NO162615B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,3,4,5-TETRAHYDROBENZ (C, D) INDOLES. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,3,4,5-TETRAHYDROBENZ (C, D) INDOLES. Download PDFInfo
- Publication number
- NO162615B NO162615B NO844868A NO844868A NO162615B NO 162615 B NO162615 B NO 162615B NO 844868 A NO844868 A NO 844868A NO 844868 A NO844868 A NO 844868A NO 162615 B NO162615 B NO 162615B
- Authority
- NO
- Norway
- Prior art keywords
- compounds
- formula
- general formula
- tetrahydrobenz
- alkyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 150000002475 indoles Chemical class 0.000 title description 3
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- GHDKZRYOSSRTLA-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-benzo[g]indole Chemical class C1C=C2C=CC=CC2=C2C1CCN2 GHDKZRYOSSRTLA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 150000002828 nitro derivatives Chemical class 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 150000001448 anilines Chemical class 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002527 isonitriles Chemical class 0.000 claims description 2
- 150000003901 oxalic acid esters Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical compound C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000001430 anti-depressive effect Effects 0.000 description 4
- 230000001568 sexual effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229960005333 tetrabenazine Drugs 0.000 description 3
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-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
- BCXUTFLDHOWIBW-UHFFFAOYSA-N 8-methoxy-5-nitro-n,n-dipropyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound COC1=CC=C([N+]([O-])=O)C2=C1CC(N(CCC)CCC)CC2 BCXUTFLDHOWIBW-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010015995 Eyelid ptosis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 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
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000027326 copulation Effects 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 201000003004 ptosis Diseases 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 230000002295 serotoninergic effect Effects 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 102000035038 5-HT1 receptors Human genes 0.000 description 1
- 108091005478 5-HT1 receptors Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010042008 Stereotypy Diseases 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002199 base oil Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001722 neurochemical effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Luminescent Compositions (AREA)
- Detergent Compositions (AREA)
- Fats And Perfumes (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Oppfinnelsen vedrører fremstilling av nye 1,3,4,5-tetrahydro-benz[c,d]indoler og deres salter med fysiologisk ufarlige syrer. 1,3,4,5-tetrahydrobenz[c,d]indolene anvendes til behandling av kardiovaskulære sykdommer og sykdommer i det sentrale nervesystem med en virkning på det serotoninerge system. The invention relates to the production of new 1,3,4,5-tetrahydro-benz[c,d]indoles and their salts with physiologically harmless acids. The 1,3,4,5-tetrahydrobenz[c,d]indoles are used to treat cardiovascular diseases and diseases of the central nervous system with an effect on the serotoninergic system.
Oppfinnelsen vedrører fremstilling av tetrahydrobenzindoler med den generelle formel I The invention relates to the preparation of tetrahydrobenzindoles with the general formula I
hvori in which
Ri og R£ betyr hydrogen, C^-C^-alkyl eller C2~C5-alkenyl, Ri and R£ mean hydrogen, C₁-C₁-alkyl or C₂-C₅-alkenyl,
X betyr 0R3 eller SR3, idet X means 0R3 or SR3, in that
R3 betyr H eller C1-C4-alkyl, R3 means H or C1-C4-alkyl,
og fysiologisk godtagbare salter derav. and physiologically acceptable salts thereof.
Forbindelsene med formel I fremstilles ifølge oppfinnelsen The compounds of formula I are produced according to the invention
ved at by that
a) forbindelser med den generelle formel II a) compounds of the general formula II
nltreres i parastilling til substituenten X, den dannede nltered in para position to the substituent X, the formed
nitroforbindelsen III i the nitro compound III i
acyleres med oksalsyreestere med formelen R4-O-CO-CO-OR4, Idet R4 betyr CH3 eller C2H5 til forbindelser med den generelle formel IV acylated with oxalic acid esters of the formula R4-O-CO-CO-OR4, Where R4 means CH3 or C2H5 to compounds of the general formula IV
i disse forsåpes estergruppene, nitrogruppene reduseres og deretter ringsluttes og dekarboksyleres i ett eller flere trinn, eller in these, the ester groups are saponified, the nitro groups are reduced and then ring-closed and decarboxylated in one or more steps, or
b) forbindelser med generell formel III b) compounds of general formula III
reduseres til aniliner med formel VII disse overføres til isonitriler med formel VIII og disse ringsluttes til slutt med en sterk base til forbindelser med formel I, og de derved oppnådde forbindelsene omdannes eventuelt til fysiologisk godtagbare salter derav. Den avsluttende ringslutning og dekarboksylering i frem-gangsmåtevariant a) forløper over mellomprodukter med formlene V og VI are reduced to anilines of formula VII these are transferred to isonitriles of formula VIII and these are finally cyclized with a strong base to compounds of formula I, and the thereby obtained compounds are optionally converted into physiologically acceptable salts thereof. The final cyclization and decarboxylation in method variant a) proceeds over intermediate products with the formulas V and VI
til forbindelser med formel I, hvor R^ , R2 og X i formlene har de overfor angitte betydningene. to compounds of formula I, where R 1 , R 2 and X in the formulas have the meanings indicated above.
De virksomme stoffene med formel I adskiller seg entydig fra kjente virksomme stoffer av tilsvarende struktur (f.eks. US-patent 4 110 339) ved substituenten X i 6-stilling av det tricykliske ringsystemet. Mens de kjente forbindelser hvor The active substances of formula I clearly differ from known active substances of similar structure (e.g. US patent 4 110 339) by the substituent X in the 6-position of the tricyclic ring system. While they knew connections where
X = H har en sterk virkning på det dopaminerge system trer ved forbindelsene med formel I, hvori X har ovennevnte betydning, virkningen på de dopaminerge system i bakgrunnen overfor en sterk virkning på det serotoninerge system. Det er vist at forbindelsene fremtilt ifølge oppfinnelsen har en høy affinitet til hjernens serotoninreseptorer, spesielt til de av 5-HT^-typen (se tabell 1). Forbindelsene av formel I er således selektive 5-HTi-reseptor-ligander. X = H has a strong effect on the dopaminergic system occurs in the compounds of formula I, in which X has the above meaning, the effect on the dopaminergic system in the background against a strong effect on the serotoninergic system. It has been shown that the compounds produced according to the invention have a high affinity to the brain's serotonin receptors, especially to those of the 5-HT 2 type (see table 1). The compounds of formula I are thus selective 5-HT 1 receptor ligands.
De virksomme stoffer fremstilt ifølge oppfinnelsen har i dyreforsøk sterk virkning på det sentrale nervesystem. Spesielt viser de virkning i forsøksanordninger, hvori det finnes anxiolyttiske og antidepressive virkninger. Dessuten fører de til en sterk stimulering av seksualforhold hos rotter. The active substances produced according to the invention have a strong effect on the central nervous system in animal experiments. In particular, they show efficacy in experimental devices, in which anxiolytic and antidepressant effects are found. Moreover, they lead to a strong stimulation of sexual relations in rats.
På grunn av disse egenskaper betyr forbindelsen fremstilt ifølge oppfinnelsen en berikning av legemidlene. De egner seg til bekjempelse av sykdommer av det sentrale nervesystem, spesielt til behandling av angst og spenningstilstander, søvnforstyrrelser og depresjoner, fortrinnsvis til behandling av problemer med seksuell potens. Because of these properties, the compound produced according to the invention means an enrichment of the medicines. They are suitable for combating diseases of the central nervous system, especially for the treatment of anxiety and tension states, sleep disorders and depression, preferably for the treatment of problems with sexual potency.
Foretrukket er fremstilling av forbindelser med formel I, hvori Preparation of compounds of formula I is preferred, in which
R^ og R2 betyr en rettlinjet eller forgrenet Ci-Cj-alkyl-eller C2-C6-alkenylrest, og R 1 and R 2 mean a straight or branched C 1 -C 6 alkyl or C 2 -C 6 alkenyl residue, and
X betyr 0CH3 eller SCH3. X means 0CH3 or SCH3.
Spesielt foretrukket er fremstilling av forbindelser med formel I, hvori Particularly preferred is the preparation of compounds of formula I, in which
Ri og R2 betyr en rettlinjet eller forgrenet C1-C4-alkylrest, og R 1 and R 2 mean a straight or branched C 1 -C 4 alkyl residue, and
X betyr 0CH3~resten. X means the 0CH3~ residue.
Fremstillingen av forbindelsene med formel I forklares eksempelvis ved følgende formelskjema: The production of the compounds of formula I is explained, for example, by the following formula:
Nitreringen av 2-aminotetralin II til nitroforbindelsene III foregår i mineralsyre eller organiske karboksylsyrer med kons. eller rykende salpetersyre eller NaNC>3 som nitrerings-reagens. Fortrinnsvis anvendes svovelsyre, salpetersyre eller trifluoreddiksyre som oppløsningsmiddel. Reaksjonen gjennomføres ved temperaturer mellom -60°C og +40°C. De foretrukne temperaturområder ligger mellom -20°C og værelsestemperatur. The nitration of 2-aminotetralin II to the nitro compounds III takes place in mineral acid or organic carboxylic acids with conc. or fuming nitric acid or NaNC>3 as nitration reagent. Sulfuric acid, nitric acid or trifluoroacetic acid are preferably used as solvent. The reaction is carried out at temperatures between -60°C and +40°C. The preferred temperature ranges are between -20°C and room temperature.
Acyleringen av forbindelsene III til forbindelsene IV med oksalsyredimetylester eller -dietylester gjennomføres i nærvær av en sterk base I et inert protisk eller aprotisk oppløsningsmiddel. Som baser til deprotonering av den aktiverte metylengruppe kommer det I betraktning metall-organiske baser, som litiumdiisopropylamid, n-butyllitium, NaH eller alkalialkoholater, som Na- eller K-metylat eller The acylation of compounds III to compounds IV with oxalic acid dimethyl ester or diethyl ester is carried out in the presence of a strong base in an inert protic or aprotic solvent. As bases for deprotonation of the activated methylene group, metal-organic bases, such as lithium diisopropylamide, n-butyllithium, NaH or alkali alcoholates, such as Na- or K-methylate or
-etylat. -ethylate.
Som oppløsningsmidler anvendes aprotiske oppløsningsmidler, spesielt etere, som dietyleter, tetrahydrofuran, dioksan, 1,2-dimetoksyetan, diglyme eller aprotiske oppløsningsmidler som dimetylformamid eller dimetylsulfoksyd eller protiske oppløsningsmidler, spesielt alkoholer, som metanol eller etanol eller blandinger av disse oppløsningsmidler. As solvents, aprotic solvents are used, especially ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme or aprotic solvents such as dimethylformamide or dimethylsulfoxide or protic solvents, especially alcohols, such as methanol or ethanol or mixtures of these solvents.
Reaksjonen gjennomføres ved temperaturer mellom -80°C og værelsestemperatur. En foretrukket utførelsesform av acyleringsreaksjonen er anvendelsen av oksalsyredietylester som acyleringsreagens, kaliumetanolat som base, en blanding av dietyleter/etanol som oppløsningsmiddel og gjennomføringen av reaksjonen ved værelsestemperatur. The reaction is carried out at temperatures between -80°C and room temperature. A preferred embodiment of the acylation reaction is the use of oxalic acid diethyl ester as acylation reagent, potassium ethanolate as base, a mixture of diethyl ether/ethanol as solvent and carrying out the reaction at room temperature.
Forsåpningen av esterfunksjonen i forbindelsene med formel IV gjennomføres fortrinnsvis i et vandig alkalisk miljø. Som baser anvendes fortrinnsvis alkali- eller Jordalkalihydrok-syder eller -karbonater. Reaksjonen gjennomføres i vann eller fortrinnsvis i en oppløsningsmiddelblanding av vann og et med vann blandbart oppløsningsmiddel, som MeOH eller EtOH. Reaksjonstemperaturen ligger mellom 0°C og værelsestemperatur . The saponification of the ester function in the compounds of formula IV is preferably carried out in an aqueous alkaline environment. Alkali or alkaline earth hydroxides or carbonates are preferably used as bases. The reaction is carried out in water or preferably in a solvent mixture of water and a water-miscible solvent, such as MeOH or EtOH. The reaction temperature is between 0°C and room temperature.
Reduksjonen av nitrogruppen i forbindelsen med formel V og ringslutningen til forbindelsene med formel VI foregår under betingelser, som er vanlige for reduksjon av en aromatisk nitrogruppe til en NH2~gruppe. Som reduksjonsmiddel lar det seg eksempelvis anvende: med edelmetallkatalysatorer som Pt eller Pd aktivert hydrogen, jern-II-salter i alkalisk resp. ammoniakalsk medium, sink i iseddik eller natriumditionit. Som oppløsningsmidler anvendes fortrinnsvis vann eller en alkohol/vannblanding eller iseddik. Reaksjonstemperaturen ligger mellom værelsestemperatur og oppløsningsmidlets koketemperatur. Fortrinnsvis gjennomføres reduksjonen med jern-II-sulfat i en vandig ammoniakalsk oppløsning ved tilbakeløpstemperatur. The reduction of the nitro group in the compound of formula V and the cyclization to the compounds of formula VI take place under conditions which are usual for the reduction of an aromatic nitro group to an NH 2 ~ group. As a reducing agent, it can be used, for example: with noble metal catalysts such as Pt or Pd activated hydrogen, iron II salts in alkaline resp. ammoniacal medium, zinc in glacial acetic acid or sodium dithionite. Water or an alcohol/water mixture or glacial acetic acid are preferably used as solvents. The reaction temperature is between room temperature and the boiling temperature of the solvent. Preferably, the reduction is carried out with iron II sulfate in an aqueous ammoniacal solution at reflux temperature.
Dekarboksyleringen av forbindelsene VI til forbindelsene ifølge oppfinnelsen med formel I gjennomføres i et inert oppløsningsmiddel ved temperaturer mellom 150 og 300°C, eventuelt i nærvær av en katalysator som Cu-pulver. Fortrinnsvis anvendes basiske organiske oppløsningsmidler, som kinolin, kinaldin eller 8-metyl-kinolin. The decarboxylation of the compounds VI to the compounds according to the invention with formula I is carried out in an inert solvent at temperatures between 150 and 300°C, optionally in the presence of a catalyst such as Cu powder. Preferably, basic organic solvents are used, such as quinoline, quinaldine or 8-methyl-quinoline.
Utgangsstoffene med formel II er litteraturkjente eller kan fremstilles analogt til kjente forbindelser (D.E. Ames u.a. , J. Chem. Soc. 1965, 2636). The starting substances with formula II are known from the literature or can be prepared analogously to known compounds (D.E. Ames et al., J. Chem. Soc. 1965, 2636).
De terapeutisk virksomme forbindelsene anvendes i vanlige farmasøytiske preparater, fortrinnsvis i en konsentrasjon på 0,1 til 99,5, fortrinnsnvis på 0,5 til 95 vekt-£ av den samlede blandingen. The therapeutically active compounds are used in common pharmaceutical preparations, preferably in a concentration of 0.1 to 99.5, preferably of 0.5 to 95% by weight of the total mixture.
De ovenfor anførte farmasøytiske preparatene kan foruten forbindelser med formel (I) og/eller deres salter også inneholde andre farmasøytisk virksomme stoffer. The pharmaceutical preparations listed above may, in addition to compounds of formula (I) and/or their salts, also contain other pharmaceutically active substances.
Fremstillingen av de ovenfor anførte farmasøytiske preparatene foregår på vanlig måte etter kjente metoder, f.eks. ved blanding av det eller de virksomme stoffene med bærestof-fet eller bærestoffene. The production of the above-mentioned pharmaceutical preparations takes place in the usual way according to known methods, e.g. by mixing the active substance(s) with the carrier oil or carriers.
Forbindelsene med formel (I) og/eller deres salter samt farmasøytiske tilberedninger som inneholder en eller flere av forbindelsene med formel (I) og/eller deres salter anvendes også i humanmedisinen for å forebygge, forbedre og/eller helbrede de ovenfor anførte sykdommer. The compounds of formula (I) and/or their salts as well as pharmaceutical preparations containing one or more of the compounds of formula (I) and/or their salts are also used in human medicine to prevent, improve and/or cure the diseases listed above.
