 53.6 g (0.19 mole) 3,4dimethoxy-phenanthrene-9-carboxylic acid and the mixture is stirred for 10 minutes.After the mixture is cooled to -5®, 15.2 g (0.234 mole) sodium azide are carefully added in solid form, the mixture is stirred for 3 hours at 2°, poured onto ice and the resulting suspension worked up in known manner to give 9-amino-3,4-dimethoxy-phenanthrene as a solid. The hydrochloride melts at over 215° with decomposition, b) 9-acetylamino-3,^dimethoxy^ghenanthrene [compound of formula IX] ml (0.319 mole) N-ethyldiisopropylamine are added to a solution of 38.2 g (0.151 mole) 9-amino3,4-dimethoxy-phenanthrene in 200 ml methylene chloride. To the resulting mixture is added dropwise over 20 minutes a solution of 20.8 ml (0.292 mole) acetyl chloride in 250 ml methylene chloride. During the addition, the temperature of the reaction mixture is maintained at 20° by cooling with a ice bath.
The reaction mixture is stirred for 14 hours at lo room temperature and worked up in known manner to afford 9-acetylamino-3,4-dimethoxy-phenanthrene; M.pt. 190-195° after recrystallisation from ether . c) 9-ethylamino-3,42dimethoxy-ghenanthrene [compound of formula VIII] 34 g (0.124 mole) 9-acetylamino-3,4dimethoxy-phenanthrene in suspension in 450 ml anhydrous tetrahydrofuran are reduced with 500 ml (0.5 mole) of a molar solution of diborane in anhydrous tetrahydrofuran and worked up in known manner to give 9-ethylamino-3,420 dimethoxy-phenanthrene; M.pt. 94-95°. d) 4i5-dihydro-9L102dimethoxy25-ethyl^4-oxo-dibenz[cd^f]indole [compound of formula VII 122 ml [0.2 mole) of a 15% solution of n^butyl-lithium in hexane are added at 0°, under a nitrogen atmosphere , to a solution of 28.1 g (0.1 mole) of 9-ethylamino-3,4-dimethoxy-phenanthrene in 300 ml anhydrous tetrahydrofuran; the reaction mixture becomes bright red,Dry ice is then added until the colouration disappears : the formation of a solution χ0 with yellow-green fluorescence is observed. After the temperature of the reaction mixture is allowed to reach room temperature, the mixture is poured onto water/ice, extracted three times with methylene chloride and the organic phase dried over sodium sulfate and evaporated. There is thus obtained 4,5-dihydro-9,10-dimethoxy-5-ethyl-4-oxo-dibenz[cd,f ]— indole which melts at 125-126° (vzith decomposition) after crystallisation from ether/petroleum ether, e, (£PS^-5-etny 1-4, 4-n-gropyl-dibenz[cd,fl indole_ [compound of formula XII] 2.1 ml (33 mM) of a solution of n-propylmagnesium bromide in ether are added dropwise at room temperature to a solution of 10 g (33 mM) of 4,5-dihydro9,10-dimethoxy-5-e thy1-4-oxo-dibenz[cd,f]indole in 300 ml anhydrous tetrahydrofuran. After 30 minutes, a solution of ammonium chloride is added, the mixture extracted with methylene chloride and the organic phase dried and evaporated to give (4RS)-5-ethyl4,5-dihydro-4~hydroxy-9,10-dimethoxy-4-n-propyl-dibenz fed,£]indole in the form of a yellow green foam. flR Spectrum (CH2C12) s 3540 cm 1 (OH)]. The crude product is directly used for the next step.
EXAMPLE 3: (-)- (4R*, 5aS*) -S-ethyl-^a^Sa^lS-tetrahydro;;9i10-dih^drox^-4-n-grogvl-dibenz^cdif ]_indole 10 20 g (27..66 mM) (ί) - (4R*, 5aS*)-5-ethyl4,5,5a,C-tetrahydro-9,lO-dimethoxy-4-n-propyl-dibenz fed,f)indole in 200 ml of a 47% aqueous solution of hydrobromic acid are warmed for 6 hours at reflux, at a bath temperature of 150°. After evaporation of the reaction mixture to dryness, the crystalline residue is stirred in acetone and filtered under suction. The precipitate is washed with acetone then with ether and dried under high vacuum. There is thus obtained {-)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetra20 hydro-9,10-dihydroxy-4-n-propyl-dibenz[cd,f]indole hydrobromide which melts at 200° with decomposition.
The following compounds may be prepared in analogous manner from the appropriate starting materials : a) (-)- (4R*,5aS*)-4,5-diethyl-4,5,5a,6-tetrahydro-9,1Odihydroxy-dibenz[cd,f)indole(hydrobromide, M.pt >175° with decomposition); b) (-)-(4Λ*,5aS*)-4,5,5a,6-tetrahydro-9,10-dihydroxy5 4,5-di-n-propy1-diben 2[cd,f]indole(hydrobromide, M.pt>190° with decomposition). c) (-)-(4R*,5aS*)-4-ethy1-4,5,5a,6-tetrahydro-9,10dihydroxy-5-n-propyl-dibenz[cd,f) indole .
EXAMPLE 4 : (-)-(4S,SaR)-5-ethyl-4,5,5a,6-tetrahydro10 9,10-dihydroxy-4-n-propyl-dibenz[cd,f) indole a) {-) - j 4S£5aR) ^S-e thy 1-4,5, Saj^te trahvdro^SjJO^ dimethoxy-4-n-prop^)-di ben ?._[cd£fl. indole g (89 mM) of (^)-(4R*,5aS*)-5-ethyl15 4,5,5a, 6-tetrahydro-9,10-dime thoxy-4-_rv-propyl-dibenz [cd,flindole are dissolved in 300 ml ether and a solution of 35.95 g of (-)-di-0,0-p-toluoyl—Ltartaric acid monohydrate in 300 ml ether is added with stirring. The mixture is further stirred for one hour at room temperature, a total of 1 litre ether being added in portions during this period. The resultant precipitate is filtered off under suction, washed with ethyl acetate until it remains light yellow, and dried. 61.88 g of the crystals obtained frcm the first crystallisation are dissolved in 1 litre acetcnc and 300 ml mathanol at reflux and the solution is filtered and concentrated until a major part of the product crystallizes out.
The mixture is stirred for about 15 minutes, the product is filtered off under suction, washed with ethyl acetate until it remains colourless and dried.
The resulting product is recrystallised in the same manner by using 1.7 litres acetone and 35 ml methanol to qive colourless crystals.
The resulting crystals are recrystallised in the same manner, by using 1.2 litres acetone and 60 ml methanol. There is thus obtained (-)- (4S,5aR)-5-ethy1-4,5,5a,6-tetrahydro-9,10-dimethoxy15 4-n-propyl-dibenz[cd,f]indole (-)-di-0,0-p-toluoylL-tartrate in form of colourless crystals which melt at 178-179°; [a]* =-138° (c= 0.29 in methanol).
The following compounds may be prepared in analogous manner from the appropriate starting materials: _ )- (4s,5aR)-4,5-diethy1-4,5,5a,6-tetrahydro9, ΙΟ-dime thoxy-dibenz (cd, f] indole (-)-di-O,O-ptoluoy 1-1.-tartrate, M.pt 187-189°; (σ]θ°= -138° (c=0.5 in methanol); the racemic starting material is reacted first with (+)-di-O.O-p-toluoyl-Dtartaric acid instead of the L—isomer and the mother liquor obtained on crystallisation is treated with NHjOH to liberate the base. The base is reacted 5 with (-)-di-0,0-p-toluoyi-L-tartarie acid and the crystals obtained from an ether solution. - (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dimethoxy4,5-di-n-propyl-dibenz[cd,f]indole (-)-di-O,O-ptoluoyl-L-tartrate, M.pt 165-166°; [α]^° = -123° (c = 0.27 in methanol). b) (-)- KJbSaRb^S-ethyl-^SJjaJj-tetrahydro^Siig;; dihydroxyi4-n2gropyl-dibenz^cd±f^indole Proceding as described in Example 3, (-) - (4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy 15 4-n-propyl-dibenz[cd,f)indole hydrobromide is obtained from the tartrate obtained above under a). It melts above 210°; [α)θ° - -64° (c = 0.245 in methanol).
The corresponding hydrochloride malts at above 185° with decomposition; [a] 20 = -75° (c = 0.28 in methanol).
EXAMPLE 5: The following compounds may be prepared in analogous manner as described in Example 4b) from the appropriate starting materials: a) (-)-(4S,5aR)-4,5-diethy 1-4,5,5a,6-tetrahydro-9,1020 dihydroxy*-dibenz [cd, f] indole hydrochloride.M.pt. 200° vith 20 decomposition; [α]β = -72° (c = 0.25 in methanol); b) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dihydroxy-4,5-dirt-propyl-dibenz [cd, f] indole hydrochloride, M.pt ^187° with decomposition; [α]θ° = -58.5° (c = 0.35 in methanol). c) (-)- (4S,5aR)-4-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy5-n-propyl-dibenz[cd,f]indole · EXAMPLE 6: (+)-(4S,5aR)-5-ethy1-9,lO-dibcnzoyloxy4,5,5a,6-tetrahydro-4-n-propyl-dibenz[cd,f] indole 0.376 ml (3.23 mM) of benzoyl chloride are added dropwise with stirring, over 5 minutes and at a temperature of +5°, to a solution of 600 mg (1.54 mM) of (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro15 9,lO-dihydroxy-4-ii-propyl-dibenz[cd,f]indole hydrobromide in 5 ml anhydrous pyridine and the reaction mixture is further stirred for 14 hours at room temperature. The mixture is then evaporated to dryness, the residue is dissolved in methylene chloride and the solution is washed first witn a mixture of ice and a saturated solution of potassium bicarbonate, and then with water. The aqueous phases are extracted twice with methylene chloride and .the caibined organic §1341 phases are dried and evaporated. The residue is dissolved in methylene chloride and the solution evaporated under high vacuum. The procedure of dissolving the residue in methylene chloride and evaporating is repeated twice more, 550 mg of the resulting product are dissolved in acetone and this solution is added dropvise to a solution of 156 mg L(+)-tartaric acid in acetone. The resultant precipitate is filtered off and dried -to give (+)-(4S,5aR)-5-ethy1-9,10-dibenzoyloxy4,5,5a,6-tetr ally dro-4-npprcpy 1-dibenz [ cd,f]indole 1,(+) tartrate; it melts at 161-162° after crystallisation in ethyl acetate/e ther; [α]θ^= +23.5° (c - 0.28 in methanol).
The following compounds may be prepared in analogous manner from the appropriate starting materials - . (r)-(4S,5aR)-9,10-diacetoxy-5-ethy1-4,5,5a,6-tetrahy dro-4-n-propy1-dibenz(cd,f) indole hydrochloride, M.pt ^188° (with decomposition); [α]^θ= -99° 2q (c = 0.28 in methanol); - (-)-(4S,5aR)~5-ethy1-4,5,5a,6-tetrahydro-4-npropyl-9,10-dipropionyloxy-dibenz[cd,f) indole hydrochloride, M.pt ^175° (with decomposition); [a)p°= -76° (c = 0.25 in methanol); - (-)-(4S,5aR)-9,10-dibutyryloxy-5-ethyl-4,5,5a,622 tetrahydro-4-n-propyl-dibenz (cd, ΐ] ir.dole hydrochloride, M.pt >105° (with deccnpceition); [η)2θ= -77 (c=O.?8 in methanol) - (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10diisobutyryloxy-4-n-propyl-dibenz[al,f]indole hydrochloride, ΛΛ M.pt >165 (with decnriXffiiticn)'; (ti]^ =-96 (c=0,29 in methanol). " (-)"(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-4-npropyl-9,10-divaler.yloxy-dibenz (cd, f) indole hydrochloride; " (-)- (4S, 5aR)-5-ethyl-4,5,5a, 6-tetrahydro-4-ii10 propyl-9,10-dipivaloyloxy-dibenz[cd,f) indole hydrochloride: - (-)-(4S,5aR)-4,5,5a,6 -tetrahydro-9,10-dipropionyloxy4,5-di-n-propyl-dibenz[cd,f]indole, M.pt. 115°; [a]20 =-67° (c = 0.51 in methanol).
