CN1156454A - N-取代的3-氮杂双环[3,2,0]庚烷衍生物及其制备方法和应用 - Google Patents
N-取代的3-氮杂双环[3,2,0]庚烷衍生物及其制备方法和应用 Download PDFInfo
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- CN1156454A CN1156454A CN95194835A CN95194835A CN1156454A CN 1156454 A CN1156454 A CN 1156454A CN 95194835 A CN95194835 A CN 95194835A CN 95194835 A CN95194835 A CN 95194835A CN 1156454 A CN1156454 A CN 1156454A
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- azabicyclo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 N-substituted 3-azabicyclo [3, 2, 0] heptane Chemical class 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 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
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- NEOIOGUWEUTYIH-UHFFFAOYSA-N 3-azabicyclo[3.2.0]heptane Chemical class C1NCC2CCC21 NEOIOGUWEUTYIH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 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
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 4
- 230000000561 anti-psychotic effect Effects 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- 239000003814 drug Substances 0.000 description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- MYWUZJCMWCOHBA-UHFFFAOYSA-N n-methyl-1-phenylpropan-2-amine Chemical compound CNC(C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-UHFFFAOYSA-N 0.000 description 5
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000003042 antagnostic effect Effects 0.000 description 4
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- 239000012442 inert solvent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical group ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 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
- 230000037396 body weight Effects 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
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002994 raw material Substances 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
- 239000000126 substance Substances 0.000 description 3
- 229940125725 tranquilizer Drugs 0.000 description 3
- 239000003204 tranquilizing agent Substances 0.000 description 3
- 230000002936 tranquilizing effect Effects 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
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical class C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 2
- UUAVYXKRUSVCDJ-UHFFFAOYSA-N 1-cycloheptylazepane Chemical class C1CCCCCC1N1CCCCCC1 UUAVYXKRUSVCDJ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DSWICQDUYHOEPQ-UHFFFAOYSA-N [Mg]C=C Chemical compound [Mg]C=C DSWICQDUYHOEPQ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
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- 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
- 238000000605 extraction Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 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
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 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
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- 238000007106 1,2-cycloaddition reaction Methods 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 class 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
- PMGYJTHQBWJRDY-UHFFFAOYSA-N 5-(2-chloroethyl)-3,6-dimethyl-2-(methylamino)pyrimidin-4-one Chemical compound CNC1=NC(C)=C(CCCl)C(=O)N1C PMGYJTHQBWJRDY-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- NUNHUUHFYQHVGO-UHFFFAOYSA-N C1=CC=C2C(C(=C)CO)=CC=CC2=C1 Chemical compound C1=CC=C2C(C(=C)CO)=CC=CC2=C1 NUNHUUHFYQHVGO-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
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- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229940099340 desoxyn Drugs 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
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- 239000001530 fumaric acid Substances 0.000 description 1
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- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
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- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
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- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 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
- A61P25/22—Anxiolytics
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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Abstract
式I的化合物其中R1,R2,A,X,Y和Z具有说明书中所述含义,并记述了其制备方法。该新化合物用于控制疾病。
Description
本发明涉及新的N-取代的氮杂双环庚烷衍生物及其制备方法和用于制备药剂的用途。
已知N-取代的氮杂双环庚烷衍生物对多巴胺和血清素受体亚型具有出人意料的亲和性(DE 4243287,DE 4219973)。据观察对D4多巴胺受体亚型的高度亲和性在其中起主要作用。
现在我们发现式I的N-取代的3-氮杂双环[3.2.0]庚烷衍生物及其生理可耐受酸的盐具有有用的药理学特性,式I中R1是未取代的或者被卤素原子单取代或双取代的萘基或菲基,n是0,1,2,3或4,R2是氢,羟基,C1-C4烷基,C1-C4烷氧基,或者与相邻碳原子一起是C=O或C=S,X和Y是碳原子,CH,CH2,NH或C1-C4烷基-N基团或者氮原子,Z是一直接键,CO或CS基或者其中的一个氢原子可被羟基、氨基或C1-C4烷氧基或者卤素原子替代的CH或CH2基,A是氢,羟基,氨基,巯基,C1-C4烷基氨基,二-C1-C4烷基氨基,C1-C4烷硫基或C1-C4烷氧基,或者与相邻的碳原子一起是C=O,或者A是与Y相连的C3-C4亚烷基,它可含有一个或两个非累积双键,其中的一个CH或CH2可被氮原子、硫原子、NH或N-CH3基替代并且其中的环可被氟或氯原子或者被甲基、甲氧基、硝基或氨基单取代,或在苯环的情形下,环可被氟或氯原子或者甲基、三氟甲基、硝基、羟基、甲氧基、氨基、甲氨基或二甲氨基单取代,双取代或者三取代,并且式I中右边环在1位氮原子上可带有C1-C4烷基并含有1-3个非累积双键。
取代基R1和R2及n尤其提到下述含义:R1:未取代的或者被氟或氯取代的萘基,R2:甲基和羟基,n:2。
具体地说,优选的化合物是那些其中分子的右环系来自7-甲基-5H-噻唑并[3,2-a]嘧啶-5-酮,2,4(1H,3H)-喹唑啉二酮,2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮,2-甲氨基-3,6-二甲基-4(3H)-嘧啶酮,2(1H)-喹诺酮,二氢吲哚-2-酮,2(3H)-苯并咪唑酮。
本发明的式I化合物可通过将式II化合物式II中n,R2,X,Y,Z和A具有上述含义,且Nu是一离核离去基团,与其中R1具有上述含义的式III的3-氮杂双环[3.2.0]庚烷衍生物反应,任选地再将所得化合物转化成生理可耐受酸的盐,
适当的和优选的离核离去基团Nu优选是卤原子,尤其是溴或氯。
该反应可在惰性碱(以结合酸)的存在下在惰性溶剂中方便的进行,所述惰性碱如三乙胺或碳酸钾,所述惰性溶剂如饱和环醚,尤其是四氢呋喃或二恶烷,或者芳烃,例如甲苯或二甲苯。
该反应一般在20-150℃进行,尤其是80-140℃,并且通常在1-10小时内完成。
本发明的式I化合物可通过在常规有机溶剂(优选低级醇如乙醇)中重结晶或者采用柱色谱纯化。
外消旋物可以简单方式,使用旋光活性羧酸,如酒石酸衍生物在惰性溶剂,如低级醇中通过传统拆分成对映体。
式I的游离3-氮杂双环[3.2.0]庚烷衍生物可以常规方式转化为药理适宜酸的盐,优选用一当量的适宜酸溶液处理。药学上适宜酸的实例是盐酸,磷酸,硫酸,甲磺酸,氨基磺酸,马来酸,富马酸,草酸,酒石酸或柠檬酸。
本发明的化合物具有有用的药理学特性。它们可用作安定药(尤其是非典型的),抗抑郁药,镇静剂,催眠药,CNS保护剂或肌松剂。本发明的化合物可结合表现出数种所述类型作用。体内和体外的药理学作用均表明该类物质尤其具有亲和性的特征,该亲和性在某些情况下是很高的并对受体亚型具有选择性,尤其多巴胺D4受体。
下列方法用于体内定性:a) 对方向运动性的影响
在新环境中,小鼠显示探险性行为,表现为运动性增强。将动物(NMRI
小鼠,雌性)放在笼中后,在光屏障笼(LichtschranKenKfigen)
中测定运动性0-30分钟。ED50:与安慰剂处理的对照组相比,降
低运动性50%的剂量。b) 阿朴吗啡拮抗作用
雌性NMRI小鼠皮下接受1.21mg/kg阿朴吗啡。在该剂量,阿朴吗啡
导致运动兴奋,当动物在线编笼中时表现为持久攀爬。在30分钟里,
每2分钟对攀爬计分:
0:动物的四只爪都在地板上
1:动物有两只爪在线上
2:动物有四只爪在线上(在攀爬)
用精神抑制药预处理可抑制攀爬行为。
ED50:与安慰剂处理的对照组相比,抑制动物攀爬活动50%的剂量。c) 脱氧麻黄碱拮抗作用
雌性NMRI小鼠经口接受1mg/kg脱氧麻黄碱,30分钟后,将它们放
在光屏障笼中测定其运动性(2只动物/笼,4个笼/剂量)。在给予脱
氧麻黄碱前30分钟口服给予试验物质。在动物放在笼中后15-60分
钟内计算因脱氧麻黄碱的运动性增强,以此作为脱氧麻黄碱对照组和安
慰剂对照组间的差,并将其设为100%。ED100是完全消除运动性增
强的试验物质的剂量。d) L-5-HTP拮抗作用
雌性Sprague-Dawley大鼠腹膜内接受316mg/kg剂量的L-5-HTP。动
物然后发展成焦躁综合症,其中在施予L-5-HTP后20-60分钟内每
10分钟对症状
-对爪踩踏和
-颤抖
进行评分(0=没有,1=中度,2=显著)。施予L-5-HTP后的平
均分值是17。在施予L-5-HTP前60分钟经口给予试验物质。ED50
是计算出的平均降低对照组评分50%的剂量。
列出的方法适于描述物质作为精神抑制药的性质;据认为对脱氧麻黄碱诱发的运动兴奋的抑制作用尤其可论断精神抑制作用。血清素拮抗作用可通过对L-5-HTP综合症的抑制来揭示,该类作用是非典型安定药的特性。
在这些试验中,新化合物均表现出良好的效果。
因此,本发明还涉及治疗组合物,除常规赋形剂和稀释剂外,它含有式I化合物或其药理学上适宜酸的加成盐为活性成分;以及该新化合物用于控制疾病的用途。
本发明的化合物可以口服或经非胃肠道,静脉或肌内的常见方式施予。
剂量取决于年龄,患者的状况和体重及给药方式。原则上,活性成分的每日口服剂量是约1-100mg/kg体重,非胃肠道给药的剂量为0.1-10mg/kg体重。
该新化合物可以常规的固体或液体药物形式使用,如作为未包衣或(膜)包衣片剂,胶囊,粉末,颗粒剂,栓剂,溶液,软膏剂,霜剂或气雾剂。它们可以常规方法进行生产。为此,活性成分可与常用药物助剂一起加工,所述助剂是例如片剂粘合剂,填充剂,防腐剂,片剂崩解剂,流动调节剂,增塑剂,润湿剂,分散剂,乳化剂,溶剂,缓释剂,抗氧剂和/或抛射气(参见H.Sucker等:制药技术,Thieme-Verlag,Stuttgart,1978)。以此方式获得的给药形式一般含有1-99%重量的活性成分。
需用作合成新化合物的原料的式II化合物是已知的,或者可采用文献所述的方法由类似的原料合成。
式III化合物可通过使式IV的胺进行光化学[2+2]环加成反应制备,式IV中,R1具有上述含义,且R3是氢、乙酰基、苄基或三氟乙酰基,如果适当,可消除酰基或苄基。
光化学反应宜在惰性溶剂,优选丙酮中,在20-80℃下进行。一种特别适宜的光源是高压汞灯。在石英装置中,氮气氛下,对每摩尔胺可加或不加入约1摩尔盐酸均有益于光环加成反应。
通过外消旋拆分,如采用旋光活性酒石酸衍生物可分离纯化两种对映体。
下列实施例将说明本发明:A原料的制备aa)1-(1-萘基)烯丙醇
在氮气氛下,将277ml(360mM[原文如此])的1.3M乙烯基镁氯化
物的四氢呋喃溶液加到2升搅拌的烧瓶中。然后,在60分钟时间内,
在30-35℃、氮气氛和搅拌下加入50g(320mM[原文如此])溶于250ml
四氢呋喃中的1-萘甲醛。然后,将该混合物在室温和氮气氛下搅拌4.5
小时。之后搅拌下加入90ml饱和氯化铵溶液,再用冰冷却,将该混合
物进行吸滤,滤器上的残余物用150ml四氢呋喃洗三次。将滤液合并,
用硫酸镁干燥并浓缩。得到棕色油状粗产物58.3g(99%)。ab)3-(1-萘基)烯丙基氯
搅拌下,将58.3g(317mM[原文如此])1-(1-萘基)烯丙醇溶于400ml
二氯甲烷。然后通入氯化氢至饱和,此间温度升至37℃。然后将该混
合物搅拌1小时。有机相用200ml冰冷的水洗涤,经硫酸钠干燥并浓
缩。得到59.2g(92%)棕色固体。ac)N-烯丙基-N-[3-(1-萘基)烯丙基]胺
在回流下,用1小时的时间将溶于250ml甲苯的59.2g(0.29M[原
文如此])3-(1-萘基)烯丙基氯加到167g(2.9M[原文如此])烯丙胺中。然后
将该混合物回流2小时。之后浓缩溶液,残余物加到250ml水中,用
50%的氢氧化钠溶液将PH调至12。水相用二氯甲烷萃取,有机相经
硫酸钠干燥并浓缩。得到67.6g(97%)暗棕色油。ad)外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷
将50.0g(193mM[原文如此])N-烯丙基-N-[3-(1-萘基)烯丙基]铵氯
化物溶于1600ml丙酮中,并加入210ml 10%强度的盐酸。室温氮气氛
下在石英装置中用700瓦高压汞灯照射该透明黄色溶液4小时。然后
浓缩该溶液,残余物加入水中,并用50%强度的氢氧化钠溶液将PH
调至12。之后将该混合物搅拌30分钟,再用叔丁基甲基醚萃取两次。
将合并的有机相经硫酸钠干燥并浓缩。
将暗棕色油残余物(43.2g)溶于150ml异丙醇,并加入溶于220ml
异丙醇中的25.5g(220mM[原文如此])马来酸。吸滤出沉淀的马来酸
盐,用异丙醇洗并在40℃真空干燥箱中干燥过夜。得到43.9g(67%)
无色粉末,熔点162-164℃(马来酸盐)。下列物质可采用类似方法制备:ae)外向-6-(2-萘基)-3-氮杂双环[3.2.0]庚烷,熔点145-147℃(马来酸盐)af)外向-6-(5-氯-1-萘基)-3-氮杂双环[3.2.0]庚烷,ag)外向-6-(9-菲基)-3-氮杂双环[3.2.0]庚烷,ah)外向-6-(6-氯-2-萘基)-3-氮杂双环[3.2.0]庚烷。B终产物的制备实施例13,6-二甲基-2-甲氨基-5-[2-(外向-6-(2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-3H-嘧啶-4-酮二盐酸盐
将2.9g(13.5mM[原文如此])3,6-二甲基-2-甲氨基-5-(2-氯乙基)-3H-嘧啶-4-酮,2.8g(20.3mM[原文如此])细粉碳酸钾和0.5g碘化钾加到在70ml二甲苯中的3.0g(13.5mM[原文如此])外向-6-(2-萘基)-3-氮杂双环-[3.2.0]庚烷中,将该混合物回流12小时。
冷却后,在旋转蒸发器中浓缩,然后加将残余物分配到二氯甲烷和水中。水相用二氯甲烷萃取两次,有机相用硫酸钠干燥并浓缩。粗产物(5.0g)采用柱色谱纯化(硅胶,流动相为二氯甲烷/甲醇90/10)。
将游离碱(2.8g)加到150丙酮中,加入过量盐酸乙醚。然后在氮气氛下冷却下吸滤出固体盐酸盐,用少量丙酮洗并在氮气氛下在漏斗上干燥。分离出3.2g(46%)产物×2HCl,熔点225-228℃。
下列化合物可以类似方法制备:2. 3,6-二甲基-2-甲氨基-5-[2-(外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-3H-嘧啶-4-酮,熔点138-140℃(二盐酸盐)3. 3,6-二甲基-2-甲氨基-5-[2-(外向-6-(5-氯-1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-3H-嘧啶-4-酮,4. 3,6-二甲基-2-甲氨基-5-[2-(外向-6-(6-氯-2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-3H-嘧啶-4-酮,熔点:260-262℃(二盐酸盐×2H2O),5. 3,6-二甲基-2-甲氨基-5-[2-(外向-6-(9-菲基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-3H-嘧啶-4-酮,255-258℃(盐酸盐)6. 7-甲基-6-[2-(外向-6-(2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-5H-噻唑并[3,2-a]嘧啶-5-酮,7. 3-[2-外向-6-(2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-1H,3H-喹唑啉-2,4-二酮,熔点161-164℃,8. 3-[2-外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-1H,3H-喹唑啉-2,4-二酮,熔点211℃以上分解,9. 6-氟-3-[2-(外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-1H,3H-喹唑啉-2,4-二酮,熔点196-198℃,10. 3-[2-(外向-6-(5-氯-2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)乙基]-1H,3H-喹唑啉-2,4-二酮。11. 3-[2-(外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)-乙基]-2-甲基-4H-吡啶并[1,2-a]-嘧啶-4-酮,12. 1-[2-(外向-6-(2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)-乙基]-2(1H)-喹诺酮,13. 1-[2-(外向-6-(2-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)-乙基]-二氢吲哚-2-酮,14. 1-[2-(外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)-乙基]-2(3H)-苯并咪唑酮,15. 1-[2-(外向-6-(1-萘基)-3-氮杂双环[3.2.0]庚烷-3-基)-乙基]-3-甲基-2(3H)-苯并咪唑酮。
Claims (4)
1.式I的N-取代的3-氮杂双环[3.2.0]庚烷衍生物及其生理学上可耐受酸的盐,式I中R1是未取代的或者被卤素原子单取代或双取代的萘基或菲基,n是0,1,2,3或4,R2是氢,羟基,C1-C4烷基,C1-C4烷氧基,或者与相邻碳原子一起是C=O或C=S,X和Y是碳原子,CH,CH2,NH或C1-C4烷基-N基团或者氮原子,Z是一直接键,CO或CS基或者其中的一个氢原子可被羟基、氨基或C1-C4烷氧基或者卤素原子替代的CH或CH2基,A是氢,羟基,氨基,巯基,C1-C4烷基氨基,二-C1-C4烷基氨基,C1-C4烷硫基或C1-C4烷氧基,或者与相邻的碳原子一起是C=O,或者A是与Y相连的C3-C4亚烷基,它可含有一个或两个非累积双键,其中的一个CH或CH2可被氮原子、硫原子、NH或N-CH3基替代并且其中的环可被氟或氯原子或者被甲基、甲氧基、硝基或氨基单取代,或在苯环的情形下,环可被氟或氯原子或者甲基、三氟甲基、硝基、羟基、甲氧基、氨基、甲氨基或二甲氨基单取代,双取代或者三取代,并且式I中右边环在1位氮原子上可带有C1-C4烷基并含有1-3个非累积双键。
2.权利要求1的式I化合物用于控制疾病。
3.治疗精神病的方法,包括将有效剂量的权利要求1的式I化合物施用于病人。
4.权利要求1的式I化合物的制备方法,包括将式II化合物 式II中n,R2,X,Y,Z和A具有上述含义,且Nu是一离核离去基团,与其中R1具有上述含义的式III的3-氮杂双环[3.2.0]庚烷衍生物反应,任选地再将所得化合物转化成生理可耐受酸的盐。
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DEP4427648.6 | 1994-08-04 | ||
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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DE (2) | DE4427648A1 (zh) |
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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 |
DE19836406A1 (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 |
EP1812389B1 (en) * | 2004-10-14 | 2011-08-17 | Abbott GmbH & Co. KG | Azabicycloheptyl compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor |
WO2015006280A1 (en) | 2013-07-10 | 2015-01-15 | Vertex Pharmaceuticals Incorporated | Fused piperidine amides as modulators of ion channels |
MX2016016383A (es) * | 2014-06-26 | 2017-05-01 | Hoffmann La Roche | Derivados de indolin-2-ona o pirrolo-piridin-2-ona. |
JP6839184B2 (ja) | 2015-11-06 | 2021-03-03 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | インドリン−2−オン誘導体 |
EP3371169B1 (en) | 2015-11-06 | 2019-07-17 | H. Hoffnabb-La Roche Ag | Indolin-2-one derivatives for use in the treatment of cns and related disorders |
MY197370A (en) | 2015-11-06 | 2023-06-14 | Hoffmann La Roche | Indolin-2-one derivatives |
CN108137555B (zh) | 2015-11-06 | 2021-02-19 | 豪夫迈·罗氏有限公司 | 可用于治疗cns疾病的二氢吲哚-2-酮衍生物 |
US20220227773A1 (en) * | 2019-05-30 | 2022-07-21 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Fused ring compound, preparation method therefor and use thereof |
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AU696230B2 (en) | 1998-09-03 |
BG101220A (en) | 1997-08-29 |
PT775135E (pt) | 2003-10-31 |
HUT77772A (hu) | 1998-08-28 |
DE59510713D1 (de) | 2003-07-10 |
CN1066145C (zh) | 2001-05-23 |
DK0775135T3 (da) | 2003-09-29 |
JPH10503503A (ja) | 1998-03-31 |
US6028073A (en) | 2000-02-22 |
CZ287862B6 (en) | 2001-02-14 |
AU3116295A (en) | 1996-03-04 |
FI970448A (fi) | 1997-04-03 |
CZ31097A3 (en) | 1997-10-15 |
EP0775135A1 (de) | 1997-05-28 |
ES2201111T3 (es) | 2004-03-16 |
WO1996004272A1 (de) | 1996-02-15 |
EP0775135B1 (de) | 2003-06-04 |
RU2163604C2 (ru) | 2001-02-27 |
CA2196809A1 (en) | 1996-02-15 |
NO970473L (no) | 1997-04-01 |
ZA956477B (en) | 1997-02-03 |
FI970448A0 (fi) | 1997-02-03 |
UA44903C2 (uk) | 2002-03-15 |
PL183526B1 (pl) | 2002-06-28 |
NO970473D0 (no) | 1997-02-03 |
NZ290426A (en) | 1998-02-26 |
SI9520094B (sl) | 2002-02-28 |
HRP950438A2 (en) | 1997-10-31 |
ATE242236T1 (de) | 2003-06-15 |
MX9700807A (es) | 1997-05-31 |
BG63633B1 (bg) | 2002-07-31 |
SI9520094A (en) | 1997-08-31 |
NO312243B1 (no) | 2002-04-15 |
DE4427648A1 (de) | 1996-02-08 |
PL318460A1 (en) | 1997-06-09 |
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