De virksomme stoffer eller de farmasøytiske tilberedninger kan fortrinnsvis administreres oralt, parenteralt og/eller rektalt, fortrinnsvis oralt eller parenteralt, spesielt oralt og intravenøst. The active substances or the pharmaceutical preparations can preferably be administered orally, parenterally and/or rectally, preferably orally or parenterally, especially orally and intravenously.
Generelt har det vist seg fordelaktig å administrere det eller de virksomme stoffer ved parenteral (i.v. eller i.m.) anvendelse i mengder på 0,005 til 5, fortrinnsvis på 0,01 til 1 mg/kg legemsvekt pr. 24 timer og ved oral anvendelse i mengder på 0,01 til 10, fortrinnsvis 0,05 til 5 mg/kg legemsvekt pr. 24 timer, eventuelt i form av flere enkelt-inngivninger for å oppnå de ønskede resultater. In general, it has proven advantageous to administer the active substance(s) by parenteral (i.v. or i.m.) application in amounts of 0.005 to 5, preferably of 0.01 to 1 mg/kg body weight per 24 hours and when used orally in amounts of 0.01 to 10, preferably 0.05 to 5 mg/kg body weight per 24 hours, possibly in the form of several individual submissions to achieve the desired results.
Følgende tabell 1 forklarer eksempelvis den høye affinitet av forbindelsene fremstilt ifølge oppfinnelsen til hjernens serotoninreseptorer. Forbindelsene ble undersøkt med henblikk på antidepressive og på seksualforhold-påvirkende effekter. Som prøve for den antidepressive virkning tjente amfetaminpotensierings- og antitetrabenazinprøven. Antidepressivt virkende stoffer potensierer amfetamin-indusert stereotype forhold hos rotte og antagoniserer den ved tetrabenazin induserte ptosis hos mus. Den angitte EDsQ-verdi er den dose, hvor forholdet etter Inngivning av 2 mg/kg DL-amfetaminsulfat i.v. for-sterkes rundt 50$ resp. den ved hjelp av 20 mg/kg i.p. tetrabenazin indusert ptosis reduseres til 50$. The following table 1 explains, for example, the high affinity of the compounds produced according to the invention to the brain's serotonin receptors. The compounds were examined with a view to antidepressant and sexual relationship-influencing effects. The amphetamine potentiation and anti-tetrabenazine test served as a test for the antidepressant effect. Antidepressant substances potentiate amphetamine-induced stereotypy in rats and antagonize tetrabenazine-induced ptosis in mice. The indicated EDsQ value is the dose at which the ratio after administration of 2 mg/kg DL-amphetamine sulfate i.v. reinforced around $50 resp. it using 20 mg/kg i.p. tetrabenazine induced ptosis is reduced to 50$.
Litteratur: J.L. Howard et al. i: "Antidepressants: Neurochemical, behavioral and clinical perspec-tives Eds.: S.J. Enna et al., Raven Press, New York, s. 107-120, 1981. Literature: J.L. Howard et al. in: "Antidepressants: Neurochemical, behavioral and clinical perspectives Eds.: S.J. Enna et al., Raven Press, New York, pp. 107-120, 1981.
Som prøve på seksulforhold-påvirkende effekt tjente måling av ejakulasjonslatensen og antall kopulasjonsforsøk. Verdiene angir tiden som går mellom sammenføring av mannlige og hunnlige dyr og hannens første ejakulasjon og antall kopulasjonsforsøk. Measurement of the ejaculation latency and the number of copulation attempts served as a test of the sexual relationship-influencing effect. The values indicate the time that elapses between the mating of male and female animals and the male's first ejaculation and the number of copulation attempts.
Litteratur: Larsson K. , Fuxe K. ; Everitt B.J., Holmgren M. Literature: Larsson K., Fuxe K.; Everitt B.J., Holmgren M.
og Sodersten P. (1978). Sexual behaviour in male rats after intercerebral injection of 5-7-dihydrotryptamin, Brain Research, 151, 293-303. and Sodersten P. (1978). Sexual behavior in male rats after intercerebral injection of 5-7-dihydrotryptamine, Brain Research, 151, 293-303.
Eksempel 1 Example 1
6-metoksy-4-dipropylamino-l,3,4,5-tetrahydrobenz[c,d]-indol 6-methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenz[c,d]-indole
En oppløsning av 0,35 g (0,00106 mol) 6-metoksy-4-dipropyl-amino-1,3,4,5-tetrahydrobenz[c,d]-indol-2-karboksylsyre i A solution of 0.35 g (0.00106 mol) of 6-methoxy-4-dipropyl-amino-1,3,4,5-tetrahydrobenz[c,d]-indole-2-carboxylic acid in
10 ml 8-metylkinolin ble blandet med 0,2 g Cu-pulver og deretter oppvarmet under nitrogenspyling I kustlllator 1 1/2 time ved 250°C. Den mørkerødfargede reaksjonsoppløsning ble hatt på en søyle fylt med klselgel (Kleselgel 60 fra firma 10 ml of 8-methylquinoline was mixed with 0.2 g of Cu powder and then heated under nitrogen purging in a custllator for 1 1/2 hours at 250°C. The dark red colored reaction solution was applied to a column filled with Kleselgel (Kleselgel 60 from
E.Merck, Darmstadt). Til adskillelse av 8-metylkinolin ble det eluert med CH2Cl2 og deretter med CH2CI2 : MeOH / 20:4 eluert reaksjonsproduktet. Råstoffet ble igjen kromatografert på kiselgel (Kleselgel 60 fra firma E. Merck, Darmstadt) med eddIkester/Me0H/20 :2. Reaksjonsproduktet ble oppløst i eter og ved tilsetning av eterisk saltsyre overført til hydrokloridet. Hydrokloridet ble tørket i eksikkator over NaOH. E. Merck, Darmstadt). To separate 8-methylquinoline, the reaction product was eluted with CH 2 Cl 2 and then with CH 2 Cl 2 : MeOH / 20:4. The raw material was again chromatographed on silica gel (Kleselgel 60 from the company E. Merck, Darmstadt) with ethyl acetate/MeOH/20:2. The reaction product was dissolved in ether and, by addition of ethereal hydrochloric acid, transferred to the hydrochloride. The hydrochloride was dried in a desiccator over NaOH.
Utbytte: 0,226 g . Smp. 134-136°C. Yield: 0.226 g. Temp. 134-136°C.
Fremstilling av utgangsforbindelsen: 6-metyl - 4 - dipropylamino-1,3,4,5-tetrahydrobenz[c,d]-indol-2-karboksylsyre Preparation of the starting compound: 6-methyl-4-dipropylamino-1,3,4,5-tetrahydrobenz[c,d]-indole-2-carboxylic acid
En oppløsning av 2 g (0,005285 mol) 4-(5-nitro-8-metoksy-2-dipropylamlno-l,2,3,4-tetrahydronaftalin)-2-okso-eddiksyre i 7,5 ml 25#-ig vandig ammoniakk ble blandet under omrøring med en varm oppløsning av 9,69 g (0,03485 mol) FeS04 . 7 H20 I 10,6 ml H2O og deretter oppvarmet 1 time under tilbakeløp. Etter avkjøling til værelsestemperatur ble det uoppløselig sorte residuet frafiltrert og vasket med en blanding e MeOH:CH2Cl2/50:50. Etter fjerning av oppløsningsmidlet b] residuet kromatografert på kiselgel (Kleselgel 60 fra firn E. Merck, Darmstadt) med CH2C12 : MeOH/20 : 6. Det sålede fremstilte produkt ble krystallisert med utdrivning me CH2C12 og tørket i eksikkator over P205. A solution of 2 g (0.005285 mol) of 4-(5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene)-2-oxo-acetic acid in 7.5 ml of 25#- 1 g aqueous ammonia was mixed with stirring with a hot solution of 9.69 g (0.03485 mol) FeSO 4 . 7 H 2 O in 10.6 ml H 2 O and then heated for 1 hour under reflux. After cooling to room temperature, the insoluble black residue was filtered off and washed with a mixture of MeOH:CH2Cl2/50:50. After removal of the solvent b] the residue chromatographed on silica gel (Kleselgel 60 from firn E. Merck, Darmstadt) with CH 2 Cl 2 : MeOH/20 : 6. The filtered product was crystallized by expulsion with CH 2 Cl 2 and dried in a desiccator over P 2 O 5 .
Utbytte: 0,35 g Yield: 0.35 g
4-(5-nitro-8-metoksy-2-dipropylamino-l,2,3,4-tetrahydrc naftalin)-2-oksoeddiksyre 4-(5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene)-2-oxoacetic acid
11,5 g (0,0283 mol) etyl-2-(5-nitro-8-metoksy-2-dipropyl-amino-1,2,3,4-tetrahydronaftalin)-2-oksacetat ble oppløst i 300 ml MeOH og blandet under nitrogenspyling ved 18°C med 100 ml (0,1 mol) 1 n NaOH. Den rødfargede reaksjonsoppløsning lot man deretter stå 14 timer ved 4°C. Reaksjonsoppløsningen ble nøytralisert med 100 ml (0,1 mol) 1 n HC1 og befridd for MeOH på rotasjonsfordamper. Den gjenblivende vandige fase ble ekstrahert med CH2C12. Etter fjerning av oppløsnings-midlet tørket man residuet i eksikkatoren over P205. 11.5 g (0.0283 mol) of ethyl 2-(5-nitro-8-methoxy-2-dipropyl-amino-1,2,3,4-tetrahydronaphthalene)-2-oxaacetate was dissolved in 300 ml of MeOH and mixed under a nitrogen purge at 18°C with 100 mL (0.1 mol) 1 N NaOH. The red colored reaction solution was then allowed to stand for 14 hours at 4°C. The reaction solution was neutralized with 100 mL (0.1 mol) 1 N HCl and freed from MeOH on a rotary evaporator. The remaining aqueous phase was extracted with CH 2 Cl 2 . After removal of the solvent, the residue was dried in the desiccator over P2O5.
Utbytte: 10,2 g gulfarget krystallinsk produkt. Yield: 10.2 g of yellow crystalline product.
Smp. (Mettler FP 61 ) = 200,9°C. Temp. (Mettler FP 61 ) = 200.9°C.
Etyl-2-(5-nitro-8-metoksy-2-dipropylamino-l,2,3, 4-tetrahydronaftalin)-2-oksoacetat Ethyl 2-(5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene)-2-oxoacetate
0,94 g (0,024 mol) kalium ble under nitrogen og fuktighetsutelukkelse dekket med 22 ml absolutt dietyleter og deretter blandet under omrøring ved værelsestemperatur i 5 porsjoner med hver gang 1,11 ml (0,0191 mol) abs. etanol. Etter at kalium hadde oppløst seg satte man til reaksjons-oppløsningen 3,26 ml (0,024 mol) oksalsyredietylester og en oppløsning av 7,4 g (0,02415 mol) 5-nitro-8-metoksy-2-dipropylamino-1,2,3,4-tetrahydronaftal in i 7,5 ml abs. dietyleter, lot det omrøre i 1 1/2 time, tilsatte deretter annen del på 3,26 ml (0,024 mol) oksalsyredietylester og fullstendiggjorde reaksjonen ved 18 timers omrøring ved 18"C. Reaksjonsoppløsningen ble blandet med 150 ml CH2CI2 og filtrert over kiselgur. Filtratet befridde man for 0.94 g (0.024 mol) of potassium was covered under nitrogen and moisture exclusion with 22 ml of absolute diethyl ether and then mixed with stirring at room temperature in 5 portions with each time 1.11 ml (0.0191 mol) abs. ethanol. After the potassium had dissolved, 3.26 ml (0.024 mol) of diethyl oxalic acid and a solution of 7.4 g (0.02415 mol) of 5-nitro-8-methoxy-2-dipropylamino-1,2 ,3,4-tetrahydronaphthalene in 7.5 ml abs. diethyl ether, allowed to stir for 1 1/2 hours, then added another portion of 3.26 mL (0.024 mol) oxalic acid diethyl ester and completed the reaction by stirring for 18 hours at 18"C. The reaction solution was mixed with 150 mL of CH 2 Cl 2 and filtered over diatomaceous earth. The filtrate was freed from
oppløsningsmiddel og kromatograferte det oljeaktige residuet på kiselgel (Kleselgel 60 fra firma E. Merck, Darmstadt, 0,04- 0,063 mm kornstørrelse) med elueringsmiddelblanding CH2C12 : MeOH/20 : 0,5. solvent and chromatographed the oily residue on silica gel (Kleselgel 60 from the company E. Merck, Darmstadt, 0.04-0.063 mm grain size) with eluent mixture CH 2 Cl 2 : MeOH/20 : 0.5.
Utbytte: 4,3 g; 1,4 g utgangsprodukt ble gjenvunnet. Yield: 4.3 g; 1.4 g of starting product was recovered.
5-nitro-8-metoksy-2-dipropylamlno-l,2,3, 4-tetrahydronaftalin 5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene
En oppløsning av 5,5 g (0,02106 mol) 8-metoksy-2-dipropyl-amino-1,2,3,4-tetrahydronaftalin i 152 ml (1,976 mol) tri-fluoreddlksyre ble under omrøring, fuktighetsutelukkelse og nitrogenspyling ved en temperatur på 5"C blandet med 2,9 g (0,0341 mol) natriumnitrat og deretter omrørt 1 time ved 5°C. A solution of 5.5 g (0.02106 mol) of 8-methoxy-2-dipropyl-amino-1,2,3,4-tetrahydronaphthalene in 152 ml (1.976 mol) of trifluoroacetic acid was stirred, moisture excluded and nitrogen purged at a temperature of 5°C mixed with 2.9 g (0.0341 mol) of sodium nitrate and then stirred for 1 hour at 5°C.
Reaksjonsoppløsningen ble helt på is og med en 30#-ig vandig NaOH-oppløsning innstilt på pH 10. Deretter ekstraherte man med metylenklorid. Residuet fra Cl^C^-fasen ble kromatografert på AI2O3 (AI2O3 90 fra firma Merck, Darmstadt, korn-størrelse 0,063 - 0,200 mm) med toluen som elueringsmiddel. The reaction solution was poured onto ice and adjusted to pH 10 with a 30% aqueous NaOH solution. Extraction was then carried out with methylene chloride. The residue from the Cl^C^ phase was chromatographed on AI2O3 (AI2O3 90 from Merck, Darmstadt, grain size 0.063 - 0.200 mm) with toluene as eluent.
Utbytte: 3,3 g gulfarget olje (50,8& av det teoretiske). Yield: 3.3 g of yellow oil (50.8& of the theoretical).
