HRP950438A2 - N-substituted 3-azabicyclo (3.2.0) heptane derivatives, their preparation and use - Google Patents
N-substituted 3-azabicyclo (3.2.0) heptane derivatives, their preparation and use Download PDFInfo
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- HRP950438A2 HRP950438A2 HRP4427648.6A HRP950438A HRP950438A2 HR P950438 A2 HRP950438 A2 HR P950438A2 HR P950438 A HRP950438 A HR P950438A HR P950438 A2 HRP950438 A2 HR P950438A2
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- Prior art keywords
- group
- formula
- atom
- azabicyclo
- hydroxy
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- -1 N-substituted 3-azabicyclo (3.2.0) heptane Chemical class 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 8
- NEOIOGUWEUTYIH-UHFFFAOYSA-N 3-azabicyclo[3.2.0]heptane Chemical class C1NCC2CCC21 NEOIOGUWEUTYIH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 230000001186 cumulative effect Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 230000000269 nucleophilic effect Effects 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005561 phenanthryl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000002831 pharmacologic agent Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 6
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000009194 climbing Effects 0.000 description 5
- 230000037023 motor activity Effects 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 4
- 229960001252 methamphetamine Drugs 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000011785 NMRI mouse Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000164 antipsychotic agent Substances 0.000 description 3
- 229940005529 antipsychotics Drugs 0.000 description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 3
- 229960004046 apomorphine Drugs 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- WOSAIZGZGABYOJ-UHFFFAOYSA-N 1-(3-chloroprop-1-enyl)naphthalene Chemical compound C1=CC=C2C(C=CCCl)=CC=CC2=C1 WOSAIZGZGABYOJ-UHFFFAOYSA-N 0.000 description 2
- UUAVYXKRUSVCDJ-UHFFFAOYSA-N 1-cycloheptylazepane Chemical class C1CCCCCC1N1CCCCCC1 UUAVYXKRUSVCDJ-UHFFFAOYSA-N 0.000 description 2
- BDTRIDKONHOQQN-UHFFFAOYSA-N 4h-pyrimidin-5-one Chemical compound O=C1CN=CN=C1 BDTRIDKONHOQQN-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000010453 quartz Substances 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
- 208000011580 syndromic disease Diseases 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- SDQJTWBNWQABLE-UHFFFAOYSA-N 1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=C1 SDQJTWBNWQABLE-UHFFFAOYSA-N 0.000 description 1
- UUXFTJCUPHVPKZ-UHFFFAOYSA-N 2-methylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=CC=CC2=NC(C)=CC(=O)N21 UUXFTJCUPHVPKZ-UHFFFAOYSA-N 0.000 description 1
- RMCCXFINVVHKRJ-UHFFFAOYSA-N 3,6-dimethyl-2-(methylamino)pyrimidin-4-one Chemical compound CNC1=NC(C)=CC(=O)N1C RMCCXFINVVHKRJ-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 239000004971 Cross linker Substances 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
- 102000003962 Dopamine D4 receptors Human genes 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 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
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
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- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Description
Opis
Izum se odnosi na nove N-supstituirane derivate azabicikloheptana, njihovu proizvodnju i upotrebu za proizvodnju lijekova.
Poznato je da N-supstituirani derivati azabiciklo-heptana pokazuju iznenađujuće afinitete prema podtipovima receptora dopamina i serotina (DE 42 43 287 , DE 42 19 973). Ovdje posebnu ulogu imaju promatrani visoki afiniteti prema podtipu D4-dopaminskog receptora.
