NO143744B - Analogifremgangsmaate for fremstilling av fysiologisk aktive benz(de)isokinolin-derivater - Google Patents
Analogifremgangsmaate for fremstilling av fysiologisk aktive benz(de)isokinolin-derivater Download PDFInfo
- Publication number
- NO143744B NO143744B NO760025A NO760025A NO143744B NO 143744 B NO143744 B NO 143744B NO 760025 A NO760025 A NO 760025A NO 760025 A NO760025 A NO 760025A NO 143744 B NO143744 B NO 143744B
- Authority
- NO
- Norway
- Prior art keywords
- benz
- isoquinoline
- dione
- acid
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 4
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 title 2
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052736 halogen Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- -1 1-substituted-4-piperidinyl) group Chemical group 0.000 description 6
- BVEQCSSYYLIIHY-UHFFFAOYSA-N 2-(4-bromobutyl)benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(N(CCCCBr)C2=O)=O)=C3C2=CC=CC3=C1 BVEQCSSYYLIIHY-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- XKPZHSCHHBRGLY-UHFFFAOYSA-N 2-(2-hydroxyethyl)benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(N(CCO)C2=O)=O)=C3C2=CC=CC3=C1 XKPZHSCHHBRGLY-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 3
- XLNYKKLAKBFEIP-UHFFFAOYSA-N 2-(5-bromopentyl)benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(N(CCCCCBr)C2=O)=O)=C3C2=CC=CC3=C1 XLNYKKLAKBFEIP-UHFFFAOYSA-N 0.000 description 3
- MLYDUNKGAQLZAO-UHFFFAOYSA-N 2-(6-bromohexyl)benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(N(CCCCCCBr)C2=O)=O)=C3C2=CC=CC3=C1 MLYDUNKGAQLZAO-UHFFFAOYSA-N 0.000 description 3
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- 150000007513 acids Chemical class 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical class C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- MRGZFRXUOCSAPS-UHFFFAOYSA-N n-[1-[2-(1,3-dioxobenzo[de]isoquinolin-2-yl)ethyl]piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCN2C(C=3C=CC=C4C=CC=C(C=34)C2=O)=O)CCC1N(C(=O)CC)C1=CC=CC=C1 MRGZFRXUOCSAPS-UHFFFAOYSA-N 0.000 description 3
- NNJGASUSNHBIMV-UHFFFAOYSA-N n-[1-[4-(1,3-dioxobenzo[de]isoquinolin-2-yl)butyl]piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCCCN2C(C=3C=CC=C4C=CC=C(C=34)C2=O)=O)CCC1N(C(=O)CC)C1=CC=CC=C1 NNJGASUSNHBIMV-UHFFFAOYSA-N 0.000 description 3
- RDRSMOCRXKAZJW-UHFFFAOYSA-N n-[1-[5-(1,3-dioxobenzo[de]isoquinolin-2-yl)pentyl]piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCCCCN2C(C=3C=CC=C4C=CC=C(C=34)C2=O)=O)CCC1N(C(=O)CC)C1=CC=CC=C1 RDRSMOCRXKAZJW-UHFFFAOYSA-N 0.000 description 3
- APKQHJYFARNCOM-UHFFFAOYSA-N n-[1-[6-(1,3-dioxobenzo[de]isoquinolin-2-yl)hexyl]piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CCCCCCN2C(C=3C=CC=C4C=CC=C(C=34)C2=O)=O)CCC1N(C(=O)CC)C1=CC=CC=C1 APKQHJYFARNCOM-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- PMCBDBWCQQBSRJ-UHFFFAOYSA-N norfentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C1CCNCC1 PMCBDBWCQQBSRJ-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- LIEGIQPEUGHGAI-UHFFFAOYSA-N 4-phenylpiperidine-2,6-dione Chemical class C1C(=O)NC(=O)CC1C1=CC=CC=C1 LIEGIQPEUGHGAI-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- SXRBHFOCAGOMOP-UHFFFAOYSA-N 6-methoxy-2-(2-piperidin-1-ylethyl)benzo[de]isoquinoline-1,3-dione Chemical compound O=C1C(C2=3)=CC=CC=3C(OC)=CC=C2C(=O)N1CCN1CCCCC1 SXRBHFOCAGOMOP-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010023230 Joint stiffness Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRSMWKLPSNHDHA-UHFFFAOYSA-N Naphthalic anhydride Chemical compound C1=CC(C(=O)OC2=O)=C3C2=CC=CC3=C1 GRSMWKLPSNHDHA-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920005557 bromobutyl Polymers 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
Forskjellige naftalimicl-forbindelser er utviklet for anvendelse som farvestoffer og optiske lysgjøringsmidler. Kimura et al., beskriver f.eks. i Chem. Abst., Vol. 62, 11950c forbind-elsen N-[2-piperidinoetyl]-4-metoksy-l,8-naftalimid (dvs. 6-metoksy-2-[2-(1-piperidinyl)etyl]-lH-benz[de]isokinolin-1,3(2H)-dion under den nuværende Chem. Abst.. nomenklatur) som optisk lysgjøringsmiddel.. Noguchi et al. i U.S. patent 3.625.947 beskriver 2-[-(2- eller 4-pyridyl)etyl]-lH-benz[de]isokinolin-1,3(2H)-dioner som fluoreserende hvitningsmidler.
Schenker et al. i U.S. patent 3.247.208 angir at 1H-benz[de]isokinolin-1,3 (2H)-dioner med en (l-substituert-4-pip-eridinyl)-gruppe i 2-stillingen har anestetiske egenskaper.
Carron et al. i fransk patent 2.167.355 angir at (4-fenyl)-piperidin-2,6-dioner med en alkylheteroalkyl-substituent i 1-stillingen har antidepressiv virkning. Imider med en nitro-imidazolyletylgruppe som N-substituent og med antibakteriell og antiprotozoisk virkning er beskrevet i U.S. patent 3.642.836
og 3.770.763. Visse imidodikarboksylsyreimider med forskjellige farmakologiske egenskaper er beskrevet i U.S. patent 3.560.4 95.
Janssen i U.S. patenter 3.164.600 og 3.161.637 beskriver N-aralkyl-4-piperidyl-N-arylalkanamider med smertestillende virkning og N-aroylpropyl-4-piperidyl-N-arylalkanamider med neuroleptisk virkning.
Denne oppfinnelse angår fremstilling av nye N-[l-[(l,3-dihydro-1,3-diokso-2H-benz[de]isokinolin-2-yl)alkyl]-4-piper-idinyl]-N-fenylalkylamider og deres syreaddisjonssalter med formelen
A er i formel I og i resten av beskrivelsen en lineær eller forgrenet alkylengruppe med 1 til 8 karbonatomer.
Lineære eller forgrenede alkylengrupper med 1 til 8 karbonatomer omfatter slike grupper som -(CI^) - hvor n er 1 til 8,
Foretrukne forbindelser med formel I er de hvor A er en lineær eller forgrenet alkylengruppe med 1 til 6 karbonatomer.
De mest foretrukne forbindelser er de hvor A er
-(CH2)n- hvor n er et helt tall fra 2 til 6.
De nye forbindelser fremstilles ved at en forbindelse med formelen
(V)
hvor Y er hydroksy eller halogen, omsettes med en forbindelse med formelen
Det følgende reaksjonsskjerna illustrerer oppfinnelsen,
Mellomproduktet med formel V kan også fremstilles ved å kombinere et substituert naftalimid med formel VIII i et organisk oppløsningsmiddel, med en polar organisk oppløs-ningsmiddeloppløsning av en base, som f.eks. en alkoholoppløs-ning av kaliumhydroksyd, fulgt av tilsetning av en oppløsning av en forbindelse med formel IX
hvor Y' og Y er like eller forskjellige og er utgående grupper valgt fra tosylat, metanosulfonat og halogen, og A er en line-
ær eller forgrenet alkylengruppe med 2 til 8 karbonatomer.
Avhengig av reaksjonsbetingelsene og de anvendte utgangs-materialer oppnåes de nye forbindelser i fri form eller i form av syreaddisjonssaltene. Saltene derav kan omdannes til de frie forbindelser på kjent måte såsom ved omsetnig med et basisk mid-del. Frie baser som oppnåes, kan omdannes til farmasøytisk akseptable syreaddisjonssalter ved omsetning med forskjellige syrer. Syrer som er egnet for fremstilling av disse syreaddisjonssalter omfatter blant annet uorganiske syrer såsom halogenhydrogensyrer (f.eks. saltsyre og bromhydrogensyre), svovelsyre, salpetersyre og fosforsyre, og organiske syrer såsom maleinsyre, fumarsyre, vinsyre, sitronsyre, eddiksyre, benzoesyre, 2-acetoksybenzoesyre, salicylsyre, ravsyre, nikotinsyre, metansulfonsyre eller cyklo-heksansulfamidsyre.
De nye forbindelser fremstilt ifølge oppfinnelsen, innbe-fattet syreaddisjonssaltene derav, er i stand til å modifisere sentralnervesystemet. Når de administreres til mus, katter, rot-ter, hunder og andre pattedyr-arter i mengder varierende fra ca. 0,5 til ca. 100 mg pr.kg kroppsvekt pr. dag, har disse forbindelser særlig antidepressiv virkning. En foretrukket dosemengde for optimale resultater er fra ca. 1 til ca. 5 mg pr. kg kroppsvekt pr. dag, og det anvendes slike doseenheter at totalt fra ca. 35 mg til ca. 3 g aktiv bestanddel administreres i en enkelt eller flere doser over en periode på 24 timer.
Den antidepressive virkning av forbindelsene med formel I påvises ved deres evne til å motvirke tetrabenazin-fremkalt ptosis ved metoden ifølge Vernier et al. ("The Pharamcodynamics of Amitriptyline", Psychosomatic Medicine, (1962), sid 683-690) og også ved deres evne til å blokkere gjenopptagelsen av mono-aminer in vitro ved metoden ifølge Horn et al. (Molecular Pharma-cology, 7th Ed., (1971), side 66).
Forbindelsene med formel I er også egnet som antiinflamma-toriske midler og kan f.eks. anvendes på samme måte som fenyl-butazon eller indometacin. De kan anvendes til å redusere hevel-ser i ledd, ømhet', smerte og stivhet i pattedyr, f.eks. ved lid-elser såsom revmatisk artritt. Den mengde som administreres, var-ierer fra ca. 1 mg til ca. 15 mg pr. kg kroppsvekt pr. dag.
For ethvert av disse farmasøytiske formål kan en forbindelse eller blanding av forbindelser med formel I eller deres farmasøy-tisk akseptable syreaddisjonssalter administreres oralt eller par-enteralt i vanlig doseringsform såsom tabletter, kapsler, inji-serbare preparater eller lignende.
Disse kan tilberedes konvensjonelt i en oral eller parent-eral doseringsform ved blanding med et vanlig bæremiddel, hjelpe-stoff, bindemiddel, konserveringsmiddel, stabilisator, smaksstoff eller lignende avhengig av hva som er nødvendig.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere og representerer foretrukne utførelsesformer. Andre modifikasjoner kan lett gjøres ved passende variasjoner av omsetningene. Alle temperaturer er i °C.
EKSEMPEL 1
N-[-[2-(l,3-dihydro-l,3-diokso-2H-benz[de]isokinolin-2-yl)-etyl]-4-piperidinyl]-N-fenylpropanamid, hydroklorid (1:1)
a) 2-( 2- hydroksyetyl)- lH- benz[ de] isokinolin- 1, 3( 2H)- dion 50 g (0,252 mol) naftalsyreanhydrid og 16 g (0,262 mol)
etanolamin tilbakeløpsbehandles i 3 timer i 200 ml vann (oppløs-ningen blir aldri fullstendig). Efter avkjøling til 25° avde-kanteres vannet, og residuet omkrystalliseres fra 95% etanol for å gi 47,8 g 2-(2-hydroksyetyl)-lH-benz[de]isokinolin-1,3(2H)-dion; sm.p. 172-173°.
b) 2-( 2- hydroksyetyl)- lH- benz[ de] isokinolin- 1, 3( 2H)- dion, 4-metylbenzensulfonat- ester
52 g (0,216 mol) 2-(2-hydroksyetyl)-lH-benz[de]isokinolin-1 ,3(2H)-dion og 100 g (0,525 mol) p-toluensulfonylklorid. settes til 600 ml pyridin som på forhånd er avkjølt til 5°. Blandingen ristes kort og får derefter stå natten over ved 5°. Blandingen helles derefter i 300 ml is og vann, omrøres i 15 minutter og filtreres. Det uoppløselige materiale omrøres med friskt vann, frafiltreres igjen og tørres natten over ved 25°
(0,1 mm Hg) for å gi 83 g 2-(2-hydroksyetyl)-lH-benz[de]isokinolin-1 , 3 ( 2H) -dion , 4-metylbenzensulfonat-ester.
c) N-[ 1-[ 2-( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-etyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid ( 1:1)
En blanding av 8,1 g (0,02 mol) av esteren fra del b), 5,0 g (0,02 mol) 4-(N-propionylanilino)piperidin og 2,66 g '
(0,02 mol) diisopropyletylamin tilbakeløpsbehandles i 400 ml toluen i 6 timer. Toluenet avdampes, og residuet oppløses i kloroform og vaskes med 10% KOH og vann (alle vandige lag til-bakevaskes). Kloroformen avdampes, og residuet krystalliseres fra dioksan/heksan. Dette materiale oppløses i toluen og ristes med 10% HC1 inntil den utfelte olje krystalliserer. Krystallene oppsamles fra de to faser og vaskes med vann og toluen for å gi 6,7 g urenset salt; sm.p. 265-270°. Omkrystallisering av det urensede salt tre ganger fra etanol fulgt av tørring ved 80° under vakuum gir 4,65 g N-[1-[2-(1,3-dihydro-l,3-diokso-2H-benz-[de]isokinolin-2-yl)-etyl]-4-piperidinyl]-N-fenylpropanamid, hydroklorid (1:1); sm.p. 270-272° (spaltning).
N-[ 1-[ 4-( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-butyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid
a) 2- ( 4- Tbrombutyl) - lH- benz [ de] isokinolin- 1, 3 ( 2H) - dion
100 g (0,5 mol) 1,8-naftalimid suspenderes i 2100 ml di-metylformamid, og blandingen oppvarmes til 90° for å danne en fullstendig oppløsning. En oppløsning av 36,3 g (0,55 mol) kaliumhydroksyd (85%) i 100 ml metanol tilsettes, hvilket resulterer i umiddelbar dannelse av et gult bunnfall. Den resulterende blanding omrøres i 1 time ved 90° og avkjøles til 25°. 245 g (1,0 mol) 1,4-dibrombutan tilsettes, og blandingen oppvarmes igjen til 90° og omrøres i ytterligere 1 time. Det blir tilbake et bunnfall i blandingen, men dette er mer kornet enn det opprin-nelige materiale. Reaksjonsblandingen avkjøles, og bunnfallet frafiltreres. Oppløsningsmidlet fjernes under vakuum, og residuet fortynnes med 500 ml heksan som umiddelbart fører til utfel-ling av urenset 2-(4-brombutyl)-lH-benz[de]isokinolin-1,3 (2H)-dion. Bunnfallet frafiltreres, vaskes med frisk heksan og tørres i 2 timer ved 50° (0,1 mm) for å gi ,2-(4-brombutyl)-lH-benz[de]-isokinolin-1,3(2H)-dion. En analytisk ren prøve fremstilles ved å oppløse det nevnte produkt i varm 95% etanol og omkrystallisere ved å la oppløsningen avkjøles til 25°. Det resulterende bunnfall tørres i 2 timer ved 50° (0,1 mm) for å gi rent 2-(4-brombutyl)-lH-benz[de]isokinolin-1,3(2H)-dion, sm.p. 113-115°.
b) N-[ 1-[ 4-( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-butyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid
En ekvimolar blanding av 2-(4-brombutyl)-lH-benz[de]-isokinolin-1,3(2H)-dion, fra del a), og 4-(N-propionylanilin)-piperidin og et molart overskudd av natriumkarbonat blandes i 200 ml toluen og tilbakeløpsbehandles i ca. 24 timer. Blandingen avkjøles til romtemperatur, vann tilsettes, og den resulterende blanding ristes og filtreres. Det organiske lag vaskes med vann, tørres, og oppløsningsmidlet fjernes under vakuum. Residuet opp-, løses i varm absolutt etanol og behandles med 10% overskudd av eterisk HCl. Det resulterende bunnfall frafiltreres og tørres for å gi N-[1-[4-(1,3-dihydro-l,3-diokso-2H-benz[de]isokinolin-2-yl)butyl]-4-piperidinyl]-N-fenylpropanamid, hydrklorid.
N-[ 1-[ 5-( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-pentyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid
a) 2-( 5- brompentyl)- lH- benz[ de] isokinolin- 1, 3( 2H)- dion
Ved å følge fremgangsmåten ifølge del a) fra eksempel 2,
men under anvendelse av 1,5-dibrompentan istedenfor 1,4-dibrombutan, får man 2-(5-brompentyl)-lH-benz[de]isokinolin-1,3(2H)-dion; sm.p. 113-115°.
b) N-[ 1-[ 5- ( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-pentyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid
Ved å følge fremgangsmåten ifølge del b) fra eksempel 2, men ved å anvende 2-(5-brompentyl)-lH-benz[de]isokinolin-1,3(2H)-dion isteden for 2-(4-brombutyl)-lH-benz[de]isokinolin-1,3(2H)-dion, får man N-[1-[5-(1,3-dihydro-l,3-diokso-2H-benz[de]-isokinolin-2-yl)pentyl]-4-piperidinyl]-N-fenylpropanamid, hydroklorid.
EKSEMPEL 4
N-[ 1-[ 6-( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-heksyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid
a) 2-( 6- bromheksyl)- lH- benz[ de] isokinolin- 1, 3( 2H)- dion
Ved å følge fremgangsmåten ifølge del a) fra eksempel
31, men under anvendelse av 1,6-dibromheksan istedenfor 1,4-dibrombutan, får man 2-(6-bromheksyl)-lH-benz[de]isokinolin-1,3-(2H)-dion; sm.p. 95-96°.
b) N-[ 1-[ 6-( 1, 3- dihydro- l, 3- diokso- 2H- benz[ de] isokinolin- 2- yl)-heksyl]- 4- piperidinyl]- N- fenylpropanamid, hydroklorid
Ved å følge fremgangsmåten ifølge del b) fra eksempel 2, men under anvendelse av 2-(6-bromheksyl)-lH-benz[de]isokinolin-l,3(2H)-dion istedenfor 2-(4-brombutyl)-lH-benz[de]isokinolin-1,3-(2H)-dion, får man N-[1-[6-(1,3-dihydro-l,3-diokso-2H-benz-[de]isokinolin-2-yl)heksyl]-4-piperidinyl]-N-fenylpropanamid, hydroklorid.
Alternativt kan fremgangsmåten ifølge eksemplene 31-33 anvendes for fremstilling av forbindelsene ifølge eksemplene 1-30.
Claims (1)
- Analogifremgangsmåte for fremstilling av fysiologisk aktive forbindelser med formelen:hvor A er en lineær eller forgrenet alkylengruppe med 1 til 8 karbonatomer,og de farmasøytisk akseptable syreaddisjonssalter derav, karakterisert ved at en forbindelse med formelenhvor Y er hydroksy eller halogen, omsettes med en forbindelse med formelenog eventuelt omdannes den resulterende forbindelse til syre-addis jonssaltet derav.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/538,977 US3959286A (en) | 1975-01-06 | 1975-01-06 | N-(1-(1,3-Dihydro-1,3-dioxo-2H-benz(de)-isoquinolin-2-yl)alkyl)-4-N-piperidinyl)-n-phenylalkylamides |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO760025L NO760025L (no) | 1976-07-07 |
| NO143744B true NO143744B (no) | 1980-12-29 |
| NO143744C NO143744C (no) | 1981-04-08 |
Family
ID=24149234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO760025A NO143744C (no) | 1975-01-06 | 1976-01-05 | Analogifremgangsmaate for fremstilling av fysiologisk aktive benz(de)isokinolin-derivater |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US3959286A (no) |
| JP (1) | JPS5191271A (no) |
| BE (1) | BE837333A (no) |
| CA (1) | CA1070311A (no) |
| CH (1) | CH620210A5 (no) |
| DE (1) | DE2558023A1 (no) |
| DK (1) | DK2176A (no) |
| FR (1) | FR2296417A1 (no) |
| GB (1) | GB1528790A (no) |
| HU (1) | HU172542B (no) |
| IE (1) | IE43651B1 (no) |
| NL (1) | NL7514918A (no) |
| NO (1) | NO143744C (no) |
| PH (1) | PH11443A (no) |
| SE (1) | SE7600046L (no) |
| ZA (1) | ZA757671B (no) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4070465A (en) * | 1976-06-24 | 1978-01-24 | E. R. Squibb & Sons, Inc. | Various 2-(substituted piperazinyl)-1H-benz [de]isoquinoline-1,3 (2H) -diones |
| US4062953A (en) * | 1976-06-24 | 1977-12-13 | E. R. Squibb & Sons, Inc. | Various 2-substituted-1H-benz[de]isoquinoline-1,3(2H)-diones |
| US4051246A (en) * | 1976-09-29 | 1977-09-27 | E. R. Squibb & Sons, Inc. | 2-substituted-1h-benz(de)-isoquinoline-1,3-(2h)-diones |
| US4180579A (en) * | 1976-09-29 | 1979-12-25 | E. R. Squibb & Sons, Inc. | 2-Substituted-1H-benz[de]-isoquinoline-1,3(2H)-diones |
| US4115555A (en) * | 1976-09-29 | 1978-09-19 | E. R. Squibb & Sons, Inc. | 2-Substituted-1H-benz[de]-isoquinoline-1,3(2H)-diones |
| US4170651A (en) * | 1976-09-29 | 1979-10-09 | E. R. Squibb & Sons, Inc. | 2-Substituted-1H-benz-[de]-isoquinoline-1,3(2H)-diones |
| FR2673944B1 (fr) * | 1991-03-13 | 1995-03-10 | Sanofi Elf | Derives de l'1,8-naphtalimide, leur procede de preparation et les compositions pharmaceutiques les contenant. |
| US5235045A (en) * | 1992-03-19 | 1993-08-10 | Microbiomed Corporation | Non-azo naphthalimide dyes |
| US5766600A (en) * | 1993-08-09 | 1998-06-16 | Microbiomed Corporation | Non-azo naphtalimide dyes and uses for same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3625947A (en) * | 1957-01-30 | 1971-12-07 | Nippon Kayaku Kk | N heterocyclic ethyl naphthalimides |
| CH439286A (de) * | 1962-04-10 | 1967-07-15 | Ciba Geigy | Verfahren zur Herstellung neuer Piperidin-Verbindungen |
-
1975
- 1975-01-06 US US05/538,977 patent/US3959286A/en not_active Expired - Lifetime
- 1975-12-08 CA CA241,199A patent/CA1070311A/en not_active Expired
- 1975-12-08 ZA ZA757671A patent/ZA757671B/xx unknown
- 1975-12-16 PH PH17879A patent/PH11443A/en unknown
- 1975-12-22 IE IE2800/75A patent/IE43651B1/en unknown
- 1975-12-22 DE DE19752558023 patent/DE2558023A1/de not_active Withdrawn
- 1975-12-22 NL NL7514918A patent/NL7514918A/xx not_active Application Discontinuation
- 1975-12-22 GB GB52420/75A patent/GB1528790A/en not_active Expired
- 1975-12-23 CH CH1673875A patent/CH620210A5/de not_active IP Right Cessation
-
1976
- 1976-01-05 DK DK2176*#A patent/DK2176A/da unknown
- 1976-01-05 HU HU76SU00000909A patent/HU172542B/hu unknown
- 1976-01-05 SE SE7600046A patent/SE7600046L/xx unknown
- 1976-01-05 NO NO760025A patent/NO143744C/no unknown
- 1976-01-06 BE BE163331A patent/BE837333A/xx unknown
- 1976-01-06 FR FR7600191A patent/FR2296417A1/fr active Granted
- 1976-01-06 JP JP51001372A patent/JPS5191271A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5191271A (en) | 1976-08-10 |
| FR2296417A1 (fr) | 1976-07-30 |
| IE43651B1 (en) | 1981-04-22 |
| ZA757671B (en) | 1976-11-24 |
| NL7514918A (nl) | 1976-07-08 |
| PH11443A (en) | 1978-02-01 |
| HU172542B (hu) | 1978-09-28 |
| AU8753575A (en) | 1977-06-23 |
| IE43651L (en) | 1976-07-06 |
| US3959286A (en) | 1976-05-25 |
| NO760025L (no) | 1976-07-07 |
| CH620210A5 (no) | 1980-11-14 |
| SE7600046L (sv) | 1976-07-07 |
| CA1070311A (en) | 1980-01-22 |
| GB1528790A (en) | 1978-10-18 |
| FR2296417B1 (no) | 1978-08-18 |
| BE837333A (fr) | 1976-07-06 |
| NO143744C (no) | 1981-04-08 |
| DE2558023A1 (de) | 1976-07-15 |
| DK2176A (da) | 1976-07-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI96768C (fi) | Menetelmä valmistaa farmakologisesti arvokasta bentso/5,6/sykloheptapyridiiniä | |
| FI94413B (fi) | Menetelmä valmistaa terapeuttisesti aktiivisia 2-(1-piperatsinyyli)-4-fenyylisykloalkanopyridiinijohdannaisia | |
| AU691829B2 (en) | Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists | |
| US6642228B1 (en) | α1b-adrenergic receptor antagonists | |
| US3940398A (en) | 2-[[4-(Azine or diazine or triazine)-1-piperazinyl]alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones | |
| US4556653A (en) | Pyrido[1,5]benzodiazepinone derivatives and pharmacological activities thereof | |
| SK374892A3 (en) | Bis-benzo or benzopyrido cyclo hepta piperidene, piperidylidene and piperazine compounds and compositions | |
| NO142838B (no) | Analogifremgangsmaate for fremstilling av terapeutisk aktive isokinolinderivater. | |
| EA011635B1 (ru) | Новые производные амида гетероциклической карбоновой кислоты | |
| PT736525E (pt) | Benzonitrilos e fluoretos como agonistas e antagonistas de 5-ht | |
| AU612339B2 (en) | 6,11-dihydro-11-(4-piperidylidene)-5H-benzo(5,6) cyclohepta(1,2-b) pyridines and compositions and methods of use | |
| NO143744B (no) | Analogifremgangsmaate for fremstilling av fysiologisk aktive benz(de)isokinolin-derivater | |
| US3996363A (en) | 2-[(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)alkyl]-1H-benz[de]isoquinolin-1,3(2H)-diones | |
| AU2005266162A1 (en) | Kynurenic acid amide derivatives as NR2B receptor antagonists | |
| US5441956A (en) | Hydroisoquinoline derivatives | |
| US3947452A (en) | 2-[(Dihydroisoquinolinyl or dihydroisoindol-2-yl)alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones | |
| US3940397A (en) | 2-[(Substituted-piperazinyl)alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones | |
| JPH047745B2 (no) | ||
| US3996362A (en) | 2-[[4-(2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-1-(piperidinyl or 1,2,3,6-tetrahydro-1-pyridinyl)]alkyl]-1H-benz[de]isoquinoline-1,3(2H)-diones | |
| SK53699A3 (en) | 6-{3-[4-(fluorobenzyle)-piperidine-1-yl]-propionyl}-3h- -benzoxazole-2-one, method for its preparation, its use and pharmaceutical composition containing the same | |
| HU194228B (en) | Process for production of new, in 11-position substituated 5,11-dihydro-6h-pirido /2,3-b//1,4/-benzodiozepin-6-on and medical compounds containing thereof | |
| IE55033B1 (en) | Esters of cyproheptadine-3-carboxylic acid and structurally related compounds,process for their preparation and pharmaceutical composition containing them | |
| US4062953A (en) | Various 2-substituted-1H-benz[de]isoquinoline-1,3(2H)-diones | |
| CA2261813A1 (en) | Pharmaceutical composition containing a 5ht2c antagonist and a d2 antagonist | |
| BR112015009243A2 (pt) | composto de amina cíclico fluorosubstituído, método para preparar um composto de amina cíclico fluorosubstituído, composição farmacêutica, inibidor de acetilcolinesterase e uso do composto de amina cíclico fluorosubstituído |