Claims (2)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3346573A DE3346573A1 (en) | 1983-12-23 | 1983-12-23 | 1,3,4,5-TETRAHYDROBENZ (C, D) INDOLE, A METHOD FOR THE PRODUCTION AND THEIR USE |
Publications (3)
Publication Number | Publication Date |
---|---|
NO844868L NO844868L (en) | 1985-06-24 |
NO162615B true NO162615B (en) | 1989-10-16 |
NO162615C NO162615C (en) | 1990-01-24 |
Family
ID=6217791
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO844868A NO162615C (en) | 1983-12-23 | 1984-12-05 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,3,4,5-TETRAHYDROBENZ (C, D) INDOLES. |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0148440B1 (en) |
JP (1) | JPS60156670A (en) |
KR (1) | KR910006979B1 (en) |
AT (1) | ATE37711T1 (en) |
AU (1) | AU566758B2 (en) |
DE (2) | DE3346573A1 (en) |
DK (1) | DK157295C (en) |
ES (2) | ES8605237A1 (en) |
FI (1) | FI79299C (en) |
GR (1) | GR82577B (en) |
IL (1) | IL73875A (en) |
NO (1) | NO162615C (en) |
NZ (1) | NZ210665A (en) |
PH (1) | PH23272A (en) |
PT (1) | PT79750A (en) |
ZA (1) | ZA8410038B (en) |
Families Citing this family (24)
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 |
US4983622A (en) * | 1984-02-06 | 1991-01-08 | Eli Lilly And Company | 6-substituted-4-dialkylaminotetrahydrobenz(c,d)indoles |
US5026869A (en) * | 1984-02-06 | 1991-06-25 | Eli Lilly And Company | 6-substituted-4-dialkylaminotetrahydrobenz(c,d)indoles |
CA1266482A1 (en) * | 1984-05-24 | 1990-03-06 | Carl Kaiser | 6-oxygenated-1,3,4,5-tetrahydrobenz(cd)indol-4-amines |
DE3525564A1 (en) * | 1985-07-15 | 1987-02-05 | Schering Ag | TRICYCLIC COMPOUNDS WITH INDOLSTRUCTURE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
US4745126A (en) * | 1987-03-12 | 1988-05-17 | Eli Lilly And Company | Method of treating anxiety with tetrahydrobenz[c,d]indole-6-carboxamides |
DE3809155A1 (en) * | 1988-03-18 | 1989-09-28 | Bayer Ag | 1,3,4,5-TETRAHYDROBENZ- (C, D) indoles |
US5204340A (en) * | 1989-04-11 | 1993-04-20 | Eli Lilly And Company | Tetrahydrobenz(c,d)indole serotonin agonists |
US5273975A (en) * | 1989-06-09 | 1993-12-28 | The Upjohn Company | Heterocyclic amines having central nervous system activity |
US5212319A (en) * | 1990-02-26 | 1993-05-18 | Eli Lilly And Company | Intermediates to 4-amino-hexahydrobenz[cd]indoles and processes therefor |
US5302612A (en) * | 1990-02-26 | 1994-04-12 | Eli Lilly And Company | 6-substituted-hexahydrobenz[cd]indoles |
US5258379A (en) * | 1990-05-04 | 1993-11-02 | Eli Lilly And Company | Method of inhibiting gastric acid secretion with n-arylpiperazines |
US5096908A (en) * | 1990-05-04 | 1992-03-17 | Eli Lilly And Company | Method of inhibiting gastric acid secretion |
US5340838A (en) * | 1990-05-04 | 1994-08-23 | Eli Lilly And Company | Method of inhibiting gastric acid secretion with 2-phenylcyclopropylamines |
US5229409A (en) * | 1990-08-15 | 1993-07-20 | Eli Lilly And Company | 6-substituted-tetrahydrobenz[cd]indoles |
US5229410A (en) * | 1990-08-15 | 1993-07-20 | Eli Lilly And Company | 6-substituted-hexahydrobenz[cd]indoles |
US5347013A (en) * | 1991-03-28 | 1994-09-13 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz[cd]indoles |
US5364856A (en) * | 1991-03-28 | 1994-11-15 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz[CD]indoles |
US5643910A (en) * | 1991-03-28 | 1997-07-01 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2A,3,4,5-hexahydrobenz[CD]indoles |
US5244911A (en) * | 1991-03-28 | 1993-09-14 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,2,2a,3,4,5-hexahydrobenz(cd)indoles and pharmaceutical use thereof |
US5244912A (en) * | 1991-03-28 | 1993-09-14 | Eli Lilly And Company | 6-heterocyclic-4-amino-1,3,4,5-tetrahydrobenz(cd)indoles and pharmaceutical use thereof |
US5652245A (en) | 1993-07-27 | 1997-07-29 | Pharmacia & Upjohn Company | Heterocyclic amines having central nervous system activity |
TW430660B (en) * | 1996-05-30 | 2001-04-21 | Mochida Pharm Co Ltd | Novel benzindole derivatives for neuron cell protection, processes for production, and the pharmaceutical compounds containing them |
US7074927B2 (en) | 1999-05-13 | 2006-07-11 | Pharmacia & Upjohn Company | Heterocyclic amines having central nervous system activity |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3194811A (en) * | 1963-09-05 | 1965-07-13 | Merck & Co Inc | Aroyl-benzindolyl acids |
CH517732A (en) * | 1969-10-24 | 1972-01-15 | Sandoz Ag | Guanidine derivs - with stimulant psychotherapeutic, sali-diuretic and antipyretic activity |
US4110339A (en) * | 1977-11-25 | 1978-08-29 | Eli Lilly And Company | 4-(Di-n-propyl)amino-1,3,4,5-tetrahydrobenz[cd]indole |
US4282240A (en) * | 1979-11-23 | 1981-08-04 | Merck & Co., Inc. | Amino substituted tetrahydrobenzindoles |
FR2522658A1 (en) * | 1982-03-05 | 1983-09-09 | Roussel Uclaf | APPLICATION AS MEDICAMENTS OF 4-AMINO BENZ TRANSDUCERS (C, D) INDOL-5-OL AND THEIR SALTS, COMPOSITIONS COMPRISING THEM, NOVEL DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
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 |
CA1266482A1 (en) * | 1984-05-24 | 1990-03-06 | Carl Kaiser | 6-oxygenated-1,3,4,5-tetrahydrobenz(cd)indol-4-amines |
-
1983
- 1983-12-23 DE DE3346573A patent/DE3346573A1/en not_active Withdrawn
-
1984
- 1984-12-05 ES ES538290A patent/ES8605237A1/en not_active Expired
- 1984-12-05 NO NO844868A patent/NO162615C/en unknown
- 1984-12-12 AT AT84115218T patent/ATE37711T1/en not_active IP Right Cessation
- 1984-12-12 EP EP84115218A patent/EP0148440B1/en not_active Expired
- 1984-12-12 DE DE8484115218T patent/DE3474444D1/en not_active Expired
- 1984-12-17 PH PH31592A patent/PH23272A/en unknown
- 1984-12-17 AU AU36904/84A patent/AU566758B2/en not_active Ceased
- 1984-12-19 JP JP59266500A patent/JPS60156670A/en active Granted
- 1984-12-20 FI FI845070A patent/FI79299C/en not_active IP Right Cessation
- 1984-12-20 IL IL73875A patent/IL73875A/en unknown
- 1984-12-20 NZ NZ210665A patent/NZ210665A/en unknown
- 1984-12-21 KR KR1019840008206A patent/KR910006979B1/en not_active IP Right Cessation
- 1984-12-21 DK DK625584A patent/DK157295C/en not_active IP Right Cessation
- 1984-12-21 GR GR82577A patent/GR82577B/en unknown
- 1984-12-21 PT PT79750A patent/PT79750A/en not_active IP Right Cessation
- 1984-12-21 ZA ZA8410038A patent/ZA8410038B/en unknown
-
1985
- 1985-12-16 ES ES549978A patent/ES8701721A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPH0475909B2 (en) | 1992-12-02 |
AU3690484A (en) | 1985-07-04 |
ATE37711T1 (en) | 1988-10-15 |
KR850004462A (en) | 1985-07-15 |
DK157295B (en) | 1989-12-04 |
JPS60156670A (en) | 1985-08-16 |
FI79299C (en) | 1989-12-11 |
DE3346573A1 (en) | 1985-07-04 |
DK157295C (en) | 1990-05-07 |
EP0148440A1 (en) | 1985-07-17 |
DK625584A (en) | 1985-06-24 |
ES538290A0 (en) | 1986-03-16 |
GR82577B (en) | 1985-04-23 |
NO844868L (en) | 1985-06-24 |
DE3474444D1 (en) | 1988-11-10 |
FI79299B (en) | 1989-08-31 |
ES8605237A1 (en) | 1986-03-16 |
NZ210665A (en) | 1988-06-30 |
ZA8410038B (en) | 1985-08-28 |
AU566758B2 (en) | 1987-10-29 |
PT79750A (en) | 1985-01-01 |
FI845070L (en) | 1985-06-24 |
FI845070A0 (en) | 1984-12-20 |
PH23272A (en) | 1989-06-23 |
ES549978A0 (en) | 1986-12-01 |
EP0148440B1 (en) | 1988-10-05 |
IL73875A (en) | 1988-08-31 |
IL73875A0 (en) | 1985-03-31 |
KR910006979B1 (en) | 1991-09-14 |
ES8701721A1 (en) | 1986-12-01 |
DK625584D0 (en) | 1984-12-21 |
NO162615C (en) | 1990-01-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO162615B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,3,4,5-TETRAHYDROBENZ (C, D) INDOLES. | |
CZ280769B6 (en) | N-acyl-2,3-benzodiazepine derivative, process of its preparation and a pharmaceutical preparation containing thereof | |
JPWO2002074746A1 (en) | Benzoazepine derivatives | |
JPH0656799A (en) | Quinoxaline-2,3-(1h,4h)-dione | |
JPH0320395B2 (en) | ||
IE851633L (en) | Pyrido-indole compounds | |
NZ195504A (en) | Indolobenzoxazine derivatives and pharmaceutical compositions | |
US4510157A (en) | 6,7,8,9-Tetrahydro-1H-benz(g)indol-8-amine derivatives | |
SU1169538A3 (en) | Method of obtaining tricyclic compounds | |
AU596927B2 (en) | Pyrido (1,8) naphthyridinones and their use as pharmaceuticals | |
KR20010022658A (en) | 3-Substituted 3,4,5,7-Tetrahydro-Pyrrolo[3',4':4,5]Thieno[2,3-D]Pyrimidine Derivatives, Their Preparation and Use as 5HT Antagonists | |
US4100278A (en) | Novel benzazepines | |
US4180581A (en) | N-9,10-dihydrolysergyl-m-aminobenzoic acid amide derivative | |
TWI254707B (en) | Benzazepine derivatives as MAO-B inhibitors | |
KR880001719B1 (en) | Process for preparing 1,4,9,10-tetra hydro pyrazolo(4,3-e)pyrido(3,2-b)(1,4)diazepino-10-ones | |
US4420476A (en) | Benzofuro[3,2-c]pyrazol-3-amine derivatives | |
JPH03120271A (en) | Phenyl alkylamine derivative having anti-ischemic activity | |
KR930006777B1 (en) | Pyrido |1,2-a¨ indoles | |
US3895036A (en) | 9-Amino-3-(amino or nitro)-1,5-dioxaspiro{8 5.5{9 undecane derivatives | |
US4431657A (en) | Analgesic compositions consisting of 2H-benzothieno[3,2-c]pyrazol-3-amine derivatives | |
CZ337295A3 (en) | Naphthyridine derivatives, process of their preparation and pharmaceutical compositions containing thereof | |
EP0118566B1 (en) | INDENO[1,2-b]PYRROLE DERIVATIVES | |
EP0055043A2 (en) | 6,7,8,9-Tetrahydro-3H-benz(e)indolamine derivatives, processes for their preparation and intermediates used therein, and pharmaceutical compositions containing the indolamine derivatives | |
US3781270A (en) | Substituted methano dibenzazocines and dibenzazonines | |
US3983127A (en) | Pyrrolo[3,4-b]pyridines |