DK142115B - Analogifremgangsmaade til fremstilling af 2-(4-phenyl-4-cyanobutyl)-1,2,3,4-tetrahydro-5(h)-pyrido (4,3-b) indoler eller syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af 2-(4-phenyl-4-cyanobutyl)-1,2,3,4-tetrahydro-5(h)-pyrido (4,3-b) indoler eller syreadditionssalte deraf Download PDFInfo
- Publication number
- DK142115B DK142115B DK211077AA DK211077A DK142115B DK 142115 B DK142115 B DK 142115B DK 211077A A DK211077A A DK 211077AA DK 211077 A DK211077 A DK 211077A DK 142115 B DK142115 B DK 142115B
- Authority
- DK
- Denmark
- Prior art keywords
- pyrido
- tetrahydro
- acid addition
- addition salts
- acid
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 8
- -1 4-PHENYL-4-CYANOBUTYL Chemical class 0.000 title claims description 4
- 150000002475 indoles Chemical class 0.000 title claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- NJBMMMJOXRZENQ-UHFFFAOYSA-N 6H-pyrrolo[2,3-f]quinoline Chemical compound c1cc2ccc3[nH]cccc3c2n1 NJBMMMJOXRZENQ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 3
- 229960004046 apomorphine Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical class CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000000701 neuroleptic effect Effects 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- 0 *CCCC([C@]1C=C*(*)=C=CC1)=CC=N Chemical compound *CCCC([C@]1C=C*(*)=C=CC1)=CC=N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- VIUPTAFHLRBHBO-UHFFFAOYSA-N 2-phenylpentanenitrile Chemical class CCCC(C#N)C1=CC=CC=C1 VIUPTAFHLRBHBO-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- FEUBVJZHCNMKFH-UHFFFAOYSA-N 5-chloro-2-(4-fluorophenyl)pentanenitrile Chemical compound FC1=CC=C(C(CCCCl)C#N)C=C1 FEUBVJZHCNMKFH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000005967 Finkelstein reaction Methods 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940054053 antipsychotics butyrophenone derivative Drugs 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XRKQMIFKHDXFNQ-UHFFFAOYSA-N n-cyclohexyl-n-ethylcyclohexanamine Chemical compound C1CCCCC1N(CC)C1CCCCC1 XRKQMIFKHDXFNQ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Anesthesiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Description
(11) FREMLÆGGELSESSKRIFT 1^2115 DANMARK (ευ int.ci.3 c o? d 471/04 §(21) Ansøgning nr. 2110/77 (22) Indleveret den 13· maj 19 (24) Løbedag 13- maj 1977 (44) Ansøgningen fremlagt og fremlaeggelsesekriftet offentliggjort den 1 · Εβρ· 1 9 bi
Dl REKTORATET FOR
PATENT-OG VAREMÆRKEVÆSENET (3°) Priontet begæret fra dan
15. maj 1976, 2621729i DE
(72) C.H. BOEHRINGER SOHN, D-65O7 Ingelheim am Rhein, DE.
Opfinder: Adolf Langbein, Theodor-Fliedner-Etr. 45, 6507 Ingelheim/ Rhein, DE: Karl-Heinz Weber, Kaiser-Karl-Str. 11, 6535 Gau-Algesheim, DE: Adolf Bauer, Gabelsberger Str. 47, 8200 Rosenheim, DE: Karin Boeke, Selztalstr. 99, 6507 Ingelheim/Rhein, DE: Erich Lehr, Albert-Schweltzer-Str. 21b, 6531 Waldalgesheim, DE: Franz Josef KuHn, Melchiorstr. 6, 6530 Bingen/Rhein 13a DE.
(74) Fuldmægtig under sagens behandling:
Internationalt Patent-Bureau.
<54) Analogifremgangsmåde til fremstilling af 2-(4-phenyl-4-cyanobutyl)-132,3a4-tetrahydro-5(H)-pyrido(4,3-bJindoler eller syreadditionssalte deraf.