Sada je bilo pronađeno da derivati N-supstituiranog 3-azabiciklo[3.2.0]-heptana formule I
[image]
gdje
R1 predstavlja naftil- ili fenantrilnu skupinu, po potrebi mono- ili disupstituiranu s halogenim atomom,
n predstavlja broj 0, 1, 2, 3 ill 4,
R2 je atom vodika, hidroksi-, C1-C4-alkil ili C1-C4-alkoksi skupina, ili zajedno sa susjednim ugljikovim atomom predstavlja C=O- ili C=S-skupinu,
X i Y predstavljaju ugljikove atome, CH-, CH2-, NH-ili C1-C4-alkil-N-skupine ili dušikov atom,
Z predstavlja izravnu vezu, CO-skupinu, CS-skupinu ili jednu CH- odnosno CH2-skupinu, u kojima se jedan vodikov atom može zamijeniti s jednom hidroksi, amino ili C1-C4-alkoksi skupinom ili halogenim atomom, i
A je vodikov atom, hidroksi, amino, merkapto, C1-C4-alkilamino. di- C1-C4-alkilamino, C1-C4-alkiltio ili C1-C4-alkoksi skupina ili zajedno sa susjednim ugljikovim atomom predstavlja C=O- ili C=S-skupinu, ili
A predstavlja s jednim Y povezanu C3-C4-alkilensku skupinu, koja može sadržavati jednu ili dvije nekumulirane dvostruke veze, a u jednoj CH- ili CH2-skupini može biti zamijenjena s dušikovim ili sumporovim atomom ili s jednom NH- ili N-CH3- skupinom, i pri čemu prsten može biti monosupstituiran ili s atomom fluora ili klora ili s jednom metilnom, metoksi, nitro ili amino skupinom, ili u slučaju benzolovog prstena, on može biti mono-, di- ili trisupstituiran s atomom fluora ili klora ili metilnom, trifluormetilnom, nitro, hidroksi, metoksi, amino, monometil- ili dimetilamino skupinom,
i gdje prsten u desnom dijelu formule 1 na dušikovom atomu br. 1 nosi jednu C1-C4-alkilnu skupinu i može sadržavati i do 3 nekumulirane dvostruke veze,
i njihove soli s fiziološki podnošljivim kiselinama posjeduju dragocjena farmakološka svojstva.
Za supstituente R1 i R2, te n osobito treba navesti slijedeća značenja:
R1: naftil, po potrebi supstituiran s fluorom ili klorom,
R2: metil ili hidroksi,
n: 2.
Prstenasti sistem u desnom dijelu formule I osobito je
[image]
Prednost se daje osobito spojevima u kojima se prstenasti sistem u desnom dljelu molekule izvodi od 7-metil-5H-tiazol[3, 2-a]pirimidin-5-ona, 2,4-(1H,3H)-kinazolindiona, 2-metil-4H-pirido[1,2-a]pirimidin-4-ona, 2-metilamino-3, 6-dimetil-4 (3H) pirimidinona, 2(1H)-klnolona, indolin-2-ona ili 2(3H)-benzimidazolona.
Spojevi prema izumu formule I mogu se proizvesti tako da se spoj formule II
[image]
u kojem n, R , X, Y, Z i A imaju gore navedena značenja, a Nu predstavlja nukleofilnu polaznu skupinu, kemijski pretvara s derivatom 3-azabiciklo[3.2.0]heptana formule III
[image]
u kojoj R ima gore navedeno značenje, i tako dobiven spoj prevodi se, po potrebi, u kiselinsku adicijsku sol neke fiziološki podnošljive kiseline.
Kao nukleofilne polazne skupine za Nu ponajprije dolaze u obzir halogeni atomi, osobito brom ili klor.
Kemijska pretvorba svrhovito se provodi u prisutnosti inertne baze, kao trietilamina ili kalijevog karbonata, kao sredstva za vezanje kiseline, u inertnom otapalu, kao cikličkom zasićenom eteru, osobito tetrahidrofuranu ili dioksanu, ili benzolskom ugljikovodiku, kao toluolu ili ksllolu.
Kemijska reakcija odvija se u pravilu pri temperaturaina od 20 do 150°C, osobito od 80 do 140°C, i općenito je gotova u roku od 1 do 10 sati.
Spojevi prema izumu formule I mogu se očistiti ili prekristalizacijom iz uobičajenih organskih otapala, ponajprije iz nekog nižeg alkohola, kao što je etanol/ ili kromatografijom u koloni.
Racemati se mogu razdvojiti na enantiomere na jednostavan način klasičnim razdvajanje s optički aktivnim karbonskim kiselinama, npr. derivatima vinske kiseline, u inertnom otapalu, npr. nižim alkoholima.
Slobodni derivati 3-azabiciklo[3.2.0]-heptana formule I mogu se na uobičajen način prevesti u kiselinske adicijske soli neke farmakološki podnošljve kiseline, ponajprije miješanjem otopine s ekvivalentom odgovarajuće kiseline. Farmaceutski podnošljive kiseline su primjerice solna kiselina, fosforna kiselina, sumporna kiselina, metansulfonska kiselina, amidosulfonska kiselina, maleinska kiselina, fumarna kiselina, oksalna kiselina, vinska kiselina ili limunska kiselina.
Spojevi prenia izumu pokazuju dragocjena farmakološka svojstva. Oni se mogu primijeniti kao neuroleptici (osobito atlpični), antidepresivi, sedativi, hipnotici, protektiva središnjeg živčanog sustava ili sredstva za opuštanje mišića, osobito za liječenje psihoza.
Kod jednog spoja prema izumu može se kombinirano pojaviti više od navedenih kvaliteta djelovanja. Farmakološko dokazivanje djelovanja provodi se kako in vivo, tako također i in vitro, pri čemu je karakterizacija tvari moguća osobito pomoću djelomičnog vrlo visokog i selektivnog afiniteta prema podtipovima receptora, prije svega D4-receptorima dopamina.
Za karakterizaciju in vivo bile su primijenjene slijedeće metode:
a) Utjecaj na orijentacijski motilitet
U novoj okolini miševi pokazuju pojačano istraživačko ponašanje, koje se očituje u pojačanoj motoričkoj aktivnosti. Ta motorička aktivnost mjeri se u zasjenjenim kavezima u vremenu od 0 do 30 minuta nakon stavljanja životinja (NMRI-miševi, ženke) u kaveze.
ED50: doza koja, u usporedbi s ponašanjem kontrolne skupine koja je dobila placebo, smanjuje motorićku aktivnost za 50%.
b) Antagonizam prema apomorfinu
Ženke NMRI-miševa dobiju 1,21 mg/kg apomorfina s.c. U toj dozi apomorfin dovodi do motoričke aktivnosti koja se očituje u permanentnom penjanju kad se životinje drže u kavezu od žičane mreže. Penjanje se ocjenjuje rezultatom (svake 2 minute tijekom 30 minuta):
0: životinja ima sve četiri noge na podu,
1: životinja ima dvije noge na žici,
2: životinja ima četiri noge na žici (penje se).
Prethodnom obradom s antipsihotikom penjanje se suzbija.
ED50: Doza koja, u usporedbi s kontrolnim životinjama koje su dobile placebo, smanjuje penjanje životnja za 50%.
c) Metamfetamin-antagonizam
Ženke NMRI-miševa dobiju 1 mg/kg metamfetamina p.o. i nakon 30 minuta mjeri im se motorička aktivnost u zasjenjenim kavezima (2 životinje/kavez, 4 kaveza/doza).
Ispitine tvari daju se oralno 30 minuta prije metamfetamina. Povećanje aktivnosti zbog metamfetamina računa se za vrijeme od 15 do 60 minuta nakon stavljanja životinja u mjerne kaveze kao razlika prema kontrolnim životinjama koje su dobile palcebo i izjednači se sa 100%. ED100 je doza ispitne tvari koja potpuno poništava povećanje aktivnosti.
d) Antagonizani prema L-5-HTP
Ženke štakora Sprague-Dawley dobiju L-5-HTP dozu od 316 mg/kg i.p. Od toga životinje razvijaju sindrom uzbudenosti sa simptomima
- for paw treading i
- tremor
koji se procjenjuje pomoću rezultata (0 = nije prisutno, 1 = mjerljivo, 2 = jasno izraženo) svakih 10 minuta tijekom vremena od 20 do 60 minuta nakon davanja L-5-HTP-a. U prosjeku nakon davanja L-5-HTP-a kao rezultat postiže se vrijednost 17. Ispitne tvari daju se p.o. 60 minuta prije L-5-HTP-a. Kao ED50 računa se doza koja prosječno smanjuje kontrolni rezultat za 50%.
Navedene metode prikladne su za karakterizaciju tvari kao antipsihotika; osobito suzbijanje motoričke stimulacije inducirane metamfetaminom vrijedi kao predikativno za antipsihotičko djelovanje. Suzbijanjem sindroma L-5-HTP-a može se pokazati antagonističko djelovanje prema serotinu, kvaliteta učinkovitosti, kako je ona karakteristična za takozvane atipične neuroleptike.
U ovim ispitivanjiina novi spojevi pokazuju dobru učinkovitost.
Izum se, s tim u skladu, odnosi također i na terapeutsko sredstvo, naznačeno sadržajem spoja formule I ili njegove farmakološki podnošljive kiselinske adicijske soli kao aktivne tvari pored uobičajenih tvari nosioca i sredstava za razređenje, te upotrebu novih spojeva kod suzbijanja bolesti.
Spojevi prema izumu mogu se davati na uobičajen način oralno ili parenteralno, intravenozno ili intrarouskularno. Doziranje ovisi o starosti, stanju i težini pacijenta, te o načinu aplikacije. U pravilu dnevna učinkovita doza iznosi između otprilike 1 i 100 mg/kg tjelesne težine kod oralnog davanja i između 0,1 i 10 mg/kg tjelesne težine kod parenteralnog davanja.
Novi spojevi mogu se primjenjivati u uporabnim galenskim oblicima aplikacija čvrsti ili tekući, npr. kao tablete, tablete s filmom, kapsule, prašak, granulat, dražeje, supozitorije, otopine, masti, kreme ili sprejevi. Oni se proizvode na uobičajen način. Pri tome aktivne tvari mogu se preraditi s uobičajenim galenskim pomoćnim sredstvima kao što su veziva za tablete, punila, konzervansi, sredstva za rastvaranje tableta, sredstva za regulacinu tecivosti, omekšivala, umreživala, sredstva za dispergiranje, emulgatori, otapala, sredstva za produženje djelovanja, antioksidanti i/ili potisni plinovi (usporedi (H. Sucker et al. : Pharmazeutische Technologie, Thleme-Verlag, Stuttgart, 1978). Tako dobiveni aplikacijski oblici sadrže aktivnu tvar uobičajeno u količini od 1 do 99% tež.
Tvari formule II potrebne kao polazne tvari za sintezu novih spojeva su poznate ili se dadu pripremiti po metodama poznatim iz literature iz analognih polaznih tvari.
Tvari formule III mogu se pripremiti tako da se amin formule IV
[image]
gdje R1 ima gore navedeno značenje, a R3 je vodik, acetil, benzil ili trifluoracetil, podvrgne fotokemijskoj cikloadiciji [2+2], a po potrebi jedna acilna ili benzilna skupina se odcijepi.
Fotokemijska reakcija dobro uspijeva u inertnom otapalu, ponajprije u acetonu, pri temperaturama od 20 do 80°C. Kao izvor svjetla osobito su prikladne visokotlačne živine žarulje. Po potrebi, od prednosti je provoditi fotocikloadiciju u kvarcnoj aparaturi u atmosferi dušika, po potrebi, uz dodatak otprilike 1 mola solne kiseline po molu amina.
Fotocikloadicija odvija se u većini slučajeva visoko diastereo selektivno u bicikličke spojeve III ekso konfiguracije glede R1;
[image]
Razdvajanjern racemata, npr. pomoću optički aktivnih derivata vinske kiseline, mogu se izoliratl oba čista enantiomera.
Odcjepljenje acilne skupine vrši se po poznatim metodama. Analogno vrijedi za odcjepljenje benzilne skupine.
Amini formule IV poznati su iz literature ili se mogu pripremiti ili tako da kemijski reagira aldehid R1-CHO s vinilmagnezijevim kloridom u alilalkohol V
[image]
konačno se premješta s klorovodikom u alilklorid VI
[image]
i na kraju se supstituira s odgovarajućim alilaminom VII
[image]
ili se cimtaldehid VIII
[image]
izravno podvrgava redukcijskom aminiranju s alilaminom VII
gdje R3 je vodik.
Slijedeći primjeri služe za objašenjenje izuma:
A) Pripremanje polaznih tvari
aa) 1-(naftil)-alilalkohol
U tikvicu za miješanje od 2 litre stavi se, u atomosferi dušika, 277 ml (360 mM) 1,3 M otopine vinilmagenzijevog klorida u tetrahidrofuranu. Konačno se uz miješanje i u atmosferi dušika tijekom 60 minuta pri 30-35°C dodaje otopinu od 50 g (320 mM) 1-naftilaldehida otopljenog u 250 ml tetrahidrofurana.
Reakcijsku smjesu miješa se još 4,5 sata u atmosferi dušika pri sobnoj temperaturi. Nakon toga uz miješanje i hlađenje s ledom doda se 90 ml zasićene otopine amonijevog klorida, odsisa se i ostatak nakon filtriranja ispere se tri puta sa 150 ml tetrahidrofurana. Filtrat se zgusne, osuši pomoću natrijevog sulfata i zgusne. Dobije se 58,3 g (99%) sirovog proizvoda u obliku smeđeg ulja.
ab) 3-(1-naftil)-alilklorid
58,3 g (317 mM) 1- (1-naftil)-alilalkohola otopi se, uz miješanje, u 400 ml dikloretana. Na kraju se uvodi klorovodik do zasićenja, pri čemu temperatura poraste do 37°C. Miješa se još 1 sat. Nakon ispiranja s 200 ml ledeno hladne vode organsku fazu osuši se iznad natrijevog sulfata 1 zgusne. Doblje se 59,2 g (92%) smeđkaste čvrste tvari.
ac) N-alil-N-[3- (1-naftil) -alil]-amin
K 167 g (2,9 M) alilamina dodaje se uz miješanje pod povratnim hladilom tijekom 1 sata 59,2 g (0,29 M) 3-(1-naftil)alilklorida otopljenog u 250 ml toluola. Smjesu se mlješa još 2 sata pri temperaturi refluksa. Na kraju reakcijsku smjesu se zgusne, ostatak se preuzme u 250 ml vode i pomoću 50%-tne natrijeve lužine nanijesti se pH na 12. Vodena faza ekstrahira se s diklormetanom, organska faza se osuši iznad natrijevog sulfata i zgusne.
Iskorištenje: 67,6 g (97%) tamno smeđeg ulja.
ad) ekso-6-(1-naftil)-3-azabiciklo[3.2.0]heptan
50,0 g (193 mM) N-alil-N-[3-(1-naftil)-alil]amonij-klorida otopi se u 1600 ml acetona i pomiješa se sa 210 ml 10%-tne solne kiseline. Bistra žuta otopina u atmosferi dušika obasjava se 4 sata s visokotlačnom živinom žaruljom od 700 vata u kvarcnoj aparaturi pri sobnoj temperaturi. Konačno reakcijska smjesa se zgusne i ostatak se preuzme s vodom, a s 50%-tnom natrijevom lužinom namjesti se pH na 12. Miješa se još 30 minuta i dva puta se ekstrahira s terc.butil-metil-eterom. Sjedinjene organske faze osuše se iznad natrijevog sulfata i zgusnu.
Tamno smeđi uljasti ostatak (43,2 g) otopi se u 150 ml izopropanola i pomiješa s 25,5 g (220 mM) maleinske kiselina otopljene u 220 ml izopropanola. Istaloženi maleinat se odsisa, izopropanol se ispere i osuši se preko noći u vakuumskoj sušionici pri 40°C.
Iskorištenje 43, 9 g (67%) bezbojnog praha, talište 162-164°C (maleinat).
Analogno mogu se pripremiti slijedeće tvari :
ae) ekso-6-(2-naftil)-3-azabiciklo[3.2.0]heptan, talište 145-147°C (maleinat),
af) ekso-6-(5-klor-1-naftil)-3-azabiciklo[3.2.0]heptan,
ag) ekso-6-(9-fenantril)-3-azabiciklo[3.2.0]heptan,
ah) ekso-6-(6-klor-2-naftil)-3-azabiciklo[3.2.0]heptan.
B) Pripremanje krajnjih proizvoda
Primjer 1
3, 6-dimetil-2-metilamino-5-[2-(ekso-6-(2-naftil)-3-aza-biciklo[3.2.0]heptan-3-il)-etil]-3H-pirimidin-4-on dihidroklorid
3,0 g (13,5 mM) ekso-6-(2-naftil) -3-azabiciklo-[3.2.0]heptana u 70 ml ksilola pomiješa se s 2,9 g (13,5 mM) 3, 6-dimetil-2-metilamino-5- (2-kloretil) -3-H-pirimidin-4-ona, te s 2,8 g (20,3 mM) praškasto usitnjenog kalijevog karbonata i 0,5 g kalijevog jodida i uz dobro miješanje kuha se 12 sati pod refluksom.
Nakon hlađenja zgusne se na rotacijskom uređaju za isparavanje, a ostatak se podijeli između metilenklorida i vode. Vodena faza ekstrahira se zatim dva puta s metilenkloridom i zatim se organsku fazu zgusne nakon sušenja pomoću natrijevog sulfata. Sirovi proizvod (5,0 g) očisti se kromatografijom u koloni (silika gel, protočno sredstvo diklormetan/metanol 90/10).
Slobodna baza (2,8 g) preuzme se u 150 ml acetona i pomiješa se sa suviškom eterske solne kiseline. Konačno čvrste čestice se odsisaju, na hladnom, u atmosferi dušika, hidroklorid se ispere s malo acetona i sol se osuši na nuči u atmosferi dušika. Izolira se 3,2 g (46%) proizvoda x 2 HCl, talište 225-228°C.
Analogno se mogu pripremiti:
2.) 3, 6-dimetil-2-metilamino-5- [2- (ekso-6- (1-naftil) -3-azabiciklo[3.2.0]heptan-3-il)-etil]-3H-pirimidin-4-on, talište: 138-140°C (dihidroklorid),
3.) 3, 6-dimetil-2-metilamino-5- [2- (ekso-6- (5-klor-1-naftil)-3-azabiciklo[3.2.0]heptan-3-il)-etil]-3H-pirimidin-4-on,
4.) 3, 6-dimetil-2-metilamino-5- [2- (ekso-6- (6-klor-2-naftil)-3-azabiciklo[3.2.0]heptan-3-il)-etil]-3H-pirimidin-4-on, talište: 260-262°C (dihidroklorid x 2^0) ,
5.) 3, 6-dimetil-2-metilamino-5- [2- (ekso-6- (9-fenantril) -3-azabiciklo[3. 2.0] heptan-3-il) -etil] -3H-pirimidin-4-on, talište: 255-258°C (dihidroklorid),
6.) 7-metil-6-[2-(ekso-6-(2-naftil)-3-azabiciklo[3.2.0] -heptan-3-11) -etil] -5H-tiazol[3,2-a] pirimidin-5-on,
7.) 3-[2-ekso-6-(2-naftil)-3-azabiciklo[3.2.0]heptan-3-il]-etil)-1H,3H-kinazolin-2,4-dion, talište 161-164°C,
8.) 3-[2-ekso-6-(1-naftil)-3-azabiciklo[3.2.0]heptan-3-11]-etll)-1H,3H-kinazolin-2,4-dion, talište iznad 211°C, raspad,
9.) 6-fluor-3-[2-ekso-6-(1-naftil)-3-azabiciklo[3.2.0]-heptan-3-il]-etil)-1H,3H-kinazolin-2,4-dion, talište 196-198°C,
10.) 3-[2-ekso-6-(5-klor-2-naftil)-3-azabiciklo[3.2.0]-heptan-3-il)-etil]-1H,3H-kinazolin-2,4-dion,
11.) 3-[2-ekso-6-(1-naftil)-3-azabiciklo[3.2.0]heptan-3-il)3-etil]-2-metil-4H-pirido[1.2-a]-pirimidin-4-on,
12.) l-[2-ekso-6-(2-naftil)-3-azabiciklo[3.2.0]heptan-3-il)-etil]-2(1H)-kinolon,
13.) l-[2-ekso-6-(2-naftil)-3-azabiciklo[3.2.0]heptan-3-il)-etil]-indolin-2-on,
14.) l-[2-ekso-6-(1-naftil)-3-azabiciklo[3.2.0]heptan-3-il)-etil]-2(3H)-benzimidazolon,
15.) 1-[2-ekso-6-(1-naftil)-3-azabiciklo[3.2.0]heptan-3-il)-etil]-3-metil-2(3H)-benzimidazolon.
Claims (4)
1. N-supstituirani derivati 3-azabiciklo[3.2.0]-heptana formule I
[image]
gdje
R1 predstavlja naftil- ili fenantrilnu skupinu, po potrebi mono- ili disupstituiranu s halogeniin atomom,
n predstavlja broj 0, 1, 2, 3 ili 4,
R2 je atom vodika, hidroksi-, C1-C4-alkil ili C1-C4-alkoksi skupina, ili zajedno sa susjednim ugljikovim atomom predstavlja C=O- ili C=S-skupinu,
X i Y predstavljaju ugljikove atome, CH-, CH2-, NH-ili C1-C4-alkil-N-skupine ili dušikov atom,
Z predstavlja izravnu vezu, CO-skupinu, CS-skupinu ili CH- odnosno CH2-skupinu, u kojima se jedan vodikov atoin može zamijeniti s jednom hidroksi, amino ili C1-C4-alkoksi skupinom ili halogenim atomom, i
A je vodikov atom, hidroksi, amino, merkapto, C1-C4-alkilamino. di- C1-C4-alkilamino, C1-C4-alkiltio ili C1-C4-alkoksi skupina ili zajedno sa susjednim ugljikovim atomom predstavlja C=O- ili C=S-skupinu, ili
A predstavlja C3-C4-alkilensku skupinu povezanu s Y, koja sadrži jednu ili dvije nekumulirane dvostruke veze, a u -jednoj ili dvije CH- odnosno CH2-skupini može biti zamijenjena s dušikovim ili sumporovim atomom ili s jednom NH- ili N-CH3- skupinom, i pri čemu prsten može biti monosupstituiran ili s atomom fluora ili klora ili s jednoro metilnom, metoksi, nitro ili amino skupinom, ili u slučaju benzolovog prstena, on može biti mono-, di- ili
trisupstituiran atomom fluora ili klora ili s metilnom, trifluormetilnom, nitro, hidroksi, metoksi, amino, monometil- ili dimetilamino skupinom, i gdje prsten u desnom dijelu formule I na dušikovom atomu br. 1 može nositi C1-C4-alkilnu skupinu i može sadržavati 1 do 3 nekumulirane dvostruke veze,
i njihove soli s fiziološki podnošljivim kiselinama..
2. Spojevi formule I prema zahtjevu 1 za upotrebu pri suzbijanju bolesti.
3. Postupak za liječenje psihoza, naznačen time, da se pacijentima daje učinkovita doza jednog od spojeva formule I prema zahtjevu 1.
4. Postupak za proizvodnju spojeva formule I prema zahtjevu 1, naznačen time, da se spoj formule II
[image]
u kojem n, R2, X, Y, Z i A imaju gore navedena značenja, a Nu predstavlja nukleofilnu polaznu skupinu, kemijski pretvara s derivatom 3-azabiciklo[3.2.0]heptana formule III
[image]
u kojoj R1 ima gore navedeno značenje, i tako dobiven spoj prevodi se, po potrebi, u kiselinsku adicijsku sol neke fiziološki podnošljive kiseline.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4427648A DE4427648A1 (de) | 1994-08-04 | 1994-08-04 | N-Stubstituierte 3-Azabicyclo[3,2,0,]heptan-Derivate, ihre Herstellung und Verwendung |
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| Publication Number | Publication Date |
|---|---|
| HRP950438A2 true HRP950438A2 (en) | 1997-10-31 |
Family
ID=6524944
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP4427648.6A HRP950438A2 (en) | 1994-08-04 | 1995-08-04 | N-substituted 3-azabicyclo (3.2.0) heptane derivatives, their preparation and use |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US6028073A (hr) |
| EP (1) | EP0775135B1 (hr) |
| JP (1) | JPH10503503A (hr) |
| CN (1) | CN1066145C (hr) |
| AT (1) | ATE242236T1 (hr) |
| AU (1) | AU696230B2 (hr) |
| BG (1) | BG63633B1 (hr) |
| CA (1) | CA2196809A1 (hr) |
| CZ (1) | CZ287862B6 (hr) |
| DE (2) | DE4427648A1 (hr) |
| DK (1) | DK0775135T3 (hr) |
| ES (1) | ES2201111T3 (hr) |
| FI (1) | FI970448A (hr) |
| HR (1) | HRP950438A2 (hr) |
| HU (1) | HUT77772A (hr) |
| MX (1) | MX9700807A (hr) |
| NO (1) | NO312243B1 (hr) |
| NZ (1) | NZ290426A (hr) |
| PL (1) | PL183526B1 (hr) |
| PT (1) | PT775135E (hr) |
| RU (1) | RU2163604C2 (hr) |
| SI (1) | SI9520094B (hr) |
| UA (1) | UA44903C2 (hr) |
| WO (1) | WO1996004272A1 (hr) |
| ZA (1) | ZA956477B (hr) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19836406A1 (de) * | 1998-08-12 | 2000-02-17 | Basf Ag | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| US6458821B1 (en) | 1998-08-12 | 2002-10-01 | Abbott Laboratories | N-substituted azabicycloheptane derivatives, production and use thereof |
| DE19836404A1 (de) * | 1998-08-12 | 2000-02-17 | Basf Ag | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| DE19848521A1 (de) * | 1998-10-21 | 2000-04-27 | Basf Ag | Verfahren zur Herstellung von (+)-exo-6-Phenyl-3-azabicyclo-[3.2.0]heptanen |
| DE19854147A1 (de) * | 1998-11-24 | 2000-05-25 | Basf Ag | Verwendung von N-substituierten Azabicycloalkan-Derivaten zur Verwendung bei der Bekämpfung der Cocainsucht |
| WO2006040176A1 (en) * | 2004-10-14 | 2006-04-20 | Abbott Gmbh & Co. Kg | Azabicycloheptyl compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor |
| CN105473554B (zh) * | 2013-07-10 | 2019-08-13 | 沃泰克斯药物股份有限公司 | 作为离子通道调节剂的稠合的哌啶酰胺类 |
| AU2015279377B2 (en) * | 2014-06-26 | 2019-09-12 | F. Hoffmann-La Roche Ag | Indolin-2-one or pyrrolo-pyridin-2-one derivatives |
| JP6857651B2 (ja) | 2015-11-06 | 2021-04-14 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Ｃｎｓ疾患の処置に有用なインドリン−２−オン誘導体 |
| CN108349942B (zh) | 2015-11-06 | 2021-03-30 | 豪夫迈·罗氏有限公司 | 用于治疗cns和相关疾病的二氢吲哚-2-酮衍生物 |
| WO2017076842A1 (en) | 2015-11-06 | 2017-05-11 | F. Hoffmann-La Roche Ag | Indolin-2-one derivatives |
| CA3002489C (en) | 2015-11-06 | 2023-11-07 | F.Hoffmann-La Roche Ag | Indolin-2-one derivatives |
| EP3978497A4 (en) * | 2019-05-30 | 2022-07-13 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences | FUSED CYCLIC COMPOUND, METHOD FOR PREPARING IT AND ITS USE |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE4243287A1 (de) * | 1992-06-19 | 1993-12-23 | Basf Ag | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| DE4341402A1 (de) * | 1993-12-04 | 1995-06-08 | Basf Ag | N-substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
-
1994
- 1994-08-04 DE DE4427648A patent/DE4427648A1/de not_active Withdrawn
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1995
- 1995-07-21 EP EP95926970A patent/EP0775135B1/de not_active Expired - Lifetime
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- 1995-07-21 RU RU97103198/04A patent/RU2163604C2/ru not_active IP Right Cessation
- 1995-07-21 DK DK95926970T patent/DK0775135T3/da active
- 1995-07-21 CA CA002196809A patent/CA2196809A1/en not_active Abandoned
- 1995-07-21 US US08/776,577 patent/US6028073A/en not_active Expired - Lifetime
- 1995-07-21 AT AT95926970T patent/ATE242236T1/de not_active IP Right Cessation
- 1995-07-21 PL PL95318460A patent/PL183526B1/pl unknown
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- 1995-07-21 CZ CZ1997310A patent/CZ287862B6/cs not_active IP Right Cessation
- 1995-07-21 AU AU31162/95A patent/AU696230B2/en not_active Ceased
- 1995-07-21 WO PCT/EP1995/002893 patent/WO1996004272A1/de active IP Right Grant
- 1995-07-21 ES ES95926970T patent/ES2201111T3/es not_active Expired - Lifetime
- 1995-07-21 SI SI9520094A patent/SI9520094B/sl unknown
- 1995-07-21 CN CN95194835A patent/CN1066145C/zh not_active Expired - Fee Related
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- 1995-07-21 JP JP8506146A patent/JPH10503503A/ja not_active Ceased
- 1995-07-21 UA UA97030904A patent/UA44903C2/uk unknown
- 1995-07-21 HU HU9700329A patent/HUT77772A/hu unknown
- 1995-07-21 DE DE59510713T patent/DE59510713D1/de not_active Expired - Fee Related
- 1995-08-03 ZA ZA9506477A patent/ZA956477B/xx unknown
- 1995-08-04 HR HRP4427648.6A patent/HRP950438A2/hr not_active Application Discontinuation
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- 1997-02-03 NO NO19970473A patent/NO312243B1/no not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| MX9700807A (es) | 1997-05-31 |
| FI970448A (fi) | 1997-04-03 |
| FI970448A0 (fi) | 1997-02-03 |
| ATE242236T1 (de) | 2003-06-15 |
| BG63633B1 (bg) | 2002-07-31 |
| JPH10503503A (ja) | 1998-03-31 |
| ZA956477B (en) | 1997-02-03 |
| WO1996004272A1 (de) | 1996-02-15 |
| EP0775135B1 (de) | 2003-06-04 |
| US6028073A (en) | 2000-02-22 |
| DK0775135T3 (da) | 2003-09-29 |
| AU3116295A (en) | 1996-03-04 |
| HUT77772A (hu) | 1998-08-28 |
| CA2196809A1 (en) | 1996-02-15 |
| CZ287862B6 (en) | 2001-02-14 |
| NZ290426A (en) | 1998-02-26 |
| SI9520094A (en) | 1997-08-31 |
| NO970473D0 (no) | 1997-02-03 |
| CZ31097A3 (en) | 1997-10-15 |
| DE4427648A1 (de) | 1996-02-08 |
| RU2163604C2 (ru) | 2001-02-27 |
| BG101220A (en) | 1997-08-29 |
| EP0775135A1 (de) | 1997-05-28 |
| CN1066145C (zh) | 2001-05-23 |
| UA44903C2 (uk) | 2002-03-15 |
| CN1156454A (zh) | 1997-08-06 |
| NO970473L (no) | 1997-04-01 |
| SI9520094B (sl) | 2002-02-28 |
| ES2201111T3 (es) | 2004-03-16 |
| PL183526B1 (pl) | 2002-06-28 |
| PL318460A1 (en) | 1997-06-09 |
| PT775135E (pt) | 2003-10-31 |
| AU696230B2 (en) | 1998-09-03 |
| NO312243B1 (no) | 2002-04-15 |
| DE59510713D1 (de) | 2003-07-10 |
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