X5 In analogous manner to Example ό, the following compounds of formula I wherein R^ and R^ are each independently ethyl or n-propyl and Rg is - acetoxy - propionyloxy - butyryloxy - isobutyryloxy - valeryloxy - pivaloyloxy may be prepared .
The compounds of formula I possess pharmacological activity. In particular, the compounds are indicated for use as central dopaminergic stimulant agents, as indicated by the following standard tests: The dopaminergic activity of compounds of formula I was studied in the rat according the method described by U. Ungerstedt in Acta Physiol. Scand., Suppl. 367, 69-93 (1971). 6-hydroxydopamine is unilaterally injected in the substantia nigra which pro10 duces, after a week, unilateral degeneration of nigrostriatal pathways. Administration of from about 0.03 to about 1 mg/kg i.p. of the compounds of formula I to these rats leads to a notable turning behaviour of long duration contralateral to the lesion.
The central dopaminergic activity of compounds of formula I has been also confirmed according the following test.
Rats, 180-222 g, are placed in perspex (Trade Mark) cylinders of 30 cm diameter on a wire grid floor.
After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed for 2 minutes at 30 minutes intervals for 2 hours and then at 60 minutes intervals for total of up to 6 hours. The degree of stereotyped behaviour observed is assessed using a scoring system based on that described by Costall, Naylor and Olley [Euro J. Pharmac. 18, 83-94 (1972].
The scores and criteria are as follows : 1. Intermittent sniffing 2. Persistent sniffing, occasional licking 3. Licking, occasional biting 4. Intense and persistent biting.
Administered i.p. from about 0.03 to about 30 mg/kg animal body weight, the compounds of formula I induce stereotyped sniffing, licking and biting behaviour in the rat.
The compounds are therefore indicated for use as central dopaminergic stimulant agents, for example for treating Morbus Parkinson. Por this indication, an indicated daily dose is from about 0.1 to about 20 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.025 to about 10 mg, or in sustained release form.
The compounds of the invention exhibit furthermore anti-depressant activity, as indicated by the inhibition of catalepsy induced by reserpine in mice on s.c. administration of about 0.001 mg to about 1 mg/kg of the compounds and by the inhibition of the catalepsy induced by tetrabenazine in rats on i.p. administration of about 0.2 tb about 2 mg/kg of the compounds.
The compounds are therefore indicated 5 for use as anti-depressant agents.
An indicated daily dosage is in the range from about 0.05 to about 2 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 0.01 mg to about 1 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The compounds of formula I exhibit furthermore prolactin secretion inhibition as indicated by the lowering of serum levels of prolactin of the rat after s.c. administration of from about 0.1 to about 1 mg/kg of the compounds, using radio-immunological techniques, e.g. described by Niswender, G.D. et al., Biol. & Med. 130, 793 (1969) and Neil, J.J. et al., Endocrinology 88, 548 (1971).
The compounds of formula I are therefore indicated for use as prolactin inhibitors, e.g. in the treatment of conditions involving hyperprolactinemia, such as menstrual dysfunctions, e.g. ammenorrhea and galactorrhea, or hypertension of mammary carcinoma asso25 ciated with elevated serum prolactin levels, or in the treatment of conditions involving hypogonadism, e.g. infertility or impotence, or in the regulation of post-partem lactation.
