NO151862B - NEW HIGH-DETERGENT 5-ACRYL-2,3,4,4A, 5,9B-HEXSAHYDRO-1H-PYRIDO (4,3-B) -INDEAL DERIVATIVES SUITABLE FOR PREPARING SOFT-HEXING HYDRO-X CARBOLINE DERIVATIVES - Google Patents
NEW HIGH-DETERGENT 5-ACRYL-2,3,4,4A, 5,9B-HEXSAHYDRO-1H-PYRIDO (4,3-B) -INDEAL DERIVATIVES SUITABLE FOR PREPARING SOFT-HEXING HYDRO-X CARBOLINE DERIVATIVES Download PDFInfo
- Publication number
- NO151862B NO151862B NO831790A NO831790A NO151862B NO 151862 B NO151862 B NO 151862B NO 831790 A NO831790 A NO 831790A NO 831790 A NO831790 A NO 831790A NO 151862 B NO151862 B NO 151862B
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- Norway
- Prior art keywords
- pyrido
- derivatives
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- fluorine
- indeal
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- 239000003599 detergent Substances 0.000 title 1
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000000932 sedative agent Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000001624 sedative effect Effects 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- -1 alkyl chloroformate ester Chemical class 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- IPWQOZCSQLTKOI-QMMMGPOBSA-N d-[(amino)carbonyl]phenylalanine Chemical compound NC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IPWQOZCSQLTKOI-QMMMGPOBSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- RDMFHRSPDKWERA-UHFFFAOYSA-N 5H-Pyrido[4,3-b]indole Chemical class C1=NC=C2C3=CC=CC=C3NC2=C1 RDMFHRSPDKWERA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 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
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical class CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000008096 xylene Substances 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
-
- 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
- A61P25/22—Anxiolytics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurosurgery (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Anesthesiology (AREA)
- Psychiatry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Efter innføring av reserpin og klorpromazin i psykoterapeutisk medisin i de tidlige 1950-årene, har det vært gjort omfattende forsøk på å finne frem til andre beroligende midler med forbedrede biologiske profiler, hvor flere er y-karbolinderivater, også kjent som derivater av pyrido[4,3-b]indol. After the introduction of reserpine and chlorpromazine into psychotherapeutic medicine in the early 1950s, extensive efforts have been made to find other sedatives with improved biological profiles, several of which are γ-carboline derivatives, also known as derivatives of pyrido[4 ,3-b]indole.
Ifølge norsk patent 150,204 fremstilles visse trans-2-substituerte-5-aryl-2,3,4,4a,5,9b-heksahydro-lH-pyrido[4,3-b]indol-derivater som er meget effektive som beroligende midler. According to Norwegian patent 150,204, certain trans-2-substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives are prepared which are very effective as sedatives .
De forbindelser som fremstilles ifølge patent 150.204, er de enantiomere og racemiske forbindelser med formelen The compounds produced according to patent 150,204 are the enantiomeric and racemic compounds with the formula
og farmasøytisk godtagbare salter derav, hvor hydrogenatomene bundet til karbonatomene i 4a- og 9b-stillingen er i trans-forhold til hverandre, og X og Y er like eller forskjellige og er hver hydrogen eller fluor; M er CHOH, CH=CH eller C=0; and pharmaceutically acceptable salts thereof, wherein the hydrogen atoms attached to the carbon atoms in the 4a and 9b positions are in a trans relationship to each other, and X and Y are the same or different and are each hydrogen or fluorine; M is CHOH, CH=CH or C=O;
når M er CH=CH, er n 2, og når M er C=0 eller CHOH er n 3, when M is CH=CH, n is 2, and when M is C=0 or CHOH, n is 3,
og Z er hydrogen, fluor eller metoksy. and Z is hydrogen, fluoro or methoxy.
