IL97308A - 6-Substituted-hexahydrobenz (cd) indoles process for their preparation and pharmaceutical compositions containing them - Google Patents

6-Substituted-hexahydrobenz (cd) indoles process for their preparation and pharmaceutical compositions containing them

Info

Publication number: IL97308A
Authority: IL; Israel
Prior art keywords: alkyl; hydrogen; compound; formula; substituted
Prior art date: 1990-02-26

Application number

IL9730891A

Other languages

English (en)

Other versions

IL97308A0 (en

Original Assignee

Lilly Co Eli

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1990-02-26

Filing date

1991-02-20

Publication date

1996-10-31

1990-02-26 Priority claimed from US07/482,811 external-priority patent/US5204340A/en

1991-02-20 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

1992-05-25 Publication of IL97308A0 publication Critical patent/IL97308A0/xx

1996-10-31 Publication of IL97308A publication Critical patent/IL97308A/en

Links

238000000034 method Methods 0.000 title claims description 45
238000002360 preparation method Methods 0.000 title claims description 25
239000008194 pharmaceutical composition Substances 0.000 title claims description 6
230000008569 process Effects 0.000 title claims description 6
-1 6-Substituted-hexahydrobenz (cd) indoles Chemical class 0.000 title abstract description 55
150000001875 compounds Chemical class 0.000 claims description 113
125000000217 alkyl group Chemical group 0.000 claims description 87
239000001257 hydrogen Substances 0.000 claims description 65
229910052739 hydrogen Inorganic materials 0.000 claims description 65
150000002431 hydrogen Chemical group 0.000 claims description 37
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
150000003839 salts Chemical class 0.000 claims description 21
125000003118 aryl group Chemical group 0.000 claims description 20
229910052757 nitrogen Inorganic materials 0.000 claims description 16
125000003342 alkenyl group Chemical group 0.000 claims description 14
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
125000003107 substituted aryl group Chemical group 0.000 claims description 12
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
239000004480 active ingredient Substances 0.000 claims description 11
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
125000000753 cycloalkyl group Chemical group 0.000 claims description 11
229910052760 oxygen Inorganic materials 0.000 claims description 11
239000001301 oxygen Substances 0.000 claims description 11
230000000903 blocking effect Effects 0.000 claims description 10
229910052717 sulfur Chemical group 0.000 claims description 10
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
239000003054 catalyst Substances 0.000 claims description 9
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 9
239000011593 sulfur Chemical group 0.000 claims description 9
125000003545 alkoxy group Chemical group 0.000 claims description 8
239000003814 drug Substances 0.000 claims description 8
125000000623 heterocyclic group Chemical group 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 8
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
239000003085 diluting agent Substances 0.000 claims description 5
125000001188 haloalkyl group Chemical group 0.000 claims description 5
229910052763 palladium Inorganic materials 0.000 claims description 5
239000000546 pharmaceutical excipient Substances 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 4
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 3
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
230000004075 alteration Effects 0.000 abstract description 4
201000010099 disease Diseases 0.000 abstract description 4
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 66
239000000203 mixture Substances 0.000 description 39
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 32
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 32
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
238000006243 chemical reaction Methods 0.000 description 27
239000000243 solution Substances 0.000 description 27
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical group C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 16
239000002904 solvent Substances 0.000 description 16
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
238000007327 hydrogenolysis reaction Methods 0.000 description 13
239000003921 oil Substances 0.000 description 13
239000000047 product Substances 0.000 description 13
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
239000003153 chemical reaction reagent Substances 0.000 description 11
235000019439 ethyl acetate Nutrition 0.000 description 11
238000009472 formulation Methods 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
229920002472 Starch Polymers 0.000 description 10
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 10
229940093499 ethyl acetate Drugs 0.000 description 10
235000019698 starch Nutrition 0.000 description 10
239000002253 acid Substances 0.000 description 9
238000004458 analytical method Methods 0.000 description 9
239000000543 intermediate Substances 0.000 description 9
239000008107 starch Substances 0.000 description 9
238000003786 synthesis reaction Methods 0.000 description 9
NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 8
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
238000005481 NMR spectroscopy Methods 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
150000001414 amino alcohols Chemical class 0.000 description 8
235000019359 magnesium stearate Nutrition 0.000 description 8
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
102000005962 receptors Human genes 0.000 description 8
108020003175 receptors Proteins 0.000 description 8
150000003335 secondary amines Chemical class 0.000 description 8
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
229960000583 acetic acid Drugs 0.000 description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
230000027455 binding Effects 0.000 description 7
230000015572 biosynthetic process Effects 0.000 description 7
150000002118 epoxides Chemical class 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
KJLFFCRGGGXQKE-UHFFFAOYSA-N 1h-indole-6-carboxamide Chemical class NC(=O)C1=CC=C2C=CNC2=C1 KJLFFCRGGGXQKE-UHFFFAOYSA-N 0.000 description 6
ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
101150041968 CDC13 gene Proteins 0.000 description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
229910021529 ammonia Inorganic materials 0.000 description 6
239000001913 cellulose Substances 0.000 description 6
235000010980 cellulose Nutrition 0.000 description 6
229920002678 cellulose Polymers 0.000 description 6
238000002425 crystallisation Methods 0.000 description 6
230000008025 crystallization Effects 0.000 description 6
239000000463 material Substances 0.000 description 6
150000004702 methyl esters Chemical class 0.000 description 6
230000000707 stereoselective effect Effects 0.000 description 6
125000001424 substituent group Chemical group 0.000 description 6
239000003826 tablet Substances 0.000 description 6
238000004809 thin layer chromatography Methods 0.000 description 6
GHTDODSYDCPOCW-UHFFFAOYSA-N 1h-indole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C=CNC2=C1 GHTDODSYDCPOCW-UHFFFAOYSA-N 0.000 description 5
230000006870 function Effects 0.000 description 5
239000007903 gelatin capsule Substances 0.000 description 5
230000002829 reductive effect Effects 0.000 description 5
239000007858 starting material Substances 0.000 description 5
238000003756 stirring Methods 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
229930006000 Sucrose Natural products 0.000 description 4
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 4
125000002252 acyl group Chemical group 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
239000002775 capsule Substances 0.000 description 4
239000003795 chemical substances by application Substances 0.000 description 4
238000001914 filtration Methods 0.000 description 4
239000004615 ingredient Substances 0.000 description 4
AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 description 4
210000003739 neck Anatomy 0.000 description 4
239000012074 organic phase Substances 0.000 description 4
239000003960 organic solvent Substances 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
229940076279 serotonin Drugs 0.000 description 4
239000000741 silica gel Substances 0.000 description 4
229910002027 silica gel Inorganic materials 0.000 description 4
239000005720 sucrose Substances 0.000 description 4
235000002906 tartaric acid Nutrition 0.000 description 4
239000011975 tartaric acid Substances 0.000 description 4
238000005406 washing Methods 0.000 description 4
125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 3
GSKGPIBNCNXXEJ-UHFFFAOYSA-N 1H-indole-6-carbothioic S-acid Chemical compound N1C=CC2=CC=C(C=C12)C(O)=S GSKGPIBNCNXXEJ-UHFFFAOYSA-N 0.000 description 3
QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
208000019901 Anxiety disease Diseases 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 3
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 3
150000001298 alcohols Chemical class 0.000 description 3
125000003277 amino group Chemical group 0.000 description 3
230000036506 anxiety Effects 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
239000012267 brine Substances 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
239000011575 calcium Substances 0.000 description 3
229910002091 carbon monoxide Inorganic materials 0.000 description 3
150000001733 carboxylic acid esters Chemical group 0.000 description 3
230000003197 catalytic effect Effects 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
238000005859 coupling reaction Methods 0.000 description 3
239000012039 electrophile Substances 0.000 description 3
125000004494 ethyl ester group Chemical group 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
239000000796 flavoring agent Substances 0.000 description 3
239000012362 glacial acetic acid Substances 0.000 description 3
229910052736 halogen Inorganic materials 0.000 description 3
125000005843 halogen group Chemical group 0.000 description 3
150000002367 halogens Chemical class 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
150000002475 indoles Chemical class 0.000 description 3
150000002476 indolines Chemical class 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000010410 layer Substances 0.000 description 3
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
239000001267 polyvinylpyrrolidone Substances 0.000 description 3
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
239000000843 powder Substances 0.000 description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
238000010926 purge Methods 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
238000000926 separation method Methods 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
239000007787 solid Substances 0.000 description 3
239000000829 suppository Substances 0.000 description 3
239000000454 talc Substances 0.000 description 3
229910052623 talc Inorganic materials 0.000 description 3
235000012222 talc Nutrition 0.000 description 3
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
XCALUCYILVSFSA-GJZGRUSLSA-N (2ar,4s)-4-(dipropylamino)-1,2,2a,3,4,5-hexahydrobenzo[cd]indole-6-carbonitrile Chemical compound C1NC2=CC=C(C#N)C3=C2[C@H]1C[C@H](N(CCC)CCC)C3 XCALUCYILVSFSA-GJZGRUSLSA-N 0.000 description 2
RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 2
108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 2
MTSYZAHZABCWMS-UHFFFAOYSA-N 6-bromo-2,3-dihydro-1h-indole Chemical compound BrC1=CC=C2CCNC2=C1 MTSYZAHZABCWMS-UHFFFAOYSA-N 0.000 description 2
KGCBZEKELZUOFI-UHFFFAOYSA-N 6-iodo-2,3-dihydro-1h-indole Chemical compound IC1=CC=C2CCNC2=C1 KGCBZEKELZUOFI-UHFFFAOYSA-N 0.000 description 2
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
125000006519 CCH3 Chemical group 0.000 description 2
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
206010020772 Hypertension Diseases 0.000 description 2
229920000168 Microcrystalline cellulose Polymers 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
201000001880 Sexual dysfunction Diseases 0.000 description 2
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
230000009858 acid secretion Effects 0.000 description 2
229910000147 aluminium phosphate Inorganic materials 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
150000001541 aziridines Chemical class 0.000 description 2
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JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
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KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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TWLXDPFBEPBAQB-UHFFFAOYSA-N orthoperiodic acid Chemical compound OI(O)(O)(O)(O)=O TWLXDPFBEPBAQB-UHFFFAOYSA-N 0.000 description 1
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QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
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DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
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WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
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CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
239000012056 semi-solid material Substances 0.000 description 1
239000000952 serotonin receptor agonist Substances 0.000 description 1
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230000000391 smoking effect Effects 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
235000010356 sorbitol Nutrition 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
238000013222 sprague-dawley male rat Methods 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000012058 sterile packaged powder Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
208000011117 substance-related disease Diseases 0.000 description 1
239000000758 substrate Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
230000002459 sustained effect Effects 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000007916 tablet composition Substances 0.000 description 1
FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
235000010487 tragacanth Nutrition 0.000 description 1
239000000196 tragacanth Substances 0.000 description 1
229940116362 tragacanth Drugs 0.000 description 1
238000012546 transfer Methods 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
238000000870 ultraviolet spectroscopy Methods 0.000 description 1
125000004417 unsaturated alkyl group Chemical group 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
239000000230 xanthan gum Substances 0.000 description 1
235000010493 xanthan gum Nutrition 0.000 description 1
229920001285 xanthan gum Polymers 0.000 description 1
229940082509 xanthan gum Drugs 0.000 description 1
229940071104 xylenesulfonate Drugs 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
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Indole Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

IL9730891A 1990-02-26 1991-02-20 6-Substituted-hexahydrobenz (cd) indoles process for their preparation and pharmaceutical compositions containing them IL97308A (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US48519490A	1990-02-26	1990-02-26
US07/482,811 US5204340A (en)	1989-04-11	1990-02-26	Tetrahydrobenz(c,d)indole serotonin agonists
US56798690A	1990-08-15	1990-08-15

Publications (2)

Publication Number	Publication Date
IL97308A0 IL97308A0 (en)	1992-05-25
IL97308A true IL97308A (en)	1996-10-31

Family

ID=27413631

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9730891A IL97308A (en)	1990-02-26	1991-02-20	6-Substituted-hexahydrobenz (cd) indoles process for their preparation and pharmaceutical compositions containing them

Country Status (16)

Country	Link
EP (1)	EP0444854B1 (de)
JP (1)	JP3135591B2 (de)
AT (1)	ATE143362T1 (de)
AU (1)	AU645779B2 (de)
BR (1)	BR9100769A (de)
DE (1)	DE69122281T2 (de)
DK (1)	DK0444854T3 (de)
ES (1)	ES2094789T3 (de)
FI (1)	FI102173B (de)
GR (1)	GR3021930T3 (de)
HU (1)	HU224213B1 (de)
IE (1)	IE76285B1 (de)
IL (1)	IL97308A (de)
NO (1)	NO176757C (de)
NZ (3)	NZ247227A (de)
PT (1)	PT96862B (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL97309A (en) *	1990-02-26	1996-11-14	Lilly Co Eli	Intermediates for hexahydrobenz Úcd¾ indoles and process for the preparation of pure enantiomers thereof
US5229410A (en) *	1990-08-15	1993-07-20	Eli Lilly And Company	6-substituted-hexahydrobenz[cd]indoles
EP0502418A1 (de) *	1991-02-26	1992-09-09	Basf Corporation	Verwendung von Levemopamil zur Herstellung eines Arzneimittels zur Behandlung von Alkoholmissbrauch
NZ314570A (en) *	1993-06-10	2000-11-24	Lilly Co Eli	Treatment of emesis using tetrahydrobenz[cd]indole-6-carboxamides
US5990114A (en) *	1996-02-28	1999-11-23	Recordati, S.A., Chemical And Pharmaceutical Company	Use of 5-HT1A receptor antagonists for the treatment of urinary incontinence

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL74222A (en) *	1984-02-06	1988-07-31	Lilly Co Eli	6-substituted-4-dialkylamino tetrahydrobenz(c,d)indoles,their preparation and pharmaceutical compositions comprising them
US5204340A (en) *	1989-04-11	1993-04-20	Eli Lilly And Company	Tetrahydrobenz(c,d)indole serotonin agonists
IL97309A (en) *	1990-02-26	1996-11-14	Lilly Co Eli	Intermediates for hexahydrobenz Úcd¾ indoles and process for the preparation of pure enantiomers thereof
TW219933B (de) *	1990-02-26	1994-02-01	Lilly Co Eli
US5039820A (en) *	1990-02-26	1991-08-13	Eli Lilly And Company	4-amino-6-iodo-hexahydrobenz(cd)indoles

1991
- 1991-02-20 IL IL9730891A patent/IL97308A/en not_active IP Right Cessation
- 1991-02-25 PT PT96862A patent/PT96862B/pt not_active IP Right Cessation
- 1991-02-25 HU HU9100628A patent/HU224213B1/hu active IP Right Grant
- 1991-02-25 NZ NZ247227A patent/NZ247227A/en unknown
- 1991-02-25 AU AU71970/91A patent/AU645779B2/en not_active Ceased
- 1991-02-25 IE IE62691A patent/IE76285B1/en not_active IP Right Cessation
- 1991-02-25 NO NO910736A patent/NO176757C/no unknown
- 1991-02-25 FI FI910896A patent/FI102173B/fi active
- 1991-02-25 NZ NZ237213A patent/NZ237213A/en unknown
- 1991-02-25 NZ NZ247226A patent/NZ247226A/en unknown
- 1991-02-26 BR BR919100769A patent/BR9100769A/pt not_active Application Discontinuation
- 1991-02-26 ES ES91301503T patent/ES2094789T3/es not_active Expired - Lifetime
- 1991-02-26 DK DK91301503.8T patent/DK0444854T3/da active
- 1991-02-26 EP EP91301503A patent/EP0444854B1/de not_active Expired - Lifetime
- 1991-02-26 DE DE69122281T patent/DE69122281T2/de not_active Expired - Fee Related
- 1991-02-26 JP JP03055929A patent/JP3135591B2/ja not_active Expired - Fee Related
- 1991-02-26 AT AT91301503T patent/ATE143362T1/de not_active IP Right Cessation
1996
- 1996-12-06 GR GR960403340T patent/GR3021930T3/el unknown

Also Published As

Publication number	Publication date
JP3135591B2 (ja)	2001-02-19
EP0444854A3 (en)	1992-02-26
NO176757B (no)	1995-02-13
PT96862B (pt)	1998-07-31
ES2094789T3 (es)	1997-02-01
HU224213B1 (hu)	2005-06-28
DE69122281T2 (de)	1997-03-06
IE910626A1 (en)	1991-08-28
PT96862A (pt)	1991-10-31
NO910736D0 (no)	1991-02-25
NO176757C (no)	1995-05-24
NZ237213A (en)	1994-06-27
BR9100769A (pt)	1991-10-29
FI910896A0 (fi)	1991-02-25
DK0444854T3 (da)	1996-11-11
AU7197091A (en)	1991-08-29
IE76285B1 (en)	1997-10-08
EP0444854B1 (de)	1996-09-25
ATE143362T1 (de)	1996-10-15
NO910736L (no)	1991-08-27
GR3021930T3 (en)	1997-03-31
FI102173B1 (fi)	1998-10-30
HUT56541A (en)	1991-09-30
JPH04211654A (ja)	1992-08-03
NZ247226A (en)	1994-06-27
AU645779B2 (en)	1994-01-27
NZ247227A (en)	1994-06-27
DE69122281D1 (de)	1996-10-31
FI102173B (fi)	1998-10-30
EP0444854A2 (de)	1991-09-04
IL97308A0 (en)	1992-05-25
FI910896L (fi)	1991-08-27

Legal Events

Date	Code	Title
1997-03-18	FF	Patent granted
1997-06-10	KB	Patent renewed
2001-06-14	KB	Patent renewed
2010-05-17	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
US5244912A (en)	1993-09-14	6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz(cd)indoles and pharmaceutical use thereof
US5302612A (en)	1994-04-12	6-substituted-hexahydrobenz[cd]indoles
US5229410A (en)	1993-07-20	6-substituted-hexahydrobenz[cd]indoles
US5244911A (en)	1993-09-14	6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indoles and pharmaceutical use thereof
AU645779B2 (en)	1994-01-27	6-substituted hexahydrobenz(cd)indoles
US5229409A (en)	1993-07-20	6-substituted-tetrahydrobenz[cd]indoles
CA2037100C (en)	2003-10-21	6-substituted-hexahydrobenz ¢cd! indoles
US5665744A (en)	1997-09-09	6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenzn [cd] indoles
KR0176247B1 (ko)	1999-03-20	6-치환된-헥사하이드로벤즈인돌
US5783590A (en)	1998-07-21	6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz CD!indoles
CA2049176A1 (en)	1992-02-16	6-substituted-hexahydrobenz [cd] indoles
HK1013824B (en)	2000-10-13	6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[cd]indoles