CN1047385C - 3-吲哚基哌啶和含有它们的药物组合物 - Google Patents
3-吲哚基哌啶和含有它们的药物组合物 Download PDFInfo
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- CN1047385C CN1047385C CN95104705A CN95104705A CN1047385C CN 1047385 C CN1047385 C CN 1047385C CN 95104705 A CN95104705 A CN 95104705A CN 95104705 A CN95104705 A CN 95104705A CN 1047385 C CN1047385 C CN 1047385C
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- XKJJOWGAKBYIQV-UHFFFAOYSA-N 2-piperidin-3-yl-1h-indole Chemical compound C1CCNCC1C1=CC2=CC=CC=C2N1 XKJJOWGAKBYIQV-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims description 101
- 239000002585 base Substances 0.000 claims description 49
- 239000002253 acid Substances 0.000 claims description 35
- -1 butyl piperidine 4-yl Chemical group 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 21
- 230000009467 reduction Effects 0.000 claims description 18
- 230000007062 hydrolysis Effects 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 230000004048 modification Effects 0.000 claims description 6
- 238000012986 modification Methods 0.000 claims description 6
- 238000007614 solvation Methods 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 238000003797 solvolysis reaction Methods 0.000 claims description 2
- HNQZRUDJRPSFAU-UHFFFAOYSA-N 2-piperidin-1-yl-1h-indole Chemical compound C1CCCCN1C1=CC2=CC=CC=C2N1 HNQZRUDJRPSFAU-UHFFFAOYSA-N 0.000 claims 1
- 241000790917 Dioxys <bee> Species 0.000 claims 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 150000003053 piperidines Chemical class 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- IENZCGNHSIMFJE-UHFFFAOYSA-N indole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NC=CC2=C1 IENZCGNHSIMFJE-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000007796 conventional method Methods 0.000 description 14
- 150000004702 methyl esters Chemical class 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
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- 239000011734 sodium Substances 0.000 description 10
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 230000009435 amidation Effects 0.000 description 8
- 238000007112 amidation reaction Methods 0.000 description 8
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- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 6
- 208000005156 Dehydration Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
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- 229910052708 sodium Inorganic materials 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 150000001408 amides Chemical class 0.000 description 5
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- IRDLINHXNFIJTM-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-indole Chemical class C1=CC=C2C(CCCCCl)=CNC2=C1 IRDLINHXNFIJTM-UHFFFAOYSA-N 0.000 description 4
- NJJWMEJWFYRORL-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-indole-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(CCCCCl)=CNC2=C1 NJJWMEJWFYRORL-UHFFFAOYSA-N 0.000 description 4
- CYWSSELLAZKYQM-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-indole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NC=C(CCCCCl)C2=C1 CYWSSELLAZKYQM-UHFFFAOYSA-N 0.000 description 4
- FKYYQTPGCWRMGM-UHFFFAOYSA-N 3-piperidin-4-yl-1h-indole-5-carbonitrile Chemical class C12=CC(C#N)=CC=C2NC=C1C1CCNCC1 FKYYQTPGCWRMGM-UHFFFAOYSA-N 0.000 description 4
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 4
- VQFAITGIMWXQQK-UHFFFAOYSA-N 5-fluoro-3-piperidin-4-yl-1h-indole Chemical class C12=CC(F)=CC=C2NC=C1C1CCNCC1 VQFAITGIMWXQQK-UHFFFAOYSA-N 0.000 description 4
- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical class FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000006239 protecting group Chemical group 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
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 4
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 4
- JRASUUTVFCLPPO-UHFFFAOYSA-N 3-(2-chloroethyl)-1h-indole Chemical class C1=CC=C2C(CCCl)=CNC2=C1 JRASUUTVFCLPPO-UHFFFAOYSA-N 0.000 description 3
- KAIRZPVWWIMPFT-UHFFFAOYSA-N 3-piperidin-4-yl-1h-indole Chemical class C1CNCCC1C1=CNC2=CC=CC=C12 KAIRZPVWWIMPFT-UHFFFAOYSA-N 0.000 description 3
- DEIYMTQMNDLJHX-UHFFFAOYSA-N 4-fluoro-3-piperidin-4-yl-1h-indole Chemical class C1=2C(F)=CC=CC=2NC=C1C1CCNCC1 DEIYMTQMNDLJHX-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- 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
- C07D401/14—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 three or more hetero rings
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Abstract
式I3-吲哚基哌啶及其生理适用盐，式中各基团定义详见说明书。这些化合物对中枢神经系统有作用，特别具有多巴胺兴奋作用或多巴胺拮抗作用。
Description
本发明涉及式Ⅰ3-吲哚基哌啶及其生理适用盐，其中，R1、R2、R3和R4为相互独立的H、A、OH、OA、F,Cl,Br,I,CN,
CF3,COOH,CONH2,CONHA,CONA2或COOA，或R1和R2一起、R3和R4一起均为亚甲二氧基，R5 为H或OH，R6 为H，或R5和R6 一起为一个键，A 为C1-6烷基，n 为2,3,4,5或6。
本发明的目的为发现新型的用于药物制备的化合物。
现已发现式Ⅰ化合物及其生理适用酸加成盐具有良好的药理性质。具体而言，其对中枢神经系统具有活性，特别是可用作5-羟色胺的兴奋剂和拮抗剂。此化合物可抑制氚代5-羟色胺配位体与海马受体的结合。(见Cossery et al.,European J.Pharmacol.140(1987),143-155)。其还可改善在纹状体中的DOPA的聚集和在核逢中的5-HTP的聚集。(见Seyfried et al.,European J.Pharmacol.160(1989),31-41)。其还有止痛和降压作用，可通过给实施导管插入的、清醒、自发高血压的大鼠口服这种化合物后直接测得的血压下降来证实(见Strain:SHR/Okametol NIH-MO-CHB-Kisolegy；method:g.v.Weeks and Jones,Proc.Soc.Exptl.Biol.Med.104(1960),646-648)。它们也可用于预防和控制大脑梗塞如中风和大脑缺血的后遗症，及用于治疗神经病症和帕金森氏疾病的锥体束外运动原的副作用。
因此，式Ⅰ及其生理适用酸加成盐可用作抗焦虑药、抗抑郁药和/或降压药的活性成分，也可用作制备其他药物活性成分的中间体。
本发明涉及式Ⅰ及其生理适用酸加成盐的吲哚衍生物。
基团A为C1-6烷基，特别是C1-2烷基，优选甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。OA优选为甲氧基，乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。NHA优选为甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、异丁氨基、仲丁氨基或叔丁氨基。NA2优选为二甲氨基、N-乙基-N-甲基氨基、二乙基氨基、二正丙基氨基、二异丙基氨基或二正丁基氨基。
因此，CO-NHA优选为N-甲基氨基甲酰基或N-乙基氨基甲酰基，而CO-NA2优选为N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基。
吲哚基可未取代、一取代或二取代。优选一取代物，优选在5位取代，但也可在2-、4-、6-或7-位取代。如果两个吲哚-3-基被取代，则分别的取代基可相同或不同。在两个吲哚基上的取代基个数也可相互不同。
如，在吲哚基上的取代基R1、R2、R3和R4可为CO2H、CO2CH3、OCH3、OH、O-CH2-O、F、CN或CONH2。
如果在2-位取代吲哚基，取代基优选A。
参数n为2、3、4、5或6，优选3或4。
R5和R6各优选为H，但也可一起为一个键。
类似地，本发明涉及那些至少所述基团之一具有上述优选意义之一的式Ⅰ化合物。可用下列式Ⅰa-Ⅰh表示化合物的一些优选化合物，这些化合物与式Ⅰ相对应，其中未作进一步描述的基团的定义如式Ⅰ所述，然而在Ⅰa中，R2和R4为H,R1和R3为分别在吲哚基5位的相同基团；在Ⅰb中，R2和R4为H,R1和R3分别为在吲哚基5位上的COOH、
COOA、CONH2、CONHA、CONA2或CN；在Ⅰc中，R2和R4为H,R1和R3分别为在吲哚基5位上的OH、OA、
F、Cl、Br、I或CF3；在Ⅰd中，R1和R2一起、R3和R4一起为亚甲二氧基；在Ⅰe中，R2、R4、R5和R6各为H；在Ⅰf中，R2和R4为H,R5和R6一起为一个化学键；在Ⅰg中，R2、R4、R5和R6各为H,R1和R3均为F、CN、OA或CONH2；在Ⅰh中，R2、R4、R5和R6各为H,R1和R3相互不同，分别为H、
COOH、COOA、OCH3、OH、CN、CONH2、CONA2或CONHA；在Ⅰi中，R1和/或R3为A，特别是在吲哚基2位上的甲基。
然而，特别优选那些具有分式Ⅰk和Ⅰak-Ⅰhk的化合物，其对应分式Ⅰa-Ⅰk和式Ⅰ，而n为2,3或4。
本发明还涉及制备式Ⅰ哌啶衍生物及其盐的方法，其特征在于：将式Ⅱ化合物其中X1为X或NH2，X为Cl、Br、I、OH或OH功能修饰成为一个反应活性基团R1、R2和n如上述定义
与式Ⅲn化合物反应
其中X2和X3可相同或不同，当X1=NH2时，各为X，其他条件下，一起
为NH，R3和R4如上述定义，或将式Ⅳ化合物其中，R1,R2和n如上述定义，
与式Ⅴ吲哚反应其中，R3、R4如上述定义，
或将R5为OH和R6为H的式Ⅰ化合物脱水而转化为式Ⅰ的另一化合物，
或将一个或多个H被一个或多个还原基团和/或一个或多个附加的C-C和/或C-N键所取代的式Ⅰ化合物与还原剂反应，
或将一个或多个H被一个或多个溶剂化基团所取代的式Ⅰ化合物与溶剂化试剂反应，和/或通这酯化、水解、醚化、醚裂解、全部或部分水解或通过烷基化，将R1、R2、R3和/或R4基转变为另一种R1、R2、R3和/或R4基团，和/或通过与酸或碱反应，将得到的式Ⅰ碱或酸变成盐。
通过已知方法制备式Ⅰ化合物，如在下列文献中所述
(e.g.in the standard workssuch as Houben-Weyl,Methoden der Organischen Chemie(Methods of Organic Chemistry ),Georg-Thieme-Verlag,Stuttgart；Organic Reactions,John Wiley & Sons,Inc.,New York；J.March,Adv.Org.Chem.,3rd Ed.J.Wiley &Sons (1985),即选择那些已知的适于所述反应的反应条件。也可使用那些已知的、未在此进一步提及的有所改进的方法。
如有必要，也可就地形成用于所述方法的起始原料，即这些起始原料不从反应混合物中分离出来而马上进一步反应得到式Ⅰ化合物。
在式Ⅱ吲哚衍生物中，X1优选为X；相应地，在式Ⅱ化合物中，X2和X3一起优选为NH。X优选为Cl或Br，也可为I,OH或OH功能修饰为反应活性基团的OH，特别是C1-6的烷基磺酰氧基(如甲基磺酰氧基)或C6-10芳基磺酰氧基(如苯磺酰氧基、对-甲苯磺酰氧基，萘基-1-或-2-磺酰氧基)。
相应地，通过将3-(氯烷基)-或3-(溴烷基)吲哚与X2和X3一起为NH基的3-哌啶-4-基-吲哚(以下以Ⅲa表示)反应，可制备式Ⅰ吲哚衍生物。
式Ⅱ和Ⅲ的一些化合物为已知化合物，对于式Ⅱ和Ⅲ的未知化合物，可通过与已知化合物类似的方法方便地制备。
通过还原适宜羧酸或其酯，可获得式Ind-CnH2n-OH伯醇，其中Ind为由R1和R2或R3和R4取代的吲哚-3-基。通过与亚硫酰氯、溴化氢、三溴化磷或相似卤代化合物反应，可制备相应的式Ind-CnH2n-Hal(Hal:Br,Cl)的卤化物。通过与适宜的磺酰氯反应，可从醇Ind-CnH2n-OH制备相应的磺酰氧基化合物。
通过将碘化钾与适宜的对-甲苯磺酸酯反应，可得到式ⅠInd-CnH2n-I的吲哚化合物。通过卤化物与苯邻二甲酰亚胺钾反应或还原相应腈，可制备式Ind-CnH2n-NH2的胺。
通过将在1位用已知氨基保护基保护的4-哌啶酮与被R3和/或R4基任意取代的吲哚反应，可制备大部分已知的哌啶衍生物Ⅱ-Ⅰa。这些反应优选在催化剂，如酸存在下进行。在除去保护基团后，将得到的产物直接与式Ⅱ化合物反应或先脱水生成1,2,5,6-四氢哌啶衍生物，然后再氢化。
按文献中有关吲哚亲电取代反应的那些已知方法，进行式Ⅱ和式Ⅲ化合物的反应。各组分在无溶剂的条件下、必要时在封闭管器或在加压釜中一起反应。然而优选在惰性溶剂中使化合物进行反应。适宜溶剂的实例为烃化合物，如苯、甲苯或二甲苯；酮，如丙酮或丁酮；醇，如甲醇、乙醇、异丙醇或正-丁醇；醚，如四氢呋喃(THF)或二噁烷；酰胺，如二甲基甲酰胺(DMF)或N-甲基吡咯烷酮；或腈，如乙腈，或如有必要，这些溶剂之间组成的混合物或其与水组成的混合物。
根据所使用的条件，反应时间在几分钟到14天之间，反应温度在0和150℃之间，通常在20-130℃之间。
在某些条件下，加入酸结合剂，如碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐或另一种碱金属或碱土金属弱酸盐，优选钾盐、钠盐成钙盐，或加入有机碱，如三乙胺、二甲基苯胺、吡啶或喹啉，将有利于此反应的进行。在其他条件下，加入催化剂量的酸，优选无机酸，如HCl，将有利于此反应的进行。
也可通过将式Ⅳ化合物与式Ⅴ吲哚衍生物反应而制备式Ⅰ化合物。
式Ⅳ或Ⅴ的一部分化合物为已知化合物；对于未知化合物，可通过与已知化合物类似的方法方便地制备。通过将Ind-CnH2n-NH2与1,5-二卤代戊-3-酮(卤素优选Cl或Br)反应，可方便地制备式Ⅳ化合物。也可通过将Ind-CnH2n-Cl、Ind-CnH2n-Br或Ind-CnH2n-I与4-哌啶酮反应而制备式Ⅳ化合物。
可通过已知的多种吲哚合成方法制备式Ⅴ吲哚，如Fischen吲哚合成法。
按照文献中有关烯胺与亲电反应组分反应的已知方法，进行式Ⅳ和Ⅴ化合物的反应。这些组分可互相直接反应，反应在无溶剂条件下，必要时在封闭管器或加压釜中，在常压或通入惰性气体(如N2)加压下进行。然而，也可在惰性溶剂存在下使化合物反应。适宜溶剂为那些上文中所述的用于式Ⅱ和Ⅲ化合物反应的溶剂。
在所选用的反应条件下，适宜的反应时间在几分钟到14天之间，反应温度在0°-150℃之间，通常在20°-130℃之间。
通过在-80-+250℃下且在至少一种惰性溶剂存在下，将氢原子被一个或多个还原基团和/或一个或多个附加C-C和/或C-N键所取代的前体与还原剂反应，也可制备式Ⅰ化合物。
还原基团(基团可被H取代)为羰基、羟基、芳基碳酰氧基(如对甲苯磺酰氧基)、N-苯磺酰基、N-苯甲基或O-苯甲基中的氧。
原则上，通过还原可将含一个上述基团或附加键的化合物或含有相邻的二个或多个上述基团或附加键的化合物变为式Ⅰ化合物，同时也可还原起始化合物中吲哚基团中的取代基数。该反应可用初生氢或络合金属氢化物进行或通过Wolft-Kishnor反应还原或在过渡金属催化剂作用下氢气还原进行。
优选的用于还原反应的起始物具有式Ⅵ结构其中，R7和R8为H或，如，芳基磺酰基和/或苄基，L 为CnH2n或与之相对应的链，而其中的一个或多个-CH2-基团
已被-CO-取代，R1、R2、R3、R4、R5和R6如上述定义，但是R7和R8不能同时为H且L为CnH2n。
在式Ⅵ化合物中，L优选为-CO-(CH2)n-2-CO-[具体为-COCO-、-COCH2CO-、-CO(CH2)2-CO、-CO-(CH2)3-CO-]、-(CH2)n-1-CO-[具体为-CH2-CO-、-CH2CH2-CO、-(CH2)3-CO或-(CH2)4-CO-]，其他实例为-CO-CH2CH2-、-CO-(CH2)3-、-CH2-CO-CH2CH2-、-CH2CH2-CO-CH2-、-CO-(CH2)4-、-CH2-CO-(CH2)3-、-CH2CH2-CO-CH2CH2-或-(CH2)3-CO-CH2-。
在上述式Ⅱ和Ⅲ化合物反应条件下，通过将先在1位任意取代的式Ⅲ化合物与式Ⅶ化合物反应，可制备式Ⅵ化合物。其中，R1、R2、R7、L和X1如上定义，
如果用初生氢作还原剂，可通过将金属与弱酸或弱碱反应而制备。因而可使用锌与碱金属氢氧化物溶液的混合物或铁与乙酸的混合物。也可在醇中，如乙醇、异丙醇、丁醇、戊醇或异戊醇或苯酚，使用钠或其他碱金属。也可在碱水溶液中，必要时加入乙醇，用铝镍合金。在醇水或水溶液中的钠汞齐或铝汞剂也适于制备初生氢。也可在混和相中进行此反应，此时可选用水相和苯相或甲苯相。
其他优选的还原剂为络合金属氢化物、如LiAlH4、NaBH4、二异丁基氢化铝或NaAl(OCH2CH2OCH3)2H2、乙硼烷，必要时加入催化剂，如BF3、AlCl3或LiBr。适于此反应的溶剂具体为醚，如乙醚、二正丁基醚、THF、二噁烷、二甘醇二甲醚或1,2-二甲氧基乙烷和烃化合物，如苯。用于采用NaBH4进行还原的溶剂主要为醇，如甲醇或乙醇、水和醇水化物。这些方法的还原反应优选在-80-+150℃之间，特别是0-100℃之间。
在约0-66℃下，在溶于THF的LiAlH4作用下，可将酸式酰胺(如L为-(CH2)n-1-CO基的式Ⅵ的酰胺)中的-CO基还原为CH2基。通过还原反应可同时消除位于吲哚环的1-位的芳基磺酰基保护基团。通过用液氨中的钠还原，可消除N-苯甲基。
也可按照Wolff-Kishner法，即在约150-250℃下加压，通过用溶于无水乙醇中的无水肼处理，将一个或多个羰基还原为CH2基。优选醇钠为催化剂。此还原反应也可按Huang Minlon法进行，即在碱金属(如钠)的氢氧化物存在下，在高沸点水溶性溶剂(如二甘醇或三甘醇)中与水合肼反应。通常将反应混合物沸腾3-4小时。而后将水蒸出，在高达200℃下分解得到的腙。也可在室温、在二甲亚砜中用肼进行Wotff-Kishner还原反应。
此外，也可在过渡金属(如RaneyNi或Pd)的催化下用H2进行一些还原反应。此时，Cl、Br、I、SH、甚至OH可被H取代。通过在甲醇中用Pd/H2进行催化氢化，也可使NO2变为NH2。
其中一个或多个H被一个或多个溶剂化基团取代的式Ⅰ化合物可被溶剂化、特别是水解，从而得到式Ⅰ化合物。
例如，可通过将Ⅲa与其一个或多个H被一个或多个溶剂化基团取代的式Ⅱ化合物(X′=X)反应而得到用于溶剂解的起始物。具体而言，将1-酰基吲哚衍生物(具有式Ⅰ结构，且在吲哚基的1-位含有酰基，优选少于C10的链烷酰基、烷基磺酰基或芳基磺酰基，如甲基磺酰基、苯磺酰基或对甲苯磺酰基)水解而得到在吲哚1位未取代的相应吲哚衍生物，反应在酸性、中性或碱性介质中进行，温度为0-200℃之间。碱可选用钠、钾或钙的氢氧化物、钠或钾的碳酸盐，或氨。溶剂优选水；低级醇，如甲醇或乙醇；醚，如THF或二噁烷；砜，如环丁砜，或其混合物，尤其是含水混合物。也可在沸点，直接与水反应进行水解。
通过已知方法，可将式Ⅰ化合物进一步变为式Ⅰ的另一种化合物。
通过衍生相应的羧基吲哚-3-基化合物，可得到其吲哚部分被COOA、CONH2、CONHA、CONA2取代的式Ⅰ化合物。可通过已知方法或类似方法之一，用醇或醇盐将酸或其反应活性衍生物(如其酰卤或酸酐)酯化。也可用伯或仲、脂肪或环胺将酸、酰卤或酯酰胺化。优选在肽合成条件下，将游离羧酸与胺反应。该反应优选在脱水剂存在下进行，其脱水剂可为碳化二亚胺，如二环己基碳化二亚胺或N-(3-二甲基氨基丙基)-N-乙基碳化二亚胺，或丙烷磷酸酐(q.v.Angew.Chem.92,129(1980))，二苯基磷酰基叠氮化物或2-乙氧基-N-乙氧基-羰基-1,2-乙羟基喹啉。反应选择惰性溶剂，如卤代烃，如二氯甲烷，醚，如THF、或二噁烷、酰胺，如DMF、或二甲基乙酰胺、或腈，如乙腈，温度选择在-10-40℃之间，优选0-30℃之间。
也可在反应中不用酸或酰胺，而选用这些物质的反应活性衍生物，其中，其反应活性基团在中间步骤被保护基保护起来。也可用酸的活性酯形式，活化酯可通过加入1-羟基苯三唑或N-羟基-琥珀酰亚胺在原地形成。
另外，将氰取代吲哚-3-基水解；可得到羧基吲哚-3-基或脲基-吲哚-3-基。
将吲哚基被O-烷基-取代或二取代的式Ⅰ化合物醚裂解而得到相应的羟基衍生物。可通过在甲苯、醚(如THF或二甲亚砜)中用二甲硫-三溴化硼络合物处理，或通过在约150-250℃，与吡啶或苯胺氢卤酸(优选盐酸啶啶)共熔而断开醚基。
式Ⅰ化合物可任意占据不对称中心。因而在制备时可得到外消旋体或在选用光活性起始物时以光活性形式生成。必要时，可用已知方法将得到的外消旋体采用物理或化学方法拆分为其光学对映体。优选通过与光活性拆分剂反应而将外消旋体变为非对映异构体。适宜的拆分剂的实例为光活性酸，如D式和L型酒石酸、二苯甲酰酒石酸、二乙酰酒石酸、樟脑磺酸、扁桃酸、苹果酸或乳酸。可用已知方法，如分步结晶法，可将非对映异构体的不同形式拆分，也可用已知方法将式Ⅰ光活性化合物从非对映异构体中分离出来。
将得到的式Ⅰ碱与酸反应，生成相应的酸加成盐。可生成生理适用盐的酸均适用于此反应。因而可选用无机酸，如硫酸、氢卤酸、如盐酸或氢溴酸、磷酸，如正磷酸、硝酸和氨基磺酸，及有机酸，即脂肪酸、脂环酸、芳基脂肪酸、芳香酸或杂环一元或多元羧酸、磺酸或硫酸，如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙乙酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、苯甲酸、水杨酸、2-苯基丙酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸、乙二磺酸、2-羟基乙磺酸、苯磺酸、对-甲苯磺酸、萘-磺酸和萘二磺酸及月桂硫酸。
必要时，若在分子中无其他酸性基团，可用强碱，如NaOH或KOH、Na2CO3或K2CO3，将式Ⅰ的游离碱从其盐中分离出来。当式Ⅰ化合物有游离酸性基团时，也可用碱生成盐。适宜的碱为碱金属氢氧化物、碱土金属氢氧化物或伯、仲或叔胺等有机碱。
本发明还涉及式Ⅰ化合物及其生理适用盐在药物制剂生产上的用途，特别是通过非化学途径的生产。因而，它们可与至少一种赋形剂或添加剂，必要时，与一种或多种附加的活性成分一起成为一种适宜剂量制剂。
本发明还涉及含有至少一种式Ⅰ化合物和/或其生理适用盐的组合物，特别是药物制剂。这些制剂可用作人用或兽用药物。可选用的赋形剂为适于肠道(如口服)、非肠道或局部给药并不与此新化合物反应的有机或无机物，此赋形剂的实例为水、植物油、苯甲醇、聚乙二醇、明胶、碳水化合物，如乳糖或淀粉、硬脂酸镁、滑石粉和凡士林。片剂、包衣片剂、胶囊剂、糖浆剂、汁剂、滴剂或栓剂主要用于肠道给药，溶液剂(油剂或水剂)、悬浮剂、乳剂或植入剂主要用于非肠道给药，软膏剂、乳膏剂或粉剂主要用于局部给药。也可将新化合物冷冻干燥，得到的冷冻干燥物可用于生产注射制剂。
所述制剂可无菌消毒和/或含有添加剂，如润滑剂、防腐剂、稳定剂和/或湿润剂、乳化剂、渗透压调节盐、缓冲物质、着色剂、调味剂和/或香料。必要时，其也可含一种或多种附加的活性成分，如一种或多种维生素。
式Ⅰ化合物及其生理适用盐可用于人体或动物体疾病的治疗。其可用于治疗安定药引起的锥体束外运动原副作用、中枢神经系统紊乱，如紧张、抑郁和/或精神病、治疗高血压时的副作用(如使用a-甲基多巴)。本化合物还可用于内分泌学和妇科学，如用于治疗肢端肥大症、性腺机能减退继发性经闭、经前综合症和异常产后泌乳)，也可用于预防和治疗大脑疾病(如偏头痛)，特别是对老年医学，作用方式类似于麦角生物碱，还用于治疗大脑梗塞后遗症，如中风和脑局部缺血。
在这些治疗中，通常本发明的化合物的给药方式类似于已知市场有售的制剂，如bromocriptine、二氢麦角科尔宁，剂量优选在约0.2-500mg之间，特别优选在约0.2-50mg之间。每天剂量优选在约0.001-100mg/kg体重。低剂量(约0.2-1mg/单位剂量；约0.001-0.005mg/kg体重)特别适用作抗偏头痛制剂；10-50mg/单位剂量的剂量适用于其它所述疾病的治疗。然而，对于不同病人的具体剂量由许多因素决定，如所用具体化合物的活性，年龄、体重、身体状况、性别、饮食、给药时间和方式、排泄速度、药物配伍、所治疗的各种疾病的严重程度。优选口服给药。
在下列实例中，“以常规方法处理”是指：必要时加水，用二氯甲烷萃取，分离有机相，用Na2SO4干燥并过滤，蒸发滤液并用硅胶层析和/或结晶纯化残余物。温度以℃计。实例1
将1.2g 3-(4-氯丁基)-5-甲氧基吲哚(可通过将5-甲氧基吲哚与4-氯丁酰氯反应得到3-(4-氯丁酰基)-5-甲氧基吲哚，再用乙硼烷还原而制备)和1.0g 4-(吲哚-3-基)哌啶[可通过用吲哚还原N-BOC-4-哌啶酮，再将生成的双键脱水和氢化并除去保护基而制备)溶于200ml乙腈，在室温下搅拌此混合物8小时。经常规方法处理后得到3-[1-(4-甲氧基吲哚-3-基)-丁基)-4-哌啶基]吲哚，盐酸盐，m.p.138-141℃(分解)。
类似地，可得到下列产物：将3-(4-氯丁基)吲哚-5-羧酸甲酯与4-(5-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-4-哌啶
基]-5-甲氧基吲哚，盐酸盐，m.p.222-224℃；将3-(4-氯丁基)吲哚与4-(5-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(吲哚-3-基)丁基)-4-哌啶基]-5-甲
氧基-吲哚，盐酸盐，m.p.213-216℃；将3-(4-氯丁基)-5-甲氧基吲哚与4-(5,6-亚甲二氧吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-4-哌啶
基]-5,6-亚甲二氧基吲哚，盐酸盐，m.p.144-146℃。将3-(4-氯丁基)-5-甲氧基吲哚与4-(5-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-4-哌啶
基]-5-甲氧基吲哚；将3-(4-氧丁基)吲哚与4-(3-吲哚基)哌啶反应，可得到：
3-[1-(4-(吲哚-3-基)丁基)-4-哌啶基]吲哚；将3-(4-氯丁基)-5-甲氧吲哚与4-(5-羟基-吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-4-哌啶
基]-5-羟基吲哚，m.p.203-204℃；将3-(4-氯丁基)-5-氰基吲哚与4-(5-氨基甲酰基-吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-氰基吲哚-3-基)丁基)-4-哌啶基]吲
哚-5-羧酰胺，半水合物，m.p.227-228℃；将3-(4-氯丁基)-5-氰基吲哚与4-(5-氰基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-氰基吲哚-3-基)丁基)-4-哌啶基]-
5-氰基吲哚，二水合物，m.p.95-101℃；将3-(4-氯丁基)-5-甲氧羰基吲哚与4-(5-氨基甲酰基吲哚-3-基)哌啶反应，可得到：
3[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-4-哌啶
基]吲哚-5-羧酰胺，水合物，m.p.228-231℃；将3-(4-氯丁基)吲哚-5-羧酰胺与4-(5-氨基甲酰基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-氨基甲酰基吲哚-3-基)丁基)-4-哌
啶基]-吲哚-5-羧酰胺，三盐酸盐，m.p.202-203℃；将3-(4-氯丁基)-5-氟代吲哚与4-(5-氟代吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-氟代吲哚-3-基)丁基)-4-哌啶基]-
5-氟代吲哚；将3-(4-氯丁基)吲哚-5-羧酸甲基酯与4-(5-甲氧羰基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-4-哌啶
基]吲哚-5-羧酸甲基酯；将3-(4-氯丁基)吲哚-5-羧基酰胺与4-(5-氰基吲哚-3-基)哌啶反应，可得到：
3-[1-(4-(5-氨基甲酰基吲哚-3-基)丁基)-4-哌
啶基]-5-氰基吲哚。实例2
将0.8g 3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酸甲基酯[由实例1制备]在100ml 2N乙醇KOH溶液中沸腾0.5小时，经常规方法处理后，可得到 3-[1-(4-(5-羧基吲哚-3-基)丁基)-4-哌啶基]-吲哚-5-羧酸。
类似地，可得到下列产物：水解从3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-4-哌啶基]-5-甲氧基吲哚得到的相应酯，可得到：
3-[1-(4-(5-羧基吲哚-3-基)丁基)-4-哌啶]-
5-甲氧基吲哚，盐酸水合物，m.p.248℃(分解)；水解从3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酰胺得到的相应酯，可得到：
3-[1-(4-(5-羧基吲哚-3-基)丁基)-4-哌啶基]吲
哚-5-羧酰胺，盐酸，m.p.282-185℃；实例3
类似于实例1，从3-(3-氯苯基)…5-甲氧基吲哚[通过将5-甲氧基吲哚与3-氯丙酰氯反应得到3-(3-氯丙酰基)-5-甲氧基吲哚，再用乙硼烷还原而制备)和1.0g 4-(吲哚-3-基)哌啶[通过将N-BOC-4-哌啶酮与吲哚反应，再脱水、氢化得到的双键并除去保护基团而制备]反应，经常规方法处理后，可得到3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚。
类似地，可得到下列产物：将3-(3-氯丙基)吲哚-5-羧酸甲酯与4-(5-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基)-4-哌啶
基]-5-甲氧基吲哚；将3-(3-氯丙基)吲哚与4-(5-甲氧-3-基)哌啶反应，可得到：
3-[1-(3-(吲哚-3-基)丙基)-4-哌啶基]-5-甲
氧基吲哚，盐酸盐；将3-(3-氯丙基)-5-甲氧基吲哚与4-(5,6-亚甲二氧吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶
基]-5,6-亚甲二氧基吲哚；将3-(3-氯丙基)-5-甲氧基吲哚与4-(5-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-甲氧基吲哚3-基)丙基)-4-哌啶
基]-5-甲氧基吲哚；将3-(3-氯丙基)吲哚与4-(3-吲哚基)哌啶反应，可得到：
3-[1-(3-(吲哚-3-基)丙基)-4-哌啶基]吲哚；将3-(3-氯丙基)-5-甲氧基吲哚与4-(5-羟基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶
基]-5-羟基吲哚；将3-(3-氯丙基)-5-氰基吲哚与4-(5-氨基甲酰基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-氰基吲哚-3-基)丙基)-4-哌啶基]吲
哚-5-羧酰胺；将3-(3-氯丙基)-5-氰基吲哚与4-(5-氰基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-氰基吲哚-3-基)丙基)-4-哌啶基]-
5-氰基吲哚；将3-(3-氯丙基)-5-甲氧羰基吲哚与4-(5-氨基甲酰基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧基酰胺，m.p.195-196℃；将3-(3-氯丙基)吲哚-5-羧酰胺与4-(5-氨基甲酰基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-氨基甲酰基吲哚-3-基)丙基)-4-哌
啶基]-吲哚-5-羧基酰胺，倍半盐酸盐，异丙醇酯，m.p.
102-105℃(分解)；将3-(3-氯丙基)-5-氟代吲哚与4-(4-氟代吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-氟代吲哚-3-基)丙基)-4-哌啶基]-
4-氟代吲哚；盐酸盐，m.p.269-270℃；将3-(3-氯丙基)吲哚-5-羧酸甲基酯与4-(5-甲氧羰基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧酸甲基酯；将3-(3-氯丙基)吲哚-5-羧基酰氨与4-(5-氰基吲哚-3-基)哌啶反应，可得到：
3-[1-(3-(5-氨基甲酰基吲哚-3-基)丙基)-4-哌
啶基]-5-氰基吲哚，水合物，m.p.102-104℃(分解)；实施例4
类似于实例2，水解3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸甲基酯，可得到3-[1-(3-(5-羧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸。
类似地，可得到下列产物：水解从3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基)-4-哌啶基]-5-甲氧基吲哚生成的相应酯，可得到：
3-[1-(3-(5-羧基吲哚-3-基)丙基)-4-哌啶基]-
5-甲氧基吲哚；水解从3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸甲基酯生成的相应酯，可得到：
3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧酸酯；水解从3-[1-(3-(6-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸甲基酯生成的相应酯，可得到：
3-[1-(3-(6-甲氧基吲哚-3-基)丙基)-4-哌啶
基]-吲哚-5-羧酸酯；水解从3-[1-(3-(4-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸甲基酯生成的相应酯，可得到：
3-[1-(3-(4-甲氧基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧酸；水解从3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酰胺生成的相应酯，可得到：
3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酰胺，盐酸盐，m.p.278-280℃；实例5
将2.1g 3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酸悬浮于100ml N-甲基吡咯烷酮中。然后加入3.2g 2-氯-1-甲基吡啶鎓甲磺酸盐并在室温搅拌此混合物12小时。将干燥NH3气通入得到的溶液直至饱和，再搅拌10小时。经常规方法处理后，可得到3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酰胺。
类似地，用2-氯-1-甲基吡啶鎓甲磺酸盐酰胺化下列羧酸，可分别得到下列产物：酰胺化3-[1-(4-(6-甲氧基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酸，可得到：
3-[1-(4-(6-甲氧基吲哚-3-基)丁基)-4-哌啶
基]吲哚-5-羧酰胺；酰胺化3-[1-(4-(4-甲氧基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酸，可得到：
3-[1-(4-(4-甲氧基吲哚-3-基)丁基)-4-哌啶
基]-吲哚-5-羧酰胺；酰胺化3-[1-(3-(5-羧酸吲哚-3-基)丙基)-4-哌啶基]-吲哚-5-羧酸；可得到：
3-[1-(3-(5-氨基甲酰基吲哚-3-基)丙基)-4-哌
啶基]吲哚-5-羧酰胺；酰胺化3-[1-(3-(5-羧基吲哚-3-基)丙基)-4-哌啶基]-5-甲氧基吲哚，可得到：
3-[1-(3-(5-氨基甲酰基吲哚-3-基)丙基)-4-哌
啶基]-5-甲氧基吲哚；酰胺化3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸，可得到：
3-[1-(3-(5-甲氧基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧酰胺；酰胺化3-[1-(3-(6-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸，可得到：
3-[1-(3-(6-甲氧基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧酰胺；酰胺化3-[1-(3-(4-甲氧基吲哚-3-基)丙基)-4-哌啶基]吲哚-5-羧酸，可得到：
3-[1-(3-(4-甲氧基吲哚-3-基)丙基)-4-哌啶
基]吲哚-5-羧酰胺。实例6
将250ml含3.9g 3-[1-(4-(5-羧基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酸的DMF溶液与1g N-甲基吗啉反应。在搅拌下加入5ml含2当量叔丁胺的DMF溶液、1.3g 1-羟基苯并三唑和20ml含1.9g N-(3-二甲基氨基丙基)-N’-乙基碳化二亚胺盐酸盐的DMF溶液。在室温下搅拌此混合物16小时并将滤液蒸干。经常规方法处理后，得到3-[1-(4-(5-N-叔丁基氨基甲酰基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-N-叔丁基羧酰胺。
类似地，与叔丁胺反应可得到下列产物：从3-[1-(4-(5-羧基吲哚-3-基)丁基)-4-哌啶基]-5-甲氧基吲哚，可得到：
3-[1-(4-(5-N-叔丁基氨基甲酰基吲哚-3-基)丁
基)-4-哌啶基]-5-甲氧基吲哚；从3-[1-(4-(5-羧基吲哚-3-基)丁基)-4-哌啶基]吲哚-5-羧酰胺，可得到：
3-[1-(4-(5-N-叔丁基氨基甲酰基吲哚-3-基)丁
基)-4-哌啶基]吲哚-5-羧酰胺；从3-[1-(3-(5-羧基吲哚-3-基)丙基)-4-哌啶基]-5-甲氧基吲哚，可得到：
3-[1-(3-(5-N-叔丁基氨基甲酰基吲哚-3-基)丙
基)-4-哌啶基]-5-甲氧基吲哚。实例7
将由1.6g 3-[1-(4-(吲哚-3-基)-丁基)-4-哌啶基]-5-甲氧基吲哚[可按实例1所述方法制备]、1.8g吡啶盐酸盐和50ml吡啶组成的混合物加热3小时。冷却混合物，蒸去溶剂，按常规方法处理残余物，可得到3-[1-(4-(吲哚-3-基)-丁基)-4-哌啶基]-5-羟基吲哚，m.p.178-180℃。
类似地，可得到下列产物：从3-[1-(4-(5-甲氧基吲哚-3-基)丁基-4-哌啶基]吲哚，可得到：
3-[1-(4-(5-羟基吲哚-3-基)丁基-4-哌啶基]吲
哚；从3-[1-(4-(5-甲氧基吲哚-3-基)丁基-4-哌啶基]5-甲氧基吲哚，可得到：
3-[1-(4-(5-羟基吲哚-3-基)丁基-4-哌啶基]5-
羟基吲哚；从3-[1-(4-(6-甲氧基吲哚-3-基)丁基-4-哌啶基]-5-羟基吲哚，可得到：
3-[1-(4-(6-羟基吲哚-3-基)丁基-4-哌啶基]5-
羟基吲哚；从3-[1-(3-(吲哚-3-基)丙基-4-哌啶基]-5-甲氧基吲哚，可得到：
3-[1-(3-(吲哚-3-基)丙基-4-哌啶基]-5-甲氧
基吲哚；从3-[1-(3-(5-甲氧基吲哚-3-基)丙基-4-哌啶基]5-甲氧基吲哚，可得到：
3-[1-(3-(5-羟基吲哚-3-基)丙基-4-哌啶基]-
5-羟基吲哚。实例8
将40ml含3.6g 3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基-4-哌啶基]吲哚的THF溶液在搅拌下滴加到20ml含0.6gLiAlH4的THF悬浮液中。然后将此混合液在25℃下再搅拌1小时，加入20ml稀释NaOH溶液，过滤此混合液，按常规方法处理滤液。可得到3-[1-(4-(5-羟基甲基吲哚-3-基)丁基-4-哌啶基]吲哚。
类似地，可得到下列产物：还原3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基-4-哌啶基]-5-甲氧基吲哚，可得到：
3-[1-(4-(5-羟甲基吲哚-3-基)丁基-4-哌啶基]-
5-甲氧基吲哚；还原3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基-4-哌啶基]吲哚-5-羧酸甲基酯，可得到：
3-[1-(4-(5-羟甲基吲哚-3-基)丁基-4-哌啶基]-
5-羟甲基吲哚；还原3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基-4-哌啶基]-5-甲氧基吲哚，可得到：
3-[1-(3-(5-羟甲基吲哚-3-基)丙基-4-哌啶基]-
5-甲氧基吲哚；还原3-[1-(3-(5-甲氧羰基吲哚-3-基)丙基-4-哌啶基]吲哚-5-羧基酰胺，可得到：
3-[1-(3-(5-羟甲基吲哚-3-基)丙基-4-哌啶基]吲
哚-5-羧基酰胺。实例9
向50ml含2.5g 3-[1-(4-(5-羧基吲哚-3-基)丁基-4-哌啶基]-5-氟代吲哚的沸腾的无水甲醇溶液中通入HCl气2小时。然后再让混合物沸腾1小时，经常规方法处理后得到3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基-4-哌啶基]-5-氟代吲哚。实例10
类似于实例1，在200ml乙腈中，将3-(4-氯丁基)吲哚[通过吲哚与4-氯丁酰氯反应得到3-(4-氯-丁酰基)吲哚，再用乙硼烷还原而制备]与4-(吲哚-3-基)-1,2,5,6-四氢吡啶[通过N-BOC-4-哌啶酮与吲哚反应，经脱水及除去保护基而制备]反应，经常规方法处理，可得到3-[1-(4-(吲哚-3-基)丁基)-1,2,5,6-四氢吡啶-4-基]吲哚，盐酸盐，m.p.190-192℃。
类似地，可得到下列产物：将3-(4-氯丁基)吲哚-5-羧酸甲基酯与4-(5-甲氧基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-1,2,5,
6-四氢吡啶-4-基]-5-甲氧基吲哚；将3-(4-氯丁基)吲哚与4-(5-甲氧基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(吲哚-3-基)丁基)-1,2,5,6-四氢吡
啶-4-基]-5-甲氧基吲哚；将3-(4-氯丁基)-5-甲氧基吲哚与4-(5,6-亚甲二氧基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-1,2,5,6-
四氢吡啶-4-基]-5,6-亚甲二氧基吲哚；将3-(4-氯丁基)-5-甲氧基吲哚与4-(5-甲氧基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-1,2,5,6-
四氢吡啶-4-基]-5-甲氧基吲哚；将3-(4-氯丁基)吲哚与4-(3-吲哚基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(吲哚-3-基)丁基)-1,2,5,6-四氢吡
啶-4-基]-吲哚；将3-(4-氯丁基)-5-甲氧基吲哚与4-(5-羟基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-甲氧基吲哚-3-基)丁基)-1,2,5,6-
四氢吡啶-4-基]-5-羟基吲哚；将3-(4-氯丁基)-5-氰基吲哚与4-(5-氨基甲酰基-吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-氰基吲哚-3-基)丁基)-1,2,5,6-
四氢吡啶-4-基]吲哚-5羧基酰胺；将3-(4-氯丁基)-5-氰基吲哚与4-(5-氰基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-氰基吲哚-3-基)丁基)-1,2,5,6-
四氢吡啶-4-基]-5-氰基吲哚；将3-(4氯丁基)-5甲氧羰基吲哚与4-(5-氨基甲酰基吲哚3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5甲氧羰基吲哚-3-基)丁基)-1,2,5,
6-四氢吡啶-4-基]吲哚-5-羧基酰胺；将3-(4-氯丁基)吲哚-5羧基酰胺与4-(5-氨基甲酰基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-氨基甲酰基吲哚-3-基)丁基)-1,2,
5,6四氢吡啶-4-基]吲哚-5-羧酰胺；将3-(4-氯丁基)-5-氟代吲哚与4-(5-氟代吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-氟代吲哚-3-基)丁基)-1,2,5,6-
四氢哌啶-4-基]-5-氟代吲哚；将3-(4-氯丁基)吲哚-5-羧酸甲基酯与4-(5-甲氧羰基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
甲基3-[1-(4-(5-甲氧羰基吲哚-3-基)丁基)-1,2,
5,6-四氢吡啶-4-基]-5-羧酸酯；将3-(4-氯丁基)吲哚-5-羧酰胺与4-(5-氰基吲哚-3-基)-1,2,5,6-四氢吡啶反应，可得到：
3-[1-(4-(5-氨基甲酰基吲哚-3-基)丁基)-1,2,
5,6-四氢吡啶-4-基]-5-氰基吲哚。实例11
类似于实例1，将3-(2-氯乙基)-2-甲基-5-甲氧基吲哚[通过2-甲基-5-甲氧基吲哚与2-氯乙酰基氯反应得到3-(2-氯乙酰基)-2-甲基-5-甲氧基吲哚，再用乙硼烷还原而制备]和1.0g 4-(5-氟代吲哚-3-基)哌啶[通过N-BOC-4-哌啶酮与5-氟代吲哚反应，脱水、氢化所生成的双键并除去保护基而制备]反应，经常规方法处理后得到3-[1-(2-(2-甲基-5-甲氧基吲哚-3-基)乙基)-4-哌啶基]-5-氟代吲哚，盐酸盐，Rf=0.31。
类似地，可得到下列产物：将3-(2-氯乙基)吲哚与4-(5-氟代吲哚-3-基)哌啶反应，可得到：
3-[1-(2-吲哚-3-基)乙基)-4-哌啶基]-5-氟代
吲哚，盐酸盐，Rf=0.20；将3-(2-氯乙基)吲哚与4-(4-氟代吲哚-3-基)哌啶反应，可得到：
3-[1-(2-吲哚-3-基)乙基)-4-哌啶基]-4-氟代
吲哚，盐酸盐，m.p.297℃；将3-(2-氯乙基)-2-甲基-5-甲氧基吲哚与4-(4-氟代吲哚-3-基)哌啶反应，可得到：
3-[1-(2-(2-甲基-5-甲氧基-吲哚-3-基)乙基)-
4-哌啶基]-4-氟代吲哚，盐酸盐，m.p.215℃；将3-(2-氯乙基)吲哚与4-(5-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(2-吲哚-3-基)乙基-4-哌啶基]-5-甲氧基
吲哚；将3-(2-氯乙基)-2-甲基-5-甲氧基吲哚与4-(4-甲氧基吲哚-3-基)哌啶反应，可得到：
3-[1-(2-(2-甲基-5-甲氧基吲哚-3-基)乙基-4-
哌啶基]-4-甲氧基吲哚。实例12
将0.4g 3-[1-((5-氟代吲哚-3-基)甲基羰基)-4-哌啶基]-5-氟代吲哚[通过5-氟吲哚与2-氯乙酰氯反应而得到3-(2-氯乙酰基)-5-甲氧基吲哚，再与4-(5-氟代吲哚-3-基)哌啶反应而制备]溶于30ml THF，室温逐滴加入10ml含1.3当量的NaAl(OCH2CH2OCH3)2H2的甲苯溶液。在室温下搅拌此混合物2小时，经常规方法处理后得到3-[1-(2-(5-氟代吲哚-3-基)乙基)-4-哌啶基]-5-氟代吲哚，盐酸盐，Rf=0.27。
类似地，用NaAl(OCH2CH2OCH3)2H2还原，可得到下列产物；还原3-[1-(2-(5-氟代吲哚-3-基)乙基羰基)-4-哌啶基]-4-氟代吲哚，可得到：
3-[1-(3-(5-氟代吲哚-3-基)丙基)-4-哌啶基]4-
氟代吲哚；还原3-[1-((5-氟代吲哚-3-基)甲基羰基)-4-哌啶基]-4-氟代吲哚，可得到：
3-[1-(2-(5-氟代吲哚-3-基)乙基)-4-哌啶基]-
4-氟代吲哚，盐酸盐，m.p.260℃。下列实例涉及药物制剂：实例A：注射瓶剂
用2N盐酸将3l含有1O0g式Ⅰ活性成分和5g Na2HPO4的双蒸水溶液调至pH6.5，无菌过滤，装入注射瓶中，无菌冷却干燥并无菌封口。每支注射瓶含5mg活性成分。实例B：栓剂
将含20g式Ⅰ活性成分与100g大豆卵磷脂和1400g可可脂的混合物一起熔化，倒入模具后冷却。每支栓剂含20mg活性成分。实例C：溶液剂
将1g式Ⅰ活性成分，9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g氯化苄烷铵溶于940ml双蒸水中而制成溶液。将pH调至6.8，将溶液加至11，光照消毒。该溶液剂可用于滴眼剂。实例D：软膏剂
在无菌条件下，将500mg式Ⅰ活性成分与49.5g凡士林混合而成。实例E：片剂
按常规方法，将含有1kg式Ⅰ活性成分、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物压制成片，每片含10mg活性成分。实例F：包衣片剂
类似于实例E进行压片，然后按常规方法，用蔗糖、马铃薯淀粉、滑石粉、黄薯胶和着色剂包衣。实例G：胶囊剂
按常规方法，将2kg式Ⅰ活性成分装入硬明胶胶囊中，每支胶囊含20mg活性成分。实例H：安瓿瓶剂
将60l含1kg式Ⅰ活性成分的双蒸水溶液无菌过滤，装入安瓿瓶中，在无菌下冷冻干燥，并无菌封口。每支安瓿瓶含10mg活性成分。
Claims (4)
1．式Ⅰ吲哚基哌啶及其生理适用盐
其中，R1、R2、R3和R4互相独立为H、OH、OA、F、CN、COOH、CONH2或COOA，或
R1和R2,R3和R4也可一起共为亚甲基二氧基，
A为C1-6烷基，
n为4。
2．根据权利要求1的化合物，其中所述化合物和其生理适用盐为：
(a)3-(1-(4-(5-甲氧羰基-3-吲哚基)丁基)哌啶-4-基)吲哚-5-甲氧吲哚；
(b)3-(1-(4-(5-氰基-3-吲哚基)丁基哌啶4-基)吲哚-5-腈。
3．制备权利要求1中化合物的方法，其特征在于：将式Ⅱ化合物
其中，X1为X或NH2，
X为Cl、Br、I、OH或OH功能修饰的反应活性基团，
R1,R2和n如权利要求1中定义，
与式Ⅲ化合物反应
其中，
X2和X3可相同或不同，X1=NH2时，均为X，或在其它条件X2和X3一起为NH，
R3和R4如权利要求1中定义；
或将式Ⅳ化合物
其中R1、R2和n均为前述定义，
与式Ⅴ吲哚反应
其中R3和R4如上述定义，
或将一个或多个H被一个或多个还原基团和/或一个或多个附加的C-C和/或C-N键取代的式Ⅰ化合物与还原剂反应；
或将一个或多个H被一个或多个溶剂化基团取代的式Ⅰ化合物与溶剂解试剂反应；
和/或通过酯化、水解、醚化、醚裂解、全部或部分水解或烷基化，将R1、R2、R3和/或R4变为其它的R1、R3、R3和/或R4。
和/或通过与酸或碱反应，得到式Ⅰ碱或酸加成盐。
4．药物组合物，其特征在于：其含至少一种权利要求1所述的式Ⅰ化合物及其生理适用盐。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4414113A DE4414113A1 (de) | 1994-04-22 | 1994-04-22 | 3-Indolylpiperidine |
| DEP4414113.0 | 1994-04-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1114651A CN1114651A (zh) | 1996-01-10 |
| CN1047385C true CN1047385C (zh) | 1999-12-15 |
Family
ID=6516183
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95104705A Expired - Fee Related CN1047385C (zh) | 1994-04-22 | 1995-04-20 | 3-吲哚基哌啶和含有它们的药物组合物 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5693655A (zh) |
| EP (1) | EP0683166B1 (zh) |
| JP (1) | JPH07291969A (zh) |
| KR (1) | KR100361950B1 (zh) |
| CN (1) | CN1047385C (zh) |
| AT (1) | ATE172730T1 (zh) |
| AU (1) | AU697749B2 (zh) |
| CA (1) | CA2147451C (zh) |
| CZ (1) | CZ285369B6 (zh) |
| DE (2) | DE4414113A1 (zh) |
| DK (1) | DK0683166T3 (zh) |
| ES (1) | ES2125508T3 (zh) |
| HU (1) | HUT74096A (zh) |
| NO (1) | NO307831B1 (zh) |
| PL (1) | PL180781B1 (zh) |
| RU (1) | RU2151148C1 (zh) |
| SK (1) | SK280881B6 (zh) |
| TW (1) | TW401416B (zh) |
| UA (1) | UA41333C2 (zh) |
| ZA (1) | ZA953260B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4414113A1 (de) * | 1994-04-22 | 1995-10-26 | Merck Patent Gmbh | 3-Indolylpiperidine |
| GB9523462D0 (en) * | 1995-11-16 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
| ZA9711376B (en) | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
| DE19707628A1 (de) * | 1997-02-26 | 1998-08-27 | Merck Patent Gmbh | Oxazolidinone |
| WO1999005140A1 (en) * | 1997-07-25 | 1999-02-04 | H. Lundbeck A/S | Indole and 2,3-dihydroindole derivatives, their preparation and use |
| WO1999009025A2 (en) * | 1997-08-15 | 1999-02-25 | Pfizer Products Inc. | 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives interacting with the dopamine d4 receptor |
| US7189753B1 (en) | 1997-11-06 | 2007-03-13 | Cady Roger K | Preemptive prophylaxis of migraine |
| DK1065205T3 (da) | 1998-03-18 | 2003-06-23 | Taisho Pharmaceutical Co Ltd | Heteroaromatiske derivater |
| EP1070715A4 (en) | 1998-03-19 | 2002-10-17 | Nihon Nohyaku Co Ltd | ARYLPIPERIDINE AND THEIR USE |
| US6310066B1 (en) | 1998-04-29 | 2001-10-30 | American Home Products Corp. | Antipsychotic indolyl derivatives |
| US6204274B1 (en) | 1998-04-29 | 2001-03-20 | American Home Products Corporation | Indolyl derivatives as serotonergic agents |
| IL139962A0 (en) | 1998-06-19 | 2002-02-10 | Lundbeck & Co As H | 4,5,6 and 7-indole and indoline derivatives, their preparation and use |
| US6066637A (en) * | 1998-06-19 | 2000-05-23 | American Home Products Corporation | Indolyl derivatives as serotonergic agents |
| AU765317C (en) * | 1998-06-19 | 2004-05-20 | H. Lundbeck A/S | 4,5,6 and 7-indole and indoline derivatives, their preparation and use |
| AR020773A1 (es) | 1998-10-16 | 2002-05-29 | Duphar Int Res | Compuesto derivados de 3-(tetrahidropiridin-4-il)indol, metodo para prepararlo, una composicion farmaceutica que los contiene, metodo para preparar dicha composicion y uso del compuesto |
| WO2000069424A2 (en) * | 1999-05-12 | 2000-11-23 | Solvay Pharmaceuticals B.V. | Method of treating psychotic disorders |
| SK287018B6 (sk) | 1999-08-23 | 2009-09-07 | Solvay Pharmaceuticals B. V. | Deriváty fenylpiperazínov, spôsob ich prípravy, farmaceutická kompozícia s ich obsahom a ich použitie |
| US6806275B2 (en) | 2000-09-13 | 2004-10-19 | Nihon Nohyaku Co., Ltd. | Arylpiperidine derivatives and use thereof |
| AR032712A1 (es) | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Un mesilato de derivados de fenilpiperazina y composiciones farmaceuticas que lo contienen |
| WO2003010169A1 (en) * | 2001-07-25 | 2003-02-06 | Wyeth | Antidepressant azaheterocyclylmethyl derivatives of 7, 8-dihydro-6h-5-oxa-1-aza-phenanthrene |
| DE10217006A1 (de) * | 2002-04-16 | 2003-11-06 | Merck Patent Gmbh | Substituierte Indole |
| US7235569B2 (en) * | 2003-05-02 | 2007-06-26 | Wyeth | Piperidinyl indole and tetrohydropyridinyl indole derivatives and method of their use |
| WO2016192657A1 (en) | 2015-06-03 | 2016-12-08 | Sunshine Lake Pharma Co., Ltd. | Substituted piperazine compounds and methods of use and use thereof |
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| GB2184444A (en) * | 1985-12-23 | 1987-06-24 | Wyeth John & Brother Ltd | Indole derivatives |
| FR2675801A1 (fr) * | 1991-04-24 | 1992-10-30 | Rhone Poulenc Rorer Sa | Piperidines, leur preparation et les medicaments les contenant. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2675801A (en) * | 1954-04-20 | Intramedbllary nail | ||
| FR2349331A1 (fr) * | 1976-04-30 | 1977-11-25 | Roussel Uclaf | Nouveaux derives de 2,3 dihydro a/4-(3-indolyl) 1-piperidinyl/methyl 1,4-benzodioxin-2-methanol, un procede pour leur preparation et leur application comme medicaments |
| US4359468A (en) * | 1981-02-25 | 1982-11-16 | Boehringer Ingelheim Ltd. | Antiallergic N-[4-(indolyl)-piperidino-alkyl]-benzimidazolones |
| HU198036B (en) * | 1983-08-22 | 1989-07-28 | Hoechst Roussel Pharma | Process for production of derivatives of 3-piperidil-/1h/-indasole and medical preparatives containing them |
| US5256673A (en) * | 1983-11-25 | 1993-10-26 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Indole-3-yl-A-tetrahydropyridyl or piperidyl compounds |
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| IE58370B1 (en) * | 1985-04-10 | 1993-09-08 | Lundbeck & Co As H | Indole derivatives |
| JP2860688B2 (ja) * | 1990-03-14 | 1999-02-24 | 第一製薬株式会社 | インドール誘導体 |
| DE4414113A1 (de) * | 1994-04-22 | 1995-10-26 | Merck Patent Gmbh | 3-Indolylpiperidine |
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-
1994
- 1994-04-22 DE DE4414113A patent/DE4414113A1/de not_active Withdrawn
-
1995
- 1995-03-22 UA UA95038268A patent/UA41333C2/uk unknown
- 1995-04-07 ES ES95105227T patent/ES2125508T3/es not_active Expired - Lifetime
- 1995-04-07 AT AT95105227T patent/ATE172730T1/de not_active IP Right Cessation
- 1995-04-07 EP EP95105227A patent/EP0683166B1/de not_active Expired - Lifetime
- 1995-04-07 DE DE59504032T patent/DE59504032D1/de not_active Expired - Lifetime
- 1995-04-07 DK DK95105227T patent/DK0683166T3/da active
- 1995-04-13 AU AU16488/95A patent/AU697749B2/en not_active Ceased
- 1995-04-17 JP JP7091077A patent/JPH07291969A/ja active Pending
- 1995-04-19 SK SK508-95A patent/SK280881B6/sk unknown
- 1995-04-20 TW TW084103916A patent/TW401416B/zh active
- 1995-04-20 CA CA002147451A patent/CA2147451C/en not_active Expired - Fee Related
- 1995-04-20 CN CN95104705A patent/CN1047385C/zh not_active Expired - Fee Related
- 1995-04-21 US US08/426,405 patent/US5693655A/en not_active Expired - Lifetime
- 1995-04-21 HU HU9501139A patent/HUT74096A/hu unknown
- 1995-04-21 CZ CZ951035A patent/CZ285369B6/cs not_active IP Right Cessation
- 1995-04-21 PL PL95308287A patent/PL180781B1/pl not_active IP Right Cessation
- 1995-04-21 NO NO951529A patent/NO307831B1/no not_active IP Right Cessation
- 1995-04-21 RU RU95106675/04A patent/RU2151148C1/ru not_active IP Right Cessation
- 1995-04-21 ZA ZA953260A patent/ZA953260B/xx unknown
- 1995-04-22 KR KR1019950009554A patent/KR100361950B1/ko not_active IP Right Cessation
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| GB2044254A (en) * | 1979-01-26 | 1980-10-15 | Wyeth John & Brother Ltd | Novel piperidine derivatives |
| GB2184444A (en) * | 1985-12-23 | 1987-06-24 | Wyeth John & Brother Ltd | Indole derivatives |
| FR2675801A1 (fr) * | 1991-04-24 | 1992-10-30 | Rhone Poulenc Rorer Sa | Piperidines, leur preparation et les medicaments les contenant. |
Also Published As
| Publication number | Publication date |
|---|---|
| UA41333C2 (uk) | 2001-09-17 |
| RU95106675A (ru) | 1997-03-20 |
| US5693655A (en) | 1997-12-02 |
| KR950032176A (ko) | 1995-12-20 |
| ZA953260B (en) | 1996-01-09 |
| CA2147451A1 (en) | 1995-10-23 |
| NO951529D0 (no) | 1995-04-21 |
| PL180781B1 (pl) | 2001-04-30 |
| CZ103595A3 (en) | 1995-12-13 |
| HU9501139D0 (en) | 1995-06-28 |
| CN1114651A (zh) | 1996-01-10 |
| EP0683166B1 (de) | 1998-10-28 |
| NO307831B1 (no) | 2000-06-05 |
| RU2151148C1 (ru) | 2000-06-20 |
| EP0683166A1 (de) | 1995-11-22 |
| DE59504032D1 (de) | 1998-12-03 |
| NO951529L (no) | 1995-10-23 |
| KR100361950B1 (ko) | 2003-02-05 |
| ES2125508T3 (es) | 1999-03-01 |
| HUT74096A (en) | 1996-11-28 |
| ATE172730T1 (de) | 1998-11-15 |
| CA2147451C (en) | 2006-03-28 |
| PL308287A1 (en) | 1995-10-30 |
| CZ285369B6 (cs) | 1999-07-14 |
| AU697749B2 (en) | 1998-10-15 |
| DK0683166T3 (da) | 1999-07-12 |
| DE4414113A1 (de) | 1995-10-26 |
| AU1648895A (en) | 1995-11-02 |
| SK50895A3 (en) | 1995-11-08 |
| SK280881B6 (sk) | 2000-08-14 |
| TW401416B (en) | 2000-08-11 |
| JPH07291969A (ja) | 1995-11-07 |
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