Foreliggende oppfinnelse angår nye forbindelser som er egnet som utgangsmaterialer ved fremstilling av visse av de ovennevnte forbindelser med formel II, nemlig de hvor minst én av X og Y The present invention relates to new compounds which are suitable as starting materials in the production of certain of the above-mentioned compounds of formula II, namely those in which at least one of X and Y
er fluor. is fluorine.
De nye forbindelser er høyredreiende 5-aryl-2,3,4,4a,5,9b-hekshydro-lH-pyrido[4,3-b]-indol-derivater med formelen og syreaddisjonssalter derav, hvor hydrogenatomene bundet til karbonatomene i 4a- og 9b-stillingene er i trans-forhold til hverandre; én av X_ og Y2er fluor og den annen er hydrogen eller fluor, og fortrinnsvis er X_ fluor og Y^p-fluor. The new compounds are dextrorotatory 5-aryl-2,3,4,4a,5,9b-hexhydro-1H-pyrido[4,3-b]-indole derivatives with the formula and acid addition salts thereof, where the hydrogen atoms are bound to the carbon atoms in 4a - and the 9b positions are in a trans relationship to each other; one of X 1 and Y 2 is fluorine and the other is hydrogen or fluorine, and preferably X 2 is fluorine and Y 2 is fluorine.
Det følgende reaksjonsskjema illustrerer fremstillingen av 4a,9b-trans-2,3,4,4a,5,9b-heksahydro-lH-pyrido[4,3-b]-indol-utgangsmaterialene (i fri baseform) av formel (X) hvor X2og Y^er som ovenfor angitt: The following reaction scheme illustrates the preparation of the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]-indole starting materials (in free base form) of formula (X) where X2 and Y^ are as stated above:
Av økonomiske grunner er benzyl en foretrukken betydning for 1*2- Andre betydninger for R2kan imidlertid også forekomme i det ovenstående skjema, slik som det vil være åpenbart for fagfolk. For economic reasons, benzyl is a preferred meaning for 1*2- However, other meanings for R2 may also occur in the above scheme, as will be apparent to those skilled in the art.
Reduksjonen av tetrahydro-Y-karbolinene med formel (VIII) for å danne 4a,9b-trans-heksahydro-forbindelsene med formel (IX) utføres i et eteroppløsningsmiddel, vanligvis tetrahydrofuran. For å sikre fullstendig reduksjon anvendes vanligvis et molart overskudd av boran/tetrahydrofuran-kompleks (BH"THF), og 100 til 200% molart overskudd av nevnte kompleks foretrekkes. Selv om omsetningen kan utføres ved en temperatur i området fra ca. -10 til 80°C, foretrekkes en temperatur fra ca. 0 til 65°C. Vanligvis settes en oppløsning av utgangsmaterialet med formel (VIII) The reduction of the tetrahydro-Y-carbolines of formula (VIII) to form the 4a,9b-trans-hexahydro compounds of formula (IX) is carried out in an ether solvent, usually tetrahydrofuran. To ensure complete reduction, a molar excess of borane/tetrahydrofuran complex (BH"THF) is usually used, and 100 to 200% molar excess of said complex is preferred. Although the reaction can be carried out at a temperature in the range from about -10 to 80° C., a temperature of from about 0 to 65° C. is preferred. Usually a solution of the starting material of formula (VIII) is placed
i tetrahydrofuran til en isavkjølt oppløsning av BH^"THF. Efter at tilsetningen er fullstendig, oppvarmes reaksjonsblandingen til tilbakeløpstemperatur og holdes ved denne temperatur i en periode på ca. en til to timer eller mer. Omsetningen utføres vanligvis i nærvær av en inert gass så som nitrogen. Når omsetningen er tilnærmet fullstendig, avdampes oppløsningsmidlet, og residuet surgjøres med et overskudd av en syre så som 2 til 12 molar saltsyre. Et foretrukket surgjørende middel er en blanding av like volum-mengder eddiksyre og 5 molar saltsyre. Den surgjorte blanding oppvarmes vanligvis ved tilbakeløpstemperatur i 1 til 2 timer eller mer. Det ønskede produkt kan derefter isoleres, for eksempel ved avdampning av eventuelt gjenværende eter-oppløsningsmiddel og noe av syreblandingen, og det utfelte produkt oppsamles ved filtrering og vaskes. Ved en alternativ metode for isolering av produktet (IX) filtreres reaksjonsblandingen efter tilbakeløpsperioden, filtratet avkjøles og gjøres alkalisk ved tilsetning av for eksempel natriumhydroksyd, kaliumhydroksyd eller natriumkarbonat. Den basiske blanding ekstraheres med et ikke-vannblandbart organisk oppløsningsmiddel som f.eks. kloroform, metylenklorid eller benzen, ekstraktene inndampes, og residuet renses ved kolonnekromatografi på silikagel ved eluering med for eksempel etylacetat eller blandinger av heksan/etylacetat. in tetrahydrofuran to an ice-cooled solution of BH^"THF. After the addition is complete, the reaction mixture is heated to reflux temperature and maintained at this temperature for a period of about one to two hours or more. The reaction is usually carried out in the presence of an inert gas so as nitrogen. When the reaction is nearly complete, the solvent is evaporated, and the residue is acidified with an excess of an acid such as 2 to 12 molar hydrochloric acid. A preferred acidifying agent is a mixture of equal volumes of acetic acid and 5 molar hydrochloric acid. The acidified mixture is usually heated at reflux temperature for 1 to 2 hours or more. The desired product may then be isolated, for example by evaporation of any remaining ether solvent and some of the acid mixture, and the precipitated product collected by filtration and washed. By an alternative method of isolation of the product (IX), the reaction mixture is filtered after the reflux period, the filtrate is cooled and made alkaline by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is extracted with a non-water-miscible organic solvent such as e.g. chloroform, methylene chloride or benzene, the extracts are evaporated, and the residue is purified by column chromatography on silica gel by elution with, for example, ethyl acetate or mixtures of hexane/ethyl acetate.
Reduksjonen av tetrahydro-Y-karboliner med BH^THF fulgt av syrebehandling gir heksahydro-T-karboliner i hvilke hydrogenatomene som er bundet til karbonatomene i 4a- og 9b-stillingene, er i trans-forhold, se f.eks. U.S.-patent 3.991.199. The reduction of tetrahydro-Y-carbolines with BH^THF followed by acid treatment gives hexahydro-T-carbolines in which the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions are in a trans relationship, see e.g. U.S. Patent 3,991,199.
2-benzyl-forbindelsene med formel (IX) omdannes derefter til de tilsvarende 2-hydrogen-forbindelser med formel (X). Generelt kan dette oppnås ved behandling av forbindelsen med formel (IX)<1>med et molart overskudd av en lavere alkyl-klorformiat-ester som for eksempel metyl-, etyl-, propyl- eller isobutylester i nærvær av et egnet reaksjons-inert organisk opp-løsningsmiddel, fulgt av alkalisk hydrolyse. Foretrukket som klorformiat-ester er etyl-klorformiat på grunn av dennes til-gjengelighet og effektivitet. Med et egnet reaksjons-inert organisk oppløsningsmiddel skal forstås et som i alt vesentlig vil oppløse reaksjonskomponentene under reaksjonsbetingelsene uten at det dannes biprodukter. Eksempler på slike oppløsnings-midler er aromatiske hydrokarboner så som benzen, toluen og xylen; klorerte hydrokarboner så som kloroform og 1,2-dikloretan, dietylenglykol-dimetyleter og dimetylsulfoksyd. Et særlig foretrukket oppløsningsmiddel er toluen. The 2-benzyl compounds of formula (IX) are then converted into the corresponding 2-hydrogen compounds of formula (X). In general, this can be achieved by treating the compound of formula (IX)<1> with a molar excess of a lower alkyl chloroformate ester such as, for example, methyl, ethyl, propyl or isobutyl ester in the presence of a suitable reaction-inert organic solvent, followed by alkaline hydrolysis. Ethyl chloroformate is preferred as chloroformate ester because of its availability and effectiveness. A suitable reaction-inert organic solvent is to be understood as one which will essentially dissolve the reaction components under the reaction conditions without by-products being formed. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene and xylene; chlorinated hydrocarbons such as chloroform and 1,2-dichloroethane, diethylene glycol dimethyl ether and dimethyl sulfoxide. A particularly preferred solvent is toluene.
Til blandingen av utgangsmateriale med formel (IX) i nevnte reaksjonsinerte organiske oppløsningsmiddel settes opptil et ti molart overskudd av klorformiat-esteren. Av økonomiske grunner foretrekkes et molart overskudd på ca. 3 til 5. Den resulterende blanding oppvarmes derefter ved en temperatur fra ca. 80 til l50°C, typisk ved blandingens tilbakeløpstemperatur, Up to a ten molar excess of the chloroformate ester is added to the mixture of starting material with formula (IX) in said reaction-initiated organic solvent. For economic reasons, a molar excess of approx. 3 to 5. The resulting mixture is then heated at a temperature from approx. 80 to 150°C, typically at the reflux temperature of the mixture,
i en periode på ca. 6 til 24 timer eller mer. Vanligvis utføres tilbakeløpsbehandlingen natten over av praktiske grunner. for a period of approx. 6 to 24 hours or more. Usually, the reflux treatment is carried out overnight for practical reasons.
, Reaksjonsblandingen inndampes derefter i vakuum, og residuet opptas i en alkohol-vann-blanding, et alkali, f.eks. natriumhydroksyd eller kaliumhydroksyd, tilsettes i ca. 10-30 molart overskudd basert på mengden av utgangsmateriale med formel (IX), og den resulterende blanding oppvarmes ved tilbakeløpstemperatur, hensiktsmessig natten over. Oppløsningsmidlet avdampes derefter, og residuet fordeles mellom vann og et ikke-vannblandbart organisk oppløsningsmiddel som f.eks. kloroform, metylenklorid eller , The reaction mixture is then evaporated in vacuo, and the residue is taken up in an alcohol-water mixture, an alkali, e.g. sodium hydroxide or potassium hydroxide, is added for approx. 10-30 molar excess based on the amount of starting material of formula (IX), and the resulting mixture is heated at reflux temperature, conveniently overnight. The solvent is then evaporated, and the residue is distributed between water and a non-water-miscible organic solvent such as chloroform, methylene chloride or
etyleter, og den organiske fase inndampes til tørrhet. Det gjenværende produkt med formel (X) kan anvendes som sådan eller renses ytterligere ved i og for seg kjente standardmetoder, f.eks. ved- kolonnekromatografi på silikagel. ethyl ether, and the organic phase is evaporated to dryness. The remaining product of formula (X) can be used as such or purified further by standard methods known per se, e.g. by column chromatography on silica gel.
De optiske isomerer av det nye amin (X) erholdes ved spaltning av de racemiske forbindelser. Spaltningen utføres ved hjelp av et salt dannet mellom aminet (X) og en optisk aktiv syre. Selv om det er kjent en rekke syrer som er nyttige for spaltningen av aminer, se f.eks. Fieser et al., nevnt ovenfor, er foretrukne syrer som medfører en lett spaltning av aminet (X), de optiske isomerer (D- og L-) av N-karbamoylfenylalanin. Sistnevnte erholdes ved at de isomere fenylalaniner omsettes med natrium-cyanat ved i og for seg kjente metoder. Spaltningen oppnåes ved omsetning av en av de isomere N-karbamoylfenylalaniner, f.eks. L-isomeren, men en racemisk forbindelse med formel (X) i ekvimolare mengder i nærvær av et egnet reaksjonsinert oppløsnings-middel for å danne en homogen oppløsning av saltene. Ved av-kjøling erholdes saltet av en av de optiske isomerer av (X) som et krystallinsk, fast stoff som eventuelt kan renses videre. Moderlutene som hovedsakelig inneholder saltet av den annen isomer, inndampes til tørrhet, og saltet dekomponeres med vandig base som f.eks. natriumkarbonat, kaliumhydroksyd eller kalsium-karbonat, og den frie base ekstraheres ved hjelp av et vannblandbart oppløsningsmiddel, typisk etylacetat, tørres, og oppløsnings-midlet inndampes for å gi et residuum som er anriket med den annen isomer av aminet (X). Dette residuum opptas derefter i et reaksjonsinert oppløsningsmiddel og behandles med en ekvimolar mengde av den annen isomer av N-karbamoylfenylalanin, f.eks. The optical isomers of the new amine (X) are obtained by cleavage of the racemic compounds. The cleavage is carried out using a salt formed between the amine (X) and an optically active acid. Although a number of acids are known which are useful for the cleavage of amines, see e.g. Fieser et al., mentioned above, are preferred acids which cause a slight cleavage of the amine (X), the optical isomers (D- and L-) of N-carbamoylphenylalanine. The latter is obtained by reacting the isomeric phenylalanines with sodium cyanate by methods known per se. The cleavage is achieved by reacting one of the isomeric N-carbamoylphenylalanines, e.g. the L-isomer, but a racemic compound of formula (X) in equimolar amounts in the presence of a suitable reaction-initiated solvent to form a homogeneous solution of the salts. Upon cooling, the salt of one of the optical isomers of (X) is obtained as a crystalline, solid substance which can optionally be purified further. The mother liquors, which mainly contain the salt of the other isomer, are evaporated to dryness, and the salt is decomposed with an aqueous base such as e.g. sodium carbonate, potassium hydroxide or calcium carbonate, and the free base is extracted with a water-miscible solvent, typically ethyl acetate, dried, and the solvent is evaporated to give a residue which is enriched with the other isomer of the amine (X). This residue is then taken up in a reaction-inert solvent and treated with an equimolar amount of the other isomer of N-carbamoylphenylalanine, e.g.
D-isomeren, og oppløsningen avkjøles for å utfelle krystaller the D-isomer, and the solution is cooled to precipitate crystals
av N-karbamoylfenylalanin-saltet av den annen isomer med formel (X). of the N-carbamoylphenylalanine salt of the second isomer of formula (X).
Hvert av saltene som inneholder en enkel enantiomer av aminet (X), dekomponeres derefter som beskrevet ovenfor for å Each of the salts containing a single enantiomer of the amine (X) is then decomposed as described above to
gi henholdsvis de tilnærmet rene høyredreiende og venstredreiende isomerer av (X). give respectively the approximately pure dextrorotatory and levorotatory isomers of (X).
Forbindelsen ifølge oppfinnelsen med formel (X) kan omdannes forbindelser med beroligende virkning som er de enantiomere og racemiske forbindelser med formelen. The compound according to the invention with formula (X) can be converted into compounds with a sedative effect which are the enantiomeric and racemic compounds with the formula.
og farmasøytisk godtagbare salter derav, hvor hydrogenatomene bundet til karbonatomene i 4a- og 9b-stillingene er i trans-forhold til hverandre, og X2og Y2er som ovenfor angitt; and pharmaceutically acceptable salts thereof, where the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions are in a trans relationship to each other, and X2 and Y2 are as indicated above;
og Z er hydrogen, fluor eller metoksy. and Z is hydrogen, fluoro or methoxy.
Denne omdannelse er beskrevet i stamansøkningen som det henvises til. This conversion is described in the original application to which reference is made.
De mono- eller di-fluorsubstituerte tetrahydro-y-karbolin-utgangsmaterialer med formel (VIII) hvor minst én av X2og Y2er fluor og R2er benzyl, fremstilles fra de tilsvarende forbindelser med formel (VIII) hvor R2er hydrogen, ved omsetning med et benzylhalogenid så som benzylbromid, i ekvimolare mengder. De nødvendige forbindelser med nevnte formel (VIII, R2=H' fremstilles som beskrevet i U.S.-patent 4.001.263. The mono- or di-fluoro-substituted tetrahydro-y-carboline starting materials of formula (VIII) where at least one of X2 and Y2 is fluorine and R2 is benzyl, are prepared from the corresponding compounds of formula (VIII) where R2 is hydrogen, by reaction with a benzyl halide so as benzyl bromide, in equimolar amounts. The necessary compounds of said formula (VIII, R2=H' are prepared as described in U.S. Patent 4,001,263.
Eksempel I Example I
dl-trans-8-f luor-^5- (p-f luorf enyl) -2 , 3 , 4 , 4a, 5 , 9b-heksahydro-lH-pyrido[ 4, 3- b] indol dl-trans-8-fluoro-[5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole
A. Til en oppløsning av 5,6 g (12,4mmol) dl-trans-8-fluor-5-(p-fluorfenyl)-2-[4-hydroksy-4-(p-fluorfenyl)butyl]-2,3,4,4a,5,9b-heksahydro-lH-pyrido[4,3-b]indol i 40 ml toluen ble satt 5,3 ml (55,7 mmol) etyl-klorformiat. Den resulterende blanding ble tilbakeløpsbehandlet natten over og derefter inndampet til tørrhet hvorved man fikk en gjenværende gummi. Til gummien ble satt 200 ml av en 9:1, efter volum, blanding av etanol og vann. Efter at blandingen var oppløst, ble 15 g kaliumhydroksyd tilsatt, og den resulterende blanding ble til-bakeløpsbehandlet natten over. Oppløsningsmidlet ble avdampet i vakuum, og residuet ble fordelt mellom vann og kloroform. De organiske ekstrakter ble vasket med vann, tørret over natrium- sulfat og inndampet til tørrhet. Den gjenværende olje ble tatt opp i etylacetat og ført gjennom en silikagel-kolonne ved først å eluere med etylacetat for å fjerne biprodukter og derefter eluere det ønskede produkt med 1:1, efter volum, etylacetat/ metanol. Fraksjonene inneholdende tittelforbindelsen ble kombi-nert og inndampet til tørrhet for å gi 1,5 g (43%) gul gummi som krystalliserte ved henstand, sm.p. 115-117°C. A. To a solution of 5.6 g (12.4 mmol) of dl-trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2, 3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 40 ml of toluene was added 5.3 ml (55.7 mmol) of ethyl chloroformate. The resulting mixture was refluxed overnight and then evaporated to dryness to give a residual gum. 200 ml of a 9:1, by volume, mixture of ethanol and water was added to the rubber. After the mixture dissolved, 15 g of potassium hydroxide was added and the resulting mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform. The organic extracts were washed with water, dried over sodium sulphate and evaporated to dryness. The remaining oil was taken up in ethyl acetate and passed through a silica gel column by first eluting with ethyl acetate to remove byproducts and then eluting the desired product with 1:1, by volume, ethyl acetate/methanol. The fractions containing the title compound were combined and evaporated to dryness to give 1.5 g (43%) of a yellow gum which crystallized on standing, m.p. 115-117°C.
B. Alternativt tilbakeløpsbehandles dl-trans-2-benzyl-8-fluor-5-(p-fluorfenyl)-2,3,4,4a,5,9b-heksahydro-lH-pyrido-[4,3-b]indol-hydroklorid i nærvær av overskudd av etyl-klorformiat eller de tilsvarende metyl-, isopropyl- eller n-butyl-klorformiat-estere, hydrolyseres derefter og opparbeides ved fremgangsmåten beskrevet ovenfor for å gi tittelforbindelsen. B. Alternatively, dl-trans-2-benzyl-8-fluoro-5-(p-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole is refluxed -hydrochloride in the presence of an excess of ethyl chloroformate or the corresponding methyl, isopropyl or n-butyl chloroformate esters, is then hydrolysed and worked up by the method described above to give the title compound.
Eksempel II Example II
Ved å anvende det passende utgangsmateriale i hvert til-felle og å anvende fremgangsmåten ifølge Eksempel IA eller IB, fremstilles de følgende produkter på tilsvarende måte: dl-trans-5-(p-fluorfenyl)-2,3,4,4a,5,9b-heksahydro-lH-pyrido [4,3-b]indol, hydrokloridsalt, sm.p. 235-238°C dl-trans-8-fluor-5-fenyl-2,3,4,4a,5,9b-heksahydro-lH-pyrido [4,3-b]indol, hydrokloridsalt, sm.p. 244-246°C. By using the appropriate starting material in each case and applying the procedure according to Example IA or IB, the following products are prepared in a similar manner: dl-trans-5-(p-fluorophenyl)-2,3,4,4a,5 ,9b-hexahydro-1H-pyrido[4,3-b]indole, hydrochloride salt, m.p. 235-238°C dl-trans-8-fluoro-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, hydrochloride salt, m.p. 244-246°C.
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NO831790A NO151862C (en) | 1977-05-23 | 1983-05-20 | NEW HIGH-DETERGENT 5-ACRYL-2,3,4,4A, 5,9B-HEXSAHYDRO-1H-PYRIDO (4,3-B) -INDEAL DERIVATIVES SUITABLE FOR PREPARING SOFT-HEXING HYDRO-X CARBOLINE DERIVATIVES |
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US4224329A (en) * | 1979-01-23 | 1980-09-23 | Pfizer Inc. | 2-Substituted-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles |
US4451655A (en) * | 1982-05-17 | 1984-05-29 | Pfizer Inc. | Process for preparing carboline derivatives and compounds used in their preparation |
RU2106864C1 (en) * | 1995-10-23 | 1998-03-20 | Николай Серафимович Зефиров | New approach to treatment of alzheimer's disease |
SE9604786D0 (en) * | 1996-12-20 | 1996-12-20 | Astra Pharma Inc | New compounds |
US6974825B1 (en) | 1996-12-20 | 2005-12-13 | Astrazeneca Canada Inc. | Compounds with analgesic effect |
SE9904675D0 (en) | 1999-12-20 | 1999-12-20 | Astra Pharma Inc | Novel compounds |
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JPS50126699A (en) * | 1974-03-20 | 1975-10-04 | ||
US4001263A (en) * | 1974-04-01 | 1977-01-04 | Pfizer Inc. | 5-Aryl-1,2,3,4-tetrahydro-γ-carbolines |
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1978
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- 1978-04-18 YU YU00914/78A patent/YU91478A/en unknown
- 1978-04-20 NL NL7804210A patent/NL7804210A/en not_active Application Discontinuation
- 1978-04-24 AU AU35377/78A patent/AU499618B1/en not_active Expired
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- 1978-05-18 PL PL1978206903A patent/PL114547B1/en unknown
- 1978-05-18 HU HU822638A patent/HU188802B/en unknown
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- 1978-05-18 PL PL1978215921A patent/PL117107B1/en unknown
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- 1978-05-20 GR GR56281A patent/GR69985B/el unknown
- 1978-05-22 IT IT23673/78A patent/IT1096307B/en active
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- 1978-05-22 JP JP6087278A patent/JPS53144600A/en active Granted
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- 1978-05-22 IE IE1013/78A patent/IE46975B1/en unknown
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1979
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1982
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1983
- 1983-05-20 NO NO831790A patent/NO151862C/en unknown
- 1983-10-27 SE SE8305917A patent/SE448459B/en not_active IP Right Cessation
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