An indicated daily dosage is in the range 5 from about 5 to about 50 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 1.25 mg to about 25 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The compounds of the invention exhibit furthermore antipsychotic activity as indicate by the inhibition of the locomotion in mice on s.c. administration Of from about 0.001 mg to about 0.1 mg/kg of the compounds and by the dopamine agonistic action on the presynaptic receptors of the rat at doses of from about 1 mg to about 10 mg/kg of the compounds, according the following test.
The dopamine agonistic action of the compounds of formula I on the presynaptic receptors was studied on the rat using the in vivo method described by J.R. Walters and coll, in Naunyn Schmiedeberg's Arch. Pharmacol. 296, 5-14 (1976). The dopaminergic inpulse flow was inhibited pharmacologically by ^-butyrolactone. The activity of the aromatic amino acid decarboxylase was inhibited by hydroxy27 benzyIhydrazine (NSD 1015) and half an hour later the rats were sacrificed. The resulting accumulation of DOPA during 30 minutes in striatal tissue was taken as a measure of the in vivo activity of tyrosine hydroxylase. Administration per os of the compounds reversed the effects of /-butyrolactone in a dose dependent manner.
The compounds of formula I are therefore indicated for use as antipsychotic agents, for example for the treatment of schizophrenia. An indicated daily dosage is in the range from about 0.01 to about 1 mg, conveniently given in divided doses 2 or 4 times a day in unit dosage form containing from about 0.0025 mg to about 0.5 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The preferred indication is the antiparkinson indication.
The compounds (4S,5aR)-5-ethyl-4,5,5a,620 tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz[cd,f] indole, (4S, 5aR)-4-ethyl-4, 5, 5a, 6-tetra'nydro-9,10dihydroxy-5-n-propyl-9,10-dihydroxy-dibenz[cd,f]indole, (4S,5aR)-4,5-diethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy dibenz[cd,f]indole and (4S,5aR)-4,5,5a,6-tetrahydro25 9,10-dihydroxy-4,5-di-n-propyl-dibenz[cd,f]indole and the corresponding di-n-propionyl-and di-isobutyrylester-derivatives are the preferred compounds.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. These salt forms exhibit the same order of activity as the free base forms.
The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutically acceptable diluent or carrier.
These compositions may be formulated in conventional manner so as to be, for example, a solution, a capsule or a tablet.
Claims (7)
1. A process for the production of a compound of formula I wherein and R 2 independently are ethyl or n-propyl radicals, and the R 3 substituents are the same and are hydroxy or acyloxy radicals, in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR, which comprises a) producing a compound of formula Ia Ia wherein Rj, and R 2 are as defined above, by splitting the ether groups Z of a compound of formula II wherein R^ and Rj are defined above and Z is a splittable ether group, in racemic form having the relative configuration 4R*,5aS*,or in optically active isaner form having the absolute configuration 4S,5aR, or b) producing a compound of formula lb wherein Rj and Rj are defined above and the radicals R^ are identical acyloxy radicals,by acylating a compound of formula Ia in racemic form having the relative configuration 4R*,5aS* or in optically active isomer form having the absolute configuration 4S,5aR.
2. A process for the production of a compound of formula I defined in Claim 1 substantially as hereinbefore described with reference to any one of the examples 3 to 6.
3. A compound of formula I whenever produced by a process as claimed in Claim 1. S1341 4. A compound of formula I as defined in Claim 1. 5. A compound of Claim 4 wherein each R g is hydroxy. 6. A compound of Claim 4 wherein each R^ is acyloxy. 7. A compound of claim 6 wherein each acyloxy radical is of formula R - CO - 0a wherein R g is an alkyl radical, (C 3 _y)cyeloalkyl, a phenyl radical or a 5- or 6-membered heterocyclic ring. 8. A compound of Claim 7 wherein R COOcl is propionyloxy. 9. A compound of Claim 7 wherein R^COOis isobutyryloxy. 10. A compound of any one of Claims 4 to 9 wherein Rj and R 2 are each ethyl. 11. A compound of any one of Claims 4 to 9 wherein R^ and R 2 are each n-propyl. 12. A compound of any one of Claims 4 to 9 wherein R^ is ethyl and R 2 is n-propyl. 13. A compound of any one of Claims 4 to 9 wherein is n-propyl and R 2 is ethyl. 14. A compound of any one of Claims 4 to 13 in racemic form having the relative configuration
4. R*,5aS*. 15. A compound of any one of Claims 4 to 13 in optically active isomer form having the absolute
5. Configuration 4S,5aR. 16. (-)-(4R* f 5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-4-n-propy1-dibenz[cd,f]indole. 17. (-)-{4R*,5aS*)-4,5-diethyl-4,5,5a,6tetrahydro-9,10-dihydroxy-dibenz[cd,f]indole.
6. 10 18. (-)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10dihydroxy-4,5-di-n-propy1-dibenz[cd,f]indole, 19. (-)-(4R*,5aS*)~4-ethy1-4,5,5a,6-tetrahydro-9, 10-dinydroxy-5-n-propy1-dibenz[cd,f]indole. 20. (4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro15 9,10-dihydroxy-4-n-propyl-dibenz[cd,f]indole. 21. (4S,5aR)-4-ethy1-4,5,5a,6-tetrahydro9, 10-dihydroxy-5-n-propy1-dibenz[cd,f]indole. 22. (4S,5aR)-4,5-diethyl-4,5,5a,6-tetrahydro-9 ,10-dihydroxy-dibenz[cd,f]indole. 20 23. (4S,5aR)-4,5,5a,6-tetrahydro-9,lOdihydroxy-4,5-di-n-propy1-dibenz[cd,f]indole. 24. (4S,5aR)-5-ethyl-9,10-dibenzoyloxy4,5,5a,6-tetrahydro-4-n-propy1-dibenz[cd,f]indole. 25. (4S,5aR)-9,10-diacetoxy-5-ethyl-4,5,5a,6tetrahydro-4-n-propyl-dibenz[cd,f]indole. 2 6. {4S, 5 aR)-5-ethy1-4,5,5a,6-tetrahydro4-n-propyl-9,10-dipropionyloxy-dibenz[cd,f]indole. 5 27. (4S,5aR)-9,10-dibutyryloxy-5-ethyl4,5,5a,6-tetrahydro-4-n-propyl-dibenz[cd,f]indole. 28. (4S, 5aR)-5-ethyl-4,5,5a,6-tetrahydro9,10-diisobutyryloxy-4-n-propyl-dibenz[cd, f ]indole. 29. (4S,5aR)-4,5,5a,6-tetrahydro-9,1010 dipropionyloxy-4,5-di-n-propyl-dibenz[cd,f]indole. 30. A compound of any one of Claims 4 to 29 in free base form. 31. A compound of any one of Claims 4 to 29 in acid addition salt form.
7. 15 32. A pharmaceutical composition which comprises a compound of any one of Claims 4 to 29, in free base form or in pharmaceutically acceptable acid addition salt form,in association with a pharmaceutical carrier or diluent.
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AU (1) | AU546599B2 (en) |
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DE (1) | DE3124086A1 (en) |
DK (1) | DK285481A (en) |
ES (3) | ES503432A0 (en) |
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AT381090B (en) * | 1983-04-12 | 1986-08-25 | Sandoz Ag | MANUFACTURE OF NEW (4R *, 5AS *) 2,4,5-TRIALKYLCH8204132231 / 8 |
US4795759A (en) * | 1985-07-27 | 1989-01-03 | Sandoz Ltd. | Use of dibenz(CD,F)indoles |
US5422861A (en) * | 1989-09-01 | 1995-06-06 | Quantronix, Inc. | Measuring method and apparatus |
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