I US-patentskrifterne nr. 3.419.568, nr. 3.448.114 og nr. 3.466.293 er beskrevet butyrophenonderivater af tetrahydropyrido-indoler med den almene formel (i) (se formelblad), hvilke forbindelser har analgetiske og neuroleptiske egenskaber.
Det har nu vist sig, at der ved ændring af den ovenfor nævnte molekylstruktur kan tilvejebringes hidtil ukendte forbindelser, der med hensyn til deres farmakologiske egenskaber er de kendte derivater overlegne. Den foreliggende opfindelse angår derfor en analogifremgangsmåde til fremstilling af hidtil ukendte 2-(4-phenyl-4-cyanobutyl)-1,2,3,4-tetrahydro-5(H)-pyrido[4,3-b]indoler med den almene formel I (se formelblad) eller deres fysiologisk acceptable syreadditionssalte.
2 142115 I formlen I er R^" et hydrogen- eller halogenatom eller en me~ 2 thylgruppe, og R er et hydrogen- eller halogenatom eller en methyl-eller methoxygruppe.
Fremgangsmåden ifølge opfindelsen til fremstilling af de hidtil ukendte forbindelser med formlen I eller deres syreadditionssalte er ejendommelig ved, at en pyridoindol med den almene formel IX (se formelblad), hvor R^ er som ovenfor defineret, omsættes med et halogenid eller en aktiv ester af en substitueret 2-phenylvaleroni- 2 tril med den almene formel III (se formelblad), hvor R har ovennævnte betydning, og Y er en ved omsætningen fraspaltelig gruppe, især et halogenatom eller en arylsulfonyloxy- eller alkylsulfonyloxygrup-pe, og at det vundne produkt med formlen I, om ønsket, overføres i et fysiologisk acceptabelt syreadditionssalt.
Der anvendes den beregnede mængde af alkyleringsmidlet med formlen III eller et overskud deraf, og der arbejdes hensigtsmæssigt i nærværelse af et syrebindende stof, såsom triethylamin, dicyclo-hexylethylamin, natriumcarbonat, calciumcarbonat, calciumoxid eller fortrinsvis natriumbicarbonat. Selvom opløsningsmiddel kan udelades, er omsætning i indifferente opløsningsmidler, såsom chloroform, toluen, ethanol, nitromethan, tetrahyd.ro fur an eller fortrinsvis dimethylformamid, mere hensigtsmæssig. Reaktionstemperaturen kan varieres inden for vide grænser. Temperaturer mellem 50° og 150°C er hensigtsmæssige, fortrinsvis 100°C. Tilsætningen af katalytiske til molære mængder af kaliumiodid eller natriumiodid har vist sig gunstig.
De vundne reaktionsprodukter isoleres fra reaktionsblandingen ved kendte metoder, og eventuelt kan de således fremstillede råprodukter renses yderligere under anvendelse af særlige fremgangsmåder, f.eks. ved søjlechromatografi, førend de krystalliseres i form af baser eller egnede syreadditionsforbindelser.
Til fremstillingen af syreadditionssalte kan anvendes sådanne syrer, der danner fysiologisk acceptable salte, f.eks. hydrogen-halogenidsyrer, salpetersyre, svovlsyre, o-phosphorsyre, oxalsyre, citronsyre, vinsyre, fumarsyre, maleinsyre, propionsyre, smørsyre, eddikesyre, methansulfonsyre, toluensulfonsyre, sulfanilsyre, ravsyre eller ethanphosphonsyre.
Udgangsforbindelseme med den almene formel II kan fremstilles efter forskrifterne i DT—offentliggørelsesskrift nr. 1.67o.olo. Udgangsforbindelseme med den almene formel III vindes ved omsætning af et substitueret 2 benzylcyanid med den almene formel IV (se formelblad), hvor R er 3 142115 som ovenfor defineret, med l-chloro-3-bromo-n-propan. De vundne chlorider kan ved Finkelstein-reaktion overføres i andre halogeni-der. Ud fra halogeniderne er tilsvarende sulfonsyreestere med formlen III tilgængelige ved omsætning med sulfonsyreester.
De hidtil ukendte forbindelser med den almene formel 1 og deres syreadditionssalte viser det typiske virkningsbillede fpr neuroleptica og kan derfor anvendes som ZNS-dæmpende middel, som sedativa og beroligende midler. Kendte neuroleptica udmærker sig blandt andet ved antagonistiske virkninger over for adrenalin (P.A.J. Janssen et al., Arzneimittelforschung (Drug Research) 13 (1963) 205), amphetamin (J.H.Bura, R.Hobbs, Arch.inter.Pharmcodyn.
113 (1958) 290) og apomorfin ved dyreforsøg. Endvidere har de ved adfærdsprøver, såsom hulbrædtprøven, hæmmende virkning på udforskning (J.R.Borssin, P. Simin, J.M. Lwoff, Therapie 19 (1964) 571) og lokomotion (P.A.J. Janssen, A.H.M.Jagenau, K.H.L.Schellekens, Psychopharmacologia 1 (1960) 389). Endelig hæmmer de også den konditionerede adfærd hos smådyr, f.eks. ved Dobrin-prøven (P.B.
Dobrin et al., Arch.inter.Pharmacodyn 178 (1969) 351).
De omhandlede forbindelser er de tidligere nævnte kendte bu-tyrophenoner overlegne i henseende til deres neuroleptiske virkning. Endvidere skal fremhæves den væsentligt forringede toxicitet.
I nedenstående tabel er der for en række af de omhandlede forbindelser anført forsøgsresultater vedrørende apomorfinantagonis-me på mus, udtrykt som ED,-q, og toxicitet, udtrykt som LD^q, idet der som sammenligningsforbindelse er benyttet den kendte, særligt virksomme butyrophenonforbindelse 2-[4-(p-fluorophenyl)-4-oxybutyl]- 8-fluoro-l,2,3,4-tetrahydro-5(H)-pyrido[4,3-b]indol.
R1 .. r,—
il-i N - CH~ - CH0 - CH„ - A-e A
UCXj ^
H
142115 4
Forbindelse Apomorfin- LD50' p*°* η 0 antagonisme „ R1 R2 A ED5Qf mg/kg mg/kg
Sammenlignings- forbindelse: F 4—F >C0 23 270
Fremstillet ifølge opf.: F 4—F CH-CN 0,56 1400
Cl 4-F " 4,5 F H " 9,7 F 2-F " 6,8 F 3“CH3 " 14 F 3-OCH3 " 5 F 4-OCH3 " 0,52 H 4-F " 1,85
De ifølge opfindelsen fremstillede forbindelser kan anvendes alene eller i kombination med andre af de omhandlede virksomme forbindelser.
Fremgangsmåden ifølge opfindelsen beskrives nærmere gennem følgende eksempler.
Eksempel 1 2-[4-(p-Fluorophenyl)-4-cyanobutyl]-8-fluoro-1,2,3,4-tetrahydro-5(H)-pyrido[4,3-b]indol.
3,8 g (20mmol) 8-Fluoro-l,2,3,4-tetrahydro-5(H)-pyrido[4,3-b] indol, 4,2 g(20 mmol) 5-chloro-2-(p-fluorophenyl)-valeronitril, 2,52 g (30 mmol) natriumbicarbonat og 200 mg kaliumiodid blev i 50 ml dimethylformamid omrørt så længe ved 100°C, at der i tyndlagschroma-togrammet ikke længere kunne fastslås nogen omsætning (2 til 4 timer). Suspensionen blev inddampet ved 70°C på rotationsfordamper. Indamp-ningsresten blev fordelt mellem 250 ml methylenchlorid og 100 ml vand. Den organiske fase blev derefter rystet kraftigt 5 gange med hver gang 100 ml vand, tørret over natriumsulfat og inddampet. Der vandtes en gullig olie, der blev opløst i 15 ml ethanol. Efter tilsætning af 20 mmol ethanolisk saltsyre blev der forsigtigt tilsat ether, indtil uklarheden netop atter forsvandt. Efter nogen tid udkrystalliserede hydrochloridet af titelforbindelsen, der blev omkrystalliseret af alkohol/ether. Der vandtes 6,8 g hydrochlorid svarende til 85,2% af det teoretiske, med smp. 235-237°C.
Claims (2)
1421 1B 5 Analogt med eksempel 1 blev der fremstillet de i følgende tabel anførte derivater i form af deres hydrochlorider: Eksempel R1 R2 Udbytte smp. °C Nr._% af det teoretiske__ 2 8-C1 4-F 47,9 219 - 221 3 8-Br 4-F 34,6 215 - 218 4 8-F H 67,8 225 - 227 5 8-F 2-F 69,8 217 - 220 6 8-F 2-Br 67 237 - 239 7 8-F 3-CH3 33 208 - 211 8 8-F 3-OCH3 33,9 197 - 203 9 8-F 4-OCHj 31,4 191 - 195
10 H 4-F 78 135 - 143 11 8-CH3 4-f 30 153 " 160 12 8-F 2-CH3 67,8 215 - 217 13 8-F 4-CH3 78 219 “ 220 14 8-F 2-OCH3 62,9 203 - 207 15 8-F 3-cl 57,3 217 - 220 16 8-F 4-Cl 55 234 - 237 17 8-F 4-Br 88,7 233 - 235 Analogifremgangsmåde til fremstilling af 2-(4-phenyl-4-cyano-butyl)-1,2,3,4-tetrahydro-5(H)-pyrido[4,3-b]indoler med den almene formel I: R1 I '2 H R hvor R^· er et hydrogen- eller halogenatom eller en methylgruppe, og R er et hydrogen- eller halogenatom eller en methyl- eller methoxy-gruppe, eller syreadditionssalte deraf, kendetegnet ved, at en pyridoindol med den almene formel II:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2621729 | 1976-05-15 | ||
| DE19762621729 DE2621729A1 (de) | 1976-05-15 | 1976-05-15 | Neue 2-(4-phenyl-4-cyanobutyl)-1,2, 3,4-tetrahydro-5(h)-pyrido- eckige klammer auf 4,3-b eckige klammer zu -indole und verfahren zu ihrer herstellung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK211077A DK211077A (da) | 1977-11-16 |
| DK142115B true DK142115B (da) | 1980-09-01 |
| DK142115C DK142115C (da) | 1981-02-02 |
Family
ID=5978115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK211077A DK142115C (da) | 1976-05-15 | 1977-05-13 | Analogifremgangsmaade til fremstilling af 2-(4-phenyl-4-cyanobutyl)-1,2,3,4-tetrahydro-5(h)-pyrido(4,3-b)indoler eller syreadditionssalte deraf |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4085216A (da) |
| JP (1) | JPS52139099A (da) |
| AU (1) | AU506230B2 (da) |
| BE (1) | BE854643A (da) |
| CA (1) | CA1069508A (da) |
| CH (1) | CH632269A5 (da) |
| DE (1) | DE2621729A1 (da) |
| DK (1) | DK142115C (da) |
| ES (1) | ES458810A1 (da) |
| FI (1) | FI60708C (da) |
| FR (1) | FR2351116A1 (da) |
| GB (1) | GB1553645A (da) |
| GR (1) | GR66106B (da) |
| IE (1) | IE44951B1 (da) |
| IL (1) | IL52086A (da) |
| LU (1) | LU77333A1 (da) |
| MX (1) | MX4289E (da) |
| NL (1) | NL7705305A (da) |
| NO (1) | NO146240C (da) |
| NZ (1) | NZ184095A (da) |
| PH (1) | PH12203A (da) |
| PT (1) | PT66546B (da) |
| SE (1) | SE432422B (da) |
| ZA (1) | ZA772855B (da) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636563A (en) * | 1985-09-16 | 1987-01-13 | American Home Products Corporation | Antipsychotic γ-carbolines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR6909M (da) * | 1966-12-07 | 1969-04-28 |
-
1976
- 1976-05-15 DE DE19762621729 patent/DE2621729A1/de not_active Withdrawn
-
1977
- 1977-04-25 FI FI771306A patent/FI60708C/fi not_active IP Right Cessation
- 1977-05-03 GR GR53348A patent/GR66106B/el unknown
- 1977-05-09 US US05/794,937 patent/US4085216A/en not_active Expired - Lifetime
- 1977-05-12 MX MX775738U patent/MX4289E/es unknown
- 1977-05-12 CH CH596977A patent/CH632269A5/de not_active IP Right Cessation
- 1977-05-13 IE IE984/77A patent/IE44951B1/en unknown
- 1977-05-13 JP JP5520377A patent/JPS52139099A/ja active Pending
- 1977-05-13 DK DK211077A patent/DK142115C/da not_active IP Right Cessation
- 1977-05-13 NZ NZ184095A patent/NZ184095A/xx unknown
- 1977-05-13 BE BE177588A patent/BE854643A/xx not_active IP Right Cessation
- 1977-05-13 SE SE7705633A patent/SE432422B/xx unknown
- 1977-05-13 LU LU77333A patent/LU77333A1/xx unknown
- 1977-05-13 FR FR7714796A patent/FR2351116A1/fr active Granted
- 1977-05-13 IL IL52086A patent/IL52086A/xx unknown
- 1977-05-13 PT PT66546A patent/PT66546B/pt unknown
- 1977-05-13 GB GB20295/77A patent/GB1553645A/en not_active Expired
- 1977-05-13 NL NL7705305A patent/NL7705305A/xx not_active Application Discontinuation
- 1977-05-13 NO NO771695A patent/NO146240C/no unknown
- 1977-05-13 AU AU25130/77A patent/AU506230B2/en not_active Expired
- 1977-05-13 CA CA278,323A patent/CA1069508A/en not_active Expired
- 1977-05-13 PH PH19767A patent/PH12203A/en unknown
- 1977-05-13 ZA ZA00772855A patent/ZA772855B/xx unknown
- 1977-05-14 ES ES458810A patent/ES458810A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| US4085216A (en) | 1978-04-18 |
| IE44951L (en) | 1977-11-15 |
| ZA772855B (en) | 1979-01-31 |
| FI60708C (fi) | 1982-03-10 |
| GB1553645A (en) | 1979-09-26 |
| BE854643A (fr) | 1977-11-14 |
| PT66546A (de) | 1977-06-01 |
| IE44951B1 (en) | 1982-05-19 |
| DK142115C (da) | 1981-02-02 |
| PH12203A (en) | 1978-11-28 |
| NO146240B (no) | 1982-05-18 |
| SE432422B (sv) | 1984-04-02 |
| IL52086A0 (en) | 1977-07-31 |
| SE7705633L (sv) | 1977-11-16 |
| CH632269A5 (de) | 1982-09-30 |
| AU506230B2 (en) | 1979-12-20 |
| DE2621729A1 (de) | 1977-12-08 |
| ES458810A1 (es) | 1978-03-16 |
| LU77333A1 (da) | 1978-06-26 |
| NZ184095A (en) | 1979-08-31 |
| MX4289E (es) | 1982-03-16 |
| PT66546B (de) | 1979-04-12 |
| NO146240C (no) | 1982-08-25 |
| NL7705305A (nl) | 1977-11-17 |
| FI771306A7 (da) | 1977-11-16 |
| IL52086A (en) | 1979-12-30 |
| FR2351116B1 (da) | 1980-04-18 |
| NO771695L (no) | 1977-11-16 |
| DK211077A (da) | 1977-11-16 |
| JPS52139099A (en) | 1977-11-19 |
| GR66106B (da) | 1981-01-16 |
| AU2513077A (en) | 1978-11-16 |
| CA1069508A (en) | 1980-01-08 |
| FI60708B (fi) | 1981-11-30 |
| FR2351116A1 (fr) | 1977-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4076820A (en) | Benzoquinolizines and hypotensive compositions containing them | |
| US4254122A (en) | Triazine derivatives | |
| JPH0245629B2 (da) | ||
| US3120540A (en) | Bis (polymethyl)-4-piperidinol alkanoates | |
| NO852133L (no) | Analogifremgangsmaate for fremstilling av terapeutisk aktive pyrrolidinon-derivater. | |
| DK168010B1 (da) | Tetrahydroisoquinolinforbindelser og farmaceutisk middel indeholdende en saadan forbindelse | |
| US3751416A (en) | 3-(2-(4-phenyl-1-piperazinyl)-ethyl)indolines | |
| EP0328700A1 (en) | 4,7-Dihydropyrazolo(1,5-a)pyrimidine compound and pharmaceutical use thereof | |
| DK142115B (da) | Analogifremgangsmaade til fremstilling af 2-(4-phenyl-4-cyanobutyl)-1,2,3,4-tetrahydro-5(h)-pyrido (4,3-b) indoler eller syreadditionssalte deraf | |
| FR2522000A1 (fr) | Nouvelles thiopyrannopyrimidines, utiles notamment comme agents hypoglycemiants, et leur fabrication | |
| DK160875B (da) | Analogifremgangsmaade til fremstilling af 3,7-diazabicyklooe3.3.1aa-nonanforbindelser eller farmaceutisk acceptable syreadditionssalte deraf | |
| NO130329B (da) | ||
| EP0073645A2 (en) | 2-Cyclic amino-2-(1,2-benzisoxazol-3-yl)acetic acid ester derivatives, process for the preparation thereof and composition containing the same | |
| FI62664C (fi) | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara 6-piperazinyl-11-metylen-morfantridin-derivat | |
| HU192876B (en) | Process for producing 5,10-dihydro-11h-dibenzo/b,e//1,4/ diazepin-11-one derivatives substitutes at the 5 position and pharmaceutical compositions containing them | |
| FI63578C (fi) | Analogifoerfarande foer framstaellning av nya farmakologiskt verksamma 1,3,4,14b-tetrahydro-2h 10h-pyrazino(1,2-a)pyrrolo(2,1-c)(1,4)bensodiazepiner | |
| HU188178B (en) | Process for preparing 2-/acyl-amino-methyl/-1,4-benzodiazepine derivatives | |
| US3412097A (en) | Indole derivatives | |
| DK145225B (da) | Analogifremgangsmaade til fremstilling af 1-(3-trimethoxyphenoxy-2-hydroxy-propyl)-4-phenyl-piperazinderivater eller syreadditionssalte deraf | |
| PL163370B1 (pl) | Sposób wytwarzania nowych pochodnych 1-oksa-2-okso-8-azaspiro-[4. 5] dekanu PL PL | |
| NO743683L (da) | ||
| KR850000061B1 (ko) | 아미딘의 제조방법 | |
| DK145949B (da) | Analogifremgangsmaade til fremstilling af i 3-stillingen substituerede rifamycin s-forbindelser eller sv-forbindelser ellersyreadditionssalte eller kvaternaere ammoniumsalte deraf | |
| JPS6028825B2 (ja) | 新規トリアゾ−ル誘導体の製法 | |
| JPH0631231B2 (ja) | 抗精神病性４―［４―（３―ベンズイソチアゾリル）―１―ピペラジニルブチル架橋二環式イミド |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |