CN1235606A - 2-甲氧基苯基哌嗪衍生物 - Google Patents
2-甲氧基苯基哌嗪衍生物 Download PDFInfo
- Publication number
- CN1235606A CN1235606A CN97199313A CN97199313A CN1235606A CN 1235606 A CN1235606 A CN 1235606A CN 97199313 A CN97199313 A CN 97199313A CN 97199313 A CN97199313 A CN 97199313A CN 1235606 A CN1235606 A CN 1235606A
- Authority
- CN
- China
- Prior art keywords
- imidazo
- group
- formula
- compound
- thiazolyl
- 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.)
- Pending
Links
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical class COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000000034 method Methods 0.000 claims abstract description 42
- -1 2-indolizinyl Chemical group 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 208000022821 personality disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 6
- INKLSJITWMAFRT-UHFFFAOYSA-N 2-(4-methoxyphenyl)piperazine Chemical compound C1=CC(OC)=CC=C1C1NCCNC1 INKLSJITWMAFRT-UHFFFAOYSA-N 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 230000008451 emotion Effects 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 229910052728 basic metal Inorganic materials 0.000 claims 1
- 239000000890 drug combination Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000000561 anti-psychotic effect Effects 0.000 abstract description 3
- 230000036506 anxiety Effects 0.000 abstract description 3
- 208000019022 Mood disease Diseases 0.000 abstract description 2
- 208000027626 Neurocognitive disease Diseases 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 58
- 239000002585 base Substances 0.000 description 34
- 230000000694 effects Effects 0.000 description 26
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 24
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 20
- 239000002994 raw material Substances 0.000 description 20
- 229960003750 ethyl chloride Drugs 0.000 description 19
- 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 14
- 229960004046 apomorphine Drugs 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 125000000335 thiazolyl group Chemical group 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
- 239000003176 neuroleptic agent Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000001939 inductive effect Effects 0.000 description 8
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 8
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 7
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 230000009194 climbing Effects 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229960003878 haloperidol Drugs 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 208000027776 Extrapyramidal disease Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 241001062472 Stokellia anisodon Species 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 102000015554 Dopamine receptor Human genes 0.000 description 3
- 108050004812 Dopamine receptor Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000002197 limbic effect Effects 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ZSVPGAKGHWAPAM-UHFFFAOYSA-N Cl.Cl.COc1ccc(cc1)C1CNCCN1 Chemical compound Cl.Cl.COc1ccc(cc1)C1CNCCN1 ZSVPGAKGHWAPAM-UHFFFAOYSA-N 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 102100025841 Cholecystokinin Human genes 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 208000027691 Conduct disease Diseases 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010026749 Mania Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 102000015006 alpha2-adrenergic receptor activity proteins Human genes 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 208000026725 cyclothymic disease Diseases 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910001511 metal iodide Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229950001675 spiperone Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/22—Anxiolytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurosurgery (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及如式(Ⅰ)所示的新的具有环连接点为氮原子的稠杂环化合物,其中Q所代表的是2-中氮茚基团、2-咪唑并[1,2-a]吡啶基团、2-咪唑并[1,2-a]嘧啶基团、6-(2,3-二氢)咪唑并[2,1-b]噻唑基团或6-咪唑并[2,1-b]噻唑基团;和n为2-4的整数:以及其可治疗用盐。本发明还涉及含有这些化合物的药物组合物以及上述化合物和组合物的制备方法。由于式(Ⅰ)所示的新的化合物具有明显的抗精神病的效果,因此本发明也涉及一种治疗精神分裂症、器质性的精神紊乱、情感紊乱症、焦虑紊乱症以及人格紊乱症的方法。
Description
其中Q所代表的是2-中氮茚基团、2-咪唑并[1,2-a]吡啶基团、2-咪唑并[1,2-a]嘧啶基团、6-(2,3-二氢)咪唑并[2,1-b]噻唑基团或6-咪唑并[2,1-b]噻唑基团;和
n为2-4的整数
其中Q和n如上述定义,X为卤素,与式(Ⅲ)所示的(2-甲氧基苯基)哌嗪反应。
根据本发明式(Ⅰ)所示的化合物是新的并具有显著的生物活性,尤其是具有明显的抗精神病作用。
本发明也涉及一种治疗方法,该方法包括对被治疗的病人给药有效剂量的一种式(Ⅰ)所示的化合物或一种其可治疗用盐。
在起始原料中,式(Ⅱ)所示的一些氯代烃醚衍生物是文献曾记载过的。例如3-[4-(2-咪唑并[1,2-a]吡啶基)-苯氧基]氯丙烷,3-[4-(2-咪唑并[1,2-a]嘧啶基)-苯氧基]氯丙烷,或3-[4-(6-咪唑并[2,1-b]噻唑基)-苯氧基]氯丙烷[J.Med.Chem.31,2221(1988)]。式(Ⅱ)所示的其它起始原料可按照上述所引用的文献方法制备获得。
式(Ⅲ)所示的(2-甲氧基苯基)哌嗪是已知的可以买到的物质。(Ⅲ)
结构类似于式(Ⅰ)所示原料的一些化合物是文献记载过的。例如(被取代的氨基)丙氧基苯基咪唑并[1,2-a]吡啶,(被取代的氨基)丙氧基苯基咪唑并[1,2-a]嘧啶,和(被取代的氨基)丙氧基苯基咪唑并[2,1-b]噻唑在上述所引用的文献[J.Med.Chem.31,2221(1988)]中有所描述,但是,与本发明的化合物不同,这些化合物具有钙通道封闭和局部麻醉的作用。
与这些结构十分类似的已知的化合物不同,本发明式(Ⅰ)所示的新的化合物具有口服疗效和显著的神经安定活性。基于它们的生物活性,这些化合物可被用作非典型的抗精神病剂,抗焦虑剂,神经保护和/或识别功能改善剂,止吐剂或抗嗜癖剂。
从70年代以来,抗精神病剂一直被成功地用于治疗精神分裂症。直到现在氟哌啶醇仍被非常广泛的用于临床。吩噻嗪和氟哌啶醇在这个治疗领域中起着先锋作用并且对精神分裂症的多巴胺理论的发展作出了巨大贡献。后来的研究也证实了5-羟色胺和一系列其它神经递质系统,例如组胺素、α-肾上腺素、缩胆囊素等在这些紊乱中的作用。然而,氟哌啶醇和其它典型的抗精神病剂仅改善了这种疾病的阳性症状,例如幻觉、妄想、焦虑和思考障碍,而阴性症状,例如情感障碍、孤独症、社会隔离、个人卫生的忽略等没有得到改善。另外,近30%的病人对治疗没有反应并且也不能排除一系列的不希望得到的副作用。这些副作用中,最严重的副作用就是由于D-2多巴胺受体的强的但非区域选择性的拮抗作用而使锥体束外症状(EPS)的出现,由抗胆碱能效应所引起的识别功能的恶化,直体张力减退(α-肾上腺素的拮抗作用),和高催乳素血症。
现在,对非典型的抗精神病剂的深入细致的研究表明,此药剂能够同时改善阳性和阴性症状,而不会引起锥体束外症状的出现或仅在超治疗剂量服用时,只有少数的没有反应的病人须考虑是否还可忽略了任何和其它副作用。氯氮平如不引起粒细胞缺乏症,本应是这样一种理想的抗精神病剂。
现在的研究集中在寻找与氯氮平类似的非典型的抗精神病剂上。氯氮平样作用是指化合物分子具有一种强的抗精神病疗效但不出现上述副作用。这类化合物对脑边缘系统的多巴胺通道具有一种直接或间接的选择性作用并且这种作用与一个复合受体的特征相关联。在这个复合受体内,氟哌啶醇的D-2受体的拮抗作用特征不显著。
本发明式(Ⅰ)所示的新的化合物其抗精神病的疗效类似于非典型的抗精神病剂氯氮平。这些化合物的抗精神病的和口服的活性都可通过体内的阿朴吗啡诱导的攀爬和嗅探试验得到证实。这些化合物的作用机理通过体外受体结合试验来表征。
阿朴吗啡(APO)诱导的攀爬和嗅探的抑制
将体重为22-24克的CD-1(Charles River)雄鼠用所要试验的化合物的1%吐温80溶液进行予处理。55分钟以后,将这些雄鼠一对对地放在试验笼中[P.Potrais et al.:Psychopharmacol 50,1-6(1976)]。每组用六只雄鼠。在予处理后60分钟,用1毫克/千克的阿朴吗啡(APO)对这些雄鼠进行皮下注射处理。在APO处理后从第10-25分钟之间每分钟对试验动物进行如下打分记录:0:动物所有四条腿均站在地上;1:动物用其两条前腿在格栅上攀爬;2:动物用其所有四条腿在格栅上攀爬。抑制效果与APO控制组相比,最高值可达32分。
APO诱导的嗅探的机械重复行为的抑制测定是按照S.Gerhardt[S.Gerhardt et al.:Life Sci.37,2355-2363(1985)]的方法,在以APO给药后的第10-25分钟之间与攀爬抑制的测定同时进行。
受体结合测定
D-2
与D-2多巴胺受体结合的研究按照P.Seeman[P.Seeman et al.:J.Neurochem.43,221-235(1984)]的方法进行,该方法用0.5nM 3H-螺环哌丁苯作为配体;在10μM(±)-舒宁存在下测定非特异性结合。
5-HT1A
5-羟色胺受体的5-HT1A亚型的测定是采用对Peroutka[S.J.Peroutka:J.Neurochem.47,529-540(1986)]所描述的方法改进的方法[M.D.Hall et al,:J.Neurochem 44,1685-1696(1985);H.Gozlan et.al.;Nature 305,140-142(1983)进行的。该方法用0.5nM 3H-8-OH-DPAT作为配体;其中用10μM的5-羟色胺测定非特异性结合。
α-1
按照Greengrass和Horung[P.Greengrass et.al.:Eur.J.Pharmacol 55,323-326(1979);R.Homng et.al.:Naunyn-Schmiedeb.Arch.Pharmacol.308,223-230(1979)的方法进行这些化合物的α-1受体活性的测定,采用3H-哌唑嗪作为配体。用10μM的(±)-吩妥胺测定非特异性结合。
体内和体外的试验结果总结列于表1,其中
Q:A代表2-中氮茚基团,
Q:B代表2-咪唑并[1,2-a]吡啶基团,
Q:C代表2-咪唑并[1,2-a]嘧啶基团,
Q:D代表6-(2,3-二氢)咪唑并[2,1-b]噻唑基团,和
Q:E代表6-咪唑并[2,1-b]噻唑基团;
表1
化合物序号 | Q | n | ED50(mg/kgp.o.) | 嗅探/攀爬 | 受体IC50(nM) | |||
APO诱导的攀爬的抑制 | APO诱导的嗅探的抑制 | D-2 | 5-HT1A | α-1 | ||||
4510407 | A | 2 | 》30 | - | - | 258 | 802 | 542 |
4510423 | A | 3 | 4.1 | >10 | >2.4 | 77 | 1000 | 359 |
4510613 | A | 4 | 14.8 | >30 | >2.0 | 99 | 243 | 842 |
4510408 | B | 2 | 2.4 | ≈10 | 4.1 | 56 | 70 | 36 |
4510067 | B | 3 | 7.2 | 16.2 | 2.3 | 17 | 202 | 57 |
4510915 | B | 4 | 10.7 | - | - | 69 | 21 | 34 |
4510411 | C | 2 | 3.4 | 》30 | >8.8 | 133 | 10 | 63 |
4510424 | C | 3 | 8.9 | 》30 | 3.4 | 34 | 66 | 30 |
4510645 | C | 4 | 20.5 | 》30 | >1.5 | 55 | 12 | 22 |
4510471 | D | 2 | 6.3 | 》30 | 4.8 | 117 | 29 | 75 |
4510473 | D | 3 | 15.3 | >30 | >2.0 | 29 | 122 | 48 |
4510991 | D | 4 | ≈30 | 》30 | >1.0 | 56 | 9 | 16 |
4510470 | E | 2 | 0.8 | 4.5 | 5.6 | 73 | 38 | 101 |
4510472 | E | 3 | 3.4 | ≈10 | 2.9 | 23 | 96 | 56 |
4510916 | E | 4 | 6.1 | ≈30 | >4.9 | 55 | 8 | 28 |
氟哌啶醇 | 0.19 | 0.4 | 2.1 | 3 | 3860 | 19 | ||
氯氮平 | 3.3 | 12.3 | 3.7 | 159 | 647 | 35 |
从表1所示的APO诱导的攀爬的抑制的ED50值明显地看出绝大多数本发明化合物以低剂量口服给药时已经抑制了APO诱导的攀爬,此结果支持了本发明化合物的体内抗精神病活性。活性最强的化合物No.4510470其口服活性是氯氮平的10倍,但是几种其它分子,如化合物No.4510408、No.4510411或No.4510472其ED50值低于或等于氯氮平的ED50值。同时,通过在此情况下嗅探的发生而测得的APO诱导的机械重复行为只有在施用极高剂量,通常是大于30毫克/千克本发明化合物时才会被阻止。上述结果,包括嗅探/攀爬的比率,证实了本发明化合物具有体内脑边缘系统的选择性并且这钟选择性比氯氮平的更好。基于脑边缘系统的选择性,本发明化合物的作用与非典型的抗精神病剂类似,因此,预计不会出现锥体束外症状(EPS)或只有在超剂量服用下该症状才出现。
基于表1所示的受体结合测定结果的作用机理进一步证实了本发明化合物的非典型的抗精神病的性质。因此,它们的D-2多巴胺受体的活性与典型的抗精神病剂氟哌啶醇(3nM)相比更不明显而与非典型的抗精神病剂氯氮平更相似。但是,本发明化合物在这个受体的亚型上的活性更高。它们的氯氮平样的α-肾上腺素受体的活性进一步证实了其为非典型抗精神病的特征。本发明化合物及其代表性的化合物,例如No.4510916分子和No.4510991分子,在5-HT1A受体亚型上产生特别强的活性。这种效果极不同于氯氮平的弱的5-HT1A受体活性,并且同样地其强度也不同于直到现在仍可以买到的其它非典型的抗精神病剂的活性强度。这种差别通过D-2/5-HT1A比率的表示而更加明显。例如,对于氯氮平而言它的比率为0.2,而No.4510470化合物其比率为1.9和No.4510916化合物其比率则为6.9。5-HT1A受体活性也指明了本发明化合物的一种具有抗焦虑症疗效的成分。
总之,本发明的新的化合物是非典型的抗精神病剂,经过口服给药后,其活性实质上高于氯氮平。类似于氯氮平的是它们有一个复合受体的特征,但是,本发明化合物的受体亚型和它们的活性强度包括参与作用的机理都不同于氯氮平。因此,本发明化合物具有其它特征并表现出新的复合物作用机理。所以,本发明化合物能非常有效地治疗急慢性精神分裂症,妄想狂和其它精神错乱;器质性的精神紊乱,如妄想、痴呆、孤独综合症、嗜癖症、精神发育迟缓症、抽搐紊乱;情感紊乱症,如躁狂、两极神经细胞紊乱、躁忧性气质,精神抑郁症;焦虑紊乱症,包括恐慌紊乱症、恐怖症、强迫观念与行为紊乱症、一般焦虑综合症;和人格紊乱症,例如强迫的、类妄想狂的、类精神分裂症的、反社会的和任何其它的与精神运动性的不安有关的紊乱症。本发明化合物所预期的治疗剂量为每千克体重0.01和50毫克,每天一次或低剂量分次采取口服给药、腹膜内或皮下方式给药。
下面详述本发明式(Ⅰ)所示的新的化合物的制备方法。
将式(Ⅱ)所示的卤代烃醚衍生物,优选的是可从文献中获知的或用已知方法制备的2-卤代烃醚衍生物,与同样已知的(2-甲氧基苯基)哌嗪或其盐,优选的是可以买到的(2-甲氧基苯基)哌嗪二盐酸盐,于有机质子性溶剂如一种醇类或任何一种有机两极非质子性溶剂,如一种脂族酮或乙氰、二甲基甲酰胺中,在有或没有一种碱和一种碱金属碘化物如碘化钠的存在下反应。可适用的碱类是无机碱,如碳酸钾、碳酸钠;或有机碱,如三乙胺。反应是在所用溶剂的沸点温度下进行的,反应时间为5-10小时。将含有式(Ⅰ)所示化合物的反应混合物蒸发后,用水处理干的残渣并用与水不混溶的溶剂提取,最后得到式(Ⅰ)所示化合物的粗产品,如有必要,可将粗产品进行重结晶纯化。
如果需要,可将式(Ⅰ)所示化合物通过上述已知的方法就地转化成其酸加成盐。
盐的形成是通过已知的方法在惰性溶剂或溶剂混合物中按照这样一种方式完成的,即,将式(Ⅰ)所示化合物溶于所选的溶剂中,接着向上述溶液中分批加入合适的酸直到所得混合液呈强酸性(PH值约为1)。另外向上述溶液中加入计算量的溶于所选溶剂中的酸溶液,也可使盐形成。之后,将沉淀出的酸加成盐以适当的方法,如用过滤法,与反应混合物分离。
通过将式(Ⅰ)所示的活性成分与普遍用于肠内或非肠内治疗用的非毒性的、惰性固体或液体载体混合而将之转化成药物组合物。如水、明胶、乳糖、淀粉、果胶、硬脂酸镁、硬脂酸、滑石粉、植物油如橄榄油或花生油等都是可用的载体。这个活性成分可以通常的药物组合物形式进行配制,特别是以固体形式配制,例如,片剂、糖衣剂、胶囊剂、丸剂、栓剂等。固体载体的用量可在较宽的范围内变化,优选的用量为约25毫克至1克。这些组合物可任意地含有普遍使用的药物助剂(添加剂),例如,防腐剂、稳定剂、润湿剂或乳化剂等。这些组合物的制备可通过普通方法完成,例如在制备固体组合物的情况下可通过筛分、混合、造粒然后压缩所用组分而完成。可对该组合物做进一步的常规处理,如灭菌处理。
本发明通过下列非限定的实施例得到详细说明。实施例1
1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪
[式(Ⅰ),Q=2-中氮茚基,n=2]
使含有2.72克(10mmol)的2-[4-(2-中氮茚基)苯氧基]乙基氯、2.74克(12mmol)的(2-甲氧基苯基)哌嗪二盐酸盐、2.54克(24mmol)的碳酸钠、0.3克(2mmol)的无水碘化钠和40ml的甲基异丁基酮的混合物沸腾回流10小时。减压蒸发溶剂后,将残渣与20ml的水充分研制,然后用80ml的氯仿提取。有机相用水提取两次每次用水15ml,将有机相用无水硫酸钠干燥并过滤掉干燥剂。滤液与1克的活性炭和0.5克的氧化铝混合搅拌20分钟,然后过滤并将滤液减压蒸发至原体积的一半。在向残渣中加入40ml乙醇后,将其减压蒸发至15ml。将沉淀物质过滤并干燥。将所得到的2.9克粗产品溶于30ml氯仿中,再加入30ml乙醇,所得的溶液减压蒸发至15ml。将沉淀物质过滤和干燥后,获得标题化合物2.61克,产率为61%,m.p.:159-161℃。实施例2
1-(2-甲氧基苯基)-4-{3-[4-(2-中氮茚基)苯氧基]丙基}哌嗪
[式(Ⅰ),Q=2-中氮茚基,n=3]
所用方法与实施例1描述的基本相同,所不同的只是用3-[4-(2-中氮茚基)苯氧基]丙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为157-158℃。实施例3
1-(2-甲氧基苯基)-4-{4-[4-(2-中氮茚基)苯氧基]丁基}哌嗪
[式(Ⅰ),Q=2-中氮茚基,n=4],化合物序号为4510613
所用方法与实施例1描述的基本相同,所不同的只是用4-[4-(2-中氮茚基)苯氧基]丁基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为153-155℃。实施例4
1-(2-甲氧基苯基)-4-{2-[4-(2-咪唑并[1,2-a]吡啶基)苯氧基]乙基}哌嗪
[式(Ⅰ),Q=2-咪唑并[1,2-a]吡啶基,n=2],化合物序号为4510408
所用方法与实施例1描述的基本相同,所不同的只是用2-[4-(2-咪唑并[1,2-a]吡啶基)苯氧基]乙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为151-153℃。实施例5
1-(2-甲氧基苯基)-4-{3-[4-(2-咪唑并[1,2-a]吡啶基)苯氧基]丙基}哌嗪
[式(Ⅰ),Q=2-咪唑并[1,2-a]吡啶基,n=3],化合物序号为4510067
所用方法与实施例1描述的基本相同,所不同的只是用3-[4-(2-咪唑并[1,2-a]吡啶基)苯氧基]丙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为149-150℃。实施例6
1-(2-甲氧基苯基)-4-{4-[4-(2-咪唑并[1,2-a]吡啶基)苯氧基]丁基}哌嗪
[式(Ⅰ),Q=2-咪唑并[1,2-a]吡啶基,n=4],化合物序号为4510915
所用方法与实施例1描述的基本相同,所不同的只是用4-[4-(2-咪唑并[1,2-a]吡啶基)苯氧基]丁基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为144-145℃。实施例7
1-(2-甲氧基苯基)-4-{2-[4-(2-咪唑并[1,2-a]嘧啶基)苯氧基]乙基}哌嗪
[式(Ⅰ),Q=2-咪唑并[1,2-a]嘧啶基,n=2],化合物序号为4510911
所用方法与实施例1描述的基本相同,所不同的只是用2-[4-(2-咪唑并[1,2-a]嘧啶基)苯氧基]乙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为150-152℃。实施例8
1-(2-甲氧基苯基)-4-{3-[4-(2-咪唑并[1,2-a]嘧啶基)苯氧基]丙基}哌嗪
[式(Ⅰ),Q=2-咪唑并[1,2-a]嘧啶基,n=3],化合物序号为4510924
所用方法与实施例1描述的基本相同,所不同的只是用3-[4-(2-咪唑并[1,2-a]嘧啶基)苯氧基]丙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为156-158℃。实施例9
1-(2-甲氧基苯基)-4-{4-[4-(2-咪唑并[1,2-a]嘧啶基)苯氧基]丁基}哌嗪
[式(Ⅰ),Q=2-咪唑并[1,2-a]嘧啶基,n=4],化合物序号为4510645
所用方法与实施例1描述的基本相同,所不同的只是用4-[4-(2-咪唑并[1,2-a]嘧啶基)苯氧基]丁基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为151-153℃。实施例10
1-(2-甲氧基苯基)-4-{2-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]乙基}哌嗪
[式(Ⅰ),Q=6-(2,3-二氢)咪唑并[2,1-b]噻唑基,n=2],
所用方法与实施例1描述的基本相同,所不同的只是用2-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]乙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为145-147℃。实施例11
1-(2-甲氧基苯基)-4-{3-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]丙基}哌嗪
[式(Ⅰ),Q=6-(2,3-二氢)咪唑并[2,1-b]噻唑基,n=3],化合物序号为4510473
所用方法与实施例1描述的基本相同,所不同的只是用3-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]丙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为142-144℃。实施例12
1-(2-甲氧基苯基)-4-{4-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]丁基}哌嗪
[式(Ⅰ),Q=6-(2,3-二氢)咪唑并[2,1-b]噻唑基,n=4],化合物序号为4510991
所用方法与实施例1描述的基本相同,所不同的只是用4-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]丁基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为139-140℃。实施例13
1-(2-甲氧基苯基)-4-{2-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]乙基}哌嗪
[式(Ⅰ),Q=6-咪唑并[2,1-b]噻唑基,n=2],
所用方法与实施例1描述的基本相同,所不同的只是用2-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]乙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为158-161℃。实施例14
1-(2-甲氧基苯基)-4-{3-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]丙基}哌嗪
[式(Ⅰ),Q=6-咪唑并[2,1-b]噻唑基,n=3],化合物序号为4510472
所用方法与实施例1描述的基本相同,所不同的只是用3-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]丙基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为130-132℃。实施例15
1-(2-甲氧基苯基)-4-{4-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]丁基}哌嗪
[式(Ⅰ),Q=6-咪唑并[2,1-b]噻唑基,n=4],
所用方法与实施例1描述的基本相同,所不同的只是用4-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]丁基氯作起始原料替代2-[4-(2-中氮茚基)苯氧基]乙基氯,所获得标题化合物的熔点为128-130℃。实施例16
1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪二盐酸盐
[式(Ⅰ),Q=2-中氮茚基,n=2],化合物序号为4510407
将实施例1中所制备的1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪21.5克(0.05mol)溶于50ml氯仿中,再向溶液中加入50ml乙醇,然后向反应混合溶液中加入20-30%的盐酸乙醇溶液使混合物液酸化至PH值=1。将沉淀过滤,用少量的乙醇洗涤后干燥,获得24.5克的标题化合物,产率98%,熔点为220-222℃。实施例17
1-(2-甲氧基苯基)-4-{3-[4-(2-中氮茚基)苯氧基]丙基}哌嗪二盐酸盐
[式(Ⅰ),Q=2-中氮茚基,n=3],化合物序号为4510423
所用方法与实施例16描述的基本相同,所不同的只是用1-(2-甲氧基苯基)-4-{3-[4-(2-中氮茚基)苯氧基]丙基}哌嗪作起始原料替代1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪,所获得标题化合物的熔点为239-241℃。实施例18
1-(2-甲氧基苯基)-4-{2-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]乙基}哌嗪三盐酸盐
[式(Ⅰ),Q=6-(2,3-二氢)咪唑并[2,1-b]噻唑基,n=2],化合物序号为4510471
所用方法与实施例16描述的基本相同,所不同的只是用1-(2-甲氧基苯基)-4-{2-[4-(6-(2,3-二氢)咪唑并[2,1-b]噻唑基)苯氧基]乙基}哌嗪作起始原料替代1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪,所获得标题化合物的熔点为214-216℃。实施例19
1-(2-甲氧基苯基)-4-{2-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]乙基}哌嗪三盐酸盐
[式(Ⅰ),Q=6-咪唑并[2,1-b]噻唑基,n=2],化合物序号为4510470
所用方法与实施例16描述的基本相同,所不同的只是用1-(2-甲氧基苯基)-4-{2-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]乙基}哌嗪作起始原料替代1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪,所获得标题化合物的熔点为254-256℃。实施例20
1-(2-甲氧基苯基)-4-{4-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]丁基}哌嗪三盐酸盐
[式(Ⅰ),Q=6-咪唑并[2,1-b]噻唑基,n=4],化合物序号为4510916
所用方法与实施例16描述的基本相同,所不同的只是用1-(2-甲氧基苯基)-4-{4-[4-(6-咪唑并[2,1-b]噻唑基)苯氧基]丁基}哌嗪作起始原料替代1-(2-甲氧基苯基)-4-{2-[4-(2-中氮茚基)苯氧基]乙基}哌嗪,所获得标题化合物的熔点为227-229℃。
Claims (9)
1.新的如式(Ⅰ)所示的具有环连接点为氮原子的稠杂环化合物及其可治疗用盐,(Ⅰ)
其中
Q所代表的是2-中氮茚基团、2-咪唑并[1,2-a]吡啶基团、2-咪唑并[1,2-a]嘧啶基团、6-(2,3-二氢)咪唑并[2,1-b]噻唑基团或6-咪唑并[2,1-b]噻唑基团;和
n为2-4的整数。
2.根据权利要求1的式(Ⅰ)所示的化合物及其可治疗用盐,其中Q所代表的是2-咪唑并[1,2-a]吡啶基团或6-咪唑并[2,1-b]噻唑基团;n与权利要求1中的定义相同。
5.根据权利要求4所述的方法,该方法包括将式(Ⅱ)所示的化合物与式(Ⅲ)所示的化合物在碱和碱金属碘化合物的存在下反应。
8.式(Ⅰ)所示的化合物或其可治疗用盐的用途,(Ⅰ)
其中
Q所代表的是2-中氮茚基团、2-咪唑并[1,2-a]吡啶基团、2-咪唑并[1,2-a]嘧啶基团、6-(2,3-二氢)咪唑并[2,1-b]噻唑基团或6-咪唑并[2,1-b]噻唑基团;和
n为2-4的整数,
将该化合物或其盐用于制备治疗精神分裂症、器质性的精神紊乱、情感紊乱症、焦虑紊乱症以及人格紊乱症的药物组合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9603001A HUP9603001A3 (en) | 1996-10-30 | 1996-10-30 | Heterocycle compounds comprising nitrogen, process for producing them and pharmaceutical compositions containing the same |
HUP9603001 | 1996-10-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1235606A true CN1235606A (zh) | 1999-11-17 |
Family
ID=89994394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN97199313A Pending CN1235606A (zh) | 1996-10-30 | 1997-10-22 | 2-甲氧基苯基哌嗪衍生物 |
Country Status (25)
Country | Link |
---|---|
US (1) | US6103724A (zh) |
EP (1) | EP0935599A1 (zh) |
JP (1) | JP2001503048A (zh) |
KR (1) | KR20000052872A (zh) |
CN (1) | CN1235606A (zh) |
AP (1) | AP9901532A0 (zh) |
AR (1) | AR010260A1 (zh) |
AU (1) | AU4962097A (zh) |
BG (1) | BG103370A (zh) |
BR (1) | BR9712588A (zh) |
CA (1) | CA2269814A1 (zh) |
CZ (1) | CZ132099A3 (zh) |
EA (1) | EA199900433A1 (zh) |
EE (1) | EE9900182A (zh) |
HU (1) | HUP9603001A3 (zh) |
IL (1) | IL129418A0 (zh) |
IS (1) | IS5026A (zh) |
NO (1) | NO992059D0 (zh) |
OA (1) | OA11041A (zh) |
PL (1) | PL333076A1 (zh) |
SK (1) | SK49499A3 (zh) |
TR (1) | TR199900946T2 (zh) |
TW (1) | TW406083B (zh) |
WO (1) | WO1998018797A1 (zh) |
ZA (1) | ZA979617B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106187873A (zh) * | 2016-07-25 | 2016-12-07 | 宜春学院 | 一种芳胺基烷基氧类化合物及其制备方法 |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2383327C (en) * | 1999-09-14 | 2009-11-03 | Aventis Pharmaceuticals Inc. | Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists |
US7125903B1 (en) | 1999-09-14 | 2006-10-24 | Aventis Pharmaceuticals Inc. | Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists |
SK3512002A3 (en) * | 1999-09-14 | 2003-03-04 | Aventis Pharma Inc | Thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists |
US7091199B1 (en) | 1999-09-14 | 2006-08-15 | Aventis Pharmaceuticals Inc. | Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists |
US7253165B2 (en) * | 1999-09-14 | 2007-08-07 | Aventis Pharmaceuticals Inc. | Benzisoxazolyl-, pyridoisoxazolyl-and benzthienyl-phenoxy derivatives useful as D4 antagonists |
EP1268478B1 (en) | 2000-03-31 | 2007-05-02 | Ortho-McNeil Pharmaceutical, Inc. | Phenyl-substituted imidazopyridines |
TW200811175A (en) * | 2006-06-21 | 2008-03-01 | Nihon Mediphysics Co Ltd | Novel compound with affinity with amyloid |
KR20100091965A (ko) * | 2007-10-24 | 2010-08-19 | 니혼 메디피직스 가부시키가이샤 | 신규 아밀로이드 친화성 화합물 |
CA2704027A1 (en) * | 2007-10-26 | 2009-04-30 | Nihon Medi-Physics Co., Ltd. | Novel compound having affinity for amyloid |
US7985752B2 (en) | 2008-05-29 | 2011-07-26 | Sk Holdings Co., Ltd. | Phenyl piperazine compounds, pharmaceutical composition including the same and use thereof |
US7964605B2 (en) | 2008-05-29 | 2011-06-21 | Sk Holdings Co., Ltd. | Phenyl piperazine compounds, pharmaceutical composition comprising the same, and use thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880824A (en) * | 1987-09-21 | 1989-11-14 | Ortho Pharmaceutical Corporation | Phenyl and benzoyl substituted imidazo-fused heterocyclic calcium channel blockers |
US5688949A (en) * | 1991-04-22 | 1997-11-18 | Otsuka Pharmaceutical Factory, Inc. | Pyrazolo 1,5-A!pyrimidine derivatives and anti-inflammatory agent containing the same |
US5486517A (en) * | 1994-05-10 | 1996-01-23 | Warner-Lambert Company | Benzimidazoles and imidazopyridines as central nervous system agents |
US6013654A (en) * | 1997-08-14 | 2000-01-11 | Pharmacia & Upjohn Company | Imidazo[1,2-A]pyridines for the treatment of CNS and cardiac diseases |
-
1996
- 1996-10-30 HU HU9603001A patent/HUP9603001A3/hu unknown
-
1997
- 1997-10-22 CN CN97199313A patent/CN1235606A/zh active Pending
- 1997-10-22 SK SK494-99A patent/SK49499A3/sk unknown
- 1997-10-22 CA CA002269814A patent/CA2269814A1/en not_active Abandoned
- 1997-10-22 KR KR1019990703721A patent/KR20000052872A/ko not_active Application Discontinuation
- 1997-10-22 IL IL12941897A patent/IL129418A0/xx unknown
- 1997-10-22 EE EEP199900182A patent/EE9900182A/xx unknown
- 1997-10-22 US US09/284,313 patent/US6103724A/en not_active Expired - Fee Related
- 1997-10-22 AP APAP/P/1999/001532A patent/AP9901532A0/en unknown
- 1997-10-22 AU AU49620/97A patent/AU4962097A/en not_active Abandoned
- 1997-10-22 EA EA199900433A patent/EA199900433A1/ru unknown
- 1997-10-22 EP EP97912393A patent/EP0935599A1/en not_active Withdrawn
- 1997-10-22 WO PCT/HU1997/000069 patent/WO1998018797A1/en not_active Application Discontinuation
- 1997-10-22 BR BR9712588-1A patent/BR9712588A/pt not_active Application Discontinuation
- 1997-10-22 PL PL97333076A patent/PL333076A1/xx unknown
- 1997-10-22 CZ CZ991320A patent/CZ132099A3/cs unknown
- 1997-10-22 JP JP10520214A patent/JP2001503048A/ja active Pending
- 1997-10-22 TR TR1999/00946T patent/TR199900946T2/xx unknown
- 1997-10-27 ZA ZA9709617A patent/ZA979617B/xx unknown
- 1997-10-31 AR ARP970105061A patent/AR010260A1/es unknown
- 1997-11-17 TW TW086117150A patent/TW406083B/zh active
-
1999
- 1999-04-15 IS IS5026A patent/IS5026A/is unknown
- 1999-04-29 BG BG103370A patent/BG103370A/bg unknown
- 1999-04-29 NO NO992059A patent/NO992059D0/no not_active Application Discontinuation
- 1999-04-30 OA OA9900092A patent/OA11041A/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106187873A (zh) * | 2016-07-25 | 2016-12-07 | 宜春学院 | 一种芳胺基烷基氧类化合物及其制备方法 |
CN106187873B (zh) * | 2016-07-25 | 2019-11-05 | 宜春学院 | 一种芳胺基烷基氧类化合物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
OA11041A (en) | 2003-03-07 |
NO992059L (no) | 1999-04-29 |
TW406083B (en) | 2000-09-21 |
JP2001503048A (ja) | 2001-03-06 |
KR20000052872A (ko) | 2000-08-25 |
PL333076A1 (en) | 1999-11-08 |
HU9603001D0 (en) | 1996-12-30 |
AR010260A1 (es) | 2000-06-07 |
BR9712588A (pt) | 1999-10-26 |
SK49499A3 (en) | 2000-03-13 |
TR199900946T2 (xx) | 1999-07-21 |
HUP9603001A2 (hu) | 1998-07-28 |
BG103370A (bg) | 2000-05-31 |
IL129418A0 (en) | 2000-02-17 |
IS5026A (is) | 1999-04-15 |
AP9901532A0 (en) | 1999-06-30 |
NO992059D0 (no) | 1999-04-29 |
US6103724A (en) | 2000-08-15 |
EA199900433A1 (ru) | 1999-10-28 |
EE9900182A (et) | 1999-12-15 |
CZ132099A3 (cs) | 1999-08-11 |
ZA979617B (en) | 1998-05-21 |
AU4962097A (en) | 1998-05-22 |
HUP9603001A3 (en) | 1999-07-28 |
EP0935599A1 (en) | 1999-08-18 |
CA2269814A1 (en) | 1998-05-07 |
WO1998018797A1 (en) | 1998-05-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7220741B2 (en) | 1,4-diazabicycloalkane derivatives, their preparation and use | |
DE60210944T2 (de) | N-substituierte heterocyclische nichtaryl-nmda/nr2b-antagonisten | |
DE60225563T2 (de) | 4-amino-6-phenyl-pyrroloä2,3-düpyrimidin derivate | |
US6284757B1 (en) | Pyrrolo[1,2-a]pyrazine derivatives as 5HT1A ligands | |
AU2018347516A1 (en) | Pyridine, pyrazine, and triazine compounds as allosteric SHP2 inhibitors | |
JP5576802B2 (ja) | C−Metチロシンキナーゼ介在疾患の治療用のイミダゾ[1,2−b]ピリダジン誘導体 | |
CN1235606A (zh) | 2-甲氧基苯基哌嗪衍生物 | |
WO2014001973A1 (en) | NOVEL 4-(SUBSTITUTED-AMINO)-7H-PYRROLO[2,3-d]PYRIMIDINES AS LRRK2 INHIBITORS | |
CN104530052A (zh) | 用于激酶调节的5h-吡咯[2,3-b]吡嗪衍生物和其适应症 | |
TW200911242A (en) | Novel compounds | |
TW201121966A (en) | Fused heterocyclic compounds as orexin receptor modulators | |
CA2940918A1 (en) | Substituted 4,5,6,7-tetrahydro-pyrazolo[1,5-.alpha.]pyrazine derivatives and 5,6,7,8-tetrahydro-4h-pyrazolo[1,5-.alpha.][1,4]diazepine derivatives as ros1 inhibitors | |
DE2502966A1 (de) | Neue derivate von 1,7-dihydro-2h- pyrazolo(4',3' zu 5,6)pyrido(4,3-d)pyrimidin-2,4-(3h)-dionen | |
CN1037770C (zh) | 制备取代的噻唑基和取代的吡啶基衍生物的方法 | |
US6231833B1 (en) | 2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine derivatives as ligands for serotonin receptors | |
IL166821A (en) | 1,4-diazabicyloalkane derivatives, their preparation and use | |
CN1237179A (zh) | 1,2,3,4-四氢-苯并呋喃并[3,2,-c]吡啶衍生物类 | |
CN106687464A (zh) | 大环rip2激酶抑制剂 | |
CN1259954A (zh) | 3-取代的吡啶并[3',4':4,5]噻吩并[2,3-d]嘧啶衍生物,其制备及用途 | |
DE69830595T2 (de) | 5-substituiertes 3-Oxadiazolyl-1,6-naphthyridin-2(1H)-on-Derivat | |
CN1085981C (zh) | 烟酸酯化合物及其盐,它们的制法及含有该化合物的药物组合物 | |
PL183686B1 (pl) | Nowy związek, pochodna podstawionej tetracyklicznej azepiny, kompozycja farmaceutyczna, sposób wytwarzania pochodnej podstawionej tetracyklicznej azepiny | |
CN1264848C (zh) | 吡咯并[2,1-b][1,3]苯并硫杂氮杂䓬类及其用于制备具有抗精神病活性药物的用途 | |
EP1764134B1 (en) | Purine derivatives linked to arylpiperazines | |
WO2023244691A1 (en) | Compositions, and methods for inhibiting dcn1-ubc12 interaction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |