CN112851656B - 内酰胺类化合物衍生物及其应用 - Google Patents
内酰胺类化合物衍生物及其应用 Download PDFInfo
- Publication number
- CN112851656B CN112851656B CN202110181460.9A CN202110181460A CN112851656B CN 112851656 B CN112851656 B CN 112851656B CN 202110181460 A CN202110181460 A CN 202110181460A CN 112851656 B CN112851656 B CN 112851656B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- methyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 Lactam compound Chemical class 0.000 title claims abstract description 79
- 239000003814 drug Substances 0.000 claims abstract description 36
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 118
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 150000002367 halogens Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 229940079593 drug Drugs 0.000 abstract description 30
- 238000002360 preparation method Methods 0.000 abstract description 16
- 239000000203 mixture Substances 0.000 abstract description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 51
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 26
- 239000000872 buffer Substances 0.000 description 25
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 24
- 238000012360 testing method Methods 0.000 description 24
- 238000000034 method Methods 0.000 description 19
- 239000007858 starting material Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000007853 buffer solution Substances 0.000 description 17
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 239000012528 membrane Substances 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000003446 ligand Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 14
- 230000027455 binding Effects 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 12
- 229960001534 risperidone Drugs 0.000 description 12
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 10
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000006228 supernatant Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 9
- 230000009870 specific binding Effects 0.000 description 9
- 230000002932 anti-schizophrenic effect Effects 0.000 description 8
- 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 8
- 229960004046 apomorphine Drugs 0.000 description 8
- 238000005119 centrifugation Methods 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 239000012154 double-distilled water Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 239000007983 Tris buffer Substances 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000001525 receptor binding assay Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000012449 Kunming mouse Methods 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 230000009194 climbing Effects 0.000 description 6
- 229960004170 clozapine Drugs 0.000 description 6
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 238000003304 gavage Methods 0.000 description 6
- 229960003878 haloperidol Drugs 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 229960004372 aripiprazole Drugs 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229960003638 dopamine Drugs 0.000 description 5
- 239000003365 glass fiber Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000009871 nonspecific binding Effects 0.000 description 5
- 229960005017 olanzapine Drugs 0.000 description 5
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000002285 radioactive effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229960000607 ziprasidone Drugs 0.000 description 5
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 5
- HYNQTSZBTIOFKH-UHFFFAOYSA-N 2-Amino-5-hydroxybenzoic acid Chemical compound NC1=CC=C(O)C=C1C(O)=O HYNQTSZBTIOFKH-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 229960005070 ascorbic acid Drugs 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 208000010877 cognitive disease Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 210000004744 fore-foot Anatomy 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229960004431 quetiapine Drugs 0.000 description 4
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- BLHRHYLDWYYUCO-UHFFFAOYSA-N 6-[4-(4-benzylpiperazin-1-yl)butoxy]-3-methylquinazolin-4-one Chemical compound C(C1=CC=CC=C1)N1CCN(CC1)CCCCOC=1C=C2C(N(C=NC2=CC=1)C)=O BLHRHYLDWYYUCO-UHFFFAOYSA-N 0.000 description 3
- JSYJUUGAOMCCSL-UHFFFAOYSA-N 7-[3-[4-(2-fluorophenyl)piperazin-1-yl]propoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound FC1=C(C=CC=C1)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C JSYJUUGAOMCCSL-UHFFFAOYSA-N 0.000 description 3
- OFNWXXGHORGIMJ-UHFFFAOYSA-N 7-[3-[4-(4-chlorophenyl)piperazin-1-yl]propoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound ClC1=CC=C(C=C1)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C OFNWXXGHORGIMJ-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229930003268 Vitamin C Natural products 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012549 training Methods 0.000 description 3
- 235000019154 vitamin C Nutrition 0.000 description 3
- 239000011718 vitamin C Substances 0.000 description 3
- KPJZHOPZRAFDTN-ZRGWGRIASA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CN(C)C3=C1 KPJZHOPZRAFDTN-ZRGWGRIASA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 2
- KKIMDKMETPPURN-UHFFFAOYSA-N 1-(3-(trifluoromethyl)phenyl)piperazine Chemical compound FC(F)(F)C1=CC=CC(N2CCNCC2)=C1 KKIMDKMETPPURN-UHFFFAOYSA-N 0.000 description 2
- AVJKDKWRVSSJPK-UHFFFAOYSA-N 1-(4-fluorophenyl)piperazine Chemical compound C1=CC(F)=CC=C1N1CCNCC1 AVJKDKWRVSSJPK-UHFFFAOYSA-N 0.000 description 2
- ZHBTYBBXWTXWRS-UHFFFAOYSA-N 2,3-dimethyl-6-[3-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]propoxy]quinazolin-4-one Chemical compound CC1=NC2=CC=C(C=C2C(N1C)=O)OCCCN1CCN(CC1)C1=CC(=CC=C1)C(F)(F)F ZHBTYBBXWTXWRS-UHFFFAOYSA-N 0.000 description 2
- YLTGLYZGVGBBTF-UHFFFAOYSA-N 2-methyl-7-[3-(4-naphthalen-1-ylpiperazin-1-yl)propoxy]-3,4-dihydroisoquinolin-1-one Chemical compound CN1C(C2=CC(=CC=C2CC1)OCCCN1CCN(CC1)C1=CC=CC2=CC=CC=C12)=O YLTGLYZGVGBBTF-UHFFFAOYSA-N 0.000 description 2
- SJQGLRPDBHCHCW-UHFFFAOYSA-N 2-methyl-7-[3-(4-phenylpiperazin-1-yl)propoxy]-3,4-dihydroisoquinolin-1-one Chemical compound CN1C(C2=CC(=CC=C2CC1)OCCCN1CCN(CC1)C1=CC=CC=C1)=O SJQGLRPDBHCHCW-UHFFFAOYSA-N 0.000 description 2
- JLHMEGWPLLZUIA-UHFFFAOYSA-N 2-methyl-7-[3-(4-pyridin-2-ylpiperazin-1-yl)propoxy]-3,4-dihydroisoquinolin-1-one Chemical compound CN1C(C2=CC(=CC=C2CC1)OCCCN1CCN(CC1)C1=NC=CC=C1)=O JLHMEGWPLLZUIA-UHFFFAOYSA-N 0.000 description 2
- SKUUWDIJGSUACY-UHFFFAOYSA-N 2-methyl-7-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propoxy]-3,4-dihydroisoquinolin-1-one Chemical compound CN1C(C2=CC(=CC=C2CC1)OCCCN1CCN(CC1)C1=NC=CC=N1)=O SKUUWDIJGSUACY-UHFFFAOYSA-N 0.000 description 2
- VFDLYPNEKROUJA-UHFFFAOYSA-N 2-methyl-7-[3-(4-quinolin-2-ylpiperazin-1-yl)propoxy]-3,4-dihydroisoquinolin-1-one Chemical compound N1=C(C=CC2=CC=CC=C12)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C VFDLYPNEKROUJA-UHFFFAOYSA-N 0.000 description 2
- NWSWBVKRQJZUCZ-UHFFFAOYSA-N 2-methyl-7-[4-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydroisoquinolin-1-one Chemical compound CN1C(C2=CC(=CC=C2CC1)OCCCCN1CCN(CC1)C1=CC(=CC=C1)C(F)(F)F)=O NWSWBVKRQJZUCZ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- SVLITLSFAOPGTD-UHFFFAOYSA-N 3-methyl-6-[4-(4-pyridin-2-ylpiperazin-1-yl)butoxy]quinazolin-4-one Chemical compound CN1C=NC2=CC=C(C=C2C1=O)OCCCCN1CCN(CC1)C1=NC=CC=C1 SVLITLSFAOPGTD-UHFFFAOYSA-N 0.000 description 2
- IGGKHEHGJTUIOP-UHFFFAOYSA-N 3-methyl-6-[4-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]butoxy]quinazolin-4-one Chemical compound CN1C=NC2=CC=C(C=C2C1=O)OCCCCN1CCN(CC1)C1=CC(=CC=C1)C(F)(F)F IGGKHEHGJTUIOP-UHFFFAOYSA-N 0.000 description 2
- CGBSETBXUKRGJF-UHFFFAOYSA-N 6-[4-(3,4-dihydro-1H-isoquinolin-2-yl)butoxy]-3-methylquinazolin-4-one Chemical compound C1N(CCC2=CC=CC=C12)CCCCOC=1C=C2C(N(C=NC2=CC=1)C)=O CGBSETBXUKRGJF-UHFFFAOYSA-N 0.000 description 2
- ZEGLGARCMOTFDG-UHFFFAOYSA-N 6-[4-[4-(4-fluorophenyl)piperazin-1-yl]butoxy]-3-methylquinazolin-4-one Chemical compound FC1=CC=C(C=C1)N1CCN(CC1)CCCCOC=1C=C2C(N(C=NC2=CC=1)C)=O ZEGLGARCMOTFDG-UHFFFAOYSA-N 0.000 description 2
- QIMOBLHMKZLPIE-UHFFFAOYSA-N 7-[3-[4-(2-chlorophenyl)piperazin-1-yl]propoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound ClC1=C(C=CC=C1)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C QIMOBLHMKZLPIE-UHFFFAOYSA-N 0.000 description 2
- SLPNWORIUMAUFP-UHFFFAOYSA-N 7-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C SLPNWORIUMAUFP-UHFFFAOYSA-N 0.000 description 2
- RMXGCHHYNPXIEU-UHFFFAOYSA-N 7-[3-[4-(4-fluorophenyl)piperazin-1-yl]propoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound FC1=CC=C(C=C1)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C RMXGCHHYNPXIEU-UHFFFAOYSA-N 0.000 description 2
- AXTPDHOKNPRWNN-UHFFFAOYSA-N 7-[3-[4-(4-methoxyphenyl)piperazin-1-yl]propoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound COC1=CC=C(C=C1)N1CCN(CC1)CCCOC1=CC=C2CCN(C(C2=C1)=O)C AXTPDHOKNPRWNN-UHFFFAOYSA-N 0.000 description 2
- YCZWURFQDCDNKN-UHFFFAOYSA-N 7-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]-2-methyl-3,4-dihydroisoquinolin-1-one Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)CCCCOC1=CC=C2CCN(C(C2=C1)=O)C YCZWURFQDCDNKN-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000003946 Prolactin Human genes 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- 101000858014 Rattus norvegicus Coxsackievirus and adenovirus receptor homolog Proteins 0.000 description 2
- 101001124271 Rattus norvegicus Nuclear receptor subfamily 1 group I member 3 Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000013043 chemical agent Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- FVWDBVACVTXVJN-UHFFFAOYSA-L dipotassium;propan-2-one;carbonate Chemical compound [K+].[K+].CC(C)=O.[O-]C([O-])=O FVWDBVACVTXVJN-UHFFFAOYSA-L 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229960005417 ketanserin Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 150000002690 malonic acid derivatives Chemical class 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 229960000582 mepyramine Drugs 0.000 description 2
- 229960001186 methysergide Drugs 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229960002508 pindolol Drugs 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 210000002442 prefrontal cortex Anatomy 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 229950001675 spiperone Drugs 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- VNICFCQJUVFULD-UHFFFAOYSA-N 1-(1-naphthalenyl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=CC=CC=C12 VNICFCQJUVFULD-UHFFFAOYSA-N 0.000 description 1
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 1
- PWZDJIUQHUGFRJ-UHFFFAOYSA-N 1-(2-chlorophenyl)piperazine Chemical compound ClC1=CC=CC=C1N1CCNCC1 PWZDJIUQHUGFRJ-UHFFFAOYSA-N 0.000 description 1
- IVTZRJKKXSKXKO-UHFFFAOYSA-N 1-(2-fluorophenyl)piperazine Chemical compound FC1=CC=CC=C1N1CCNCC1 IVTZRJKKXSKXKO-UHFFFAOYSA-N 0.000 description 1
- ZCGYIRXIAQVDFM-UHFFFAOYSA-N 2-(2-fluoro-4-methoxyphenyl)ethanamine Chemical group COC1=CC=C(CCN)C(F)=C1 ZCGYIRXIAQVDFM-UHFFFAOYSA-N 0.000 description 1
- GEMYZBZNBCDFGW-UHFFFAOYSA-N 2-(4-methoxy-2-methylphenyl)ethanamine Chemical compound COC1=CC=C(CCN)C(C)=C1 GEMYZBZNBCDFGW-UHFFFAOYSA-N 0.000 description 1
- LUOOSDUSUYCCFY-UHFFFAOYSA-N 2-(4-methoxyphenyl)propan-1-amine Chemical compound COC1=CC=C(C(C)CN)C=C1 LUOOSDUSUYCCFY-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 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
- MRMGJMGHPJZSAE-UHFFFAOYSA-N 6-fluoro-3-piperidin-4-yl-1,2-benzoxazole Chemical compound N=1OC2=CC(F)=CC=C2C=1C1CCNCC1 MRMGJMGHPJZSAE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000317410 Arisaema dracontium Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000035859 Drug effect increased Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- XFYIHRTWDXNCTA-UHFFFAOYSA-N Eugenin Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OC1CCC2C(C)(CCC3C2(C)CCC4(C)C5CC(C)(C)CCC5(C)CCC34C)C1C XFYIHRTWDXNCTA-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- KRDOFMHJLWKXIU-UHFFFAOYSA-N ID11614 Chemical compound C1CNCCN1C1=NSC2=CC=CC=C12 KRDOFMHJLWKXIU-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 150000000994 L-ascorbates Chemical class 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- JGTQINGICQVMIN-UHFFFAOYSA-N POPOPOPOP Chemical compound POPOPOPOP JGTQINGICQVMIN-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical class CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000518 effect on emotion Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- SUTUBQHKZRNZRA-UHFFFAOYSA-N eugenin Chemical compound O1C(C)=CC(=O)C=2C1=CC(OC)=CC=2O SUTUBQHKZRNZRA-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000005612 glucoheptonate group Chemical group 0.000 description 1
- 150000002315 glycerophosphates Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical class CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 210000001153 interneuron Anatomy 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 description 1
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- NOHPWENBDQVVJH-UHFFFAOYSA-N n-(4-methoxyphenoxy)methanamine Chemical group CNOC1=CC=C(OC)C=C1 NOHPWENBDQVVJH-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
- MRDGZSKYFPGAKP-UHFFFAOYSA-N para-methoxyphenylpiperazine Chemical compound C1=CC(OC)=CC=C1N1CCNCC1 MRDGZSKYFPGAKP-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- XRXDAJYKGWNHTQ-UHFFFAOYSA-N quipazine Chemical compound C1CNCCN1C1=CC=C(C=CC=C2)C2=N1 XRXDAJYKGWNHTQ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—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
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
本发明涉及内酰胺类化合物衍生物、包含该内酰胺类化合物衍生物的药物组合物以及该组合物和该内酰胺类化合物衍生物在制备用于预防或治疗精神分裂症中的用途,其中所述内酰胺类化合物衍生物具有式I的结构。
Description
本申请是2016年11月21日提交的发明名称为“内酰胺类化合物衍生物及其应用”的中国专利申请201680067130.4号的分案申请。
技术领域
本发明涉及医药领域,具体地,涉及内酰胺类化合物衍生物、包含该内酰胺类化合物衍生物的药物组合物以及该组合物和该内酰胺类化合物衍生物用于预防或治疗精神分裂症的用途。
背景技术
精神分裂症是所有精神疾病中最严重、危害最大的一种疾病,全球发病率约为1-2%。精神分裂症患者终生患病率为0.7-0.8%,与性别,种族,或社会界限没有明显相关性,同时死亡率比一般人群高出2-3倍。最新研究显示,精神疾病的社会负担在中国疾病中排名居首,超过了心脑血管、呼吸系统及恶性肿瘤等疾患。
现有精神分裂药物主要有两大类:典型抗精神分裂药物和非典型抗精神分裂药物。典型抗精神分裂药物(如氯丙嗪和氟哌啶醇)阻断多巴胺D2受体,对精神分裂症阳性症状具有良好疗效。但由于强烈阻断多巴胺受体,导致了锥体外系反应(EPS)、迟发性运动障碍以及泌乳素增加等不良反应,而且对精神分裂症阴性症状无效。
以氯氮平和利培酮为代表的非典型抗精神分裂药物不仅对多巴胺(D2)受体有较强作用,同时对5-羟色胺(5-HT2A)受体也有较强作用。与典型抗精神分裂药物相比这类药物有很大的优势:对精神分裂症阳性症状有良好疗效,锥体外系反应和迟发性运动障碍等副作用显著降低,并且部分非典型抗精神分裂药物对阴性症状和认知障碍有一定改善作用。然而,目前临床应用的非典型抗精神分裂药物都有不同程度的QT间期延长和高泌乳素等不良反应。因此,寻找新的既能有效地治愈精神分裂症而且副作用小的药物是非常重要。
经过研究发现D2、5-HT1A、5-HT2A和H1等受体对精神分裂症具有非常重要的作用。通过D2受体作用能有效治疗精神分裂症阳性症状。前额叶皮层的锥体神经元和GABA中间神经元包含5-羟色胺受体5-HT1A和5-HT2A。5-羟色胺系统在调节的前额叶皮层的功能中起着重要作用,包括情绪控制、认知行为和工作记忆。5-HT1A与非典型抗精神病药物的治疗效果相关,能改善阴性症状和认知障碍。5-HT2A受体涉及到感知、情绪调节以及运动控制的各个方面,阻断5-HT2A受体可使多巴胺的释放正常化,而起到抗精神病作用。5-HT7受体mRNA既存在于外周组织,也表达于中枢神经系统,主要位于丘脑、下丘脑、大脑皮层、海马和杏仁核。该受体对体温、生物节律、睡眠、情绪、学习和记忆等均有调节作用。5-HT7受体在正常和病理状态下对中枢神经系统活动具有重要的调节作用,可作为治疗精神疾病的一个重要靶点。同时,在治疗精神分裂的长期服药过程中,部分药物易于引起体重增加的副作用。研究表明这些副作用与组胺H1受体密切相关。
因此,具有多受体结合方式,作用范围较高,并且能降低EPS和体重增加等副作用的新型抗精神分裂药物是期望的。
发明内容
在一个方面,本发明提供式I所示的化合物或其药学上可接受的盐或前药:
其中:
X为C、O、N或NH;
Z为未取代的或者被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代的-(CH2)n-,n为2~7的整数;
R1和R2分别独立地为氢或任选地被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代的含有1~5个碳原子的直链或支链烷基;
R3为氢、卤素或任选地被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代的含有1~5个碳原子的直链或支链烷基;
P为CH或N;
Ar为选自式II-VII的基团:
L和M独立地为CH或N;
Q为O或S;
R4、R5、R6、R7和R8分别独立地为氢、卤素、含有1~5个碳原子的直链或支链烷基或含有1~5个碳原子的烷氧基,所述烷基和烷氧基任选地被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代。
在另一方面,本发明还提供了一种药物组合物,其包含本发明的化合物或其药学上可接受的盐或前药以及药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
在又一方面,本发明的化合物或其药学上可接受的盐或前药或者本发明的药物组合物可用于预防或治疗神经精神类疾病,特别是精神分裂症。
本发明还涉及一种预防或治疗神经精神类疾病,特别是精神分裂症的方法,所述方法包括向有此需要的个体给药有效量的本发明的化合物或其药学上可接受的盐或前药或者本发明的药物组合物。
本发明进一步涉及本发明的化合物或其药学上可接受的盐或前药或者本发明的药物组合物在制备用于预防或治疗神经精神类疾病,特别是精神分裂症的药物中的用途。
具体实施方式
定义和一般术语
除非另外说明,应当应用本文所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》(第75版,1994)一致。此外,有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
本发明所使用的术语“患者”或“个体”是指人(包括成人和儿童)或者其他动物(包括哺乳动物)。根据本发明的一些实施例,“患者”或“个体”是指人。
术语“任选”、“任选地”或“任选存在”是指随后描述的事件或情形可以但不一定出现,并且该描述包括其中所述事件或情形出现的情况和不出现的情况。例如,“任选存在的键”是指该键可以存在或可以不存在,并且该描述包括单键、双键或三键等。
本发明中的“任选取代的”这个术语与“取代或未取代的”这个术语可以交换使用。一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个任选的取代基团可以在其各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
除非以其他方式明确指出,在本发明中所采用的描述方式“分别(或各自)独立地”应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-5烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基和C5烷基。
本文所列举的范围,如数值范围涵盖其中的每个数值以及由其中的每个数值组成的亚范围,例如“n为2~7”包括2、3、4、5、6、7以及由这些数值组成的各个亚范围,包括但不限于2~6、2~5、2~4、3~6、3~5、4~6等。
本文的描述“一个或多个”可以表示1、2、3、4、5、6、7个或更多个。
在式I中,含有虚线的部分可以表示单键或双键。本领域技术人员应当容易地理解,在表示单键或双键的情况下,出于化学键的合理选择和获得稳定化合物的考虑,X表示的原子或原子团可以相应和任选地连接有一个或多个氢原子。例如,如果含有虚线的部分表示单键,当X的选择为C时,应当理解其可以相应地表示CH2。如果含有虚线的部分表示双键,当X选择为C时,应当理解其可以相应地表示CH。同样,如果含有虚线的部分表示双键,出于化学键的合理选择和获得稳定化合物的目的,本领域技术人员应当理解,X为NH的选择可以相应地表示N。在一实施方案中,上述原子团(例如CH、CH2、NH)可以是任选地被取代的,例如被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代。
除非明确描述,本发明使用的术语“烷基”或“烷基基团”,表示含有1-20个碳原子,饱和的直链或支链一价烃基基团,其中所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明,烷基基团含有1-20个碳原子。根据本发明的一个实施方案,烷基基团含有1-12个碳原子。根据本发明的另一个实施方案,烷基基团含有1-6个碳原子。根据本发明的一个实施方案,烷基基团含有1-5或1-4个碳原子。根据本发明的另一个实施方案,烷基基团含有1-3个碳原子。烷基基团的实例包括但并不限于,甲基(Me、-CH3)、乙基(Et、-CH2CH3)、正丙基(n-Pr、-CH2CH2CH3)、异丙基(i-Pr、-CH(CH3)2)、正丁基(n-Bu、-CH2CH2CH2CH3)、异丁基(i-Bu、-CH2CH(CH3)2)、仲丁基(s-Bu、-CH(CH3)CH2CH3)、叔丁基(t-Bu、-C(CH3)3)、正戊基(-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、正己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)、正庚基、正辛基,等等。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“含有1~5个碳原子的烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有上文所述的含义。除非另外详细说明,烷氧基基团含有1-5个碳原子。
烷氧基基团的实例包括但并不限于甲氧基(MeO、-OCH3)、乙氧基(EtO、-OCH2CH3)、1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)、2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)、1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)、2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)、2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)、2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)、1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)、2-戊氧基(-OCH(CH3)CH2CH2CH3)、3-戊氧基(-OCH(CH2CH3)2)。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,J.PharmaceuticalSciences,66:1-19,1977所记载。药学上可接受的无毒的酸形成的盐包括,但并不限于,与无机酸盐反应形成的盐,如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐;与有机酸反应形成的盐,如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐;或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括但不限于己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐,等等。通过适当的碱得到的盐包括但不限于碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。
术语“治疗”可以指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“预防”指发展疾病或病症的风险的减少(即,使疾病的至少一种临床症状在主体内停止发展,该主体可能面对或预先倾向面对这种疾病,但还没有经历或表现出疾病的症状)。
本发明的药学上可接受的盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言,这样的盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应,或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。这样的反应通常在水或有机溶剂或二者的混合物中进行。一般地,在适当的情况中,需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”,第20版,Mack PublishingCompany,Easton,Pa.,(1985);和“药用盐手册:性质、选择和应用(Handbook ofPharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
本发明所使用的术语“代谢产物”是指特定化合物或其盐在体内通过代谢作用所得到的产物。化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以通过给药的化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、酶裂解等等方法得到。相应地,本发明涵盖本发明的化合物的代谢产物,例如将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。应当理解,本发明还涵盖本发明的化合物或其盐的立体异构体、互变异构体、氮氧化物、溶剂化物(如水合物)、代谢产物等。这些形式优选为药学上可接受的。
本发明所使用的术语“前药”代表可以在体内转化为式I所示的化合物的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。关于前体药物的详细讨论可以参考以下文献:Higuchi et al.,Pro-drugs as Novel DeliverySystems,Vol.14,A.C.S.Symposium Series;Roche et al.,ed.,Bioreversible Carriersin Drug Design,American Pharmaceutical Association and Pergamon Press,1987;Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews DrugDiscovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates andPhosphonates,J.Med.Chem.,2008,51,2328-2345,每篇文献通过引用包含于此。
本发明的化合物
本发明提供式I所示化合物或其药学上可接受的盐或前药:
其中:
X为C、O、N或NH;
Z为未取代或被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代的-(CH2)n-,n为2~7的整数;
R1或R2分别独立地为氢、任选地被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代的含有1~5个碳原子的直链或支链烷基;
R3为氢、卤素或任选地被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代的含有1~5个碳原子的直链或支链烷基;
P为CH或N;
Ar为选自式II-VII中的基团:
L和M独立地为CH或N;
Q为O或S;
R4、R5、R6、R7或R8分别独立地为氢、卤素、含有1~5个碳原子的直链或支链烷基或含有1~5个碳原子的烷氧基,所述烷基和烷氧基任选地被一个或多个选自烷基、氰基、羟基和卤素中的取代基取代。
在一实施方案中,通式I中的R1和R2分别独立地为氢、甲基、乙基、丙基、正丁基、异丁基、三氟甲基、三氟乙基或三氟丙基。
在另一实施方案中,通式I中的R3为氢、氟、氯、溴、碘、甲基、乙基、丙基、正丁基或异丁基。
在另一实施方案中,通式I中的R4、R5和R8分别独立地为氢、卤代C1-5烷基、甲氧基、乙氧基、丙氧基、氯、氟或溴。
在优选的实施方案中,卤代C1-5烷基为三氟甲基、三氟乙基、三氟丙基或三氟丁基。
在一实施方案中,卤素为氟、氯、溴或碘。
在本发明的一优选实施方案中,
X为C、O、N或NH;
Z为未取代或被一个或多个羟基取代的-(CH2)n-,n为2~5的整数;
R1为氢、甲基或乙基;
R2为氢、甲基或乙基;
R3为氢、甲基或氟。
具体地,本发明涉及以下的化合物中的至少一种或者其药学上可接受的立体异构体、互变异构体、氮氧化物、溶剂化物(如水合物)、代谢产物、盐或前药:
药物组合物和给药
本发明提供一种药物组合物,其包含式I化合物或其药学上可接受的盐以及药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
本发明的药物组合物可通过任何适当的途径施用,例如胶囊形式口服,以注射液的形式胃肠外施用,以膏剂或洗剂的形式局部施用,以栓剂的形式直肠施用,以贴片的传递系统的形式经皮施用。
根据本发明的一实施方案,有效量的本发明的化合物或其药学上可接受的盐可与载体如惰性稀释剂一起口服。药学上可接受的适当的载体的实例包括但不限于惰性固体填充剂或稀释剂和无菌水溶液或有机溶液。根据本发明的一些实施方案,可将本发明的化合物或其药学上可接受的盐包于明胶胶囊中或压制成片。为口服治疗的目的,本发明的化合物或其药学上可接受的盐可与赋形剂一起使用,并例如以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。
本发明的化合物可以与适当的固体或液体载体或稀释剂组合形成胶囊、片剂、丸剂、散剂、糖浆剂、溶液剂等。片剂、丸剂、胶囊等,这样的形式可以包含约0.01-约99重量%的活性成分(如本发明的化合物或其药学上可接受的盐)以及粘合剂例如明胶、玉米淀粉、阿拉伯树胶;赋形剂例如磷酸氢钙;崩解剂例如玉米淀粉、马铃薯淀粉或藻酸;润滑剂例如硬脂酸镁;和甜味剂例如蔗糖、乳糖。当使用胶囊时,其还可包含液体载体,例如油脂。当用于胃肠外施用时,可将本发明的化合物或其药学上可接受的盐与无菌水或有机介质组合形成可注射的溶液或悬液。
根据本发明的实施方案,这样的制剂可以含有至少0.5重量%的本发明的化合物或其药学上可接受的盐,但根据特定的剂型变化,约4重量%-约70重量%也可以是有利的。本发明优选的口服单位剂量可以含有1.0-300毫克的本发明的化合物或其药学上可接受的盐。
本发明的药物组合物的每单位剂量能提供约0.01-1000mg的活性成分。本发明的化合物的用量取决于疾病或病症的类型和严重性,还取决于对象的特征,例如一般健康、年龄、性别、体重和药物耐受性。技术人员能够根据这些或其它因素来确定适当的剂量。通常所用的中枢神经系统药物的有效剂量是技术人员熟知的。每日总剂量通常为约0.05mg-2000mg。
本发明的有益效果
体外受体结合试验表明,本发明的化合物对多巴胺D2、5-HT1A和5-HT2A受体具有较高的亲和力,具有抗神经精神类疾病活性,也即具有治疗或预防神经精神类疾病、特别是具有抗精神分裂症的作用。同时,本发明的化合物与H1亲和力低(降低肥胖风险,可以增加药物的作用(如改善阴性症状)、降低副作用(如EPS、乳泌素增加、体重增加和使得QI间隙延长)。优选地,本发明的化合物对5HT7受体也具有较高的亲和力,可有助于改善认知障碍的功能。
动物试验结果显示,本发明的化合物既能明显改善MK-801诱导的高活动性,又能有效的改善阿扑吗啡诱导的攀爬症状,并且在有效剂量下不引起EPS。这表明其有明显的抗精神分裂作用。由于这些体外作用靶点和体内药理模型与多巴胺功能紊乱导致的神经系统疾病,特别是精神分裂症密切相关,因此提示本发明的化合物具有治疗或预防神经精神类疾病的作用,特别是精神分裂症。
一般合成方案
本发明化合物中X为C时的通用合成方法可以包括使4-甲氧基苯乙胺与氯甲酸乙酯反应,然后在甲磺酸和五氧化二磷的存在下自身环合,用碘甲烷对酰胺的N上进行甲基化反应,用氢溴酸水溶液脱去甲氧基上的甲基,再分别与1,3-二溴丙烷或1,4-二溴丁烷反应,最后与相应的哌嗪或哌啶反应得到目标产物。具体反应路线示例如下:
(a)Et3N,CH2Cl2,0℃-rt;(b)P2O5,MSA(甲磺酸),10h;(c)CH3I,NaH,DMF;(d)HBr/H2O;(e)K2CO3,丙酮;(f)K2CO3,CH3CN。
本发明化合物中X为N(方案中的Y可以为N)时的通用合成方法可以包括使2-氨基-5羟基苯甲酸分别与乙酸酐和N-甲基甲酰胺反应得到产物,再分别与1,3-二溴丙烷或1,4-二溴丁烷反应,最后与相应的哌嗪或哌啶反应得到得到目标产物。具体反应路线示例如下:
(a)吡咯烷,CH3CN;(b)K2CO3,丙酮;(c)K2CO3,CH3CN。
合成实施例
下面详细描述本发明的实施例。下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。除非另外指明,本文所指的比例、百分比等均以重量计。以下合成实施例1-31,均是基于上述的一般方法进行的,其中各实施例制备的化合物见表1。
实施例1、7-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丁氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(1)
(1)将4-甲氧基苯乙胺(0.1mol)溶于二氯甲烷(300ml)中,将混合物冰浴冷却至0℃,向其中加入三乙胺(20ml),然后缓慢滴加氯甲酸乙酯(0.15mmol)。加完后在室温下反应12h。反应完毕,将反应液用水、10%稀盐酸溶液洗,将有机层用无水硫酸镁干燥,减压蒸去溶剂,将剩余物用石油醚洗,干燥后得黄色油状物20.3g。收率91%,
MS(ESI)m/z 223.3([M+H]+)
(2)将五氧化二磷(0.2mol)溶于甲磺酸(200ml)中,向其中分批加入第(1)步中制备的黄色油状物(0.1mol),在140℃下反应。反应完毕后,将反应液倒入冰水(500ml)中终止,用二氯甲烷萃取,将有机层用饱和碳酸钠洗,用无水硫酸镁干燥,减压蒸去溶剂。将剩余物过柱(洗脱剂为石油醚:乙酸乙酯=10:1)获得褐色油状物12.9g。收率73%。
MS(ESI)m/z 177.1([M+H]+)
(3)将第(2)步制备的油状物(0.1mol)加入溶解有0.2mol氢氧化钠的200ml N,N-二甲基甲酰胺中,在冰浴中搅拌反应0.5h。向其中缓慢滴加碘甲烷(0.15mol)。滴加完毕后,将反应在室温下反应10h。反应完毕后,将反应液倒入1L冰水中终止反应,用乙酸乙酯萃取,将有机层用饱和食盐水洗,用无水硫酸镁干燥,旋干溶剂获得棕色固体17.8g。收率93%。
MS(ESI)m/z 191.1([M+H]+)
(4)使第(3)步制备的棕色固体(0.1mmol)在48%氢溴酸水溶液(100ml)中于100℃下反应10h。反应完毕,加水终止反应,用乙酸乙酯萃取,用饱和碳酸氢钠溶液洗,将有机层用无水硫酸镁干燥,旋干溶剂。将剩余物过柱(洗脱剂为石油醚:乙酸乙酯=1:1)获得褐色固体8.1g。收率46%。
MS(ESI)m/z 177.2([M+H]+)
(5)将第(4)步制备的褐色固体(0.1mmol)、1,4-二溴丁烷(0.12mmol)和碳酸钾(0.3mmol)加入丙酮(200ml)中,回流反应12h。反应完毕,抽滤得有机溶液。将其减压蒸干,将剩余物柱层析(洗脱剂为石油醚:乙酸乙酯=10:1)得浅黄色油状物26.4g。收率89%。
MS(ESI)m/z 297.0([M+H]+)
(6)将第(5)步制备的浅黄色油状物(2mmol)、6-氟-3-(哌啶基-4-基)苯并[d]异噁唑(2mmol)和碳酸钾(6mmol)加入乙腈(50ml)中,回流反应10h。反应完毕,抽滤,得到有机溶液。蒸干乙腈,将剩余物柱层析(洗脱剂为CH2Cl2:甲醇=10:1)得到黄色油状物0.38g。收率87%。
MS(ESI)m/z 437.2([M+H]+)。结构式如表1中编号(1)所示。
1H-NMR(600MHz,CDCl3)δ1.74-1.87(m,8H),2.05-2.19(m,6H),2.48(t,2H,J=12Hz),2.93(t,2H,J=12Hz),3.07-3.11(m,2H),3.16(s,3H),3.55(t,2H,J=12Hz),4.06(t,2H,J=6Hz),6.96-6.98(m,1H),7.04-7.09(m,2H),7.24-7.26(m,1H),7.61(d,1H,J=6Hz),7.73-7.74(m,1H).MS(ESI)m/z 452.2([M+H]+)。
1H-NMR(600MHz,CDCl3)δ1.74-1.86(m,8H),2.55-2.56(m,2H),2.71-2.73(m,2H),2.93(t,2H,J=12Hz),3.10(t,2H,J=12Hz),3.14(s,3H),3.53(t,2H,J=12Hz),4.03(t,2H,J=6Hz),6.94-6.97(m,2H),7.05-7.16(m,3H),7.58(d,1H,J=6Hz).MS(ESI)m/z462.1([M+H]+)。
实施例2、7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(2)
按实施例1的方法制备目标化合物,但用1-(2-甲氧基苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(2)所示。
1H-NMR(600MHz,CDCl3)δ1.72-1.86(m,4H),2.50(t,2H,J=12Hz),2.69-2.70(m,3H),2.94(t,2H,J=12Hz),3.12-3.16(m,2H),3.18(s,3H),3.54(t,2H,J=12Hz),3.87(s,3H),4.05(t,2H,J=6Hz),6.86-6.88(m,1H),6.91-7.07(m,5H),7.61(d,1H,J=6Hz).MS(ESI)m/z 424.3([M+H]+)。
实施例3、2-甲基-7-(4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁氧基)-3,4-二氢异喹啉-1(2H)-酮(3)
按实施例1的方法制备目标化合物,但用1-(3-(三氟甲基)苯基)代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(3)所示。
1H-NMR(600MHz,CDCl3)δ1.73-1.88(m,4H),2.21-2.22(m,2H),2.50(t,2H,J=12Hz),2.64-2.66(m,3H),2.94(t,2H,J=12Hz),3.18(s,3H),3.26-3.28(m,3H),3.55(t,2H,J=12Hz),4.06(t,2H,J=6Hz),6.96-6.98(m,1H),7.06-7.10(m,3H),7.12-7.14(m,1H),7.34-7.36(m,1H),7.61(d,1H,J=6Hz).MS(ESI)m/z 462.2([M+H]+)。
实施例4、7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)-2-羟基丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(4)
按实施例1的方法制备目标化合物,但用2-(氯甲基)环氧乙烷代替1,4-二溴丁烷。结构式如表1中编号(4)所示。
1H-NMR(600MHz,CDCl3)δ1.22-1.25(m,2H),2.09-2.13(m,4H),2.24-2.26(m,1H),2.53-2.65(m,3H),2.94(t,2H,J=12Hz),3.13-3.17(m,4H),3.19(s,3H),3.21-3.23(m,2H),3.53(t,2H,J=12Hz),4.05-34.17(m,2H),7.03-7.11(m,3H),7.21-7.26(m,1H),7.64(d,1H,J=6Hz),7.70-7.72(m,1H).MS(ESI)m/z 453.3([M+H]+)。
实施例5、7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉
-1(2H)-酮(5)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(5)所示。
1H-NMR(600MHz,CDCl3)δ2.02-2.19(m,8H),2.60(t,2H,J=12Hz),2.96(t,2H,J=12Hz),3.09-3.11(m,3H),3.18(s,3H),3.56(t,2H,J=12Hz),4.11(t,2H,J=6Hz),6.98-7.00(m,1H),7.06-7.10(m,2H),7.24-7.26(m,1H),7.64(d,1H,J=6Hz),7.74-7.76(m,1H).MS(ESI)m/z 438.2([M+H]+)。
实施例6、2-甲基-7-(3-(4-(萘-1-基)哌嗪-1-基)丙氧基)-3,4-二氢异喹啉-1(2H)-酮(6)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(萘-1-基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(6)所示。
1H-NMR(600MHz,CDCl3)δ1.83-2.07(m,4H),2.58-2.67(m,4H),2.94(t,2H,J=12Hz),3.16(s,3H),3.21-3.25(m,4H),3.56(t,2H,J=12Hz),4.10(t,2H,J=6Hz),6.89-7.10(m,6H),7.27-7.29(m,2H),7.62(d,1H,J=6Hz),7.74-7.76(m,2H).MS(ESI)m/z 430.2([M+H]+)。
实施例7、7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-2-乙基-3,4-二氢异喹啉-1(2H)-酮(7)
按实施例1的方法制备目标化合物,但用碘乙烷代替碘甲烷,用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(7)所示。
1H-NMR(600MHz,CDCl3)δ1.78(t,3H,J=12Hz),2.01-2.18(m,8H),2.61(t,2H,J=12Hz),2.95(t,2H,J=12Hz),3.09-3.14(m,5H),3.56(t,2H,J=12Hz),4.10(t,2H,J=6Hz),6.97-7.00(m,1H),7.07-7.10(m,2H),7.24-7.26(m,1H),7.65(d,1H,J=6Hz),7.75-7.77(m,1H).MS(ESI)m/z 453.2([M+H]+)。
实施例8、7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-2,5-二甲基-3,4-二氢异喹啉-1(2H)-酮(8)
按实施例1的方法制备目标化合物,但用2-甲基-4-甲氧基苯乙胺代替4-甲氧基苯乙胺,用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(8)所示。
1H-NMR(600MHz,CDCl3)δ2.01-2.18(m,8H),2.60(t,2H,J=12Hz),2.71(s,3H),2.95(t,2H,J=12Hz),3.09-3.12(m,3H),3.18(s,3H),3.57(t,2H,J=12Hz),4.10(t,2H,J=6Hz),6.96-7.00(m,1H),7.07-7.11(m,1H),7.24-7.25(m,1H),7.66(d,1H,J=6Hz),7.75-7.78(m,1H).MS(ESI)m/z 453.1([M+H]+)。
实施例9、5-氟-7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(9)
按实施例1的方法制备目标化合物,但用2-氟-4-甲氧基苯乙胺代替4-甲氧基苯乙胺,用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(9)所示。
1H-NMR(600MHz,CDCl3)δ2.03-2.20(m,10H),2.62(t,2H,J=12Hz),2.97(t,2H,J=12Hz),3.09-3.12(m,3H),3.19(s,3H),3.56(t,2H,J=12Hz),4.12(t,2H,J=6Hz),7.02-7.11(m,2H),7.24-7.27(m,1H),7.66(d,1H,J=6Hz),7.75-7.78(m,1H).MS(ESI)m/z453.3([M+H]+)。
实施例10、7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-2,4-二甲基-3,4-二氢异喹啉-1(2H)-酮(10)
按实施例1的方法制备目标化合物,但用2-(4-甲氧基苯基)丙-1-胺代替4-甲氧基苯乙胺,用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(10)所示。
1H-NMR(600MHz,CDCl3)δ1.75(d,3H,J=8Hz),2.01-2.19(m,8H),2.61(t,2H,J=12Hz),2.95(t,2H,J=12Hz),3.08-3.10(m,3H),3.17(s,3H),3.55(t,2H,J=12Hz),4.10(t,2H,J=6Hz),6.97-7.00(m,1H),7.05-7.10(m,2H),7.24-7.25(m,1H),7.63(d,1H,J=6Hz),7.74-7.76(m,1H).MS(ESI)m/z 438.2([M+H]+)。
实施例11、6-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-3-甲基-2H-苯并[e][1,3]噁嗪-4(3H)-酮(11)
按实施例1的方法制备目标化合物,但用(4-甲氧基苯氧基)甲胺代替4-甲氧基苯乙胺,用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(11)所示。
1H-NMR(600MHz,CDCl3)δ2.01-2.19(m,4H),2.62(t,2H,J=12Hz),2.96(t,2H,J=12Hz),3.10-3.12(m,3H),3.19(s,3H),3.57(t,2H,J=12Hz),4.12(t,2H,J=6Hz),4.18(s,2H),7.00-7.09(m,3H),7.24-7.27(m,1H),7.66(d,1H,J=6Hz),7.74-7.77(m,1H).MS(ESI)m/z 440.2([M+H]+)。
实施例12、7-(3-(4-(6-氟苯并[d]异噁唑-3-基)哌啶基-1-基)丙氧基)-3,4-二氢异喹啉-1(2H)-酮(12)
按实施例1的方法制备目标化合物,但不使用碘甲烷,并用1,3-二溴丙烷代替1,4-二溴丁烷。结构式如表1中编号(12)所示。
1H-NMR(600MHz,CDCl3)δ2.03-2.20(m,8H),2.61(t,2H,J=12Hz),2.96(t,2H,J=12Hz),3.08-3.11(m,3H),3.57(t,2H,J=12Hz),4.10(t,2H,J=6Hz),6.97-7.00(m,1H),7.07-7.10(m,2H),7.25-7.27(m,1H),7.64(d,1H,J=6Hz),7.74-7.76(m,1H).MS(ESI)m/z424.3([M+H]+)。
实施例13、7-(3-(4-(苯并[d][1,3]二噁-5-基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(13)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(苯并[d][1,3]二噁茂-5-基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(13)所示。
1H-NMR(600MHz,CDCl3)δ1.80-2.02(m,8H),2.57(t,2H,J=12Hz),2.96(t,2H,J=12Hz),3.09-3.15(m,2H),3.19(s,3H),3.58(t,2H,J=12Hz),4.12(t,2H,J=6Hz),4.20(s,2H),6.98-7.00(m,1H),7.06-7.15(m,3H),7.63(d,1H,J=6Hz),7.98-8.02(m,2H).MS(ESI)m/z 424.3([M+H]+)。
实施例14、7-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(14)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用3-(哌嗪-1-基)苯并[d]异噻唑代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(14)所示。
1H-NMR(600MHz,CDCl3)δ2.01-2.18(m,6H),2.61(t,2H,J=12Hz),2.97(t,2H,J=12Hz),3.09-3.13(m,4H),3.18(s,3H),3.57(t,2H,J=12Hz),4.11(t,2H,J=6Hz),6.97-7.00(m,2H),7.07-7.10(m,2H),7.23-7.26(m,1H),7.63(d,1H,J=6Hz),7.75-7.77(m,1H).MS(ESI)m/z 438.2([M+H]+)。
实施例15、7-(3-(4-(喹啉-2-基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(15)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(喹啉-2-基)-哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(15)所示。
1H-NMR(600MHz,CDCl3)δ1.81-2.06(m,4H),2.59-2.65(m,4H),2.94(t,2H,J=12Hz),3.18(s,3H),3.21-3.25(m,4H),3.57(t,2H,J=12Hz),4.11(t,2H,J=6Hz),6.56-6.58(m,1H),6.85-7.10(m,5H),7.26-7.27(m,1H),7.63(d,1H,J=6Hz),7.74-7.76(m,2H).MS(ESI)m/z 431.2([M+H]+)。
实施例16、2-甲基-7-(3-(4-苯基哌嗪-1-基)丙氧基)-3,4-二氢异喹啉-1(2H)-酮(16)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-苯基哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑为原料。结构式如表1中编号(16)所示。
1H-NMR(600MHz,CDCl3)δ1.81-2.07(m,4H),2.59-2.67(m,4H),2.95(t,2H,J=12Hz),3.17(s,3H),3.22-3.25(m,4H),3.56(t,2H,J=12Hz),4.11(t,2H,J=6Hz),6.85-7.10(m,4H),7.26-7.27(m,1H),7.63(d,1H,J=6Hz),7.74-7.76(m,2H).MS(ESI)m/z 380.2([M+H]+)。
实施例17、7-(3-(4-(4-氯苯基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(17)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(4-氯苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(17)所示。
1H-NMR(600MHz,CDCl3)δ2.03-2.08(m,2H),2.61-2.69(m,6H),2.96(t,2H,J=12Hz),3.09-3.12(m,4H),3.19(s,3H),3.56(t,2H,J=12Hz),4.10(t,2H,J=6Hz),6.97-7.00(m,1H),7.06-7.10(m,4H),7.39-7.42(m,2H),7.65(d,1H,J=6Hz).MS(ESI)m/z 414.2([M+H]+)。
实施例18、7-(3-(4-(2-氯苯基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(18)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(2-氯苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(18)所示。
1H-NMR(600MHz,CDCl3)δ2.02-2.07(m,2H),2.60-2.69(m,6H),2.95(t,2H,J=12Hz),3.09-3.11(m,4H),3.18(s,3H),3.55(t,2H,J=12Hz),4.11(t,2H,J=6Hz),6.96-7.00(m,1H),7.06-7.10(m,2H),7.22-7.26(m,1H),7.35-7.38(m,1H),7.63(d,1H,J=6Hz).MS(ESI)m/z 414.3([M+H]+)。
实施例19、7-(3-(4-(4-氟苯基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(19)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(4-氟苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(19)所示。
1H-NMR(600MHz,CDCl3)δ2.04-2.08(m,2H),2.61-2.69(m,6H),2.97(t,2H,J=12Hz),3.10-3.12(m,4H),3.19(s,3H),3.57(t,2H,J=12Hz),4.12(t,2H,J=6Hz),6.99-7.02(m,1H),7.07-7.10(m,3H),7.40-7.44(m,2H),7.66(d,1H,J=6Hz).MS(ESI)m/z 398.2([M+H]+)。
实施例20、7-(3-(4-(2-氟苯基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(20)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(2-氟苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(20)所示。
1H-NMR(600MHz,CDCl3)δ1.73-2.07(m,4H),2.60-2.69(m,6H),2.96(t,2H,J=12Hz),3.13-3.15(m,4H),3.17(s,3H),3.57(t,2H,J=12Hz),4.11(t,2H,J=6Hz),6.947.10(m,6H),7.63(d,1H,J=6Hz).MS(ESI)m/z 398.2([M+H]+)。
实施例21、7-(3-(4-(4-甲氧基苯基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(21)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(4-甲氧基苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(21)所示。
1H-NMR(600MHz,CDCl3)δ1.75-2.05(m,4H),2.61-2.69(m,6H),2.95(t,2H,J=12Hz),3.11-3.14(m,4H),3.17(s,3H),3.56(t,2H,J=12Hz),3.79(s,3H),4.11(t,2H,J=6Hz),6.85-7.00(m,5H),7.08-7.10(m,1H),7.63(d,1H,J=6Hz).MS(ESI)m/z 410.2([M+H]+)。
实施例22、7-(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(22)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(2-甲氧基苯基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(22)所示。
1H-NMR(600MHz,CDCl3)δ1.07-2.05(m,4H),2.61-2.68(m,6H),2.96(t,2H,J=12Hz),3.13-3.15(m,4H),3.18(s,3H),3.57(t,2H,J=12Hz),3.78(s,3H),4.11(t,2H,J=6Hz),6.88-7.10(m,6H),7.64(d,1H,J=6Hz).MS(ESI)m/z 410.3([M+H]+)。
实施例23、2-甲基-7-(3-(4-(吡啶-2-基)哌嗪-1-基)丙氧基)-3,4-二氢异喹啉-1(2H)-酮(23)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(吡啶-2-基)哌嗪代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(23)所示。
1H-NMR(600MHz,CDCl3)δ1.98-2.03(m,2H),2.54-2.67(m,6H),2.91(t,2H,J=12Hz),3.13(s,3H),3.50-3.55(m,6H),4.08(t,2H,J=6Hz),6.58-6.84(m,2H),6.94-7.06(m,2H),7.44-7.46(m,1H),7.60(d,1H,J=6Hz),8.16-8.18(m,1H).MS(ESI)m/z 381.2([M+H]+)。
实施例24、2-甲基-7-(3-(4-(嘧啶-2-基)哌嗪-1-基)丙氧基)-3,4-二氢异喹啉-1(2H)-酮(24)
用1,3-二溴丙烷代替1,4-二溴丁烷,2-(哌嗪-1-基)嘧啶代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑为原料,按实施例1的方法制备目标化合物,结构式如表1中编号(24)所示。
1H-NMR(600MHz,CDCl3)δ1.81-2.05(m,4H),2.59-2.67(m,4H),2.96(t,2H,J=12Hz),3.17(s,3H),3.54(t,2H,J=12Hz),3.84-3.88(m,4H),4.11(t,2H,J=6Hz),6.48-6.51(m,1H),6.97-7.10(m,2H),7.63(d,1H,J=6Hz),8.32(d,2H,J=6Hz).MS(ESI)m/z382.3([M+H]+)。
实施例25、7-(3-(4-(4-氟苯甲酰)哌啶基-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(25)
按实施例1的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用(4-氟苯基)(哌啶基-4-基)甲酮代替6-氟-3-(哌啶基-4-基)苯并[d]异噁唑用作原料。结构式如表1中编号(25)所示。
1H-NMR(600MHz,CDCl3)δ1.82-2.02(m,6H),2.10-2.17(m,2H),2.55(t,2H,J=12Hz),2.92(t,2H,J=12Hz),3.00-3.05(m,2H),3.17(s,3H),3.53(t,2H,J=12Hz),4.06(t,2H,J=6Hz),6.94-6.97(m,1H),7.05-7.15(m,3H),7.60(d,1H,J=6Hz),7.95-7.98(m,2H).MS(ESI)m/z 425.3([M+H]+)。
实施例26、6-(4-(4-苄基哌嗪-1-基)丁氧基)-3-甲基喹唑啉-4(3H)-酮(26)
(1)使2-氨基-5-羟基苯甲酸(0.1mol)和N-甲基甲酰胺在160℃下反应10h。反应完毕,用冰水终止反应,用乙酸乙酯萃取,将有机层用无水硫酸镁干燥,减压蒸去溶剂。将剩余物柱层析(洗脱剂为石油醚:乙酸乙酯=1:1)获得棕色固体13g。收率74%。
MS(ESI)m/z 176.1([M+H]+)。
(2)将第(1)步制备的棕色固体(0.1mmol)、1,4-二溴丁烷(0.12mmol)和碳酸钾(0.3mmol)加入丙酮(200ml)中,回流反应12h。反应完毕,抽滤得有机溶液,将其减压蒸干。将剩余物柱层析(洗脱剂为石油醚:乙酸乙酯=10:1)获得浅黄色油状物25.8g。收率87%。
MS(ESI)m/z 296.0([M+H]+)。
(3)将取第(2)步制备的浅黄色油状物(2mmol)、苄基哌嗪(2mmol)和碳酸钾(6mmol)加入乙腈(50ml)中,回流反应10h。反应完毕,抽滤得到有机溶液。蒸干乙腈,将剩余物柱层析(洗脱剂为CH2Cl2:甲醇=10:1)获得黄色油状物0.78g。收率90%。
1H-NMR(600MHz,CDCl3)δ1.72-1.88(m,4H),2.49-2.57(m,8H),2.97(t,2H,J=12Hz),3.59(s,3H),3.61(s,2H),4.09(t,2H,J=6Hz),7.22-7.35(m,4H),7.63(d,2H,J=6Hz),7.95(d,2H,J=6Hz).MS(ESI)m/z 407.5([M+H]+)。
实施例27、6-(4-(3,4-二氢异喹啉-2(1氢)-基)丁氧基)-3-甲基喹唑啉-4(3H)-酮(27)
按实施例26的方法制备目标化合物,但用1,2,3,4-四氢异喹啉代替1-苄基哌嗪用作原料。结构式如表1中编号(27)所示。
1H-NMR(600MHz,CDCl3)δ1.81-1.95(m,4H),2.60-2.77(m,4H),2.93(t,2H,J=12Hz),3.59(s,3H),3.61(s,2H),4.12(t,2H,J=6Hz),7.02-7.14(m,4H),7.63(d,2H,J=6Hz),7.95(d,1H,J=6Hz)..MS(ESI)m/z 364.3([M+H]+)。
实施例28、3-甲基-6-(4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁氧基)喹唑啉-4(3H)-酮(28)
按实施例26的方法制备目标化合物,但用1-(3-(三氟甲基)苯基)哌嗪代替1-苄基哌嗪作为原料。结构式如表1中编号(28)所示。
1H-NMR(600MHz,CDCl3)δ1.75-1.95(m,4H),2.51(t,2H,J=12Hz),2.64(t,4H,J=12Hz),3.27(t,4H,J=12Hz),3.61(s,3H),4.14(t,2H,J=6Hz),7.06-7.14(m,2H),7.34-7.37(m,2H),7.65(d,2H,J=6Hz),7.97(s,1H).MS(ESI)m/z 461.3([M+H]+)。
实施例29、6-(4-(4-(4-氟苯基)哌嗪-1-基)丁氧基)-3-甲基喹唑啉-4(3H)-酮(29)
按实施例26的方法制备目标化合物,但用1-(4-氟苯基)哌嗪代替1-苄基哌嗪用作原料。结构式如表1中编号(29)所示。
1H-NMR(600MHz,CDCl3)δ1.72-1.93(m,4H),2.48(t,2H,J=12Hz),2.63(t,4H,J=12Hz),3.12(t,4H,J=12Hz),3.58(s,3H),4.11(t,2H,J=6Hz),6.86-6.96(m,4H),7.32-7.37(m,2H),7.65(d,1H,J=6Hz),7.94(s,1H).MS(ESI)m/z 411.2([M+H]+)。
实施例30、3-甲基-6-(4-(4-(吡啶-2-基)哌嗪-1-基)丁氧基)喹唑啉-4(3H)-酮(30)
按实施26的方法制备目标化合物,但用1-(吡啶-2-基)哌嗪代替1-苄基哌嗪用作原料。结构式如表1中编号(30)所示。
1H-NMR(600MHz,CDCl3)δ1.75-1.93(m,4H),2.49(t,2H,J=12Hz),2.60(t,4H,J=12Hz),3.57(t,4H,J=12Hz),3.61(s,3H),4.13(t,2H,J=6Hz),6.61-6.66(m,2H),7.32-7.36(m,1H),7.46-7.50(m,1H),7.65(d,2H,J=6Hz),7.96(s,1H),8.19(d,1H,J=6Hz).MS(ESI)m/z 394.3([M+H]+)。
实施例31、2,3-二甲基-6-(3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙氧基)喹唑啉-4(3H)-酮(31)
按实施26的方法制备目标化合物,但用1,3-二溴丙烷代替1,4-二溴丁烷,用1-(3-(三氟甲基)苯基)哌嗪代替1-苄基哌嗪作为原料。结构式如表1中编号(31)所示。
1H-NMR(600MHz,CDCl3)δ1.26-1.31(m,6H),2.51(t,2H,J=12Hz),2.64(t,4H,J=12Hz),2.82(s,3H),3.27(t,4H,J=12Hz),3.35-3.50(m,3H)3.65(s,3H),4.17(t,2H,J=6Hz),7.09-7.21(m,3H),7.34-7.37(m,2H),7.57(d,1H,J=6Hz),7.63(d,1H,J=6Hz),.MS(ESI)m/z 461.3([M+H]+)。
表1实施例1~31制备的化合物编号及其结构式
药理实施例
实施例32
5-HT1A膜的制备
将大鼠断头,冰上操作,迅速取脑皮层,加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含0.1%的抗坏血酸、10μm优降宁和4mM CaCl2)匀浆,然后加入5ml缓冲液(0.05M的Tris-HCl缓冲液,含0.1%的抗坏血酸、10μm优降宁和4mM CaCl2),于37℃下温育10min。温育完后,将试管用天平调整重量,在12000rpm和4℃下离心20min。弃上清液,加入3ml缓冲液,用旋涡混合器混匀,再加入5ml缓冲液,离心,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃下储存备用。
受体结合实验材料
同位素配基3H-8-OH-DPAT(67.0Ci/mmol)购自PerkinElmer公司;5-HT购自RBI公司;GF/C玻璃纤维滤纸购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液购自上海试剂厂。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法
(1)将制备好的膜用适量的缓冲液通过匀浆机分散均匀,将15只试管混入100ml的容器中,加入适量的缓冲液获得50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μL缓冲液,非特异性结合管(NB)加入5-HT 100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)。
(4)各反应管分别加入放射性配体3H-8-OH-DPAT 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管在37℃下温育10min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀。
(6)将闪烁杯放入液闪计数仪计数
抑制率(I%)=(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。实验结果见表2。
实施例33
5-HT2A膜的制备
将大鼠断头,冰上操作,迅速取脑皮层,加入3ml缓冲液(0.05M的Tris-HCl缓冲液:取6.05g Tris溶于1000ml双蒸水中,用浓HCl调PH为7.5)匀浆,然后加入5ml缓冲液,于37℃下温育10min。温育完后试管用天平调整重量,在12000rpm和4℃下离心20min。弃上清液,加入3ml缓冲液,用旋涡混合器混匀,再加入5ml缓冲液,离心(重复三次离心)。离心完毕,弃上清液,将沉淀于-80℃下储存备用。
受体结合实验材料:
同位素配基[3H]-Ketanserin(67.0Ci/mmol)购自PerkinElmer公司;Methysergide购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液购自上海试剂厂。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)将制备好的膜用适量的缓冲液通过匀浆机分散均匀,将15只试管混入100ml的容器中,加入适量的缓冲液获得50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μL缓冲液,非特异性结合管(NB)加入Methysergide 100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)。
(4)各反应管分别加入放射性配体3H-Ketanserin 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管在37℃下温育15min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀。
(6)将闪烁杯放入液闪计数仪计数
抑制率(I%)=(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。实验结果见表2。
实施例34
D2膜的制备
将大鼠断头,冰上操作,迅速取脑纹状体,加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含NaCl 120mM、KCl 5mM、MgCl2 1mM、CaCl2 1mM)匀浆,然后加入5ml缓冲液,将匀浆完的试管用天平调整重量,离心,弃上清液,加入3ml缓冲液,用旋涡混合器混匀,再加入5ml缓冲液,离心,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃下储存备用。
受体结合实验材料:
同位素配基3H-Spiperone(67.0Ci/mmol)购自PerkinElmer公司;Butaclamol购自RBI公司;GF/C玻璃纤维滤纸购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液上海试剂厂。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)将制备好的膜用适量的缓冲液通过匀浆机分散均匀,将15只试管混入100ml的容器中,加入适量的缓冲液呈50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μL缓冲液,非特异性结合管(NB)加入100μL Butaclamol(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)。
(4)各反应管分别加入放射性配体3H-Spiperone 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管在37℃下温育20min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀。
(6)将闪烁杯放入液闪计数仪计数
抑制率(I%)=(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。实验结果见表2。
实施例35 5-HT7受体结合实验
5-HT7膜的制备
在冰上将成年SD大鼠断头,迅速取出下丘脑,加入3ml缓冲液(0.05M的Tris-HCl缓冲液:取6.05gTris溶于1000ml双蒸水中,用浓HCl调PH为7.5)于4档下匀浆3-4s,匀浆4次,然后加入5ml缓冲液,于37℃下温育10min。温育完后将试管用天平调整重量,在4℃离心,弃上清液,加入3ml缓冲液。用旋涡混合器混匀,再加入5ml缓冲液,离心(重复三次离心)。离心完毕,弃上清液,将沉淀于-80℃下储存备用。
受体结合实验材料:
同位素配基3H-5-CT(85.4Ci/mmol)购自PerkinElmer公司;(±)-pindolol购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液购自上海试剂厂。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法:
(1)将制备好的膜用适量的缓冲液通过匀浆机分散均匀,将15只试管混入100ml的容器中,加入适量的缓冲液获得50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μL缓冲液,非特异性结合管(NB)加入(±)-pindolol100μL(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10- 5M)。
(4)各反应管分别加入放射性配体3H-5-CT 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管在25℃下温育120min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀。
(6)将闪烁杯放入液闪计数仪计数
抑制率(I%)=(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。实验结果见表2
实施例36
组胺H1受体膜的制备
将豚鼠断头,冰上操作,迅速取豚鼠小脑,加入3mL缓冲液(将磷酸二氢钾钾1.36克和0.1mol/L氢氧化钠79mL用双蒸水稀释至200mL),用旋涡混合器混匀,在48000g和4℃下离心10min,弃上清液,取沉淀,再加入缓冲液洗涤,重复三次离心,离心完毕,弃上清液,将沉淀于-80℃下储存备用。
受体结合实验材料
同位素配基3H-pyrilamine(67.0Ci/mmol)购自PerkinElmer公司;promethazine购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液购自上海试剂厂。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法
(1)制备好的膜用适量的缓冲液通过匀浆机分散均匀,将15只试管混入100ml的容器中,加入适量的缓冲液(将磷酸二氢钾1.36克和0.1mol/L氢氧化钠79mL用双蒸水稀释至200mL)获得50ml膜的混悬液,备用。
(2)各反应管分别加入膜制备物100μL。
(3)总结合管(TB)加入100μL缓冲液,非特异性结合管(NB)加入100μLpromethazine(终浓度10-5M),各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)。
(4)各反应管分别加入放射性配体3H-pyrilamine 10μL(各反应管均设2个平行管,加样时各管置于冰上)。
(5)将各反应管在30℃下温育60min,反应完毕,结合的配基通过减压快速过滤,用冰冷的试验缓冲液充分洗涤,将滤片取出放到3ml闪烁杯中,加入2ml的甲苯闪烁液并混匀。
(6)将闪烁杯放入液闪计数仪计数。
抑制率(I%)=(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100%
化合物每次实验做两复管,进行两次单独实验。实验结果见表2。
表2化合物对各受体的Ki(nM)
结果表明本发明的化合物(特别是化合物5)对三种受体(D2、5-HT1A和5-HT2A)有较强的亲和力,对H1的亲和力低,对5HT7亲和力高,与利培酮相比,产生体重增加的副作用风险较低。5HT7受体对情绪、学习和记忆等均有调节作用,与该受体的作用可有助于改善认知障碍的功能。
实施例37、MK-801诱导的高活动性:化合物体内抗精神分裂活性
实验动物及试剂
健康昆明种小鼠,雌雄各半,体重(20±2)g,由南京青龙山动物养殖中心提供。
抗坏血酸购自国药集团化学试剂有限公司;
MK-801由美国Sigma公司生产;配制方法:用0.1%的维生素C配成1mg/ml的溶液;
受试阳性药物:氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平;
吐温80:浓度10%。
实验方法
选择体重合格的小鼠,随机分为空白组、模型组、阳性对照组(利培酮组)、药物组。将空白组、模型组灌胃给药10%吐温0.1ml/10g,阳性对照组灌胃给药利培酮0.1mg/kg,药物组分别灌胃给药相应剂量的药物。给药后1h,空白组腹腔注射0.1%抗坏血酸0.1ml/10g;模型组、阳性对照组(30min)和药物组腹腔注射MK-801溶液0.1mg/kg。然后测定各组小鼠90分钟内自发活动。结果见表3。
实施例38、阿扑吗啡诱导小鼠攀爬实验
实验动物:健康KM小鼠,雄性,体重18~22g,由南京青龙山动物养殖中心提供。
主要试剂
受试阳性药物:氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平;
阿扑吗啡由Sigma公司提供,临用前0.9%NaCl(含0.1%维生素C)溶解,现配现用;
维生素C,F20061113购自国药集团化学试剂有限公司;
氯化钠注射液,H32026305购自徐州市第五制药厂有限公司。
仪器:自制攀爬笼,秒表。
实验方法:阿扑吗啡诱导小鼠攀爬实验
将KM小鼠(雄性,体重18~22g)随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组(具体给药剂量见下表),每组10只。阴性对照组和模型组灌胃给药相应的溶剂双蒸水,阳性药物组灌胃给药相应的阳性药物(溶解时先加微量乙酸,再加双蒸水),化合物各剂量组灌胃给药相应剂量的化合物,灌胃体积为0.1ml/10g。灌胃给药1小时后皮下注射阿扑吗啡(1mg/kg),体积为0.1ml/10g。注射阿扑吗啡后,将动物立即放入攀爬笼中,适应5分钟,观察注射阿扑吗啡后第10-11,20-21,30-31分钟的行为并进行评分。评分标准:四足在地板上得分为0;两前足在网笼上得分为1;四只足在网笼上得分为2。结果见表3。
实施例39、大鼠条件回避(CAR)模型的实验
试验动物:SD大鼠,雄性,1700只左右。
首先用穿梭箱对大鼠进行训练:
①使大鼠适应5分钟;
②开始进行20s的条件刺激(CS,光和噪声),在第10s进行10s的非条件刺激(US,1.5mA电击);
③每天训练30次,两次间隔时间在20-30s之间随机确定,训练9天;
④观察指标:
在条件刺激期间动物跑到另一个隔间记录为“回避”;
在电击期间动物跑到另一个隔间记录为“逃避”;
在电击期间动物不跑到另一个隔间记录为“逃避失败”;
⑤训练合格标准:连续3天(第7、8、9天)回避率大于80%。
对合格大鼠分组:按照随机原则分为阴性对照组、阳性药各剂量组、化合物各剂量组,每组8只。
给药方法:阴性对照组灌胃给药相应的溶剂,阳性药各剂量组灌胃给药相应剂量的阳性药,化合物各剂量组灌胃给药相应的剂量化合物。
CAR实验:灌胃给药1小时后进行CAR实验,方法同CAR训练。观察指标为回避次数、逃避次数、逃避失败次数。
数据统计处理:实验数据用均数±标准差(Mean±SD)表示,比较用One-way ANOVA结合post-hoc LSD进行。采用概率单位法计算ED50。结果见表4。
实施例40、僵住症实验方法
实验动物:健康昆明种小鼠,雌雄各半,(22±2)g,由南京青龙山动物养殖中心提供。
主要试剂:受试药、氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮仪器:自制抓棒器材,小鼠盒内放置直径0.3cm,高于工作台5cm的不锈钢棒。
实验方法:将KM小鼠(雌雄各半,体重20~24g)随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组,每组10只。阴性对照组和模型组灌胃给药相应的溶剂双蒸水,阳性药物组灌胃给药相应的阳性药物(溶解时先加微量乙酸,再加双蒸水),化合物各剂量组灌胃给药相应剂量的化合物,灌胃体积为0.1ml/10g。灌胃给药30min、60min、90min时,将小鼠两只前爪轻柔地放在长20cm,直径0.3cm,高于工作台5.5cm的小棒上,再将动物后肢轻放于盒底面,记录小鼠两只前爪在棒上保持姿势的持续时间,以30s僵直不动为阳性反应。如果小鼠前爪一直没有放下,则60s时终止观察。统计每个化合物剂量组阳性反应动物数。结果见表3。
实施例41、急性毒性研究
序贯法之限度实验:将KM大鼠或小鼠(雌雄各半)随机分为若干组,每组2-5只,分别为各化合物2000mg/kg组和溶剂组,按0.2ml/10g灌胃给药。观察动物3日内的死亡情况。如果动物在三日内有3只或3只以上存活,生命状态无明显异常,继续观察,直至7日后实验结束。如果动物在三日内3只或3只以上死亡时,采用半数致死量法测定其LD50。
半数致死量法预试验:将KM小鼠(雌雄各半)随机分若干组,每组4只,分别为各化合物500mg/kg、200mg/kg、50mg/kg组和溶剂组,按0.2ml/10g灌胃给药,观察动物1-3日内的死亡情况。
结果:本发明的化合物具有较小的急性毒性。例如化合物5的小鼠灌胃LD50为257.5mg/kg,大鼠灌胃LD50为167.5mg/kg,治疗指数明显高于阳性药物利培酮,具有较小的急性毒性。结果见表3和表4。
表3.化合物体内动物模型试验结果(小鼠)
表4.大鼠CAR试验结果
上述动物实验结果表明:与阳性药(利培酮)相比,本发明的化合物(特别是化合物5、14、22)既能明显改善MK-801诱导的高活动性,又能有效的改善阿扑吗啡诱导的攀爬症状,在大鼠的CAR模型中明显优于利培酮,并且在有效剂量下不引起EPS。这表明其有明显的抗精神分裂作用,且效果优于现有的药物。
制剂实施例
实施例42片剂的制备
将原辅料过80目筛备用,称取处方量活性成分、微晶纤维素、乳糖和聚维酮K30,加入到高速混合制剂机中,低速搅拌混合均匀,加入适量纯化水,低速搅拌,高速切割制粒,将湿颗粒在60℃下干燥3h,24目筛整粒,加入处方量羧甲淀粉钠、二氧化硅和硬脂酸镁,总混,旋转压片机压片。
Claims (10)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R1和R2分别独立地为氢、甲基、乙基、丙基、正丁基、异丁基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R4为乙氧基、丙氧基或氟,R5为卤代C1-5烷基。
4.根据权利要求3所述的化合物或其药学上可接受的盐,其特征在于,所述卤代C1-5烷基为三氟乙基、三氟丙基或三氟丁基。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述卤素为氟、氯、溴或碘。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
虚线处为单键时,X为CH2;
虚线处为双键时,X为N;
Z为未取代的-(CH2)n-,n为2~5的整数;
R1为氢、甲基或乙基;
R2为氢、甲基或乙基。
8.一种药物组合物,其包含权利要求1~7中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
9.权利要求1~7中任一项所述的化合物或其药学上可接受的盐或者权利要求8的药物组合物在制备用于治疗或预防神经精神类疾病的药物中的应用。
10.权利要求9的应用,其特征在于,所述神经精神类疾病为精神分裂症。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510811995.4A CN106749219A (zh) | 2015-11-20 | 2015-11-20 | 一种内酰胺类衍生物及其应用 |
CN2015108119954 | 2015-11-20 | ||
CN201680067130.4A CN108290880B (zh) | 2015-11-20 | 2016-11-21 | 内酰胺类化合物衍生物及其应用 |
PCT/CN2016/106591 WO2017084627A1 (zh) | 2015-11-20 | 2016-11-21 | 内酰胺类化合物衍生物及其应用 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680067130.4A Division CN108290880B (zh) | 2015-11-20 | 2016-11-21 | 内酰胺类化合物衍生物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112851656A CN112851656A (zh) | 2021-05-28 |
CN112851656B true CN112851656B (zh) | 2022-07-12 |
Family
ID=58717382
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510811995.4A Withdrawn CN106749219A (zh) | 2015-11-20 | 2015-11-20 | 一种内酰胺类衍生物及其应用 |
CN201680067130.4A Active CN108290880B (zh) | 2015-11-20 | 2016-11-21 | 内酰胺类化合物衍生物及其应用 |
CN202110181460.9A Active CN112851656B (zh) | 2015-11-20 | 2016-11-21 | 内酰胺类化合物衍生物及其应用 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510811995.4A Withdrawn CN106749219A (zh) | 2015-11-20 | 2015-11-20 | 一种内酰胺类衍生物及其应用 |
CN201680067130.4A Active CN108290880B (zh) | 2015-11-20 | 2016-11-21 | 内酰胺类化合物衍生物及其应用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US10501452B2 (zh) |
EP (1) | EP3381915B1 (zh) |
JP (2) | JP6755950B2 (zh) |
CN (3) | CN106749219A (zh) |
WO (1) | WO2017084627A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749219A (zh) * | 2015-11-20 | 2017-05-31 | 江苏恩华药业股份有限公司 | 一种内酰胺类衍生物及其应用 |
CN111285862A (zh) * | 2018-12-07 | 2020-06-16 | 江苏恩华药业股份有限公司 | 一种丙酰胺类衍生物的结晶形式及其制备方法 |
CN111320619A (zh) * | 2018-12-17 | 2020-06-23 | 江苏恩华药业股份有限公司 | 一种类酰胺类衍生物的杂质及用途 |
CN111320582A (zh) * | 2018-12-17 | 2020-06-23 | 江苏恩华药业股份有限公司 | 一种类酰胺类衍生物及其中间体的制备方法 |
CN112480102B (zh) * | 2020-12-02 | 2022-04-22 | 江苏恩华药业股份有限公司 | 一种丙酰胺衍生物及其用于精神分裂症的用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012003418A2 (en) * | 2010-07-02 | 2012-01-05 | The University Of North Carolina At Chapel Hill | Functionally selective ligands of dopamine d2 receptors |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2608788B2 (ja) | 1988-10-31 | 1997-05-14 | 大塚製薬 株式会社 | 精神分裂病治療剤 |
AU2003263413A1 (en) | 2002-09-17 | 2004-04-08 | Warner-Lambert Company Llc | Heterocyclic substituted piperazines for the treatment of schizophrenia |
CA2576153A1 (en) * | 2004-08-05 | 2006-02-16 | Acadia Pharmaceuticals Inc. | Use of n-desmethylclozapine to treat human neuropsychiatric disease |
JP4315393B2 (ja) * | 2005-04-14 | 2009-08-19 | 大塚製薬株式会社 | 複素環化合物 |
TWI320783B (en) * | 2005-04-14 | 2010-02-21 | Otsuka Pharma Co Ltd | Heterocyclic compound |
AR055203A1 (es) * | 2005-08-31 | 2007-08-08 | Otsuka Pharma Co Ltd | Derivados de benzotiofeno con propiedades antipsicoticas |
WO2008020306A2 (en) | 2006-08-18 | 2008-02-21 | Pfizer Products Inc. | Isoindole derivatives |
ATE548367T1 (de) * | 2007-03-15 | 2012-03-15 | Aryx Therapeutics Inc | Dibenzoäb,füä1,4üoxazapinverbindungen |
EP1972628A1 (en) | 2007-03-21 | 2008-09-24 | Schwarz Pharma Ag | Indolizines and aza-analog derivatives thereof as CNS active compounds |
NZ582124A (en) * | 2007-05-21 | 2012-07-27 | Reviva Pharmaceuticals Inc | Compositions, synthesis, and methods of using quinolinone based atypical antipsychotic agents |
WO2009082268A2 (ru) * | 2007-12-21 | 2009-07-02 | Alla Chem, Llc | ЛИГАНДЫ α-АДРЕНОЦЕПТОРОВ, ДОПАМИНОВЫХ, ГИСТАМИНОВЫХ, ИМИДАЗОЛИНОВЫХ И СЕРОТОНИНОВЫХ РЕЦЕПТОРОВ И ИХ ПРИМЕНЕНИЕ |
US8653069B2 (en) | 2008-07-28 | 2014-02-18 | Jiangsu Hengyi Pharmaceutical Co., Ltd. | Aralkyl substituted piperidine or piperazine derivatives and their use for treating schizophrenia |
US8899539B2 (en) * | 2010-07-05 | 2014-12-02 | Edward Antony Oliver | Guard assembly and method |
PL392436A1 (pl) * | 2010-09-17 | 2012-03-26 | Adamed Spółka Z Ograniczoną Odpowiedzialnością | Pochodne arylosulfonamidów do leczenia chorób odśrodkowego układu nerwowego |
CN102206214B (zh) * | 2011-04-07 | 2014-03-12 | 华中科技大学 | 苯并吡喃酮类衍生物及其应用 |
PL395470A1 (pl) * | 2011-06-29 | 2013-01-07 | Adamed Spólka Z Ograniczona Odpowiedzialnoscia | Sulfonamidowe pochodne amin alicyklicznych do leczenia chorób osrodkowego ukladu nerwowego |
PL395469A1 (pl) * | 2011-06-29 | 2013-01-07 | Adamed Spólka Z Ograniczona Odpowiedzialnoscia | Pochodne indoloamin do leczenia chorób osrodkowego ukladu nerwowego |
CN102267966B (zh) * | 2011-08-01 | 2013-02-27 | 华中科技大学 | 取代的苯并吡喃酮类衍生物及其应用 |
CN104059046B (zh) | 2013-03-18 | 2017-02-08 | 江苏恩华药业股份有限公司 | 黄酮类衍生物及其应用 |
CN104292226B (zh) * | 2013-07-16 | 2016-12-28 | 江苏恩华药业股份有限公司 | 帕利哌酮氨基酸类衍生物及其应用 |
CN106749219A (zh) * | 2015-11-20 | 2017-05-31 | 江苏恩华药业股份有限公司 | 一种内酰胺类衍生物及其应用 |
-
2015
- 2015-11-20 CN CN201510811995.4A patent/CN106749219A/zh not_active Withdrawn
-
2016
- 2016-11-21 JP JP2018526201A patent/JP6755950B2/ja active Active
- 2016-11-21 EP EP16865804.5A patent/EP3381915B1/en active Active
- 2016-11-21 US US15/776,645 patent/US10501452B2/en active Active
- 2016-11-21 CN CN201680067130.4A patent/CN108290880B/zh active Active
- 2016-11-21 WO PCT/CN2016/106591 patent/WO2017084627A1/zh active Application Filing
- 2016-11-21 CN CN202110181460.9A patent/CN112851656B/zh active Active
-
2020
- 2020-06-15 JP JP2020102914A patent/JP7035118B2/ja active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012003418A2 (en) * | 2010-07-02 | 2012-01-05 | The University Of North Carolina At Chapel Hill | Functionally selective ligands of dopamine d2 receptors |
Also Published As
Publication number | Publication date |
---|---|
EP3381915B1 (en) | 2023-01-18 |
EP3381915A1 (en) | 2018-10-03 |
CN112851656A (zh) | 2021-05-28 |
CN106749219A (zh) | 2017-05-31 |
US10501452B2 (en) | 2019-12-10 |
JP2019500329A (ja) | 2019-01-10 |
JP7035118B2 (ja) | 2022-03-14 |
JP2020158520A (ja) | 2020-10-01 |
US20180327397A1 (en) | 2018-11-15 |
JP6755950B2 (ja) | 2020-09-16 |
CN108290880B (zh) | 2021-03-09 |
WO2017084627A1 (zh) | 2017-05-26 |
EP3381915A4 (en) | 2019-07-17 |
CN108290880A (zh) | 2018-07-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112851656B (zh) | 内酰胺类化合物衍生物及其应用 | |
EP3283077B1 (en) | Bromodomain inhibitors | |
TW200804401A (en) | Novel compounds | |
CA2889378A1 (en) | Benzoxazolinone compounds with selective activity in voltage-gated sodium channels | |
CA2953004C (en) | Aromatic heterocyclic derivatives and pharmaceutical applications thereof | |
CN113717157A (zh) | 用作cdk7激酶抑制剂的化合物及其应用 | |
KR20120060835A (ko) | 크로몬 유도체, 그 제조방법 및 그들의 치료 분야 | |
EP2970179A1 (en) | Phthalazines as potassium ion channel inhibitors | |
IL300352A (en) | The compositions for cutting and fusion modulation | |
WO2013017071A1 (zh) | 脂环并[c]苯并吡喃酮衍生物及其应用 | |
CN108368106B (zh) | 稠和杂环类化合物衍生物及其应用 | |
CN114728956B (zh) | 稠和杂环类衍生物及其应用 | |
CN109232362B (zh) | 芳杂环类衍生物及其在药物上的应用 | |
CN106995410B (zh) | 一种内酰胺类衍生物及其应用 | |
AU2016295693A1 (en) | Substituted quinazoline compounds and preparation and uses thereof | |
CN107793362B (zh) | 一种苯基哒嗪酮类衍生物的合成及其应用 | |
WO2014146553A1 (zh) | 黄酮类衍生物及其应用 | |
CN111377911B (zh) | 一种吗啉苯甲酰胺类化合物及其应用 | |
CN111153859B (zh) | 哒嗪酮类衍生物及其应用 | |
US20080167319A1 (en) | 7-(4-(4-[3-chloro-2-(trifluoromethyl)phenyl]piperazin-1-yl)butoxy)-[1,8]-naphthyridin-2(1h)-one |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |